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Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted., (© 2024. The Author(s).)

Importance: Immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined., Objective: To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs., Design, Setting, and Participants: This retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line., Exposure: Developing an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs)., Main Outcomes and Measures: The primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS., Results: Among the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001)., Conclusions and Relevance: In this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

Study Objective: The purpose of this study is to rank the factors that are most and least important to patients with symptomatic uterine fibroids when considering surgical treatment options., Materials and Methods: Using a best worst scaling (BWS) preference elicitation approach, participants completed an online survey to rank factors associated with fibroid surgical treatments. Survey content was based on a literature review and included the following factors: symptom relief; surgical complications; repeat treatment; recovery time; cosmetic effects; risk of spreading undiagnosed cancer; sexual outcomes; maintenance of child-bearing; continuation of menses; unpredictable menses; and location of procedure. Participants completed 11 BWS tasks. For each task, we presented participants with a subset of 5 factors from the possible 11, and participants chose the most important and least important factor. Participants' responses were analyzed using conditional logistic regression to determine the relative importance of factors. Patient priorities were further explored via age and race., Results: 285 respondents with symptomatic uterine fibroids (69 physician-confirmed and 216 self-reported) who had not undergone prior surgical treatment completed the survey. Respondents were enrolled from two clinical sites (clinical site cohort) and an online consumer panel (panel cohort). Both cohorts identified symptom relief, cancer risk, repeat treatment and complications as the most important factors in selecting surgical treatment options and location of procedure, return to normal activities after surgery, and cosmetic effects like presence of a scar after the surgical treatment as the least important factors. Of note, younger women (≤ 40) placed greater importance on the ability to have children after the procedure., Conclusion: Information regarding the factors most and least important to patients with symptomatic uterine fibroids might inform development and regulatory evaluation of new technologies and procedures. Study results may be useful in efforts to develop a set of outcomes to include in future fibroids clinical studies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction/background: Immune checkpoint inhibitors (ICI) have revolutionized non-small cell lung cancer (NSCLC). We aimed to identify baseline characteristics, that are prognostic factors for overall survival (OS) in patients with NSCLC treated with ICI monotherapy, in order to derive the Lung Immune Therapy Evaluation (LITE) risk, a prognostic model., Materials and Methods: Multi-center observational cohort study of patients with advanced NSCLC that received ≥1 dose of ICI monotherapy. The training set (n=342) consisted of patients with NSCLC who received first line ICI. The test set (n=153) used for external validation was a discrete cohort of patients who received second line ICI. 20 candidate prognostic factors were examined. Penalized Cox regression was used for variable selection. Multiple imputation was used to address missingness., Results: Three baseline characteristics populated the final model: ECOG (0, 1 or ≥2), lactate dehydrogenase>upper limit of normal, and derived neutrophil to lymphocyte ratio ≥3. Patients were parsed into 3 risk groups; favorable (n=146, risk score 0-1), intermediate (n=101, risk score 2) and poor (n=95, risk score ≥3). The c-statistic of the training cohort was 0.702 and 0.694 after bootstrapping. The test cohort c-statistic was 0.664. The median OS for favorable, intermediate and poor LITE risk were; 28.3 months, 9.1 months and 2.1 months respectively. Improving LITE risk group was associated with improved OS, intermediate vs favorable HR 2.08 (95%CI 1.46-2.97, P < .001); poor vs favorable HR 5.21 (95%CI 3.69-7.34, P < .001)., Conclusion: A simple prognostic model, utilizing accessible clinical data, can discriminate survival outcomes in patients with advanced NSCLC., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status., Methods: Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life., Results: At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed., Conclusion: With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer.

Introduction: The expensive modern therapeutic regimens for advanced lung cancer (LC) stages have been recently approved. We evaluated whether low-dose computed tomography (LDCT) LC screening of high-risk Albertans is cost saving., Methods: We used a decision analytical modeling technique with a health system perspective and a time horizon of 3 years to compare benefits associated with reduced health service utilization (HSU) from earlier diagnosis to the costs of screening. Using patient-level data, HSU costs by stage of disease were estimated for patients with LC, including inpatient, outpatient, and physician services, and costs for prescription drugs and cancer treatments., Results: Of 101,000 people aged 55 to 74 years eligible for screening, an estimated 88,476 scans would be performed in Alberta in 3 years. Given LDCT sensitivity and specificity of 90.5% and 93.1%, respectively, we estimated that a stage shift toward earlier diagnosis would be expected whereby 43% more patients would be identified at stage 1 or 2 as compared with without screening. The estimated cost of screening is $35.6 million (M), whereas the stage shift associated with screening would avoid $42M in HSU costs. The net cost avoidance associated with screening is therefore $6.65M. The probability for the screening to be cost saving is estimated at 72%., Conclusions: This study has revealed that LDCT LC screening is likely to be cost saving in Alberta. Adoption of this program into the provincial health care system is worth considering provided constraints in the system related to surgical capacity and CT wait times could be addressed., (© 2022 The Authors.)

The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014-2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.

