Citations

The treatment paradigm for deficient mismatch repair (dMMR) colorectal cancer (CRC) has evolved substantially in recent years. Universal mismatch repair testing and broad use of next-generation sequencing have increased the detection of dMMR tumours, which exhibit microsatellite instability-high (MSI-H), hypermutation and abundant neoantigens. The presence of dMMR/MSI-H serves as a robust predictive biomarker for immune checkpoint inhibitor (ICI) therapy, which has demonstrated superior efficacy to cytotoxic chemotherapy in the metastatic setting and led to the first tumour-agnostic Food and Drug Administration approval in 2017 for metastatic dMMR/MSI-H solid tumours. Recent evidence also supports the benefit of ICIs in non-metastatic dMMR CRC. Neoadjuvant immunotherapy has produced high rates of pathological response in both colon and rectal cancers. In locally advanced dMMR rectal cancer, ICI therapy has enabled omission of chemoradiation and surgery in most patients. In resected node-positive dMMR colon cancer, the addition of ICI therapy to chemotherapy has substantially improved disease-free survival, expanding its role earlier in the disease course. Despite these advances, the optimal treatment strategy for non-metastatic dMMR CRC remains undefined due to the lack of direct comparative studies. Importantly, a subset of patients derives limited or no benefit from ICIs despite dMMR/MSI-H status, underscoring the need to further elucidate resistance mechanisms and to develop strategies to overcome them.

ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.

ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.

ABSTRACT Background Many older adults undergo gastrointestinal (GI) cancer surgery, yet the relative impacts of advanced age, comorbidity, and frailty on postoperative mortality and failure to rescue (FTR) remain unclear. We aimed to compare the impacts of these factors on postoperative outcomes in a large population‐based cohort. Method We conducted a national retrospective linked database study of patients aged ≥ 65 years who underwent resection for GI or hepatobiliary cancer in Aotearoa New Zealand between 2005 and 2020. Age, comorbidity (C3 Comorbidity Score), and frailty (Hospital Frailty Risk Score) were examined as independent predictors of 90‐day mortality, complications, and FTR (death following a complication). Logistic regression models were adjusted for demographic and clinical covariates. Results Among 21,729 patients (mean age 75.8 ± 6.8 years), 49.3% experienced one or more complications and 6.1% died within 90 days (FTR rate of 12.3%). In adjusted models, each additional 5 years of age increased 90‐day mortality odds by 40% (adjusted odds ratio [aOR] 1.40 and 95% CI 1.34–1.46). Although higher comorbidity (C3 > 3) and frailty (Hospital Frailty Risk Score > 15) also independently raised mortality risk (aOR 1.98 and 2.04, respectively), age exerted the largest effect on mortality and FTR. Conclusion Chronological age, comorbidity, and frailty each predict worse outcomes following GI cancer surgery, but advanced age remains the dominant driver of 90‐day mortality and FTR. These findings underscore the need for risk stratification, shared decision‐making, and preoperative optimization as wells as intense surveillance for complications and early definitive care of older adults undergoing major oncologic operations.

ABSTRACT This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt “fatty pancreas” as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta‐cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high‐quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence‐based clinical practice in this emerging field.

Abstract Background Intravesical Mycobacterium bovis bacillus Calmette-Guérin (BCG) is standard therapy for high-risk nonmuscle-invasive bladder cancer. However, M bovis infections can occur and are not well understood. We aimed to characterize clinical phenotypes, diagnosis, management, and outcomes of culture-confirmed M bovis BCG infections following intravesical therapy for urothelial carcinoma. Methods A retrospective single-center review of adults with culture-confirmed M bovis infection after intravesical BCG (May 2009–July 2024) was conducted, abstracting clinical, microbiologic, treatment, and outcome data. Results Twenty-two White male patients (median age, 77 years) were included; 8 (36.4%) had localized genitourinary infection, 6 (27.3%) had dissemination limited to blood, and 8 (36.4%) had dissemination to other organs. Patients with bloodstream-only infection presented acutely (median 1.5 days after last BCG), whereas those with localized or organ-disseminated disease presented months to years after BCG, with the longest diagnostic delays in organ-disseminated infection. Despite all cases had culture-proven M bovis BCG infection, acid-fast smear, Mycobacterium tuberculosis complex polymerase chain reaction, and histopathology had limited sensitivity. All isolates were susceptible to rifampin, isoniazid, and ethambutol; all were resistant to pyrazinamide. Median treatment duration exceeded 9 months, 94.7% achieved cure, and attributable mortality was 5.0% (1 vascular graft infection). Conclusions M bovis BCG infections following intravesical therapy have favorable outcomes but are often associated with diagnostic delays and prolonged treatment. Early suspicion, comprehensive diagnostic evaluation, and timely surgical source control when indicated are critical. Management strategies should be tailored based on the extent of disease dissemination and individual host factors.

Background/Objectives: Precocious puberty (PP), defined as the onset of secondary sexual characteristics before 8 years in girls and 9 years in boys, is associated with psychosocial distress, compromised adult height, and long-term metabolic risk. Early identification remains challenging, as current diagnostic approaches are largely reactive and rely on invasive or resource-intensive testing. This narrative review examines how artificial intelligence (AI) can support earlier risk prediction and detection of PP through integration of clinical, hormonal, imaging, lifestyle, and environmental data. Methods: A narrative literature review was conducted using PubMed, Scopus, Embase, Web of Science, and Google Scholar to identify relevant studies published between 2005 and 2025. Eligible studies included original research and high-quality reviews that examined AI-based approaches, such as machine learning and deep learning, in pediatric endocrinology, particularly for the prediction or diagnosis of central or peripheral precocious puberty. Studies incorporating clinical, hormonal, radiological, lifestyle, environmental, or multi-omics data relevant to AI modeling were included. Results: AI models, including XGBoost, random forest, convolutional neural networks, and regression-based approaches, have demonstrated potential utility in predicting central precocious puberty using hormonal, imaging, and growth data. Reported applications include automated bone age assessment, lifestyle and dietary risk stratification, and exploratory use of wearable-derived behavioral data. However, progress is limited by small pediatric datasets, population bias, limited interpretability, and unresolved ethical challenges related to privacy, consent, and equity. Conclusions: Artificial intelligence represents a promising decision-support approach for earlier, non-invasive, and individualized risk assessment in precocious puberty. Future progress will depend on the integration of longitudinal, multimodal data, the development of ethical models, and interdisciplinary collaboration among pediatric endocrinologists, data scientists, and public health stakeholders.