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INTRODUCTION: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS). METHODS: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples, and follow-up re-biopsies were included. For tumour grading, apart from 2017 WHO classification system, we applied a recently proposed SI-NET site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10%. RESULTS: We included 45 patients. Median Ki-67 index at SI-NET diagnosis was 2% (range 0.5-15%). Thirty-three patients had Ki67 indices <5% (70.2%), 6 had Ki67: 5-10% (12.8%) and 8 had Ki67 ≥10% (17%). Mean time to re-biopsy was 48.8 months (SD: +/-162.5). At re-biopsy, the median change in Ki-67 index (absolute value; follow-up minus time of diagnosis) was 1% (range -10 to +38%). An increase in Ki-67 occurred in 20 patients (42.6%); in 14 patients the change in Ki-67 resulted in progression to higher tumour grade following the modified grading system. Patients with an increment in Ki-67≥1% had a median OS of 32.9 months vs. 80.5 months in patients without (HR 5.6, 95% CI: 1.42-22.02, p=0.014). When applying the novel modified histopathological grading system for SI-NETs, patients with grade progression had a median OS of 32.9 months vs. 53.7 months in those without (HR=4.61, 95%CI: 1.22-13.54; p=0.022). At multivariable analysis, grade progression was confirmed as an independent predictor for death (HR=7.2, 95%CI: 1.58-32.82; p=0.011). CONCLUSIONS: Metachronous increment in Ki-67 indices and related grade progression over time following a site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10% is observed in approximately 1/3 of SI-NETs included in this study and it is associated with worse survival outcomes.
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CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index. OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs). DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months. MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates. RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death. CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.
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The improving effectiveness of health care leads inevitably to a rapid increase in the elderly population worldwide. At advanced ages, however, people experience chronic disabilities, which significantly increase the social and economic burden while curtailing survival, independence, and quality of life of the aging population. As aging is a multifactorial process, apart from genetic predisposition, other environmental factors, such as chronic sterile inflammation and cellular senescence, contribute as crucial participants and have been targeted to reverse their deleterious effects on tissue homeostasis and functional integrity. Cellular senescence refers to the essentially irreversible inhibition of cellular proliferation when cells are subjected to extrinsic or endogenous stress. Although the process of cellular senescence has long been known, recent evidence demonstrated that it characterizes many aging phenotypes and that elimination of senescent cells at the tissue level can improve age-related tissue dysfunction. These observations have renewed scientific interest in possible therapeutic interventions. Two major chronic diseases associated with aging that impose an enormous burden on global health systems are type 2 diabetes and osteoporosis. This review presents current data on (i) the underlying molecular mechanisms of cellular senescence, (ii) its relationship to these two endocrine diseases that are today prevalent worldwide, and (iii) future prospects of targeted intervention with the aim of simultaneously improving the progression and prognosis of these serious problems of aging.