The multicenter, phase Ib CC-122-DLBCL-001 dose-expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m 2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [ n  = 27], FL [ n  = 41; 31 lenalidomide-naïve, 10 lenalidomide-treated]). Median age was 62 years (range, 33-84 years), and patients had received a median of 3 (range, 1-8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab-refractory at study entry and 10.0% were lenalidomide-refractory. The most common any-grade avadomide-related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide-related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide-naïve and -treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL., Competing Interests: Loretta J. Nastoupil received honoraria from ADC Therapeutics, Bayer, Celgene, a Bristol Myers Squibb Company, Epizyme, Genentech, Gilead, Janssen, MorphoSys, Novartis, Pfizer, and TG Therapeutics; and received research funding from Bristol Myers Squibb/Celgene, Epizyme, Genentech, Janssen, Novartis, and TG Therapeutics. John Kuruvilla received honoraria from Amgen, Antengene, AstraZeneca, Celgene, a Bristol Myers Squibb company Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics, and TG Therapeutics; served as a consultant or advisor for AbbVie, Bristol Myers Squibb, Gilead, Karyopharm, Merck, Roche, and Seattle Genetics; and received research funding from AstraZeneca, Janssen, Roche, and Merck. Julio C. Chavez served as a consultant or advisor for AstraZeneca, Bayer, Celgene, a Bristol Myers Squibb Company, Genentech, Karyopharm, Morphosys, Novartis, Verastem, and Pfizer; received research funding from Merck; and served on the speaker's bureau for Genentech and AstraZeneca. Fontanet Bijou served as consultant or advisor for Bristol Myers Squibb and AbbVie. Armando Santoro served as consultant or advisor for Arqule, Bayer, Bristol Myers Squibb, Eisai, Gilead, Merck Sharp & Dohme, Pfizer, Sanofi, and Servier, and served on speaker's bureau for AbbVie, Amgen, Arqule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, a Bristol Myers Squibb Company, Eisai, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda. Ian W. Flinn served as consultant or advisor for AbbVie, AstraZeneca, BeiGene, Genentech, Gilead Sciences, Great Point Partners, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, and Yingli Pharmaceuticals; and received research funding from AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, a Bristol Myers Squibb Company, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty‐Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, and Verastem. Vaishalee P. Kenkre received research funding from AbbVie, Celgene, a Bristol Myers Squibb Company, MEI Pharma, and Novartis. P. Corradini received honoraria from AbbVie, ADC Therapeutics, Amgen, Celgene, a Bristol Myers Squibb Company, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin, Novartis, Roche, Sanofi, and Takeda; served as consultant or advisor for AbbVie, ADC Therapeutics, Amgen, Celgene, a Bristol Myers Squibb Company, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin, Novartis, Roche, Sanofi, and Takeda; and received travel funding from Novartis, Janssen, Celgene, a Bristol Myers Squibb Company, Bristol Myers Squibb, Takeda, Gilead, Amgen, and AbbVie. Iris Isufi served as a consultant or advisor for AstraZeneca, Bayer, Celgene, a Bristol Myers Squibb Company, Epizyme, and Kite. David J. Andorsky served as consultant or advisor for AbbVie and Bristol Myers Squibb and received research funding from AstraZeneca, Celgene, a Bristol Myers Squibb company, and Epizyme. Daniel Greenwald served as consultant or advisor for AstraZeneca and served on the speaker's bureau for Genentech and Jazz. R. Sangha received honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli‐Lilly, Merck, Mylan, Pfizer, Roche/Genentech, Sanofi, Takeda, and Teva, and served as consultant or advisor for AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli‐Lilly, Merck, Roche/Genentech, Sanofi, Takeda, and Teva. Patrick Hagner, Nian Gong, Shailaja Uttamsingh, and Michael Pourdehnad are employed by and have equity ownership with Bristol Myers Squibb. Frank Shen, Yan Li, and Juergen Dobmeyer are employed by Bristol Myers Squibb. Vincent Ribrag received honoraria from AstraZeneca, Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, and Roche; served as a consultant or advisor for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; received research funding from argenX, Astex, and GlaxoSmithKline; and received travel funding from AstraZeneca. No disclosures were reported by the other authors., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Sepsis-induced coagulopathy (SIC) scoring and D-dimer can be used to recognize COVID-19-induced coagulopathy, but the utility of these is largely unknown in the peripartum setting and leaves anticoagulation guidance unclear. We present the case of a critically ill postpartum patient with COVID-19 infection. This patient presented with clinical signs of COVID-19 infection and developed acute respiratory failure requiring invasive mechanical ventilation and subsequent cesarean delivery at 34 weeks. She initially improved postoperatively but deteriorated after postoperative day 5. She was found to have a very elevated D-dimer of 58 μg/mL and anticoagulation was escalated to full dosing. She required prolonged mechanical ventilation and deceased after developing gram-positive cocci bacteremia. This case demonstrates that recognition and management of COVID-19-associated coagulopathy can be confusing in the peripartum period and studies are needed to validate D-dimer and SIC scoring in this population of patients., Competing Interests: Conflict of Interest Dr Roopina Sangha declares the following conflict of interest: received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from John Peter Smith Hospital, Fort Worth, Texas., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Introduction: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., Methods: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs)., Results: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population., Conclusions: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design., Competing Interests: Vincent Ribrag received honoraria from Gilead, Infinity, ArgenX, Merck Sharp & Dohme, Bristol Myers Squibb, Epizyme, Nanostring, Incyte, Roche, and AstraZeneca; served as a consultant or advisor for Servier; and received research funding from ArgenX. Julio C. Chavez served as a consultant or advisor for Novartis, Celgene, a Bristol‐Myers Squibb Company, Bayer, Morphosys, Karyopharm, AstraZeneca, Verastem, Pfizer, and Genentech; received research funding from Merck; and served on the speaker's bureau for Genentech and AstraZeneca. Jason Kaplan served as a consultant or advisor for and received research funding from Seattle Genetics, and received travel funding from Curis. Jason C. Chandler served as a consultant or advisor for Janssen and Axess Oncology. Armando Santoro served as a consultant or advisor for ArQule, Sanofi, Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and Merck Sharpe and Dohme; and served on the speaker's bureau for Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, a Bristol‐Myers Squibb company, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, and Merck Sharpe and Dohme. Paolo Corradini received honoraria from Janssen, Gilead, AbbVie, Takeda, Roche, Novartis, and Celgene, a Bristol‐Myers Squibb Company; served as a consultant or advisor for Novartis, Janssen, Celgene, a Bristol‐Myers Squibb company, and Gilead; received travel funding from Novartis, AbbVie, and Gilead; and served on the speaker's bureau for Novartis. Ian W. Flinn received research funding from AbbVie, Acerta, Agios, ArQule, BeiGene, Calithera, Celgene, a Bristol‐Myers Squibb Company, Constellation, Curis, Forma, Forty‐Seven Inc, Genentech, Gilead, Incyte, Infinity, Janssen, Karyopharm, Kite, Merck, Novartis, Pfizer, Portola, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, and Verastem. Ranjana Advani served as a consultant or advisor for AstraZeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Genentech/Roche, Gilead Kite Pharma, Kyowa, Seattle Genetics, and Takeda; and received research funding from Agensys, Celgene, a Bristol‐Myers Squibb company, Forty‐Seven Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, and Seattle Genetics. Philippe A. Cassier received honoraria from Amgen, AstraZeneca, Blueprint Medicines, Novartis, and Roche/Genentech; received research funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, GlaxoSmithKline, Innate Pharma, Janssen, Lilly, Loxo, Merck Serono, Merck Sharp & Dohme, Novartis, Plexxikon, Roche/Genentech, Taiho Pharmaceutical, Toray Industries, and Transgene; and received travel funding from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Netris Pharma, Novartis, and Roche. Randeep Sangha received honoraria from Pfizer, Boehringer Ingelheim, AstraZeneca, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, and Takeda; served as a consultant or advisor for Boehringer Ingelheim, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, Takeda, and Teva; and received research funding from Bristol Myers Squibb, AbbVie, Takeda, Pharmacyclics, Morphosys, Roche, Merck, Celgene, a Bristol‐Myers Squibb company, and Novartis. Iris Isufi served as a consultant or advisor for AstraZeneca, Celgene, a Bristol‐Myers Squibb company/Jazz Pharmaceuticals, and Kite Pharma; and received travel funding from Celgene, a Bristol‐Myers Squibb company, and Kite Pharma. Shailaja Uttamsingh, Patrick R. Hagner, Anita K. Gandhi, and Michael Pourdehnad are employed by and have equity ownership with Bristol Myers Squibb. Harald Haeske has equity ownership with Pieris AG and served as a consultant or advisor for Celgene, a Bristol‐Myers Squibb company, and 4SC AG. Kristen Hege is employed by and holds patents with Bristol Myers Squibb; has equity ownership with Bristol Myers Squibb, Arcus Biosciences, and Mersana Therapeutics; and served on the Board of Directors for Arcus Biosciences, Mersana Therapeutics, and the Society for Immunotherapy of Cancer. John Kuruvilla received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, Gilead, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, and Seattle Genetics; and served as a consultant or advisor for AbbVie, Bristol Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche, and Seattle Genetics; and received research funding from Janssen and Roche. All other authors declare no conflict of interest., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: This study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK -rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada., Methods: Demographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK -rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis., Results: A total of 92 patients with ALK -rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK -rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK -wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement ( ALK -rearranged versus ALK -wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p  = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p  = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p  = 0.04)., Conclusions: Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK -rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer., (© 2021 The Authors.)

