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Background: Measurement of tumor markers from peripheral venous blood is an emerging tool to assist in the early diagnosis of lung cancer. Samples from the pulmonary artery and pulmonary artery wedge position (trans-pulmonary samples) are accessible via right-heart catheterization and, by virtue of their proximity to lung tumors, may increase diagnostic yield., Case Presentation: We report a case of a 64 year-old woman from whom trans-pulmonary samples were obtained and who was diagnosed 16 months later with recurrent metastatic small cell lung cancer. Carcinoembryonic antigen, cytokeratin fragment 21 - 1 (CYFRA), and human epididymis protein 4 (HE4) levels demonstrated increasing concentrations across the pulmonary circulation. These gradients exceeded the assays' coefficient of variation by several-fold. For CYFRA and HE4, pulmonary artery wedge concentrations exceeded peripheral venous levels by more than 10% and peripheral arterial levels were up to 8% higher than peripheral venous levels., Conclusions: Evaluating the feasibility and utility of trans-pulmonary tumor markers for lung cancer diagnosis in a larger cohort should be considered. The addition of a peripheral arterial sample to standard peripheral venous samples may be a more practical alternative., (© 2024. The Author(s).)

Purpose: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy., Patients and Methods: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated., Results: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2)., Conclusions: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors., Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively., Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p  = 0.029 and odds ratio = 1.90, p  = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively)., Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy., Competing Interests: Dr. McCoach reports working as an employee at Genentech. Dr. G. Liu reports receiving institutional grants from NCI, CIHR, CCSRI, AstraZeneca, 10.13039/100016040Takeda, Boehringer Ingelheim, AMGEN, EMD Serono, 10.13039/100004319Pfizer, and 10.13039/100004326Bayer; receiving personal honoraria from AstraZeneca, Pfizer, EMD Serono, and Takeda; and participating on the Data Safety Monitoring Board/Advisory Board for AstraZeneca, Pfizer, EMD Serono, Merck, AbbVie, Jazz, Takeda, Anheart, Roche, Bristol-Myers Squibb, Novartis, and Lilly. Dr. Nieva reports receiving institutional grants from 10.13039/100004328Genentech and Merck; receiving consulting fees from ANP Technologies, Aadi Biosciences, AstraZeneca, BioAtla, G1 Therapeutics, Genentech, Mindmed, Naveris, and Sanofi; receiving travel support from 10.13039/100004325AstraZeneca; having a patent planned with Cansera; participating on the Data Safety Monitoring Board/Advisory Board for Kalivir; and having stock in Amgen, Novartis, Johnson & Johnson, and Cansera. Dr. Marrone reports receiving grants from 10.13039/100016957Mirati Therapeutics and Bristol-Myers Squibb; receiving consulting fees from Daiichi Sankyo, Regeneron, Janssen, Mirati, Amgen, and AstraZeneca; receiving honoraria from Merck, Regeneron, Bristol-Myers Squibb, and AstraZeneca; and participating on the Data Safety Monitoring Board/Advisory Board for Puma. Dr. Lam reports receiving grants from 10.13039/100002491Bristol-Myers Squibb, Merck, SeaGen, and AstraZeneca; receiving consulting fees from SeaGen, Bristol-Myers Squibb, AstraZeneca, Guardant Health, Takeda, and Anheart Therapeutics; and participating on the Data Safety Monitoring Board/Advisory Board for Iovance Therapeutics. Dr. Velcheti reports receiving consulting fees from Bristol-Myers Squibb, Merck, OnCOC4, AstraZeneca, Roche, Novocure, Takeda, Taiho, and Regeneron. Dr. S. Liu reports receiving institutional grants from 10.13039/100006483AbbVie, 10.13039/100018529Alkermes, AstraZeneca, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, OSE Immunotherapeutics, Puma, RAPT, and Turning Point Therapeutics; receiving consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, RAPT, Regeneron, Revolution Medicines, Sanofi, and Takeda; and participating on a Data Safety Monitoring Board/Advisory Board for Candel Therapeutics. Dr. Patil reports receiving research funding from 10.13039/100004755EMD Serono, 10.13039/100005565Janssen, and 10.13039/100005564Gilead; receiving consulting fees from AstraZeneca, Biocept, Boehringer Ingelheim, Bristol-Myers Squibb, Bicara, Caris, Daiichi, Guardant Health, Guidepoint, EMD Serono, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Natera, Pfizer, Sanofi, Regeneron, Roche/Genentech, and Takeda; and participating on the Data Safety Monitoring Board/Advisory Board for Elevation Oncology. Dr. Weiss reports receiving institutional grants from AstraZeneca, 10.13039/100019799G1, Loxo/10.13039/100019518Lilly, Mirati, SDP, BI, and PDS; receiving consulting fees from AZD, EMD Serono, Genentech, G1, Jounce, AbbVie, Nanobiotix, Merck, Sanofi, Gilead, PDS, and AMGEN; participating on a Data Safety Monitoring Board or Advisory Board for Jounce and Beigene; having a leadership or fiduciary role for Cancergrace; and having stock/stock options for Nektar, Vesselon, Achilles, Nuvalent, Lyell, En Fuego, and Vertex. Dr. Dowell reports receiving consulting fees from Takeda, Catalyst, Beigene, and Janssen. Dr. Villaruz reports receiving consulting fees from Sanofi, Gilead, Johnson & Johnson, EMD Serono, Daiichi Sankyo, AstraZeneca, and Janssen. Dr. Cass reports receiving honoraria from OncLive, Medscape, and PharmacyTimes; and participating on the Data Safety Monitoring Board/Advisory Board for G1 Therapeutics, Takeda, and Regeneron. Dr. Iams reports receiving consulting fees from OncLive, Clinical Care Options, Chardan, Cello Health, and Curio Science; and participating on the Data Safety Monitoring Board/Advisory Board for Genentech, Mirati, Outcomes Insights, Jazz Pharmaceuticals, G1 Therapeutics, Takeda, AstraZeneca, Sanofi, Janssen, Amgen, Bristol Myers Squibb, and NovoCure. Dr. Aisner reports receiving consulting fees from Merus, Genentech, Bayer, AbbVie, and AstraZeneca; receiving support for attending meetings from AstraZeneca; and serving as Chair of Board for Genomics Organization for Academic Laboratories. Dr. Aggarwal reportsreceiving consulting fees from Genentech, Lilly, Merck, AstraZeneca, Daiichi Sankyo, Sanofi/Regeneron, Pfizer, Janssen, Boehringer-Ingelheim, Takeda, Arcus Biosciences, Mirati Therapeutics, Gilead Sciences, Novocure, AbbVie, and Jazz Pharmaceuticals; receiving speaking fees from AstraZeneca and Roche/Genentech; and receiving research funding from 10.13039/100004334Merck Sharp & Dohme, AstraZeneca/10.13039/501100004628MedImmune, 10.13039/501100022274Daiichi Sankyo, Loxo@Lilly, and Candel Therapeutics. Dr. Camidge reports receiving honoraria for consulting from AbbVie, Anheart, Beigene, Eli Lilly, Immunocore, Janssen, Prelude, Seattle Genetics, Valence, Appolomics, AstraZeneca/Daiichi, Dizal, EMD Serono, Elevation, Hengrui, Hummingbird, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Regeneron, Roche, Sanofi, Takeda, Theseus, and Xcovery. Dr. Marmarelis reports receiving research funding from Eli Lilly, AstraZeneca, and Merck; receiving consulting fees from AstraZeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bayer, Bristol Myers Squibb, Ikena, and Regeneron; receiving honoraria from Thermo Fisher; and having stock in Merck and Johnson & Johnson. Dr. Sun reports receiving honoraria from Bayer and participating on the Data Safety Monitoring Board/Advisory Board for Seagen, Sanofi Genzyme, and Regeneron. The remaining authors declare no conflict of interest., (Crown Copyright © 2024 Published by Elsevier Inc. on behalf of the AGA Institute.)

