Primary Resistance to RET Inhibition in a RET Fusion-Positive Pancreatic Neuroendocrine Carcinoma.

We present a 54-year-old White male with a diagnosis of stage IV pancreatic neuroendocrine carcinoma. Next-generation sequencing of the tumor/blood identified a complex tumor genome, which included a rearranged during transfection (RET) gene fusion. The patient initially received cytotoxic chemotherapy with a significant radiographic response. After 4 cycles of chemotherapy, the patient was transitioned to a clinical trial using selpercatinib, a RET inhibitor, as maintenance therapy. Unfortunately, our patient developed progression of disease at the first treatment monitoring scan. Our patient suffered primary resistance to RET-targeted therapy. Proposed mechanisms of resistance include intrinsic resistance of the nuclear receptor co-activator 4-RET fusion to RET inhibition, the RET fusion representing a passenger alteration to another tumorigenic driver pathway and/or decreased efficacy of RET inhibition after platinum-based chemotherapy. Our patient's clinical course highlights the fact that "actionable" genomic alterations do not always equate to patient benefit.

Sex differences in fat taste responsiveness are modulated by estradiol.

Sex as a biological variable has been the focus of increasing interest. Relatively few studies have focused, however, on differences in peripheral taste function between males and females. Nonetheless, there are reports of sex-dependent differences in chemosensitivity in the gustatory system. The involvement of endogenous changes in ovarian hormones has been suggested to account for taste discrepancies. Additionally, whether sex differences exist in taste receptor expression, activation, and subsequent signaling pathways that may contribute to different taste responsiveness is not well understood. In this study, we show the presence of both the nuclear and plasma membrane forms of estrogen receptor (ER) mRNA and protein in mouse taste cells. Furthermore, we provide evidence that estrogen increases taste cell activation during the application of fatty acids, the chemical cue for fat taste, in taste receptor cells. We found that genes important for the transduction pathway of fatty acids vary between males and females and that these differences also exist across the various taste papillae. In vivo support for the effect of estrogens in taste cells was provided by comparing the fatty acid responsiveness in male, intact female, and ovariectomized (OVX) female mice with and without hormone replacement. In general, females detected fatty acids at lower concentrations, and the presence of circulating estrogens increased this apparent fat taste sensitivity. Taken together, these data indicate that increased circulating estrogens in the taste system may play a significant role in physiology and chemosensory cellular activation and, in turn, may alter taste-driven behavior.NEW & NOTEWORTHY Using molecular, cellular, and behavioral analyses, this study shows that sex differences occur in fat taste in a mouse model. Female mice are more responsive to fatty acids, leading to an overall decrease in intake and fatty acid preference. These differences are linked to sex hormones, as estradiol enhances taste cell responsiveness to fatty acids during periods of low circulating estrogen following ovariectomy and in males. Estradiol is ineffective in altering fatty acid signaling during a high-estrogen period and in ovariectomized mice on hormone replacement. Thus, taste receptor cells are a direct target for actions of estrogen, and there are multiple receptors with differing patterns of expression in taste cells.

Early discontinuation of immune checkpoint inhibitor therapy prior to disease progression in patients with metastatic non-small cell lung cancer: a survival analysis.

Introduction: Limited survival data are available for patients with metastatic non-small cell lung cancer (mNSCLC) who stop immune checkpoint inhibitor therapy (ICI) early for reasons other than progression of disease (POD), such as immune-related adverse events (irAEs). Methods: We conducted a retrospective observational study of all patients with mNSCLC treated with ICIs, with or without combination chemotherapy, at 3 Mayo Clinic sites between 2011 and 2022. Separate analyses were conducted at 6- and 12-month intervals. Patients who discontinued ICI due to POD prior to these time points were excluded from the analysis. Results: A total of 246 patients with stage IV NSCLC used ICIs. Patients were then excluded if they had experienced POD prior to 6 or 12 months, resulting in 81 and 63 patients, respectively, for each timepoint. Sixty-four patients continued treatment beyond 6 months and were found to have longer progression-free survival (PFS) compared to the 17 patients who discontinued treatment (22.8 months vs 11.8 months, P =1.1E-04), as well as a significant increase in overall survival (OS) (33.9 months vs 14.4 months, P =7.2E-08). Forty patients continued treatment beyond 12 months and had longer PFS compared to the 23 patients that discontinued treatment (27.9 months vs 14.8 months, P =1.1E-04), as well as a significant increase in OS (39.7 months vs 18.0 months, P =2.0E-07). The most common reason for ICI discontinuation was irAEs. Other common reasons for stopping ICI were non-irAEs and stable disease. At both time points, 12 patients continued or restarted ICI after experiencing an irAE, and 2 patients experienced recurrent/new grade 1-2 irAEs. More patients continued/rechallenged with ICI after experiencing an irAE in the groups that continued ICI compared to those that discontinued ICI. Conclusions: Patients with mNSCLC and no POD who continued ICI beyond 6 months and 12 months, experienced significantly increased PFS and OS compared to patients who discontinued ICI, with larger increases in those who continued ICI past 12 months. Oncology providers should discuss the survival benefits of continuing ICI and offer support to overcome obstacles to continuation of treatment, if possible, particularly management of grade 1 and 2 irAEs.

