Podcasts about j clin oncol

The International Psycho-Oncology Society (IPOS) deemed April 9th, 2025, the first-ever World Psycho-Oncology Day (WPOD). This day was meant to spread awareness of the importance of prioritizing psychosocial care for patients with all types of cancer as well as to honor Jimmie C. Holland, MD. Prior to WPOD, CancerNetwork® spoke with Cristiane Decat Bergerot, PhD, BS, MS, a psychologist and the head of supportive care at Grupo Oncoclinicas in Brazil, and a member of IPOS, about the importance of psychosocial care and the impact it has on patients with cancer. As stated by Bergerot and listed on the official IPOS website, the primary goals of WPOD are as follows: raise awareness, honor Jimmie Holland, engage stakeholders, promote action, and support fundraising efforts.1 These goals are geared towards paying homage to the history of psycho-oncology and pushing for a more advanced future. “We aim to empower patients, caregivers, and healthcare professionals, fostering a future where psychosocial support is an integral part of oncology worldwide,” Bergerot said.  Psycho-oncology has become more prevalent as a cancer care field since Jimmie C. Holland, MD, worked to help found it in the 1970s. Holland, a “pioneer” of psycho-oncology, was the first ever Chief of Psychiatry Services—a department that was the first of its kind anywhere in the world—at Memorial Sloan Kettering Cancer Center, and a founding member of IPOS.  Bergerot stated that, in her work, she sees that patients who receive psychological support exhibit improved pain management and quality of life. Trials now focus more on end points such as quality of life and patient-reported outcomes, and guidelines have emerged to create standards of care. The National Comprehensive Cancer Network and the American Society of Clinical Oncology each offer guidelines that detail how to manage patient distress as they progress through cancer therapy.2,3 Distress screenings and earlier recommendations for palliative care have also become more standard in treatment.  As for the future, Bergerot highlighted that psychosocial care needs to be more integrated into care as a necessary, rather than optional, component. New developments around the world, however, have created a landscape where telehealth and new research demonstrate the potential to help psycho-oncology grow rapidly.  References 1.        World Psycho-Oncology Day (WPOD). IPOS. Accessed April 2, 2025. https://tinyurl.com/43c9rr2c 2.        Distress during cancer care. NCCN. 2024. Accessed April 2, 2025. https://tinyurl.com/ycxxvnmt 3.        Andersen BL, Lacchetti C, Ashing K, et al. Management of anxiety and depression in adult survivors of cancer: ASCO guideline update. J Clin Oncol. 2023;41(18):3426-3453. doi:10.1200/JCO.23.00293

La neutropénie fébrile est une urgence oncologique qui nécessite des interventions rapides, sans quoi elle peut mener à des complications importantes. Pour ce premier épisode d'une série de deux, Trait pharmacien reçoit Benoît Crevier et Barbara Vadnais, pharmaciens au CISSS de la Montérégie-Centre et détenteurs de la certification américaine du Board of Pharmacy Specialties en soins critiques et en oncologie, respectivement. Référence : Klastersky J, Paesmans M, Rubenstein EB et coll. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-51.

In a conversation with CancerNetwork®, Marwan G. Fakih, MD, spoke about the FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix), and how it may affect the treatment paradigm for patients with KRAS G12C-mutant metastatic colorectal cancer (CRC). Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California. According to Fakih, the approval of this combination regimen is a “welcome step” for those with metastatic CRC harboring KRAS G12C mutations. Based on supporting data from the phase 3 CodeBreaK 300 trial (NCT05198934), sotorasib/panitumumab may prolong progression-free survival (PFS) and reduce disease burden in patients while offering improvements in other outcomes vs prior standards of care (SOC) like trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga). Topline data at the time of the approval showed a median PFS of 5.6 months (95% CI, 4.2-6.3) with sotorasib at 960 mg plus panitumumab vs 2.0 months (95% CI, 1.9-3.9) in the SOC arm, in which patients were assigned to receive trifluridine/tipiracil or regorafenib (HR, 0.48; 95% CI, 0.30-0.78; P = .005). Additionally, the overall response rate was 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in each respective arm. Looking ahead, Fakih highlighted the potential next steps for research associated with the sotorasib combination as well as other novel therapeutic strategies in the gastrointestinal cancer space. For example, he described the phase 3 CodeBreaK 301 study (NCT06252649), which will evaluate sotorasib/panitumumab as frontline therapy when administered in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI) vs FOLFIRI plus bevacizumab (Avastin) in metastatic KRAS G12C-mutant CRC. Other novel agents under development in the space include RAS inhibitors and immunotherapy regimens combining CTLA-4 inhibitors with anti–PD-L1 agents. References 1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 12, 2025. https://shorturl.at/1WviB 2. Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301). J Clin Oncol. 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326

Featuring an interview with Dr Seth Wander, including the following topics: The clinical utility of ESR1 mutations in HR-positive, HER2-negative advanced breast cancer Grinshpun A et al. The clinical utility of ESR1 mutations in hormone receptor-positive, HER2-negative advanced breast cancer. Hematol Oncol Clin North Am 2023;37(1):169-81. Abstract (0:00) Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy for ER-positive, HER2-negative advanced breast cancer Jhaveri KL et al. Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy in estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Phase Ia/Ib EMBER study. J Clin Oncol 2024;[Online ahead of print]. Abstract (6:01) EORTC-2129-BCG: Elacestrant for ER-positive/HER2-negative breast cancer patients with ctDNA relapse Ignatiadis M et al. EORTC-2129-BCG: Elacestrant for treating ER+/HER2- breast cancer patients with ctDNA relapse (TREAT ctDNA). ESMO 2024;Abstract 338TiP. (8:20) CME information and select publications  

CancerNetwork® collaborated with CURE® to speak with Samantha Shenoy, NP, MSN, a nurse practitioner at the Cancer Immunotherapy Clinic of University of California San Francisco (UCSF) Health, about the role she plays when treating patients with multiple myeloma who are receiving talquetamab-tgvs (Talvey). Of note, emphasis was placed on managing treatment-emergent adverse effects (TRAEs) and toxicities that may impact quality of life. Shenoy foregrounded the discussion by outlining the role of nurses in facilitating the management of toxicities and providing education to patients in both an inpatient and outpatient capacity. She subsequently discussed common skin, oral, and dermatologic toxicities, as well as how they impact patient quality of life.  Furthermore, she touched upon taking an aggressive approach to addressing early-grade cytokine release syndrome (CRS), placing an emphasis on close adherence to UCSF clinical guidelines for treating it. Additionally, Shenoy acknowledged the possibility of neurological effects occurring as a result of treatment with talquetamab, although she stated she has not observed any in her experiences with using the bispecific.  Shenoy disclosed talquetamab-related monitoring parameters, indicating that taste changes and weight loss were notable risks. Particularly for weight loss, she mentioned that she regularly checks in with patients about their eating habits and weight. Furthermore, methods for living with taste changes were discussed, which included recommendations for prophylactics, dietary modifications, and dry mouth remedies. Shenoy continued by suggesting that the efficacy seen with talquetamab, particularly as part of a combination therapy, makes it an impactful agent. Citing her experience as part of the phase 1 TRIMM-2 trial (NCT04108195), where talquetamab was assessed in combination with daratumumab (Darzalex) in relapsed or refractory multiple myeloma, she claimed that combination therapies for bispecifics would become the new standard in this patient population. She concluded by expressing her passion for educating patients about management strategies for multiple myeloma. Additionally, she further illustrated the sentiment through her experience witnessing patients continue treatment for several years while overcoming toxicities associated with talquetamab. “I feel passionately about the fact that we can educate patients who are struggling at the beginning [to] hang in there. It is not going to last forever,” Shenoy stated. “I can imagine how frustrating it is [when you are not] able to taste, your mouth is dry, and your hands are peeling. Just know that it is not forever.” Reference Dholaria, BR, Weisel K, Mateos MV, et al. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): updated TRIMM-2 results. J Clin Oncol. 2023;41(suppl 16). doi:10.1200/JCO.2023.41.16_suppl.8003

In a conversation with CancerNetwork®, Nader Sanai, MD discussed the current state of the glioblastoma field, highlighting ongoing research efforts to help improve outcomes among patients with this disease.  Sanai is the director of the Ivy Brain Tumor Center and J.N Harber Professor of Neurological Surgery, Francis and Dionne Najafi chair for Neurosurgical Oncology, and chief of neurological oncology at Barrow Neurological Institute. Specifically, Sanai described plans to assess treatment with niraparib (Zejula) compared with temozolomide (Temodar) in a population of patients with newly diagnosed MGMT unmethylated glioblastoma as part of the phase 3 Gliofocus study (NCT06388733).1 He contextualized the rationale for conducting this study by focusing on findings from a proof-of-concept hybrid study (NCT05076513) and detailing how they supported additional investigation into the utility of niraparib.  According to findings from this proof-of-concept study presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the median overall survival (OS) was 20.3 months among patients who received niraparib in combination with radiotherapy.2 Additionally, data showed that niraparib reached drug concentrations in Gadolinium-nonenhancing newly diagnosed glioblastoma tissue exceeding those of any other evaluated PARP inhibitors; investigators identified no new safety signals after combining niraparib with radiotherapy in this population. With the Gliofocus trial, Sanai and co-investigators aim to provide a clinically meaningful quality of life benefit with niraparib-based therapy beyond a marginally valuable statistical advantage. By evaluating treatment with niraparib, investigators look to improve historical survival rates reported with standard-of-care options among patients with unmethylated disease. “What we're looking to do with this trial is set a benchmark that's clinically relevant for patients and providers. The [OS] target for the study is 18 months, which is to effectively convert [a] 12-month natural history to a natural history closer to the methylated glioblastoma population,” Sanai said. “We think that is a meaningful transformation of a difficult patient population, a significant chunk of survival time that would be beneficial to patients, providers, and caregivers. Importantly, [it may also mean] an advantage for quality of life, which is of paramount importance for this patient population.” References 1.        A study comparing niraparib with temozolomide in adult participants with newly-diagnosed, MGMT unmethylated glioblastoma. ClinicalTrials.gov. Updated June 24, 2024. Accessed September 16, 2024. https://tinyurl.com/y25er8p9 2.        Sanai N, Umemura Y, Margaryan T, et al. Niraparib efficacy in patients with newly-diagnosed glioblastoma: Clinical readout of a phase 0/2 "trigger" trial. J Clin Oncol. 2024;42(suppl 16):2002. doi:10.1200/JCO.2024.42.16_suppl.2002

Following the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Neil M. Iyengar, MD, and Paolo Tarantino, MD, co-hosted a live X Space with CancerNetwork® and discussed the latest trial updates that may impact clinical practice in the breast cancer field. Iyengar is an associate attending physician at Memorial Sloan Kettering Cancer Center and a co-editor-in-chief of ONCOLOGY®. Tarantino is a clinical research fellow at Dana-Farber Cancer Institute and Harvard Medical School.  Iyengar and Tarantino discussed data regarding several trials and studies presented at the meeting. These presentations included:  ·      Phase 3 DESTINY-Breast06 Trial (NCT04494425)1 o   Investigators evaluated treatment with trastuzumab deruxtecan (T-DXd; Enhertu) compared with investigator's choice of chemotherapy among patients with hormone receptor (HR)–positive, HER2-low or HER2-ultralow metastatic breast cancer. o   The median progression-free survival (PFS) was 13.2 months with T-DXd compared with 8.1 months in patients who received chemotherapy across the HER2-low population (HR, 0.62; 95% CI, 0.51-0.74; P

This podcast “Apalutamide in Metastatic Castration-Sensitive Prostate Cancer (mCSPC): A Case-Based Discussion” was originally presented as an AUA newsworthy webinar and contains data regarding the clinical efficacy and safety of apalutamide. It is presented on behalf of Janssen and is not certified for CME; speakers were compensated. For full details, see the video webinar here. TITAN, a Phase 3 double-blind study, randomized patients with metastatic castration-sensitive prostate cancer (mCSPC) to apalutamide (Apa; 240 mg oral once daily) + androgen deprivation therapy (ADT; n=525) or placebo + ADT (n=527).1,2 All patients received a concomitant gonadotropin-releasing hormone analog or had prior bilateral orchiectomy.3 Patients who received prior treatment for localized disease or received but did not progress on docetaxel were permitted. Dual primary endpoints were radiographic progression-free survival and overall survival (OS).1,2 At primary analysis (median follow-up: 22.7 months), Apa + ADT reduced the risk of radiographic progression or death by 52% vs placebo + ADT (HR: 0.48; 95% CI: 0.39–0.60). Apa + ADT also reduced the risk of death by 33% vs placebo + ADT (HR: 0.67; 95% CI: 0.51–0.89).1 At primary analysis cutoff, TITAN was unblinded and 39.5% of patients who received placebo + ADT crossed over to receive Apa + ADT; these patients were analyzed as part of the placebo + ADT population in the intent-to-treat analyses. The IPCW log-rank test was performed to account for crossover and showed a 48% reduction in the risk of death for Apa + ADT vs placebo + ADT (HR: 0.52; 95% CI: 0.42–0.64). At final analysis (median follow-up: 44.0 months), Apa + ADT reduced the risk of death by 35% vs placebo + ADT (median OS: NE vs 52.2 months; HR: 0.65; 95% CI: 0.53–0.79). In a prespecified subgroup analysis, Apa + ADT improved OS vs placebo + ADT, regardless of disease volume. In patients with high-volume disease, Apa + ADT reduced the risk of death by 30% vs placebo + ADT (HR: 0.70; 95% CI: 0.56–0.88); for low-volume disease, Apa + ADT reduced the risk of death by 48% vs placebo + ADT (HR: 0.52; 95% CI: 0.35–0.79).2 The following post hoc analyses data are not included in the full ERLEADA® (apalutamide) Prescribing Information. Post hoc exploratory analyses investigated PSA kinetics.4,5 After 3 months of Apa treatment, median OS was not reached in patients with a PSA response. In patients without a PSA response, median OS was 37.7 months.5 Most Apa + ADT-treated patients had undetectable PSA at 3 months. By 12 months, 64% of Apa-treated patients had undetectable PSA vs 23% of patients treated with placebo + ADT.5 Please see the full Prescribing Information for ERLEADA® (apalutamide) at www.erleadahcp.com. Chi KN, et al. N Engl J Med. 2019;381:13–24. Chi KN, et al. J Clin Oncol. 2021;39:2294–2303. ERLEADA® (apalutamide) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc. Chowdhury S, et al. Ann Oncol. 2023;34:477–485. Chi KN, et al. Presented at AUA; September 10–13, 2021; Las Vegas, Nevada.

In dieser Episode begrüßen wir Dr. Udo E. Beckenbauer, er ist Internist, Sportmediziner und Experte für "Healthy Living". Wir diskutieren wichtige medizinische Themen wie Prävention, die Rolle der Check-up Medizin und Strategien für eine gesunde Lebensführung. Dr. Beckenbauer erklärt, wie durch präventive Maßnahmen bis zu 50% der Krebserkrankungen und 70% der Herz-Kreislauf-Erkrankungen vermieden werden könnten. Er beleuchtet den Stellenwert regelmäßiger medizinischer Check-ups und wie moderne diagnostische Verfahren, wie z.B. das CardioCT, zur Krankheitsprävention beitragen können. Abschließend teilt er praktische Ratschläge für eine gesunde Ernährung und aktive Lebensgestaltung, die das allgemeine Wohlbefinden steigern und vor Krankheiten schützen. Fachartikel: Hörder H, Johansson L, Guo X, et al.: Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology 2018; 90: e1298-e1305: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894933/ Ross R, Blair SN, Arena R, et al.: Importance of Assessing Cardiorespiratory Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign: A Scientific Statement From the American Heart Association. Circulation 2016; 134: e653–99: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.025646 Guthold R, Stevens GA, Riley LM, Bull FC: Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants. Lancet Glob Health 2018; 6: e1077–86: https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(18)30357-7/fulltext Stamatakis E, Gale J, Bauman A, et al.: Sitting Time, Physical Activity, and Risk of Mortality in Adults. J Am Coll Cardiol 2019; 73: 2062–72: https://www.sciencedirect.com/science/article/pii/S0735109719337891?via%3Dihub Wen CP, Wai JP, Tsai MK, et al.: Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet 2011; 378: 1244–53: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60749-6/abstract Kenfield SA, Stampfer MJ, Giovannucci E, Chan JM: Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. J Clin Oncol 2011; 29: 726–32: https://ascopubs.org/doi/10.1200/JCO.2010.31.5226

In a conversation with CancerNetwork®, Gregory Peter Kalemkerian, MD, spoke about the publication of updated guidelines for managing small cell lung cancer (SCLC) with systemic therapy, which was developed by the American Society of Clinical Oncology (ASCO) in collaboration with Ontario Health (Cancer Care Ontario).1 Kalemkerian, a clinical professor at The University of Michigan and senior author of the guidelines, discussed developments in the SCLC field that inspired the creation of the revised guidelines since the last publication from ASCO in 2015.2 Although the latest guidelines contained recommendations concerning treatment modalities such as surgery and radiotherapy, Kalemkerian said that the biggest advances related to the integration of immunotherapy into frontline treatment for patients with extensive-stage SCLC (ES-SCLC). Specifically, Kalemkerian highlighted the use of immunotherapeutic agents such as durvalumab (Imfinzi) and atezolizumab (Tecentriq), which have demonstrated long-term improvements in survival of those with ES-SCLC. The guideline authors issued a strong recommendation backed by high-quality evidence for the frontline use of carboplatin plus etoposide or cisplatin plus atezolizumab or durvalumab followed by maintenance immunotherapy in patients with ES-SCLC who have no contraindications to immunotherapy.1 Additionally, there was no evidence supporting the continuation of immunotherapy for those with relapsed SCLC and progressive disease following maintenance immunotherapy based on an informal consensus. With respect to other updates in the guidelines, Kalemkerian spoke about optimal treatment strategies for patients with poorer performance statuses as well as the potential role of biomarkers in SCLC. Although there are currently no validated biomarkers that have demonstrated utility in the management of SCLC, he stated that it was necessary to overhaul how practices understand how diseases like SCLC develop and grow to help improve patient outcomes. “I would like people to pay attention to SCLC a little bit,” Kalemkerian said. “Non–small cell lung cancer has gotten a lot of the press and hype over the last 20 years or so since targeted therapy came out for that disease. Before that, we all thought SCLC was where we were going to be making advances, and we were wrong. We're on the cusp of understanding the disease better and utilizing that understanding to advance newer strategies for trying to treat these patients.” References 1.        Khurshid H, Ismaila N, Bian J, et al. Systemic therapy for small-cell lung cancer: ASCO-Ontario Health (Cancer Care Ontario) guideline. J Clin Oncol. 2023;41(35):5448-5472. doi:10.1200/JCO.23.01435 2.        Rudin CM, Ismaila N, Hann CL, et al. Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians Guideline. J Clin Oncol. 2015;33(34):4106-4111. doi:10.1200/JCO.2015.63.7918.

In unserer neuen Folge ist Prof. Mantke zu Gast. Wir diskutieren die Ergebnisse der Synchronous und CCRe-IV Studie. Welchen Einfluss hat die Resektion des metastasierten kolorektalen Primärtumors auf das Langzeitüberlebens. Eine Seltenheit! Ergebnisse zweier sehr langsam rekrutierender Studienprojekte wurden kombiniert. Viel Spaß Rahbari NN, Biondo S, Frago R, Feißt M, Kreisler E, Rossion I, Serrano M, Jäger D, Lehmann M, Sommer F, Dignass A, Bolling C, Vogel I, Bork U, Büchler MW, Folprecht G, Kieser M, Lordick F, Weitz J; SYNCHRONOUS and CCRe-IV Trial Groups. Primary Tumor Resection Before Systemic Therapy in Patients With Colon Cancer and Unresectable Metastases: Combined Results of the SYNCHRONOUS and CCRe-IV Trials. J Clin Oncol. 2024 Feb 27:JCO2301540. doi: 10.1200/JCO.23.01540. Epub ahead of print. PMID: 38412408.

CancerNetwork® collaborated with OncLive® to speak with Edward S. Kim, MD, MBA, and Richard T. Lee, MD, about ongoing initiatives to expand integrative oncology for patients with cancer at City of Hope. Kim is the physician-in-chief and senior vice president at City of Hope Orange County as well as the Construction Industries Alliance City of Hope Orange County physician-in-chief chair. Lee is the Cherng Family Director's Chair of the Center for Integrative Oncology and a medical director of Supportive & Integrative Medicine in the Department of Supportive Care Medicine as well as a clinical professor of Supportive & Integrative Medicine at City of Hope. The discussion partly focused on how integrative oncology is practiced at City of Hope. The institution's style of integrative care derives inspiration from traditional Eastern medicine and encompasses modalities such as acupuncture, meditation, yoga, and massages to help treat patients with cancer more holistically. Lee cited updates in integrative therapy guidelines published by the Society for Integrative Oncology (SIO) in partnership with the American Society of Clinical Oncology (ASCO) to illustrate how integrative care can benefit patient quality of life.1 For example, he highlighted that there was strong evidence in support of implementing mindfulness-based interventions to help reduce anxiety and stress among patients. “These types of integrative therapies are a great way to complement many of the standard-of-care options that we have and provide even further benefit in controlling these symptoms and allowing patients to have a better quality of life as they go through treatment and as they head into survivorship,” Lee said. The conversation also pertained to the institution's efforts to expand the Cherng Family Center for Integrative Oncology, a first-of-its-kind national integrative oncology program, following receipt of a $100 million gift from Andrew and Peggy Cherng, co-founders and co-chief executive officers at Panda Express, supporting its creation.2 This initiative will include conducting rigorous research in a clinical program that may inform future integrative oncology guidelines, pursuing natural product drug development, and instituting educational programs that may train future integrative oncologists. "The only way we're going to be able to increase access to these important programs to more people is to do the rigorous, level 1 research that's needed in order to prove that there is a benefit of any particular area,” Kim said. “Because if we're rigorous and we show the results are positive, then we would expect them to be on the guidelines like the National Comprehensive Cancer Network, and then payers would then provide support to patients who want to have these services.” References 1.        Carlson LE, Ismaila N, Addington EL, et al. Integrative oncology care of symptoms of anxiety and depression in adults with cancer: Society for Integrative Oncology–ASCO guideline. J Clin Oncol. 2023;41(28):4562-4591. doi:10.1200/JCO.23.00857 2.        Logsdon Z. City of Hope receives $100 million gift to create first-of-its-kind national integrative oncology program. News release. City of Hope. September 12, 2023. Accessed March 13, 2024. https://tinyurl.com/26y3xj87

After the 2024 Gastrointestinal Cancers Symposium, Jun Gong, MD, and Daneng Li, MD, sat down to discuss the most relevant trial data to have come from the conference. They convened for a live X Space hosted by CancerNetwork®. During the discussion, they covered different trials across the gastrointestinal space, which included those evaluating different disease states from hepatocellular carcinoma (HCC) to colorectal cancer (CRC), and those assessing circulating tumor DNA (ctDNA) dynamics. Gong, a hematologic oncologist focusing on gastrointestinal and genitourinary cancers at Cedars-Sinai Medical Center, and Li, an associate professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, each gave their perspective on the clinical trial data and discussed if they had implemented any of these study treatments into clinical practice.  The studies they covered included:  1.        Phase 3 NETTER-2 Trial (NCT03972488)1: - Investigated lutetium Lu 177 dotatate (Lutathera) plus octreotide vs octreotide alone for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). - Lutetium Lu 177 significantly improved progression-free survival (PFS) and overall response rate (ORR) compared with octreotide alone. - The agent may be considered for patients with high-grade GEP-NETs who desire significant tumor shrinkage. 2.        Phase 3 EMERALD-1 Trial (NCT03778957)2: - Studied transarterial chemoembolization (TACE) plus durvalumab (Imfinzi) with or without bevacizumab (Avastin) for unresectable HCC. - Durvalumab/bevacizumab plus TACE improved PFS compared with placebo plus TACE. - TACE may be preferred over transarterial radioembolization (TARE) due to faster patient recovery. 3.        Phase 3 CheckMate-8HW Trial3: - Evaluated nivolumab (Opdivo) plus ipilimumab (Yervoy) vs chemotherapy for first-line treatment of microsatellite instability-high/mismatch repair deficient metastatic CRC. - Nivolumab/ipilimumab demonstrated superior PFS compared with chemotherapy. - Chemotherapy may no longer be the standard first-line treatment for this patient population. 4.        BESPOKE Study (NCT04264702)4: - Assessed the impact of minimal residual disease (MRD) detected by ctDNA on disease recurrence in patients with stage II and III CRC receiving adjuvant chemotherapy. - MRD positivity was associated with worse disease-free survival (DFS). - ctDNA clearance at 12 weeks indicated improved DFS.  5.        GALAXY Trial5: - ctDNA is a promising biomarker that can be used to predict recurrence in patients with CRC. - Patients with ctDNA-positive disease had a worse DFS than patients with ctDNA-negative disease. - This suggests that ctDNA may be useful for making treatment decisions, but more research is needed before it can be used in clinical practice. 6.        Phase 3 FRESCO-2 Trial (NCT04322539)6: - Fruquintinib (Fruzaqla) improved the quality of life in patients with metastatic CRC when combined with best supportive care and significantly improved quality-adjusted time without symptoms of disease or toxicity compared with placebo and best supportive care. - The study showed positive effects on PFS, response rate, disease control, and duration of response with the fruquintinib combination. - The findings from this trial supported the FDA approval of fruquintinib for metastatic CRC in November 2023.7 References 1.        Singh S, Halperin D, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol. 2024(suppl 3):LBA588. doi:10.1200/JCO.2024.42.3_suppl.LBA588 2.        Lencioni R, Kudo M, Erinjeri J, et al. EMERALD-1: a phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. J Clin Oncol. 2024;42(suppl 3):LBA432. doi.10.1200/JCO.2024.42.3_suppl.LBA432 3.        Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl_3):LBA768. doi.10.1200/JCO.2024.42.3_suppl.LBA768 4.        Kasi P, Aushev V, Ensor J, et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): interim analysis of BESPOKE CRC study. J Clin Oncol. 2024;42 (suppl _3):9. doi:10.1200/JCO.2024.42.3_suppl.9 5.        Yukami H, Nakamura Y, Mishima S, et al. Circulating tumor DNA (ctDNA) dynamics in patients with colorectal cancer (CRC) with molecular residual disease: Updated analysis from GALAXY study in the CIRCULATE-JAPAN. J Clin Oncol. 2024;42(suppl_3):6. doi:10.1200/JCO.2024.42.3_suppl.6 6.        Stintzing S, Tabernero J, Satoh T, et al. Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): results from the FRESCO-2 trial. J Clin Oncol. 2024;42(suppl 3):116. doi:10.1200/JCO.2024.42.3_suppl.116 7.        FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. News release. November 8, 2023. Accessed February 7, 2024. https://shorturl.at/isJW2

Integrative therapies have been proven to help reduce the adverse effects (AEs) of anxiety and depression in patients with cancer, according to Linda E. Carlson, PhD, RPsych.  Carlson, Enbridge Research Chair in Psychosocial Oncology and a professor in the Department of Oncology, Cumming School of Medicine at the University of Calgary, explained how different therapies such as mindfulness-based interventions, yoga, and relaxation could work to manage anxiety and depression in patients with cancer. Specifically, she talked about the new recommendations published by The Society for Integrative Oncology (SIO) in collaboration with the American Society of Clinical Oncology (ASCO), which highlighted integrative approaches to managing AEs related to anxiety and depression.1 During the interview, Carlson spoke about the current guidelines, which recommendations clinicians can begin to use in their everyday practices, and what aspects future research should focus on. Specifically, she highlighted the benefits of yoga, tai chi, and relaxation as possible therapies that can help mitigate the AEs of anxiety and depression. “For the clinician, [it's important to understand] that these options are available and that they're evidence-based,” Carlson said.  “Then, [it's important to figure] out where in your local area these kinds of treatments are available. Many comprehensive cancer centers have integrative therapies; they have yoga, tai chi, mindfulness-based interventions, relaxation, and imagery. Many counselors can offer those kinds of services and cognitive behavioral therapy. Being aware that [these options are] effective and that they are first-line treatments, finding out where they're available, knowing how patients can access them, facilitating the treatments in whatever way [clinicians] can, and advocating for more of these programs within cancer treatment centers will be important.”  Carlson is also the past president of SIO and a current editorial advisory board member of ONCOLOGY®. Reference Carlson LE, Ismaila N, Addington EL, et al. Integrative oncology care of symptoms of anxiety and depression in adults with cancer: Society for Integrative Oncology–ASCO guideline. J Clin Oncol. 2023;41(28):4562-4591. doi:10.1200/jco.23.00857

In a recent discussion with CancerNetwork®, Joleen Hubbard, MD, research collaborator with Mayo Clinic and deputy director for clinical research at Allina Health Cancer Institute in Minneapolis, Minnesota, discussed new opportunities for patients with colorectal cancer (CRC).   In the discussion, Hubbard highlighted the potential of trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with HER2-expressing metastatic CRC based on studies including the phase 2 DESTINY-CRC01 trial (NCT03384940), which assessed the efficacy and safety of the agent in those who progressed after 2 or more prior regimens.1  These trials may play a role in continuing HER2 inhibition downstream after the FDA approval of trastuzumab (Herceptin) plus tucatinib (Tukysa) in patients with metastatic HER2-positive CRC.2   Hubbard also discussed the phase 3 MOUNTAINEER-03 study (NCT03043313) and its effects in the CRC space.3 This trial assessed the safety and efficacy of frontline tucatinib and trastuzumab in patients with treatment-refractory, RAS wild-type, HER2-positive metastatic CRC. Primary endpoints for this analysis showed a clinically meaningful overall response rate of 38.1% and a median duration of response of 12.4 months. Additionally, the treatment combination was well tolerated.   She said she is “optimistic” that moving HER2-directed therapy to the first-line setting, as seen in the MOUNTAINEER-03 study, may help outcomes for patients with metastatic CRC.  “It's a very exciting space,” Hubbard said. “Because it's only 5% to 8% of patients [who have CRC], it may not get as much attention, but there's 150,000 new cases of [CRC] diagnosed each year. So, 5% to 8% of that is a large number of patients [whom] we need to be looking at, studying, and potentially impact with these treatments.”  References  Yoshino T, Di Bartolomeo M, Raghav K, et al. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun. 2023;14(1):1-13. doi:10.1038/s41467-023-38032-4   Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. FDA. January 19, 2023. Accessed December 6, 2023. https://bwnews.pr/3Xpzbqn  Bekaii-Saab TS, Van Cutsem E, Tabernero J, et al. MOUNTAINEER-03: phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress. J Clin Oncol. Published online January 24, 2023. doi:10.1200/jco.2023.41.4_suppl.tps261 

In deze podcast bespreekt dr. Tessa Steenbruggen met arts-onderzoeker Veerle Geurts de resultaten van haar onderzoek naar de prognostische waarde van stromale tumor infiltrerende lymfocyten bij patiënten met stadium I triple negatieve borstkanker, die geen systemische therapie hebben gekregen. Het onderzoek is gepresenteerd tijdens het San Antonio Breast Cancer Symposium 2023.Referenties Cohort stadium 1 TNBC IKNL: https://www.ejcancer.com/article/S0959-8049(20)30237-9/fulltext TILs scoren: https://www.tilsinbreastcancer.org/ STILs bij jonge patiënten met TNBC: De Jong VM, et al. J Clin Oncol 2022;40(21):2361-74.

