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Mesonephric and mesonephric-like adenocarcinomas of the gynecologic tract are a rare subset of gynecologic tumors that are frequently associated with the presence of somatic KRAS mutations. Owing to their rare nature and ability to arise in different gynecologic sites, pathologic diagnosis is often challenging and under-represented. Immunohistochemistry and routine use of next-generation sequencing has allowed these cases to be more readily identified; however, there is still a paucity of clinical outcomes data, and the efficacy of treatment paradigms remains largely unknown. Historically, mesonephric and mesonephric-like adenocarcinomas were considered to be less responsive to systemic treatment, but response rates to first-line platinum-doublet chemotherapy for metastatic disease may be higher than initially suspected. Recurrent disease is often distant and located in the lungs, suggesting an important role of surveillance chest imaging. Given that most of these tumors are associated with somatic mitogen-activated protein kinase pathway mutations, a currently open phase II trial is assessing the dual RAF/MEK clamp avutometinib in combination with the FAK inhibitor defactinib in patients with recurrent mesonephric and mesonephric-like adenocarcinomas. Continued multi-institutional prospective trials are necessary to elucidate additional treatment options for these rare tumors., Competing Interests: Declaration of Competing Interests CA reports Clinical Trial funding paid to institution from AbbVie – MSKPI – GOG 3005; AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator and MSK PI, DO81RC00001; ENGOT-ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 &3; Genentech/Roche – MSK PI, GOG3015 (IMagyn050). She also participates on an advisory board for Blueprint Medicine – advisory board June 30, 2021 (no consulting fee); Merck – Global Cervical and Ovarian Cancer virtual advisory board July 10, 2023 (no consulting fee); and AstraZeneca – AZ Evolve dmc April 26, 2023 to present. She also serves on the GOG Foundation, Board of Directors (unpaid, occasional travel cost reimbursement to attend meetings), and NRG Oncology Board of Directors (unpaid). RG reports honoraria from GlaxoSmithKline, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. The remaining authors report no competing interests., (Copyright © 2025 European Society of Gynaecological Oncology and the International Gynecologic Cancer Society. Published by Elsevier Inc. All rights reserved.)

