Citations

Noncirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology—such as idiopathic portal hypertension (IPH), noncirrhotic portal fibrosis (NCPF), obliterative portal venopathy, and nodular regenerative hyperplasia—leading to substantial variability in diagnosis, reporting, and international research collaboration. Differences in guideline definitions from major societies (AASLD, EASL, and APASL), together with the presence of characteristic histologic lesions in patients without clinically overt portal hypertension, have further complicated disease classification. To address these challenges, a large, multisociety, international initiative was convened to harmonize nomenclature and diagnostic criteria. Representatives from liver, pathology, and pediatric hepatology societies across the Americas, Europe, and Asia participated in a structured consensus process that included specialized working groups and external Delphi validation. The initiative produced a globally harmonized and implementable diagnostic framework. Consensus was reached that the terms porto-sinusoidal vascular disorder (PSVD) and NCPF may be used interchangeably when identical diagnostic criteria are applied, and that they should be written as PSVD or NCPF . The diagnosis was defined as fundamentally clinicopathological, requiring integrated assessment. Core principles include the need for a high-quality liver biopsy (≥10 mm), mandatory exclusion of cirrhosis, and systematic exclusion of specific alternative conditions. Importantly, the consensus recognizes that PSVD or NCPF may be diagnosed even without clinical portal hypertension and may coexist with other liver diseases, provided cirrhosis is excluded. Standardized major and minor histologic criteria were developed collaboratively by expert pathologists and externally validated. Features of portal hypertension were harmonized into specific and nonspecific categories applicable to routine clinical practice. An integrated diagnostic scoring system incorporating histology, clinical features, associated conditions, and concommitant etiologies was developed and validated using the Delphi method. This consensus provides the first internationally endorsed, unified framework for the diagnosis of PSVD or NCPF. Its global implementation is expected to reduce diagnostic variability, improve comparability across regions, and facilitate the development of robust, internationally harmonized clinical and translational research cohorts.

Lactococcosis has emerged as an economically and ecologically significant disease in aquatic animals worldwide. This study employed multilocus sequence typing (MLST) to investigate the genetic diversity of Lactococcus spp. strains from Brazilian fish species and evaluate their phylogenetic relationships with global isolates to elucidate potential epidemiological connections involving multiple host species and distinct geographic regions. A total of 55 isolates from different laboratories had their DNA extracted, followed by the amplification and sequencing of the internal fragments of seven housekeeping genes (als, atpA, tuf, gapC, gyrB, rpoC and galP). Sequence types (STs) and clonal complexes (CCs) were defined. An unrooted neighbor-joining phylogenetic tree was generated using allele profiles from this study and those previously reported from other aquatic animal species. The isolates comprised 29 STs (11 previously reported, 18 novel ones), which were grouped into species-specific CCs: CC5 (L. formosensis); CC4, CC17, CC62 (L. garvieae); CC24, CC29, CC97 (L. petauri). Considerable genetic divergence was observed, with L. formosensis and L. garvieae forming heterogeneous populations, while L. petauri was more homogeneous. These findings describe the MLST structure of the sampled isolates and should be interpreted as hypothesis-generating rather than population-level estimates of genotype prevalence. Phylogenetics confirmed groupings within the CCs and revealed additional phylogenetic clustering patterns. In conclusion, the Brazilian Lactococcus spp. strains analyzed in this study constitute a genetically diverse population based on their STs. MLST and phylogenetic analysis demonstrated genetic relatedness between the L. garvieae and L. formosensis isolates from this study and those from other aquatic animal species. In contrast, all the STs identified for L. petauri in this study were unrelated to the MLST lineages responsible for outbreaks in Brazilian Nile tilapia (Oreochromis niloticus) and North American rainbow trout (Oncorhynchus mykiss). This suggests that piscine L. petauri populations in the Americas evolved from distinct ancestral origins.

PURPOSE Hepatopancreatobiliary (HPB) cancers—including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), pancreatic ductal adenocarcinoma (PDAC), and gallbladder cancer—are aggressive malignancies with limited treatment options and poor prognosis. The emergence of personalized liquid biopsy technologies, particularly bespoke circulating tumor DNA (ctDNA), offers new opportunities for improving clinical management. Traditional methods like imaging and tumor markers may miss early recurrence or evolving disease. This study explores the real-world application of ctDNA in HPB cancers, focusing on its use for surveillance, diagnostic clarification, treatment monitoring, and recurrence detection. Methods We retrospectively analyzed the use of a personalized ctDNA assay (Signatera, Natera) in 54 patients with HPB cancers at a single academic cancer center. The cohort included PDAC (22/54), HCC (11/54), and CCA (21/54). ctDNA was assessed longitudinally for surveillance, treatment monitoring, or diagnostic clarification. Concordance with imaging and tumor markers, as well as lead time to recurrence detection, was descriptively analyzed. RESULTS ctDNA was evaluable in 37/54 patients (84.6%), with ctDNA positivity in 22/37 (59.5%). Success rates by tumor type were 16/22 (72.7%) in PDAC, 10/11 (90.9%) in HCC, and 11/21 (52.4%) in CCA. ctDNA concordance with imaging was observed in 69/85 assessments (72.6%) and with tumor markers (carbohydrate antigen 19-9 or alpha fetoprotein) in 39/95 (41%). Clinical applications included disease surveillance (21/54, 38.9%), treatment monitoring (24/54, 44.4%), and diagnostic clarification (16/54, 29.6%). In patients with recurrence, ctDNA detected disease before imaging in several cases, with a median lead time of 28 days (range, 1 month to 7 months). CONCLUSION Personalized ctDNA testing demonstrated meaningful utility across HPB cancers, enabling early recurrence detection and guiding clinical decision making as a complementary tool in multidisciplinary care.