The AUA Expert Exchange Podcast: Discussions in Managing GU Cancer: Treatment Intensification for Advanced Prostate Cancer CME Available: https://auau.auanet.org/node/39486 At the conclusion of these activities, participants will be able to: 1. Identify the latest developments in hormone therapy for advanced prostate cancer, including the use of novel treatments and combinations. 2. Discuss the concept of doublet and triplet therapy in advanced prostate cancer and its rationale in enhancing treatment efficacy. 3. Consider the challenges and future directions in implementing doublet and triplet therapy in clinical practice, including cost, accessibility, and patient selection. This series is supported by independent educational grants from: Astellas and Pfizer, Inc. AstraZeneca Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC Lantheus Medical Imaging Merck & Co., Inc. REFERENCES: Freedland SJ, et al. Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer. NEJM Evidence. 2023. Smith MR, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med 2022. Fizazi K, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022. Clarke NW, et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evidence. 2022 Chi KN, et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2023. Agarwal N, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023.

Kristen K. Ciombor, MD, MSCI, an assistant professor in the Division of Hematology/Oncology in the Department of Medicine at the Vanderbilt University Medical Center, recently spoke at an Around the Practice discussion regarding updates in the world of metastatic colorectal cancer (CRC). In this episode of the ONCOLOGY® On the Go Podcast, she discusses treatment updates, molecular testing options, and emerging targets in CRC. Ciombor also highlighted ongoing research in the space, including the phase 3 BREAKWATER (NCT04607421)1 trial and the phase 3 MOUNTAINEER-03 (NCT05253651)2 trial. She also discussed some of the most important presentations from the 2023 European Society for Medical Oncology (ESMO) Congress, including those covering the phase 2 MOUNTAINEER study (NCT03043313)3 and the phase 3 KEYNOTE-811 trial (NCT03615326).4 Additionally, she spoke about her work in the phase 2 ECOG-ACRIN trial (NCT04751370) assessing neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with microsatellite instability-high or mismatch repair deficient rectal cancer.5 “I'm hoping that we see more treatment options for patients [and that] we identify more patient subtypes that we can target and find actionable alterations for,” Ciombor said. References 1. Kopetz S, Grothey A, Yaeger R, et al. BREAKWATER: randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC). J Clin Oncol. Published online May 28, 2021. doi:10.1200/jco.2021.39.15_suppl.tps3619 2. Bekaii-Saab TS, Van Cutsem E, Tabernero J, et al. MOUNTAINEER-03: phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress. J Clin Oncol. Published online January 24, 2023. doi:10.1200/jco.2023.41.4_suppl.tps261 3. Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. Published online May 24, 2023. doi:10.1016/S1470-2045(23)00150-X  4. Janjigian YY, Kawazoe A, Bai Y, et al. embrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424 5. Ciombor KK, Hong SC, Eng C, et al. EA2201: An ECOG-ACRIN phase II study of neoadjuvant nivolumab plus ipilimumab and short course radiation in MSI-H/dMMR rectal tumors. J Clin Oncol. Published online June 2, 2022. doi:10.1200/jco.2022.40.16_suppl.tps3644

In de podcastserie proefschriften spreekt aios interne geneeskunde dr. Tessa Steenbruggen met promovendi. In deze aflevering spreekt zij met aios interne geneeskunde Karima Amaador over haar proefschrift, getiteld ‘Understanding Waldenstrom´s Macroglobulinemia: a multimodal approach'. Aan bod komen verschillende studies naar de behandeling van Waldenström's macroglobulinemie en de voorkeuren van patiënten en daarnaast wat haar toekomstplannen zijn. Karima zal op 10 november a.s. haar proefschrift verdedigen aan de Universiteit van Amsterdam. Referenties Mukherjee S. (2011). The emperor of all maladies - Siddhartha Mukherjee. Simon & Schuster. Kersten MJ, et al. J Clin Oncol 2022;40:40-51. Amadoor K, et al. Cancer Med 2023;12(3):3376-86. Amadoor K, et al. Leukemia Lymphoma 2022;63:1469-73.

In de podcastserie Proefschriften spreekt aios interne geneeskunde dr. Tessa Steenbruggen met promovendi. In deze aflevering spreekt zij met aios pathologie Gwen Dackus over haar proefschrift, getiteld Treatment optimization for breast cancer patients according to age and tumor subtype. Aan bod komen onder andere hoe zij haar onderzoek aangepakt heeft, de belangrijkste resultaten, analyses die nog gepland staan en wat haar toekomstplannen zijn. Gwen zal op 26 september 2023 haar proefschrift verdedigen aan de Universiteit van Utrecht. Referenties PARADIGM-cohort. Dackus GM, et al. BMJ Open 2017;7(11):e017842. TIL's jonge patiënten TNBC. De Jong VM, et al. J Clin Oncol 2022;40(21):2361-74. Hormonale therapie voor peri-menopauzale patiënten. Dackus GM, et al. J Natl Cancer Inst 2021;113:1506-14. Deep learning-based breast cancer grading and survival analysis on whole-slide histopathology images. Wetstein SC, et al. Sci Rep 2022;12:15102.

6 Brüste: Große Freude! Evelyn Weigert von „Heinlein & Weigert“ und „Hoppe Hoppe Scheitern“ ist heute bei Sophia und Paula zu Gast. Zu dritt galoppieren die bayerischen Berlinerinnen durch ein herzliches und herrlich witziges Gespräch mit vielen persönlichen Storys zum Thema Streiten – egal ob mit dem Partner, Passanten, Nachbarn, Freunden oder Familie. Paula liebt Evelyns positiven Blick aufs Leben. Evelyn übt gerade ihren inneren Arsch mehr zurückzuhalten und Sophia nahm schon früh die roten Gummistiefel und flüchtete. Beide finden Paula unglaublich sexy. Harmonie!

In deze podcast bespreken internist-oncoloog Koos van der Hoeven en internist-oncoloog Inge Konings, Amsterdam UMC de primaire resultaten van de SONIA-studie gepresenteerd tijdens de 2023 ASCO Annual Meeting. Aan bod komen de belangrijkste resultaten en wat dit kan betekenen voor de dagelijkse praktijk.Deze studie is gereed gekomen door participatie van vrijwel alle internist-oncologen in Nederland samenwerkend in de Borstkanker Onderzoek Groep (BOOG), met betrokkenheid van Borstkankervereniging Nederland (BVN) en intensieve samenwerking met het Integraal Kankercentrum Nederland (IKNL) en het instituut Beleid & Management Gezondheidszorg (iMTA). Een resultaat waar we als Nederland trots op kunnen zijn.Sonke G, et al. J Clin Oncol 2023;41 (suppl 17): abstr LBA1000.

In deze podcast spreken AIOS Interne geneeskunde Tessa Steenbruggen en AIOS Interne oncologie Annemiek van Ommen-Nijhof met elkaar over de OLIGO-studie (NCT01646034), waarvan de primaire resultaten tijdens ASCO23 gepresenteerd zijn. In deze studie werd de meerwaarde van hoge-dosischemotherapie ten opzichte van standaard chemotherapie onderzocht voor patiënten met oligogemetastaseerde borstkanker en homologe recombinatiedeficiëntie. Beiden hebben zich de afgelopen jaren tijdens hun promotieonderzoek in het Antoni van Leeuwenhoek te Amsterdam intensief beziggehouden met deze studie.Referenties Van Ommen-Nijhof et al. J Clin Oncol 2023;41 (suppl 16): abstr 1097. Steenbruggen T, et al. JNCI Cancer Spectrum 2021; 5: pkab010.

Receber um diagnóstico de uma doença como o câncer pode gerar várias sensações no paciente, entre elas, a negação, que, por muitas vezes, é o primeiro sentimento nesta fase. A negação pode vir antes mesmo da confirmação do problema, como quando o paciente sabe que tem algo errado com seu corpo, como um caroço na mama, por exemplo, e deixa de ir a uma consulta ou não leva os exames para o médico avaliar. A negação é o tema do primeiro episódio da série de podcasts #Borafalardecâncer, que discute a jornada do paciente. Esta série é patrocinada pela Pfizer e apresentada pela jornalista Rita Lisauskas. Ouça! Pergunta 1 https://www.inca.gov.br/noticias/confira-recomendacoes-do-ministerio-da-saude-para-o-rastreamento-do-cancer-de-mama https://www.sbmastologia.com.br/sociedades-medicas-brasileiras-recomendam-mamografia-anual-a-partir-dos-40-anos/ https://www.scielo.br/j/rb/a/ndjRGNCLF5TSKLkV59ZbQbx/?format=pdf&lang=en Acessado em: 10/05/2023 Pergunta 2 https://www.inca.gov.br/noticias/confira-recomendacoes-do-ministerio-da-saude-para-o-rastreamento-do-cancer-de-mama https://sbmastologia.com.br/cartilhas/ Acessado em: 10/05/2023 Pergunta 3 https://www.gov.br/inca/pt-br/assuntos/gestor-e-profissional-de-saude/controle-do-cancer-de-mama/fatores-de-risco Acessado em: 10/05/2023 Obesity and Breast Cancer: A Multipartite Connection Dipali Sharma & Nancy E. Davidson J Mammary Gland Biol Neoplasia (2013) 18:253–255 DOI 10.1007/s10911-013-9306-4 American Society of Clinical Oncology Position Statement on Obesity and Cancer Jennifer A et al  JCO VOLUME 32 NUMBER 31 NOVEMBER 1 2014 J Mammary Gland Biol Neoplasia(2013) 18:253-255 DOI 10.1007/s10911-013-9306-4 Acessado em: 10/05/2023 Pergunta 4 Guindalini RS et al, J Clin Oncol 36, 2018 (suppl; abstr e13610) Guindalini RSC et al. Sci Rep. 2022 Mar 9;12(1):4190. doi: 10.1038/s41598-022-07383-1 ROL de procedimentos e eventos em saúde 2021 Anexo II Diretrizes de utilização para cobertura de procedimentos na saúde suplementar RN 465/2021 Acessado em: 10/05/2023 Pergunta 5 https://www.gov.br/inca/pt-br/assuntos/gestor-e-profissional-de-saude/controle-do-cancer-de-mama/fatores-de-risco Obesity and Breast Cancer: A Multipartite Connection Dipali Sharma & Nancy E. Davidson J Mammary Gland Biol Neoplasia (2013) 18:253–255 DOI 10.1007/s10911-013-9306-4 American Society of Clinical Oncology Position Statement on Obesity and Cancer Jennifer A et al  JCO VOLUME 32 NUMBER 31 NOVEMBER 1 2014 J Mammary Gland Biol Neoplasia(2013) 18:253-255 DOI 10.1007/s10911-013-9306-4 Acessado em: 10/05/2023 Pergunta 6 https://www.gov.br/inca/pt-br/assuntos/gestor-e-profissional-de-saude/controle-do-cancer-de-mama/acoes/deteccao-precoce Acessado em: 10/05/2023 Pergunta 7 Instituto Inteligência em Pesquisa e Consultoria (Ipec) com 1.397 mulheres, a pedido da Pfizer Acessado em: 10/05/2023 Pergunta 8 https://www.gov.br/inca/pt-br/assuntos/gestor-e-profissional-de-saude/controle-do-cancer-de-mama/acoes/tratamento Acessado em: 10/05/2023 Código: PP-UNP-BRA-1804See omnystudio.com/listener for privacy information.

In deze podcast bespreekt internist-oncoloog Koos van der Hoeven recente ontwikkelingen op het gebied van de behandeling van het niet-kleincellig longcarcinoom. Hij bespreekt met longarts Egbert Smit de resultaten van de CheckMate 9LA-studie die hebben geleid tot een nieuwe behandeloptie: eerstelijnsbehandeling van patiënten met gevorderd niet-kleincellig longcarcinoom met nivolumab plus ipilimumab in combinatie met twee cycli chemotherapie versus chemotherapie alleen. Daarnaast worden de PD-L1-expressie en de consequenties voor de behandeling besproken.Referenties 1. Nederlandse richtlijn Niet-kleincellig longcarcinoom. Te raadplegen via richtlijnendatabase.nl/richtlijn/niet_kleincellig_longcarcinoom 2. Hendriks LE, et al. Ann Oncol 2023;34:358-76. 3. Overleving bij stadium IV-NSCLC zonder TKI-gevoelige mutaties (IKNL 2023). Te raadplegen via iknl.nl/kankersoorten/longkanker/registratie/overleving 4. Reck M, et al. J Clin Oncol 2021;39:2339-49. 5. Jassem J, et al. J Thorac Oncol 2021;16:1872-82. 6. Hellmann MD, et al. N Engl J Med 2019;381:2020-31. 7. Paz-Ares L, et al. Lancet Oncol 2021;22:198-211. 8. Reck M, et al. ESMO Open 2021;6:100273. 9. Paz-Ares LG, et al. J Thorac Oncol 2023;18:P204-22. 10. Gandhi L, et al. N Engl J Med 2018;378:2078-92. 11. West H, et al. Lancet Oncol 2019;20:924-37. 12. Samenvatting van de productkenmerken van Opdivo® (nivolumab). Te raadplegen via www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf 13. Advies van de commissie BOM (2021). Te raadplegen via www.nvmo.org/bom/nivolumab-en-ipilimumab-gecombineerd-met-2-cycli-chemotherapie-als-eerstelijnsbehandeling-voor-gemetastaseerd-niet-kleincellig-longcarcinoom/ 14. Van den Heuvel M, et al. Medische Oncologie 2021.Disclosures Prof. dr. E. Smit: Personal financial interests: none. Institutional financial interests: fees have been paid to my institution for speaker engagements and attendance to advisory boards of AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Bayer, DSI, Eli Lilly, MSD, Merck, Novartis, Pfizer, Sanofi, Takeda, Regeneron, Roche Genentech, Roche Diagnostics. Research support: AstraZeneca, Bristol Myers Squibb, Merck, MSD. PI for clinical studies sponsored by Amgen, AstraZeneca, Bayer, Clovis, Cullingan, Eli Lilly, Merck, MSD, Novartis, PharmaMar, Roche Genentech, Takeda. Prof. dr. ir. J.J.M. van der Hoeven: Astellas, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Gilead, Novartis, medisch directeur van Hartwig Medical Foundation, voorzitter Oncomid, lid Adviescollege VIG en lid RVT DICA. 7356-NL-2300020

De novo metastatic breast cancer represents 6% of all new breast cancer diagnoses. This figure has not changed at all over the past 20 years; however, systemic therapy options have evolved dramatically during this time and have significantly increased life expectancy for these patients. While surgical management of the primary tumor in the setting of metastatic disease has typically been reserved for palliative indications, surgeons are now being asked to consider resecting the primary tumor to potentially increase overall survival. In this episode, we will use a case study to examine the data that should inform our conversations and decisions when we encounter patients with metastatic breast cancer who are interested in having their primary tumor resected. Links: Khan, S.A., S. Schuetz, and O. Hosseini (2022). Primary-Site Local Therapy for Patients with De Novo Metastatic Breast Cancer: An Educational Review. Ann Surg Oncol; 29: 5811-5820. https://link.springer.com/article/10.1245/s10434-022-11900-x Khan, S.A. et al (2022). Early Local Therapy for the Primary Site in De Novo Stage IV Breast Cancer: Results of a Randomized Clinical Trial (E2108). J Clin Oncol; 40(9): 978-987. https://ascopubs.org/doi/10.1200/JCO.21.02006?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed Badwe, R. et al (2015). Locoregional treatment versus no treatment of the primary tumor in metastatic breast cancer: an open-label randomized controlled trial. Lancet Oncol; 16: 1380-1388. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00135-7/fulltext Fitzal, F. et al (2019). Impact of Breast Surgery in Primary Metastasized Breast Cancer: Outcomes of the Prospective Randomized Phase III ABCSG-28 POSYTIVE Trial. Ann Surg; 269(6): 1163-1169. https://journals.lww.com/annalsofsurgery/Abstract/2019/06000/Impact_of_Breast_Surgery_in_Primary_Metastasized.24.aspx Soran, A. et al (2018). Randomized Trial Comparing Resection of Primary Tumor with No Surgery in Stage IV Breast Cancer at Presentation: Protocol MF07-01. Ann Surg Oncol; 25: 3141-3149. https://link.springer.com/article/10.1245/s10434-018-6494-6 Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more.   If you liked this episode, check out other breast surgery episodes here: https://behindtheknife.org/podcast-category/breast/

Both interviews in this episode are with presenters at the 2023 ASCO Gastrointestinal Cancers symposium. Dr. Myriam Chalabi (Netherlands Cancer Institute) discusses the TARZAN trial, which found that, in patients with rectal cancer, neoadjuvant radiotherapy followed by atezolizumab and bevacizumab resulted in an encouraging complete response rate. The findings of this phase 1 study demonstrate that total mesorectal excision may be prevented in a significant proportion of patients, increasing the chance for organ preservation and reducing the risk for long-term morbidity related to surgery. It is a small but very exciting study!But first, Dr. Laura Dawson (Princess Margaret Cancer Centre, Toronto, Canada) reviews her phase 3 study of single-dose radiotherapy to manage pain from hepatocellular carcinoma and liver metastases. The results of this trial delivered encouragingly good results, beyond even the palliative endpoint.  Enjoy listening!Additional reading:1.    Dawson LA, et al. Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases. LBA492, Rapid Abstract Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract, ASCO-GI 2023, San Francisco, CA, USA, 19-21 January.2.    Soliman H, Ringash J, Jiang H, Singh K, Kim J, Dinniwell R, Brade A, Wong R, Brierley J, Cummings B, Zimmermann C, Dawson LA. Phase II trial of palliative radiotherapy for hepatocellular carcinoma and liver metastases. J Clin Oncol. 2013 Nov 1;31(31):3980-6.3.    Verschoor YL, et al. Radiotherapy, atezolizumab, and bevacizumab in rectal cancers with the aim of organ preservation: The TARZAN study. Poster Session C: Cancers of the Colon, Rectum, and Anus, Abstract 158, 2023 ASCO GI Cancers Symposium, San Francisco, CA, USA, 19-21 January.4.      Chalabi M. Defying all odds in MMR-deficient rectal cancers. Cancer Cell. 2022 Sep 12;40(9):914-916. Let us know what you thought of this week's episode on Twitter: @physicianswkly Want to share your medical expertise, research, or unique experience in medicine on the PW podcast? Email us at editorial@physweekly.com! Thanks for listening!

In this episode, Holly Fernandez Lynch and I continue our discussion of clinical research ethics with co-hosts Rahima Ghafoori and Caroline Gozigian (UVA Law '23). In this Part 2 of our interview, we focus on questions of payment, exploitation, and trust. As a reminder, in Part I, Holly introduced the basic regulatory framework governing clinical trials, with a focus on laws and rules impacting payment. She also discussed the benefits of and concerns about human challenge studies, and shared some historical examples. Holly Fernandez Lynch, JD, MBE, is Assistant Professor of Medical Ethics in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine (PSOM), University of Pennsylvania. She has a secondary appointment as an Assistant Professor of Law at the University of Pennsylvania Carey Law School.A lawyer and bioethicist by training, Professor Fernandez Lynch's scholarly work focuses on Food and Drug Administration (FDA) pharmaceutical policy, access to investigational medicines outside clinical trials, clinical research ethics, and the ethics of gatekeeping in health care. Her specific areas of expertise include Institutional Review Board (IRB) quality, payment to research participants, research prioritization, pre-approval access pathways (e.g., Expanded Access, Emergency Use Authorization, and Right to Try), and efforts to balance speed and certainty in drug approvals, including pathways that rely on post-approval trials such as accelerated approval. Links:Lynch HF, Darton TC, Levy J, McCormick F, Ogbogu U, Payne RO, Roth AE, Shah AJ, Smiley T, Largent EA. Promoting Ethical Payment in Human Infection Challenge Studies. Am J Bioeth. 2021 Mar;21(3):11-31. doi: 10.1080/15265161.2020.1854368. Epub 2021 Feb 4. PubMed PMID: 33541252.Shah SK, Miller FG, Darton TC, Duenas D, Emerson C, Lynch HF, Jamrozik E, Jecker NS, Kamuya D, Kapulu M, Kimmelman J, MacKay D, Memoli MJ, Murphy SC, Palacios R, Richie TL, Roestenberg M, Saxena A, Saylor K, Selgelid MJ, Vaswani V, Rid A. Ethics of controlled human infection to address COVID-19. Science. 2020 May 22;368(6493):832-834. doi: 10.1126/science.abc1076. Epub 2020 May 7. PubMed PMID: 32381590.Largent EA, Heffernan KG, Joffe S, Lynch HF. Paying Clinical Trial Participants: Legal Risks and Mitigation Strategies. J Clin Oncol. 2020 Feb 20;38(6):532-537. doi: 10.1200/JCO.19.00250. Epub 2019 Jun 14. PubMed PMID: 31199697.

Holly Fernandez Lynch and I discuss clinical research ethics, including challenge trials, research subject payment, and diversity in medical research with co-hosts Rahima          Ghafoori and Caroline Gozigian (UVA Law '23). In this episode, Holly introduces the basic regulatory framework governing clinical trials, with a focus on laws and rules impacting payment. She also discusses the benefits of and concerns about human challenge studies, and shares some historical examples. In the next episode, Part II of our interview, we explore issues of coercion, inducement, and exploitation more explicitly.Holly Fernandez Lynch, JD, MBE, is Assistant Professor of Medical Ethics in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine (PSOM), University of Pennsylvania. She co-chairs the PSOM Research Ethics and Policy Series (REPS) and serves as Assistant Faculty Director of Online Educational Initiatives in the Department, where she helps lead the Master of Health Care Innovation. She has a secondary appointment as an Assistant Professor of Law at the University of Pennsylvania Carey Law School.A lawyer and bioethicist by training, Professor Fernandez Lynch's scholarly work focuses on Food and Drug Administration (FDA) pharmaceutical policy, access to investigational medicines outside clinical trials, clinical research ethics, and the ethics of gatekeeping in health care. Her specific areas of expertise include Institutional Review Board (IRB) quality, payment to research participants, research prioritization, pre-approval access pathways (e.g., Expanded Access, Emergency Use Authorization, and Right to Try), and efforts to balance speed and certainty in drug approvals, including pathways that rely on post-approval trials such as accelerated approval.Links:Lynch HF, Darton TC, Levy J, McCormick F, Ogbogu U, Payne RO, Roth AE, Shah AJ, Smiley T, Largent EA. Promoting Ethical Payment in Human Infection Challenge Studies. Am J Bioeth. 2021 Mar;21(3):11-31. doi: 10.1080/15265161.2020.1854368. Epub 2021 Feb 4. PubMed PMID: 33541252.Shah SK, Miller FG, Darton TC, Duenas D, Emerson C, Lynch HF, Jamrozik E, Jecker NS, Kamuya D, Kapulu M, Kimmelman J, MacKay D, Memoli MJ, Murphy SC, Palacios R, Richie TL, Roestenberg M, Saxena A, Saylor K, Selgelid MJ, Vaswani V, Rid A. Ethics of controlled human infection to address COVID-19. Science. 2020 May 22;368(6493):832-834. doi: 10.1126/science.abc1076. Epub 2020 May 7. PubMed PMID: 32381590.Largent EA, Heffernan KG, Joffe S, Lynch HF. Paying Clinical Trial Participants: Legal Risks and Mitigation Strategies. J Clin Oncol. 2020 Feb 20;38(6):532-537. doi: 10.1200/JCO.19.00250. Epub 2019 Jun 14. PubMed PMID: 31199697.