Background: Intracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism., Methods: This prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks., Results: Amongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes., Conclusions: Despite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes., Trial Registration: ClinicalTrials.gov: NCT02121028., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This study sought to identify patterns of self-reported regret after hysterectomy., Methods: Women undergoing hysterectomy for a benign indication were recruited in the 2 weeks prior to surgery. Women reported demographics and completed validated questionnaires (Decisional Regret Scale, Patient Health Questionnaire-9, Decisional Conflict Scale, and the Comprehensive Score for Financial Toxicity) up to 7 times over the first year postsurgery. Medical records were reviewed for clinical and operative details. Latent class growth mixture models were applied to the repeated regret scores to identify patterns after hysterectomy. Clinical and other participant characteristics were compared across the classes., Results: Three latent classes were identified among the 459 participants (422 of whom completed questionnaires at 12 months): "High Regret" (7.4%), women with a high regret score at baseline that did not improve over time; "Decreasing Regret" (13.3%), women with high baseline levels of regret but whose regret scores improved over time; and "Least Regret" (79.3%), women with the lowest baseline regret scores that remained low after surgery. These classes did not vary with respect to indication for surgery, clinical characteristics, age, or body mass index. Disproportionately more African American women (adjusted odds ratio: 1.99, 95% CI: 1.01-3.9) were in the "Decreasing Regret" versus "Least Regret" classes. Baseline satisfaction varied between the classes, with the "Least Regret" group having higher baseline satisfaction with their decision. Women with "Decreasing Regret" reported worse financial toxicity associated with surgery versus women in the "Least Regret" class (adjusted odds ratio: 0.95, 95% CI: 0.92-0.99)., Conclusions: For some women, decisional regret may worsen after hysterectomy. More often, initial regret lessens over time. Future studies that identify factors strongly associated with self-reported regret could lead to improved counseling about postsurgical expectations., Competing Interests: Conflicts of Interest None., (© 2020 Aurora Health Care, Inc.)

