Citations

AbstractCases of myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) co‐occurring with neoplasms have been reported. In this international, retrospective cohort study in South Korea and the USA, 16 of 445 (3.6%) patients with MOGAD had concurrent neoplasm within 2 years of MOGAD onset, resulting in a standardized incidence ratio for neoplasm of 3.10 (95% confidence interval [CI], 1.77–4.81; P < 0.001) when compared to the age‐ and country‐adjusted incidence of neoplasm in the general population. However, none of the nine tumor tissues obtained demonstrated MOG immunostaining. The slightly increased frequency without immunohistopathological evidence suggest with true paraneoplastic MOGAD is extremely rare.

Intrahepatic cholangiocarcinoma is an aggressive malignancy with rising incidence and poor outcomes. This review examines recent advancements in locoregional therapies for unresectable intrahepatic cholangiocarcinoma, focusing on external beam radiotherapy, transarterial radioembolization (TARE), hepatic artery infusion pump (HAIP) chemotherapy, and liver transplantation. Stereotactic body radiation therapy and proton beam therapy have shown promise in achieving local control and improving survival. TARE, with personalized dosimetry, has demonstrated encouraging results in select patient populations. HAIP chemotherapy, primarily studied using floxuridine, has yielded impressive survival outcomes in phase II trials. Liver transplantation, once contraindicated, is now being reconsidered for carefully selected patients with localized disease. While these locoregional approaches show potential, randomized controlled trials comparing them to standard systemic therapy are lacking. Patient selection remains crucial, with factors such as liver function, tumor burden, and molecular profile influencing treatment decisions. Ongoing research aims to optimize treatment sequencing, explore combination strategies with systemic therapies, and refine phenotype identification and patient selection criteria. As the landscape of intrahepatic cholangiocarcinoma management evolves, a multidisciplinary approach is essential to tailor treatment strategies and improve outcomes for patients with this challenging disease.

AbstractAutoimmune pancreatitis (AIP) is identified as a severe chronic immune‐related disorder in pancreas, including two subtypes. In this study, pancreatic lesions in patients diagnosed as either type 1 AIP or type 2 AIP are examined, and these patients’ peripheral blood at single‐cell level. Furthermore, flow cytometry, immunofluorescence, and functional assays are performed to verify the identified cell subtypes. In type 1 AIP, there is a notable increase in the amount of B cells and plasma cells, and IgG4+ plasma cells are key pathogenic cells of AIP. The differentiation path of naïve‐stage B cells into IgG4+ produced plasma cells is observed, and an increased amount of T helper cells and T follicular helper (Tfh) cells. This study also reveals that HIF‐1α, an activated transcriptional factor, can directly bind to promoter site of NAMPT, promoting higher levels of visfatin production in HIF1A+ classical monocytes. Pancreatic stellate cells can be activated by extracellular visfatin and promote the development of fibrotic response in pancreatic lesions across both AIP subtypes. The current findings shed light on the exploration of dynamic alterations in peripheral blood cells and cell subgroups in pancreatic lesions of AIP, while elucidating a pathogenic cell subset and potential fibrosis mechanism of AIP.

Encompassing a broad spectrum of abnormalities from diffuse liver disorders to focal liver lesions, hypointense findings on hepatobiliary phase MR images offer valuable diagnostic information, provide insight on the functional status of the liver, and aid in characterization of other imaging features.