Objective: We sought to determine the safety and efficacy of the oral progesterone antagonist onapristone in combination with anastrozole in patients with recurrent progesterone receptor-positive adult-type granulosa cell tumor of the ovary., Methods: This was a single-institution phase II study of patients with progesterone receptor-positive adult-type granulosa cell tumor who received at least 1 prior line of chemotherapy. Patients were enrolled from November 2021 to August 2022 and tissue was evaluated for progesterone receptor status via immunohistochemistry. Eligible patients had progesterone receptor expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone extended-release twice daily and 1 mg of anastrozole by mouth daily until progression of disease or discontinuation of treatment. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary end point was the overall response rate by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were response duration, clinical benefit rate, progression-free survival, and safety., Results: Fourteen patients with adult-type granulosa cell tumor enrolled and completed stage 1 accrual. There were no objective responses seen during the study period. The study was closed when further development of onapristone extended-release was discontinued. All 14 patients were evaluable, with median progression-free survival of 3.6 months (range; 1.7-7.1), a 6-month progression-free survival rate of 28.6% (range; 8.8%-52.4%), a 12-month progression-free survival rate of 10.7% (range; 0.8%-35.4%), and a clinical benefit rate of 42.9% (range; 17.7%-71.7%)., Conclusion: The study did not meet its primary end point. Although the combination of onapristone extended-release and anastrozole was well-tolerated, there were no objective responses in patients with progesterone receptor-positive adult-type granulosa cell tumor., Competing Interests: Declaration of Competing Interests B.W. reports a research grant from REPARE Therapeutics paid to the institution and has an immediate family member who is employed by AstraZeneca, outside the submitted work. D.S.C. reports personal fees from AstraZeneca, Biom’Up, and Verthemia; he also has stock in BioN Tech and Doximity. V.M. reports institutional grants or contracts from AstraZeneca, Bristol Myers Squibb, Cullinan Oncology, DualityBio, Eisai, Faeth Therapeutics, Karyopharm Therapeutics, Merck, Takeda, and Zymeworks; personal meeting/travel support from AstraZeneca and Karyopharm; and consultant relations (unpaid) from Clovis Oncology, Cullinan Oncology, DualityBio, Eisai, Faeth Therapeutics, GlaxoSmithKline, Immunocore, iTeos Therapeutics, Karyopharm Therapeutics, Lilly, Merck, Mereo BioPharma, MorphoSys, MSD, Novartis, Regeneron, Sutro Biopharma, and Zymeworks. R.G. reports honoraria from GlaxoSmithKline, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. C.A. reports clinical trial funding paid to institution from AbbVie - MSKPI - GOG 3005; AstraZeneca - MSK PI, SOLO1/GOG 3004; National Coordinating Investigator and MSK PI, DO81RC00001; ENGOT-ov46; AGO-OVAR 23; GOG-3025; Clovis - MSK PI, ARIEL 2 &3; Genentech/Roche - MSK PI, GOG3015 (IMagyn050). She also participates on an Advisory Board for Blueprint Medicine - Advisory Board 6/30/21 (no consulting fee); Merck - Global Cervical and Ovarian Cancer Virtual Advisory Board 7/10/23 (no consulting fee) and AstraZeneca - AZ Evolve dmc 4/26/23-ongoing. She also serves on the GOG Foundation, Board of Directors (unpaid, occasional travel cost reimbursement to attend meetings), and NRG Oncology Board of Directors (unpaid). R.O. reports funding paid to the institution from Bayer/Celgene/Juno, Arsenalbio, Tesaro/GSK, Merck, Ludwig Cancer Institute, AbbVie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Genentech, Alkermes/Mural Oncology, Kite Pharma, Acrivon, OnCusp Therapeutics, and Gynecologic Oncology Foundation, Lyell Immunopharma; payments for lectures from GSK, Curio/Onclive/PER/MJH/Aptitude Health, SITC, Gynecologic Oncology Canada; support for meetings/travel from Hitech Health, Gathering Around Cancer (Ireland), GOG Foundation, SGO; steering committee participation (unpaid) from AstraZeneca (DU0-0) GSK (Moonstone, Prima) Acrivon Mural Oncology, OnCusp Therapeutics; advisory role (unpaid) from Carina Biotech, Link therapeutics; advisory board participation from Seattle Genetics/SeaGen/Pfizer Immunogen, Bayer, R-Pharm, Miltenyi, 2seventybio, Bayer, Loxo, OnCusp Therapeutics, GSK; and leadership positions at CPC, SGO (Vice Chair) and NRG Oncology (Chair, DT Committee). C.F. reports ongoing institutional research support from Merck, Bristol Myers Squibb, AstraZeneca, Mersana, Hotspot Therapeutics, Immunocore, Marengo, and Volastra; consulting fees from Bristol Myers Squibb, Seagen, Aadi Biosciences, and Eli Lily; honoraria for lectures from OncLive; meeting/travel support by Puma Biotechnology; and participation on data safety monitoring board or advisory board of Merck, Genentech, and Marengo (all uncompensated). C.K. received honoraria from OncLive, and Total Health, consults/has consulted for Scenic Immunology BV, and has received research funding from Bristol Myers Squibb, Merus, Gritstone bio, and Acrivon. The other authors report no disclosures., (Copyright © 2024 European Society of Gynaecological Oncology and the International Gynecologic Cancer Society. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC)., Methods: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety., Results: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%)., Conclusions: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed., Competing Interests: Declaration of competing interest Alexia Iasonos reports consulting fees from Mylan. Chrisann Kyi reports grant funding from Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone, and BMS; and consulting fees from Scenic Immunology B.V. and OncLive. Rachel N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. Carol Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). Claire F. Friedman reports ongoing institutional research support from Merck, BMS, AstraZeneca, Mersana, Hotspot Therapeutics, Immunocore, Marengo and Volastra; consulting fees from BMS, Seagen, Aadi Biosciences, and Eli Lilly; honoraria for lectures from Onclive; meeting/travel support by Puma Biotechnology; and participation on Data Safety Monitoring or Advisory Board of Merck, Genentech, and Marengo (all uncompensated). Roisin E. O'Cearbhaill reports personal fees from Tesaro/GSK, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen, and other from Hitech Health, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK), and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Gynecologic Oncology Foundation, Genentech, Kite Pharma, Tesaro/GSK, Ludwig Cancer Institute, TCR2 Therapeutics, Genmab/Seagen Therapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Merck, Sellas Therapeutics, Abbvie/StemCentrx, Regeneron, Lyell Immunopharma, Acrivon, and Atara Biotherapeutics. Britta Weigelt reports a research grant from REPARE Therapeutics paid to the institution and has an immediate family member who is employed by AstraZeneca, outside the submitted work. Vicky Makker reports unpaid consulting/advisory roles with the following: Duality, Novartis, Morphosys, AstraZeneca, Eisai, Clovis Oncology, Karyopharm Therapeutics, GlaxoSmithKline, Merck, ArQule, Cullinan, Faeth Therapeutics, Jazz, Immunocore, Iteos Therapeutics, Ideaya, Kartos Therapeutics, Lilly, Moreo, Prelude, Takeda, and Zymeworks; research funding from the following: Merck (Inst), Eisai (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Bayer (Inst), Takeda (Inst), Duality (Inst), Zymeworks (Inst), Karyopharm Therapeutics (Inst), Faeth Therapeutics (Inst), Bristol-Myers Squibb (Inst), Lilly (Inst), and Cullinan (Inst); travel, accommodations, and expenses from the following: Eisai, Merck, AstraZeneca; and a relationship with IBM. Dennis S. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. The other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

BACKGROUNDObesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.METHODSWe analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status.RESULTS524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox's regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals.CONCLUSIONObesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype.FUNDINGNIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.

