Lung Cancer in Women: The Past, Present, and Future.

Lung cancer is the leading cause of cancer death for women in multiple countries including the United States. Women are exposed to unique risk factors that remain largely understudied such as indoor pollution, second-hand tobacco exposure, biological differences, gender differences in tolerability and response to therapy in lung cancer, and societal gender roles, that create distinct survivorship needs. Women continue to lack representation in lung cancer clinical trials and are typically treated with data generated from majority male patient study populations, which may be inappropriate to extrapolate and generalize to females. Current lung cancer treatment and screening guidelines do not incorporate sex-specific differences and physicians also often do not account for gender differences when choosing treatments or discussing survivorship needs. To best provide targeted treatment approaches, greater representation of women in lung cancer clinical trials and further research is necessary. Clinicians should understand the unique factors and consequences associated with lung cancer in women; thus, a holistic approach that acknowledges environmental and societal factors is necessary.

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload.

Antibody-drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components-an antibody, a linker molecule, and a cytotoxic agent ("payload"), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs' effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

Role of Neoadjuvant Immune Checkpoint Inhibitors in Resectable Non-Small Cell Lung Cancer.

The neoadjuvant use of immune checkpoint inhibitors (ICI) in resectable non-small cell lung cancer (NSCLC) is being increasingly adopted, but questions about the most appropriate applications remain. Although patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy or targeted therapies +/- radiotherapy, they still have a high risk of recurrence and death. In recent years, immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1 and anti-CTLA-4) have provided a new and effective therapeutic strategy for the treatment of advanced NSCLC. Therefore, it is possible that ICIs for early-stage NSCLC may follow the pattern established in metastatic disease. Currently, there are several ongoing trials to determine the efficacy in the neoadjuvant setting for patients with local or regional disease. To date, only nivolumab in combination with chemotherapy has been approved by the U.S. FDA in the preoperative setting, but data continue to evolve rapidly, and treatment guidelines need to be determined. In this article, we review the current preclinical and clinical evidence on neoadjuvant ICIs alone and combination in the treatment of early-stage NSCLC.

Race/Ethnicity and Gender Representation in Hematology and Oncology Editorial Boards: What is the State of Diversity?

INTRODUCTION: Women and underrepresented groups in medicine hold few academic leadership positions in the field of hematology/oncology. In this study, we assessed gender and race/ethnicity representation in editorial board positions in hematology/oncology journals. MATERIALS AND METHODS: Editorial leadership board members from 60 major journals in hematology and oncology were reviewed; 54 journals were included in the final analysis. Gender and race/ethnicity were determined based on publicly available data for Editor-in-Chief (EiC) and Second-in-Command (SiC) (including deputy, senior, or associate editors). Descriptive statistics and chi-squared were estimated. In the second phase of the study, editors were emailed a 4-item survey to self-identify their demographics. RESULTS: Out of 793 editorial board members, 72.6% were men and 27.4% were women. Editorial leadership were non-Hispanic white (71.1%) with Asian editorial board members representing the second largest majority at 22.5%. Women comprised only 15.9% of the EiC positions (90% White and 10% Asian). Women were about half as likely to be in the EiC position compared with men [pOR 0.47 (95% CI, 0.23-0.95, P = .03)]. Women represented 28.3% of SiC editorial positions. Surgical oncology had the lowest female representation at 2.3%. CONCLUSION: Women and minorities are significantly underrepresented in leadership roles on Editorial Boards in hematology/oncology journals. Importantly, the representation of minority women physicians in EiC positions is at an inexorable zero.

Challenges Faced by J-1 International Medical Graduates (IMGs) During COVID-19 Pandemic.

In March 2020, WHO declared COVID-19 a global pandemic which led to many countries closing their borders to contain the spread of the virus, stay-at-home mandates were announced and governmental entities started working on minimal capacity. Delays in visa processing and renewal is one aspect that was hugely impacted by the pandemic and led to interruption in the training of many international medical graduates (IMGs). In this manuscript, we share our stories and perspective on the challenges faced by IMGs holding J-1 visa during COVID-19 pandemic.