Introduction: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors., Materials and Methods: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B., Results: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional., Conclusions: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited., Gov Identifier: NCT03724890., Competing Interests: Disclosure BP has received institutional funding from Bristol Myers Squibb; has served in a consulting or advisory role for AstraZeneca and G1 Therapeutics; and has received honoraria from Daiichi Sankyo. RA has received institutional funding from Merck; has served in a consulting or advisory role for AstraZeneca; has received honoraria from AstraZeneca; and has served in a leadership role for SWOG and NRG (uncompensated). TUM has received institutional funding from Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Merck, and Regeneron; has served in a consulting or advisory role for AbbVie, Arcus, Astellas, Celldex, Genentech, Glenmark, NGM Biopharmaceuticals, Regeneron, and Rockefeller University; and has received travel, accommodations, and expenses from Arcus. MRS has received research funding from Daiichi Sankyo, Jazz Pharmaceuticals, and Pfizer; and has served in a consulting or advisory role for Jazz Pharmaceuticals. HB has received institutional funding from AbbVie, Agios, ARMO BioSciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, Biotheryx, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, Celgene, CicloMed, Coordination Pharmaceuticals, eFFECTOR Therapeutics, Lilly, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Genentech/Roche, GSK, Gossamer Bio, Harpoon Therapeutics, Jiangsu Hengrui Pharmaceuticals, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicines, Ryvu Therapeutics, Foundation Medicine, Seagen, Tesar, TG Therapeutics, Verastem, Vertex Pharmaceuticals, XBiotech, and Zymeworks; has served in a consulting or advisory role for Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Incyte, Novartis, TG Therapeutics, GRAIL, Roche, and Vincerx Pharma; and holds stock in HCA Healthcare. WTI has served in a consulting or advisory role for Amgen, AstraZeneca, Bristol Myers Squibb, Catalyst, Elevation Oncology, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, G1 Therapeutics, Genentech, Janssen, Jazz Pharmaceuticals, Mirati, NovoCure, Sanofi, and Takeda. SJC has immediate family members employed by Astellas Pharma and Takeda; has received honoraria from RefleXion Medical; has served in a consulting or advisory role for AstraZeneca and Genentech; has received research funding from Merck, Bristol Myers Squibb, and AstraZeneca/MedImmune; and holds patents, royalties, or other intellectual property with UpToDate. JJL has received research funding from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, F-Star, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MacroGenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; has served in a consulting or advisory role for 7 Hills, AbbVie, Actym, Alnylam, Alphamab Oncology, Arch Oncology, Atomwise, Bayer, Bright Peak, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Duke Street Bio, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Endeavor, Exo, Flame, F-Star, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Immatics, Immunocore, Incyte, Instil, Inzen, IO Biotech, MacroGenics, Mavupharma, Merck, Mersana, Nektar, NeoTX, Novartis, Onc.AI, OncoNano, Partner, Pfizer, Pioneering Medicines, PsiOxus, Pyxis, Kanaph, RefleXion, Regeneron, Ribon, Roivant, Saros, Servier, Stingthera, STipe, Synlogic, Synthekine, Tempest, and Xilio; holds provisional patents Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof); has served in a consulting or advisory role for AbbVie, Evaxion, and Immutep; holds stock or other ownership in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavupharma, NeoTX, Onc.AI, OncoNano, Pyxis, Saros, STipe, and Tempest; and serves in a leadership role for the Society for Immunotherapy of Cancer. DS has received institutional funding from Aadi, Ability Pharma, Amgen, Apexigen, Astellas, AstraZeneca, Bexion, Bristol Myers Squibb, FibroGen, Genentech, Jiangsu Hengrui Pharmaceuticals, Merck, Mirati, NextCure, PanCAN, Regeneron, and Roche; has received speaker fees from Genentech, Incyte, and Seagen; and has received honoraria and served in a consulting or advisory role for Aadi, AstraZeneca, Elevar, Cancer Commons, TransThera, Totus Medicines, and Valar Labs. XL reports employment with Merck Serono Co., Ltd., Beijing, China, an affiliate of Merck KGaA. CB reports employment with Merck. AM reports employment with EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. JS reports employment with Merck and has served in a consulting or advisory role for Merck. AB reports employment with and has served in a consulting or advisory role for Merck. BG reports employment with Merck and holds stock or other ownership in Merck. AR-G reports employment with Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA. SJA reports honoraria from Achilles Biotech, Amgen, AstraZeneca, Caris Life Sciences, Celsius Therapeutics, G1 Therapeutics, GSK, Memgen, Merck, Nektar, Rapt Therapeutics, Venn Therapeutics, Glympse, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, and Samyang; has received research funding from Cellular Biomedicine Group; has received nonfinancial support from Amgen; and has served in a consulting or advisory role for Bristol Myers Squibb. WE has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Whether influenza vaccination (FV) is associated with the severity of immune-related adverse events (IRAEs) in patients with advanced thoracic cancer on immune checkpoint inhibitors (ICIs) is not fully understood., Methods: Patients enrolled in this