Objectives: Mesonephric (MA) and mesonephric-like (MLA) adenocarcinomas are rare cancers, and data on clinical behavior and response to therapy are limited. We sought to report molecular features, treatment, and outcomes of MA/MLA from a single institution., Methods: Patients with MA (cervix) or MLA (uterus, ovary, other) treated at Memorial Sloan Kettering Cancer Center (MSK) from 1/2008-12/2021 underwent pathologic re-review. For patients with initial treatment at MSK, progression-free survival (PFS1) was calculated as time from initial surgery to progression or death; second PFS (PFS2) was calculated as time from start of treatment for recurrence to subsequent progression or death. Overall survival (OS) was calculated for all patients. Images were retrospectively reviewed to determine treatment response. Somatic genetic alterations were assessed by clinical tumor-normal sequencing (MSK-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT])., Results: Of 81 patients with confirmed gynecologic MA/MLA, 36 received initial treatment at MSK. Sites of origin included cervix (n = 9, 11%), uterus (n = 42, 52%), ovary (n = 28, 35%), and other (n = 2, 2%). Of the 36 patients who received initial treatment at MSK, 20 (56%) recurred; median PFS1 was 33 months (95% CI: 17-not evaluable), median PFS2 was 8.3 months (95% CI: 6.9-14), and median OS was 87 months (95% CI: 58.2-not evaluable). Twenty-six of the 36 patients underwent MSK-IMPACT testing, and 25 (96%) harbored MAPK pathway alterations., Conclusion: Most patients diagnosed with early-stage disease ultimately recurred. Somatic MAPK signaling pathway mutations appear to be highly prevalent in MA/MLA, and therapeutics that target this pathway are worthy of further study., Competing Interests: Declaration of competing interest B. Weigelt reports research funding by Repare Therapeutics, outside the current work. N. R. Abu-Rustum reports grant funding from GRAIL paid to the institution. A. Iasonos reports consulting fees from Mylan. C. Aghajanian reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai/Merck, Roche/Genentech, Abbvie, AstraZeneca/Merck, and Repare Therapeutics; advisory board participation (no fee) for Blueprint Medicine; and leadership/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and NRG Oncology Board of Directors (unpaid). D. Chi reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. R.N. Grisham reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. The other authors do not have potential conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC)., Experimental Design: A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies., Results: In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9-19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5-11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1-8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2-2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7-2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients)., Conclusions: The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Data on platinum sensitivity of low-grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease., Methods: Patients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum-based chemotherapy and to second- to fifth-line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank-sum and two-tailed Fisher exact tests were employed., Results: Of 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p = .027). The 15 remaining patients had stable disease on first-line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST-evaluable responses to second-line and 27 to third-line chemotherapy. Objective response rates to platinum-based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively., Conclusions: Primary platinum-based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates., (© 2023 American Cancer Society.)

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8-20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively ( p  < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p  < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance.

Purpose: Preoperative radiographic differentiation of mucinous cystic neoplasms (MCN) and simple cysts (SLC) of the liver is challenging. Previous data have demonstrated that the finding of septations arising from the cyst wall without indentation on cross-sectional imaging is associated with MCN. We aim to assess whether this radiographic feature is diagnostic of MCN., Methods: A prospectively maintained database was queried for patients with a preoperative diagnosis of a cystic liver lesion who subsequently underwent operative intervention. The feature of septations without indentation of the cyst wall was evaluated on cross-sectional imaging obtained within 3 months of operation. Imaging was independently evaluated by three radiologists blinded to pathology and interobserver agreement was compared to assess the diagnostic accuracy of this feature as well as the overall likelihood of the lesion representing a MCN., Results: There were 95 patients who met inclusion criteria; 80 (84%) had SLC on pathology, while 15 (16%) had MCN. Presence of septa without indentation of cyst wall had high sensitivity (range 80-87%), but low specificity (range 48-66%). Interobserver percent agreement (PA) was 51% [κ = 0.35 (95% CI 0.22-0.47)]. Sensitivity among the three radiologists ranged between 20 and 80% and specificity between 71 and 91% for the likelihood of the lesion representing MCN versus SLC, with an area under the curve (AUC) of 0.67-0.79; however, interobserver agreement was fair [κ = 0.40 (95% CI 0.25-0.55), PA = 67%]., Conclusion: The presence of septations without indentation of cyst wall demonstrates adequate sensitivity to differentiate MCN and SLC. However, there is variability for detection of this feature and therefore, it alone is of limited clinical value., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The success of an active surveillance management approach to low-risk papillary thyroid cancer (PTC) is heavily dependent on proper patient selection. For example, primary tumors located in a subcapsular position immediately adjacent to the trachea or a recurrent laryngeal nerve (RLN) are considered to be inappropriate for active surveillance. Since preoperative imaging cannot reliably rule out extrathyroidal extension or reveal the full course of the RLN relative to the thyroid gland, it is important for clinicians to understand subcapsular tumor locations and minimum tumor sizes that are most likely to be associated with gross invasion of the RLNs. Methods: We assessed the medical records of 123 patients treated at Memorial Sloan Kettering Cancer Center (MSK) between 1986 and 2015 who had a primary PTC tumor demonstrating gross extrathyroidal extension to either the right or left RLN. Thirty patients with a primary tumor ≤2 cm in diameter demonstrating extrathyroidal extension into an RLN were included in the analysis. Results: Gross invasion of an RLN by tumors ≤2 cm is a rare event that was seen in only 0.8% (35/4334) of patients with PTC who underwent initial thyroid surgery at MSK between 1986 and 2015. Gross RLN invasion was associated with subcapsular PTC tumors located in either the right paratracheal area (60%), left paratracheal area (36.7%), or right lateral posterior lobe area not adjacent to the trachea (3.3%). Only a quarter of the patients had imaging findings suggestive of extrathyroidal extension and only 30% had clinically apparent vocal paresis/paralysis on preoperative examination. Invasion of the RLN was not observed for primary tumors <0.9 cm in diameter, regardless of tumor location. Conclusions: Well-differentiated PTC tumors ≥0.9 cm in maximal diameter that are located in the right paratracheal, left paratracheal, and right lateral posterior lobe subcapsular positions are usually not appropriate for active surveillance even in the absence of definitive evidence for nerve invasion on preoperative imaging or vocal cord examination. Patient selection for active surveillance management should take into account not only the size and growth rate of a tumor but also its location in relation to the expected course of RLNs.