Implementing Perioperative Cardiac Risk Assessment in an Internal Medicine Residency Program: Experience from a Community Hospital.

Background: ACGME requires all Internal Medicine training programs to structure the curriculum to optimize resident educational experiences, including perioperative medicine. Teaching residents about perioperative risk management is challenging in a community hospital with limited resources and low surgical volume. Objective: Our goal was to introduce an interactive educational module on perioperative cardiac risk assessment and management in a community residency training program. Methods: The study was a single-center online education-based intervention from September 2020 to January 2021. 24 categorical internal medicine residents at MetroWest Medical center were included. A self-paced online education program followed by two sessions of a 30-minute, group modulated review and discussion were provided monthly. The pre- and post-evaluation with 20 questions were conducted to assess perioperative cardiac risk assessment and peri-operative cardiac risk management before and after education. Results: 20 out of 24 residents (83%) were included in the analysis. Medicine residents performed significantly better after involvement with the educational module by comparing the pre- and post-evaluation score (10.7 ± 2.7 vs. 13.8 ± 1.8, p < 0.001, respectively). The most significant improvement was noticed in postgraduate year PGY-1 residents (5.1 ± 2.5, p < 0.001), followed by PGY-2 (2.7 ± 1.6, p = 0.004), but not significant in PGY-3 residents (1.6 ± 2.3, p > 0.05). Conclusion: Implementing an interactive multi-modular curriculum in a community hospital increased residents' awareness and knowledge of perioperative cardiac risk assessment and management. We are confident that this will result in improved performance on the consult services.

HOLA COVID-19 Study: Evaluating the Impact of Caring for Patients With COVID-19 on Cancer Care Delivery in Latin America.

PURPOSE: The HOLA COVID-19 study sought to evaluate the impact of COVID-19 on oncology practices across Latin America (LATAM), challenges faced by physicians, and how practices and physicians adapted while delivering care to patients with cancer. METHODS: This international cross-sectional study of oncology physicians in LATAM included a 43-item anonymous online survey to evaluate changes and adaptations to clinical practice. Multivariable logistic regression analyses were used to evaluate the association of caring for patients with COVID-19 and changes to clinical practice. RESULTS: A total of 704 oncology physicians from 19 countries completed the survey. Among respondents, the most common specialty was general oncology (34%) and 56% of physicians had cared for patients with COVID-19. The majority of physicians (70%) noted a decrease in the number of new patients evaluated during the COVID-19 pandemic when compared with prepandemic, and 73% reported adopting the use of telemedicine in their practice. More than half (58%) of physicians reported making changes to the treatments that they offered to patients with cancer. In adjusted models, physicians who had cared for patients with COVID-19 had higher odds of changing the type of chemotherapy or treatments that they offered (adjusted odds ratio 1.81; 95% CI, 1.30 to 2.53) and of delaying chemotherapy start (adjusted odds ratio 2.05; 95% CI, 1.49 to 2.81). Physicians identified significant delays in access to radiation and surgical services, diagnostic tests, and supportive care. CONCLUSION: The COVID-19 pandemic has significantly disrupted global cancer care. Although changes to health care delivery are a necessary response to this global crisis, our study highlights the significant disruption and changes to the treatment plans of patients with cancer in LATAM resulting from the COVID-19 health care crisis.

Increased family history documentation in internal medicine resident continuity clinic at a community hospital through resident-led structured genetic education program.

We aim to assess residents' perspectives and clinical utility of obtaining family history (FH) as well as to improve the rate of FH documentation in electronic medical record (EMR) at an internal medicine resident continuity clinic at a community hospital. The residents' perspectives were assessed with questionnaires. The study period was divided into the first 10-week Phase 1 in which genetic education interventions were delivered by residents, and the second 10-week Phase 2 with minimal intervention. FH documentation in EMR was reviewed and compared to a 4-week baseline (Phase 0). We found that time constraint was the most reported barrier. We reviewed 1197 patient visits; FH was recorded in 34% (67/200), 52% (272/522), and 50% (239/475) during Phase 0, Phase1, and Phase 2, respectively. Genetic education significantly increased the rate of FH documentation in Phase 1 from baseline, which was maintained in Phase 2 despite removal of interventions. The mean age of patients with documented FH was younger than those without documentation (48 years vs 51 years; p < 0.001). Documented FH of cancers and coronary artery disease lacked important details, such as age at diagnosis, in 62% (86/138) and 51% (41/81) of them, respectively. Out of 511 patients that had documented FH, we identified 66 patients (13%) where positive family history could alter medical management. In conclusion, resident-led structured genetic education effectively increased family history documentation in EMR in internal medicine resident continuity clinic and showed clinical utility.