retrospective cohort study were identified from the Vanderbilt BioVU database and their medical records were reviewed. Patients with advanced thoracic cancer who received FV within 3 months prior to or during their ICI treatment period were enrolled in the FV-positive cohort and those who did not were enrolled in the FV-negative cohort. The primary objective was to detect whether FV is associated with decreased IRAE severity. The secondary objectives were to evaluate whether FV is associated with a decreased risk for grade 3-5 IRAEs and better survival times. Multivariable ordinal logistic regression was used for the primary analysis., Results: A total of 142 and 105 patients were enrolled in the FV-positive and FV-negative cohorts, respectively. There was no statistically significant difference in patient demographics or cumulative incidences of IRAEs between the two cohorts. In the primary analysis, FV was inversely associated with the severity of IRAEs (OR 0.63; p=0.046). In the secondary analysis, FV was associated with a decreased risk for grade 3-5 IRAEs (OR 0.42; p=0.005). Multivariable Cox regression showed that FV was not associated with survival times., Conclusions: Our study showed that FV does not increase toxicity for patients with advanced thoracic cancer on ICIs and is associated with a decreased risk for grade 3-5 IRAEs. No statistically significant survival differences were found between patients with and without FV., Competing Interests: Conflict of interest: E.P-Y. Lin has received support for the present manuscript from the Ministry of Science and Technology Taiwan (MOST107-2314-B-002-231, MOST108-2314-B-030-014, MOST109-2314-B-038-150 and MOST108-2314-B-002-197-MY2) and National Health Research Institute Taiwan (NHRI-EX109-10937BC). T. Osterman has received grants or contracts from Microsoft, outside the submitted work; consulting fees from AstraZeneca, outside the submitted work; and has a collaboration with GE Healthcare. W. Iams has received grants or contracts from the National Cancer Institute Vanderbilt Clinical Oncology Research Career Development Award (VCORCDP) 2K12CA090625-17, American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award, and National Comprehensive Cancer Network Young Investigator Award, outside the submitted work; consulting fees from OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health and Curio Science, outside the submitted work; and participation on advisory boards for Genentech, Jazz Pharma, G1 Therapeutics and Mirati, outside the submitted work. A. Cass has received payment or honoraria for speakers’ bureaus from Jazz, outside the submitted work; and participation on an advisory board for Roche-Genentech and Novartis, outside the submitted work. Y. Shyr has received support for the present manuscript from the National Institutes of Health (P30CA068485, U24CA163056, U24CA213274, P50CA236733, P50CA098131 and U54CA163072). L. Horn reports grants or contracts from Xcovery and Bristol Myers Squibb, outside the submitted work; consulting fees from AstraZeneca, Xcovery and Amgen, outside the submitted work; and participation on an advisory board for Roche-Genentech, Bristol Myers Squibb, Merck, Incyte and Tesaro, outside the submitted work. She is an employee of AstraZeneca. The remaining authors have nothing to disclose., (Copyright ©The authors 2022.)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Background: Over the past few years, tumor next-generation sequencing (NGS) panels have evolved in complexity and have changed from selected gene panels with a handful of genes to larger panels with hundreds of genes, sometimes in combination with paired germline filtering and/or testing. With this move toward increasingly large NGS panels, we have rapidly outgrown the available literature supporting the utility of treatments targeting many reported gene alterations, making it challenging for oncology providers to interpret NGS results and make a therapy recommendation for their patients., Methods: To support the oncologists at Vanderbilt-Ingram Cancer Center (VICC) in interpreting NGS reports for patient care, we initiated two molecular tumor boards (MTBs)-a VICC-specific institutional board for our patients and a global community MTB open to the larger oncology patient population. Core attendees include oncologists, hematologist, molecular pathologists, cancer geneticists, and cancer genetic counselors. Recommendations generated from MTB were documented in a formal report that was uploaded to our electronic health record system., Results: As of December 2020, we have discussed over 170 patient cases from 77 unique oncology providers from VICC and its affiliate sites, and a total of 58 international patient cases by 25 unique providers from six different countries across the globe. Breast cancer and lung cancer were the most presented diagnoses., Conclusion: In this article, we share our learning from the MTB experience and document best practices at our institution. We aim to lay a framework that allows other institutions to recreate MTBs., Implications for Practice: With the rapid pace of molecularly driven therapies entering the oncology care spectrum, there is a need to create resources that support timely and accurate interpretation of next-generation sequencing reports to guide treatment decision for patients. Molecular tumor boards (MTB) have been created as a response to this knowledge gap. This report shares implementation strategies and best practices from the Vanderbilt experience of creating an institutional MTB and a virtual global MTB for the larger oncology community. This report describe a reproducible framework that can be adopted to initiate MTBs at other institutions., (© 2021 AlphaMed Press.)