Objectives: We sought to determine the safety and efficacy of the oral androgen receptor antagonist enzalutamide in patients with previously treated, recurrent, AR-positive (AR+) ovarian cancer., Methods: This was a single-institution phase II study of patients with AR+ ovarian cancer with measurable disease with 1-3 prior lines of chemotherapy; patients were screened for enrollment from 11/2013-7/2018. Following consent, archival tissue was evaluated for AR+. Enrolled patients received daily enzalutamide 160 mg until progression of disease or treatment discontinuation. Adverse events were graded by CTCAE v4.0. Co-primary endpoints were 6-month progression-free survival (PFS 6 ) and overall response rate (ORR) by RECIST 1.1 criteria., Results: During the study period, 160 patients were screened and 59 (45 high-grade serous [HGS] and 14 low-grade serous [LGS]) consented to treatment on study. There was 1 confirmed and 1 unconfirmed partial response. The ORR was 1.7% (90% CI: 0.2-100%). The overall PFS 6 rate (as binary) was 22% (90% CI: 15.1-100%). The 6-month PFS rate (as time to event) was 19.8% for HGS patients (90% CI: 12.7-100%) and 38.5% (90% CI: 21.7%-100%) for LGS patients. Grade 3 toxicities occurred in 6 patients (one toxicity (Grade 3 rash) was considered a dose-limiting toxicity). One patient died of cardiac arrest after 42 days on treatment of a cardiac arrest not attributed to study drug., Conclusions: The study met its primary endpoint, with a PFS 6 rate of 22% (n = 13); however, the overall response rate was low. Enzalutamide was well tolerated and may be a potential treatment option in select patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To investigate the inter- and intra-reader agreement of immune Response Evaluation Criteria in Solid Tumors (iRECIST) and Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in patients with lung cancer treated with immunotherapy., Materials and Methods: This retrospective study included 85 patients with lung cancer treated with PD-1 blockade. Four radiologists evaluated computed topography (CT) scans before and after initiation of immunotherapy using iRECIST and RECIST 1.1. Weighted kappa (k) with equal weights was used to assess the intra-reader agreement between 2 repeated reads on overall response at all time points, best overall response, and the response at the time point of progression, as well as the intra-reader agreement between iRECIST and RECIST. The inter-reader agreement was calculated using Light's kappa., Results: Intra-reader agreement for overall response at all time points, best overall response, and time point of progression was substantial to almost perfect for both iRECIST and RECIST 1.1 (k = 0.651-0.983). Inter-reader agreement was substantial for iRECIST (κ = 0.657-0.742) while RECIST 1.1 was moderate to substantial (κ = 0.587-0.686). The level of inter-reader agreement was not higher on repeat read for iRECIST (κ = 0.677-0.709 and κ = 0.657-0.742 for first and second read, respectively) as well as for RECIST 1.1 (κ = 0.587-0.659 and κ = 0.633-0.686 for first and second read, respectively). Almost perfect agreement was observed between RECIST 1.1 and iRECIST at first (κ = 0.813-0.923) and second read (κ = 0.841-0.912)., Conclusion: The inter- and intra-reader agreement of iRECIST is high and similar to RECIST 1.1 in patients with lung cancer treated with immunotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance., Patients and Methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16 low cells (immature) by flow cytometry., Results: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%., Conclusion: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance., Competing Interests: Conflict of interest statement LM: Sponsored Research: Amgen, Bristol-Myers Squibb, Boehringer Ingelheim. Consulting, advisory role: Roche Diagnostics, Takeda, Roche. Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca. IP has served as a consultant for AstraZeneca, Pfizer and BluePrint Medicines. EA: Travel expenses: Mundipharma. Lectures and educational activities: Sanofi Genzymes. DS, HR, JR, SP, SC, FB, FT, MLR, PS, JG, AJP, MC, MN, CR, APM, LC and WPhad nothing to disclose. LH: none related to the current article, outside of the current article: research funding Roche Genentech, Boehringer Ingelheim, AstraZeneca (all institution), advisory board: Boehringer, BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Boehringer Ingelheim, Amgen (all institution), speaker: MSD, travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Quadia (self), interview sessions funded by Roche Genentech (institution), local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD/Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Cilag. EN: none related to the current article, outside of the current article: research support from Roche and Pfizer; advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Amgen and AstraZeneca. PM: Principal/subinvestigator of Clinical Trials for Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Xencor Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. CAV: Personal fees from Roche, AbbVie, MSD, Bristol-Myers Squibb, Novartis, Astra Zeneca, Takeda and Ipsen. PB: Speaker bureau: AstraZeneca, BMS, Roche, MSD. Honoraria: Beigene. SN: Speaker Bureau/Advisor: Amgen, AstraZeneca, Boehringer, Beigene, MSD, Roche, Takeda, Pfizer. MDH receives research support from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles and Arcus; received travel support/honoraria from AstraZeneca, Eli Lilly and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai and Arcus; has a patent filed by his institution related to the use of tumour mutation burden to predict response to immunotherapy (PCT/US2015/062,208), which has received licensing fees from PGDx. GZ: Grants and personal fees from BMS, non-financial support from MSD, personal fees from Borhinger, non-financial support from Roche, personal fees from Astra-Zeneca, non-financial support from Abbvie, outside the submitted work. MM: Grants and personal fees from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from BOEHRINGER INGELHEIM, personal fees, non-financial support and other from ASTRA ZENENCA, personal fees, non-financial support and other from ROCHE, personal fees from KYOWA KYRIN, personal fees from PIERRE FABRE, outside the submitted work. LPA: Honoraria (self): Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, Ipsen, Merck, Merck Sharp and Dohme, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Leadership role: Altum sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer; Officer/Board of Directors Genómica. AMD: Consulting, advisory role or lectures: Roche, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda, Pharmamar. Research support: Amgen, Abbvie, BMS. DP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer; Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer. CME, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene. Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. NC: Sponsored Research at Gustave Roussy Cancer Center BMS fondation, GSK, Sanofi, advisory role and lectures: AstraZeneca. These are outside the scope of this work. GL: Research support Merck serono, BMS, Pfizer, AstraZeneca, Blueprint medicines. KA: Consultant for Astrazeneca and Iovance Biotherapeutics. Her institution has received non-monetary research support from Takeda and Novartis on her behalf. BB: Sponsored Research at Gustave Roussy Cancer Center Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: mTOR inhibitor-associated pneumonitis is common and often asymptomatic. We describe a waxing and waning pattern of pneumonitis observed on computed tomography (CT) scans of patients with renal cell carcinoma who were being treated with mTOR inhibitor molecular targeted therapy., Materials and Methods: In this HIPAA-compliant, IRB-approved retrospective single-institution study, 25 renal cell carcinoma patients were identified who received single-therapy temsirolimus or everolimus between January 2011 and June 2015 and who had chest CT scans available for review both before and after initiation of mTOR inhibitor treatment. A detailed review of the electronic medical record and serial chest CT examinations was performed., Results: Radiologic findings compatible with pneumonitis were identified in 13/25 (52%) patients on mTOR inhibitors in our study. Of the patients with CT findings of pneumonitis, 8/13 (62%) demonstrated a waxing and waning pattern; of whom 7 had clinical symptoms of pneumonitis. Of the 17 patients who received temsirolimus, 9/17 (53%) developed radiologic findings compatible with pneumonitis and 4/9 (44%) developed a waxing and waning pattern. Of the 8 patients who received everolimus, 4/8 (50%) had radiologic findings compatible with pneumonitis and 4/4 (100%) developed a waxing and waning pattern., Conclusion: Waxing and waning is an unrecognized pattern of mTOR inhibitor-associated pneumonitis. Recognition of this pattern will promote clinical-radiologic concordance and may facilitate patient management., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed., Experimental Design: We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of MET exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated., Results: Seventy-five of 168 MET exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS ( P > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS ( N = 15) or immunochemistry ( N = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; P = 0.02)., Conclusions: In MET exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials., (©2020 American Association for Cancer Research.)