Evaluating Internal Medicine Residents' Awareness on Cancer Survivorship Care Plan: A Pilot Survey.

Introduction: Survivorship care plan (SCP) is a tool to improve communication between oncologists and primary care physicians. Internal medicine residency curricula are lacking training for cancer survivorship and SCPs. Here, we aimed to assess the awareness and utilization of SCPs in medicine trainees. Methods: A pilot survey investigating awareness and experience with SCPs was distributed among internal medicine trainees in an outpatient setting. Participants were stratified by program type (transitional and categorical) and year of training. Differences in proportions were tested with parametric and non-parametric tests. Results: All thirty-seven participants who were administered a survey responded; 32.4% and 67.6% were transitional and categorical trainees, respectively; 54% were PGY-1, 21.6% PGY-2, and 24.3% PGY-3. None of the trainees reported following a SCP for cancer-free patients nor plans to use SCP as a source to obtain information. Up to 78.3% and 92.6% of participants reported that they were not taught about SCPs during their residency or medical school, respectively. The most frequent barriers to discuss cancer history and SCP with their patients were: insufficient or lack of information about SCPs (83.8%), patients' information as a source deemed "unreliable" (81.1%), and uncertainty if the patient has SCP (81.1%). Conclusions: Awareness and use of cancer SCPs among internal medicine trainees is limited, furthermore, a sizeable proportion reported not having accessed or received any training for SCPs. Efforts intended to facilitate SCP use and educate trainees about cancer survivorship may prove to be an effective strategy to increase the quality of care to cancer survivors.

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by a rapid initial response and early development of resistance to systemic therapy and radiation. The management of SCLC significantly changed for the first time in decades with the introduction of immune checkpoint inhibitors. Pembrolizumab, a humanized IgG4 isotype antibody, targets the programmed cell death protein 1 (PD-1) pathway to restore anti-tumor immunity. Prospective trials of pembrolizumab in patients with previously treated SCLC showed significant durability of responses. These results led to the U.S. Food and Drug Administration (FDA) granting pembrolizumab accelerated approval as second- or third-line monotherapy for patients with extensive-stage (ES) SCLC. In a recent clinical trial that included patients with previously untreated ES-SCLC, pembrolizumab in combination with platinum/etoposide met its progression-free survival endpoint, but overall survival (OS) did not cross the threshold for superiority. With the therapeutic landscape for SCLC rapidly evolving, we review prior experience and future directions of pembrolizumab in ES-SCLC.

The prognostic and predictive impact of BRAF mutations in deficient mismatch repair/microsatellite instability-high colorectal cancer: systematic review/meta-analysis.

Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I-IV patients (hazard ratio: 1.57; 95% CI: 1.23-1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48-2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

Lay abstract Patients with colorectal cancer who have mutations in the BRAF gene fare worse compared with those without the mutation, whereas those who have a feature called microsatellite instability-high tend to live longer compared with those who do not have this feature. However, it is unclear whether the presence of BRAF gene mutation changes the course of the disease or response to novel immunotherapy treatment in patients with microsatellite instability-high colorectal cancer. The authors found that patients without the BRAF mutation live longer than their counterparts with the mutation. The two groups did not respond differently to immunotherapy. Therefore, BRAF mutations are important in dictating the disease course in patients with microsatellite instability-high colorectal cancer.

A Rare Cause of Isolated Prolonged Activated Partial Thromboplastin Time: An Overview of Prekallikrein Deficiency and the Contact System.