Metastatic Non-Small Cell Lung Cancer Mimicking Metaplastic Breast Cancer: A Case Report.

NGS used to diagnose and treat NSCLC patient with initial concern for metaplastic breast cancer.

Photodistributed Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and proposal for a new diagnostic classification.

BACKGROUND: Ultraviolet radiation (UVR) exposure is commonly reported as a risk factor for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, minimal evaluation of photo-induced SJS/TEN has been conducted. Thus, this review identifies all cases of SJS/TEN that are linked to an acute exposure of UVR and outlines the unifying characteristics of these cases. Furthermore, the theoretical pathogenesis, differential diagnoses, and proposed diagnostic criteria are defined. METHODS: PubMed, Google Scholar, and other databases and websites were searched from inception to September 2021 to identify studies that met inclusion criteria. The following keywords were utilized: "Stevens-Johnson syndrome" and "toxic epidermal necrolysis" with "ultraviolet," "photodistributed," "photo-induced," "photosensitivity," and "photo." One reviewer assessed study characteristics, with confirmation by a second. The risk of bias was assessed independently by another. RESULTS: Thirteen patient cases were identified, all reporting ultraviolet radiation prior to rash onset and an underlying causal drug. Case classifications included 7/13 SJS and 6/13 TEN. All cases described the rash as photodistributed with UVR exposure prior to rash onset (delay of 1-3 days) and a causal drug. 10 cases provided evidence that the photodistributed rash lacked linear demarcation (as in a sunburn) with satellite target-like lesions. No cases described a flu-like prodrome. DISCUSSION: Mucositis, palmar and plantar rash, a positive Nikolsky sign, and a prolonged disease course can help distinguish from photosensitive reactions, while a negative direct immunofluorescence test is important to distinguish from other photo-induced disorders. CONCLUSION: Physicians should be aware that UVR may precipitate SJS/TEN in patients taking susceptible drugs. After a 24-h delay from UVR exposure, a non-distinct, photodistributed rash appears with no flu-like prodrome and progresses for at least 48 h to include vesiculobullous eruptions and mucous membrane involvement. Photodistributed SJS/TEN appears to be photo-drug-induced with a unique onset and rash presentation that should be recognized as a distinct diagnosis.

Pneumatosis Intestinalis Induced by Alpha-Glucosidase Inhibitors in Patients with Diabetes Mellitus.

Alpha-glucosidase inhibitor (αGIs)-induced pneumatosis intestinalis (PI) has been narrated in case reports but never systematically investigated. This study aimed to investigate the concurrency of PI and αGIs. A literature search was performed in PubMed, Google Scholar, WorldCat, and the Directory of Open-Access Journals (DOAJ) by using the keywords "pneumatosis intestinalis", "alpha-glucosidase inhibitors", and "diabetes". In total, 29 cases of αGIs-induced PI in 28 articles were included. There were 11 men, 17 women, and one undefined sex, with a median age of 67. The most used αGI was voglibose (44.8%), followed by acarbose (41.4%) and miglitol (6.8%). Nine (31%) patients reported concomitant use of prednisone/prednisolone with or without immunosuppressants. The main symptoms were abdominal pain (54.5%) and distention (50%). The ascending colon (55.2%) and the ileum (34.5%) were the most affected. Nineteen (65.5%) patients had comorbidities. Patients with comorbidities had higher rates of air in body cavities, the portal vein, extraintestinal tissues, and the wall of the small intestine. Only one patient was found to have non-occlusive mesenteric ischemia. Twenty-five patients were treated with conservative therapy alone, and two patients received surgical intervention. All patients recovered. In conclusion, comorbidities, glucocorticoids, and immunosuppressants aggravate αGIs-induced PI. Conservative therapy is recommended when treating αGIs-induced PI.

Mental health and sleep habits during preclinical years of medical school.

OBJECTIVES: The purpose of this non interventional study was to define changes in anxiety, depression, and sleep quality of medical students in their first two years of medical school while considering potential risk factors of self-reported chronic disease, sleep quantity, year of medical school and exercise habits. Since this study was ongoing during the COVID-19 pandemic, its effect was also evaluated. PARTICIPANTS: /METHODS: A cohort of 197 medical students was evaluated longitudinally using survey methods to quantify changes from pre-medical school and summer break to each semester in medical school throughout years one and two. This study was performed from July 2019 through June 2021. Data was analyzed using Generalized Linear Mixed Models (GLMMs) on the numeric responses of General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Sleep Quality (SQ-3) and Pittsburg Sleep Quality Index (PSQI). Additional assessments evaluated exercise habits, chronic disease, and impact of COVID-19 Pandemic. The COVID-19 Pandemic was evaluated directly in the model (pre- and post-COVID-19 period variable), and through additional questions on their perceived effect. RESULTS: Depression, anxiety, and sleep habits displayed a cyclical change that was associated with the academic/seasonal cycle. The COVID-19 pandemic was never found significant. Medical students who had a chronic disease diagnosis and fewer hours of sleep had increased severity. Exercise did not play a role. CONCLUSION: Based on our sample, the main driver for depression, anxiety, and poor sleep quality appears to be the academic/seasonal cycle, while the COVID-19 pandemic did not have an impact on mental health.