Objectives: The aim of this study was to delineate computed tomography (CT) features of stage IIIA non-small cell lung cancers on pre-treatment staging studies and identify features that could predict local recurrence after definitive concurrent chemoradiotherapy., Materials and Methods: We retrospectively reviewed pre- and post-treatment CT scans for 91 patients with Stage IIIA non-small cell lung cancer undergoing definitive concurrent chemoradiotherapy. Pre-treatment CT qualitative features were evaluated by consensus. The primary endpoint was local recurrence as determined on post-treatment CT scans along with the radiotherapy fields. Local recurrence was defined as intrathoracic in-field and marginal as opposed to out-of-field failures. Competing risk regressions were used to examine associations between CT features and recurrence., Results: The median follow-up was 51.5 months (range 2.4-111.2). Median overall survival was 25.6 months (95% CI: 20.4-30). At last follow-up, 72 (79.1%) patients had died, 48 (52.7%) had in-field recurrence, and 30 (32.9%) presented with out-of-field recurrence. On pre-treatment CT scans, tumors presenting as pulmonary consolidations (hazard ratio = 2.34, 95% CI: 1.05-5.22; p 0.038) were more likely to have in-field failure. Tumors with 50-100% necrosis (hazard ratio = 0.15, 95% CI: 0.02-1.06) were associated with decreased out-of-field failure (overall p = 0.038). However, these were rare features in our sample which limit the ability of these features to be associated with such outcomes., Conclusions: Pre-treatment CT features alone are limited in predicting locoregional recurrence. Larger studies using quantitative tools are needed to predict such outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Real-world evidence (RWE), conclusions derived from analysis of patients not treated in clinical trials, is increasingly recognized as an opportunity for discovery, to reduce disparities, and to contribute to regulatory approval. Maximal value of RWE may be facilitated through machine-learning techniques to integrate and interrogate large and otherwise underutilized datasets. In cancer research, an ongoing challenge for RWE is the lack of reliable, reproducible, scalable assessment of treatment-specific outcomes. We hypothesized a deep-learning model could be trained to use radiology text reports to estimate gold-standard RECIST-defined outcomes. Using text reports from patients with non-small cell lung cancer treated with PD-1 blockade in a training cohort and two test cohorts, we developed a deep-learning model to accurately estimate best overall response and progression-free survival. Our model may be a tool to determine outcomes at scale, enabling analyses of large clinical databases. SIGNIFICANCE: We developed and validated a deep-learning model trained on radiology text reports to estimate gold-standard objective response categories used in clinical trial assessments. This tool may facilitate analysis of large real-world oncology datasets using objective outcome metrics determined more reliably and at greater scale than currently possible. This article is highlighted in the In This Issue feature, p. 1 ., (©2020 American Association for Cancer Research.)

