Theo Heller’s research while affiliated with National Institutes of Health and other places

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). Palifermin, a recombinant N-truncated keratinocyte growth factor (KGF), protects epithelial tissues, including the thymus and gut. While high-dose KGF prevents GVHD in preclinical models, lower doses of palifermin were ineffective in humans. We conducted a phase 1/2 trial evaluating high-dose palifermin for preventing severe chronic GVHD (GVHD) in matched unrelated donor T-cell replete peripheral-blood HCT following reduced-intensity conditioning (RIC). Using a 3+3 design, we determined the recommended phase 2 dose (RP2D), followed by an expansion phase. Palifermin (180-720 μg/kg) was given on day −7 before HCT. All 31 patients received fludarabine/cyclophosphamide RIC with tacrolimus, methotrexate, and sirolimus for GVHD prophylaxis. Palifermin was well tolerated, with self-limiting rash and pancreatic enzyme elevations as notable grade 3/4 adverse events. The RP2D was 720 μg/kg. Remarkably, no patients at this dose developed grade II-IV acute GVHD (0/19), though severe chronic GVHD rates (primary endpoint) remained unchanged compared to historical controls. Post-transplant lymphocyte phenotyping suggests palifermin modulates Treg and naïve CD4+ T-cell numbers. These findings indicate high-dose palifermin with RIC is safe and may prevent acute GVHD, though it did not impact chronic GVHD rates in this study. NCT02356159

Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multiomic analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of extracellular matrix remodeling in SRC lesions compared with unaffected adjacent gastric epithelium. Single-cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, and KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin reexpression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared with SRC lesions. Implications: The marked differences in the genomic and transcriptomic profiles of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.

The term porto-sinusoidal vascular disease (PSVD) was introduced in 2019 to describe a group of liver conditions that can lead to portal hypertension (PH) in the absence of cirrhosis or portal vein thrombosis, with or without specific findings on liver histology. The new nomenclature has facilitated the consolidation of knowledge on diseases previously referred to by various terms, including Banti’s disease, non-cirrhotic portal hypertension, non-cirrhotic portal fibrosis, and idiopathic portal hypertension, while excluding certain etiologies like sarcoidosis, congenital hepatic fibrosis, and Budd-Chiari syndrome. The prevalence and recognition of the disorder has been increasing. Advances in diagnostics and treatment have improved life expectancy for patients with associated conditions, such as immunodeficiencies and autoimmune diseases. Similar to cirrhosis, patients with PSVD may experience complications of PH, including variceal bleeding and ascites. However, less is known about its natural history, screening strategies, prognosis, and treatment options. This review discusses methods for assessing PSVD, including clinical and histological features, imaging techniques, and currently available treatments. It also addresses the challenges posed by the new nomenclature and the remaining questions in disease assessment.

Background Cytotoxic T-lymphocyte-associated protein 4 deficiency (CTLA4-D) is an inborn error of immunity (IEI) caused by heterozygous mutations, and characterized by immune cell infiltration into the gut and other organs, leading to intestinal disease, immune dysregulation and autoimmunity. While regulatory T-cell dysfunction remains central to CTLA4-D immunopathogenesis, mechanisms driving disease severity and intestinal pathology are unknown but likely involve intestinal dysbiosis. We determined whether the intestinal microbiome and metabolome could distinguish individuals with severe CTLA4-D and identify biomarkers of disease severity. Results The genera Veillonella and Streptococcus emerged as biomarkers that distinguished CTLA4-D from healthy cohorts from both the National Institutes of Health (NIH) Clinical Center, USA (NIH; CTLA-D, n = 32; healthy controls, n = 16), and a geographically distinct cohort from the Center for Chronic Immunodeficiency (CCI) of the Medical Center - University of Freiburg, Germany (CCI; CTLA4-D, n = 25; healthy controls, n = 24). Since IEIs in general may be associated with perturbations of the microbiota, a disease control cohort of individuals with common variable immunodeficiency (CVID, n = 20) was included to evaluate for a CTLA4-D-specific microbial signature. Despite common IEI-associated microbiome changes, the two bacterial genera retained their specificity as biomarkers for CTLA4-D. We further identified intestinal microbiome and metabolomic signatures that distinguished patients with CTLA4-D having severe vs. mild disease. Microbiome changes were associated with distinct stool metabolomic profiles and predicted changes in metabolic pathways. These differences were impacted by the presence of gastrointestinal manifestations and were partially reversed by treatment with abatacept and/or sirolimus. Conclusions Loss of intestinal microbial diversity and dysbiosis causing metabolomic changes was observed in CTLA4-D. Albeit some of these features were shared with CVID, the distinct changes associated with CTLA4-D highlight the fact that IEI-associated microbiome changes likely reflect the underlying immune dysregulation. Identified candidate intestinal microbial and metabolic biomarkers distinguishing individuals with CTLA4-D based on severity should be studied prospectively to determine their predictive value, and investigated as potential therapeutic targets. 5D3rs3jgvo7MqmP_TFVE2KVideo Abstract