Abstract Background: Patients (pts) with myeloma (MM) receiving CAR-T therapy have usually been exposed to many prior therapies. Melphalan (HDM) and other chemotherapies can induce cellular senescence. It has recently been shown that MM cells can also exhibit features of therapy-induced senescence (TIS). TIS tumor cells are associated with resistance to therapy and relapse. To investigate the presence of TIS MM cells prior to CAR-T and association with response, we examined the transcriptome and phenotype of MM prior to CAR-T. Method: We used scRNA-seq data from bone marrow (BM) MM cells: Boiarsky, et al. (GSE193531, dbGaP: phs001323.v3.p1) newly diagnosed MM (NDMM) pts; Dhodapkar, et al. (GSE210079), pre- and post CAR-T; pts who received CAR-T at Mayo Clinic, pre- (N=10) and post- (N=2). To evaluate TIS, single-cell gene set enrichment analysis (scGSEA) for several gene sets (PMID: 40164720): SenUp (Senescence Upregulated), SenGA (Senescence Growth Arrest), and SCAPs (Senescent Cell Anti-apoptosis Pathways); and a Plasma Cell Senescence (PCSen) gene set (GSE5900, GSE47552). To assess TIS and myeloid phenotype, BM MM cells (CD138+) were stained for CD14, CD16, KLRG1 and GPNMB and analyzed by CytoFlex and Kaluza. Results: In the integrated dataset, scGSEA showed significantly higher enrichment of PCSen, SenUp, SenGA, and SCAPs in late-stage MM cells (both pre- and post-CAR-T) compared to NDMM and healthy donors (p<0.05, Kruskal-Wallis with Dunn’s posttest). Conversely, the Normal gene set was significantly enriched in healthy plasma cells relative to MM (p<0.05). Expression of CDKN2A, which encodes the senescence marker p16, was also increased in late-stage MM relative to NDMM or healthy plasma cells. Notably, in our newly generated scRNA-seq samples collected within 6 months before CAR-T, a significant inverse correlation between senescence marker expression and progression free survival (PFS) post-CAR-T was seen, suggesting that MM cells exhibiting TIS may be more resistant to T cell mediated cytotoxicity. We found that 62.5% (25/40) of pts had >1% MM cells that were CD14+. Among them, the median CD14+ MM cells were 5.5% (1-71%); and median CD14+CD16+ MM cells were 2.14% (0.4-67%). Among 7 pts with available samples for KLRG1 and GPNMB assessment, 100% (7/7) had KLRG+ MM cells (median: 59% (24-99%)) and 57% (4/7) had GPNMB+ MM cells (median: 15% (3.9-30%)), and KLRG1+GPNMB+ MM cells (median: 9.6% (3.8-17%)). Conclusion: Our study shows that late-line MM cells exhibit transcriptional and phenotype profiles consistent with TIS. This senescent phenotype may contribute to resistance to immunotherapies, including CAR-T. Additional phenotype data is collected and will be presented. A phase II clinical trial is ongoing (NCT06940297) to assess for the combined treatment with senolytic drugs dasatinib and quercetin peri-CART to deepen clinical response. Citation Format: Sofia Arbelaez, Andre De Menezes Silva Corraes, Gabriel Alvares Borges, Chen Wu, Christoph Schaefers, Malvika Gupta, Zuoyi Shao, Kevin Regan, Rayaan Kamal, Angelo Jose Guilatco, Neal I. Sannuli, Ying Li, Taxiarchis Kourelis, Wilson Gonsalves, Moritz Binder, Melinda Tan, Nadine Abdallah, Megan Weivoda, Yi Lin. Myeloma cells with therapy-induced senescence-like phenotype are associated with resistance to CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6467.