We explore Dr. Harvey Max Chochinov's work on dignity therapy, its application in practice, and ways we can enhance humanism in medicine. Dr. Chochinov is a psychiatrist and researcher in palliative and end-of-life care. Our discussion also touches on burnout and systemic challenges the field of medicine faces. Hosts: Eyrn, Toshia Guests: Harvey Max Chochinov, MD, PhD, FRCPC, Yasmine Dakhama, MS4 References: Website to learn more about online dignity therapy training workshops: https://dignityincare.ca/en/ Chochinov HM, Hack T, Hassard T, Kristjanson LJ, McClement S, Harlos M. Dignity therapy: a novel psychotherapeutic intervention for patients near the end of life. J Clin Oncol. 2005 Aug 20;23(24):5520-5. doi: 10.1200/JCO.2005.08.391. PMID: 16110012. Chochinov HM. The platinum rule: a new standard for person-centered care. J Palliat Med. 2022;25(6):854-856. doi:10.1089/jpm.2022.0075 Chochinov HM. The Platinum Rule: A New Standard for Person-Centered Care. J Palliat Med. 2022 Jun;25(6):854-856. doi: 10.1089/jpm.2022.0075. Epub 2022 Feb 25. PMID: 35230173; PMCID: PMC9145569. Chochinov HM, McClement S, Hack T, Thompson G, Dufault B, Harlos M. Eliciting Personhood Within Clinical Practice: Effects on Patients, Families, and Health Care Providers. J Pain Symptom Manage. 2015 Jun;49(6):974-80.e2. doi: 10.1016/j.jpainsymman.2014.11.291. Epub 2014 Dec 17. PMID: 25527441. Chochinov HM. Dignity and the essence of medicine: the A, B, C, and D of dignity conserving care. BMJ. 2007 Jul 28;335(7612):184-7. doi: 10.1136/bmj.39244.650926.47. PMID: 17656543; PMCID: PMC1934489.

De novo metastatic breast cancer represents 6% of all new breast cancer diagnoses. This figure has not changed at all over the past 20 years; however, systemic therapy options have evolved dramatically during this time and have significantly increased life expectancy for these patients. While surgical management of the primary tumor in the setting of metastatic disease has typically been reserved for palliative indications, surgeons are now being asked to consider resecting the primary tumor to potentially increase overall survival. In this episode, we will use a case study to examine the data that should inform our conversations and decisions when we encounter patients with metastatic breast cancer who are interested in having their primary tumor resected. Links: §  Khan, S.A., S. Schuetz, and O. Hosseini (2022). Primary-Site Local Therapy for Patients with De Novo Metastatic Breast Cancer: An Educational Review. Ann Surg Oncol; 29: 5811-5820. https://link.springer.com/article/10.1245/s10434-022-11900-x §  Khan, S.A. et al (2022). Early Local Therapy for the Primary Site in De Novo Stage IV Breast Cancer: Results of a Randomized Clinical Trial (E2108). J Clin Oncol; 40(9): 978-987. https://ascopubs.org/doi/10.1200/JCO.21.02006?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed §  Badwe, R. et al (2015). Locoregional treatment versus no treatment of the primary tumor in metastatic breast cancer: an open-label randomized controlled trial. Lancet Oncol; 16: 1380-1388. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00135-7/fulltext §  Fitzal, F. et al (2019). Impact of Breast Surgery in Primary Metastasized Breast Cancer: Outcomes of the Prospective Randomized Phase III ABCSG-28 POSYTIVE Trial. Ann Surg; 269(6): 1163-1169. https://journals.lww.com/annalsofsurgery/Abstract/2019/06000/Impact_of_Breast_Surgery_in_Primary_Metastasized.24.aspx §  Soran, A. et al (2018). Randomized Trial Comparing Resection of Primary Tumor with No Surgery in Stage IV Breast Cancer at Presentation: Protocol MF07-01. Ann Surg Oncol; 25: 3141-3149. https://link.springer.com/article/10.1245/s10434-018-6494-6 Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more.   If you liked this episode, check out our other clinical challenges episodes here: https://behindtheknife.org/podcast-series/clinical-challenges/

In this episode, we invite Dr. Amir Ali, PharmD, BCOP to discuss with us the pathophysiology, risk factors, prevention, and treatment clinical pearls of tumor lysis syndrome TLS). Key Concepts TLS is caused by rapid cell death of cancerous cells that results in intracellular contents “spilling” into the blood – this leads to high serum uric acid, high serum potassium, high serum phosphate, and LOW calcium. These laboratory abnormalities cause acute kidney injury (via crystal formation in the kidney), arrhythmias (from hyperkalemia), and seizures (from high phosphate and low calcium). Patients at highest risk for TLS are those with hematologic malignancies (lymphomas and leukemias), especially if WBC or LDH labs are very high. Prevention is the Key! The primary prevention approach for TLS is hydration, allopurinol, and sometimes a low dose of rasburicase. The treatment of TLS involves more aggressive hydration and rasburicase. References Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review [published correction appears in J Clin Oncol. 2010 Feb 1;28(4):708]. J Clin Oncol. 2008;26(16):2767-2778. doi:10.1200/JCO.2007.15.0177 Cairo MS, Coiffier B, Reiter A, Younes A; TLS Expert Panel. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149(4):578-586. doi:10.1111/j.1365-2141.2010.08143.x Jones GL, Will A, Jackson GH, Webb NJ, Rule S; British Committee for Standards in Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2015;169(5):661-671. doi:10.1111/bjh.13403

For this episode, we have two fascinating interviews in honor of National Breast Cancer Awareness Month, when we raise awareness for the prevention, early detection, treatment, and survivorship of breast cancer. To that end, we speak with Dr. Tania Španić, President of Europa Donna, The European Breast Cancer Patient Organization, who is a survivor herself. She is also Chair of the European Society of Medical Oncology's Patient Advocacy Working Group. We also talk to Dr. Ines-Maria Vaz-Duarte-Luis from the Cancer Institute Gustave Roussy in Paris, about her recent articles on the dynamics of patient-reported outcomes after adjuvant breast cancer chemotherapy. We hope these 2 interviews provide the lens of the patient perspective and physician-researcher on various QOL aspects that patients affected by breast cancer must face. Enjoy Listening!Additional readingPaluch-Shimon S, et al. ESO-ESMO fifth international consensus guidelines for breast cancer in young women (BCY5). Ann Oncol. 2022 Aug 4:S0923-7534(22)01858-0. Di Meglio A, et al. Dynamics of Long-Term Patient-Reported Quality of Life and Health Behaviors After Adjuvant Breast Cancer Chemotherapy. J Clin Oncol. 2022 Sep 20;40(27):3190-3204. Vaz-Luis I, et al. ESMO Expert Consensus Statements on Cancer Survivorship: promoting high-quality survivorship care and research in Europe. Ann Oncol. 2022 Aug 10:S0923-7534(22)03792-9.  

In deze podcast kunt u luisteren naar een gesprek tussen nucleair geneeskundige prof. dr. Lioe-Fee de Geus-Oei en interventie-radioloog dr. Mark Burgmans, beiden uit het Leidsch Universitair Medisch Centrum, waarin zij praten over de plaats van transarteriële radio-embolisatie in de behandeling van hepatocellulair carcinoom. Tijdens dit gesprek nemen zij door wat de behandelopties zijn bij very early en early stage HCC, intermediate stage HCC en advanced stage HCC.Klik hier voor de podcast met prof. dr. Marnix Lam over de procedurele aspecten van geïndividualiseerde radio-embolisatie. Referenties BCLC-richtijn: Reig M, et al. J Hepatol 2022;76:681-93. Salem R, et al. Hepatology 2021;74:2342-52. Kim E, et al. Lancet Gastroenterol Hepatol 2022;7:843-50. Dhondt E, et al. Radiology 2022;303:699-710. Chow PK, et al. J Clin Oncol 2018;36:1913-21. Vilgrain V, et al. Lancet Oncol 2017;18:1624-36.

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. An important component of treatment in lung cancer (and many other cancers) is the use of radiation. This week, we continue our discussion about the fundamentals of Radiation Oncology with our guest, Dr. Evan Osmundson. *We hear the terms “hypo-fractioned” and “hyper-fractionated” radiation. What do those mean?- Fractionation, that is breaking up the total dose of radiation into smaller ones, has allowed patients to tolerate the radiation better. The repeat exposure allows the healthy tissue to repair, whereas the tumor is not able to heal as well- Standard fractionation involves keeping the maximum dose per session at 1.8-2Gy/fraction. - Hyper-fractionation is when a patient gets multiple doses per day, each less than 2Gy. This is important in small cell lung cancer, where the standard dose of radiation is 1.5Gy twice daily- Hypo-fractionation os when larger doses are given in each session, typically larger than 2.5-3Gy, often 4-5Gy per fraction. This is analogous to SBRT. *With regards to SBRT, how do you determine the number of sessions? - Typically 3-5 sessions, and this is based on data run through their computer algorithm that allows the dose to be tumoricidal. - More sessions (more likely 5 sessions) if central tumor (

SURVEY LINK: https://bit.ly/feedback_UltraSounds SUMMARY: Rachel and Sanaya discuss 3 clinical vignettes regarding cancer genetics with Dr. Versha Pleasant, MD, MPH. TIMESTAMPS: 00:41 Dr. Versha Pleasant Biography 02:18 Case 1: 42-year-old woman presents to establishcare 11:01 Case 2: 34-year-old woman presents to discuss risk reducing surgery for breast cancer. 07:35 Case 3: 47-year-old patient with abnormal uterine bleeding on Tamoxifen. 24:12 Wrap-up LINKS: Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome, Obstetrics & Gynecology: September 2017 - Volume 130 - Issue 3 - p e110-e126 doi: 10.1097/AOG.0000000000002296 Daly MB, Pal T, Berry MP, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(1):77-102. doi:10.6004/jnccn.2021.0001 Pleasant VA, Griggs JJ. Contemporary Residential Segregation and Cancer Disparities. J Clin Oncol. 2021 Sept;39(25):2739-2741. DOI: 10.1200/JCO.21.01328 Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2019 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1311/ Kumamoto T, Yamazaki F, Nakano Y, et al. Correction to: Medical guidelines for Li-Fraumeni syndrome 2019, version 1.1. Int J Clin Oncol. 2022;27(1):262-263. doi:10.1007/s10147-021-02086-5 Idos G, Valle L. Lynch Syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; February 5, 2004. McGarrity TJ, Amos CI, Baker MJ. Peutz-Jeghers Syndrome. In: Adam MP, MirzaaGM, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; February 23, 2001. TRANSCRIPT: https://bit.ly/ultrasounds_CancerGenetics DISCLOSURES/DISCLAIMERS: The OBGYN Delivered student team has no relevant financial disclosures. The Ultrasounds podcast is for educational and informational purposes only and should not be considered medical advice. Please do not use any of the information presented to treat, diagnose, or prevent real life medical concerns. The statements made on this podcast are solely those of the OB/GYN Delivered hosts and guests and do not reflect the views of any specific institution or organization.

In de laatste decennia is de overleving van patiënten met kanker sterk verbeterd. Dit is onder andere te danken aan screening voor bepaalde kankers maar vooral aan steeds effectievere, gerichtere behandelingen. Deze ontwikkeling maakt dat we onze focus ook moeten verschuiven van ‘overleven van kanker' naar ‘leven met kanker'. Wat komt daarbij kijken? Hoe kan je de patiënt en naasten begeleiden? In deze podcastserie over 'Leven met kanker', spreekt Tessa Steenbruggen met Kelly de Ligt en Lonneke van de Poll over hoe we kunnen toewerken naar gepersonaliseerde follow-up van patiënten met borstkanker en de waarde van PROM's, patiënt-reported outcome measures, in de huidige klinische praktijk. Referenties De Ligt K, et al. Support Care Cancer 2022 Jun 21. Epub ahead of print. Abrahams HJ, et al. Ann Oncol 2016;27:965-74. Basch E, et al. J Clin Oncol 2016;34:557-65.

Bernie Marini and Anthony Perissinotti discuss the following paper on whether or not event-free survival (EFS) is an appropriate surrogate endpoint for overall survival (OS) in AML: Norsworthy KJ, et al. Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses. J Clin Oncol. 2022 Mar 10;40(8):847-854. PMID: 34890212.

Ce cinquième épisode du podcast Resilience est consacré à Lili. Lili a été diagnostiquée d'un cancer du sein à 29 ans alors qu'elle vivait à Montréal. Graphiste de formation, elle lance presque immédiatement un blog pour raconter à sa façon sa maladie à ses proches. Peu de temps après, elle l'ouvre au public et fait le buzz, jusqu'à publier quelques mois plus tard une BD. Depuis, elle utilise son art pour briser les tabous et parler des sujets difficiles, que ce soit sur le corps féminin et le féminisme plus globalement, la maternité et le cancer. Parce que oui, avoir un cancer du sein ne veut pas dire renoncer à être maman ! Lili prend aujourd'hui le temps de nous raconter son parcours de patiente du cancer du sein, d'illustratrice engagée et de mère. L'étude "FEERIC" de l'institut Curie, mentionnée par Lili : https://www.seintinelles.com/etude/28. Réalisation : Jasmine Manet Musique : BPC Studio Sources : • Lambertini M, Ameye L, Hamy AS, et al. Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations. J Clin Oncol. 2020;38(26):3012-3023. doi:10.1200/JCO.19.02399 • Poorvu PD, Gelber SI, Zheng Y, et al. Pregnancy after breast cancer: Results from a prospective cohort of young women with breast cancer. Cancer. 2021;127(7):1021-1028. doi:10.1002/cncr.33342 • Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy After Breast Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol. 2021;39(29):3293-3305. doi:10.1200/JCO.21.00535

Ce cinquième épisode du podcast Resilience est consacré à Lili. Lili a été diagnostiquée d'un cancer du sein à 29 ans alors qu'elle vivait à Montréal. Graphiste de formation, elle lance presque immédiatement un blog pour raconter à sa façon sa maladie à ses proches. Peu de temps après, elle l'ouvre au public et fait le buzz, jusqu'à publier quelques mois plus tard une BD. Depuis, elle utilise son art pour briser les tabous et parler des sujets difficiles, que ce soit sur le corps féminin et le féminisme plus globalement, la maternité et le cancer. Parce que oui, avoir un cancer du sein ne veut pas dire renoncer à être maman ! Lili prend aujourd'hui le temps de nous raconter son parcours de patiente du cancer du sein, d'illustratrice engagée et de mère. L'étude "FEERIC" de l'institut Curie, mentionnée par Lili : https://www.seintinelles.com/etude/28. Réalisation : Jasmine Manet Musique : BPC Studio Sources : • Lambertini M, Ameye L, Hamy AS, et al. Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations. J Clin Oncol. 2020;38(26):3012-3023. doi:10.1200/JCO.19.02399 • Poorvu PD, Gelber SI, Zheng Y, et al. Pregnancy after breast cancer: Results from a prospective cohort of young women with breast cancer. Cancer. 2021;127(7):1021-1028. doi:10.1002/cncr.33342 • Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy After Breast Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol. 2021;39(29):3293-3305. doi:10.1200/JCO.21.00535

In this episode of SurgOnc Today®,  Dr. Jennifer Plichta is joined by Dr. Ann Partridge and Dr. Kristin Rojas to discuss practical pearls for addressing women's sexual health concerns during breast cancer treatment and prevention using case-based discussions to illustrate common scenarios that breast surgeons may encounter in their clinic. These may include managing sexual health concerns in the neoadjuvant and adjuvant setting, as well as how to approach symptom management for patients seen in a high-risk program. Jennifer Plichta, MD, MS is an Associate Professor of Surgery at Duke University Ann Partridge, MD, MPH is a Professor of Medicine at Harvard Medical School, and Vice Chair of Medical Oncology at Dana-Farber Cancer Institute Kristin Rojas, MD is an Assistant Professor of Surgery at the University of Miami, Sylvester Comprehensive Cancer Center  References: ASCO Guideline: Carter J, Lacchetti C, Anderson B, et al. Interventions to Address Sexual Problems in People With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Adaptation of Cancer Care Ontario Guideline. Journal of Clinical Oncology 2018 36:5, 492-511https://ascopubs.org/doi/full/10.1200/JCO.2017.75.8995 ACOG Supports Use of Vaginal Estrogen in Breast Cancer Survivors: https://www.acog.org/news/news-releases/2016/02/acog-supports-the-use-of-estrogen-for-breast-cancer-survivors Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric. 2003 Mar;6(1):45-52. PMID: 12725664. Le Ray I, Dell'Aniello S, Bonnetain F, Azoulay L, Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study. Breast Cancer Res Treat. 2012 Sep;135(2):603-9. doi: 10.1007/s10549-012-2198-y. Epub 2012 Aug 19. PMID: 22903687.https://link.springer.com/article/10.1007%2Fs10549-012-2198-y Studies on Risk of Recurrence With Vaginal Estrogen:  American Association of Sexuality Educators, Counselors, and Therapists (AASECT): https://www.aasect.org/ PROSE Study: Rebbeck TR, Friebel T, Wagner T, et a. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005 Nov 1;23(31):7804-10. doi:10.1200/JCO.2004.00.8151. Epub 2005 Oct 11. PMID: 16219936.

Adjuvant?  Neoadjuvant?  Short course?  Long course?  The treatment of rectal cancer treatment has come a long way.  Tune in to learn more about Total Neoadjuvant Therapy (TNT) and the mysterious HOLY PLANE. Learning Objectives: 1.    Describe the rationale for Total Neoadjuvant Therapy (TNT) for rectal cancer 2.    Review the history of chemo and radiation therapy in treatment of rectal cancer 3.    Describe total mesorectal excision  References Bahadoer RR, Dijkstra EA, van Etten B et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. doi: 10.1016/S1470-2045(20)30555-6. Epub 2020 Dec 7 https://doi.org/10.1016/S1470-2045(20)30555-6 Fokas E, Allgäuer M, Polat B et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019 Dec 1;37(34):3212-3222. doi: 10.1200/JCO.19.00308 https://ascopubs.org/doi/10.1200/JCO.19.00308 Colorectal Surgery 2021-2022 Virtual Education Series Follow us on Twitter @CRSVirtualEd Email us: colorectal.educational.series@gmail.com www.crsvirtualed.org Please visit behindtheknife.org to access other high-yield surgical education podcasts, videos and more.  

This episode features a conversation between Emmy Ganos, PhD, Senior Program Officer at the Robert Wood Johnson Foundation and Stacie Dusetzina, PhD, Associate Professor of Health Policy and Ingram Associate Professor of Cancer Research at Vanderbilt University Medical Center. This session is the last of four talks focused on health care sector efforts to Adjust clinical care based on information about patients' social circumstances. In this conversation, Emmy and Stacie dive into the implications of real-time pharmacy benefit tools and explore what we know about patient and provider preferences when it comes to conversations about medication costs.Recommended references: Everson J, Frisse ME, Dusetzina SB. Real-Time Benefit Tools for Drug Prices. JAMA. 2019. Doshi JA, Li P, Huo H et al. Association of Patient Out-of-Pocket Costs with Prescription Abandonment and Delay in Fills of Novel Oral Anticancer Agents. J Clin Oncol. 2018. Sloan CE, Ubel PA. The 7 Habits of Highly Effective Cost-of-Care Conversations. Annals Intern Med supplement issue on cost-of-care conversations. 2019. America's Essential Hospitals. Cost of Care Conversations Resources. Web collection.

Eric Kuelker Ph.D. R.Psych. discusses reliable but little-known research linking cancer and heart disease to traumatic life events and stress. It turns out that psychotherapy and relationship repair reduces the chances of cancer and factors like marriage extend life more than medical treatments do. This may extend it down to the cellular level.Eric's website is https://psychologicalinjuryindex.com/References:Hughes K, Bellis MA, Hardcastle KA, Sethi D, Butchart A, Mikton C, Jones L, Dunne MP. (2017) The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis. Lancet Public Health. Aug;2(8):e356-e366. https://pubmed.ncbi.nlm.nih.gov/29253477/Roberts AL, Huang T, Koenen KC, Kim Y, Kubzansky LD, Tworoger SS. (2019) Post-traumatic stress disorder is associated with increased risk of ovarian cancer: A prospective and retrospective longitudinal cohort study. Cancer Res. Oct 1;79(19): 5113-5120. https://pubmed.ncbi.nlm.nih.gov/31488422/ Lu D, Sundström K, Sparén P, Fall K, Sjölander A, Dillner J, Helm NY, Adami HO, Valdimarsdóttir U, Fang F. (2016). Bereavement is associated with an increased risk of HPV infection and cervical cancer: An epidemiological study in Sweden. Cancer Res. Feb 1;76(3): 643-51. https://pubmed.ncbi.nlm.nih.gov/26634926/Flaherty RL, Owen M, Fagan-Murphy A, Intabli H, Healy D, Patel A, Allen MC, Patel BA, Flint MS. (2017) Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer. Breast Cancer Res. Mar 24;19(1):35. https://pubmed.ncbi.nlm.nih.gov/28340615/ Morath J, Moreno-Villanueva M, Hamuni G, Kolassa S, Ruf-Leuschner M, Schauer M, Elbert T, Bürkle A, Kolassa IT. (2014) Effects of psychotherapy on DNA strand break accumulation originating from traumatic stress. Psychotherapy and Psychosomatics. 83(5):289-97. https://pubmed.ncbi.nlm.nih.gov/25116690/ Bellis MA, Hughes K, Ford K, Ramos Rodriguez G, Sethi D, Passmore J. (2019) Life course health consequences and associated annual costs of adverse childhood experiences across Europe and North America: a systematic review and meta-analysis. Lancet Public Health. Oct;4(10): e517-e528. https://pubmed.ncbi.nlm.nih.gov/31492648/Ziegler C, Richter J, Mahr M, Gajewska A, Schiele MA, Gehrmann A, Schmidt B, Lesch KP, Lang T, Helbig-Lang S, Pauli P, Kircher T, Reif A, Rief W, Vossbeck-Elsebusch AN, Arolt V, Wittchen HU, Hamm AO, Deckert J, Domschke K. (2016). MAOA gene hypomethylation in panic disorder: Reversibility of an epigenetic risk pattern by psychotherapy. Transl Psychiatry. Apr 5;6(4):e773. doi: 10.1038/tp.2016.41 https://pubmed.ncbi.nlm.nih.gov/27045843/Roberts S, Lester KJ, Hudson JL, Rapee RM, Creswell C, Cooper PJ, Thirlwall KJ, Coleman JR, Breen G, Wong CC, Eley TC. (2014). Serotonin transporter [corrected] methylation and response to cognitive behavior therapy in children with anxiety disorders. Transl Psychiatry. Sep 16;4(9):e444. https://pubmed.ncbi.nlm.nih.gov/25226553/Roberts S, Keers R, Breen G, Coleman JRI, Jöhren P, Kepa A, Lester KJ, Margraf J, Scheider S, Teismann T, Wannemüller A, Eley TC, Wong CCY. (2019). DNA methylation of FKBP5 and response to exposure-based psychological therapy. Am J Med Genet B Neuropsychiatr Genet. Mar;180(2):150-158. https://pubmed.ncbi.nlm.nih.gov/30334356/Levy-Gigi E, Szabó C, Kelemen O, Kéri S. (2013). Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy. Biol Psychiatry. Dec 1;74(11): 793-800. doi: 10.1016/j.biopsych.2013.05.017 https://pubmed.ncbi.nlm.nih.gov/23856297/Quidé Y, Witteveen AB, El-Hage W, Veltman DJ, Olff M. (2012). Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: A systematic review. Neurosci Biobehav Rev. Jan;36(1): 626-44. https://pubmed.ncbi.nlm.nih.gov/21963442/Bossini L, Santarnecchi E, Casolaro I, Koukouna D, Caterini C, Cecchini F, Fortini V, Vatti G, Marino D, Fernandez I, Rossi A, Fagiolini A. (2017). Morphovolumetric changes after EMDR treatment in drug-naïve PTSD patients. Riv Psichiatr. Jan-Feb;52(1): 24-31. https://pubmed.ncbi.nlm.nih.gov/28287194/Aizer AA, Chen MH, McCarthy EP, et al. Marital status and survival in patients with cancer. (2013) J Clin Oncol. 31: 3869‐3876. https://pubmed.ncbi.nlm.nih.gov/24062405/Mirosevic S, Jo B, Kraemer HC, Ershadi M, Neri E, Spiegel D. (2019). "Not just another meta-analysis": Sources of heterogeneity in psychosocial treatment effect on cancer survival. Cancer Med. Jan;8(1): 363-373. https://pubmed.ncbi.nlm.nih.gov/30600642/https://www.health.harvard.edu/heart-health/the-genetics-of-heart-disease-an-updateLevin M (2019) The Computational Boundary of a “Self”: Developmental Bioelectricity Drives Multicellularity and Scale-Free Cognition. Front. Psychol. 10:2688. https://pubmed.ncbi.nlm.nih.gov/31920779/ See acast.com/privacy for privacy and opt-out information.

Updates on COVID-19 vaccination in cancer patients on immune-checkpoint inhibitors (new data!) and those getting imaging studies after vaccination. We quickly run through the AMBORO (April 6 published online in J Clin Oncol) trial demonstrating improvements in patient care with the inclusion of a clinical pharmacist (or pharmacologist) in managing PO antineoplastics.

