Citations

The WHO 2019 classification of digestive tract tumors introduced a high-grade (G3) category for well-differentiated neuroendocrine tumors (NETs). These neoplasms appear to have a better prognosis than poorly differentiated neuroendocrine carcinomas (NECs) and may not respond to platinum-based chemotherapy, which is the treatment of choice for NECs, justifying the creation of this new category. Most existing data on G3 NETs are derived from pancreatic neuroendocrine neoplasms, as the majority of G3 neuroendocrine neoplasms (NENs) arise there. G3 NETs are rare at extrapancreatic sites, and their prognosis and behavior are not well studied. We collected and analyzed a multi-institutional cohort of 24 extrapancreatic primary gastrointestinal G3 NETs based on mitotic rate and/or Ki67 index (5 gastric, 13 small bowel, 6 colorectal/anal). Mean Ki67 index was 29.3% (range: 10.5% to 50.2%). Cases generally showed typical well-differentiated NET morphology. Nodal metastases were present in 17/17 (100%) patients; 13/24 (45%) had distant metastases at initial presentation, and 7 patients developed them on follow-up. With a median of 29 months of follow-up, only 2 patients (8%) were alive without disease. Outcomes of G3 NETs were compared with a separate cohort of 125 extrapancreatic G1/G2 gastrointestinal NETs. G3 tumors presented at a higher pT-category stage ( P <0.001) and overall stage ( P =0.002), and patients with G3 disease were more likely to die than those with G1/G2 disease ( P <0.001). Our data show that, like pancreatic G3 NETs, rare extrapancreatic gastrointestinal G3 NETs exhibit aggressive behavior compared with their G1/G2 counterparts (although small bowel NETs tend to recur irrespective of grade). In most cases, the G3 designation is driven by Ki67 index, though exceptions exist, emphasizing the need for reviewing mitotic count in every case.

BACKGROUND: While health systems have implemented resources to improve lipid management in people with atherosclerotic cardiovascular disease, the population-level effectiveness is unclear. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease between January 1, 2021, and December 31, 2023, across 16 US academic health systems were analyzed. Atherosclerotic cardiovascular disease (defined by diagnosis and procedure codes) was established on or before the index date defined as the date of the most recent LDL-C (low-density lipoprotein-cholesterol) or the last day of the study period for those without an LDL-C available. Systems were surveyed to identify lipid management programs (eg, prevention/lipid clinic, electronic health record–based tools, and lipid management algorithms). Sequential multilevel multivariable logistic regression modeling was used to (1) assess the system-level association between an LDL-C <70 mg/dL and the presence of lipid management programs, adjusting for patient-level demographic and clinical characteristics, and (2) whether system-level uptake of statin or nonstatin lipid-lowering therapy was associated with an LDL-C <70 mg/dL. RESULTS: We included 1 738 042 patients with atherosclerotic cardiovascular disease (median, 88 365 per system; range, 17 086–2 48 371). About 81% of the health systems had prevention or lipid clinics. The proportion of those on statins ranged from 31.0% to 60.4% across health systems (median, 46.3%). Lower proportions were observed in the use of high-intensity statins (16.2%–33.1%), nonstatins (2.6%–8.1%), and combination lipid-lowering therapy (1.7%–6.3%). Among those with an LDL-C level available (n=890 521), 42.5% had an LDL-C <70 mg/dL, ranging 35.8% to 49.4% across systems. There was no association between the odds of achieving LDL-C <70 mg/dL and health system lipid management algorithm, prevention clinics/lipid clinics, or electronic health record–based tools. Neither system-level high-intensity statin utilization nor nonstatin use was associated with an LDL-C <70 mg/dL. CONCLUSIONS: Despite variability in lipid management resources and lipid-lowering therapy use across systems, many did not reach an LDL-C <70 mg/dL, and there was low uptake of lipid-lowering therapy. Innovative implementation strategies are needed for system-level lipid management.