Thoracic tumors are a leading cause of cancer-related morbidity and mortality. In recent years, developments in oncologic treatments for these tumors have ushered in an era of targeted therapy, and, in many cases, these novel treatments have replaced conventional strategies to become standard therapeutic options, particularly in those with lung cancer. Targeted medical therapies for lung cancer now include angiogenesis inhibitors, tyrosine kinase inhibitors, and immunotherapeutic agents. Several novel ablative therapies have also gained widespread acceptance as alternatives to conventional surgical options in appropriately selected patients. Tumors treated with targeted medical therapies can respond to treatment differently when compared with conventional therapies. For example, pseudoprogression is a well-described phenomenon in patients receiving checkpoint inhibitor immunotherapy in which an initial increase in tumor burden is followed by a decrease in tumor burden and sometimes partial or complete response, while the frequent cavitating responses seen when antiangiogenic agents are used can be difficult to quantify using existing response assessment criteria. In some cases, novel response assessment criteria are needed to adequately capture response. In addition, numerous treatment-related side effects have been described, which are important to recognize, both to ensure appropriate treatment and to avoid misclassification as worsening tumor. Imaging plays a vital role in the assessment of patients receiving targeted medical therapy, and it is essential that thoracic radiologists are familiar with the rationale underpinning these treatments and the expected posttherapy findings.

Conventional approaches to the treatment of early-stage lung cancer have focused on the use of surgical methods to remove the tumor. Recent progress in radiation therapy techniques and in the field of interventional oncology has seen the development of several novel ablative therapies that have gained widespread acceptance as alternatives to conventional surgical options in appropriately selected patients. Local control rates with stereotactic body radiation therapy for early-stage lung cancer now approach those of surgical resection, while percutaneous ablation is in widespread use for the treatment of lung cancer and oligometastatic disease for selected other malignancies. Tumors treated with targeted medical and ablative therapies can respond to treatment differently when compared with conventional therapies. For example, after stereotactic body radiation therapy, radiologic patterns of posttreatment change can mimic disease progression, and, following percutaneous ablation, the expected initial increase in the size of a treated lesion limits the utility of conventional size-based response assessment criteria. In addition, numerous treatment-related side effects have been described that are important to recognize, both to ensure appropriate treatment and to avoid misclassification as worsening tumor. Imaging plays a vital role in the assessment of patients receiving targeted ablative therapy, and it is essential that thoracic radiologists become familiar with these findings.