Introduction: The programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors, atezolizumab and durvalumab, have received regulatory approval for the first-line treatment of patients with extensive-stage SCLC. Nevertheless, when used in combination with platinum-based chemotherapy, these PD-L1 inhibitors only improve overall survival by 2 to 3 months. This may be due to the observation that less than 20% of SCLC tumors express PD-L1 at greater than 1%. Evaluating the composition and abundance of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to therapeutic targeting., Methods: We analyzed RNA-sequencing data from SCLC cell lines (n = 108) and primary tumor specimens (n = 81) for expression of 39 functionally validated inhibitory checkpoint ligands. Furthermore, we generated tissue microarrays containing SCLC cell lines and patient with SCLC specimens to confirm expression of these molecules by immunohistochemistry. We annotated patient outcomes data, including treatment response and overall survival., Results: The checkpoint protein B7-H6 (NCR3LG1) exhibited increased protein expression relative to PD-L1 in cell lines and tumors (p < 0.05). Higher B7-H6 protein expression correlated with longer progression-free survival (p = 0.0368) and increased total immune infiltrates (CD45+) in patients. Furthermore, increased B7-H6 gene expression in SCLC tumors correlated with a decreased activated natural killer cell gene signature, suggesting a complex interplay between B7-H6 expression and immune signature in SCLC., Conclusions: We investigated 39 inhibitory checkpoint molecules in SCLC and found that B7-H6 is highly expressed and associated with progression-free survival. In addition, 26 of 39 immune checkpoint proteins in SCLC tumors were more abundantly expressed than PD-L1, indicating an urgent need to investigate additional checkpoint targets for therapy in addition to PD-L1., (Published by Elsevier Inc.)