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 Advanced chronic diseases, or multicomplexity in older adults presents unique challenges. Transthyretin cardiac amyloidosis (ATTR‐CA) is one such scenario where heart failure is a common presentation, and management remains challenging. We describe the challenges involved in the diagnosis of ATTR‐CA in older adults, which has implications on treatment options. We discuss the application of comprehensive geriatric assessment (CGA) and shared decision making (SDM) in the context of these challenges. Based on geriatric medicine principles, an innovative framework for applying SDM in ATTR‐CA patients is proposed, including consideration of the patient priorities care approach. The proposed framework emphasizes assessing functionality, frailty, and life expectancy to help categorize risk. This framework can be applied in various advanced chronic diseases or multicomplexity. Based on risk categorization, treatment burden, and alignment with values and preferences, management pathways are suggested for each risk category. Incorporating CGA and SDM, the proposed framework supports patient‐centered care, ensuring that clinical recommendations are tailored to each older adult's unique needs and goals. In ATTR‐CA, a collaboration between cardiology and geriatric medicine provides significant value in managing older adults. The need to prevent age‐related bias in clinical decision‐making exists across all health conditions, and the proposed framework allows for a thorough evaluation of multimorbidity, frailty, disability, and patient preferences. While ATTR‐CA is used as a prototype, this integrated approach can be applied across all health conditions and is essential for delivering holistic care, improving communication, and aligning treatment plans with patient values.

Background and Aims: Hypothermic oxygenated machine perfusion (HOPE) improves outcomes in orthotopic liver transplantation (OLT), but reliance on University of Wisconsin machine perfusion solution (UW-MPS) increases costs and logistical burden. Histidine-tryptophan-ketoglutarate (HTK) has potential as a single-solution alternative for HOPE. This study evaluated the safety and efficacy of HTK versus UW-MPS during HOPE. Methods: A retrospective, propensity score-matched cohort study including 46 patients who received donation after brain death (DBD) grafts that were preserved with HOPE at the Medical University of Vienna between May 2018 and October 2024 was conducted. A total of 23 patients received grafts perfused with HTK; another 23 patients transplanted with organs perfused with UW-MPS were matched based on recipient age and sodium model of end-stage liver disease score, donor age and sex, cold ischemia time, and perfusion time. Postoperative outcomes, perfusion parameters, and cost differences were assessed. Results: The HTK and UW-MPS cohorts demonstrated comparable perfusion dynamics and vascular resistance. While arterial pressure and flow were higher in the UW-MPS group, clinical outcomes—including early allograft dysfunction (47.8% each), ICU stay, and comprehensive complication index—were statistically similar. A trend toward fewer biliary complications (13.0% vs. 30.4%) and reduced hemodialysis requirement (17.4% vs. 30.4%) was observed in the HTK group. Use of HTK reduced perfusion-related costs by approximately EUR 560 per procedure. Conclusion: HTK is a viable alternative to UW-MPS during HOPE in OLT of DBD grafts, offering comparable short-term outcomes and relevant cost savings. Prospective studies are warranted to validate these findings and explore broader applications of single-solution perfusion strategies.

Background This review evaluates the current evidence for the role of venoactive drugs (VADs) for venous origin chronic pelvic pain (VO-CPP) and provide insights to inform the design of an ideal randomized controlled trial (RCT) for future research. Methods A search was performed in the following databases: Ovid MEDLINE, Ovid EMBASE, Cochrane Library, and Scopus. Studies retrieved were screened for eligibility using Covidence software following PRISMA reviews’ methodology. The quality of RCTs and cross-over RCTs was assessed using the Cochrane review tools. Studies were reviewed by 3 physicians, with discrepancies resolved by consensus. A narrative review of the studies was conducted to identify and synthesize clinical outcomes and safety profile of VADs. Results Eleven studies (n = 748) were identified: 3 RCTs and 8 open-label prospective studies. Most participants were reproductive-age women with confirmed VO-CPP, diagnosed via imaging or laparoscopy. Micronized Purified Flavonoid Fraction (MPFF) was the most studied VAD. Pain assessment with VAS scores was the primary endpoint in all studies, with significant benefit in patients consistently demonstrated. Other endpoints included Pelvic Venous Clinical Severity Score (PVCSS) and Pelvic Varicose Vein Questionnaire (PVVQ), with improved symptoms and quality of life. Quantitative outcomes were also reported (reduced pelvic vein diameter; better venous hemodynamics). MPFF was safe, with few adverse events reported. Three RCTs had methodological limitations, with two judged high-risk for bias. Conclusions While many identified studies appear to be of low quality, the consistent beneficial effect on VO-CPP scores and the safety profile observed across all reviewed studies suggest that flavonoids have a positive role in the conservative management of pelvic venous disease (PeVD). Future well-designed RCTs are needed to confirm these findings. In the meantime, flavonoids should be considered a therapeutic option for symptomatic patients with PeVD who are not qualified for, not wishing, or are awaiting intervention.

Abstract Background Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined. Methods We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as “Astroblastoma, MN1-altered” under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses. Results DNA methylation analyses identified 3 groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Groups A and C. Conclusions Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.