Background Adolescents and young adults (AYA) with germline CDH1 variants are at risk of overtreatment when precancer lesions are detected with endoscopic screening. We characterize diffuse-type gastric cancer prevalence and survival in AYA managed with prophylactic total gastrectomy (PTG) or endoscopic surveillance. Methods Prospective cohort study of 188 individuals aged 39 and younger enrolled from January 27, 2017, to May 1, 2023. Clinicopathologic data, prevalence of early gastric signet ring cell (SRC) lesions, advanced gastric cancer diagnoses, and cancer-specific survival were measured. Results Among 188 AYA patients, 104 chose surveillance and 67 pursued PTG for management of elevated gastric cancer risk. AYA who enrolled early in the study period and had SRC lesions detected on preoperative endoscopy were more likely to elect for PTG compared to surveillance. SRC were detected on preoperative endoscopy in 48% of patients who subsequently had PTG, yet nearly all (93%, 62/67) had multifocal SRC (pT1aN0) on final pathology. Median age at enrollment (30 vs. 31 years, p = .21), biologic sex (p = .17), and median number of family members with gastric cancer (3 vs. 4, p = .14) were not different between groups. No patients under surveillance developed advanced cancer or developed cancer recurrence after PTG with a median follow-up of 2.5 years (IQR 1.6-4.0) from initial endoscopy. Conclusions Cancer-specific outcomes were not different in AYA who harbored SRC and were managed with surveillance or PTG. Lack of cancer-specific deaths and low prevalence of advanced gastric cancer underscore the risk of overtreatment of SRC lesions and suggest that active surveillance is warranted.

Background Prophylactic total gastrectomy (PTG) is performed in carriers of CDH1 pathogenic and likely pathogenic (P/LP) variants and is becoming more frequent with broader use of germline genetic testing. There is an unmet need to standardize care and enhance outcomes among patients undergoing surgery for the prevention of gastric cancer. Methods This was a retrospective analysis of 150 individuals with germline CDH1 P/LP variants who underwent PTG as part of a prospective natural history study from October 2017 to May 2023. All individuals received multidisciplinary, protocolized care before and after total gastrectomy. Results A total of 150 asymptomatic patients with germline CDH1 P/LP variants underwent PTG with the aid of a multidisciplinary enhanced recovery after surgery (ERAS) pathway. This study demonstrated that acute major morbidity (Clavien-Dindo grade of ≥3) was low (17/150 [11.3%]) and that the most common complication was anastomotic leak (11/150 [7.3%]) in the setting of a comprehensive preoperative and postoperative care pathway. Nearly all gastrectomy specimens (132/150 [88.0%]) harbored occult signet ring cell lesions on final pathology. There were no gastric cancer recurrences or gastric cancer-related deaths during the study period, with a median overall follow-up of 36 months (IQR, 24–48) from gastrectomy. Conclusion PTG can be performed with low surgical morbidity in a high-volume center. The delivery of patient-centered care by a multidisciplinary team and the application of an ERAS pathway may improve short-term outcomes. However, interventions that can reduce chronic morbidity associated with total gastrectomy warrant further study.