Emerging New Targets in Systemic Therapy for Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM.

An Era of Advances in Systemic Therapies for Advanced Thyroid Cancer.

Thyroid carcinomas comprise distinct pathologic subtypes. However, advancements in characterizing the molecular tumorigenesis of thyroid cancers have changed the treatment paradigm in the past decade. Genetic profiling has become an integral component of personalizing cancer care. Oral kinase inhibitors are currently standard-of-care therapies for progressive, radioactive iodine (RAI)-refractory differentiated thyroid carcinomas (DTCs) and medullary thyroid carcinomas (MTCs). Sorafenib, lenvatinib, and cabozantinib are multikinase inhibitors approved for patients with metastatic RAI-refractory DTC, whereas vandetanib and cabozantinib are approved for patients with MTC. Management of thyroid carcinomas has evolved such that targeted therapies have become therapeutic options for patients with BRAF, RET, NTRK, ALK, and ROS1 alterations and even have reported efficacy in anaplastic thyroid carcinomas. In this article, we review the advances made over the years in the treatment of metastatic thyroid carcinoma and focus on the systemic therapies that have recently transformed the treatment landscape of advanced disease.

Repotrectinib in a Patient With NTRK Fusion-Positive Pancreatic Carcinoma and Congenital Long QT Syndrome.

Repotrectinib in a patient with NTRK fusion-positive pancreatic carcinoma and congenital long QT syndrome.

Metastatic HER2-amplified non-small-cell lung cancer treated with trastuzumab deruxtecan.

Human epidermal growth factor receptor 2 (HER2) alterations can occur as gene mutations, gene amplification or protein overexpression. DESTINY-Lung01 and DESTINY-Lung02 demonstrated the efficacy of trastuzumab deruxtecan in the subsequent line setting in patients with unresectable or metastatic HER2-mutated non-small-cell lung cancer (NSCLC). Trastuzumab deruxtecan has not been studied in select patients with HER2-amplified NSCLC. Here, we present the first reported case of metastatic HER2-amplified NSCLC treated with trastuzumab deruxtecan with a durable response to therapy.

Management of toxicities associated with immune checkpoint inhibitors.

Immune-related adverse events (irAEs) encompass a diverse range of toxicities following treatment with immune checkpoint inhibitors (ICIs), each with distinctive symptoms, severities, and outcomes. irAEs can affect any organ and are potentially fatal, so early diagnosis is key in preventing serious events. irAEs can be fulminant, requiring immediate attention and intervention. Management of irAEs involves the use of systemic corticosteroids and immunosuppressive agents in addition to any disease-specific therapeutics. Making the decision to rechallenge with ICIs is not always clear and involves weighing the risks and clinical benefits of continuing ICI therapy. Here, we review the consensus recommendations on managing irAEs and discuss current challenges in clinical care caused by these toxicities.

Immune Checkpoint Inhibitor Rechallenge After Prior Immune Toxicity.

OPINION STATEMENT: Immune checkpoint inhibitors (ICIs) have become an essential part of treatment for many cancer types. These monoclonal antibodies remove a critical negative regulatory signal that allows the immune system to recognize and destroy malignant cells that were previously undetectable. Unfortunately, their use has ushered in a whole new form of drug toxicity whereby the immune system attacks normal tissues in the body, referred to hereafter as immune-related adverse events (irAEs). irAEs are common and can result in treatment discontinuation, hospitalization, and death. When alternative modes of treatment are limited, or considered less efficacious, there may be a desire to resume treatment with ICIs after an irAE. Rechallenge with ICIs carries with it a heightened risk of subsequent toxicity, but with careful consideration and appropriate patient selection, this can be considered a reasonable approach.

Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC.

Lorlatinib is an oral third-generation inhibitor of anaplastic lymphoma kinase (ALK) with activity in advanced ALK-positive non-small cell lung cancer (NSCLC) in both the first and subsequent line setting. Superior systemic and intracranial efficacy of lorlatinib over crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), in treatment-naïve patients with advanced ALK-positive NSCLC was demonstrated by the phase 3 CROWN trial. Lorlatinib retains anti-tumor effect against single and some compound ALK resistance mutations after disease progression on first- and second-generation ALK TKIs. Currently, alectinib, brigatinib, ceritinib, crizotinib and lorlatinib are approved for treatment of advanced ALK-positive NSCLC. However, no head-to-head studies have directly compared lorlatinib to second-generation ALK inhibitors. Herein, we aim to provide an overview of the efficacy and safety of lorlatinib and discuss where lorlatinib stands in the therapeutic approach to advanced ALK-positive NSCLC.

Rapid onset type 1 diabetes with anti-PD-1 directed therapy.

Type 1 diabetes is a rare immune-related adverse event (irAE) caused by checkpoint inhibitors with serious risk for diabetic ketoacidosis (DKA). Using our electronic medical record, we identified 1327 adult patients who received PD-(L)1 or CTLA-4 inhibitors from 2013 to 2018. Of the patients who received immunotherapy, 5 (0.38%) patients were found to have type 1 diabetes, all of whom presented with DKA requiring insulin at 20 to 972 days from their first anti-PD-(L)1 dose. All patients were treated with anti-PD-1 therapy (nivolumab or pembrolizumab). Four patients had new onset diabetes with mean HbA1c of 9.1% on DKA presentation and persistent elevations over time. Two patients who tested positive for glutamic acid decarboxylase (GAD) antibodies presented with DKA at 20 and 106 days from first anti-PD-1 administration whereas patients who were autoantibody negative had DKA more than a year later. Type 1 diabetes occurs within a wide time frame after anti-PD-1 initiation and commences with an abrupt course. Our case series suggests that monitoring glycemia in patients on PD-1 inhibitors is not predictive for diabetes occurrence. GAD autoantibodies could portend earlier onset for diabetes, although further prospective studies are needed to elucidate their diagnostic utility and contribution in therapeutic interception.