Prekallikrein (PK) deficiency, also known as Fletcher factor deficiency, is a very rare disorder inherited as an autosomal recessive trait. It is usually identified incidentally in asymptomatic patients with a prolonged activated partial thromboplastin time (aPTT). In this article, we present the case of a 52-year-old woman, with no prior personal or family history of thrombotic or hemorrhagic disorders, who was noted to have substantial protracted aPTT through the routine coagulation assessment before a kidney biopsy. The patient had an uneventful biopsy course after receiving fresh frozen plasma (FFP). Laboratory investigations performed before the biopsy indicated normal activity for factors VIII, IX, XI, XII, and von Willebrand factor (vWF) as well as negative lupus anticoagulant (LA) screen. The plasma PK assay revealed low activity at 15% consistent with mild PK deficiency. The deficit of PK is characterized by a severely prolonged aPTT and normal prothrombin time (PT) in the absence of bleeding tendency. PK plays a role in the contact-activated coagulation pathway and the inflammatory response. Thus, other differential diagnoses of isolated prolonged aPTT include intrinsic pathway factor deficiencies and nonspecific inhibitors such as LA. We concluded that the initial evaluation of a prolonged aPTT with normal PT should appraise the measurement of contact activation factors and factor inhibitors. PK deficiency should be considered in asymptomatic patients with isolated aPTT prolongation, which corrects on incubation, with normal levels of the contact activation factors and factor inhibitors.

Comparison of Efficacy of Systemic Therapies in Advanced Hepatocellular Carcinoma: Updated Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Several systemic agents have been approved for use in advanced hepatocellular carcinoma (aHCC). However, it is unclear which treatment is superior in either the first- or second-line settings due to the paucity of head-to-head comparative trials. Therefore, we have conducted a systematic review and network meta-analysis for the indirect comparison of the systemic agents in the first line and second line settings. METHODS: Randomized clinical trials evaluating systemic agents in first and second line settings in aHCC from inception to April 2020 were identified by searching PubMed, EMBASE, and Cochrane Databases and the annual ASCO and ESMO conferences from 2017 to 2020. Studies in English reporting clinical outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were included. The primary outcomes of interest were pooled hazard ratios (HR) of OS and pooled odds ratios (OR) of ORR in first line studies and pooled HR of PFS and OR of ORR for second line studies. Additionally, OS for second line agents were reported in the qualitative analysis. RESULTS: Overall, first line studies comprised 8335 patients (13 studies) and second line studies comprised 4612 patients (11 studies). In the first line setting, atezolizumab plus bevacizumab was associated with the highest OS benefit over sorafenib (HR 0.58, 95% CI, 0.42-0.80; P-score 0.993). Additionally, lenvatinib was associated with the greatest ORR benefit (OR 3.34, 95% CI, 2.17-5.14; P-score 0.080) in the first line setting. In the second line setting, cabozantinib was associated with the highest PFS benefit over placebo (HR 0.44, 95% CI, 0.29-0.66; P-score 0.854) as well as the highest ORR benefit (OR 9.40, 95% CI, 1.25-70.83, P-score, 0.266). CONCLUSION: Atezolizumab plus bevacizumab appears to have superior efficacy among first line agents whereas cabozantinib appears to be superior in the second line setting. Further studies are warranted to determine whether the type of prior therapy received affects the efficacy of subsequent second line therapy.

Incidence, Mortality, and Survival Trends of Primary CNS Tumors in Cali, Colombia, From 1962 to 2019.