Introduction: We aimed to describe the physical and cognitive health of patients with differing levels of post-stroke disability, as defined by modified Rankin Scale (mRS) scores. We also compared cross-sectional correlations between the mRS and the Quality of Life in Neurological Disorders (Neuro-QoL) T-scores to longitudinal correlations of change estimates from each measure., Methods: Mean Neuro-QoL T-scores representing mobility, dexterity, executive function, and cognitive concerns were compared among mRS subgroups. Fixed-effects regression models with robust standard errors estimated correlations among mRS and Neuro-QoL domain scores and correlations among longitudinal change estimates. These change estimates were then compared to distribution-based estimates of minimal clinically important differences., Results: Seven hundred forty-five patients with ischemic stroke (79%) or transient ischemic attack (21%) were enrolled in this longitudinal observational study of post-stroke outcomes. Larger differences in cognitive function were observed in the severe mRS groups (ie, 4-5) while larger differences in physical function were observed in the mild-moderate mRS groups (ie, 0-2). Cross-sectional correlations among mRS and Neuro-QoL T-scores were high (r = 0.61-0.83), but correlations among longitudinal change estimates were weak (r = 0.14-0.44)., Conclusions: Findings from this study undermine the validity and utility of the mRS as an outcome measure in longitudinal studies in ischemic stroke patients. Nevertheless, strong correlations indicate that the mRS score, obtained with a single interview, is efficient at capturing important differences in patient-reported quality of life, and is useful for identifying meaningful cross-sectional differences among clinical subgroups., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Rationale: Intracranial atherosclerotic disease (ICAD) is the most common cause of ischemic stroke with the highest rate of recurrence, despite aggressive medical management. Diverse mechanisms may be responsible for ICAD-related cerebral ischemia, with potential therapeutic implications. Here we present the rationale, design and methods of the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study. The aim of MyRIAD is to determine the mechanisms of stroke in ICAD through physiologic imaging biomarkers that evaluate impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, artery to artery embolism, and their interaction., Methods and Design: This is a prospective observational study of patients with recently symptomatic (<21 days) ICAD with 50-99% stenosis treated medically and monitored for up to 1 year. An estimated 110 participants are recruited at 10 sites to identify the association between the presence of each mechanism of ischemia and recurrent stroke. The primary outcome is ischemic stroke in the territory of the symptomatic artery. Secondary outcomes include new cerebral infarction on MRI at 6-8 weeks and recurrent TIA in the territory of the symptomatic artery., Discussion: MyRIAD is positioned to define the role of specific mechanisms of recurrent ischemia in patients with symptomatic ICAD. This knowledge will allow the development and implementation of effective and specific treatments for this condition., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Approximately 3-7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase ( ALK ) rearrangement. Crizotinib, ceritinib, alectinib, and brigatinib are active ALK inhibitors (ALKi) used to treat this oncogene-driven subset of NSCLC. Resistance occurs with time to ALKi and new therapeutics are being developed. Lorlatinib is an efficacious third-generation ALKi with an ability to overcome resistance mutations that develop with first- or second-generation ALKi., Areas Covered: Herein, the authors review the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of lorlatinib and provide their future perspectives on this drug., Expert Commentary: Lorlatinib is a potent ALK and ROS-1 inhibitor that also has activity against many acquired ALK resistance mutations. Clinical trials show the robust systemic and intracranial anti-tumor activity of lorlatinib in ALK rearranged advanced NSCLC. Adverse events of lorlatinib are unique and manageable. These include hypocholesteremia, hypertriglyceridemia, edema, cognitive effects, weight gain, and diarrhea. Loratinib will play an increasing role in the management of ALK -rearranged NSCLC with the optimal sequencing of ALKi undergoing further research.

