Extrahepatic biliary neuroendocrine tumors: A national cancer database analysis.

Background: Extrahepatic biliary neuroendocrine tumors (EBNETs) are rare. We aimed to characterize EBNETs including factors associated with survival. Methods: The National Cancer Database was queried for patients with EBNETs from 2004 to 2016. Patients who underwent resection were examined using Cox proportional hazards regression and the Kaplan-Meier method. We compared overall survival (OS) among patients with EBNETs to those with NETs from other primary sites. Results: Overall, 223 patients with EBNETs were identified. Patients were predominantly male (n = 113, 50.7 %), white (n = 177, 79.4 %) and presented without distant metastasis (n = 182, 81.6 %). The majority underwent operation (n = 127, 57.9 %) with resection of the primary tumor (n = 89, 70 %). Among patients who underwent resection (n = 71), multivariable regression demonstrated older age (HR 1.11, 95 % C.I. 1.04-1.17), lymph node metastases (HR 1.19, 95 % C.I. 1.02-1.38) and poorly/undifferentiated tumors [HR 22.3, 95 % C.I. 3.78-131]) were associated with worse overall survival. Patients with EBNETs experienced abbreviated OS compared to patients with small bowel or pancreas NETs (p < 0.001), but improved OS when compared to patients with gallbladder NETs (p = 0.001). Conclusions: Tumor differentiation and lymph node status significantly impact overall survival.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

Does generative artificial intelligence pose a risk to performance validity test security?

OBJECTIVE: We examined the performance validity test (PVT) security risk presented by artificial intelligence (AI) chatbots asking questions about neuropsychological evaluation and PVTs on two popular generative AI sites. METHOD: In 2023 and 2024, multiple questions were posed to ChatGPT-3 and Bard (now Gemini). One set started generally and refined follow-up questions based on AI responses. A second set asked how to feign, fake, or cheat. Responses were aggregated and independently rated for inaccuracy and threat. Responses not identified as inaccurate were assigned a four-level threat rating (no, mild, moderate, or high threat). Combined inaccuracy and threat ratings were examined cross-sectionally and longitudinally. RESULTS: Combined inaccuracy rating percentages were 35 to 42% in 2023 and 16 to 28% in 2024. Combined moderate/high threat ratings were observed in 24 to 41% of responses in 2023 and in 17 to 31% of responses in 2024. More ChatGPT-3 responses were rated moderate or high threat compared to Bard/Gemini responses. Over time, ChatGPT-3 responses became more accurate with a similar threat level, but Bard/Gemini responses did not change in accuracy or threat. Responses to how to feign queries demonstrated ethical opposition to feigning. Responses to similar queries in 2024 showed even stronger ethical opposition. CONCLUSIONS: AI chatbots are a threat to PVT test security. A proportion of responses were rated as moderate or high threat. Although ethical opposition to feigning guidance increased over time, the natural language interface and the volume of AI chatbot responses represent a potentially greater threat than traditional search engines.

Germline CDH1 Variants and Lifetime Cancer Risk.

Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

Predicting Survival in Mucinous Adenocarcinoma of the Appendix: Demographics, Disease Presentation, and Treatment Methodology.

BACKGROUND: Mucinous adenocarcinoma of the appendix (MACA) follows a complex disease course with variable survival. Large-scale predictive modeling may determine subtle yet important prognostic factors otherwise unseen in smaller cohort analyses. METHODS: Patients with MACA were identified from the Surveillance, Epidemiology, and End Results (SEER) Research Plus database (2005-2019). Primary, secondary, and tertiary outcomes were disease-specific survival (DSS), overall survival (OS), and average annual percent change (AAPC) in incidence. RESULTS: Among 4,258 included patients, MACA was most frequently diagnosed at 50 to 69 years (52.0%), with female preponderance (55.9%). MACA incidence AAPC was 3.8 (95% confidence interval [CI] 1.9-5.9). For patients with exclusive, first-diagnosis MACA included in survival analysis (3,222 patients), median DSS and OS were 118 and 88 months, respectively. In DSS-based multivariable analysis, worse prognosis was associated with non-Hispanic Black background (HR 1.36, 95% CI 1.02-1.82; p = 0.036), high grade (grade 3 HR 3.10, 95% CI 2.44-3.92; p < 0.001), lymphatic spread (HR 2.73, 95% CI 2.26-3.30; p < 0.001), and distant metastasis (HR 5.84, 95% CI 3.86-8.83; p < 0.001). In subcohort analysis of patients with rationale for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC, 2,387 patients), CRS-HIPEC was associated with survival benefit compared with surgery alone but only for moderate-grade tumors (median DSS/OS 138/138 vs. 116/87 months; p < 0.001). CONCLUSIONS: Mucinous adenocarcinoma of the appendix incidence is increasing in the United States. Survival rates are affected by both demographics and classical risk factors, and CRS-HIPEC-associated survival benefit predominantly occurs in moderate-grade tumors. Further exploration of biologic and clinicopathologic features may enhance risk stratification for this disease.