The NCI-MATCH trial was designed to reveal mutations in underexplored cancer types, allowing researchers to match patients to appropriate targeted therapies. Study investigator Alice P. Chen, MD, from the National Cancer Institute, reviews the goals and results of NCI-MATCH with host David H. Henry, MD, in this episode. Trial details NCI-MATCH has more than 1,000 participating sites. The trial is open to patients with advanced cancers that have progressed on standard treatment or rare cancers for which there is no standard treatment. Investigators use next-generation sequencing to identify mutations in tumor biopsies taken before the start of therapy. Sequencing is performed at MD Anderson Cancer Center, Houston; Massachusetts General Hospital, Boston; MoCha at NCI’s Frederick (Md.) National Lab; Yale University, New Haven, Conn.; and commercial labs. Matching patients to treatment When a patient is found to have an actionable mutation, that patient is assigned to an investigational treatment, typically monotherapy. A patient cannot be assigned to a treatment that is already known to be effective against their cancer; for example, patients with BRAF-mutated melanoma were excluded. The NCI’s Cancer Therapy Evaluation Program sends the patient's targeted therapy to the participating site within 24 hours of notification. CT imaging is done prior to the start of treatment, and patients are monitored with repeat scans every two cycles. Results Data on 5,954 patients with refractory malignancies were recently reported (J Clin Oncol. 2020 Nov 20;38[33]:3883-94). About 38% of those patients had an actionable mutation, and about 18% were assigned to a targeted therapy. Reports have shown varying response rates to matched therapy, ranging from 2% to 38%, Dr. Chen said. Results from the trial's treatment arms can be found here: https://ecog-acrin.org/nci-match-eay131-findings. Dr. Chen noted that this trial was designed to match patients with single agents. Combination therapy has only been used in one arm of the study (J Clin Oncol. 2020 Aug 06. doi: 10.1200/JCO.20.00762). Future directions Nine treatment arms are still open, and one arm has yet to open. Conclusions are still pending the completion of the treatment arms. The next step for this research is expanding to include more combination therapies. There is also interest in comparing biopsies of tissue obtained at initial diagnosis and after treatment to further improve understanding of mutations. For more information on NCI-MATCH, visit: https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCT02465060. Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia. Disclosures Dr. Chen and Dr. Henry have no conflicts of interest. *  *  * For more MDedge Podcasts, go to www.mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

FDA 批准布格替尼作为ALK阳性的非小细胞肺癌的一线用药Lancet Respir Med 急性呼吸衰竭患者机械通气强度与死亡率的关系NEJM 对危重机械通气患者采取非镇静或浅镇静的比较JAMA 质子泵抑制剂或H2受体抑制剂对机械通气患者住院死亡率的影响Nature Fc区优化的抗体可以诱导CD8对病毒性呼吸道感染的免疫布格替尼（brigatinib）布格替尼（Brigatinib）是一种间变性淋巴瘤激酶（ALK）抑制剂。2017年布格替尼被批准用于治疗ALK阳性的晚期非小细胞肺癌；2020年5月，布格替尼被FDA批准用于治疗ALK阳性的转移性非小细胞肺癌的一线治疗。《ALTA研究2年随访：布格替尼在克唑替尼难治性、ALK阳性的非小细胞肺癌的2期临床研究》Journal of Thoracic Oncology，2020年3月 (1)这项多中心、随机对照、2期临床研究，纳入克唑替尼难治性、ALK阳性的非小细胞肺癌患者共222人，随机分为口服布格替尼 90mg qd组（A组）、 布格替尼 180mg qd 7天后90mg qd 维持治疗组（B组），中位随访时间:19.6个月和24.3个月经治疗后客观缓解率分别为46%对56%，无进展生存期为9.2个月和16.7个月，总生存期为29.5个月和34.1个月。基线时，A组和B组分别有71%和67%的脑转移。脑转移患者经治疗后，颅内客观缓解率为50%和67%，颅内缓解持续时间为9.4和16.6个月，颅内无进展生存期为12.8个月和18.4个月。随访中没有观察到新发的安全事件。结论：克唑替尼难治性、ALK阳性的非小细胞肺癌中，布格替尼180 mg qd 7天后、予90mg qd维持治疗，显示了良好而持久的抗肿瘤效果，显著延长生存期和颅内病灶缓解时间。《ALTA-1L研究的第二个中期分析：布格替尼与克唑替尼在治疗晚期ALK阳性的非小细胞肺癌疗效的比较》Journal of Clinical Oncology，2020年11月 (2)在开放标签3期ALTA-1L试验中，纳入晚期ALK阳性、非小细胞肺癌患者共275人，随机分为布格替尼组（180 mg qd，7天后90mg qd），或克唑替尼250 mg bid。中位随访时间为24.9个月，布格替尼显著延长无进展生存期（P < .0001，24.0 vs 11.0个月）。布格替尼延缓了生活质量评分恶化的进展（P = 0.049）。研究同时发现，布格替尼的血浆浓度-时间曲线下的面积不是无进展生存期的预测因子。结论：布格替尼作为一种一日一次的ALK抑制剂在疗效上优于克唑替尼，有望成为ALK阳性的非小细胞肺癌的一线疗法。机械通气机械通气又称为正压通气，可完全替代或部分替代自主呼吸，目的是改善氧合不足、肺泡通气不足或两者同时。在急性和慢性呼吸衰衰竭期间，机械通气的主要受益是改善气体交换和减少呼吸做功。正压通气的肺部不良影响包括：肺气压伤、呼吸机相关肺损伤、内源性呼气末正压通气、通气/血流比例失调、膈肌萎缩、呼吸机无力和黏液腺毛运动减弱。此外，正压通气可能降低心输出量并影响血液动力学检测，与胃肠道应激性溃疡、内脏灌注减少、胃肠动力不足、液体潴留、急性肾衰竭、颅内压升高、肌无力、炎症和睡眠障碍相关。《前瞻性队列研究：急性呼吸衰竭患者机械通气强度与死亡率的关系》Lancet Respiratory Medicine，2020年9月 (3)尽管使用了肺保护性通气，但急性呼吸衰竭的死亡率仍然很高。最近的研究表明，基线通气参数与急性呼吸窘迫综合征患者预后之间存在相关性。该前瞻性队列研究的目的是评估急性呼吸衰竭患者长期暴露于不同强度的、机械通气与ICU死亡率之间的关系，共纳入13408例、接受≥4小时机械通气的患者。研究中，18%的患者死于ICU，对年龄和疾病严重程度进行调整后，发现机械通气驱动力 （driving pressure）与死亡风险显著升高有关（风险比1·064）；机械通气的机械功率（mechanical power）与死亡风险显著升高有关（风险比1·060）。这些关联在机械通气期间持续存在。结论：即使持续时间很短，高强度机械通气的累计暴露量是有害的。在进一步的研究中，应当对限制高强度机械通气以降低急性呼吸衰竭患者死亡率的治疗策略进行评估。《对照研究：健康受试者和危重病人膈肌的组织多普勒成像》American Journal of Respiratory and Critical Care Medicine，2020年10月 (4)组织多普勒成像是一种测量组织运动速度的超声心动图方法。该研究将此技术应用于膈肌，以评估膈肌在收缩和放松时的运动速度。研究对20名健康志愿者进行膈肌组织多普勒检查，以评估膈肌运动速度模式，测量其正常值，并确定测量值在观察者间的变异性。然后，在116例连续的ICU患者中，对脱机期间膈肌的偏移、增厚和组织多普勒参数（峰值收缩速度、峰值松弛速度、速度-时间积分和组织多普勒导出的最大松弛率）进行了评估。在一个18例患者亚组中，同时使用组织多普勒记录跨膈压（Pdi）、峰值Pdi、压力-时间乘积和膈肌最大舒张率。在可重复性方面，所有组织多普勒参数的相关系数为>0.89（P < 0.001）。除速度-时间积分外，健康志愿者和脱机成功患者的组织多普勒参数均低于脱机失败患者，分别为：峰值收缩速度1.35±0.34 cm/s、1.50±0.59 cm/s、2.66±2.14 cm/s（P < 0.001）；峰值松弛速度1.19±0.39 cm/s、1.53±0.73 cm/s、3.36±2.40 cm/s（P < 0.001）；组织多普勒最大舒张率分别为3.64±2.02 cm/s2、10.25±5.88 cm/s2、29.47±23.95 cm/s2（P < 0.001）。收缩速度峰值、与跨膈压峰值和压力-时间乘积有显著相关性，而最大舒张速率与最大舒张速率有显著相关性。结论：膈组织多普勒可实时评估膈肌组织的运动速度。膈肌组织多普勒衍生参数区分了脱机试验失败的患者和成功的患者，并与Pdi衍生参数有良好的相关性。《荟萃分析：危重病人的肌力与临床预后之间的关系》European Respiratory Journal，2020年9月 (5)研究的目的是评估肌无力与机械通气死亡率、或脱机成功率之间的联系，以及每种评估工具预测结果的能力。荟萃分析共分析了60项研究，包括4382名患者。ICU相关肌无力与总死亡率增加相关，风险比从1.2到4.48不等。其中刺激双侧膈神经产生的颤搐性跨膈压（transdiaphragmatic twitch pressure，TwPdi）对总死亡率的预测能力最高，敏感度为87%、特异性36%、曲线下面积 0.74。肌无力与机械通气脱机失败率增加相关，风险比为2.64至19.07不等。隔肌 增厚分数（diaphragm thickening fraction，DTF）对脱机失败率的预测能力最高，敏感性76%、特异性86%、曲线下面积为0.86。结论：ICU相关肌无力与高死亡率和更长时间机械通气相关。《综述：肺和膈保护通气》American Journal of Respiratory and Critical Care Medicine，2020年6月 (6)机械通气可引起急性膈肌萎缩和损伤，这与不良临床结果有关。肺部保护性通气的重要性和影响已得到广泛认识和确认，而膈肌保护性通气的概念最近已成为一种潜在的补充治疗策略。这一观点是在欧洲重症医学学会胸膜压工作组召开的一次国际专家会议的讨论中提出的，基于越来越多的损伤机制的证据，提出了一种综合肺和膈膜保护机械通气的概念框架。文章提出隔肌保护的目标基于呼吸努力和病人-呼吸机同步。讨论了在一定条件下隔肌保护与肺保护之间可能发生的冲突；我们强调，当冲突发生时，肺保护必须优先于隔肌保护。为了实施肺和膈保护通气，需要新的监测、设置呼吸机和滴定镇静的方法。未来，体外生命支持技术、膈神经刺激和临床决策支持系统等辅助干预措施也可能在特定的患者中发挥重要作用。由于干预的复杂性，评估这种新模式的临床影响将具有挑战性。结论：肺和膈保护通气的概念为显著改善危重病人的临床结果提供了一个引人注目的新理念。小羽点评：机械通气本身会导致膈肌功能障碍（ventilator induced diaphragmatic dysfunction，VIDD），控制型机械通气时甚至在第一天就可以发生，显著延长了通气和住院时间、导致撤机困难、并发症风险升高，这可能与膈肌损伤、萎缩、蛋白水解有关，通过氧化应激介导，但临床上有效避免该现象的最佳方法尚无定论。目前主要的策略是：保持适当水平的自主呼吸、避免病人-呼吸机不同步、根据膈肌活动监测指标调整呼吸机参数等。 《随机对照研究：对危重机械通气患者采取非镇静或浅镇静的比较》New England Journal of Medicine，2020年3月 (7)在危重的机械通气患者中，每日唤醒已被证明能够缩短通气时间和ICU住院时间。该研究的目的是讨论非镇静与浅镇静计划相比是否会影响死亡率。这项多中心、随机、对照试验中，随机分为非镇静组、和每日唤醒的浅镇静组，共纳入700名患者。非镇静组的平均Richmond躁动和镇静评分（RASS评分）从第1日的－1.3分提高至第7日的－0.8分；浅镇静组则从第1日的－2.3分提高至第7日的－1.8分。非镇静组和镇静组的90日死亡率分别为42.4%和37.0%（P=0.65）。两组患者离开ICU的天数、和不使用呼吸机的天数无显著差异。非镇静组患者中，无昏迷且无谵妄的中位天数为27日；浅镇静组患者中，无昏迷且无谵妄的中位天数为26日。非镇静组1例患者和浅镇静组10例患者发生了血栓栓塞事件。结论：在接受机械通气的ICU患者中，非镇静和浅镇静治疗策略90天死亡率无显著差异。《PEPTIC研究：质子泵抑制剂与抗组胺-2受体抑制剂剂对ICU有创机械通气患者住院死亡率的影响》JAMA，2020年1月 (8)研究的目的比较应用质子泵抑制剂（PPI）与组胺-2受体抑制剂（H2RB），在ICU有创机械通气患者中，预防应激性溃疡的疗效和对住院死亡率的影响。共26 982名患者被随机分配至PPI组或H2RB组，平均年龄58岁。PPI组和H2RB组中，90天住院死亡率分别为18.3%和17.5%（P=0.054），严重上消化道出血发生率分别为1.3%和1.8%的H2RB组（P = .009)。治疗组艰难梭菌感染率、ICU和住院时间无显著差异。在PPI组1例患者出现过敏反应。结论：在需要机械通气的ICU患者中，使用质子泵抑制剂与组胺-2受体阻滞剂相比，在预防应激性溃疡的医院死亡率方面没有统计学差异。呼吸机相关性肺炎呼吸机相关性肺炎（VAP）是指患者气管插管48小时后发生的肺炎，与以下因素相关：进入下呼吸道的微生物数量和宿主的机械、体液、细胞防御受损。约75%的重症患者在入院48小时内发生院内微生物定植。此外，肺部感染的主要途径是微量吸入已定植于口咽部、胃肠道的微生物，因此广泛使用的抑酸药提高胃液的pH值会改变上消化系统几乎无菌的状态，增加呼吸机相关性肺炎的发生几率。多重耐药菌危险因素包括：住院时间较长（>5天）和/或过去90天使用过抗生素。《双盲随机对照研究：心脏停搏后早发性呼吸机相关性肺炎的预防》New England Journal of Medicine，2019年11月 (9)院外心脏停搏、电击复律后后，接受体温管理的患者发生呼吸机相关性肺炎的风险增加。目前尚未证明抗生素短期预防性用药的益处。这项多中心、双盲、随机、安慰剂对照试验，纳入心脏停搏后、在ICU接受机械通气治疗、并且接受32～34℃目标体温管理的成人患者共 198例。于入院6小时内开始阿莫西林克拉维酸或安慰剂2日。7天内，抗生素预防组的早发呼吸机相关性肺炎发生率低于安慰剂组（19% vs 34%；风险比 0.53；P=0.03）。晚发性呼吸机相关性肺炎发生率、不使用呼吸机的天数、ICU停留时间和第28天时死亡率，两组均无差异。第7天未发现耐药菌增多。结论：院外发生心脏停搏后，接受32～34℃目标体温管理策略的患者，2日的阿莫西林克拉维酸降低了早发性呼吸机相关性肺炎的发生率。《2项前瞻性研究：英国ICU疑似呼吸机相关肺炎患者的肺曲霉菌病》American Journal of Emergency Medicine，2020年11月 (10)疑似呼吸机相关肺炎患者中，曲霉菌感染仍然缺乏十分敏感的诊断。这篇文章的目的是评估疑似呼吸机相关肺炎的曲霉菌感染的患病率和预后。文章纳入的这2项前瞻性研究招募了360名影像学、临床、实验室检查疑似的、呼吸机相关性肺炎的危重症患者，并获得了194名患者的血清样本和肺泡灌洗液，并进行了真菌学测试。最后根据临床、影像学和真菌学标准的定义诊断曲霉菌感染。在评估的194名患者中，曲霉菌感染患病率为12.4%，24例曲霉菌感染中有4人血清中半乳甘露聚糖阳性，16例肺泡灌洗液中半乳甘露聚糖阳性，两者均阳性共4例，3例肺泡灌洗液中培养出曲霉菌。疑似曲霉菌感染的患者ICU住院时间更长（25.5天 vs 15.5天，P = 0.02），死亡率略高（33.3% vs. 22.8%，P = 0.23）。结论：在调查疑似呼吸机相关肺炎患者时，即使不是曲霉菌感染高危，仍应考虑曲霉菌感染的可能。《DEDECAP研究：气管切开拔管前应用高流量氧疗联合堵管或联合吸引的比较》New England Journal，2020年9月 (11)应用气管切开套管的患者拔管前，通常做法是将气管切开套管堵管24小时，确定患者可否能自主呼吸。该研究的目的是比较这种做法是否比根据呼吸道吸引频率更好决定是否能够拔管更好。来自西班牙的研究人员在5个ICU进行了这项研究，纳入330例、气管切开后、有意识的、危重成人患者，患者的平均年龄58岁，68.2%为男性。一组接受24小时堵管试验+间歇性高流量氧疗（对照组），另一组接受连续高流量氧疗+将吸引频率作为拔管准备指标（干预组）。干预组至拔管的时间比对照组短（中位数，6天 vs. 13天）。干预组的肺炎和气管支气管炎发生率低于对照组，住院时长也比对照组短。 结论：与24小时堵管试验+间歇性高流量吸氧相比，依据吸引频率制定的拔管决策+连续高流量氧疗缩短了拔管时间，失败率不存在差异。《基础研究：Fc区优化的抗体可以诱导CD8对病毒性呼吸道感染的免疫》Nature，2020年10月(12)针对病毒病原体的抗体是控制病毒感染的一种很有前途的治疗方式，之前的一些研究已经证实，抗体的抗病毒效果需要Fab区和Fc区的协同作用。抗体Fc区在免疫系统中的各类细胞上的受体结合，激活免疫系统清除病毒、杀死被感染的细胞。这项研究的目的是，通过对抗流感IgG单抗的Fc区选择性的修饰，使之能够特异性的与已激活的Fcγ受体、Fcγ IIa受体结合，则能够进一步增强树突状细胞成熟、诱导保护性CD8+T细胞应答，从而提高预防或治疗致命性呼吸道病毒感染的疗效。结论：当IgG抗体选择性激活树突状细胞-T细胞通路时，能够诱导对病毒感染的保护性、适应性免疫，这对发展抗体疗法，提高对抗病毒的疗效具有重要意义。参考文献1.Huber RM, Hansen KH, Paz-Ares Rodríguez L, West HL, Reckamp KL, Leighl NB, et al. 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FDA 批准布格替尼作为ALK阳性的非小细胞肺癌的一线用药Lancet Respir Med 急性呼吸衰竭患者机械通气强度与死亡率的关系NEJM 对危重机械通气患者采取非镇静或浅镇静的比较JAMA 质子泵抑制剂或H2受体抑制剂对机械通气患者住院死亡率的影响Nature Fc区优化的抗体可以诱导CD8对病毒性呼吸道感染的免疫布格替尼（brigatinib）布格替尼（Brigatinib）是一种间变性淋巴瘤激酶（ALK）抑制剂。2017年布格替尼被批准用于治疗ALK阳性的晚期非小细胞肺癌；2020年5月，布格替尼被FDA批准用于治疗ALK阳性的转移性非小细胞肺癌的一线治疗。《ALTA研究2年随访：布格替尼在克唑替尼难治性、ALK阳性的非小细胞肺癌的2期临床研究》Journal of Thoracic Oncology，2020年3月 (1)这项多中心、随机对照、2期临床研究，纳入克唑替尼难治性、ALK阳性的非小细胞肺癌患者共222人，随机分为口服布格替尼 90mg qd组（A组）、 布格替尼 180mg qd 7天后90mg qd 维持治疗组（B组），中位随访时间:19.6个月和24.3个月经治疗后客观缓解率分别为46%对56%，无进展生存期为9.2个月和16.7个月，总生存期为29.5个月和34.1个月。基线时，A组和B组分别有71%和67%的脑转移。脑转移患者经治疗后，颅内客观缓解率为50%和67%，颅内缓解持续时间为9.4和16.6个月，颅内无进展生存期为12.8个月和18.4个月。随访中没有观察到新发的安全事件。结论：克唑替尼难治性、ALK阳性的非小细胞肺癌中，布格替尼180 mg qd 7天后、予90mg qd维持治疗，显示了良好而持久的抗肿瘤效果，显著延长生存期和颅内病灶缓解时间。《ALTA-1L研究的第二个中期分析：布格替尼与克唑替尼在治疗晚期ALK阳性的非小细胞肺癌疗效的比较》Journal of Clinical Oncology，2020年11月 (2)在开放标签3期ALTA-1L试验中，纳入晚期ALK阳性、非小细胞肺癌患者共275人，随机分为布格替尼组（180 mg qd，7天后90mg qd），或克唑替尼250 mg bid。中位随访时间为24.9个月，布格替尼显著延长无进展生存期（P < .0001，24.0 vs 11.0个月）。布格替尼延缓了生活质量评分恶化的进展（P = 0.049）。研究同时发现，布格替尼的血浆浓度-时间曲线下的面积不是无进展生存期的预测因子。结论：布格替尼作为一种一日一次的ALK抑制剂在疗效上优于克唑替尼，有望成为ALK阳性的非小细胞肺癌的一线疗法。机械通气机械通气又称为正压通气，可完全替代或部分替代自主呼吸，目的是改善氧合不足、肺泡通气不足或两者同时。在急性和慢性呼吸衰衰竭期间，机械通气的主要受益是改善气体交换和减少呼吸做功。正压通气的肺部不良影响包括：肺气压伤、呼吸机相关肺损伤、内源性呼气末正压通气、通气/血流比例失调、膈肌萎缩、呼吸机无力和黏液腺毛运动减弱。此外，正压通气可能降低心输出量并影响血液动力学检测，与胃肠道应激性溃疡、内脏灌注减少、胃肠动力不足、液体潴留、急性肾衰竭、颅内压升高、肌无力、炎症和睡眠障碍相关。《前瞻性队列研究：急性呼吸衰竭患者机械通气强度与死亡率的关系》Lancet Respiratory Medicine，2020年9月 (3)尽管使用了肺保护性通气，但急性呼吸衰竭的死亡率仍然很高。最近的研究表明，基线通气参数与急性呼吸窘迫综合征患者预后之间存在相关性。该前瞻性队列研究的目的是评估急性呼吸衰竭患者长期暴露于不同强度的、机械通气与ICU死亡率之间的关系，共纳入13408例、接受≥4小时机械通气的患者。研究中，18%的患者死于ICU，对年龄和疾病严重程度进行调整后，发现机械通气驱动力 （driving pressure）与死亡风险显著升高有关（风险比1·064）；机械通气的机械功率（mechanical power）与死亡风险显著升高有关（风险比1·060）。这些关联在机械通气期间持续存在。结论：即使持续时间很短，高强度机械通气的累计暴露量是有害的。在进一步的研究中，应当对限制高强度机械通气以降低急性呼吸衰竭患者死亡率的治疗策略进行评估。《对照研究：健康受试者和危重病人膈肌的组织多普勒成像》American Journal of Respiratory and Critical Care Medicine，2020年10月 (4)组织多普勒成像是一种测量组织运动速度的超声心动图方法。该研究将此技术应用于膈肌，以评估膈肌在收缩和放松时的运动速度。研究对20名健康志愿者进行膈肌组织多普勒检查，以评估膈肌运动速度模式，测量其正常值，并确定测量值在观察者间的变异性。然后，在116例连续的ICU患者中，对脱机期间膈肌的偏移、增厚和组织多普勒参数（峰值收缩速度、峰值松弛速度、速度-时间积分和组织多普勒导出的最大松弛率）进行了评估。在一个18例患者亚组中，同时使用组织多普勒记录跨膈压（Pdi）、峰值Pdi、压力-时间乘积和膈肌最大舒张率。在可重复性方面，所有组织多普勒参数的相关系数为>0.89（P < 0.001）。除速度-时间积分外，健康志愿者和脱机成功患者的组织多普勒参数均低于脱机失败患者，分别为：峰值收缩速度1.35±0.34 cm/s、1.50±0.59 cm/s、2.66±2.14 cm/s（P < 0.001）；峰值松弛速度1.19±0.39 cm/s、1.53±0.73 cm/s、3.36±2.40 cm/s（P < 0.001）；组织多普勒最大舒张率分别为3.64±2.02 cm/s2、10.25±5.88 cm/s2、29.47±23.95 cm/s2（P < 0.001）。收缩速度峰值、与跨膈压峰值和压力-时间乘积有显著相关性，而最大舒张速率与最大舒张速率有显著相关性。结论：膈组织多普勒可实时评估膈肌组织的运动速度。膈肌组织多普勒衍生参数区分了脱机试验失败的患者和成功的患者，并与Pdi衍生参数有良好的相关性。《荟萃分析：危重病人的肌力与临床预后之间的关系》European Respiratory Journal，2020年9月 (5)研究的目的是评估肌无力与机械通气死亡率、或脱机成功率之间的联系，以及每种评估工具预测结果的能力。荟萃分析共分析了60项研究，包括4382名患者。ICU相关肌无力与总死亡率增加相关，风险比从1.2到4.48不等。其中刺激双侧膈神经产生的颤搐性跨膈压（transdiaphragmatic twitch pressure，TwPdi）对总死亡率的预测能力最高，敏感度为87%、特异性36%、曲线下面积 0.74。肌无力与机械通气脱机失败率增加相关，风险比为2.64至19.07不等。隔肌 增厚分数（diaphragm thickening fraction，DTF）对脱机失败率的预测能力最高，敏感性76%、特异性86%、曲线下面积为0.86。结论：ICU相关肌无力与高死亡率和更长时间机械通气相关。《综述：肺和膈保护通气》American Journal of Respiratory and Critical Care Medicine，2020年6月 (6)机械通气可引起急性膈肌萎缩和损伤，这与不良临床结果有关。肺部保护性通气的重要性和影响已得到广泛认识和确认，而膈肌保护性通气的概念最近已成为一种潜在的补充治疗策略。这一观点是在欧洲重症医学学会胸膜压工作组召开的一次国际专家会议的讨论中提出的，基于越来越多的损伤机制的证据，提出了一种综合肺和膈膜保护机械通气的概念框架。文章提出隔肌保护的目标基于呼吸努力和病人-呼吸机同步。讨论了在一定条件下隔肌保护与肺保护之间可能发生的冲突；我们强调，当冲突发生时，肺保护必须优先于隔肌保护。为了实施肺和膈保护通气，需要新的监测、设置呼吸机和滴定镇静的方法。未来，体外生命支持技术、膈神经刺激和临床决策支持系统等辅助干预措施也可能在特定的患者中发挥重要作用。由于干预的复杂性，评估这种新模式的临床影响将具有挑战性。结论：肺和膈保护通气的概念为显著改善危重病人的临床结果提供了一个引人注目的新理念。小羽点评：机械通气本身会导致膈肌功能障碍（ventilator induced diaphragmatic dysfunction，VIDD），控制型机械通气时甚至在第一天就可以发生，显著延长了通气和住院时间、导致撤机困难、并发症风险升高，这可能与膈肌损伤、萎缩、蛋白水解有关，通过氧化应激介导，但临床上有效避免该现象的最佳方法尚无定论。目前主要的策略是：保持适当水平的自主呼吸、避免病人-呼吸机不同步、根据膈肌活动监测指标调整呼吸机参数等。 《随机对照研究：对危重机械通气患者采取非镇静或浅镇静的比较》New England Journal of Medicine，2020年3月 (7)在危重的机械通气患者中，每日唤醒已被证明能够缩短通气时间和ICU住院时间。该研究的目的是讨论非镇静与浅镇静计划相比是否会影响死亡率。这项多中心、随机、对照试验中，随机分为非镇静组、和每日唤醒的浅镇静组，共纳入700名患者。非镇静组的平均Richmond躁动和镇静评分（RASS评分）从第1日的－1.3分提高至第7日的－0.8分；浅镇静组则从第1日的－2.3分提高至第7日的－1.8分。非镇静组和镇静组的90日死亡率分别为42.4%和37.0%（P=0.65）。两组患者离开ICU的天数、和不使用呼吸机的天数无显著差异。非镇静组患者中，无昏迷且无谵妄的中位天数为27日；浅镇静组患者中，无昏迷且无谵妄的中位天数为26日。非镇静组1例患者和浅镇静组10例患者发生了血栓栓塞事件。结论：在接受机械通气的ICU患者中，非镇静和浅镇静治疗策略90天死亡率无显著差异。《PEPTIC研究：质子泵抑制剂与抗组胺-2受体抑制剂剂对ICU有创机械通气患者住院死亡率的影响》JAMA，2020年1月 (8)研究的目的比较应用质子泵抑制剂（PPI）与组胺-2受体抑制剂（H2RB），在ICU有创机械通气患者中，预防应激性溃疡的疗效和对住院死亡率的影响。共26 982名患者被随机分配至PPI组或H2RB组，平均年龄58岁。PPI组和H2RB组中，90天住院死亡率分别为18.3%和17.5%（P=0.054），严重上消化道出血发生率分别为1.3%和1.8%的H2RB组（P = .009)。治疗组艰难梭菌感染率、ICU和住院时间无显著差异。在PPI组1例患者出现过敏反应。结论：在需要机械通气的ICU患者中，使用质子泵抑制剂与组胺-2受体阻滞剂相比，在预防应激性溃疡的医院死亡率方面没有统计学差异。呼吸机相关性肺炎呼吸机相关性肺炎（VAP）是指患者气管插管48小时后发生的肺炎，与以下因素相关：进入下呼吸道的微生物数量和宿主的机械、体液、细胞防御受损。约75%的重症患者在入院48小时内发生院内微生物定植。此外，肺部感染的主要途径是微量吸入已定植于口咽部、胃肠道的微生物，因此广泛使用的抑酸药提高胃液的pH值会改变上消化系统几乎无菌的状态，增加呼吸机相关性肺炎的发生几率。多重耐药菌危险因素包括：住院时间较长（>5天）和/或过去90天使用过抗生素。《双盲随机对照研究：心脏停搏后早发性呼吸机相关性肺炎的预防》New England Journal of Medicine，2019年11月 (9)院外心脏停搏、电击复律后后，接受体温管理的患者发生呼吸机相关性肺炎的风险增加。目前尚未证明抗生素短期预防性用药的益处。这项多中心、双盲、随机、安慰剂对照试验，纳入心脏停搏后、在ICU接受机械通气治疗、并且接受32～34℃目标体温管理的成人患者共 198例。于入院6小时内开始阿莫西林克拉维酸或安慰剂2日。7天内，抗生素预防组的早发呼吸机相关性肺炎发生率低于安慰剂组（19% vs 34%；风险比 0.53；P=0.03）。晚发性呼吸机相关性肺炎发生率、不使用呼吸机的天数、ICU停留时间和第28天时死亡率，两组均无差异。第7天未发现耐药菌增多。结论：院外发生心脏停搏后，接受32～34℃目标体温管理策略的患者，2日的阿莫西林克拉维酸降低了早发性呼吸机相关性肺炎的发生率。《2项前瞻性研究：英国ICU疑似呼吸机相关肺炎患者的肺曲霉菌病》American Journal of Emergency Medicine，2020年11月 (10)疑似呼吸机相关肺炎患者中，曲霉菌感染仍然缺乏十分敏感的诊断。这篇文章的目的是评估疑似呼吸机相关肺炎的曲霉菌感染的患病率和预后。文章纳入的这2项前瞻性研究招募了360名影像学、临床、实验室检查疑似的、呼吸机相关性肺炎的危重症患者，并获得了194名患者的血清样本和肺泡灌洗液，并进行了真菌学测试。最后根据临床、影像学和真菌学标准的定义诊断曲霉菌感染。在评估的194名患者中，曲霉菌感染患病率为12.4%，24例曲霉菌感染中有4人血清中半乳甘露聚糖阳性，16例肺泡灌洗液中半乳甘露聚糖阳性，两者均阳性共4例，3例肺泡灌洗液中培养出曲霉菌。疑似曲霉菌感染的患者ICU住院时间更长（25.5天 vs 15.5天，P = 0.02），死亡率略高（33.3% vs. 22.8%，P = 0.23）。结论：在调查疑似呼吸机相关肺炎患者时，即使不是曲霉菌感染高危，仍应考虑曲霉菌感染的可能。《DEDECAP研究：气管切开拔管前应用高流量氧疗联合堵管或联合吸引的比较》New England Journal，2020年9月 (11)应用气管切开套管的患者拔管前，通常做法是将气管切开套管堵管24小时，确定患者可否能自主呼吸。该研究的目的是比较这种做法是否比根据呼吸道吸引频率更好决定是否能够拔管更好。来自西班牙的研究人员在5个ICU进行了这项研究，纳入330例、气管切开后、有意识的、危重成人患者，患者的平均年龄58岁，68.2%为男性。一组接受24小时堵管试验+间歇性高流量氧疗（对照组），另一组接受连续高流量氧疗+将吸引频率作为拔管准备指标（干预组）。干预组至拔管的时间比对照组短（中位数，6天 vs. 13天）。干预组的肺炎和气管支气管炎发生率低于对照组，住院时长也比对照组短。 结论：与24小时堵管试验+间歇性高流量吸氧相比，依据吸引频率制定的拔管决策+连续高流量氧疗缩短了拔管时间，失败率不存在差异。《基础研究：Fc区优化的抗体可以诱导CD8对病毒性呼吸道感染的免疫》Nature，2020年10月(12)针对病毒病原体的抗体是控制病毒感染的一种很有前途的治疗方式，之前的一些研究已经证实，抗体的抗病毒效果需要Fab区和Fc区的协同作用。抗体Fc区在免疫系统中的各类细胞上的受体结合，激活免疫系统清除病毒、杀死被感染的细胞。这项研究的目的是，通过对抗流感IgG单抗的Fc区选择性的修饰，使之能够特异性的与已激活的Fcγ受体、Fcγ IIa受体结合，则能够进一步增强树突状细胞成熟、诱导保护性CD8+T细胞应答，从而提高预防或治疗致命性呼吸道病毒感染的疗效。结论：当IgG抗体选择性激活树突状细胞-T细胞通路时，能够诱导对病毒感染的保护性、适应性免疫，这对发展抗体疗法，提高对抗病毒的疗效具有重要意义。参考文献1.Huber RM, Hansen KH, Paz-Ares Rodríguez L, West HL, Reckamp KL, Leighl NB, et al. Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial. J Thorac Oncol. 2020;15(3):404-15.2.Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020;38(31):3592-603.3.Urner M, Juni P, Hansen B, Wettstein MS, Ferguson ND, Fan E. Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study. Lancet Respir Med. 2020;8(9):905-13.4.Soilemezi E, Savvidou S, Sotiriou P, Smyrniotis D, Tsagourias M, Matamis D. Tissue Doppler Imaging of the Diaphragm in Healthy Subjects and Critically Ill Patients. Am J Respir Crit Care Med. 2020;202(7):1005-12.5.Medrinal C, Combret Y, Hilfiker R, Prieur G, Aroichane N, Gravier FE, et al. ICU outcomes can be predicted by noninvasive muscle evaluation: a meta-analysis. Eur Respir J. 2020;56(4).6.Goligher EC, Dres M, Patel BK, Sahetya SK, Beitler JR, Telias I, et al. Lung and Diaphragm-Protective Ventilation. Am J Respir Crit Care Med. 2020.7.Olsen HT, Nedergaard HK, Strøm T, Oxlund J, Wian K-A, Ytrebø LM, et al. Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. New England Journal of Medicine. 2020;382(12):1103-11.8.Australian PIft, New Zealand Intensive Care Society Clinical Trials Group AHSCCSCN, the Irish Critical Care Trials G, Young PJ, Bagshaw SM, Forbes AB, et al. Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial. JAMA. 2020;323(7):616-26.9.François B, Cariou A, Clere-Jehl R, Dequin P-F, Renon-Carron F, Daix T, et al. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. New England Journal of Medicine. 2019;381(19):1831-42.10.Loughlin L, Hellyer TP, White PL, McAuley DF, Conway Morris A, Posso RB, et al. Pulmonary Aspergillosis in Patients with Suspected Ventilator-associated Pneumonia in UK ICUs. Am J Respir Crit Care Med. 2020;202(8):1125-32.11.Hernández Martínez G, Rodriguez ML, Vaquero MC, Ortiz R, Masclans JR, Roca O, et al. High-Flow Oxygen with Capping or Suctioning for Tracheostomy Decannulation. N Engl J Med. 2020;383(11):1009-17.12.Bournazos S, Corti D, Virgin HW, Ravetch JV. Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection. Nature. 2020.