Introduction: Blood-based next-generation sequencing assays of circulating tumor DNA (ctDNA) have the ability to detect tumor-associated mutations in patients with SCLC. We sought to characterize the relationship between ctDNA mean variant allele frequency (VAF) and radiographic total-body tumor volume (TV) in patients with SCLC., Methods: We identified matched blood draws and computed tomography (CT) or positron emission tomography (PET) scans within a prospective SCLC blood banking cohort. We sequenced plasma using our previously developed 14-gene SCLC-specific ctDNA assay. Three-dimensional TV was determined from PET and CT scans using MIM software and reviewed by radiation oncologists. Univariate association and multivariate regression analyses were performed to evaluate the association between mean VAF and total-body TV., Results: We analyzed 75 matched blood draws and CT or PET scans from 25 unique patients with SCLC. Univariate analysis revealed a positive association between mean VAF and total-body TV (Spearman's ρ = 0.292, p < 0.01), and when considering only treatment-naive and pretreatment patients (n = 11), there was an increase in the magnitude of association (ρ = 0.618, p  = 0.048). The relationship remained significant when adjusting for treatment status and bone metastases ( p  = 0.046). In the subgroup of patients with TP53 variants, univariate analysis revealed a significant association (ρ = 0.762, p  = 0.037) only when considering treatment-naive and pretreatment patients (n = 8)., Conclusions: We observed a positive association between mean VAF and total-body TV in patients with SCLC, suggesting mean VAF may represent a dynamic biomarker of tumor burden that could be followed to monitor disease status., (© 2020 The Authors.)

Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-programmed death receptor-1/programmed cell death receptor- ligand-1 (anti-PD-1/PD-L1) plus anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) monoclonal antibodies (MoAbs) is being evaluated for a wide range of tumor histologies. Furthermore, several ongoing clinical trials are investigating combination checkpoint inhibition in association with traditional treatment modalities such as chemotherapy, surgery, and radiation. In this review, we summarize the current landscape of combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC). We present a synopsis of the prospects for expanding the indications of dual immune-checkpoint inhibition therapy to a more diverse set of tumor histologies.

Immunotherapy has evolved at a phenomenal pace in cancer therapeutics. This has primarily been fueled by the much perceived necessity to procure an alternative to current standard of care chemotherapy agents, owing to several concerns such as treatment-related toxicity and poor long-term survival associated with the same. The knowledge of various mechanisms involved in regulation of immune response to cancer cells has served a fundamental role in identifying key molecules through which immune cell activity may be modulated. This in-turn led to the development of immune-checkpoint inhibitors. Presently, lung cancer is among the most enthusiastically investigated targets for treatment with immune-checkpoint inhibitors. Encouraging results with initial trials have now translated to attempts directed at further enhancement of outcomes through various strategies. Herein, we shall present a critical assessment of data from pivotal trials that led to the Food and Drug Administration (FDA) approval of various immune-checkpoint inhibitors and also discuss novel strategies that may potentially yield outcomes superior to standard of care chemotherapy in patients diagnosed with advanced non-small cell lung cancer (NSCLC)., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores derived from a previously established 16 gene signature of canonical EMT markers. EMT was associated with exclusion of immune cells critical in the immune response to cancer, with significantly lower infiltration of CD4 T-cells in lung adenocarcinoma and CD4/CD8 T-cells in squamous cell carcinoma. EMT was also associated with increased expression of multiple immunosuppressive cytokines, including IL-10 and TGF-β. Furthermore, overexpression of targetable immune checkpoints, such as CTLA-4 and TIM-3 were associated with EMT in both NSCLCs. An association may exist between immune exclusion and EMT in NSCLC. Further investigation is merited as its mechanism is not completely understood and a better understanding of this association could lead to the development of biomarkers that could accurately predict response to immunotherapy.

Purpose: Provision of high-value care is a milestone in physician training. The authors evaluated the effect of a housestaff-led initiative on laboratory testing rates., Method: Vanderbilt University Medical Center's Choosing Wisely steering committee, led by housestaff with faculty advisors, sought to reduce unnecessary daily basic metabolic panel (BMP) and complete blood count (CBC) testing on inpatient general medicine and surgical services. Intervention services received a didactic session followed by regular data feedback with goal rates and peer comparison. Testing rates during January 1, 2013-February 9, 2015, were compared on intervention services and control services using a difference-in-differences analysis and an interrupted time-series analysis with segmented linear regression., Results: Compared with concurrent controls, the mean number of BMP tests per patient day decreased by an additional 0.23 (95% CI 0.17-0.29) on medical housestaff and 0.15 (95% CI 0.09-0.21) on hospitalist intervention services. Daily CBC tests decreased by an additional 0.28 (95% CI 0.23-0.33) on medical housestaff, 0.08 (95% CI 0.03-0.13) on hospitalist, and 0.12 (95% CI 0.05-0.20) on surgical housestaff intervention services. Patients with lab-free days (0 labs ordered in 24 hours) increased by an additional 4.1 percentage points (95% CI 2.1-6.1) on medical housestaff and 9.7 percentage points (95% CI 6.6-12.8) on hospitalist intervention services. There were no adverse changes in length of stay or intensive care unit transfer, in-hospital mortality, or 30-day readmission rates., Conclusions: A housestaff-led intervention utilizing education and data feedback with goal setting and peer comparison resulted in safe, significant reductions in daily laboratory testing rates.