639 Background: Limited treatment options exist for patients with locally advanced or metastatic biliary tract cancers (BTCs). Recently, several clinical trials provided preliminary evidence for human epidermal growth factor receptor-2 (HER2) as a new target for patients with HER2 expressing BTC. We conducted a systematic review and pooled analysis of the safety and efficacy of anti-HER2 agents in patients with advanced BTC. Methods: A comprehensive search of PubMed/MEDLINE and EMBASE was performed to identify phase 1, 2, or 3 clinical trials published between January 2019 and March 2024 that evaluated anti-HER2 therapy in locally advanced or metastatic BTC. Primary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Secondary endpoints included the incidence of treatment-related adverse events (TRAEs), rate of treatment discontinuation, and death. Forest plots were generated to summarize the results and demonstrate the effect size estimates for each study, along with their confidence intervals and the pooled estimate from the random-effects model. The random-effects models were configured to use the Restricted Maximum Likelihood method for estimating between-study variance for all analyses. Results: After excluding duplicate and irrelevant articles, data extraction and analysis were performed on eight selected clinical trials. The analysis included 368 patients with a median age of 64 (range 49-68), with 55% being female. Patients were treated with several anti-HER2 agents, including zanidatamab, pertuzumab plus trastuzumab, tucatinib plus trastuzumab, trastuzumab deruxtecan, trastuzumab plus chemotherapy, trastuzumab-pkrb plus chemotherapy and neratinib. The pooled ORR and DCR were 34% (95% CI 24-44) and 64% (95% CI 51-77) respectively. The pooled weighted PFS and median OS survival were 4.8 and 9.4 months, respectively. The pooled duration of response was 5.0 months. In our subset analysis, which included only patients who had received ≥1 prior therapy, the pooled ORR was 30% (95% CI 22-39), the pooled DCR was 62% (95% CI 48-75), and the pooled median PFS was 4.4 months. In the study cohort, 82.6% of patients experienced any adverse event, and 32.1% experienced a grade 3-4 adverse event. Only 5.7% of the patients discontinued treatment secondary to TRAEs. Conclusions: In patients with HER2 expressing BTCs, anti-HER2 therapies demonstrated preliminary signals of efficacy with manageable toxicities, particularly in the second-line setting.

5 Background: Metastatic anal squamous cell carcinoma is rare and associated with a poor prognosis. There is limited evidence on the impact of local interventions on survival outcomes in patients with metastatic disease. We aimed to evaluate the survival of patients with liver-only metastatic anal cancer following definitive local management of liver lesions. Methods: This is a single-institution retrospective cohort study of patients with liver-limited metastatic anal cancer who underwent curative-intent local therapy. Clinical characteristics were collected and analyzed. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS). Prognostic factors associated with DFS and OS were assessed using Cox-proportional hazards models. Results: Twenty-five patients were included, median age was 59 years, and 92% were female. None of the patients had known HIV infection, 92% had HPV-positive disease and 76% had metachronous liver metastases following locoregional disease. All patients received chemoradiation for the primary lesion Unilobar hepatic involvement was present in 76% of the patients, with 56% having a single metastatic lesion. Pre-intervention systemic therapy was provided to 52% of the patients, including 8 who received carboplatin and paclitaxel, with a median duration of 3 months and ORR of 69%. Definitive treatment of metastatic disease included surgical resection (60%), non-surgical interventions (20%), and multimodal therapy (20%). All patients had viable tumor in the pathological specimen. With a median follow-up of 22 months, median DFS was 7.3 months, and median OS was 51.3 months. An ECOG performance status of 2, poorly differentiated histology, and extrahepatic recurrence were identified as significant prognostic factors in the univariate analysis, but not in the multivariate analysis. Conclusions: Our results demonstrate potential for long-term survival in liver-limited metastatic anal squamous cell carcinoma amenable to local therapeutic intervention combined with systemic therapy. These findings warrant further prospective study of local therapy in oligometastatic anal cancer. Characteristics N=25 (%) Median number of liver metastases (range), lesions- 1- 2-3- >3 1 (1-20)14 (56)8 (32)3 (12) Median maximal diameter of liver metastases (range), cm 3 (0.9-11.9) Best response of liver metastases to chemotherapy (N=13)- Complete response- Partial response- Stable disease- Progressive disease 2 (15)7 (54)3 (23)1 (8) Surgical procedure (N=20)- Right/left hemi-hepatectomy- Segmentectomy- Wedge resection 4 (20)14 (70)2 (10) Non-surgical procedure (N=10)- Local ablation- Radiotherapy- Other 5 (50)3 (30)2 (20) Hepatic surgical margins (N=20)- Positive margins- Close margins (<1mm)- Negative margins 02 (10)18 (90) Recurrent disease- Yeso Intrahepatico Extrahepatic- No 20 (80)14 (70)6 (30)5 (20)