Objective: Despite high rates of prenatal insomnia, efficacious treatment options for this population are quite limited. Early evidence from randomized controlled trials (RCTs) support the efficacy of face-to-face cognitive-behavioral therapy for insomnia (CBTI) for prenatal insomnia. Yet, as many patients are unable to access this specialist-driven care, a critical need exists to increase its accessibility. This RCT examined the efficacy internet-based digital CBTI in pregnant women with insomnia., Methods: Single-site RCT. A total of 91 pregnant women (29.03 ± 4.16 years) nearing/entering the third trimester who screened positive for clinical insomnia on the Insomnia Severity Index (ISI) were randomized to digital CBTI or digital sleep education control. The ISI, Pittsburgh Sleep Quality Index (PSQI), Edinburgh Postnatal Depression Scale (EPDS), and Pre-Sleep Arousal Scale's Cognitive factor (PSAS-C) served as study outcomes, which were collected before treatment and after treatment during pregnancy, then six weeks after childbirth., Results: From pre to posttreatment, CBTI patients reported reductions in ISI (-4.91 points, p < 0.001) and PSQI (-2.98 points, p < 0.001) and increases in nightly sleep duration by 32 min (p = 0.008). Sleep symptoms did not change during pregnancy in the control group. After childbirth, CBTI patients, relative to controls, slept longer by 40 min per night (p = 0.01) and reported better sleep maintenance. No pre or postnatal treatment effects on depression or cognitive arousal were observed., Conclusions: Digital CBTI improves sleep quality and sleep duration during pregnancy and after childbirth. To better optimize outcomes, CBTI should be tailored to meet the changing needs of women as the progress through pregnancy and early parenting. NAME: Insomnia and Rumination in Late Pregnancy and the Risk for Postpartum Depression. URL: clinicaltrials.gov. Registration: NCT03596879., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4., Methods: EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective., Results: Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease., Conclusion: Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

Objectives: Treatment of advanced NSCLC (aNSCLC) is rapidly evolving, as new targeted and immuno-oncology (I-O) treatments become available. The iTEN model was developed to predict the cost and survival benefits of changing aNSCLC treatment patterns from a Canadian healthcare system perspective. This report describes iTEN model development and validation., Materials & Methods: A discrete event patient simulation of aNSCLC was developed. A modified Delphi process using Canadian clinical experts informed the development of treatment sequences that included commonly used, Health Canada approved treatments of aNSCLC. Treatment efficacy and the timing of progression and death were estimated from published Kaplan-Meier progression free and overall survival data. Costs (2018 CDN$) included were: drug acquisition and administration, imaging, monitoring, adverse events, physician visits, best supportive care, and end-of-life., Results and Conclusion: Clinical validity of the iTEN model was assessed by comparing model survival predictions to published real-world evidence (RWE). Four RWE studies that reported the overall survival of patients treated with a broad sampling of common aNSCLC treatment patterns were used for validation. The validation coefficient of determination was R 2  = 0.95, with the model generally producing estimates that were neither optimistic nor conservative. The model estimated that current Canadian practice patterns yield a median survival of almost 13 months, a five-year survival rate of 3% and a life-time per-treated-patient cost of $110,806. Cost and survival estimates are presented and were found to vary by aNSCLC subtype. In conclusion, the iTEN model is a reliable tool for forecasting the impact on cost and survival of new treatments for aNSCLC., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Sleep problems and depression are highly prevalent in pregnancy. Nocturnal rumination has been linked to insomnia and depression in non-pregnant samples, but remains poorly characterized in pregnancy. This study explored relationships of depression and suicidal ideation with insomnia, short sleep, and nocturnal rumination in mid-to-late pregnancy., Methods: In this study, 267 pregnant women were recruited from obstetric clinics and completed online surveys on sleep, depression, and nocturnal rumination., Results: Over half (58.4%) of the sample reported clinical insomnia on the Insomnia Severity Index, 16.1% screened positive for major depression on the Edinburgh Postnatal Depression Scale (EPDS), and 10.1% endorsed suicidal ideation. Nocturnal rumination was more robustly associated with sleep onset difficulties than with sleep maintenance issues. Depressed women were at greater odds of sleep onset insomnia (OR = 2.80), sleep maintenance insomnia (OR = 6.50), high nocturnal rumination (OR = 6.50), and negative perinatal-focused rumination (OR = 2.70). Suicidal ideation was associated with depression (OR = 3.64) and negative perinatal-focused rumination (OR = 3.50). A four-group comparison based on insomnia status and high/low rumination revealed that pregnant women with insomnia and high rumination endorsed higher rates of depression (35.6%) and suicidal ideation (17.3%) than good-sleeping women with low rumination (1.2% depressed, 4.9% suicidal). Women with insomnia alone (depression: 3.9%, suicidal: 5.9%) or high rumination alone (depression: 10.7%, suicidal: 7.1%) did not differ from good-sleeping women with low rumination., Conclusions: High rumination and insomnia are highly common in mid-to-late pregnancy and both are associated with depression and suicidal ideation. Depression and suicidal ideation are most prevalent in pregnant women with both insomnia and high rumination. CLINICALTRIALS., Gov Identifier: NCT03596879., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To characterize sleep habits and parameters among women in mid-to-late pregnancy and to identify disparities associated with poverty, race, and obesity., Design: Cross-sectional., Setting: Large multi-site health system in Metro Detroit., Participants: A total of 267 pregnant women (27.3% non-Hispanic black; gestational age: 27.99±1.20 weeks) completed online surveys on sleep quality, insomnia symptoms, sleep aid use, signs/symptoms of sleep-disordered breathing, and sociodemographics. Body mass index (BMI) and patient insurance were derived from medical records., Results: As high as 76.2% of the women reported global sleep disturbance, 30.6% endorsed snoring, 24.3% sleep <6 hrs/night, and over half screened positive for clinical insomnia. Yet, only 3.4% of the women reported an insomnia diagnosis and 3.0% reported a sleep apnea diagnosis. In unadjusted models, poverty, Medicaid coverage, self-identifying as black, and obesity before and during pregnancy (BMI ≥ 35) were associated with a wide range of sleep problems. However, adjusted models revealed specificity. Poverty was uniquely related to increased insomnia symptoms and trouble sleeping due to bad dreams. Obesity before pregnancy was related to poor sleep quality, snoring, sleep aids, and short sleep. Black women reported shorter sleep duration than white women but differed on no other sleep parameters., Conclusion: Clinical signs of insomnia and sleep-disordered breathing are common in mid-to-late pregnancy, but most cases go undetected. Problematic sleep disproportionately affects women in poverty, who self-identify as black, and who are obese before pregnancy. Poverty-related sleep issues are linked to insomnia, obesity-related disparities center on sleep-related breathing and medication use, and racial disparities relate to short sleep., Competing Interests: Dr. Kalmbach has received research support from Merck & Co. Dr. Roth has received research support from Aventis, Cephalon, Glaxo Smith Kline, Neurocrine, Pfizer, Sanofi, Schering-Plough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth and Xenoport and has acted as a consultant for Abbott, Acadia, Acoglix, Actelion, Alchemers, Alza, Ancil, Arena, Astra Zeneca, Aventis, AVER, BMS, BTG, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, Glaxo Smith Kline, Hypnion, Impax, Intec, Intra-Cellular, Jazz, Johnson & Johnson, King, Lundbeck, McNeil, Medici Nova, Merck & Co., Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Prestwick, Procter-Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering-Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanuchi, and Xenoport. Dr. Cheng has received research support from Harmony Biosciences. Dr. Drake has received research support from Merck & Co., Eisai Co., Aladdin Dreamer, Jazz, Actelion, and Teva, and has served on speakers bureau for Merck & Co. The authors declare no other financial or non-financial interests exist in this work., (© 2019 Kalmbach et al.)

Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib. Another oral kinase inhibitor, regorafenib, is not considered standard of care treatment for differentiated thyroid cancer. The chemical structures of regorafenib and sorafenib differ by a single fluorine atom. Given the significant improvement in progression-free survival (PFS) of sorafenib compared to placebo demonstrated in the phase 3 DECISION trial, we report on a patient with iodine-refractory follicular thyroid cancer treated with regorafenib as part of a phase 1 clinical trial. A 75 year old woman was diagnosed with follicular thyroid carcinoma in 2006 and initiated on treatment with regorafenib in 2011. She has completed 76 cycles with stable disease and pulmonary metastases 34% smaller than baseline., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2019 by S. Karger AG, Basel.)

Background: Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac function, symptoms, and clinical outcomes., Methods: Treatment naïve metastatic non-small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin-based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function [LV ejection fraction, global longitudinal strain (GLS), diastolic function], computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival., Results: During 112 ± 6 days, the median change in LVM was -8.9% [95% confidence interval (95% CI) -10.8 to -4.8, P < 0.001]. Quartiles of LVM loss were -20.1%, -12.9%, -4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle [odds ratio (OR) = 4.5, 95% CI: 1.4-14.8, P=0.01] and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7-36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9-22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C-reactive protein (P=0.008), high sensitivity troponin T (hs-TnT) (P=0.03), and galectin-3 (P=0.02) increased over time, while N-terminal pro B-type natriuretic peptide and hs-cTnI did not change over time. C-reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2-46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4-153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9-22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4-35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3-18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05)., Conclusions: Intense LVM atrophy is associated with non-small cell lung cancer-induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study., (© 2019 The Authors Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Diffuse large B cell lymphoma (dlbcl) is an aggressive non-Hodgkin lymphoma, accounting for approximately 30% of lymphoma cases in Canada. Although most patients will achieve a cure, up to 40% will experience refractory disease after initial treatment, or relapse after a period of remission. In eligible patients, salvage therapy followed by high-dose therapy and autologous stem-cell transplantation (asct) is the standard of care. However, many patients are transplant-ineligible, and more than half of those undergoing asct will subsequently relapse. For those patients, outcomes are dismal, and novel treatment approaches are a critical unmet need. In this paper, we present available data about emerging treatment approaches in the latter setting and provide a perspective about the potential use of those approaches in Canada., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: Medical writing support provided by Anna Christofides of impact Medicom Inc. was funded by Hoffmann–La Roche Canada Inc. SA has received honoraria for consulting purposes from Janssen, Gilead, and Hoffmann–La Roche. DM has received honoraria for consulting purposes from Hoffmann–La Roche/Genentech, AbbVie, Amgen, AstraZeneca, Celgene, Gilead, Janssen, Lundbeck, Merck, and Seattle Genetics. AP has received honoraria for consulting purposes from AstraZeneca and AbbVie. RS has received honoraria for consulting purposes from Pfizer, Boehringer Ingelheim, AstraZeneca, Hoffmann–La Roche/Genentech, Lundbeck, Eli Lilly, Bristol–Myers Squibb, Merck, AbbVie, Novartis, and Takeda. BAM is an employee of Hoffmann–La Roche Canada Inc. LHS has received honoraria for consulting purposes from Hoffmann–La Roche/Genentech, AbbVie, Amgen, Apobiologix, AstraZeneca, Acerta Pharma, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Therapeutics, and Versatem Oncology. She has also received research funding from Hoffmann–La Roche/Genentech. PS has no conflicts to disclose.

