A Rare Case of Metastatic Spiradenocarcinoma With CDKN2A Mutation.

Spiradenocarcinomas are rare malignant skin adnexal tumors. We describe a novel case of a patient with an aggressive CDKN2A-mutated spiradenocarcinoma who responded to a CDK4/6 inhibitor. This case highlights the unique nature of spiradenocarcinomas as well as the potential benefit of targeted therapy.

Diagnosis of Metastatic Non-Small Cell Lung Cancer during Hospitalization: Missed Opportunity for Optimal Supportive Care?

PURPOSE: The usual workup for patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) occurs in the ambulatory setting. A subset of patients present with acute care needs and receive the diagnosis while hospitalized. Palliative therapies are typically initiated when patients are outpatients, even when diagnoses are made when they are inpatients. Lengthy admission, rehabilitation needs after discharge, and readmissions are possible barriers to timely and adequate outpatient follow-up. The outcomes for these patients diagnosed in the hospital are not well characterized. We hypothesized that patients have been ill-served by current treatment patterns, as reflected by low rates of cancer-directed treatment and poor survival. PATIENTS AND METHODS: We performed a retrospective study of new inpatient diagnoses of metastatic NSCLC at our institution between 1 January 2012 and 1 January 2022. The primary outcome was the proportion of patients ultimately receiving cancer-directed therapy. Other outcomes included time to treatment, use of targeted therapy, palliative care/hospice utilization, and overall survival (OS). RESULTS: Seventy-three patients were included, with a median age of 57 years. Twenty-seven patients (37%) ultimately received systemic therapy with a median time from diagnosis to treatment of 37.5 days. Overall, 5.4% patients died while admitted, 6.8% were discharged to a hospice, 21.9% were discharged to a facility, and 61.6% were discharged home. Only 20 patients (27%) received palliative care consultation. The median OS for our entire population was 2.3 months, with estimated 6-month and 1-year OS rates of 32% and 22%, respectively. CONCLUSION: Patients with new inpatient diagnoses of metastatic NSCLC have extremely poor outcomes. Current management strategies resulted in few patients starting systemic therapy, yet most of the patients did not receive palliative care or hospice involvement. These findings demonstrate that there is a high unmet need to optimally support and palliate these patients.

Durvalumab Outcomes in Stage III Non-small Cell Lung Cancer: A Single-institution Study.

BACKGROUND/AIM: The PACIFIC trial demonstrated improved survival in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with durvalumab following definitive concurrent chemoradiotherapy (CRT). This study sought to explore real-world outcomes with durvalumab consolidation therapy at our institution. PATIENTS AND METHODS: We retrospectively identified patients diagnosed with stage III NSCLC at our institution from January 2012 to January 2022. We created two cohorts: one who received durvalumab following definitive CRT and a historical one who did not. Primary outcomes of interest included median progression-free survival (PFS) and overall survival (OS). Additionally, we performed subgroup analysis on the durvalumab cohort to explore the associations between survival and time to durvalumab initiation, PD-L1 expression, and neutrophil-to-lymphocyte ratio (NLR). RESULTS: We identified 79 patients with locally advanced NSCLC who were not surgical candidates. Patients treated with durvalumab (n=44) had significantly improved survival compared to the historical cohort (n=35) including a median PFS of 17.4 months versus 8.0 months (p=0.0019) and a median OS of 37.0 months versus 17.0 months (log-rank p-value=0.07, Wilcoxon p-value=0.02). Within the durvalumab group, outcomes did not significantly differ between those who initiated therapy before or after 42 days of finishing CRT, between various PD-L1 expression levels, or between high or low NLR. CONCLUSION: Patients who received durvalumab as consolidation therapy following definitive CRT demonstrated significantly improved survival compared to a historical cohort who did not receive durvalumab. Furthermore, durvalumab appears to benefit patients regardless of time to initiation, PD-L1 expression, or NLR.