496 Background: Incidence of early-onset gastroesophageal adenocarcinoma (eoGEA, ages <50 years) has been increasing in the United States since the 1990s, the etiology of which is still unclear, and limited data exists on molecular drivers. This study evaluates somatic and germline profiles in eoGEA compared to average-onset GEA (aoGEA, ages≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of GEA (esophageal, gastroesophageal junction and gastric adenocarcinomas) patients who underwent somatic NGS testing via the Tempus xT assay (595-648 gene DNA panel) from 12/2017 to 07/2024. This assay assesses somatic tumor mutations (including SNVs, Indels, CNVs, and select SVs), MSI, TMB, and incidentally detected germline SNVs and small indels in matched normal tissue. Clinical characteristics and immunotherapy markers were compared between eoGEA and aoGEA by Wilcoxon Rank Sum or Chi-squared test. Somatic and germline mutations were compared between two age groups with false discovery rate adjustments. Results: We compared the demographic, clinical, and molecular features of a total of 5863 patients with eoGEA (n=785, median age 43) and aoGEA (n=5078, median age 68). Over 80% of patients were diagnosed with stage IV disease. The eoGEA group had a higher proportion of females, non-white, and Hispanic or Latino patients compared to the aoGEA group (p<0.001). Prevalence of MSI-H/ dMMR, and TMB-H was lower in eoGEA vs aoGEA (p<0.001), while PD-L1 expression was similar. Prevalence of somatic CDH1 , CDKN2A , and TP53 SNVs, and FGFR2 and KRAS CNAs were higher in eoGEA vs aoGEA (q<0.001). In a subset of 3286 patients with tumor/normal match testing (eoGEA=464 and aoGEA=2822), eoGEA also had a higher prevalence of germline CDH1 mutations (q<0.001). Conclusions: eoGEA has a unique somatic and germline mutation profile compared to aoGEA; further study evaluating the molecular landscape including epigenetic changes could shed light on underlying mechanisms responsible for the rising incidence of eoGEA. eoGEA (n=785) aoGEA (n=5078) p-value/q-value* Baseline characteristics Median age at diagnosis (IQR) 43 (38, 47) 68 (61,74) <0.001 Gender: male 509 (65%) 3798 (75%) <0.001 Race (white) 280 (69%) 2347 (80%) <0.001 Ethnicity (not hispanic or latino) 206 (60%) 1768 (86% <0.001 Stage IV 495 (85%) 2883 (81%) 0.073 Immunologic markers TMB ≥ 10 25 (3.2%) 519(10%) <0.001 MSI-H 13 (1.7%) 261 (5.1%) <0.001 dMMR 7 (2.2%) 120 (5.9%) 0.007 Somatic mutations profiles * CDH1 126 (16%) 334 (6.6%) <0.001 TP53 515 (66%) 3764 (74%) <0.001 CDKN2A 101 (13%) 1011 (20%) <0.001 KRAS 92 (12%) 931 (18%) <0.001 NOTCH1 12 (1.5%) 228 (4.5%) 0.002 Germline mutation profiles * eoGEA (N=464) aoGEA (N= 2,822) Overall prevalence 46 (9.9%) 207 (7.3%) CDH1 10 (2.2%) 8 (0.3%) 0.001 TP53 3 (0.6%) 0 (0%) 0.039 BRCA2 2 (0.4%) 38 (1.3%) 0.6 BRIP1 4 (0.9%) 10 (0.4%) 0.6