Abstract Background: Therapy-induced senescence (TIS), a tumor cell state associated with distinct gene expression patterns and implicated in therapy resistance, may be activated in Multiple Myeloma (MM) patients (pt) by genotoxic chemotherapies, such as high-dose melphalan (HDM). We investigated whether TIS is activated in MM cells following chemotherapy and linked to resistance to T-cell directed therapies. Method: We integrated scRNA-seq data from healthy donors (CNTRL) and MM pts (newly-diagnosed (NDMM), pre/post-CAR-T) bone marrow plasma cells (PCs) using two public datasets (Boiarsky, et al.; Dhodapkar, et al.) and a newly generated pt dataset. Senescence was evaluated using scGSEA with published gene sets (SenUp, SenGA, and SCAPs). For in vitro MM cytotoxicity assay, human H929 MM cells were treated with vehicle (Veh) or HDM (3µM, IC90) for 6h and examined for TIS features. H929VEH or H929HDM were co-cultured with CNTRL T cells with or without teclistamab (Tec, 10 nM) or with day 14 PBMCs from MM pts post-CAR-T (E:T 5:1). CAR+ T cells were high among the day 14 PBMC (median±SD: 93.4±7.2% of CD3+ cells, n=6). Results: scGSEA revealed significantly higher enrichment of SenUp, SenGA, and SCAPs in late-stage MM cells compared to NDMM and CNTRL (p<0.05). Expression of CDKN2A, encoding the senescence marker p16, was also increased in late-stage MM relative to NDMM/CNTRL PCs. Of interest, cells enriched for senescence also exhibited enrichment for myeloid markers (TET2, CEBP family). Notably, in pre-CAR-T, increased baseline senescence or myeloid marker expression showed an inverse association with CAR-T progression-free survival (PFS), suggesting TIS confers resistance to T cell mediated cytotoxicity. This may be due to myeloid plasticity. TIS MM cells generated in vitro, H929HDM, exhibited a distinct morphology characterized by increased cell size and enhanced cytoplasmic granularity. Increased CD14 expression was seen in 4 of the 6 experiments (median, range % increase: 11.2%, 2.5%-21%), consistent with myeloid plasticity; Increased KLRG1 expression was seen in 5 of the 7 experiments (median MFI ratio, range: 3.7, 1.3-471). No significant change was seen in GPNMB expression. Compared to H929VEH, H929HDM had a reduction in killing by CAR-T cells (median±SD: 22.8±32.94% n=6, p=0.016, Wilcoxon paired test). Similarly, H929HDM had a 10.69% decrease in Tec-mediated T-cell killing compared to H929VEH (n=8, p=0.02, Wilcoxon paired test). Conclusions: Late-stage MM cells exhibit transcriptional signatures consistent with TIS, which can be associated with decreased PFS to CAR-T. We report an in vitro model of TIS MM cells for testing of resistance to T cell killing. Based on these findings, a phase II trial (NCT06940297) is underway to test the hypothesis that peri-CAR-T senolytic therapy with dasatinib and quercetin will deepen responses by targeting this resistant TIS MM population. Citation Format: Christoph Schaefers, Angelo Jose Guilatco, Sofia Arbelaez, Gabriel Alvares Borges, Chen Wu, Andre de Menezes Silva Corraes, Malvika Gupta, Zuoyi Shao, Kevin Regan, Rayaan Kamal, Neal I. Sannuli, Ying Li, Taxiarchis Kourelis, Wilson Gonsalves, Melinda Tan, Nadine Abdallah, Yi Lin, Megan Weivoda. Myeloma cells with therapy-induced senescence-like phenotype have increased resistance to killing by T cell directed therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6475.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

PURPOSE For patients with advanced biliary tract cancer (BTC), cancer-related time spent in health care systems, time toxicity, represents a critical but understudied burden affecting quality of life. This study aimed to quantify time toxicity in patients receiving first-line systemic therapy and evaluate whether the addition of durvalumab to gemcitabine plus cisplatin (GC) increases health care contact time. METHODS This international, multicenter, retrospective cohort study included patients with advanced BTC seen between January 2019 and April 2024 at Mayo Clinic Enterprise (US), and between January 2021 and April 2024 at Kyorin University Hospital (Japan), and Hospital Israelita Albert Einstein (Brazil). Patients received GC plus durvalumab (GCD) or GC. Time toxicity was recorded from treatment initiation until discontinuation or last follow-up during first-line systemic therapy. Multiple regression analysis identified factors associated with high time toxicity. RESULTS Among 193 patients (102 GCD, 91 GC; median age 65 years; 50% male; 49% Eastern Cooperative Oncology Group performance status [PS] 0), median time on treatment (TOT) was 156 days (95% CI, 122 to 190). The median proportion of total time toxicity was 14.4% (IQR, 10.9-20.6). Planned visits accounted for 11.9%, while unplanned visits were infrequent (1.8%). Time toxicity strongly correlated with TOT ( r = 0.824) and progression-free survival ( r = 0.827). Despite longer treatment in the GCD group than the GC group (212 v 134 days; P = .027), total time toxicity was similar (27 v 18 days; P = .19). Younger age and poor PS were independent factors of higher time toxicity. CONCLUSION Time toxicity represents a meaningful metric that allows for more comprehensive integration of the net benefit in patients with advanced BTC with a limited lifespan.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.