Citations

Abstract Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG , remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacies of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in fusion-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG -positine patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.

Background: Historically, the standard of care for advanced biliary tract cancers (aBTCs) was gemcitabine plus cisplatin (GemCis). Immunotherapy plus GemCis is now recommended as a first-line treatment for aBTCs. Whether patients can tolerate eight cycles of GemCis in clinical practice, as per the Advanced Biliary Cancer (ABC)-02 study, remains to be assessed. We performed a retrospective observational cohort study to assess real-world treatment patterns and overall survival (OS) in patients with de novo or recurrent aBTCs treated with first-line gemcitabine-based chemotherapy in the United States. Methods: This retrospective observational cohort study used Optum’s de-identified Market Clarity Data (Market Clarity). Adults diagnosed with de novo or recurrent aBTCs in the United States who began first-line gemcitabine-based chemotherapy from January 2016–March 2022 were identified and followed from index until death, the end of continuous enrolment, or the end of study period. Treatment patterns and OS were assessed. Results: Overall, 559 patients were included (de novo, n = 462; recurrent, n = 97). GemCis was the most common first-line therapy received (de novo: 73.8%; recurrent: 57.7%). Most patients received approximately five cycles of GemCis; median (95% CI) time to discontinuation was 4.6 (4.3–5.1) months. Most patients died over the follow-up period (de novo: 70.3%; recurrent: 62.9%). Median OS (95% CI) was 14.2 (12.1–16.1) months (de novo) and 18.5 (15.6–26.9) months (recurrent). Conclusions: GemCis was the most common first-line therapy received during the study period; most patients were unable to receive eight cycles of GemCis. Survival was limited over the follow-up period, highlighting the need for new treatments for aBTCs. Future studies are warranted to understand the real-world impact of first-line immunotherapy plus GemCis for patients with aBTCs.

ABSTRACTParents of children with Down syndrome have historically reported poor experiences receiving a prenatal diagnosis. In a 2003 survey, mothers reported that their physicians pitied them, emphasized negative aspects of Down syndrome, and encouraged them to terminate the pregnancy. This study assesses whether parents' perceptions have since improved. Community‐based organizations that had distributed the original 2003 survey distributed a similar survey to parents who have had a child with Down syndrome since 2003. Compared to the 2003 survey, parents continued to report dissatisfaction with their prenatal medical care (N = 60). Though subgroups became likelier to view their testing experience positively, parents' experiences worsened on certain metrics. Most parents reported dissatisfaction when providers conveyed pity or attempted to influence their decision‐making about the pregnancy. Interventions to date have failed to improve parents' perceptions of their prenatal medical support, urging new strategies to improve parents' care.

ABSTRACT Background Myasthenia gravis (MG) is strongly associated with thymic tumors, but whether it is also associated with extrathymic cancers is debatable or whether MG can be considered a paraneoplastic disorder for extrathymic cancers. Methods This is a retrospective analysis of the MG cohort for 23 years' time (January 2000 to May 2023), extracting cancer rates with clinical, electrophysiological, and biochemical cancer associations and the effect of chronic medications. Results We identified 436 patients with MG and 3924 controls. The median age at symptom onset was 64 (5–93 years) for males and 54 (1–87 years) for females. MG symptoms at onset were recorded as ocular (60%), strictly bulbar (10%), or generalized (23%). Extrathymic cancer was found in 32% of MG patients. In 3%, thymic and extrathymic cancers co‐occurred. Compared to controls, neurology (12.2%, 159/1308), internal medicine (24.4%, 319/1308), or rheumatology (12%, 157/1308), MG patients had significantly higher rates of extrathymic cancers ( p < 0.001). Compared to the rheumatology group, the cancer relative risk of 2.97, CI = 2.5–3.4. Furthermore, the prevalence of extrathymic cancers was significantly increased within the paraneoplastic time window, defined as ±5 years from cancer diagnosis to myasthenia onset ( p < 0.01). Conclusion MG was significantly associated with an increased risk of extrathymic cancers, particularly within the paraneoplastic time window. These findings suggest that MG might potentially behave as a paraneoplastic disorder.

Background Data regarding long-term recovery from autoimmune encephalitis (AE) remain limited. Methods This retrospective observational study investigated outcomes in 182 patients who met the 2016 criteria for definite AE. Recovery data were available in 172 patients. Follow-up data at ≥24 months post-attack were available for 119. Recovery trajectory, residual symptoms, outcome predictors and causes of post-AE death were assessed. Results Of 172 patients, 138 (80%) achieved good recovery (modified Rankin Scale (mRS) ≤2) with a median recovery time of 4 months (95% CI: 2 to 6 months). Recovery varied by associated neural antibody, with the best recovery observed in leucine-rich glioma-inactivated 1 (97% good recovery, median recovery time 0 (0 to 2) months). Paraneoplastic AE (p=0.007), severe attacks (eg, mRS ≥4 at attack, p=0.007) and cerebrospinal fluid pleocytosis (p=0.005) were associated with a lower likelihood of good recovery, while seizure presentation (p=0.026) was associated with better recovery. Despite good recovery, several residual symptoms persisted ≥24 months post-AE, including cognitive deficits (53%), seizures (26%), depression (23%), sleep disorders (25%), brainstem/cerebellar symptoms (13%), other movement disorders (14%) and autonomic symptoms (12%). Predictors of long-term sequelae included disabling cognitive deficit at onset and delayed immunotherapy for post AE-dementia, and medial temporal atrophy as well as escalation to cyclophosphamide therapy for both drug-resistant epilepsy and chronic depression. Of 182 patients, 20 (11%) died; the most common cause of death was progression of AE (6/20 (30%)). Conclusion While the majority of patients achieved functional independence after AE, several residual symptoms persisted. Several clinical and paraclinical features were associated with long-term sequelae.

Cardiopulmonary resuscitation (CPR) is a life-sustaining technique for cardiac arrest that is not without its own risks. Myocardial puncture from traumatic CPR is a rare but serious potential complication of CPR that can lead to significant morbidity and mortality. Our case demonstrates posterior left ventricular wall perforation from a rib fracture during CPR and highlights the importance of post-CPR echocardiography in the assessment of CPR-associated cardiac injuries that may warrant intervention.

A woman in her 70s with well-controlled HIV on antiretroviral therapy presented with a several-month history of an asymptomatic perianal lesion. Skin examination showed a 0.5–1 cm red-pink, shiny, exophytic papule with visible telangiectasias near the anal verge. The differential diagnosis was most concerning for Kaposi sarcoma. A shave biopsy with electrodessication was performed for both diagnostic and therapeutic purposes. Histology revealed a dome-shaped lesion with a diffuse inflammatory infiltrate composed of lymphocytes and eosinophils. The vessels in the superficial and mid-dermis showed cuboidal-to-columnar endothelial cells with nuclear enlargement, conspicuous nucleoli, and ample cytoplasm. These findings were consistent with angiolymphoid hyperplasia with eosinophilia (ALHE). Only 2.4% of ALHE occur on the genitals and fewer than 1% on the buttocks. Additionally, few of these are reported in female patients and none in female patients with HIV. At 12 months post-treatment, the patient remains without evidence of recurrence.