Citations

Transgender and nonbinary individuals are historically underserved by healthcare systems. A crucial area for improvement is fertility preservation counseling and service delivery, as gender-affirming hormone therapy and gender-affirming surgery may negatively affect future fertility. The methods available for fertility preservation depend on the patient’s pubertal status and utilization of gender-affirming therapies, and counseling and delivery of these services are complex and require a multidisciplinary approach. Further research is needed to identify pertinent stakeholders in managing the care of these patients, as well as to better understand the optimal frameworks for delivering integrated and comprehensive care to this patient population. Fertility preservation is an active and exciting area of scientific discovery and offers a wealth of opportunities to improve the care of transgender and nonbinary individuals.

Abstract A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analyses revealed a Basal-like A subtype-specific transcribed enhancer program in PDAC characterized by enhancer RNA (eRNA) production that is associated with more frequent chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histologic approach for PDAC patient stratification by performing RNA-ISH analyses for subtype-specific eRNAs on pathologic tissue samples. Thus, this study provides proof-of-concept that subtype-specific epigenetic changes relevant for PDAC progression can be detected at a single-cell level in complex, heterogeneous, primary tumor material. Implications: Subtype-specific enhancer activity analysis via detection of eRNAs on a single-cell level in patient material can be used as a potential tool for treatment stratification.

Background: The use of artificial intelligence (AI) in health care has grown exponentially with the promise of facilitating biomedical research and enhancing diagnosis, treatment, monitoring, disease prevention, and health care delivery. We aim to examine the current state, limitations, and future directions of AI in thyroidology. Summary: AI has been explored in thyroidology since the 1990s, and currently, there is an increasing interest in applying AI to improve the care of patients with thyroid nodules (TNODs), thyroid cancer, and functional or autoimmune thyroid disease. These applications aim to automate processes, improve the accuracy and consistency of diagnosis, personalize treatment, decrease the burden for health care professionals, improve access to specialized care in areas lacking expertise, deepen the understanding of subtle pathophysiologic patterns, and accelerate the learning curve of less experienced clinicians. There are promising results for many of these applications. Yet, most are in the validation or early clinical evaluation stages. Only a few are currently adopted for risk stratification of TNODs by ultrasound and determination of the malignant nature of indeterminate TNODs by molecular testing. Challenges of the currently available AI applications include the lack of prospective and multicenter validations and utility studies, small and low diversity of training data sets, differences in data sources, lack of explainability, unclear clinical impact, inadequate stakeholder engagement, and inability to use outside of the research setting, which might limit the value of their future adoption. Conclusions: AI has the potential to improve many aspects of thyroidology; however, addressing the limitations affecting the suitability of AI interventions in thyroidology is a prerequisite to ensure that AI provides added value for patients with thyroid disease.

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

Pick’s disease (PiD) is a devastating neurodegenerative disease that is characterized by dementia, frontotemporal lobar degeneration, and the aggregation of 3R tau in pathognomonic inclusions known as Pick bodies. The term PiD has adopted many meanings since its conception in 1926, but it is currently used as a strictly neuropathological term, since PiD patients cannot be diagnosed during life. Due to its rarity, PiD remains significantly understudied, and subsequently, the etiology and pathomechanisms of the disease remain to be elucidated. The study of PiD and the preferential 3R tau accumulation that is unique to PiD is imperative in order to expand the current understanding of the disease and inform future studies and therapeutic development, since the lack of intervention strategies for tauopathies remains an unmet need. Yet, the lack of an antemortem diagnostic test for the disease has further complicated the study of PiD. The development of a clinical diagnostic assay for PiD will be a vital step in the study of the disease that will greatly contribute to therapeutic research, clinical trial design and patient recruitment and ultimately improve patient outcomes. Seed aggregation assays have shown great promise for becoming ante mortem clinical diagnostic tools for many proteinopathies, including tauopathies. Future research on adapting and optimizing current seed aggregation assays to successfully detect 3R tau pathogenic forms from PiD samples will be critical in establishing a 3R tau specific seed aggregation assay that can be used for clinical diagnosis and treatment evaluation.

Abstract Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA &gt;90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.

Abstract This study explores the utility of the artificial intelligence model ChatGPT in predicting neuropathologic diagnoses from clinical summaries presented at clinicopathological conferences. Twenty-five cases of various neurodegenerative disorders were analyzed using ChatGPT versions 3.5 and 4. The primary neuropathological diagnoses predicted by the models aligned with the official neuropathologic diagnoses in 32% (ChatGPT-3.5) and 52% (ChatGPT-4) of cases. When considering all proposed diagnoses, accuracy increased to 76% and 84% for ChatGPT-3.5 and ChatGPT-4, respectively. These findings highlight the potential of artificial intelligence tools like ChatGPT in neuropathology, suggesting they may facilitate more comprehensive discussions in clinicopathological conferences.

No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan–Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed.

AbstractBackgroundThis is Part 3 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy using an enhanced recovery after surgery (ERAS) approach. This paper addresses organizational aspects of care.MethodsExperts in management of the high‐risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and MEDLINE database searches were performed for ERAS elements and relevant specific topics. Studies were selected with particular attention to randomized clinical trials, systematic reviews, meta‐analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations.ResultsComponents of organizational aspects of care were considered. Consensus was reached after three rounds of a modified Delphi process.ConclusionsThese guidelines are based on best current available evidence for organizational aspects of an ERAS® approach to patients undergoing emergency laparotomy and include discussion of less common aspects of care for the surgical patient, including end‐of‐life issues. These guidelines are not exhaustive but pull together evidence on important components of care for this high‐risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.