Background: Concurrent programmed death-ligand-1 (PD-(L)1) plus osimertinib is associated with severe immune related adverse events (irAE) in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Now that PD-(L)1 inhibitors are routinely used as adjuvant and first-line treatments, sequential PD-(L)1 inhibition followed by osimertinib use may become more frequent and have unforeseen serious toxicity., Methods: We identified patients with EGFR-mutant NSCLC who were treated with PD-(L)1 blockade and EGFR- tyrosine kinase inhibitors (TKIs), irrespective of drug or sequence of administration (total n = 126). Patient records were reviewed to identify severe (NCI-CTCAE v5.0 grades 3-4) toxicity., Results: Fifteen percent [6 of 41, 95% confidence interval (CI) 7% to 29%] of all patients treated with sequential PD-(L)1 blockade followed later by osimertinib developed a severe irAE. Severe irAEs were most common among those who began osimertinib within 3 months of prior PD-(L)1 blockade (5 of 21, 24%, 95% CI 10% to 45%), as compared with >3-12 months (1 of 8, 13%, 95% CI 0% to 50%), >12 months (0 of 12, 0%, 95% CI 0% to 28%). By contrast, no severe irAEs were identified among patients treated with osimertinib followed by PD-(L)1 (0 of 29, 95% CI 0% to 14%) or PD-(L)1 followed by other EGFR-TKIs (afatinib or erlotinib, 0 of 27, 95% CI 0% to 15%). IrAEs occurred at a median onset of 20 days after osimertinib (range 14-167 days). All patients with irAEs required steroids and most required hospitalization., Conclusion: PD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L)1 blockade. No irAEs were observed when osimertinib preceded PD-(L)1 blockade or when PD-(L)1 was followed by other EGFR-TKIs. This association appears to be specific to osimertinib, as no severe irAEs occurred with administration of other EGFR-TKIs., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response., Methods: Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months., Results: TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point., Conclusion: Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.

Purpose: Some groups consider magnetic resonance imaging the gold standard to diagnose urethral diverticula with up to 100% reported sensitivity. We describe cases contradicting this paradigm and identify reasons for discrepancies., Materials and Methods: We searched a database for women who underwent urethral diverticulum surgery from 1998 to 2008 and also underwent preoperative magnetic resonance imaging. Images were reviewed by a blinded panel of urologists and a radiologist. They came to consensus on the presence or absence, site and anatomy of urethral diverticulum or cancer, and compared operative findings. Discrepancies were classified as errors in urethral diverticulum or cancer diagnosis and errors in urethral diverticulum anatomy or site., Results: Of 76 patients who underwent diverticulectomy 41 also underwent magnetic resonance imaging, of whom 10 (24.4%) had a discrepancy between magnetic resonance imaging and surgical findings. In 6 of these cases there were diagnosis errors and diverticula were not seen on magnetic resonance imaging in 3. One urethral diverticulum each was misdiagnosed as Bartholin's cyst and as a typical post-collagen injection appearance. A sterile abscess was incorrectly diagnosed as a urethral diverticulum. In 2 patients magnetic resonance imaging did not detect cancer within the diverticulum. A major discrepancy in anatomy made intraoperative decision making difficult in 2 patients., Conclusions: In cases clinically suspicious for urethral diverticulum magnetic resonance imaging had a 24.4% error rate. Serious consequences are failure to detect cancer and suboptimal treatment for urethral diverticulum. The reason for the high magnetic resonance imaging accuracy rate in other series may be that in the absence of radiological confirmation some surgeons may choose not to perform surgery. Magnetic resonance imaging is useful to assess urethral diverticula but physicians should be aware of its limitations., (Copyright 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to report on clinical experience with and observations made during primary CT-guided percutaneous catheter drainage of acute necrotizing pancreatitis and to compare results among patients with sterile and those with infected necrosis., Materials and Methods: We reviewed clinical, radiologic, and bacteriologic data on 35 patients (23 men, 12 women; mean age, 50 years; range, 21-83 years) with acute necrotizing pancreatitis refractory to standard medical care who underwent CT-guided percutaneous catheter drainage with 12- to 22-French catheters. Experiences with two subgroups were compared. One group consisted of 22 patients, 10 with multisystem organ failure, who presented with sterile necrosis (median Atlanta score, 1.3; range, 0-3). The other group consisted of 13 patients, one with multisystem organ failure, who presented with infected necrosis (median Atlanta score, 0.4; range, 0-3). Differences between the group with sterile and the group with infected necrosis were analyzed with the Fisher-Holton exact and Mann-Whitney U tests., Results: Among 35 patients, 17 (49%) were treated successfully with CT-guided percutaneous catheter drainage alone. The effectiveness of CT-guided percutaneous catheter drainage in patients with sterile necrosis (11/22, 50%) was not significantly different from that of drainage in patients with infected necrosis (6/13, 46%). Among 11 patients with multisystem organ failure (10 with sterile necrosis, one with infected necrosis), only four (36%) were treated successfully with CT-guided percutaneous catheter drainage alone; five patients (45%) died. Among 24 patients without multisystem organ failure, 13 (54%) were treated successfully with CT-guided percutaneous catheter drainage alone; one patient died., Conclusion: In our experience, primary CT-guided percutaneous catheter drainage was successful for approximately one half of the patients with acute necrotizing pancreatitis. The presence of multisystem organ failure appears to be a more important indicator of outcome than does the presence of infection.