FDA 批准首个用于治疗晚期尿路上皮癌的FGFR激酶抑制剂Nature Medicine 免疫检查点抑制剂PD-L1联合CTLA-4单抗治疗高危尿路上皮癌前沿医学 多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗CKD厄达替尼（erdafitinib）我们的节目曾在《消化科星期三 Episode 3》中介绍过培米加替尼，治疗成纤维细胞生长因子受体编码基因（FGFR）基因融合或重排的局部晚期胆管癌，胆管癌中约有20%的患者存在这种基因突变。研究人员发现FGFR突变在尿路上皮癌中也很常见，并且可能与对免疫干预的敏感性降低相关。厄达替尼（erdafitinib）是一种FGFR1-4的酪氨酸激酶抑制剂，2019年4月，FDA已经批准厄达替尼（erdafitinib）用于治疗局部晚期或转移性尿路上皮癌。《BLC2001研究：厄达替尼治疗局部晚期或转移性尿路上皮细胞癌的2期临床研究》New England Journal of Medicine，2019年8月 (1) 在这项开放标签的2期研究中，纳入了FGFR基因突变的、局部晚期和不可切除或转移性尿路上皮细胞癌的患者99人，所有患者既往均接受过化疗，并在化疗12个月内发生疾病进展。最初将患者随机分组，随后根据中期分析，将连续用药方案的起始剂量设定为8mg/d，并可在药效学指导下，将剂量增加至9mg/d。经过平均5个周期的厄达替尼治疗后，缓解率为40%（3%完全缓解，37%部分缓解）。在既往接受过免疫治疗患者中，缓解率为59%。中位无进展生存期为5.5个月，中位总生存期为13.8个月。结论：在既往接受过治疗的、有FGFR基因突变的、且患局部晚期和不可切除或转移性的尿路上皮细胞癌的患者中，厄达替尼治疗后肿瘤客观缓解率达40%。膀胱尿路上皮癌膀胱癌是最常见的泌尿系统恶性肿瘤，其中尿路上皮癌（也称移行细胞癌）是主要的组织学类型，占所有膀胱癌的90%。膀胱尿路上皮癌可表现为非肌肉浸润癌、肌肉浸润癌和转移癌，病变的程度可以反映自然病程，并决定了治疗和预后。膀胱癌通常表现为肉眼血尿或镜下血尿，刺激性或梗阻性排尿困难也可以 是首发症状。非肌肉浸润性膀胱癌的治疗对于非肌肉浸润性膀胱癌的患者，采用经尿道膀胱肿瘤切除术（TURBT），并联合膀胱内辅助治疗等保守治疗方式有可能保留膀胱功能。膀胱内辅助治疗主要包括卡介苗（牛结合分支杆菌的减毒活疫苗）和丝裂霉素C、表柔比星、吉西他滨等化疗药物。《系统回顾：膀胱治疗非肌肉浸润性膀胱癌的疗效》European Urology，2020年9月 (2)研究的目的是评价在卡介苗治疗后，保留膀胱功能的患者的疾病完全缓解率和无复发率。研究系统地回顾了42项研究，包括24种治疗方案、2254名患者。包含原位癌在内的肿瘤治疗中位完全缓解率，6个月时为26%，12个月时为17%，24个月时为8%。相比，乳头状癌的平均无进展率，6个月时为67%，12个月时为44%，24个月时为10%。特别是在卡介苗无效的、接受草分枝杆菌细胞壁-核酸复合物的患者中，6个月和12个月的完全缓解率分别为45%和27%；6、12、24个月中位不带病生存率分别为43%、35%和18%。总的中位无进展率为91%，原位癌的研究中为95%，乳头状癌的研究中为89%。膀胱内给药的不良反应少，且轻微。结论：卡介苗治疗后的、保留膀胱疗法，在非肌肉浸润性膀胱癌患者中取得了适度的疗效。《NIMBUS研究：卡介苗标准剂量和数量灌注治疗重度非肌肉浸润性膀胱癌的3期临床研究》European Urology，2020年11月 (3)膀胱内灌注卡介苗治疗是一种被广泛接受的预防非肌肉浸润性膀胱癌复发的策略，但是具有显著的毒性。研究的目的是评估了降低标准剂量卡介苗灌注的次数是否可以达到同样的疗效。研究纳入了345名非肌肉浸润性膀胱癌的患者，分别接受标准治疗（诱导6周，在第3、6和12个月时各治疗3周，共15次灌注），或低频率治疗（第1、2和6周诱导，在第3、6和12个月时各治疗2周，共9次灌注）。中位随访12个月后，标准治疗组复发率12%，低频率治疗组复发率27%。安全性分析达到了预先定义的、无效停止标准。结论：在预防膀胱癌复发方面，标准治疗方案更好，目前研究已经停止对参与者的招募。《国家质量指标项目：提高非肌肉浸润性膀胱癌经尿道膀胱肿瘤切除术的质量和有效性》European Urology，2020年8月 (4)非肌肉浸润性膀胱癌的临床预后部分取决于初始干预。为了改善和标准化癌症治疗，苏格兰实施了一项针对膀胱癌的国家质量指标项目。研究中纳入了2689例患者，标准干预包括：（1）使用膀胱图；（2）经尿道膀胱肿瘤切除术后单次膀胱内灌注丝裂霉素C一次；（3）逼尿肌活检；（4）高危膀胱癌患者中，早期行二次手术。研究中，67%患者接受了术后一次膀胱灌注；复发率、残余癌比例和继发肿瘤的比例分别为13%、33%和2.9%。术后一次膀胱灌注复发率降低相关；逼尿肌活检则癌症残留的可能性减半。结论：在苏格兰实施国家质量指标计划似乎有助于向患者提供高质量的经尿道膀胱肿瘤切除术，且降低了术后的复发率、肿瘤分期更准确。《DaBlaCa-13研究：短期强化化疗与标准辅助膀胱内灌注治疗非肌肉浸润性膀胱癌》European Urology，2020年8月 (5)膀胱灌注治疗非肌肉浸润性膀胱癌可减少复发。术前灌注化疗副作用更少，甚至一些患者在治疗后都无需接受肿瘤切除术了。研究旨在比较术前丝裂霉素C短期强化化疗治疗复发性非肌肉浸润性膀胱癌的效果。研究纳入120例患者，短期强化化疗组，膀胱灌注化疗每周3次，共2周；对照组先行经尿道膀胱肿瘤切除术，术后6周每周进行一次膀胱灌注辅助治疗。在短期强化化疗组中，有33名参与者（57%）出现了肿瘤完全缓解，且不良事件少。结论：术前短期强化化疗使一半以上的患者避免肿瘤切除术，但长期疗效仍需随访观察。肌肉浸润性膀胱癌的治疗对于肌肉浸润性膀胱癌，需行根治性膀胱切除术+尿流改道术，以及辅助化疗、免疫治疗。化疗方案中的MVAC方案（甲氨蝶呤、长春碱、多柔比星、顺铂）被认为是一线化疗方案，临床实践中多在这个方案上增减。目前已有几个免疫检查点抑制剂被获批用于膀胱尿路上皮癌的治疗：阿替利珠单抗（atezolizumab），帕博利珠单抗（pembrolizumab），纳武利尤单抗（nivolumab），阿伟鲁单抗（avelumab），德瓦鲁单抗（durvalumab）。《回顾性综述：FGFR3的水平变化与膀胱癌对铂化疗的敏感性有关》European Urology，2020年8月(6)大约15%的膀胱癌存在成纤维细胞生长因子受体3 （FGFR3）基因突变。研究人员回顾性的比较和综述三个队列的患者：（1）新辅助化疗治疗肌肉侵袭性膀胱癌患者的数据；（2）一线铂类化疗治疗转移性尿路上皮癌患者的数据；（3）来自癌症基因组图谱中的肌肉侵袭性膀胱癌患者的数据。队列一：72例新辅助化疗的肌肉侵袭性膀胱炎癌患者中有13%具有FGFR3突变，均没有达到病理完全缓解，且无复发生存期短。队列三：来自癌症基因组图谱中的肌肉侵袭性膀胱癌的患者，接受辅助化疗、且伴有FGFR3突变的无复发生存期也更短。相反，在未接受化疗的患者中，FGFR3突变与无复发生存期更长、总生存率更高。队列二：转移性尿路上皮癌的患者中，FGFR3突变虽然药物反应低，但不影响无进展生存率和总生存率。结论：肌肉浸润性膀胱癌中，FGFR3突变可能与围手术期铂类药物化疗反应差、易复发有关。《IMvigor130研究：化疗联合阿替利珠单抗治疗转移性尿路上皮癌的3期临床研究》Lancet，2020年5月 (7)这个多中心、3期、随机研究的目的是，比较阿替利珠单抗与安慰剂加铂类化疗在一线转移性尿路上皮癌的疗效。研究纳入未经治疗的、≥18岁的、局部晚期或转移性尿路上皮细胞癌患者共1213人。随机接受阿替利珠单抗+铂类化疗，或阿替利珠单抗单药治疗，或安慰剂+铂类化疗，随访11.8个月。中位无进展生存期，在阿替利珠单抗联合化疗组为8·2个月，在安慰剂联合化疗组为6.3个月（p = 0·007）。中位生存期，在阿替利珠单抗联合化疗组为16·0个月，安慰剂联合化疗组为13·4个月（p = 0·027）。阿替利珠单抗单药治疗组中位总生存期为15·7个月，与安慰剂联合化疗组无差异。结论：阿替利珠单抗联合铂类化疗延长了转移性尿路上皮癌患者的无进展生存，研究支持使用阿替利珠单抗联合铂类化疗作为转移性尿路上皮癌的潜在的、一线治疗选择。《JAVELIN Bladder200研究：PD-L1单抗阿伟鲁单抗维持治疗局部晚期、或转移性尿路上皮癌》New England Journal of Medicine，2020年9月 (8)这项3期临床试验中，研究人员纳入无法手术的局部晚期、或转移性尿路上皮癌患者共700人，在接受一线化疗后，随机给予阿伟鲁单抗维持治疗、或仅给予支持治疗。阿伟鲁单抗维持治疗能显著延长了患者的总生存期。阿伟鲁单抗组和对照组的，1年总生存率分别为71.3%和58.4%，中位总生存期分别为21.4个月和14.3个月（死亡风险比 0.69，P = 0.001）。阿伟鲁单抗也显著延长了PD-L1阳性的患者的总生存率，两组分别为79.1%和60.4%（风险比 0.56，P < 0.001）。在总体人群中，阿伟鲁单抗组的中位无进展生存期为3.7个月，对照组为2.0个月（疾病进展或死亡的风险比为0.62）；在PD-L1阳性的人群中，阿伟鲁单抗组的中位无进展生存期为5.7个月，对照组为2.1个月（风险比 0.56）。结论：一线化疗+阿伟鲁单抗维持治疗，能进一步延长了患者的总生存期。《随机对照研究：卡博替尼和纳武利尤单抗联合或不联合伊匹木单抗治疗转移性尿路上皮癌的1期临床研究》Journal of Clinical Oncology，2020年10月 (9)卡博替尼（cabozantinib）是一种酪氨酸激酶受体抑制剂 ，纳武利尤单抗（nivolumab）是一种PD-1单抗，伊匹木单抗（ipilimumab）是一种CTLA-4单抗。研究的目的是评估了卡博替尼联合纳武利尤单抗的CaboNivo方案，以及CaboNivo联合伊匹木单抗的CaboNivoIpi方案在转移性尿路上皮癌和其他泌尿生殖系统恶性肿瘤患者中的安全性和有效性，共入组54人。平均随访时间为44.6个月，转移性尿路上皮癌的客观缓解率为38.5%，平均缓解持续时间尚未达到，中位无进展生存期达12.8个月，中位总生存期为25.4个月。CaboNivo和CaboNivoIpi治疗组中，严重不良事件发生率分别为75%和87%，主要包括疲劳、腹泻、高血压、肝炎、结肠炎。II期临床研究推荐剂量为卡博替尼40 mg/d、纳武利尤单抗3 mg/kg，伊匹木单抗1 mg/kg。结论：CaboNivo方案（卡博替尼+纳武利尤单抗）和CaboNivoIpi（卡博替尼+纳武利尤单抗+伊匹木单抗）方案均显示了良好的耐受性和持久的疗效，多项II期和III期临床研究正在进行中。《随机对照临床研究：新辅助PD-L1加CTLA-4阻滞治疗顺铂化疗无法耐受的、可手术切除的、高危、尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (10)这是首个抗PD-L1单抗（德瓦鲁单抗，durvalumab）联合抗CTLA-4单抗（曲美木单抗，tremelimumab）。研究纳入在顺铂化疗无法耐受的、具有高危特征的、尿路上皮癌患者共28人（高危特征为肿块大、组织学变异、淋巴血管侵犯、肾盂积水和/或高度上尿路疾病）。在完成手术的患者中，病理完全缓解为37.5%，58%的患者达到无残余侵袭性占位。21%的患者出现免疫相关不良事件，包括无症状实验室异常、肝炎和结肠炎结论：研究提供了抗PD-L1单抗联合抗CTLA-4单抗新辅助治疗的初步安全性、有效性和生物标志物数据，这对于局限性尿路上皮癌患者，特别是具有高危特征且目前没有建立标准护理新辅助治疗的顺铂不合格患者，值得进一步发展。《NABUCCO研究：术前CTLA-4联合PD-1抑制剂治疗局部晚期尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (11)伊匹木单抗（ipilimumab）是一种CTLA-4单抗，纳武利尤单抗（nivolumab）是一种PD-1单抗，在NABUCCO研究中，纳入了24名III期、尿路上皮癌患者，术前接受两次伊匹木单抗联合纳武利尤单抗治疗后，然后在12周内接受手术切除。研究中46%的患者达到病理学完全缓解，58%达到无残余侵袭性占位。与单独使用PD-1/PD-L1抑制剂的研究相比，伊匹木单抗联合纳武利尤单抗的疗效与基线时CD8+ T细胞活性无关。3-4级免疫相关不良事件发生率分别为55%和41%。结论：在局部晚期尿路上皮癌患者中，CTLA-4联合PD-1阻断可能提供一个有效的术前治疗策略，而不用考虑先前的CD8+ T细胞的活性。纳米颗粒作为抗纤维化基因载体治疗CKD《基础研究：多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗慢性肾脏病》J American Society of Nephrology，2020年8月 (12)预防或逆转促纤维化的细胞的基因表型是治疗慢性肾脏病的一个方向，来自南开大学的研究人员开发了一种纳米颗粒，作为抗纤维化的基因的载体，为损伤组织和常驻细胞提供抗纤维化治疗，以限制促纤维化表型的表现。研究人员将表达骨形态发生蛋白7（BMP7）或肝细胞生长因子（HGF）-NK1（HGF/NK1）的质粒DNA包裹在有一层透明质酸壳的聚糖纳米颗粒内，安全地将含有质粒DNA的多功能纳米粒导入肾脏，用于抗纤维化因子的局部和持续表达。在小鼠模型中，静脉注射后，这些纳米颗粒约有10-45%的基因被肾脏摄取，减轻了纤维化的发展，并挽救了肾功能。BMP7基因逆转了纤维化进展、促进肾小管再生；HGF/NK1基因减少胶原纤维沉积。结论：纳米颗粒作为BMP7基因和HGF-NK1基因的载体，提供了今后靶向基因治疗慢性肾脏病的基础。参考文献1.Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. 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Lancet. 2020;395(10236):1547-57.8.Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-30.9.Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol. 2020;38(31):3672-84.10.Gao J, Navai N, Alhalabi O, Siefker-Radtke A, Campbell MT, Tidwell RS, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020.11.van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020.12.Midgley AC, Wei Y, Zhu D, Gao F, Yan H, Khalique A, et al. 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FDA 批准首个用于治疗晚期尿路上皮癌的FGFR激酶抑制剂Nature Medicine 免疫检查点抑制剂PD-L1联合CTLA-4单抗治疗高危尿路上皮癌前沿医学 多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗CKD厄达替尼（erdafitinib）我们的节目曾在《消化科星期三 Episode 3》中介绍过培米加替尼，治疗成纤维细胞生长因子受体编码基因（FGFR）基因融合或重排的局部晚期胆管癌，胆管癌中约有20%的患者存在这种基因突变。研究人员发现FGFR突变在尿路上皮癌中也很常见，并且可能与对免疫干预的敏感性降低相关。厄达替尼（erdafitinib）是一种FGFR1-4的酪氨酸激酶抑制剂，2019年4月，FDA已经批准厄达替尼（erdafitinib）用于治疗局部晚期或转移性尿路上皮癌。《BLC2001研究：厄达替尼治疗局部晚期或转移性尿路上皮细胞癌的2期临床研究》New England Journal of Medicine，2019年8月 (1) 在这项开放标签的2期研究中，纳入了FGFR基因突变的、局部晚期和不可切除或转移性尿路上皮细胞癌的患者99人，所有患者既往均接受过化疗，并在化疗12个月内发生疾病进展。最初将患者随机分组，随后根据中期分析，将连续用药方案的起始剂量设定为8mg/d，并可在药效学指导下，将剂量增加至9mg/d。经过平均5个周期的厄达替尼治疗后，缓解率为40%（3%完全缓解，37%部分缓解）。在既往接受过免疫治疗患者中，缓解率为59%。中位无进展生存期为5.5个月，中位总生存期为13.8个月。结论：在既往接受过治疗的、有FGFR基因突变的、且患局部晚期和不可切除或转移性的尿路上皮细胞癌的患者中，厄达替尼治疗后肿瘤客观缓解率达40%。膀胱尿路上皮癌膀胱癌是最常见的泌尿系统恶性肿瘤，其中尿路上皮癌（也称移行细胞癌）是主要的组织学类型，占所有膀胱癌的90%。膀胱尿路上皮癌可表现为非肌肉浸润癌、肌肉浸润癌和转移癌，病变的程度可以反映自然病程，并决定了治疗和预后。膀胱癌通常表现为肉眼血尿或镜下血尿，刺激性或梗阻性排尿困难也可以 是首发症状。非肌肉浸润性膀胱癌的治疗对于非肌肉浸润性膀胱癌的患者，采用经尿道膀胱肿瘤切除术（TURBT），并联合膀胱内辅助治疗等保守治疗方式有可能保留膀胱功能。膀胱内辅助治疗主要包括卡介苗（牛结合分支杆菌的减毒活疫苗）和丝裂霉素C、表柔比星、吉西他滨等化疗药物。《系统回顾：膀胱治疗非肌肉浸润性膀胱癌的疗效》European Urology，2020年9月 (2)研究的目的是评价在卡介苗治疗后，保留膀胱功能的患者的疾病完全缓解率和无复发率。研究系统地回顾了42项研究，包括24种治疗方案、2254名患者。包含原位癌在内的肿瘤治疗中位完全缓解率，6个月时为26%，12个月时为17%，24个月时为8%。相比，乳头状癌的平均无进展率，6个月时为67%，12个月时为44%，24个月时为10%。特别是在卡介苗无效的、接受草分枝杆菌细胞壁-核酸复合物的患者中，6个月和12个月的完全缓解率分别为45%和27%；6、12、24个月中位不带病生存率分别为43%、35%和18%。总的中位无进展率为91%，原位癌的研究中为95%，乳头状癌的研究中为89%。膀胱内给药的不良反应少，且轻微。结论：卡介苗治疗后的、保留膀胱疗法，在非肌肉浸润性膀胱癌患者中取得了适度的疗效。《NIMBUS研究：卡介苗标准剂量和数量灌注治疗重度非肌肉浸润性膀胱癌的3期临床研究》European Urology，2020年11月 (3)膀胱内灌注卡介苗治疗是一种被广泛接受的预防非肌肉浸润性膀胱癌复发的策略，但是具有显著的毒性。研究的目的是评估了降低标准剂量卡介苗灌注的次数是否可以达到同样的疗效。研究纳入了345名非肌肉浸润性膀胱癌的患者，分别接受标准治疗（诱导6周，在第3、6和12个月时各治疗3周，共15次灌注），或低频率治疗（第1、2和6周诱导，在第3、6和12个月时各治疗2周，共9次灌注）。中位随访12个月后，标准治疗组复发率12%，低频率治疗组复发率27%。安全性分析达到了预先定义的、无效停止标准。结论：在预防膀胱癌复发方面，标准治疗方案更好，目前研究已经停止对参与者的招募。《国家质量指标项目：提高非肌肉浸润性膀胱癌经尿道膀胱肿瘤切除术的质量和有效性》European Urology，2020年8月 (4)非肌肉浸润性膀胱癌的临床预后部分取决于初始干预。为了改善和标准化癌症治疗，苏格兰实施了一项针对膀胱癌的国家质量指标项目。研究中纳入了2689例患者，标准干预包括：（1）使用膀胱图；（2）经尿道膀胱肿瘤切除术后单次膀胱内灌注丝裂霉素C一次；（3）逼尿肌活检；（4）高危膀胱癌患者中，早期行二次手术。研究中，67%患者接受了术后一次膀胱灌注；复发率、残余癌比例和继发肿瘤的比例分别为13%、33%和2.9%。术后一次膀胱灌注复发率降低相关；逼尿肌活检则癌症残留的可能性减半。结论：在苏格兰实施国家质量指标计划似乎有助于向患者提供高质量的经尿道膀胱肿瘤切除术，且降低了术后的复发率、肿瘤分期更准确。《DaBlaCa-13研究：短期强化化疗与标准辅助膀胱内灌注治疗非肌肉浸润性膀胱癌》European Urology，2020年8月 (5)膀胱灌注治疗非肌肉浸润性膀胱癌可减少复发。术前灌注化疗副作用更少，甚至一些患者在治疗后都无需接受肿瘤切除术了。研究旨在比较术前丝裂霉素C短期强化化疗治疗复发性非肌肉浸润性膀胱癌的效果。研究纳入120例患者，短期强化化疗组，膀胱灌注化疗每周3次，共2周；对照组先行经尿道膀胱肿瘤切除术，术后6周每周进行一次膀胱灌注辅助治疗。在短期强化化疗组中，有33名参与者（57%）出现了肿瘤完全缓解，且不良事件少。结论：术前短期强化化疗使一半以上的患者避免肿瘤切除术，但长期疗效仍需随访观察。肌肉浸润性膀胱癌的治疗对于肌肉浸润性膀胱癌，需行根治性膀胱切除术+尿流改道术，以及辅助化疗、免疫治疗。化疗方案中的MVAC方案（甲氨蝶呤、长春碱、多柔比星、顺铂）被认为是一线化疗方案，临床实践中多在这个方案上增减。目前已有几个免疫检查点抑制剂被获批用于膀胱尿路上皮癌的治疗：阿替利珠单抗（atezolizumab），帕博利珠单抗（pembrolizumab），纳武利尤单抗（nivolumab），阿伟鲁单抗（avelumab），德瓦鲁单抗（durvalumab）。《回顾性综述：FGFR3的水平变化与膀胱癌对铂化疗的敏感性有关》European Urology，2020年8月(6)大约15%的膀胱癌存在成纤维细胞生长因子受体3 （FGFR3）基因突变。研究人员回顾性的比较和综述三个队列的患者：（1）新辅助化疗治疗肌肉侵袭性膀胱癌患者的数据；（2）一线铂类化疗治疗转移性尿路上皮癌患者的数据；（3）来自癌症基因组图谱中的肌肉侵袭性膀胱癌患者的数据。队列一：72例新辅助化疗的肌肉侵袭性膀胱炎癌患者中有13%具有FGFR3突变，均没有达到病理完全缓解，且无复发生存期短。队列三：来自癌症基因组图谱中的肌肉侵袭性膀胱癌的患者，接受辅助化疗、且伴有FGFR3突变的无复发生存期也更短。相反，在未接受化疗的患者中，FGFR3突变与无复发生存期更长、总生存率更高。队列二：转移性尿路上皮癌的患者中，FGFR3突变虽然药物反应低，但不影响无进展生存率和总生存率。结论：肌肉浸润性膀胱癌中，FGFR3突变可能与围手术期铂类药物化疗反应差、易复发有关。《IMvigor130研究：化疗联合阿替利珠单抗治疗转移性尿路上皮癌的3期临床研究》Lancet，2020年5月 (7)这个多中心、3期、随机研究的目的是，比较阿替利珠单抗与安慰剂加铂类化疗在一线转移性尿路上皮癌的疗效。研究纳入未经治疗的、≥18岁的、局部晚期或转移性尿路上皮细胞癌患者共1213人。随机接受阿替利珠单抗+铂类化疗，或阿替利珠单抗单药治疗，或安慰剂+铂类化疗，随访11.8个月。中位无进展生存期，在阿替利珠单抗联合化疗组为8·2个月，在安慰剂联合化疗组为6.3个月（p = 0·007）。中位生存期，在阿替利珠单抗联合化疗组为16·0个月，安慰剂联合化疗组为13·4个月（p = 0·027）。阿替利珠单抗单药治疗组中位总生存期为15·7个月，与安慰剂联合化疗组无差异。结论：阿替利珠单抗联合铂类化疗延长了转移性尿路上皮癌患者的无进展生存，研究支持使用阿替利珠单抗联合铂类化疗作为转移性尿路上皮癌的潜在的、一线治疗选择。《JAVELIN Bladder200研究：PD-L1单抗阿伟鲁单抗维持治疗局部晚期、或转移性尿路上皮癌》New England Journal of Medicine，2020年9月 (8)这项3期临床试验中，研究人员纳入无法手术的局部晚期、或转移性尿路上皮癌患者共700人，在接受一线化疗后，随机给予阿伟鲁单抗维持治疗、或仅给予支持治疗。阿伟鲁单抗维持治疗能显著延长了患者的总生存期。阿伟鲁单抗组和对照组的，1年总生存率分别为71.3%和58.4%，中位总生存期分别为21.4个月和14.3个月（死亡风险比 0.69，P = 0.001）。阿伟鲁单抗也显著延长了PD-L1阳性的患者的总生存率，两组分别为79.1%和60.4%（风险比 0.56，P < 0.001）。在总体人群中，阿伟鲁单抗组的中位无进展生存期为3.7个月，对照组为2.0个月（疾病进展或死亡的风险比为0.62）；在PD-L1阳性的人群中，阿伟鲁单抗组的中位无进展生存期为5.7个月，对照组为2.1个月（风险比 0.56）。结论：一线化疗+阿伟鲁单抗维持治疗，能进一步延长了患者的总生存期。《随机对照研究：卡博替尼和纳武利尤单抗联合或不联合伊匹木单抗治疗转移性尿路上皮癌的1期临床研究》Journal of Clinical Oncology，2020年10月 (9)卡博替尼（cabozantinib）是一种酪氨酸激酶受体抑制剂 ，纳武利尤单抗（nivolumab）是一种PD-1单抗，伊匹木单抗（ipilimumab）是一种CTLA-4单抗。研究的目的是评估了卡博替尼联合纳武利尤单抗的CaboNivo方案，以及CaboNivo联合伊匹木单抗的CaboNivoIpi方案在转移性尿路上皮癌和其他泌尿生殖系统恶性肿瘤患者中的安全性和有效性，共入组54人。平均随访时间为44.6个月，转移性尿路上皮癌的客观缓解率为38.5%，平均缓解持续时间尚未达到，中位无进展生存期达12.8个月，中位总生存期为25.4个月。CaboNivo和CaboNivoIpi治疗组中，严重不良事件发生率分别为75%和87%，主要包括疲劳、腹泻、高血压、肝炎、结肠炎。II期临床研究推荐剂量为卡博替尼40 mg/d、纳武利尤单抗3 mg/kg，伊匹木单抗1 mg/kg。结论：CaboNivo方案（卡博替尼+纳武利尤单抗）和CaboNivoIpi（卡博替尼+纳武利尤单抗+伊匹木单抗）方案均显示了良好的耐受性和持久的疗效，多项II期和III期临床研究正在进行中。《随机对照临床研究：新辅助PD-L1加CTLA-4阻滞治疗顺铂化疗无法耐受的、可手术切除的、高危、尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (10)这是首个抗PD-L1单抗（德瓦鲁单抗，durvalumab）联合抗CTLA-4单抗（曲美木单抗，tremelimumab）。研究纳入在顺铂化疗无法耐受的、具有高危特征的、尿路上皮癌患者共28人（高危特征为肿块大、组织学变异、淋巴血管侵犯、肾盂积水和/或高度上尿路疾病）。在完成手术的患者中，病理完全缓解为37.5%，58%的患者达到无残余侵袭性占位。21%的患者出现免疫相关不良事件，包括无症状实验室异常、肝炎和结肠炎结论：研究提供了抗PD-L1单抗联合抗CTLA-4单抗新辅助治疗的初步安全性、有效性和生物标志物数据，这对于局限性尿路上皮癌患者，特别是具有高危特征且目前没有建立标准护理新辅助治疗的顺铂不合格患者，值得进一步发展。《NABUCCO研究：术前CTLA-4联合PD-1抑制剂治疗局部晚期尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (11)伊匹木单抗（ipilimumab）是一种CTLA-4单抗，纳武利尤单抗（nivolumab）是一种PD-1单抗，在NABUCCO研究中，纳入了24名III期、尿路上皮癌患者，术前接受两次伊匹木单抗联合纳武利尤单抗治疗后，然后在12周内接受手术切除。研究中46%的患者达到病理学完全缓解，58%达到无残余侵袭性占位。与单独使用PD-1/PD-L1抑制剂的研究相比，伊匹木单抗联合纳武利尤单抗的疗效与基线时CD8+ T细胞活性无关。3-4级免疫相关不良事件发生率分别为55%和41%。结论：在局部晚期尿路上皮癌患者中，CTLA-4联合PD-1阻断可能提供一个有效的术前治疗策略，而不用考虑先前的CD8+ T细胞的活性。纳米颗粒作为抗纤维化基因载体治疗CKD《基础研究：多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗慢性肾脏病》J American Society of Nephrology，2020年8月 (12)预防或逆转促纤维化的细胞的基因表型是治疗慢性肾脏病的一个方向，来自南开大学的研究人员开发了一种纳米颗粒，作为抗纤维化的基因的载体，为损伤组织和常驻细胞提供抗纤维化治疗，以限制促纤维化表型的表现。研究人员将表达骨形态发生蛋白7（BMP7）或肝细胞生长因子（HGF）-NK1（HGF/NK1）的质粒DNA包裹在有一层透明质酸壳的聚糖纳米颗粒内，安全地将含有质粒DNA的多功能纳米粒导入肾脏，用于抗纤维化因子的局部和持续表达。在小鼠模型中，静脉注射后，这些纳米颗粒约有10-45%的基因被肾脏摄取，减轻了纤维化的发展，并挽救了肾功能。BMP7基因逆转了纤维化进展、促进肾小管再生；HGF/NK1基因减少胶原纤维沉积。结论：纳米颗粒作为BMP7基因和HGF-NK1基因的载体，提供了今后靶向基因治疗慢性肾脏病的基础。参考文献1.Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine. 2019;381(4):338-48.2.Li R, Sundi D, Zhang J, Kim Y, Sylvester RJ, Spiess PE, et al. Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non-muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guerin. Eur Urol. 2020;78(3):387-99.3.Grimm MO, van der Heijden AG, Colombel M, Muilwijk T, Martinez-Pineiro L, Babjuk MM, et al. Treatment of High-grade Non-muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial "NIMBUS". Eur Urol. 2020;78(5):690-8.4.Mariappan P, Johnston A, Padovani L, Clark E, Trail M, Hamid S, et al. Enhanced Quality and Effectiveness of Transurethral Resection of Bladder Tumour in Non-muscle-invasive Bladder Cancer: A Multicentre Real-world Experience from Scotland's Quality Performance Indicators Programme. Eur Urol. 2020.5.Lindgren MS, Bue P, Azawi N, Blichert-Refsgaard L, Sundelin MO, Dyrskjøt L, et al. The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial. Eur Urol. 2020.6.Teo MY, Mota JM, Whiting KA, Li HA, Funt SA, Lee CH, et al. Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma. Eur Urol. 2020.7.Galsky MD, Arija JÁ A, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-57.8.Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-30.9.Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol. 2020;38(31):3672-84.10.Gao J, Navai N, Alhalabi O, Siefker-Radtke A, Campbell MT, Tidwell RS, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020.11.van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020.12.Midgley AC, Wei Y, Zhu D, Gao F, Yan H, Khalique A, et al. 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Researchers are conducting the first U.S. trial of pressurized intraperitoneal aerosolized chemotherapy (PIPAC) for the treatment of peritoneal carcinomatosis in patients with gynecologic or gastrointestinal cancers. Coprincipal investigator Thanh H. Dellinger, MD, of City of Hope in Duarte, Calif., describes this trial and the PIPAC procedure to host David H. Henry, MD, in this episode. To start, the pair discuss a patient who might be eligible for PIPAC – one with stage 3 ovarian cancer. General approach to stage 3 ovarian cancer Therapy typically includes a combination of surgery and chemotherapy. The order in which chemotherapy is given, either pre- or postoperatively, depends on performance status and whether patients have extra-abdominal disease or parenchymal liver disease. Operative approaches, including debulking surgery, are pursued if believed to be optimal, meaning all gross residual disease can be resected. If all residual disease cannot be resected, patients are offered neoadjuvant chemotherapy, typically for three to four cycles before an interval debulking surgery, followed by postoperative adjuvant chemotherapy. Intraperitoneal chemotherapy Intraperitoneal (IP) chemotherapy is used to treat peritoneal surface malignancies. The peritoneum is a separate organ that is difficult to treat adequately with intravenous chemotherapy alone. Giving IP chemotherapy in combination with intravenous chemotherapy may be more effective than intravenous chemotherapy alone (N Engl J Med. 2006; 354:34-43; https://bit.ly/3g3lngx). However, there are many challenges in delivering IP chemotherapy, including increased side effects of abdominal pain and IP catheter failure. Recent clinical trials have shown that, with the addition of bevacizumab, the survival benefit with IP chemotherapy may not be as significant as prior trials suggested (J Clin Oncol. 2019 Jun 1;37[16]:1380-90; https://bit.ly/2VAmRVW). In general, IP chemotherapy has not been embraced by the medical oncology community as much other types of chemotherapies, Dr. Dellinger said. What is PIPAC? PIPAC is a novel therapy discovered by a German surgical oncologist, Marc A. Reymond, MD, from University of Tuebingen (Germany). PIPAC delivers chemotherapy at a reduced dose directly into the intraperitoneal cavity but in a pressurized and aerosolized form. PIPAC is done at the time of the diagnostic laparoscopy and requires a nebulizer for aerosolization of the chemotherapy as well as a high-pressure injector. This approach allows for the chemotherapy to be pushed deeper into tissues, compared with hyperthermic intraoperative peritoneal chemotherapy (HIPEC). With HIPAC, tissue penetration is typically 1 mm or less. With PIPAC, there is deeper penetration and better distribution of chemotherapy throughout the entire intraperitoneal cavity. With PIPAC, chemotherapeutic agents are given at a lower dose than is typically administered with IP or intravenous chemotherapy, which helps in reducing the toxicity. PIPAC is given every 6 weeks for three cycles, requiring three laparoscopic procedures. These laparoscopic procedures allow for the opportunity to obtain peritoneal tumor biopsies before and after to investigate the natural course of these tumors and their microenvironment. Toxicity of PIPAC PIPAC has been done in more than 800 patients with gastrointestinal and gynecologic cancers in Europe and Asia. Severe adverse events  have been minimal, with about 12%-15% grade 3/4 SAEs and very rare grade 5 SAEs. The most common side effect is typically abdominal pain, attributed to the IP administration in conjunction with the laparoscopic surgery. Renal toxicity is a concern with intravenous cisplatin use, but this has not yet been seen with PIPAC. With PIPAC, cisplatin is given at 10.1 mg/m2 and doxorubicin is given at 2.1 mg/m2, doses that are much lower than the typical doses for these drugs. PIPAC in clinical trials PIPAC clinical trials have moved into phase 2 in Europe for ovarian cancer, with a publication demonstrating an objective response rate of over 60% in platinum-resistant ovarian cancer (Gynecol Oncol. 2015 May;137[2]:223-8; https://bit.ly/2KY701r). A phase 3 trial of PIPAC was planned but was stalled because of the COVID-19 pandemic. Because of the need for Food and Drug Administration approval, researchers have just launched the first phase 1 trial of PIPAC in the United States. Phase 1 trial of PIPAC City of Hope is working with affiliates at Mayo Clinic in Jacksonville, Fla.; Northwell Health in New York; and the National Institutes of Health to enroll eligible candidates for a phase 1 trial (NCT04329494; https://bit.ly/3qs8H7U). Eligible candidates include those with gastric, uterine, colorectal, appendiceal, and ovarian cancer with evidence of peritoneal carcinomatosis who have failed at least one line of therapy. PIPAC is an outpatient procedure, but given the trial and need for monitoring, patients typically leave the hospital the following day after blood samples are obtained for the study. City of Hope has recruited seven patients since activating their study in August 2020, with a goal of enrolling 16 patients by spring 2021. Future directions Peritoneal tumor biopsies obtained during the laparoscopic procedures are being used to study the microenvironment of these cancers. In eventual phase 2 clinical trials, the researchers may include immune checkpoint inhibitors. Biomarker analyses are underway, looking at expression of PD-1 and tumor-infiltrating lymphocytes. The researchers are also studying the role of genomic sequencing and DNA repair. Disclosures: Dr. Dellinger and Dr. Henry have no financial disclosures relevant to this episode. Show notes by Sheila De Young, DO, resident at Pennsylvania Hospital, Philadelphia. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