Current management of uncommon EGFR mutations in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) mutations are frequently implicated in non-small cell lung cancer (NSCLC). Though these typically involve exon 19 in-frame deletions or L858R mutations in exon 21, uncommon EGFR mutations comprise 10-15 % of all EGFR mutations. These most frequently include G719X mutations in exon 18, L861Q mutations in exon 21, S768I mutations in exon 20, and in-frame insertions and/or duplications in exon 20. It is crucial to understand these distinct variants and their specific responses to active treatment options to optimize care. In this review, we discuss these uncommon mutations in depth and dissect the current literature regarding their treatment outcomes and subsequent evidence-based management guidelines.

Early-onset Colon Cancer Shows a Distinct Intestinal Microbiome and a Host-Microbe Interaction.

The incidence rate of colorectal cancer in younger adults has been rising in developed countries. This trend may be attributed to environmental exposures as a result of lifestyle changes. Many of the lifestyle factors that promote colorectal cancer can also affect the gut microbiome, which may be associated with colorectal cancer risks. The role of the microbiome in the ongoing rise of early-onset colorectal cancer is unknown. Here, we aimed to investigate age-related differences in the gut microbiome of patients with colorectal cancer and healthy individuals by examining both the fecal and tumor microbiomes. We utilized the publicly accessible data on fecal shotgun metagenomics from CuratedMetagenomeData and TCGA via the GDC Data Portal. Comparison of 701 colorectal cancer and 693 controls revealed that microbial features were age dependent, with a significant difference in species enrichment between early-onset (<50 years) and late-onset (>65 years) patients with colorectal cancer. Analysis of the tumor-associated microbiome in a separate dataset of 85 patients with colorectal cancer verified age-specific differences in taxon abundance between early- and late-onset patients with colorectal cancer. Finally, using host gene expression data, we found a stronger microbe-host interaction in early- vs. late-onset colorectal cancers. Altogether, these findings indicate that microbial features were age-dependent with stronger microbial-host interactions at the tumor site in early-onset colorectal cancers, suggesting a direct role of microbes in tumorigenesis via interaction with cancer-related pathways in this age group. PREVENTION RELEVANCE: Early-onset colorectal cancer is on the rise, presumably because of changes in environmental exposures. Lifestyle changes may contribute to colorectal cancer via alterations in gut microbes. Here, we show that microbial association with colorectal cancer is age-dependent, and microbe interactions with tumor pathways are stronger in young versus older colorectal cancers.

Durable and dramatic response to checkpoint inhibition combined with COX-2 inhibitor celecoxib in a patient with p16+ metastatic sinonasal undifferentiated carcinoma: A case study.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is an exceedingly rare head and neck malignancy. No consensus exists on treatment for metastatic disease. CASE: A 56-year-old female was diagnosed with SNUC after endorsing sinus congestion, diplopia, and right orbital pain. Initially treated with surgery and radiation, she later developed significant metastatic disease. She demonstrated progression of her hepatic metastases under pembrolizumab therapy. However, the addition of ipilimumab and a COX-2 inhibitor resulted in significant improvement in her lesions as well as an ongoing durable response. Her regimen was complicated by immune-related adverse events successfully treated with steroids. CONCLUSION: Dual checkpoint inhibition deserves consideration when treating metastatic SNUC, especially after single agent therapy has failed. The positive effect of this treatment may be augmented by IDO1 inhibition.

A case of metastatic adenoid cystic (basal cell) carcinoma of the prostate: Systemic therapy for a rare disease.

BACKGROUND: Metastatic adenoid cystic (basal cell) carcinoma of the prostate is an exceedingly rare disease entity. As a result, no current consensus exists for optimal systemic therapy. METHODS: We present a patient with metastatic adenoid cystic (basal cell) carcinoma of the prostate who subsequently received systemic treatment, including chemotherapy and immunotherapy. We comprehensively reviewed all published data on therapy outcomes in advanced disease. RESULTS: Our patient benefited from combination chemotherapy (carboplatin and paclitaxel), with objective radiographic response and reduction in cancer-related pain. However, chemotherapy was stopped due to cumulative neurotoxicity, and subsequent immunotherapy with atezolizumab did not produce any response. Our literature review revealed inconsistent outcomes with various treatments but showed most promise with chemotherapy. Targeted therapy and immunotherapy seem to benefit specific cases, and androgen deprivation therapy had minimal evidence of benefit. CONCLUSION: Based on the findings of our case report and literature review, we suggest platinum-based chemotherapy doublets as first-line treatment for metastatic cases of adenoid cystic (basal cell) carcinoma of the prostate, reserving targeted therapy or immunotherapy for select cases based upon molecular profiles.