Fighting the flinch: Experimentally induced compassion makes a difference in health care providers.

OBJECTIVES: Although health care providers are required to sustain care in difficult circumstances, some patients challenge this principle. Evoking compassion seems likely to be helpful in such situations. This research aimed to evaluate whether inducing compassion in health care providers might mitigate disengagement with patients who have challenging presenting features such as those with disgusting symptoms and/or are to blame for their own health problems. DESIGN: An online experimental study with clinical health care providers. METHODS: Medical students (n = 219) and qualified health care professionals (n = 108) took part in an online experiment. Participants were randomized to view a slideshow of either neutral images (control) or compassion-inducing images (compassion condition) and were then presented with a series of patient vignettes where presenting problems systematically varied on patient responsibility and disgusting symptoms. Engagement was assessed by asking participants how caring they felt, how much they would want to help, how challenging it would be, and whether they would wear a mask. RESULTS: Participants reported less engagement with patients who were responsible for their illness and who presented with disgusting symptoms. Induced compassion offset disengagement and qualified health professionals were more caring and willing to help patients than medical students. The compassion induction eliminated some differences between experienced and trainee clinicians. CONCLUSIONS: This research demonstrates that disgust and patient responsibility impacts clinical engagement and that medical students are more impacted by such scenarios than qualified health providers. Inducing compassion may help to mitigate these differences, and further investigation into strategies that foster engagement with difficult patients is warranted. Statement of contribution What is already known on the subject? Health care providers are required to sustain care across all patients; however, some patients are more difficult to engage with than others. Clinical engagement appears to be impacted when patients present with disgusting symptoms and/or are to blame for their own health problems. What does this study add? This work reports on a vignette-based study that shows that disgusting symptoms and patient responsibility impact self-reported measures of clinical engagement in response to patient scenarios. Qualified health care providers are less likely to disengage in these situations than medical students. A very brief online induction of compassion has potential to mitigate differences between trained professionals and students.

Women in Emergency Medicine Residency Programs: An Analysis of Data From Accreditation Council for Graduate Medical Education-approved Residency Programs.

OBJECTIVE: Understanding the factors associated with attracting women to a residency program would help residency program leadership build programs that are appealing to women candidates. The objective of this study was to identify factors associated with the percentage of women residents in emergency medicine (EM) residency programs. METHODS: A list of 161 Accreditation Council for Graduate Medical Education-approved EM residencies was compiled. The public websites for each of the residencies was queried for information on the following variables: residency region (Midwest, Northeast, South, West), residency length (3 years vs. 4 years), sex of the department chair, sex of the program director (PD), percentage of women faculty, and the number of residents by graduation class and sex. RESULTS: The websites of 161 EM residencies were reviewed. Complete data were available from a total of 143 programs representing 4,547 residents from the studied classes of 2014, 2015, and 2016. Overall, 38% were women (n = 1,743). The percentage of women residents per program varied from 0% to 68% across residency programs. There was no association between the percentage of women residents and residency region, sex of the department chair, and sex of the PD. CONCLUSIONS: In this study, there was no evidence that EM residencies with a greater percentage of women faculty and women in select leadership roles had a greater percentage of women residents. There was also no evidence for regional variability in women's selection of residency programs. This study was limited to publicly available data and cannot address the many other complex factors which may play a role in women's decision making when choosing a residency.

Activated type 2 innate lymphoid cells regulate beige fat biogenesis.

Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα(+) APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PAPERCLIP:

Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes.

Circadian clocks have evolved to regulate physiologic and behavioral rhythms in anticipation of changes in the environment. Although the molecular clock is present in innate immune cells, its role in monocyte homeostasis remains unknown. Here, we report that Ly6C(hi) inflammatory monocytes exhibit diurnal variation, which controls their trafficking to sites of inflammation. This cyclic pattern of trafficking confers protection against Listeria monocytogenes and is regulated by the repressive activity of the circadian gene Bmal1. Accordingly, myeloid cell-specific deletion of Bmal1 induces expression of monocyte-attracting chemokines and disrupts rhythmic cycling of Ly6C(hi) monocytes, predisposing mice to development of pathologies associated with acute and chronic inflammation. These findings have unveiled a critical role for BMAL1 in controlling the diurnal rhythms in Ly6C(hi) monocyte numbers.

Telepsychiatry services for Korean immigrants.

Asian Americans often face cultural and language barriers when obtaining mental health treatment. With the small number of Asian mental health providers, it is difficult to ensure the linguistic and ethnic matching of providers and patients. Telepsychiatry holds great promise to address the unique needs of Asian Americans. We developed a project to establish telepsychiatry services that connect Korean mental health patients in Georgia with a linguistically and culturally competent psychiatrist in California and assessed the level of acceptability of psychiatric treatment via real-time teleconferencing among these patients. Upon the completion of the program, 16 patients (5 men, 11 women) completed a questionnaire that measured their acceptability of the telepsychiatry service. The findings indicate a high level of acceptance of the program among Korean patients. The quantitative and qualitative data show that they especially appreciated the cultural sensitivity of the consultation and the comfortable interaction with the provider. However, challenges such as technical issues of teleconferencing may negatively affect the quality of the clinical interaction. Our study expands the knowledge base regarding the acceptability of such services to a population that experiences disparities in mental health care. Future research should extend telepsychiatry services to other Asian population groups that experience lower access to mental health services.