The role of adjuvant fractionated radiotherapy (aFRT) after gross total resection (GTR) of WHO-2 meningiomas remains unclear. We aimed to estimate the effect of aFRT on recurrence risk and survival following GTR and subtotal resection (STR). We analyzed 1452 patients with WHO-2 from our international, multicenter database (followed between 1989 and 2019). Outcomes were recurrence (10-year follow-up) and death (5-year follow-up). Risk estimates were obtained using competing risks and survival analysis. Average treatment effects were estimated by G-computation, adjusted for potential confounding by age, sex, Simpson grade, Ki-67 proliferation index, location, country group (universal healthcare or not), and year of treatment initiation. The robustness of findings was examined through sensitivity analyses. Overall, 276 of 1452 patients (19.0
This is the second of two articles presenting the European Crohn's and Colitis Organisation [ECCO] evidence‑based consensus guidelines on the management of adult patients with ulcerative colitis [UC]. The first article covers the medical management of UC, including acute severe colitis. The present article addresses the surgical management of medically refractory UC, including the general surgical approach and perioperative optimisation, surgical strategies and techniques, and recommended levels of centre expertise and surgical specialisation. Together, these two articles aim to inform shared decision‑making and to guide clinicians and healthcare professionals involved in the care of patients with UC, drawing on the best available evidence.
Abstract Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. In this study, we used coding and noncoding sequencing (n = 74), including whole-genome sequencing (WGS) of 24 paired tumor-normal samples, targeted sequencing (n = 55), and DNA methylation in 126 patients to characterize the disease. From WGS, we identified recurrent, predominantly clonal coding mutations in KLF2 (50%), KMT2D (25%), and NOTCH2 (25%), alongside rare mutations in FLNC (8%), novel mutations in FAM135B (17%), and noncoding mutational hot spots in BCL6, PAX5, and BACH2 linked to aberrant somatic hypermutation. At least 1 noncoding hot spot was detected in 69% of patients. Copy number aberrations were present in 73% of patients, including del(7q) (27%), gain(3q) (17%), and trisomy 12 (13%). DNA methylation profiling revealed 2 epigenetic subgroups: high-risk (HR) SMZL (n = 67) and low-risk SMZL (n = 59). SMZL-HR was associated with adverse features, including female sex, IGHV1-2∗04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epigenetically determined cumulative mitoses scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. Patients with SMZL-HR had significantly shorter time to first treatment (TTFT) (hazard ratio, 1.9; P = .003) and reduced overall survival (hazard ratio, 2.5; P = .039): 85% of patients with SMZL-HR required treatment and showed a higher frequency of transformation (P = .007) and mortality (P< .001). Multivariate analysis confirmed SMZL-HR as an independent predictor of shorter TTFT (hazard ratio, 2.4; P = .001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.
Abstract Purpose The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated. Methods We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989–2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence. Results Results demonstrated that the prognostic value of Ki-67 PI differed by subgroups defined by WHO grade and Simpson grade. For patients with the same Simpson grade (1–3), the predictive accuracy of Ki-67 PI for 10-year recurrence risk was stronger in WHO-2 than in WHO-1. Within WHO-1 and WHO-2 meningiomas, the predictive accuracy of Ki-67 PI increased with higher Simpson grade (1–3). However, no predictive value was observed in Simpson grade 4 resections regardless of WHO grade. Conclusion These findings highlight that Ki-67 PI should be interpreted in the context of both WHO grade and extent of resection, and, if done so, may offer potential value to refine individualized surveillance strategies in meningioma patients with gross total resection in the initial 10-year postoperative timeframe. Findings cannot be extrapolated beyond 10 years, which may be particularly relevant for WHO-1 tumors with low Ki-67 PI and Simpson grade 1 resection.
Background/Objective: Very late relapses (VLRs) in Hodgkin lymphoma (HL), occurring ≥5 years after initial treatment, have been well-recognized for decades. Recent studies have highlighted the persistent and linear risk of relapse extending well beyond 5 years, while also describing the incidence and risk factors. However, extremely late relapses (EXLRs) occurring ≥20 years after diagnosis remain poorly described and largely limited to case reports. In the present study, we focus on patients experiencing EXLRs after chemotherapy or combined modality therapy, aiming to define their incidence, clinical characteristics, and outcomes, and to compare them with patients with VLRs relapsing between 5 and 20 years from initial diagnosis. Methods: We performed a retrospective study of 270 patients with HL, who received chemotherapy ± radiotherapy (CT ± RT), remained in continuous remission at least 5 years from treatment initiation and had follow-up data exceeding 20 years from diagnosis. The primary endpoint was the cumulative incidence (CumInc) of VLR, considering death from any cause as a competing event. Results: EXLR occurred in 9/270 cases. The CumInc of EXLR at 25, 30 and 35.2 years was 2.23%, 4.80% and 7.87%, respectively. Compared to patients with VLRs (N = 61), patients with EXLRs had a lower incidence of anemia and a higher incidence of lymphocytopenia at diagnosis. At relapse, patients with EXLR tended to be older, had a lower frequency of extranodal disease, were more often managed with the same or similar salvage CT regimen as at initial diagnosis (reinduction), and were considered less frequently as candidates for autologous stem cell transplantation. In univariate analysis, the omission of RT at initial treatment and the histologic subtype of mixed cellularity (MC) were associated with a higher probability of EXLR. Compared to patients with VLRs, patients with EXLRs had a 10-year treatment to second failure (TT2F) of 88.9% versus 47.4%, a 10-year overall survival after relapse (O2S) of 77.8% versus 54.9% and a 10-year disease-specific survival (DSS) of 88.9% versus 70.9%. Conclusions: The study describes for the first time the incidence and characteristics of EXLRs in HL. These patients had excellent outcome despite having relapsing disease, suggesting that this subgroup of patients may have distinct biological characteristics.