532 Background: HCC accounts for 80% of primary liver cancers, and worldwide, is the third common cause of cancer-related death. Two FDA approved 1st line systemic treatment options include atezo/bev and durva ± treme. Herein we report outcomes of these regimens in the 1st line setting via a real-world, multi-institutional retrospective cohort study. Methods: We reviewed clinical outcomes of patients (pts) who initiated 1st line atezo/bev or durva ± treme for unresectable HCC between March 2017 and February 2024, across 5 institutions (Mayo Clinic, University of Alabama, Cedars-Sinai Medical Center, University Hospitals Seidman Cancer Center and University of Michigan). Time to treatment failure (TTF) and overall survival (OS) were analyzed using the Kaplan-Meier method. Best (objective) response was tabulated. Multivariable analyses were performed using Cox models and logistic regression for time-to-event and binary outcomes, respectively, while adjusting for age, sex, race, HCC etiology, Child-Pugh class, and ALBI grade. Results: A total of 433 HCC pts were included; atezo/bev (336), durva ± treme (97). Median age at the start of therapy was 68 years; 77% were male, 82% were Caucasian. Etiologies of HCC were viral hepatitis (38%), MASLD (20%), alcohol (10%), non-viral multifactorial (10%), or unknown (22%). Pts receiving durva ± treme were less likely to have cirrhosis (11% vs. 28%, p<0.01) but similar in terms of macrovascular invasion (63% vs. 58%, p=0.35) compared to pts receiving atezo/bev. Reasons for treatment discontinuation were similar between the two groups, with the most common being disease progression - atezo/bev (56%) and durva ± treme (47%). The differences in clinical outcomes were not statistically significantly and remained consistent after multivariable adjustment. (Table, atezo/bev as the reference group). Outcomes were significantly different between Child-Pugh classes (CP: A,B,C) respectively, OS: 19.0 m, 6.4 m, 1.9 m (p<0.001); TTF: 6.1 m, 2.7 m, 1.3 m (p<0.001). Conclusions: In this real-world retrospective cohort study of unresectable HCC, the differences in overall survival, objective response, and time to treatment failure were not statistically significant between atezo/bev and durva ± treme in the 1st line setting. Outcome Atezo/bev Durva±treme Univariate p-value Multivariable adjusted hazard ratio (95% CI) Multivariable adjusted odds ratio (95% CI) Overall Survival, Median (month) 14.0 14.6 0.77 0.78 (0.54-1.14) --- Time to Treatment Failure, Median (month) 4.9 4.1 0.71 0.95 (0.72-1.26) --- Objective response, % 26.3% 21.1% 0.31 --- 0.78 (0.43-1.39)

163 Background: CRC with PM has a poor prognosis and limited treatment options. Immunotherapy has shown promise in improving outcomes for patients with microsatellite instability-high (MSI-H), mismatch repair-deficient (dMMR), and high tumor mutational burden (TMB-H) tumors. However the peritoneal niche has a unique microenvironment, which can influence the effectiveness of immune check point inhibitors (ICIs). We assessed the impact of ICI on progression-free survival (PFS) and overall survival (OS) in CRC patients (pts) and PM, considering key clinical and molecular characteristics. Methods: A retrospective review aiming to identify CRC pts with MSI-H/dMMR and PM treated with immunotherapy between 2015 and 2023 was performed. Data collected included pt demographics, tumor characteristics, and treatment details. Responses were evaluated using RECIST v1.1 criteria. Results: 37 pts were included, 9 (24%) had Lynch syndrome. The median age of diagnosis was 61 years and most pts were females (65%). Most pts had MSI-H/dMMR tumors, while one pt was treated based on ultra-hypermutated phenotype (TMB 202) and POLE mutation. Among those with available TMB data, the median TMB was 52 mutations/Mb (0-202). Common mutations were PMS2 (51%), MLH1 (38%), MSH6 (16.2%), and MSH2 (16.2%). Right-sided tumors were in 54%, mucinous histology in 62%, and ascites in 54%. Pts received a median of 11 cycles of ICI (2-52). Pembrolizumab was the most frequently used ICI (78%), while Nivolumab was used either alone (11%) or in combination with Ipilimumab (11%). Median PFS in our cohort was 7.8 months and median OS was 29.9 months. The disease control rate (DCR) was 81%, with an objective response rate (ORR) of 51.3% (9 complete responses, 12 partial responses). At the time of data collection, 30% of pts were off systemic therapy and 5-FU-based chemotherapy combined with a biologic agent was the most common subsequent treatment in 32% who had PD. Univariate analysis showed no significant differences in PFS or OS based on tumor sidedness, isolated PM, liver metastases, mucinous vs. non mucinous histology or BRAF / RAS status (WT vs mutant). Malignant ascites was associated with worse OS(HR 0.3; p= 0.03). Conclusions: Treatment with ICIs in pts with MSI-H/dMMR and/or TMB-H CRC and PM improved disease control in CRC pts with PM, however, as compared to historical controls for patients with MSI-H/d-MMR disease treated with ICI, this group showed less favorable outcomes. Malignant ascites was associated with poorer overall survival. Further research of the immune response and tumor microenvironment in the peritoneal cavity is warranted.