Abstract Background: TP53-mutated myeloid neoplasms (MNs) represent one of the most lethal subgroups of blood cancers. The World Health Organization (WHO-5) recognize TP53-mutated (TP53mut) myelodysplastic syndrome (MDS) and International Consensus Classification (ICC) recognize TP53mut MDS and acute myeloid leukaemia (AML) as distinct disease entities, acknowledging their dismal prognosis and the urgent need for novel therapeutic strategies. However, key discrepancies exist between the classifications, creating uncertainty in diagnosis, influencing therapeutic decisions, and complicating clinical trial enrolment for patients with uniformly poor survival. Importantly, neither classifications included TP53-mutated myelofibrosis (MF), other myeloproliferative neoplasms (MPN), and MDS/MPN overlap syndromes, despite growing evidence that these cases carry similar adverse outcomes. To address these critical gaps, we conducted a comprehensive analysis across the full spectrum of TP53-mutated MN. Methods: We included TP53mut cases with variant allele frequency (VAF ≥2%) of AML, MDS, MDS/MPN overlap, myelofibrosis and other MPN managed at the Mayo clinic (Rochester, USA) and Local Health Network in South Australia (Australia). Cases were classified according to the revised 4th edition WHO classification (WHO-4R). Biallelic TP53 loss was defined as: (i) ≥2 mutations with VAF ≥2%; (ii) single TP53mut with VAF ≥2% plus 17p loss on karyotype, FISH, or SNP array; or (iii) single TP53mut with VAF ≥50% with or without 17p loss. Monoallelic loss was defined as a single TP53mut with VAF &lt;50% without 17p loss or copy neutral loss of heterozygosity. The primary endpoint was overall survival (OS) from diagnosis, censored at allogeneic transplantation. Conditional inference tree analysis was performed to define the effect of individual predictors on OS. Results: We identified 853 TP53mutMN cases including WHO-4R-defined AML (BM/PB blasts ≥20%, n=314; 36.8%), MDS with excess blasts-2 (EB-2; BM 10–19% or PB 5–19%, n=129; 15.1%), MDS-EB-1 (BM 5–9% or PB 2–4%, n=100; 11.7%), and MDS with low blasts (LB; BM &lt;5% and PB &lt;1%, n=228; 26.7%). MF included chronic phase (MF-CP, n=48; 5.6%), accelerated phase (MF-AP, n=7; 0.8%), and blast phase (MF-BP, n=17; 2.0%). Additional cases comprised other MPN-chronic phase (n=3, 0.4%) and MDS/MPN overlap syndromes (n=7, 0.8%). Of 848 evaluable TP53mut MN, 616 (72.6%) harbored biallelic TP53 loss and 232 (27.4%) had monoallelic loss, with 42.4% (n=98) of monoallelic cases harboring a complex karyotype (CK). Biallelic loss was highly prevalent in AML (83.1%), MDS (70.4%), and MDS/MPN overlap (71.4%), but was less frequent in cases with MPN (33.3%) and MF-chronic phase (25.0%). Across the spectrum, the frequency of biallelic loss increased stepwise with disease progression, rising from MDS-LB (62.8%) to MDS-EB1 (76.0%), MDS-EB2 (79.5%), AML (83.1%), and MF-AP/BP (79.2%) (P&lt;0.0001). In multivariable analysis, WHO-4R category, TP53mut VAF, biallelic loss and CK were independent predictors of poor survival in TP53mut MN. Conditional inference tree analysis stratified the cohort into seven prognostic groups with distinct median OS: (1) AML, MF-BP/AP, and MDS/MPN overlap regardless of mono/biallelic and CK status (n=335, 39.7%; median OS 4.0 months); (2) MDS-EB1/EB2 with biallelic loss or monoallelic plus CK (n=212, 25.1%; 7.2 months); (3) MDS-LB, MF-CP and MPN with CK (n=156, 18.5%, OS 10.2 months); (4) biallelic MDS-LB (n=28, 3.3%; OS 15.6 months), (5) monoallelic MDS-EB1/EB2 without CK (n=20, 2.4%; OS 26.2 months), (6) monoallelic MDS-LB without CK (n=57, 6.7%; OS 33.4 months), and (7) MF-CP and other MPN without CK (n=36, 4.3%; OS 37.0 months). This analysis defines a clear stepwise risk gradient, identifying subsets with extremely poor prognosis versus a relatively indolent disease. Conclusions: This is the first study to evaluate the prognostic impact of TP53mut MN across the entire MN spectrum, providing a framework for future refinement of TP53-driven disease classification. Key findings include: (i) MF-AP/BP and MDS/MPN overlap exhibit survival outcomes as dismal as AML, irrespective of the TP53 allele status; and (ii) complex karyotype is a surrogate for “biallelic equivalent”, refining risk interpretation in monoallelic cases. Overall, our study defines seven prognostic subgroups spanning all TP53mut MN, offering a foundation for risk-adapted clinical trial design and future classification updates.