Objective: The objective of our study was to evaluate whether CT can be used to predict the pathologic subtypes of pancreatic intraductal papillary mucinous neoplasms (IPMNs)., Materials and Methods: Three radiologists, blinded to the pathologic IPMN subtype, retrospectively and independently reviewed the preoperative CT scans of 38 patients with surgically resected pancreatic IPMN: 11 intraductal papillary mucinous adenomas, 11 intraductal papillary mucinous carcinomas, and 16 intraductal papillary mucinous carcinomas with invasion. The patients, 16 women and 22 men, ranged in age from 38 to 80 years (mean age, 64.3 years). CT findings were correlated with each pathologic subtype using the chi-square (two-sided) test and analysis of variance. Interobserver agreement of the CT diagnosis of pathologic subtype and agreement between the CT diagnosis and pathologic subtype were also studied (kappa statistic)., Results: Predominant main pancreatic duct (MPD) involvement (p = 0.04) and a wide (> 1 cm) connection of a side-branch lesion with the MPD (p = 0.03) correlated with intraductal papillary mucinous carcinoma with invasion. Tumor size, MPD diameter, number of tumors per patient, number of pseudoseptations per tumor, common bile duct dilatation, enlarged lymph nodes, intraductal calcifications, papillary bulging, and presence and size of a solid mass yielded no statistically significant relationship with pathologic subtype. Both interobserver agreement of CT diagnosis (range, 0.004-0.359) and agreement between CT diagnosis and pathologic subtype (range, 0.046-0.317) ranged from slight to fair., Conclusion: Prediction of the pathologic subtypes of pancreatic IPMNs by CT is limited. Predominant MPD involvement and a wide connection of a side-branch lesion with the MPD are the only CT findings that can be used to predict the pathologic subtype of pancreatic IPMN.

Anomalies of the inferior vena cava (IVC) have been recognized as one of the predisposing factors for deep vein thrombosis. Rarely, thrombosis of an anomalous retroperitoneal vein may resemble a soft tissue mass. Awareness of this fact helps preventing unnecessary interventions. We report a case of thrombosis of retroaortic left renal vein and interrupted IVC that mimicked a retroperitoneal neoplasm.

Membrane proteins are regulated by the lipid bilayer composition. Specific lipid-protein interactions rarely are involved, which suggests that the regulation is due to changes in some general bilayer property (or properties). The hydrophobic coupling between a membrane-spanning protein and the surrounding bilayer means that protein conformational changes may be associated with a reversible, local bilayer deformation. Lipid bilayers are elastic bodies, and the energetic cost of the bilayer deformation contributes to the total energetic cost of the protein conformational change. The energetics and kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel-bilayer hydrophobic interactions link a "conformational" change (the monomer<-->dimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (beta-octyl-glucoside, Genapol X-100, Triton X-100, and reduced Triton X-100) that make lipid bilayers less "stiff", as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer-protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein function.

Coronary calcium scoring is increasingly used as a screening test for coronary artery disease. Widespread agreement exists that coronary artery calcium (CAC) is a population marker for intimal atherosclerosis, However, the numerical significance of an individual's calcium score and what impact that score should have on future patient management is subject to disagreement. Questions also exist with regard to the interpretation of serial changes in CAC score. The answers to these questions heavily depend on an accurate and reproducible method of quantifying CAC. The purpose of this article is to review the alogrithms and techniques used in CAC quantification, and to identify those variables that may significantly affect its derivation.

In organic solvents gramicidin A (gA) occurs as a mixture of slowly interconverting double-stranded dimers. Membrane-spanning gA channels, in contrast, are almost exclusively single-stranded beta(6,3)-helical dimers. Based on spectroscopic evidence, it has previously been concluded that the conformational preference of gA in phospholipid bilayers varies as a function of the degree of unsaturation of the acyl chains. Double-stranded pi pi(5,6)-helical dimers predominate (over single-stranded beta(6,3)-helical dimers) in lipid bilayer membranes with polyunsaturated acyl chains. We therefore examined the characteristics of channels formed by gA in 1-palmitoyl-2-oleoylphosphatidylcholine/n-decane, 1,2-dioleoylphosphatidylcholine/n-decane, and 1,2-dilinoleoylphosphatidylcholine/n-decane bilayers. We did not observe long-lived channels that could be conducting double-stranded pi pi(5,6)-helical dimers in any of these different membrane environments. We conclude that the single-stranded beta(6,3)-helical dimer is the only conducting species in these bilayers. Somewhat surprisingly, the average channel duration and channel-forming potency of gA are increased in dilinoleoylphosphatidylcholine/n-decane bilayers compared to 1-palmitoyl-2-oleoylphosphatidylcholine/n-decane and dioleoylphosphatidylcholine/n-decane bilayers. To test for specific interactions between the aromatic side chains of gA and the acyl chains of the bilayer, we examined the properties of channels formed by gramicidin analogues in which the four tryptophan residues were replaced with naphthylalanine (gN), tyrosine (gT), and phenylalanine (gM). The results show that all of these analogue channels experience the same relative stabilization when going from dioleoylphosphatidylcholine to dilinoleoylphosphatidylcholine bilayers.