Objectives: KRAS mutations are the most commonly found mutations in patients with non-small cell lung cancer (NSCLC) adenocarcinoma histology. The clinical implications of KRAS mutations in patients with advanced NSCLC are not well defined. We sought to determine if there is a correlation between KRAS mutation status, response to cytotoxic chemotherapy, and survival in patients with metastatic or recurrent NSCLC., Materials and Methods: Patients with metastatic or recurrent NSCLC and tumor mutation analyses were analyzed for response to conventional chemotherapy. The presence or absence of tumor mutations was assessed with the SNaPshot assay, which detects >40 somatic mutations in eight genes, including KRAS. ALK fluorescence in-situ hybridization analysis was done separately. Associations between KRAS mutation status and response to chemotherapy and survival were assessed., Results: We identified 80 patients with metastatic or recurrent NSCLC and a KRAS activating mutation, and we compared these patients to 70 patients who were pan negative (no detectable mutation by the SNaPshot assay and ALK negative). Patients with KRAS-mutant advanced NSCLC demonstrated a significantly shorter progression-free survival in response to first line chemotherapy (4.5 months versus 5.7 months, p=0.008) compared to pan-mutation negative patients. Overall survival was also significantly shorter in patients with KRAS-mutant advanced NSCLC compared to patients without KRAS activating mutations (8.8 months versus 13.5 months, p=0.038)., Conclusions: Within this single institution retrospective analysis, patients with advanced NSCLC and a KRAS activating mutation exhibited inferior responses to cytotoxic chemotherapy and decreased survival compared to patients with advanced NSCLC and no KRAS mutation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Inspired by the American Board of Internal Medicine's Choosing Wisely® campaign, a group of housestaff at Vanderbilt University Medical Center created the Vanderbilt Choosing Wisely Steering Committee (VCWSC) to explore ways to apply the campaign's principles of high value care to daily practice. In this article, we propose that housestaff leadership is key in the implementation of high value care initiatives at academic health centers (AHCs). We then describe the formation and activities of the VCWSC in the hope that our success will inspire residents at other AHCs to create similar initiatives., (© 2015 Society of Hospital Medicine.)

Background: We previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer., Methods: We reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset., Results: Among 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11-2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41)., Conclusions: Among individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype.

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data.

Objective: To evaluate the aesthetic and functional outcomes of a full-thickness skin graft and a separately harvested auricular cartilage graft for nasal alar defects created by Mohs micrographic surgery., Design: Twenty patients with deep Mohs micrographic surgery defects of the nasal ala who underwent reconstruction with a full-thickness skin graft and an auricular cartilage graft were prospectively studied at a single tertiary care institution between 2010 and 2011 in a nonrandomized, nonblinded study. An ordinal 5-point Likert scale evaluation of overall outcomes was performed by 4 independent surgeon raters., Results: The mean outcome for use of the full-thickness skin and auricular cartilage graft construct was a score of 2.3 on a scale of 1 through 5, with 1 being excellent and 5 being poor. The mean duration of follow-up was 6 months, with a range of 5 weeks to 23 months. There were no clinically meaningful losses of constructs in the patients studied., Conclusion: A full-thickness skin graft and a separately harvested auricular cartilage graft are valuable and reliable tools for reconstructing deep nasal alar defects that require support to prevent alar retraction or collapse, particularly when a single-stage procedure is preferred or necessary because of medical comorbidities.

Chemotherapy-induced thrombotic microangiopathy is a severe illness that has occurred in a small number of patients treated with carboplatin and combination of docetaxel and trastuzumab chemotherapy. We describe herein the case of a patient with stage IIB breast cancer who developed thrombotic microangiopathy after five cycles of carboplatin, docetaxel, and trastuzumab.

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARgamma, alpha and delta agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARdelta agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-gamma and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARdelta agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARdelta agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.