FDA 批准新型的核输出蛋白抑制剂用于治疗多发性骨髓瘤和弥漫大B细胞淋巴瘤LANCET 利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤Blood DIC时常出现的新型的凝血机制塞利尼索（selinexor）塞利尼索（selinexor）一种口服选择性核输出蛋白抑制剂，2019年被FDA批准上市用于治疗复发或难治性多发性骨髓瘤；2020年7月，适应症扩展到弥漫大B细胞淋巴瘤。《口服塞利尼索-地塞米松治疗三重难治性多发性骨髓瘤》 New England Journal of Medicine，2019年8月 (1)研究旨在评价塞利尼索对三重难治性多发性骨髓瘤的疗效和安全性。纳入122名、中位年龄65岁、至少一种蛋白酶体抑制剂、一种免疫调节剂和达雷木单抗耐药的、多发性骨髓瘤患者。给予每周两次口服塞利尼索80mg+地塞米松20mg治疗。26%的患者出现部分或更好的缓解，2名患者完全缓解；39%的患者轻微缓解或有所好转。中位缓解时间为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。血小板减少是常见的严重不良反应。结论：塞利尼索-地塞米松使现有治疗方法难以治愈的骨髓瘤患者延长了生存期。《SADAL研究：塞利尼索（selinexor） 在复发或难治性弥漫性大B细胞淋巴瘤患者中的应用》Lancet Haematology，2020年7月 (2)SADAL研究的目的是评估单药塞利尼索对复发或难治性弥漫大B淋巴瘤患者的疗效这项多中心、跨国、开放标签的2b期研究，纳入已经接受了2 - 5种治疗、自体干细胞移植后或不适合进行自体干细胞移植的、复发难治性弥漫大B细胞淋巴瘤患者共267人，随机接受塞利尼索60mg和塞利尼索100mg治疗，研究中期100mg剂量被终止。塞利尼索的总有效率为28%，12%的患者完全缓解，17%的患者部分缓解。最常见的3-4级不良事件是血小板减少、中性粒细胞减少、贫血等。最常见的严重不良事件是发热、肺炎和脓毒症。结论：塞利尼索单药治疗复发或难治性弥漫大B患者有一定的疗效，且不良事件可控制的。弥漫性大B细胞淋巴瘤弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，占25%。最常见的症状为颈部或腹部淋巴结肿大，约30%的患者出现全身性症状（发热、体重减轻、盗汗）。骨髓受累和结外髓外病变的发生率在30%和40%。弥漫大B细胞淋巴瘤的肿瘤细胞通常广泛表达B细胞抗原（CD19、CD20、CD22和CD79a）。《XPO1的表达会恶化不利的弥漫大B细胞的预后，而在没有p53突变体的情况下，塞利尼索可以有效地靶向该细胞》Journal of Hematology Oncology，2020年11月 (3)XPO1抑制剂塞利尼索（selinexor）最近被批准用于复发/难治性的弥漫大B细胞淋巴瘤，研究的目的是评价XPO1对患者的预后影响以及高危患者的合理联合治疗方案。来自厦门大学医学院的研究人员发现XPO1高表达的544例患者，均出现显著的预后不良的情况，尤其是在BCL2过表达的患者中。通过对30个、具有不同分子和遗传背景的弥漫大B细胞淋巴瘤的、细胞株进行研究后发现，塞利尼索具有很强的细胞毒性，特别是在BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤（HGBCL-DH）中。然而，p53基因突变显著降低了塞利尼索在整个细胞系、以及BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中的细胞毒性。塞利尼索联合BET抑制剂INCB057643对MYC/BCL2双重打击的、高级别B细胞淋巴瘤的治疗效果显著增强，克服了p53基因突变的耐药性。结论：XPO1降低了BCL2过表达和双重打击等预后不良因素的、弥漫大B细胞淋巴瘤患者的生存，这与塞利尼索在这两个细胞系中显示出的更好的疗效是一致的。在MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中，联合使用INCB057643处理，可以克服p53基因突变导致的塞利尼索耐药的情况。《弥漫性大B细胞淋巴瘤的国际预后指标：IPI、R-IPI和NCCN-IPI的比较》Blood，2020年6月 (4)弥漫大B细胞淋巴瘤的患者生存率存在很大的异质性。目前临床上常用的预后评分系统包括：国际预后指数（IPI）、修订的IPI（R-IPI）和国家综合癌症网络IPI（NCCN-IPI）。这三种评分系统纳入一些简单临床参数（年龄、乳酸脱氢酶、受累个数/部位、分期、表现状态）。研究人员近20年来，接受利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和强的松治疗的2124例患者的数据用于评估哪个评分系统能最准确的预测生存率。使用IPI、R-IPI和NCCN-IPI的5年生存率估计分别为54%至88%、61%至93%和49%至92%；三组评分的一致性指数分别为0.626、0.59和0.632。NCCN-IPI在高风险、低风险和生存期评价方面都表现更高；而且NCCN-IPI风险类别与生存期显著相关(P≤.01)。结论：NCCN-IPI的预测准确性较高，NCCN-IPI低风险的患者的生存结果良好，但如果能将肿瘤的分子特征和微环境特征整合到NCCN-IPI或IPI中，可能将提高其准确性。弥漫性大B细胞淋巴瘤的治疗初始标准治疗是联合化疗（如CHOP方案，环磷酰胺、多柔比星、长春新碱和泼尼松）+抗CD20单抗（利妥昔单抗），即R-CHOP方案。复发难治性弥漫大B细胞淋巴瘤首选自体干细胞移植。治疗进展：2017年，FDA批准Axicabtagene ciloleucel（商品名Yescarta，一种自体抗CD19嵌合抗原受体CAR-T细胞疗法）治疗复发难治性弥漫大B细胞淋巴瘤。《回顾性研究：R-CHOP方案治疗原发性纵隔大B细胞淋巴瘤》Blood，2020年6月 (5)原发性纵隔大B细胞淋巴瘤的治愈率随着利妥昔单抗的结合而提高；然而，放射治疗的作用仍不明确。2005年之前，通常建议患者接受R-CHOP方案放疗；2005年之后，只有治疗结束后PET扫描呈阳性的人才接受放疗。文章回顾性的分析了共159例患者，总体的5年生存期为89%，在不同的治疗时期相似，总体来说只有10%是难治性的。2005年后，共有113例患者进行了PET扫描，其中63%阴性，37%阳性，5年生存率为97%对88%。对于PET扫描评分较高的患者，预后也较差。结论：经R-CHOP治疗的纵隔弥漫大B淋巴瘤患者的结果是良好的，使用PET评估决定是否放疗减少了不必要的放疗。《HOVON-84研究：利妥昔单抗联合早期利妥昔单抗强化治疗弥漫性大b细胞淋巴瘤的3期临床研究》Journal of Clinical Oncology，2020年10月(6)该研究的目的是评估了R-CHOP方案的、前4个周期早期、强化利妥昔单抗治疗与标准R-CHOP方案比相比是否能改善预后。研究纳入574例、弥漫大B细胞淋巴瘤的患者，给予6个或8个周期的R-CHOP-14方案治疗，随机早期强化利妥昔单抗治疗（RR-CHOP-14方案）或不强化治疗（R-CHOP-14）。R-CHOP-14组和RR-CHOP-14组的、诱导期完全缓解率分别为89%和86%。中位随访92个月后，R-CHOP-14组和RR-CHOP-14组的、3年无进展生存率分别为74%和71%（P = 0. 15），两组总生存率分别为81%和76%（P=0.09）。在RR-CHOP-14组中，年龄在66岁至80岁的患者在前4个周期中经历了明显更多的不良事件，特别是中性粒细胞减少和感染。结论：RR-CHOP-14（在R-CHOP-14基础上早期强化使用利妥昔单抗）不能改善未经治疗的弥漫大B细胞淋巴瘤患者的疗效。Burkitt淋巴瘤Burkitt淋巴瘤是一种高度侵袭性的B细胞肿瘤，目前识别出3种不同的临床形式：地方性Burkitt淋巴瘤、散发性Burkitt淋巴瘤和免疫缺陷相关性Burkitt淋巴瘤。虽然流行病学、临床表现和遗传学特征有所不同，但是组织学上相同，并具有相似的临床行为，因此通常采用相似的方法治疗。对于大多数Burkitt淋巴瘤的成人患者，通常建议选择强化短程联合化疗，或者急性淋巴细胞白血病样的诱导+巩固+维持治疗，无法耐受的患者使用剂量调整的EPOCH化疗方案（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）。近年来的一个的热点是在化疗基础上加用利妥昔单抗（抗CD20单抗）。《随机对照研究：使用风险适应性的、剂量调整的DA-EPOCH-R方案治疗Burkitt淋巴瘤》Journal of Clinical Oncology，2020年8月(7)研究的目的是评价，经剂量调整的（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）联合利妥昔单抗（DA-EPOCH-R方案）治疗Burkitt淋巴瘤的疗效。研究纳入113名未接受过治疗的Burkitt淋巴瘤患者，中位年龄49岁，25%HIV阳性，低风险患者接受了无中枢神经系统预防的、3个周期的治疗；高风险患者接受了6个周期的治疗、以及鞘内治疗。中位随访58.7个月，低危患者无进展生存率和总生存率分别为84.5%和87.0%；高危患者无进展生存率和总生存率分别为82.1%和100%和。治疗对不同年龄组、HIV阳性和各风险组都同样有效。疾病累及脑脊液的、高危患者中，药物毒性相关的死亡或治疗失败的风险最大。5例治疗相关死亡发生在治疗期间，发热性中性粒细胞减少发生在16%的周期中，肿瘤溶解综合征是罕见的。结论：DA-EPOCH-R方案治疗对成人Burkitt淋巴瘤有效，且耐受良好，无论年龄或HIV状态如何。但疾病脑脊液的患者的治疗方案仍需商榷。《开放标签对照研究：利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤的3期临床研究》Lancet，2016年6月(8)这项随机、对照、开放标签的3期临床试验中，招募了45个中心的、>18岁的、新诊断的、HIV阴性的Burkitt淋巴瘤患者。分为B组（无骨髓或中枢神经系统受累）和C组（有骨髓或中枢神经系统受累）。治疗方案为利妥昔单抗+LMB方案化疗，以及单独LMB方案化疗。共纳入260例患者，中位随访38个月。利妥昔单抗组3年无事件生存率75%，显著优于单独化疗组；不良事件在两个治疗组之间没有差异，最常见的是感染和中性粒细胞减少。结论：在短期强化化疗方案中加入利妥昔单抗可以改善成人Burkitt淋巴瘤的无事件生存率。 《队列研究：美国30个癌症中心的、真实世界的、Burkitt淋巴瘤的治疗结果与进展》Blood，2020年7月(9)研究人员对2009年至2018年的、美国30个癌症中心的、未经治疗的Burtkitt淋巴瘤的成人患者进行了分析。研究人员分析了641例Burkitt淋巴瘤患者基线特征包括：中位年龄47岁；HIV阳性 占22%；23%的患者ECOG生活质量评分 2-4分；42%患者有>1个淋巴结外病灶；晚期78%；中枢神经系统受累19%；治疗相关死亡率为10%，最常见的原因是败血症、胃肠道出血、穿孔和呼吸衰竭。在45个月的中位随访中，3年的无进展生存率和总生存率分别为64%和70%，这与是否为HIV阳性无关。接受利妥昔单抗治疗的患者生存率更更高（3年无进展生存率为为67%比38%；总生存率为72%比44%），这与是否住院治疗无关。在学术中心治疗的患者和在社区中心治疗的患者的结果也有所改善（3年无进展生存率为67%比46%；总生存率72%比53%)。多变量模型中，预测生存率较短的因素包括：年龄≥40岁、ECOG生活质量评分2-4分、乳酸脱氢酶>3xULN和中枢神经系统受累；而且，以上因素越多，生存率越低生存率。结论：真实世界的分析中，成人Burkitt淋巴瘤的临床预后比临床研究的结果更温和。此外，疾病诊断时确定的预后相关的因素可以帮助评估真实的预后。新型的DIC中由组蛋白启动的替代凝血酶通路《基础研究：弥散性血管内凝血中，由细胞外组蛋白启动的替代凝血酶通路》Blood，2020年7月 (10)凝血酶的产生、活化对弥散性血管内凝血（DIC）的病理发展都至关重要。通常，凝血酶由凝血酶原复合物产生，包括活化的X因子（FXa）、活化的辅助V因子（FVa）和磷脂（钙离子存在的情况下清除凝血酶）。在危重症中，广泛的细胞损伤可释放组蛋白进入循环，增加凝血酶的生成，引起DIC，但其分子机制尚不清楚。在本研究中，来自利物浦大学的研究人员发现：在有组蛋白，但是没有活化的辅助V因子和磷脂的情况下，机体也能形成一种替代的凝血酶。组蛋白可以直接结合凝血酶原片段F1和F2，促进X因子裂解凝血酶原、释放凝血酶，而不需要磷脂参与。小鼠体内输注组蛋白可诱导产生DIC；但如果事先输注凝血酶原F1+F2片段，再输注组蛋白则显著降低DIC出现的可能性。在重症监护病房脓毒症患者中（n=144），DIC患者的循环组蛋白水平显著升高。这些数据均表明，组蛋白诱导的替代凝血酶可诱导血管内凝血，并揭示了凝血酶产生和DIC发展的新的分子机制。此外，在这个凝血机制中，组蛋白使X因子的需求显著减少，即使VIII因子和IX缺乏的小鼠中，也能形成血栓。结论：本研究揭示了一种具有治疗潜力的、新型的凝血机制，既可以激活全身凝血功能，又可以纠正凝血因子缺陷导致的凝血功能障碍。《COVID-19及其对血栓和抗凝的影响》Blood，2020年6月 (11)COVID-19引起的严重感染可能与凝血功能障碍有关，这在感染引起的弥散性血管内凝血功能障碍（DIC）患者中观察到的炎症变化很相似。肺是COVID-19的靶器官，患者急性肺损伤可发展为呼吸衰竭，也可发生多器官衰竭。COVID-19的初始凝血病变表现为D-二聚体和纤维蛋白/纤维蛋白原降解产物显著升高，而凝血酶原时间、部分凝血酶时间和血小板数量异常相对少见。故建议对患者进行凝血功能筛查，包括测定D-二聚体和纤维蛋白原水平。治疗上，应像对待任何危重病人一样管理，遵循对危重病人采用的血栓栓塞预防、和对脓毒症引起DIC的患者采用标准支持治疗。虽然D-二聚体、脓毒症生理学和消耗性凝血障碍是死亡的预测因子，但目前的数据不建议使用足量抗凝。尽管COVID-19相关的凝血功能障碍，但出血时间尚未见报道。如果确实发生出血，应遵循DIC和出血管理的标准指南。《回顾性观察队列研究：COVID-19患者出院后的血栓和出血时间》Blood，2020年8月 (12)COVID-19肺炎与血栓前状态相关，住院期间血栓事件发生率高；然而，出院后血栓形成的数据有限。研究人员对未接受抗凝治疗的COVID-19出院患者进行了回顾性观察队列研究。该队列包括163名患者，平均随访30天，平均住院时间为6天， 26%需要重症监护。出院后第30天血栓累积发生率（包括动脉和静脉事件）为2.5%；单纯静脉血栓栓塞发生率为0.6%；大出血发生率为0.7%，非大出血发生率为2.9%。因此，COVID-19患者出院后血栓形成率和出血率似乎相似，这强调需要更多的研究来提供全面的、出院后的血栓预防建议。参考文献1.Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-38.2.Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e22.3.Deng M, Zhang M, Xu-Monette ZY, Pham LV, Tzankov A, Visco C, et al. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53. J Hematol Oncol. 2020;13(1):148.4.Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041-8.5.Hayden A, Tonseth P, Lee DG, Villa D, Gerrie AS, Scott DW, et al. Outcome of Primary Mediastinal Large B-cell Lymphoma Using R-CHOP: Impact of a PET Adapted Approach. Blood. 2020.6.Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, et al. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020;38(29):3377-87.7.Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, et al. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol. 2020;38(22):2519-29.8.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10036):2402-11.9.Evens AM, Danilov AV, Jagadeesh D, Sperling AL, Kim SH, Vaca RA, et al. Burkitt Lymphoma in the Modern Era: Real World Outcomes and Prognostication Across 30 US Cancer Centers. 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FDA 批准新型的核输出蛋白抑制剂用于治疗多发性骨髓瘤和弥漫大B细胞淋巴瘤LANCET 利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤Blood DIC时常出现的新型的凝血机制塞利尼索（selinexor）塞利尼索（selinexor）一种口服选择性核输出蛋白抑制剂，2019年被FDA批准上市用于治疗复发或难治性多发性骨髓瘤；2020年7月，适应症扩展到弥漫大B细胞淋巴瘤。《口服塞利尼索-地塞米松治疗三重难治性多发性骨髓瘤》 New England Journal of Medicine，2019年8月 (1)研究旨在评价塞利尼索对三重难治性多发性骨髓瘤的疗效和安全性。纳入122名、中位年龄65岁、至少一种蛋白酶体抑制剂、一种免疫调节剂和达雷木单抗耐药的、多发性骨髓瘤患者。给予每周两次口服塞利尼索80mg+地塞米松20mg治疗。26%的患者出现部分或更好的缓解，2名患者完全缓解；39%的患者轻微缓解或有所好转。中位缓解时间为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。血小板减少是常见的严重不良反应。结论：塞利尼索-地塞米松使现有治疗方法难以治愈的骨髓瘤患者延长了生存期。《SADAL研究：塞利尼索（selinexor） 在复发或难治性弥漫性大B细胞淋巴瘤患者中的应用》Lancet Haematology，2020年7月 (2)SADAL研究的目的是评估单药塞利尼索对复发或难治性弥漫大B淋巴瘤患者的疗效这项多中心、跨国、开放标签的2b期研究，纳入已经接受了2 - 5种治疗、自体干细胞移植后或不适合进行自体干细胞移植的、复发难治性弥漫大B细胞淋巴瘤患者共267人，随机接受塞利尼索60mg和塞利尼索100mg治疗，研究中期100mg剂量被终止。塞利尼索的总有效率为28%，12%的患者完全缓解，17%的患者部分缓解。最常见的3-4级不良事件是血小板减少、中性粒细胞减少、贫血等。最常见的严重不良事件是发热、肺炎和脓毒症。结论：塞利尼索单药治疗复发或难治性弥漫大B患者有一定的疗效，且不良事件可控制的。弥漫性大B细胞淋巴瘤弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，占25%。最常见的症状为颈部或腹部淋巴结肿大，约30%的患者出现全身性症状（发热、体重减轻、盗汗）。骨髓受累和结外髓外病变的发生率在30%和40%。弥漫大B细胞淋巴瘤的肿瘤细胞通常广泛表达B细胞抗原（CD19、CD20、CD22和CD79a）。《XPO1的表达会恶化不利的弥漫大B细胞的预后，而在没有p53突变体的情况下，塞利尼索可以有效地靶向该细胞》Journal of Hematology Oncology，2020年11月 (3)XPO1抑制剂塞利尼索（selinexor）最近被批准用于复发/难治性的弥漫大B细胞淋巴瘤，研究的目的是评价XPO1对患者的预后影响以及高危患者的合理联合治疗方案。来自厦门大学医学院的研究人员发现XPO1高表达的544例患者，均出现显著的预后不良的情况，尤其是在BCL2过表达的患者中。通过对30个、具有不同分子和遗传背景的弥漫大B细胞淋巴瘤的、细胞株进行研究后发现，塞利尼索具有很强的细胞毒性，特别是在BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤（HGBCL-DH）中。然而，p53基因突变显著降低了塞利尼索在整个细胞系、以及BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中的细胞毒性。塞利尼索联合BET抑制剂INCB057643对MYC/BCL2双重打击的、高级别B细胞淋巴瘤的治疗效果显著增强，克服了p53基因突变的耐药性。结论：XPO1降低了BCL2过表达和双重打击等预后不良因素的、弥漫大B细胞淋巴瘤患者的生存，这与塞利尼索在这两个细胞系中显示出的更好的疗效是一致的。在MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中，联合使用INCB057643处理，可以克服p53基因突变导致的塞利尼索耐药的情况。《弥漫性大B细胞淋巴瘤的国际预后指标：IPI、R-IPI和NCCN-IPI的比较》Blood，2020年6月 (4)弥漫大B细胞淋巴瘤的患者生存率存在很大的异质性。目前临床上常用的预后评分系统包括：国际预后指数（IPI）、修订的IPI（R-IPI）和国家综合癌症网络IPI（NCCN-IPI）。这三种评分系统纳入一些简单临床参数（年龄、乳酸脱氢酶、受累个数/部位、分期、表现状态）。研究人员近20年来，接受利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和强的松治疗的2124例患者的数据用于评估哪个评分系统能最准确的预测生存率。使用IPI、R-IPI和NCCN-IPI的5年生存率估计分别为54%至88%、61%至93%和49%至92%；三组评分的一致性指数分别为0.626、0.59和0.632。NCCN-IPI在高风险、低风险和生存期评价方面都表现更高；而且NCCN-IPI风险类别与生存期显著相关(P≤.01)。结论：NCCN-IPI的预测准确性较高，NCCN-IPI低风险的患者的生存结果良好，但如果能将肿瘤的分子特征和微环境特征整合到NCCN-IPI或IPI中，可能将提高其准确性。弥漫性大B细胞淋巴瘤的治疗初始标准治疗是联合化疗（如CHOP方案，环磷酰胺、多柔比星、长春新碱和泼尼松）+抗CD20单抗（利妥昔单抗），即R-CHOP方案。复发难治性弥漫大B细胞淋巴瘤首选自体干细胞移植。治疗进展：2017年，FDA批准Axicabtagene ciloleucel（商品名Yescarta，一种自体抗CD19嵌合抗原受体CAR-T细胞疗法）治疗复发难治性弥漫大B细胞淋巴瘤。《回顾性研究：R-CHOP方案治疗原发性纵隔大B细胞淋巴瘤》Blood，2020年6月 (5)原发性纵隔大B细胞淋巴瘤的治愈率随着利妥昔单抗的结合而提高；然而，放射治疗的作用仍不明确。2005年之前，通常建议患者接受R-CHOP方案放疗；2005年之后，只有治疗结束后PET扫描呈阳性的人才接受放疗。文章回顾性的分析了共159例患者，总体的5年生存期为89%，在不同的治疗时期相似，总体来说只有10%是难治性的。2005年后，共有113例患者进行了PET扫描，其中63%阴性，37%阳性，5年生存率为97%对88%。对于PET扫描评分较高的患者，预后也较差。结论：经R-CHOP治疗的纵隔弥漫大B淋巴瘤患者的结果是良好的，使用PET评估决定是否放疗减少了不必要的放疗。《HOVON-84研究：利妥昔单抗联合早期利妥昔单抗强化治疗弥漫性大b细胞淋巴瘤的3期临床研究》Journal of Clinical Oncology，2020年10月(6)该研究的目的是评估了R-CHOP方案的、前4个周期早期、强化利妥昔单抗治疗与标准R-CHOP方案比相比是否能改善预后。研究纳入574例、弥漫大B细胞淋巴瘤的患者，给予6个或8个周期的R-CHOP-14方案治疗，随机早期强化利妥昔单抗治疗（RR-CHOP-14方案）或不强化治疗（R-CHOP-14）。R-CHOP-14组和RR-CHOP-14组的、诱导期完全缓解率分别为89%和86%。中位随访92个月后，R-CHOP-14组和RR-CHOP-14组的、3年无进展生存率分别为74%和71%（P = 0. 15），两组总生存率分别为81%和76%（P=0.09）。在RR-CHOP-14组中，年龄在66岁至80岁的患者在前4个周期中经历了明显更多的不良事件，特别是中性粒细胞减少和感染。结论：RR-CHOP-14（在R-CHOP-14基础上早期强化使用利妥昔单抗）不能改善未经治疗的弥漫大B细胞淋巴瘤患者的疗效。Burkitt淋巴瘤Burkitt淋巴瘤是一种高度侵袭性的B细胞肿瘤，目前识别出3种不同的临床形式：地方性Burkitt淋巴瘤、散发性Burkitt淋巴瘤和免疫缺陷相关性Burkitt淋巴瘤。虽然流行病学、临床表现和遗传学特征有所不同，但是组织学上相同，并具有相似的临床行为，因此通常采用相似的方法治疗。对于大多数Burkitt淋巴瘤的成人患者，通常建议选择强化短程联合化疗，或者急性淋巴细胞白血病样的诱导+巩固+维持治疗，无法耐受的患者使用剂量调整的EPOCH化疗方案（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）。近年来的一个的热点是在化疗基础上加用利妥昔单抗（抗CD20单抗）。《随机对照研究：使用风险适应性的、剂量调整的DA-EPOCH-R方案治疗Burkitt淋巴瘤》Journal of Clinical Oncology，2020年8月(7)研究的目的是评价，经剂量调整的（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）联合利妥昔单抗（DA-EPOCH-R方案）治疗Burkitt淋巴瘤的疗效。研究纳入113名未接受过治疗的Burkitt淋巴瘤患者，中位年龄49岁，25%HIV阳性，低风险患者接受了无中枢神经系统预防的、3个周期的治疗；高风险患者接受了6个周期的治疗、以及鞘内治疗。中位随访58.7个月，低危患者无进展生存率和总生存率分别为84.5%和87.0%；高危患者无进展生存率和总生存率分别为82.1%和100%和。治疗对不同年龄组、HIV阳性和各风险组都同样有效。疾病累及脑脊液的、高危患者中，药物毒性相关的死亡或治疗失败的风险最大。5例治疗相关死亡发生在治疗期间，发热性中性粒细胞减少发生在16%的周期中，肿瘤溶解综合征是罕见的。结论：DA-EPOCH-R方案治疗对成人Burkitt淋巴瘤有效，且耐受良好，无论年龄或HIV状态如何。但疾病脑脊液的患者的治疗方案仍需商榷。《开放标签对照研究：利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤的3期临床研究》Lancet，2016年6月(8)这项随机、对照、开放标签的3期临床试验中，招募了45个中心的、>18岁的、新诊断的、HIV阴性的Burkitt淋巴瘤患者。分为B组（无骨髓或中枢神经系统受累）和C组（有骨髓或中枢神经系统受累）。治疗方案为利妥昔单抗+LMB方案化疗，以及单独LMB方案化疗。共纳入260例患者，中位随访38个月。利妥昔单抗组3年无事件生存率75%，显著优于单独化疗组；不良事件在两个治疗组之间没有差异，最常见的是感染和中性粒细胞减少。结论：在短期强化化疗方案中加入利妥昔单抗可以改善成人Burkitt淋巴瘤的无事件生存率。 《队列研究：美国30个癌症中心的、真实世界的、Burkitt淋巴瘤的治疗结果与进展》Blood，2020年7月(9)研究人员对2009年至2018年的、美国30个癌症中心的、未经治疗的Burtkitt淋巴瘤的成人患者进行了分析。研究人员分析了641例Burkitt淋巴瘤患者基线特征包括：中位年龄47岁；HIV阳性 占22%；23%的患者ECOG生活质量评分 2-4分；42%患者有>1个淋巴结外病灶；晚期78%；中枢神经系统受累19%；治疗相关死亡率为10%，最常见的原因是败血症、胃肠道出血、穿孔和呼吸衰竭。在45个月的中位随访中，3年的无进展生存率和总生存率分别为64%和70%，这与是否为HIV阳性无关。接受利妥昔单抗治疗的患者生存率更更高（3年无进展生存率为为67%比38%；总生存率为72%比44%），这与是否住院治疗无关。在学术中心治疗的患者和在社区中心治疗的患者的结果也有所改善（3年无进展生存率为67%比46%；总生存率72%比53%)。多变量模型中，预测生存率较短的因素包括：年龄≥40岁、ECOG生活质量评分2-4分、乳酸脱氢酶>3xULN和中枢神经系统受累；而且，以上因素越多，生存率越低生存率。结论：真实世界的分析中，成人Burkitt淋巴瘤的临床预后比临床研究的结果更温和。此外，疾病诊断时确定的预后相关的因素可以帮助评估真实的预后。新型的DIC中由组蛋白启动的替代凝血酶通路《基础研究：弥散性血管内凝血中，由细胞外组蛋白启动的替代凝血酶通路》Blood，2020年7月 (10)凝血酶的产生、活化对弥散性血管内凝血（DIC）的病理发展都至关重要。通常，凝血酶由凝血酶原复合物产生，包括活化的X因子（FXa）、活化的辅助V因子（FVa）和磷脂（钙离子存在的情况下清除凝血酶）。在危重症中，广泛的细胞损伤可释放组蛋白进入循环，增加凝血酶的生成，引起DIC，但其分子机制尚不清楚。在本研究中，来自利物浦大学的研究人员发现：在有组蛋白，但是没有活化的辅助V因子和磷脂的情况下，机体也能形成一种替代的凝血酶。组蛋白可以直接结合凝血酶原片段F1和F2，促进X因子裂解凝血酶原、释放凝血酶，而不需要磷脂参与。小鼠体内输注组蛋白可诱导产生DIC；但如果事先输注凝血酶原F1+F2片段，再输注组蛋白则显著降低DIC出现的可能性。在重症监护病房脓毒症患者中（n=144），DIC患者的循环组蛋白水平显著升高。这些数据均表明，组蛋白诱导的替代凝血酶可诱导血管内凝血，并揭示了凝血酶产生和DIC发展的新的分子机制。此外，在这个凝血机制中，组蛋白使X因子的需求显著减少，即使VIII因子和IX缺乏的小鼠中，也能形成血栓。结论：本研究揭示了一种具有治疗潜力的、新型的凝血机制，既可以激活全身凝血功能，又可以纠正凝血因子缺陷导致的凝血功能障碍。《COVID-19及其对血栓和抗凝的影响》Blood，2020年6月 (11)COVID-19引起的严重感染可能与凝血功能障碍有关，这在感染引起的弥散性血管内凝血功能障碍（DIC）患者中观察到的炎症变化很相似。肺是COVID-19的靶器官，患者急性肺损伤可发展为呼吸衰竭，也可发生多器官衰竭。COVID-19的初始凝血病变表现为D-二聚体和纤维蛋白/纤维蛋白原降解产物显著升高，而凝血酶原时间、部分凝血酶时间和血小板数量异常相对少见。故建议对患者进行凝血功能筛查，包括测定D-二聚体和纤维蛋白原水平。治疗上，应像对待任何危重病人一样管理，遵循对危重病人采用的血栓栓塞预防、和对脓毒症引起DIC的患者采用标准支持治疗。虽然D-二聚体、脓毒症生理学和消耗性凝血障碍是死亡的预测因子，但目前的数据不建议使用足量抗凝。尽管COVID-19相关的凝血功能障碍，但出血时间尚未见报道。如果确实发生出血，应遵循DIC和出血管理的标准指南。《回顾性观察队列研究：COVID-19患者出院后的血栓和出血时间》Blood，2020年8月 (12)COVID-19肺炎与血栓前状态相关，住院期间血栓事件发生率高；然而，出院后血栓形成的数据有限。研究人员对未接受抗凝治疗的COVID-19出院患者进行了回顾性观察队列研究。该队列包括163名患者，平均随访30天，平均住院时间为6天， 26%需要重症监护。出院后第30天血栓累积发生率（包括动脉和静脉事件）为2.5%；单纯静脉血栓栓塞发生率为0.6%；大出血发生率为0.7%，非大出血发生率为2.9%。因此，COVID-19患者出院后血栓形成率和出血率似乎相似，这强调需要更多的研究来提供全面的、出院后的血栓预防建议。参考文献1.Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-38.2.Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e22.3.Deng M, Zhang M, Xu-Monette ZY, Pham LV, Tzankov A, Visco C, et al. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53. J Hematol Oncol. 2020;13(1):148.4.Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041-8.5.Hayden A, Tonseth P, Lee DG, Villa D, Gerrie AS, Scott DW, et al. Outcome of Primary Mediastinal Large B-cell Lymphoma Using R-CHOP: Impact of a PET Adapted Approach. Blood. 2020.6.Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, et al. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020;38(29):3377-87.7.Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, et al. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol. 2020;38(22):2519-29.8.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10036):2402-11.9.Evens AM, Danilov AV, Jagadeesh D, Sperling AL, Kim SH, Vaca RA, et al. Burkitt Lymphoma in the Modern Era: Real World Outcomes and Prognostication Across 30 US Cancer Centers. 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In our second episode on ALL we'll be looking at adolescent and young adult (AYA) patients. Although these patients are commonly seen in the adult setting, evidence suggests that paediatric-inspired regimens may improve their outcomes. But how should these be implemented practically? Joining us this week is Dr Emily Curran, Assistant Professor in the Department of Medicine, Section of Hematology & Oncology at the UC College of Medicine. Access more free education today! Visit the website, follow us on Twitter (@onckip) or connect on LinkedIn. References - Malard F, Mohty M. Lancet 2020; 395(10230):1146-1162 - Moskoff B, et al. Blood 2016; 128(22):5195 - Huguet F, et al. J Clin Oncol. 2009; 27(6):911-8. - Burke PW, et al. Leuk Res2018; 66:49-56 - Alacacioglu I, et al. Chemotherapy. 2014;60(4):219-23 - El-Cheikh J, et al. Clin Lymphoma Myeloma Leuk. 2017; 17(3):179-185 This independent educational activity is supported by educational grants from Servier Pharmaceuticals LLC and Takeda. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; Servier and Takeda have had no influence on the content of this education.