PURPOSE: Global studies have shown varying trends of CNS tumors within geographic regions. In Colombia, the epidemiologic characteristics of CNS neoplasms are not well elucidated. We aimed to provide a summary of the descriptive epidemiology of primary CNS tumors among the urban population of Cali, Colombia. METHODS: We conducted a time-trend study from 1962 to 2019 using the Population-Based Cali Cancer Registry. The age-standardized rates per 100,000 person-years were obtained by direct method using the world standard population. Results were stratified by sex, age group at diagnosis, and histologic subtype. We used Joinpoint regression analysis to detect trends and obtain annual percentage change (APC) with 95% CIs. We estimated 5-year net survival using the Pohar-Perme method. RESULTS: During 1962 to 2016, 4,732 new cases of CNS tumors were reported. From 1985 to 2019, a total of 2,475 deaths from malignant CNS tumors were registered. A statistically significant increase in the trends of incidence (APC, 2.8; 95% CI, 2.1 to 3.5) and mortality (APC, 1.5; 95% CI, 1.1 to 2.0) rates was observed during the study. The most common malignant CNS tumor was glioblastoma (17.8% of all tumors), and the most frequent benign tumor was meningioma (17.2%). Malignancy was more common in males than in females. Unspecified malignant neoplasms represented 32% of all cases. The highest 5-year net survival was 31.4% during 2012 to 2016. CONCLUSION: Our findings demonstrate an increasing burden of primary CNS tumors for the last 60 years, with a steady rate from the early 2010s. There was an improvement of 5-year net survival for the last decade. Males had higher mortality than did females. Additional efforts are needed to fully explore the geographic, environmental, and genetic contributors of CNS malignancies within the region.

Complete Resolution of a Large, Locally-advanced Cutaneous Squamous Cell Carcinoma with the Immune-modulating PD-1 Inhibitor Pembrolizumab.

Locally advanced cutaneous squamous cell carcinoma (cSCC) represents a challenge in treatment. Only very recently (February 2020) have guidelines been released regarding the management of unresectable, locally advanced cSCC. With the introduction of check point inhibitors during the last decade, anti-PD-1 antibodies represent a novel immunotherapeutic strategy in cancer. We present a case of an advanced cSCC not amenable to surgical resection, who experienced dramatic improvement following treatment with the programmed cell death protein 1 receptor (PD-1) inhibitor pembrolizumab as an immunotherapeutic strategy.

Treatment-Related Adverse Events of Combination Immune Checkpoint Inhibitors: Systematic Review and Meta-Analysis.

Background: Although clinical practice guidelines for the management of Immune Checkpoint Inhibitor (ICI)-related adverse events have recently been published, precise and nuanced toxicity data for combination ICI therapy are lacking. Therefore, herein we have conducted a systematic review and meta-analysis of published clinical trials on combination ICI to synthesize the treatment-related adverse event (TRAE) profile of combination ICI therapy. Methods: PUBMED, EMBASE, and the Cochrane Database/EBM were searched for eligible studies. Clinical trials evaluating combination immune checkpoint inhibitor therapy in advanced unresectable cancer were included in the analysis based on prespecified criteria. Risk of bias across studies was evaluated using Begg's funnel plot and Egger's regression test. The summary outcomes were pooled risk ratios (RR) and the logit-transformed proportion for incidence data. Results: A total of 18 studies comprising 2,767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment types (PD-1 + CTLA-4 and PD-L1 + CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1, and D20T1). The incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945], and the ratio of grade 3 or higher events to all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusion: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.

Stevens-Johnson Syndrome-Like Reaction After Exposure to Pembrolizumab and Recombinant Zoster Vaccine in a Patient With Metastatic Lung Cancer.

Stevens-Johnson syndrome (SJS) is a life-threating mucocutaneous reaction predominantly induced by drugs. Targeted cancer therapies such as pembrolizumab, which has been approved for the treatment of metastatic malignancy, can cause severe skin toxicities, including SJS. They are rare and inconsistently reported. In this article, we report the case of a 80-year-old woman with metastatic non-small cell lung cancer who had a SJS-like eruption involving oral mucosa after 15 weeks of exposure of pembrolizumab (6 doses) and 7 days after 1 dose of recombinant zoster vaccine. SJS is a rare blistering disorder with high mortality rate and significant morbidity. Causes include drugs, herpes viruses, and immunization. The timing of the eruption soon after the receipt of recombinant zoster vaccine suggests a role of vaccination in our patient, yet patients receiving cancer immunotherapy may develop late-onset skin toxicity. Therefore, we recommend long-term monitoring for mucocutaneous reactions after initiation of pembrolizumab. Further research is needed to characterize the immunological pathogenesis and improve timely recognition and treatment strategies.