The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Cutaneous Applications of the Antiviral Drug Cidofovir: A Review.

Background/Objectives: Cidofovir, an antiviral drug approved for cytomegalovirus retinitis, has emerged as an alternative treatment option for virally induced cutaneous and mucocutaneous conditions, as well as being trialed as a treatment for select neoplasms. In this review, we highlight the existing evidence, clinical uses, and rationale of using cidofovir for the treatment of cutaneous pathologies. Methods: A PubMed database literature search was conducted to identify relevant articles for inclusion in this review. Results: Cidofovir has several cutaneous applications in various formulations including intravenous, topical, and subcutaneous administrations. Primarily through case reports, case series, and retrospective reviews, cidofovir has demonstrated efficacy in treating a variety of virally induced conditions-verruca vulgaris, herpes simplex virus, molluscum contagiosum-as well as in adjuvant treatment for select neoplasms. The drug has shown efficacy in immunocompromised and immunocompetent adults and children alike. Conclusions: The body of literature supports the use of cidofovir as an effective and well-tolerated treatment for many viral cutaneous pathologies, and encourages further study for its use as an adjuvant therapy for neoplastic disease.

Stool Protein Mass Spectrometry Identifies Biomarkers for Early Detection of Diffuse-type Gastric Cancer.

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of gastric cancer (GC) and individuals with hereditary diffuse gastric cancer (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of the stool of a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells [known as Triple Conditional (TCON) mice] identified differentially abundant proteins compared with littermate controls. Immunoblot assays validated a panel of proteins, including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP), as enriched in TCON stool compared with littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression compared with littermate controls. Proteomic mass spectrometry of stool obtained from patients with HDGC with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 relative to stool from healthy sex- and age-matched donors. Chemical inhibition of ASAH2 using C6 urea ceramide was toxic to GC cell lines and GC patient-derived organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, which suggested a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features that correlated with patient tumors. Herein, we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC. Prevention Relevance: This study highlights a novel panel of stool protein biomarkers that correlate with the presence of DGC and has potential use as early detection to improve clinical outcomes.

Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.

Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients.

Follicular lymphoma (FL) is a generally incurable malignancy that evolves from developmentally blocked germinal center (GC) B cells. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Dynamic interactions between tumor B cells and the tumor microenvironment (TME) are hypothesized to contribute to the broad spectrum of clinical behaviors observed among FL patients. Despite the urgent need, existing clinical tools do not reliably predict disease behavior. Using a multi-modal strategy, we examined cell-intrinsic and -extrinsic factors governing progression and therapeutic outcomes in FL patients enrolled onto a prospective clinical trial. By leveraging the strengths of each platform, we identify several tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk FL patients. These features include stromal desmoplasia and changes to the follicular growth pattern present 20 months before first progression and first relapse.

Refusals and Requests: In Defense of Consistency.

Physicians place significant weight on the distinction between acts and omissions. Most believe that autonomous refusals for procedures, such as blood transfusions and resuscitation, ought to be respected, but they feel no similar obligation to accede to requests for treatment that will, in the physician's opinion, harm the patient (e.g., assisted death). Thus, there is an asymmetry. In this paper, we challenge the strength of this distinction by arguing that the ordering of values should be the same in both cases. The reason for respecting refusals is that, in such cases, autonomy outweighs well-being. We argue that the same should be true in request cases, which means that requests should not be denied only due to the treatment being too harmful in the physician's opinion. Our strategy is to consider and reject a number of arguments for the asymmetrical view, including an appeal to the doing-allowing distinction and positive and negative rights. The duty to respect refusals is still greater than the duty to grant requests on our view, but, by arguing that the ordering of values is the same in both cases, we show that there is less of a distinction in healthcare between requests and refusals than many currently believe.