Inconsistent eating time is associated with obesity: A prospective study.

Obesity is characterized by an accumulation of redundant body fat linked to metabolic dysregulation and low-grade systemic inflammation. Lifestyle choices are imperative determining factors of obesity. The contemporary lifestyle is associated with behaviors that disrupt circadian rhythms, impacting metabolic homeostasis. Our animal and human studies suggest that circadian phenotypes could be related to the risk of metabolic dysregulation and obesity. The purpose of this study is to examine the role of inconsistent eating habits on body weight in adults. Individuals who presented for colon cancer screening were enrolled. Subjects received structured questionnaires to capture 7-day eating and sleeping times in a week prospectively. Bodyweight and height were extracted from medical records, and Body Mass Index (BMI) was calculated. Inconsistent eating times were defined as an average difference of >2 hours between the largest meal on weekdays and weekends. Forty-nine of the 61 (80.3 %) individuals enrolled in the study completed the questionnaires. The mean age and standard deviation (SD) were 60.8 (7.9), and 27 (55.1 %) were male. Subjects with inconsistent eating times had a significantly higher BMI (33.8 ± 3.6 SD, n = 9) than subjects who did not (27.5 ± 6.5 SD, n = 40; p = 0.001). The highest BMI was observed in subjects who ate inconsistently and late (35.8 ± 4.6 SD). In this cross-sectional study, time of eating habits was associated with BMI. Controlled cohort studies are needed to determine the potential link between eating time and the risk of obesity in the long term.

Burnout Among Pharmacy Preceptors in Northern California.

Objective. The objectives of this study were to investigate the incidence of burnout syndrome among pharmacy preceptors and to identify predictors for the development of burnout in this population.Methods. This cross-sectional survey study examined burnout syndrome among pharmacy preceptors in Northern California. Preceptors were included if they self-identified as a preceptor to advanced pharmacy practice experience (APPE) students or to postgraduate pharmacy residents in their first year of residency. Burnout was assessed using the Maslach Burnout Inventory Human Services Survey, and preceptors were classified as having burnout syndrome if they scored high on emotional exhaustion and also either scored high on depersonalization or scored low on personal accomplishment. Additionally, respondents' demographics, workplace environment, workload, and day-to-day workflow were queried to help determine predictors of burnout syndrome among this population.Result. The study included 113 pharmacy preceptors. Of the preceptors, 22% reported scores consistent with burnout, with 57% of preceptors scoring positive for burnout in one of the three burnout criteria. On multivariate regression analysis, two independent risk factors for burnout syndrome were identified: preceptors who precepted many difficult or unmotivated learners per year and preceptors who did not feel their contributions as preceptors were appreciated by their institution.Conclusion. The rate of burnout among pharmacy preceptors is high, with preceptors exhibiting high emotional exhaustion and low levels of personal accomplishment. Predictors of burnout syndrome for this population appear to be precepting many difficult or unmotivated learners and not feeling that one's contributions as a preceptor are appreciated.

Patient Resilience Influences Opioid Consumption in Primary Total Joint Arthroplasty Patients.