Background: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase)., Aim: To evaluate patient-reported outcomes (PROs) in this population., Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses., Results: In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures., Conclusion: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB., Clinical Trial Registration: NCT02477826., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To assess the cost-effectiveness in Canada of atezolizumab compared with docetaxel or nivolumab for the treatment of advanced NSCLC after first-line platinum-doublet chemotherapy. Materials and methods: A three-state partitioned-survival model was developed. Clinical inputs were obtained from the phase III OAK trial comparing atezolizumab with docetaxel in patients with advanced NSCLC who progressed after first-line platinum-doublet chemotherapy. Overall survival (OS) and progression-free survival (PFS) were extrapolated beyond the trial period using parametric models. A cure model assuming a 1% cure fraction was fitted to the OS data for atezolizumab. Outcomes for nivolumab were informed by a network meta-analysis (NMA) vs atezolizumab. Resource use and costs were informed by clinical expert opinion and published Canadian sources. Utility values were obtained from the OAK trial. The perspective of the analysis was that of the Canadian publicly-funded healthcare system. The base case time horizon was 10 years, and the discount rate was 1.5% annually for both costs and effects. Scenario analyses were performed to test the robustness of the results and all analyses were performed probabilistically. Results: Atezolizumab demonstrated a quality-adjusted life-year (QALY) gain of 0.60 compared with docetaxel at an incremental cost of $85,073, resulting in an incremental cost-effectiveness ratio (ICER) of $142,074/QALY. Atezolizumab dominated nivolumab (regardless of dosing regimen), based on modest differences in both QALYs and costs. Docetaxel was most likely to be cost effective at willingness-to-pay (WTP) thresholds below $125,000/QALY gained, while atezolizumab was most likely to be cost effective beyond this WTP threshold. In most scenario analyses, the results remained robust to changes in parameters. A reduced time horizon and alternative approaches to the NMA had the greatest impact on cost-effectiveness results. Conclusion: Atezolizumab represents a cost-effective therapeutic option in Canada for the treatment of patients with advanced NSCLC who progress after first-line platinum doublet chemotherapy.

Importance: Patient-centered care integrates the highest clinical standards with patient preferences surrounding their treatment. Increasing focus is being placed on the identification of patient-centered outcomes to optimize the impact of medical treatments on patient quality of life, as defined by patients themselves., Objective: This article will review the central concepts of patient-centered outcomes in benign gynecologic surgery. This expert review will serve as a practical guide for surgeons to incorporate patient preferences into shared surgical decision making., Evidence Acquisition: The current literature is examined, defining those outcomes identified by women undergoing gynecologic procedures as the most important factors in their decision making. Available literature on these patient-identified priorities is then reviewed with respect to gynecologic surgery in the preoperative, intraoperative, and postoperative periods., Results: Each section of the article concludes with Clinical Pearls, where practical tools and key elements are summarized to assist providers with incorporating these concepts into practice., Conclusions and Relevance: Many key outcomes have been identified by women undergoing benign gynecologic surgery in their decision-making process. Patient counseling should address clinically appropriate treatment modalities and include an exploration of patient expectations and preferences around nonclinical outcomes as well. This shared decision-making model will result in improved satisfaction with outcomes.

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests outside the submitted work: VH is an employee of Exactis Innovation; RF is the ceo of Exactis Innovation; GB has received research funding from several pharmaceutical companies and is the cmo of Exactis Innovation; PKC has received fees as an advisory board member for Bristol–Myers Squibb, Merck, AstraZeneca, Pfizer, and Roche; HLM has received fees as an advisory board member for Merck, Spectrums, Syndax Pharmaceuticals, obi Pharma, Calithera, Roche, Lilly, Peregrine, TapImmune, Amgen, Puma, Pfizer, and Immunomedics, and has received research funding from Bristol–Myers Squibb, MedImmune, Ziopharm, Eli Lilly, and Merck; TMP has received advisory board member fees from Bristol–Myers Squibb, Merck, and Incyte, and a grant from Roche; RS has received honoraria from Pfizer, and honoraria or advisory board fees from Boehringer Ingelheim, AstraZeneca, Roche, Lundbeck, Bristol–Myers Squibb, Merck, AbbVie, and Takeda; MFS has received honoraria from Amgen; JS is a permanent member of the scientific advisory board of Surface Oncology and owns stock in Surface Oncology; DJS has received honoraria or consulting or advisory board fees from Roche, Boehringer Ingelheim, Novartis, Merck, AstraZeneca, Bristol–Myers Squibb, and Exactis, and scientific writing or clinical trials support from Boehringer Ingelheim, AstraZeneca, Novartis, Bristol–Myers Squibb, and Celgene; SV has received fees as an advisory board member for Amgen, Lilly, AstraZeneca, Novartis, Pfizer, and Roche, and is the co-founder and medical director of OncologyEducation.com (uncompensated). BM, DM, and SSS have no conflicts of interest to disclose.