FDA 批准新药治疗β地中海贫血和骨髓增生异常综合征导致的贫血Blood 新的评分系统用以预测镰状细胞病患者、造血细胞移植治疗的预后NEJM 一周一次的Ⅷ因子替代疗法治疗血友病卢斯帕塞普（Luspatercept）卢斯帕塞普（Luspatercept）是一种重组融合蛋白，可以选择性结合转化生长因子β超家族配体，可促进红细胞成熟。2019年11月，卢斯帕塞普（Luspatercept）被FDA批准用于治疗β地中海贫血；2020年4月被FDA批准用于治疗低危骨髓增生异常综合征导致的贫血。《BELIEVE研究：卢斯帕塞普用于治疗输血依赖型β地中海贫血的3期临床研究》New England Journal of Medicine，2020年3月 (1)研究的目的是评价卢斯帕塞普治疗输血依赖型β地中海贫血患者的疗效和安全性。研究纳入224名、输血依赖型β-地中海贫血成年患者，在最佳支持性治疗基础上，随机接受卢斯帕塞普（1.00-1.25mg/kg）或安慰剂，中位治疗时间64周。在第13周-24周期间，与基线相比，卢斯帕塞普组的输血负担减少≥33%、且输血量减少≥2个单位的患者比例明显高于安慰剂组（21.4% vs 4.5%）。在任意12周的间隔期内，卢斯帕塞普组中，输血负担减少≥33%的患者比例高于安慰剂组（70.5% vs 29.5%），而输血负担减少≥50%的患者比例也高于安慰剂组(40.2% vs 6.3%）。第48周，两组间血清铁蛋白水平的最小二乘法平均差为-348μg/L， 卢斯帕塞普治疗组更佳。与安慰剂相比，卢斯帕塞普组更易出现短暂性骨痛、关节痛、头晕、高血压和高尿酸血症等不良事件。 结论：卢斯帕塞普可减少输血依赖型β地中海贫血患者的输血负担，且安全性良好。《MEDALIST研究：卢斯帕塞普治疗低风险骨髓异常增生综合征患者的3期临床研究》New England Journal of Medicine，2020年1月 (2)这个双盲、安慰剂对照的3期试验中，纳入中低风险的、骨髓增生异常综合症、伴有环形铁幼粒细胞、对促红素不敏感或不耐受、需规律输血的患者，一共229人，随机接受卢斯帕塞普（1.75mg/kg ip q3w）或安慰剂。卢斯帕塞普组和安慰剂组中，连续≥8周无需输血的患者比例分别为38%和13% （P

FDA 批准新药治疗β地中海贫血和骨髓增生异常综合征导致的贫血Blood 新的评分系统用以预测镰状细胞病患者、造血细胞移植治疗的预后NEJM 一周一次的Ⅷ因子替代疗法治疗血友病卢斯帕塞普（Luspatercept）卢斯帕塞普（Luspatercept）是一种重组融合蛋白，可以选择性结合转化生长因子β超家族配体，可促进红细胞成熟。2019年11月，卢斯帕塞普（Luspatercept）被FDA批准用于治疗β地中海贫血；2020年4月被FDA批准用于治疗低危骨髓增生异常综合征导致的贫血。《BELIEVE研究：卢斯帕塞普用于治疗输血依赖型β地中海贫血的3期临床研究》New England Journal of Medicine，2020年3月 (1)研究的目的是评价卢斯帕塞普治疗输血依赖型β地中海贫血患者的疗效和安全性。研究纳入224名、输血依赖型β-地中海贫血成年患者，在最佳支持性治疗基础上，随机接受卢斯帕塞普（1.00-1.25mg/kg）或安慰剂，中位治疗时间64周。在第13周-24周期间，与基线相比，卢斯帕塞普组的输血负担减少≥33%、且输血量减少≥2个单位的患者比例明显高于安慰剂组（21.4% vs 4.5%）。在任意12周的间隔期内，卢斯帕塞普组中，输血负担减少≥33%的患者比例高于安慰剂组（70.5% vs 29.5%），而输血负担减少≥50%的患者比例也高于安慰剂组(40.2% vs 6.3%）。第48周，两组间血清铁蛋白水平的最小二乘法平均差为-348μg/L， 卢斯帕塞普治疗组更佳。与安慰剂相比，卢斯帕塞普组更易出现短暂性骨痛、关节痛、头晕、高血压和高尿酸血症等不良事件。 结论：卢斯帕塞普可减少输血依赖型β地中海贫血患者的输血负担，且安全性良好。《MEDALIST研究：卢斯帕塞普治疗低风险骨髓异常增生综合征患者的3期临床研究》New England Journal of Medicine，2020年1月 (2)这个双盲、安慰剂对照的3期试验中，纳入中低风险的、骨髓增生异常综合症、伴有环形铁幼粒细胞、对促红素不敏感或不耐受、需规律输血的患者，一共229人，随机接受卢斯帕塞普（1.75mg/kg ip q3w）或安慰剂。卢斯帕塞普组和安慰剂组中，连续≥8周无需输血的患者比例分别为38%和13% （P

FDA 批准PARP抑制剂用于治疗前列腺癌LANCET 根治性前列腺切除术后放疗的时机Nature Biochemical Engineering 口服微生物鸡尾酒疗法用于去除肾衰竭时产生的含氮代谢物奥拉帕尼（Olaparib）奥拉帕尼（Olaparib）是一种聚ADP核糖聚合酶（PARP）抑制剂，也作用于BRCA1或BRCA2突变，之前主要用于卵巢癌、乳腺癌和胰腺癌的治疗，2020年5月被FDA批准用于治疗HRR基因突变的、去势治疗抵抗的前列腺癌。《PROfound研究：奥拉帕尼治疗转移性抗去势前列腺癌的3期临床研究》New England Journal of Medicine，2020年5月 (1)这项随机、开放标签的3期试验中，评估PARP抑制剂奥拉帕尼在去势治疗抵抗的、转移性前列腺癌患者中的疗效和安全性。队列A的245例患者存在BRCA1、BRCA2或ATM基因突变；队列B的142例患者在其他的12个预先确定的基因中存在突变。患者被随机分配至奥拉帕尼组，或对照组（接受恩扎鲁胺或阿比特龙治疗）。队列A中，奥拉帕尼组基于影像学的无进展生存期明显长于对照组（7.4个月 vs 3.6个月，P < 0.001），中位总生存期分别为18.5个月和15.1个月，在客观缓解率和疼痛程度方面奥拉帕尼组也观察到显著的益处。综合A组和B组的患者数据，奥拉帕尼组基于影像学的整体无进展生存显著优于对照组。奥拉帕尼组，贫血和恶心是主要的不良反应。结论：去势治疗抵抗的、转移性前列腺癌患者中，奥拉帕尼能显著延长无进展生存期。《PROfound研究的总体生存期分析：奥拉帕尼治疗转移性抗去势前列腺癌的生存率》New England Journal of Medicine，2020年9月 (2)PROfound研究中，奥拉帕尼组和对照组的、队列A的中位总体生存期分别为19.1个月和14.7个月（风险比 0.69，P = 0.02）；队列B的中位总生存期分别为14.1个月和11.5个月；综合队列A和队列B，中位总生存期分别为17.3个月和14.0个月。队列A中，奥拉帕尼的死亡风险比为0.42，队列B的死亡风险比为0.83，全部患者的死亡风险比为0.55。结论：去势治疗抵抗的、转移性前列腺癌患者中，奥拉帕尼显著延长总体生存时间。慢性肾脏病患者中SGLT2抑制剂的使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可以抑制近端小管对葡萄糖的重吸收，可以减重、改善血糖控制，但目前达格列净和卡格列净有急性肾损伤的报导，也有报导称SGLT2可能增加酮症酸中毒的风险。因此，目前FDA不推荐在eGFR