Abstract Introduction: Epcoritamab (epcor) was the first CD3xCD20 bispecific antibody approved for treatment of R/R DLBCL in May 2023 based on its efficacy and safety in EPCORE NHL-1. Patients (pts) enrolled in clinical trials are highly selected, and those with high-risk features, such as primary refractory disease, early post-CAR T relapse, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and CD20+ status are often underrepresented or excluded. As epcor use expands in more heterogeneous, real-world populations, there is increasing interest in understanding pt characteristics and response outcomes associated with its use outside of clinical trials. In particular, pts with DLBCL that is resistant to, or relapse soon after, CAR T are left with limited treatment options and often present with rapidly progressive, resistant disease, making them especially challenging to manage. Generating real-world evidence is critical for informing optimal use of epcor in routine practice. Methods: Real-EPCOR is a multicenter US retrospective chart review study at &gt;8 academic and community oncology centers designed to evaluate the real-world use of epcor. Eligible pts are adults (≥18 years) with R/R DLBCL and ≥2 prior lines of therapy (LOT) who initiated epcor outside of a clinical trial after 5/19/23. Pt demographic, clinical, and treatment data were collected, including ECOG PS, refractory status, prior CAR T, and CD20+ status. Overall response rate (ORR) was evaluated during epcor treatment and defined as the proportion of pts achieving complete response (CR) or partial response among pts with ≥1 evaluable response assessment or who died due to disease progression before response assessment. ORR and CR rate were calculated for the entire cohort, for pts receiving ≥2 cycles of epcor (full cycle is 28 days), and for pts who received prior CAR T. Results: This interim analysis included 34 pts from 2 centers. Data collection and analysis is ongoing and updated results with additional pts and longer follow-up may be included at time of presentation. Median age was 67 years; 68% pts were male and 85% were White. Median time from DLBCL diagnosis to initiation of epcor was 15.5 months. The most common comorbidities were cardiovascular disease (59%) and diabetes mellitus (29%). ECOG PS was ≥2 in 29% of pts, and 85% of pts had Ann Arbor stage 3-4 disease. Nearly all (97%) had CD20+ DLBCL. High-risk features were common at time of epcor initiation, including 53% with International Prognostic Index (IPI) ≥3, 26% with double-hit, and 24% with non-GCB subtype. Among pts who received ≥2 cycles of epcor (n=15), 20% had ECOG PS ≥2 and 33% had IPI ≥3; in post-CAR T pts, 22% had ECOG PS ≥2 and 57% had IPI ≥3. Median number of prior LOT was 3 (range: 2–9); 44% of pts initiated epcor as 3L therapy. Prior to epcor, 41% had primary refractory disease. Following their most recent therapy, 72% had refractory disease, and 43% had DLBCL that was refractory to all prior LOT in those with known refractory status. Most pts (68%) received prior CAR T, with a median interval of 4.6 months from infusion to epcor initiation, and 23% initiated epcor ≤2 months from CAR T. 15 pts (44%) received CAR T in the LOT immediately prior to epcor, 9 (60%) of whom were refractory to CAR T. The ORR was 50% and CR rate was 29% in the overall evaluable population (n=24). 10 pts were not evaluable, as they did not undergo a response assessment either because they remained alive without assessment or experienced a non-progression-related event. Among pts who received ≥2 cycles of epcor, ORR was 85% and CR rate was 54% in the evaluable population (n=13). Among 23 post-CAR T pts, ORR was 53% and CR rate was 33% in the evaluable population (n=15). Conclusion: In this real-world interim analysis, pts with R/R DLBCL treated with epcor had a high proportion of CD20+ disease, higher-risk clinical features, greater comorbidity burden, and more complex treatment histories, including a substantial proportion with prior CAR T, compared to pts in EPCORE NHL-1. Therefore, the ORR remains highly meaningful in the overall cohort despite being lower than the trial. Encouraging ORRs among those who received ≥2 cycles of epcor or had prior CAR T suggest that epcor monotherapy may provide clinical benefit even in difficult-to-treat pts in the real-world setting. Ongoing real-world survival analyses will inform the optimal use of epcor within the evolving treatment landscape of R/R DLBCL.