Purpose: Currently, there is no approved therapy for cancer cachexia. According to European and American regulatory agencies, physical function improvements would be approvable co-primary endpoints of new anti-cachexia medications. As physical functioning is in part dependent on cardiac functioning, we aimed to explore the cardiac status of a group of patients meeting current criteria for inclusion in cachexia clinical trials., Methods: Seventy treatment-naive patients with metastatic NSCLC [36 (51.4%) male; 96% ECOG 0-1; eligible for carboplatin-based therapy and meeting eligibility criteria for cachexia clinical trials] were recruited before the start of first-line carboplatin-based chemotherapy. Patients were evaluated by echocardiography, electrocardiography, and scales for fatigue and dyspnea. Computed tomography cross-sectional images were utilized for body composition analysis., Results: In 9/70 patients (12.8%), echocardiography allowed discovery of clinically relevant cardiac disorders [seven patients with left ventricular ejection fraction (LVEF) 32%-47%; one patient with severe right ventricular dilation and severe pulmonary hypertension and one patient with severe pericardial effusion warranted hospitalization and drainage]. Another 10/70 (14.3%) patients had diastolic dysfunction with preserved LVEF. The cardiac conditions were associated with aggravated fatigue (p < 0.05), dyspnea (p < 0.05), and anemia (p = 0.06). Five out of seven patients with LVEF < 50% were sarcopenic and one was borderline sarcopenic., Conclusion: Baseline cardiac status of the metastatic NSCLC patients adds potential heterogeneity for anti-cachexia clinical trials. Detailed cardiac screening data might be useful for inclusion/exclusion criteria, randomization, and post hoc analysis.

Purpose: Previous reports indicate many women may not have a firm grasp on likely outcomes of different hysterectomy procedures. This study aimed to assess women's self-reported expectations of how they think their anatomy will change after hysterectomy., Methods: Women scheduled for hysterectomy at a tertiary care hospital, for non-oncological reasons, reported their planned procedure type and the organs they understood would be removed 2 weeks prior to surgery. Patient reports and electronic medical records were reviewed, and kappa statistics (κ) were calculated to assess agreement for all women and within subgroups., Results: Most of the 456 study participants (mean age: 48.02 ± 8.29 years) were either white/Caucasian (n=238, 52.2%) or African American (n=196, 43.0%). Among the 145 participants who reported a partial hysterectomy, 130 (89.7%) women indicated that their uterus would be removed and 52 (35.9%) reported that their cervix would be removed. Of those whose response was total hysterectomy (n=228), 208 (91.2%) participants reported their uterus would be removed and 143 (62.7%) reported their cervix would be removed. Among 144 women reporting a planned partial hysterectomy, only 15 (10.4%, κ=0.05) had a partial hysterectomy recorded in the electronic medical record. Among the 228 women who reported a planned total hysterectomy, 6.1% (κ=0.05) had a different procedure. While 125 participants reported planned ovary removal, only 93 (74.4%, κ=0.55) had an oophorectomy. Similarly, 290 participants reported planned fallopian tube removal, with 276 (95.2%, κ=0.06) having a salpingectomy., Conclusions: A considerable proportion of women undergoing hysterectomy do not accurately report the organs that are planned be removed during their hysterectomy. This work demonstrates the need to improve patient understanding of their clinical care and its implications., Competing Interests: Conflicts of Interest None.

Importance: With the increase in patients who identify as transgender, it is crucial that gynecologists are culturally and clinically competent in understanding their unique needs., Objective: The aim of this study was to identify the key gynecologic issues facing transgender patients and develop an overarching framework of tools needed to address these issues., Evidence Acquisition: A review of the existing literature was undertaken to address the key clinical aspects of care., Results: Various aspects of the gynecologic care of transgender patients, including health maintenance and cancer screening examinations, hormone replacement therapy, hysterectomy and salpingo-oophorectomy, and referral and collaboration with the patient's care team, are outlined., Conclusions and Relevance: Transgender patients are more likely to be engaged and seek care if their identity and their needs are understood. While many aspects of transgender health care follow standard practices, there are significant and important differences, including gender-affirming therapies. This article aims to give gynecologists the necessary tools to partner in the care of transgender patients.

Background In patients with mild ischemic stroke, small but eloquent infarcts may have devastating effects, particularly on health-related quality of life. Aim This study investigates the association between acute infarct location and three-month health-related quality of life in patients with mild ischemic stroke. Methods We evaluated consecutively enrolled patients from a single center between August 2012 and July 2013. Our primary outcome at three months was impairment in any health-related quality of life domain (upper extremity, lower extremity, executive function, and general concerns) defined by a T-score <45. We analyzed the association between acute infarct locations and impaired health-related quality of life at three months in univariate and multivariable analysis. Results Among 229 patients (mean age 64.9 years, 55% male, 29.7% black, and median initial NIHSS score 1), impaired health-related quality of life was noted in 84 (36.2%) patients at three months. In univariate analysis, patients with subcortical infarcts (56.0% vs. 39.3%, p = 0.02) and brainstem infarcts (21.4% vs. 10.3%, p = 0.02) were more likely to have impaired health-related quality of life. In multivariable analysis, patients with subcortical and/or brainstem infarcts had increased odds of impaired health-related quality of life (adjusted OR 2.54, 95% CI 1.29-5.01, p = 0.01). Conclusions After mild ischemic stroke, subcortical and brainstem infarct locations predict impairment in health-related quality of life.