FDA 批准PARP抑制剂用于治疗前列腺癌LANCET 根治性前列腺切除术后放疗的时机Nature Biochemical Engineering 口服微生物鸡尾酒疗法用于去除肾衰竭时产生的含氮代谢物奥拉帕尼（Olaparib）奥拉帕尼（Olaparib）是一种聚ADP核糖聚合酶（PARP）抑制剂，也作用于BRCA1或BRCA2突变，之前主要用于卵巢癌、乳腺癌和胰腺癌的治疗，2020年5月被FDA批准用于治疗HRR基因突变的、去势治疗抵抗的前列腺癌。《PROfound研究：奥拉帕尼治疗转移性抗去势前列腺癌的3期临床研究》New England Journal of Medicine，2020年5月 (1)这项随机、开放标签的3期试验中，评估PARP抑制剂奥拉帕尼在去势治疗抵抗的、转移性前列腺癌患者中的疗效和安全性。队列A的245例患者存在BRCA1、BRCA2或ATM基因突变；队列B的142例患者在其他的12个预先确定的基因中存在突变。患者被随机分配至奥拉帕尼组，或对照组（接受恩扎鲁胺或阿比特龙治疗）。队列A中，奥拉帕尼组基于影像学的无进展生存期明显长于对照组（7.4个月 vs 3.6个月，P < 0.001），中位总生存期分别为18.5个月和15.1个月，在客观缓解率和疼痛程度方面奥拉帕尼组也观察到显著的益处。综合A组和B组的患者数据，奥拉帕尼组基于影像学的整体无进展生存显著优于对照组。奥拉帕尼组，贫血和恶心是主要的不良反应。结论：去势治疗抵抗的、转移性前列腺癌患者中，奥拉帕尼能显著延长无进展生存期。《PROfound研究的总体生存期分析：奥拉帕尼治疗转移性抗去势前列腺癌的生存率》New England Journal of Medicine，2020年9月 (2)PROfound研究中，奥拉帕尼组和对照组的、队列A的中位总体生存期分别为19.1个月和14.7个月（风险比 0.69，P = 0.02）；队列B的中位总生存期分别为14.1个月和11.5个月；综合队列A和队列B，中位总生存期分别为17.3个月和14.0个月。队列A中，奥拉帕尼的死亡风险比为0.42，队列B的死亡风险比为0.83，全部患者的死亡风险比为0.55。结论：去势治疗抵抗的、转移性前列腺癌患者中，奥拉帕尼显著延长总体生存时间。慢性肾脏病患者中SGLT2抑制剂的使用钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可以抑制近端小管对葡萄糖的重吸收，可以减重、改善血糖控制，但目前达格列净和卡格列净有急性肾损伤的报导，也有报导称SGLT2可能增加酮症酸中毒的风险。因此，目前FDA不推荐在eGFR

In this episode, we review the latest guidelines on antiemetics from the American Society of Clinical Oncology (ASCO). Host David H. Henry, MD, is joined by ASCO guideline author Paul J. Hesketh, MD, of Lahey Hospital and Medical Center in Burlington, Mass. Dr. Hesketh explains the recommendations for antiemetic use in cancer patients receiving checkpoint inhibitors (CPIs) or high-, moderate-, or low-emetic-risk antineoplastic agents. Checkpoint inhibitors The update to ASCO’s guidelines was primarily driven by questions about antiemetic use in patients receiving CPIs, according to Dr. Hesketh. After a literature review, Dr. Hesketh and coauthors concluded that: Patients receiving CPIs alone do not require an antiemetic regimen. When CPIs are given with chemotherapy, there is no need to modify the antiemetic regimen. Dexamethasone does not compromise the efficacy of CPIs. High-emetic-risk antineoplastic agents Adults treated with cisplatin and other high-emetic-risk single agents should be offered a four-drug combination: an NK1 receptor antagonist, a serotonin (5-HT3) receptor antagonist, dexamethasone, and olanzapine on day 1. Dexamethasone and olanzapine should be continued on days 2-4, as cisplatin can cause delayed emesis. Adults treated with an anthracycline plus cyclophosphamide should be offered a four-drug combination: an NK1 receptor antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine on day 1. Unlike with cisplatin, only olanzapine should be continued on days 2-4. Olanzapine is an effective antiemetic in a number of settings, Dr. Hesketh said. For example, olanzapine is useful in the setting of hematopoietic stem cell transplant. A 5-mg dose of olanzapine has proven effective and may be better tolerated than a 10-mg dose. Moderate-emetic-risk antineoplastic agents Adults treated with higher-dose carboplatin (area under the curve ≥4 mg/mL per min) should be offered a three-drug combination: an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone on day 1. Adults treated with moderate-emetic-risk antineoplastic agents (excluding higher-dose carboplatin) should be offered a two-drug combination: a 5-HT3 receptor antagonist and dexamethasone on day 1. Adults treated with cyclophosphamide, doxorubicin, oxaliplatin, and other moderate-emetic-risk antineoplastic agents known to cause delayed nausea and vomiting may be offered dexamethasone on days 2-3. Low-emetic-risk antineoplastic agents Adults treated with low-emetic-risk antineoplastic agents (e.g., fluorouracil, gemcitabine) should be offered a single dose of a 5-HT3 receptor antagonist or a single 8-mg dose of dexamethasone before antineoplastic treatment. Cannabinoids There is no good data on the use of cannabinoids, apart from those cannabinoids approved by the Food and Drug Administration, according to Dr. Hesketh. The ASCO guidelines state: There is insufficient evidence to make a recommendation regarding medical marijuana to prevent nausea and vomiting in cancer patients receiving chemotherapy or radiation. Similarly, there is insufficient evidence to make a recommendation on the use of medical marijuana in place of the approved cannabinoids dronabinol and nabilone for the treatment of nausea and vomiting in cancer patients receiving chemotherapy or radiation. SOURCE: Hesketh PJ et al. J Clin Oncol. 2020 Aug 20;38(24):2782-97. https://bit.ly/3oxahUP Show notes written by Alesha Levenson, MD, a resident at Pennsylvania Hospital, Philadelphia. Disclosures: Dr. Hesketh disclosed institutional research funding from AstraZeneca and F. Hoffmann-La Roche. Dr. Henry has no relevant disclosures. * * * For information on the negative effects of marijuana, listen to our sister podcast, Psychcast, on MDedge (https://bit.ly/3mBM6TB), Spotify (https://spoti.fi/3mwVvvn), or wherever you get your podcasts. * * * For more MDedge Podcasts, go to mdedge.com/podcasts. Email the show: podcasts@mdedge.com. Interact with us on Twitter: @MDedgehemonc. David Henry on Twitter: @davidhenrymd.

Qu’est-ce qu’un critère pronostique ? Quel est son utilité ?Quels sont les scores pronostiques disponibles dans le cancer localisé sur Rein ?Quels scores pour les formes métastatiques ?Le Dr Idir Ouzaïd (Hôpital Bichat- Claude Bernard) répond à toutes vos questions ! L’orateur n’a pas reçu de rémunération pour la réalisation de cet épisode. Pour aller plus loin :- Leibovich BC, Blute ML, Cheville JC, et al: Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: A stratification tool for prospective clinical trials. Cancer 97:1663-1671, 2003- Heng DYet al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol 2009; 27:5794–5799.Musique du générique : Via AudioNetworkResponsable projet AFUF : Dr Benjamin PradèreProduction : La Toile Sur Ecoute See acast.com/privacy for privacy and opt-out information.

While relaxing on the Jersey Shore, host and MDedge Hematology/Oncology Editor-in-Chief, David Henry, MD, dove into the July 10, 2020, issue of the Journal of Clinical Oncology. In episode 82, we do the same.   J Clin Oncol. 2020 Jul 10. 38(20). 2217-2361. (https://bit.ly/2ZQEJ27)   You can follow along with the following articles: Lumpectomy Margins for Invasive Breast Cancer and Ductal Carcinoma in Situ: Current Guideline Recommendations, Their Implications, and Impact (https://bit.ly/39m5P3W) Accelerated Partial Breast Irradiation and Intraoperative Partial Breast Irradiation: Reducing the Burden of Effective Breast Conservation (https://bit.ly/2Bm9McB) Partial Breast Irradiation Is the Preferred Standard of Care for a Majority of Women With Early‐Stage Breast Cancer (https://bit.ly/3jqAxhj) Whole-Breast Irradiation Is the Preferred Standard of Care for the Majority of Patients With Early-Stage Breast Cancer (https://bit.ly/3jwRma3) Regional Nodal Management in Patients With Clinically Node-Negative Breast Cancer Undergoing Upfront Surgery (https://bit.ly/2WI8Syj) Locoregional Management After Neoadjuvant Chemotherapy (https://bit.ly/2OOjRCc) For more MDedge Podcasts, click this link: http://bit.ly/2CfnY52   Email the show: podcasts@mdedge.com   Follow Dr. David Henry on Twitter @DavidHenryMD

Is it worthwhile to treat pancreatic cancer? Dr Michael Pishvaian from Johns Hopkins University discusses the use of the PARP inhibitor olaparib and other new developments in the disease. Additional Resources * Golan T et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317-27. Full text (https://www.nejm.org/doi/full/10.1056/NEJMoa1903387?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed) * Burris HA 3rd et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer: A randomized trial. J Clin Oncol 1997;15(6):2403-13. Abstract (https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.6.2403) * Conroy T et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. Correspondence (https://www.nejm.org/doi/full/10.1056/NEJMc1107627?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed) * Von Hoff DD et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. Full text (https://www.nejm.org/doi/10.1056/NEJMoa1304369?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov) * Doleh Y et al. Treatment patterns and outcomes in pancreatic cancer: Retrospective claims analysis. Cancer Med 2020;9:3463-76. Full text (https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.3011) * Mavros MN et al. Low rates of specialized cancer consultation and cancer-directed therapy for noncurable pancreatic adenocarcinoma: A population-based analysis. CMAJ 2019;191(21):E574-80. Full text (https://www.cmaj.ca/content/191/21/E574.long) * Lowery MA et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. JNCI 2018;110(10):1067-74. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186514/) * O’Reilly EM et al. Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation. J Clin Oncol 2020;38(13):1378-88. Full text (https://ascopubs.org/doi/full/10.1200/JCO.19.02931?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed)

Qu’est-ce qu’une tumeur réfractaire au BCG ? Quel est le traitement de référence pour ces patients ? Existe-t-il des alternatives thérapeutiques permettant de préserver la vessie ?Le Dr Géraldine Pignot (Institut Paoli Calmettes, Marseille) répond à toutes vos questions !L’intervenante n’a pas reçu de rémunération pour la réalisation de cet épisode.Pour aller plus loin :Balar AV, Kulkarni GS, Uchio EM, et al. Keynote 057: Phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG). J Clin Oncol 2019; 37(7_Suppl):350.Réalisé avec le soutien institutionnel du laboratoire JanssenMusique du générique : Via AudioNetworkResponsable projet AFUF : Dr Benjamin PradèreProduction : La Toile Sur Ecoute See acast.com/privacy for privacy and opt-out information.

Em 2012 o grupo de pesquisadores da Itália e Espanha dedicado a sarcoma se reuniu para publicar os resultados do estudo randomizado que avaliou 3 vs. 5 ciclos de QT com doxorrubicina e ifosfamida para pacientes com sarcomas de alto grau de tronco e extremidades. A motivação desse estudo veio do fato de que muitos paciente não conseguem terminar 5 ciclos desse esquema tendo em vista sua toxicidade. Neste episódio nós do Clinical Papers tivemos como convidada a Dra. Veridiana Camargo, médica oncologista que engrandeceu a discussão com sua experiência no tema. Esse foi um estudo de não inferioridade publicado no J Clin Oncol e você pode acessá-lo pelo link:https://www.ncbi.nlm.nih.gov/pubmed/22312103 Sejam muito bem vindo a mais um episódio do Clinical Papers Podcast!

Ever read through a study and wondered how to apply the hazard ratio, or if you should change your practice because of a secondary endpoint finding? In this episode, Lauren M. Catalano, MD, of the University of Pennsylvania, Philadelphia, explains all the common terms and why they matter in the context of the KEYNOTE-024 trial.  In Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about how to prepare for an unexpected bad outcome. Practice points: Don’t skip over the statistical analysis portion of a paper. Use Google to find simple definitions for unfamiliar biostatistics terms. Understanding the statistical elements is essential to determining the quality of the research. * * * Understanding statistics in the context of KEYNOTE-024 Article discussed: Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non–small cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-46.  Primary endpoint: The outcome that is necessary to ensure the efficacy of the trial. What is the study’s objective? The primary endpoint is defined prior to starting the study, which influences how many patients need to be enrolled to ensure statistical significance. This paper’s primary endpoint: Time since random assignment to disease progression or death. Secondary endpoint: These are interesting trends or observations that the investigators were able to determine, but for which the original study may not have been powered, meaning that they may not have enough data to determine the statistical significance. This paper’s secondary endpoints: Objective response rate (confirmed complete and partial responses) and safety. Hazard ratio: “Ratio” suggests that this is a comparison between the intervention and control arm. HR is a measure of an effect or intervention on the outcome of interest over a period of time (risk per unit of time). The outcome can be positive or negative. Confidence interval: Since it is not possible to survey the entire population, a confidence interval provides a range of values where the true value most likely falls. If the confidence interval crosses “1” then there is no difference between the arms of the study. Kaplan-Meier curve: Often used to illustrate survival. This is a graphical representation of hazard ratio, usually drawn as a step function. P value: The degree of error that we are willing to accept. Often P = .05, which means we are willing to accept a 5% risk that the hypothesis is incorrect. Crossover: Patients assigned in one arm of the study (usually the control arm) can be reassigned to the other arm (usually the intervention group). Intention to treat: A technique used in randomized, controlled trials in which patient outcomes are compared within the group the patient was originally assigned to. This may not reflect the treatment that the patient actually received. If the patient is in a group that is treated but then leaves that group, they are still counted in the original group. Show notes by Ronak Mistry, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

One of the benefits of identifying hereditary cancer mutations in individuals is Cascade Testing—being able to offer targeted testing to family members to identify others who are at high risk as well as those who are average risk. Yet historical studies suggest that the uptake of cascade testing is 30% or less. Certified genetic counselor Francesca Tubito was co-author of a study recently published in The Journal of Clinical Oncology that tested the feasibility of a streamlined method of cascade testing using direct contact of family members by healthcare providers, telephone genetic counseling, and (free/sponsored) saliva-based genetic testing mailed to family members’ homes. Francesca discusses the success of the study as measured by uptake of testing among at-risk-relatives a well as the challenges in implementing this approach on broader scale. Study Discussed: Frey MK, Kahn RM, Chapman-Davis E, et al. Prospective Feasibility Trial of a Novel Strategy of Facilitated Cascade Genetic Testing Using Telephone Counseling.” J Clin Oncol. 2020 Jan 10:JCO1902005. (Behind Paywall) Francesa on LinkedIn Francesca on Twitter: @FrancescaTGCA Related Articles & Resources NIH NCI definition of Cascade Testing “Precision Medicine in Action: How well does cascade screening for hereditary conditions work in the real world?” CDC Blog Post. May 2018. ACOG Committee Opinion Number 727. January 2018. “Cascade Testing: Testing Women for Known Hereditary Genetic Mutations Associated With Cancer."

David L. Streiner, PhD, of McMaster University, Hamilton, Ont., and the University of Toronto, joins Blood & Cancer host David Henry, MD, of Pennsylvania Hospital, Philadelphia, to explain what a post hoc analysis is and why it should be interpreted with caution. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, explores what to tell patients when it comes to prognostic scoring system results. * * *  Help us make this podcast better! Please take our short listener survey: https://www.surveymonkey.com/r/podcastsurveyOct2019 * * *  This week in Oncology: In rectal cancer, fragmented care linked to lower survival by Jim Kling, reporting from Clinical Congress 2019. Post hoc analyses What is a post hoc analysis? Analyzing data after a study has already had conclusions made and looking for patterns that were not prespecified. Dr. Streiner’s advice for researchers: Pick a small number of primary outcomes and develop a narrow hypothesis. Then use post hoc analysis as a means of assessing future questions that can be investigated in a subsequent study. Dr. Streiner’s advice for clinicians: Treat a post hoc analysis as a hypothesis that requires further study. It should be viewed with some degree of suspicion because it may have been significant only by chance. Show notes by Ronak Mistry, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia.   References Marcus R et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377:1331-44. Crawford ED et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-61. Streiner DL et al. Size, follow-up, data analysis – good; post hoc analysis, interpretation – not so good. Commun Oncol. 2011;8:379-80.   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz  

  William J. Gradishar, MD, of Feinberg School of Medicine and Northwestern Medicine in Chicago, chats with David H. Henry, MD, host of Blood & Cancer, to review some of the top breast cancer research presented at the 2019 annual meeting of the American Society of Clinical Oncology. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about dealing with help-seeking and help-rejecting patients.   Show notes This episode discusses three randomized, controlled phase 3 trials that were presented at ASCO 2019:  KRISTINE trial (abstract 500) Design: Patients with HER2-positive breast cancer were randomized to receive either neoadjuvant trastuzumab, pertuzumab, and chemotherapy (docetaxel, carboplatin) vs. trastuzumab emtansine plus pertuzumab. Primary endpoint: Pathological complete response rate. Secondary endpoints: Toxicity, event-free survival, invasive disease-free survival. Conclusion: Docetaxel, carboplatin, and trastuzumab plus pertuzumab resulted in a higher rate of pathological complete response than did trastuzumab emtansine plus pertuzumab, but was associated with more serious adverse events. PREDIX trial (abstract 501) Design: Patients with HER2 positive and hormone receptor positive breast cancer were randomized to receive either neoadjuvant trastuzumab emtansine monotherapy vs. docetaxel, trastuzumab, and pertuzumab. Primary endpoint: Pathological complete response rate. Secondary endpoints: Toxicity and quality of life. Conclusions: Trastuzumab emtansine monotherapy was better tolerated while maintaining comparable PCR rate as the group which received docetaxel, trastuzumab, and pertuzumab.  TAILORx trial (abstract 503) Design: Patients with node-negative, estrogen receptor–positive breast cancer with an Oncotype DX recurrence score of 11-25 were randomized to receive either hormone therapy alone or hormone therapy together with combination chemotherapy. Primary endpoint: Rate of distant recurrence at 9 years.  Conclusions: There was no benefit from chemotherapy for younger women (aged 50 years or younger) with a recurrence score of 16-20 and at low risk clinically (small tumor size and favorable histologic grade). Those age younger than age 50 years with a score of 16-20, but high risk clinically, may benefit from chemotherapy. Much of the benefit derived from chemotherapy was because of ovarian suppression. Using the recurrence score in combination with clinical risk stratification allows clinicians to identify more young women who can be spared chemotherapy, and more young women who may benefit from antiestrogen therapy.   Show notes by Sugandha Landy, MD, a resident in the department of internal medicine, University of Pennsylvania, Philadelphia.   References J Clin Oncol 37. 2019 May 20 (suppl; abstr 500). doi: 10.1200/JCO.2019.37.15_suppl.500. J Clin Oncol 37. 2019 May 20 (suppl; abstr 501). doi: 10.1200/JCO.2019.37.15_suppl.501. J Clin Oncol 37. 2019 May 20 (suppl; abstr 503). doi: 10.1200/JCO.2019.37.15_suppl.503. Lancet Oncol. 2018 Jan;19(1):115-26. N Engl J Med. 2019 Jun 20;380:2395-405.    For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz  

Ginah Nightingale, PharmD, of the Jefferson College of Pharmacy at Thomas Jefferson University in Philadelphia chats with David H. Henry, MD, host of Blood & Cancer, about the definition of polypharmacy and the challenges it poses in treating older cancer patients. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about the waiting that cancer patients face. Show notes Older adults comprise about 15% of the total population but account for more than 33% of prescription drug use. Polypharmacy can be defined as taking five or more medications (prescription and nonprescription), as well as being on medications that have adverse effects in older adults. Older adults are at increased risk for adverse effects from polypharmacy for multiple reasons, including multiple comorbidities and altered drug metabolism. In a study by Nightingale et al., 61% of patients already had a major drug-drug interaction on their medication list prior to initiation of cancer therapy. In a study by Sharma et al., 22% of patients were taking proton pump inhibitors concurrently with tyrosine kinase inhibitors, an interaction that was associated with increased risk of death at 90 days and 1 year. Patients who receive medications from multiple pharmacies, such as a specialty pharmacy for oncologic drugs, are at increased risk of polypharmacy errors. Tools to screen for polypharmacy include: Beers criteria by American Geriatrics Society STOPP/START criteria (commonly used in Europe) Medication appropriateness index Considerations such as patient’s life expectancy and quality-of-life goals should be taken into account when deciding which medications are necessary and what may be deprescribed. Clinicians should encourage patients to bring in all medications to every doctor’s visit, and certainly at the time of initiation of cancer treatment. Show notes by Sugandha Landy, MD, resident in the department of internal medicine, University of Pennsylvania, Philadelphia.   Additional reading American Geriatrics Society 2019 Updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019 Apr;67(4):674-94. O'Mahony Denis et al. STOPP/START criteria for potentially inappropriate prescribing in older people: Version 2. Age Ageing. 2015 Mar;44(2):213-8. Nightingale G et al. Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy and potentially inappropriate medication use among ambulatory senior adults with cancer. J Clin Oncol. 2015 May 1;33(13):1453-9. Sharma M et al. The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: Prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer. Cancer. 2019 Apr 1;125(7):1155-62.   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

David H. Henry, MD, host of Blood & Cancer, is joined by two experts on the financial toxicity of cancer. Melissa Monak and Kimberly Bell, both of the Cleveland Clinic, presented research at the 2019 annual meeting of the American Society of Clinical Oncology on the implementation of a financial navigation program at the Cleveland Clinic’s Taussig Cancer Center. In this podcast, they discuss the findings of their research and how just educating patients about their insurance benefits can improve access and patient satisfaction. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, revisits the “illusion of options” and what happens when this false hope originates with the treatment team. Show notes By Emily Bryer, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia   Prior authorizations, high deductibles, and out-of-pocket expenses often delay cancer treatment. Financial navigators connect with patients diagnosed with a malignancy who have not yet started treatment. These navigators identify insurance benefits, estimate out-of-pocket costs, and find copayment assistance programs or other charitable options.   Resources Development of a financial navigation program to ease the burden of financial toxicity. J Clin Oncol 37. 2019 May 26. ASCO 2019, Abstract 6565. Patient financial burden: Considerations for oncology care and access – One organization’s approach to addressing financial toxicity (Cleveland Cancer Institute white paper).   For more MDedge podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @mdedgehemonc

Episode 17: David L. Streiner, PhD, of McMaster University, Hamilton, Ont., and the University of Toronto, joins Blood & Cancer host David Henry, MD, of Pennsylvania Hospital, Philadelphia, to talk hazard ratios and P values as they examine the clinical relevance of findings from a phase 3 trial.   In Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, talks about how to balance family versus patient preferences.   Show notes By Emily Bryer, DO, resident in the department of internal medicine, University of Pennsylvania, Philadelphia  A phase 3 trial is a randomized, controlled trial testing a new intervention against placebo or treatment as usual. Randomization maximizes the chances that the groups are equivalent but does not guarantee it. With randomization, you also are accounting for variables that are unknown and/or cannot be controlled for.  Phase 3 trial discussed by Dr. Henry and Dr. Streiner: AURELIA trial: Bevacizumab plus chemotherapy vs. chemotherapy alone for platinum-resistant ovarian cancer. Inclusion criteria: Ovarian cancer that has progressed on a platinum-based therapy. Randomization: 361 patients randomized 1:1 to receive bevacizumab plus chemotherapy versus chemotherapy alone. Primary endpoint: Progression-free survival (PFS). Main outcome: PFS had a hazard ratio 0.48 (95% confidence interval, 0.38-0.60). A hazard ratio of 0.48 means that patients in the experimental group had half the risk of experiencing a bad outcome (progression) than patients in the comparison group did. The hazard ratio includes a confidence interval (CI) at the end of the value because it is an estimate. The CI represents where the true hazard will fall 95% of the time. If 1.0 is included in the range, then the result is not statistically significant, and the events could have happened by chance. An ad hoc analysis is conducted at the end of the study. It is not a prespecified statistical idea. It is thought provoking and hypothesis generating but not conclusive. Reference: AURELIA trial: J Clin Oncol. 2014;32(13):1302-8.

Dr Sikov talks to ecancertv at SABCS 2015 about survival outcomes from the CALGB 40603 study involving women with stage II-III triple-negative breast cancer (TNBC) who were treated with carboplatin, bevacizumab, or both in addition to standard neo-adjuvant chemotherapy. The aim of the study was to assess the effects of adding carboplatin or bevacizumab on complete response (pCR) rates. Standard neo-adjuvant chemotherapy used in the trial was weekly paclitaxel then dose-dense doxorubicin plus cyclophosphamide. The effect on pCR have been reported (J Clin Oncol 2015;33:13–21) and showed improved pCR with the addition of both the chemotherapy and the anti-angiogenic agent. At SABCS 2015, the effects on the secondary endpoints of event-free (EFS) and overall survival (OS) were presented, with 3-year rates of 74.1% and 83.2%, respectively, although the study was not powered to assess the different treatment effects on either of these endpoints. What it shows is that patients with TNBC who achieved pCR with study treatment had significantly better EFS and OS than patients who did not.

Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Kathy Spindler The TWiVers reveal influenza virus replication in the ferret mammary gland and spread to a nursing infant, and selection of transmissible influenza viruses in the soft palate.   Links for this episode Photos of my visit to OHSU (Facebook) 6:30 Folta departs (Facebook) 9:25 T-VEC approved for melanoma (FDA) 14:45 Talimogene laherparepvec (Wikipedia) 15:10 T-VEC phase III trial (J Clin Oncol) 17:35 How drugs are named (PopSci) 16:35 Influenza transmission in mother-child dyad (PLoS Path) 23:10 Soft palate and influenza transmission (Nature) 41:00 Image credit Letters read on TWiV 363 1:09:30 This episode is sponsored by Mt. Sinai Department of Microbiology, ASM Education, and ASM Biodefense and Emerging Diseases Conference Timestamps by Jennifer. Thanks! Weekly Science Picks 1:29:00 Kathy - Insect gearsAlan - Bye, Bye, EbolaRich - Hedy LamarrVincent - Should we resurrect extinct species? Listener Picks Jennie - Bye, Bye, EbolaPeter - Epidemics on edX Send your virology questions and comments to twiv@twiv.tv

April 25, 2011 In this third episode, host Tim Cripe, MD, PhD, asks his co-hosts to discuss two recent papers that provide new information about genetic predisposition to increased toxicity to vincristine in some children, and the results of a phase II study using a combination therapy (irinotecan and temozolomide) in relapsed or refractory neuroblastoma. 1:24 Maureen O'Brien, MD discusses "Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia" in Pediatr Blood Cancer. 2011 Mar;56(3):361-7. doi: 10.1002/pbc.22845. Epub 2010 Nov 11.http://www.ncbi.nlm.nih.gov/pubmed/21225912 22:10 Lars Wagner, MD discusses "Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study" from J Clin Oncol. 2011 Jan 10;29(2):208-13. Epub 2010 Nov 29. http://www.ncbi.nlm.nih.gov/pubmed/21115869