Background: Resilience and depression may influence opioid consumption in patients undergoing primary hip and knee arthroplasty (TJA); however, data evaluating these relationships are limited. Methods: We retrospectively identified 119 patients undergoing TJA who completed preoperative questionnaires to measure resilience (Brief Resilience Scale) and depression (PHQ-9) from 2017 to 2018 at a single institution. Patients were stratified into high, normal, and low resilience groups as well as no, mild, and major depression groups. Opioid use was recorded in morphine milligram equivalents (MMEs). Nonparametric statistical testing was performed with significance level at P < 0.05. Results: Higher levels of resilience correlated with less postoperative inpatient opioid use (P = 0.003). Patients with high resilience were less likely to use preoperative opioids compared to those with low resilience (OR = 6.08, 95% CI [1.230.5]). There was no difference in postoperative outpatient opioid prescriptions between resilience groups. Lower levels of depression correlated with less postoperative inpatient opioid use, though this did not reach statistical significance (P = 0.058). Additionally, there was no significant difference in preoperative opioid use or postoperative outpatient opioid prescriptions between depression groups. Conclusion: Patients with higher levels of resilience are less likely to use opioids before TJA and utilize lower amounts of opioids while inpatient following surgery. Depression correlated with higher postoperative inpatient opioid use; however, the present findings regarding this relationship are inconclusive. Resilience is a psychological trait that may impact opioid use in patients undergoing TJA and should be viewed as a modifiable risk factor. Level of Evidence: III.

Gut metabolite S-equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus-induced acute seizures.

OBJECTIVE: A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo. METHODS: We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability. RESULTS: We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability. SIGNIFICANCE: Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment.

Resilience and Depression Influence Clinical Outcomes Following Primary Total Joint Arthroplasty.

BACKGROUND: Resilience and depression may impact clinical outcomes following primary total joint arthroplasty (TJA). This study aimed to quantify baseline resilience and depression prevalence in patients undergoing primary TJA and evaluate their influence on patient-reported clinical outcomes. METHODS: We prospectively enrolled 98 patients undergoing primary TJA. Exclusion criteria included patients under 18 years of age, undergoing surgery for fracture, or who underwent additional surgery during the study period. Patients completed the Brief Resilience Scale to measure resilience, Patient Health Questionnaire-9 to measure depression, and Patient-Reported Outcomes Measurement Information System-10 to measure global physical and mental health preoperatively and 1 year postoperatively. RESULTS: Preoperatively, 22% and 15% of patients demonstrated major and mild depression, respectively. High resilience was identified in 34% of patients, normal resilience in 55%, and low resilience in 11%. Preoperative depression correlated with lower resilience, global physical health, and global mental health scores preoperatively as well as at 1 year after surgery (P < .001). Higher levels of preoperative resilience correlated with higher global physical and mental health scores preoperatively and at 1 year postoperatively (P < .001). CONCLUSION: Depression symptoms are common among patients undergoing primary TJA and are associated with worse patient-reported outcomes. Patients with higher levels of resilience have higher global physical and mental health scores before and after TJA. Psychological traits and depression impact clinical outcomes following TJA.

PrPSc formation and clearance as determinants of prion tropism.

Prion strains are characterized by strain-specific differences in neuropathology but can also differ in incubation period, clinical disease, host-range and tissue tropism. The hyper (HY) and drowsy (DY) strains of hamster-adapted transmissible mink encephalopathy (TME) differ in tissue tropism and susceptibility to infection by extraneural routes of infection. Notably, DY TME is not detected in the secondary lymphoreticular system (LRS) tissues of infected hosts regardless of the route of inoculation. We found that similar to the lymphotropic strain HY TME, DY TME crosses mucosal epithelia, enters draining lymphatic vessels in underlying laminae propriae, and is transported to LRS tissues. Since DY TME causes disease once it enters the peripheral nervous system, the restriction in DY TME pathogenesis is due to its inability to establish infection in LRS tissues, not a failure of transport. To determine if LRS tissues can support DY TME formation, we performed protein misfolding cyclic amplification using DY PrPSc as the seed and spleen homogenate as the source of PrPC. We found that the spleen environment can support DY PrPSc formation, although at lower rates compared to lymphotropic strains, suggesting that the failure of DY TME to establish infection in the spleen is not due to the absence of a strain-specific conversion cofactor. Finally, we provide evidence that DY PrPSc is more susceptible to degradation when compared to PrPSc from other lymphotrophic strains. We hypothesize that the relative rates of PrPSc formation and clearance can influence prion tropism.