Points to consider regarding prophylactic total gastrectomy in germline CDH1 variant carriers.

Pathogenic germline CDH1 mutation confers high risk for developing diffuse gastric and lobular breast cancers in asymptomatic carriers. In these individuals, the estimated gastric cancer risk at 80 years of age is up to 70% for males and 56% for females. Due to this high-risk predisposition, prophylactic total gastrectomy is considered a unique life-saving approach in germline CDH1 carriers, as endoscopy often fails to detect early stage diffuse gastric carcinoma. However, surgical indication is controversial in some clinical contexts, with possible contraindications. This review discusses points against and in favor of a more aggressive surgical approach for consideration during the decision-making process.

The European Lead Factory: Results from a decade of collaborative, public-private, drug discovery programs.

The European Lead Factory (ELF) is a consortium of universities and small and medium-sized enterprises (SMEs) dedicated to drug discovery, and the pharmaceutical industry. This unprecedented consortium provides high-throughput screening, triage, and hit validation, including to non-consortium members. The ELF library was created through a novel compound-sharing model between nine pharmaceutical companies and expanded through library synthesis by chemistry-specialized SMEs. The library has been screened against ∼270 different targets and 15 phenotypic assays, and hits have been developed to form the basis of patents and spin-off companies. Here, we review the outcome of screening campaigns of the ELF, including the performance and physicochemical properties of the library, identification of possible frequent hitter compounds, and the effectiveness of the compound-sharing model.

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.

PURPOSE: Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS: Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS: One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION: RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

Perceptions of Readiness for Practice After Complex General Surgical Oncology Fellowship: A Survey Study.

BACKGROUND: Surgical subspecialty training aims to meet the needs of practicing surgeons and their communities. This study investigates career preparedness of Complex General Surgical Oncology (CGSO) fellowship graduates, identifies factors associated with practice readiness, and explores potential opportunities to improve the current training model. METHODS: The Society of Surgical Oncology partnered with the National Cancer Institute to conduct a 36-question survey of CGSO fellowship graduates from 2012 to 2022. RESULTS: The overall survey response rate was 38% (221/582) with a slight male predominance (63%). Forty-six percent of respondents completed their fellowship after 2019. Factors influencing fellowship program selection include breadth of cancer case exposure (82%), mentor influence (66%), and research opportunities (38%). Overall, graduates reported preparedness for practice; however, some reported unpreparedness in research (18%) and in specific clinical areas: thoracic (43%), hyperthermic intraperitoneal chemotherapy (HIPEC) (15%), and hepato-pancreato-biliary (15%) surgery. Regarding technical preparedness, 70% reported being "very prepared". Respondents indicated lack of preparedness in robotic (63%) and laparoscopic (33%) surgery approaches. Suggestions for training improvement included increased autonomy and case volumes, program development, and research infrastructure. Current practice patterns by graduates demonstrated discrepancies between ideal contracts and actual practice breakdowns, particularly related to the practice of general surgery. CONCLUSIONS: This study of CGSO fellowship graduates demonstrates potential gaps between trainee expectations and the realities of surgical oncology practice. Although CGSO fellowship appears to prepare surgeons for careers in surgical oncology, there may be opportunities to refine the training model to better align with the needs of practicing surgical oncologists.

Protocol for isolation of signet ring cells from human gastric mucosa.

More than 90% of individuals with germline pathogenic CDH1 variants will harbor occult, microscopic foci of signet ring cell carcinomas capable of progressing to advanced diffuse-type gastric cancer. Here, we present a protocol for high viability suspension of signet ring cells from human gastric tissue. We describe the steps for gastric mucosa isolation and tissue dissociation. We then detail procedures for embedding cells into HistoGel for immunohistochemistry staining and additional applications such as flow cytometry and single-cell sequencing.