Search

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083)., (© 2024. The Author(s).)

This study delves into the intricate landscape of SARS-CoV-2 vaccine response in immunodeficient patients, focusing on the dynamics of both humoral and cell-mediated immunity. The cohort includes patients with common variable immunodeficiency (CVI), agammaglobulinemia (XLA), and combined immunodeficiency (CI). The findings reveal varying degrees of antibody production, with XLA patients exhibiting no measurable response but displaying a robust T-cell-mediated response. The study emphasizes the importance of considering both arms of the immune system in assessing vaccine immunogenicity, particularly in the context of immunodeficiency. The results challenge conventional measures of vaccine efficacy only based on antibody titers, highlighting the need for a more comprehensive understanding of the immune response in this vulnerable population. This research contributes valuable insights to guide clinical decisions regarding vaccination strategies, booster doses, and overall protection in immunodeficient individuals.

Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors., Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes., Results: A total of 1,395 patients were included. Primary tumors included non-small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07-1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03-1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16-2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04-1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM., Conclusions: In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population., (©2023 American Association for Cancer Research.)

The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.

A 68-year-old man diagnosed with cT3N2 adenocarcinoma of the rectum presented with a synchronous solitary liver metastasis on CT scan. Neoadjuvant chemoradiotherapy was started to downstage the primary tumour. Resection of the rectal tumour followed 3 months after the last radiotherapy session and primary resection of the isolated liver lesion was performed in the intervening period. Histopathological assessment of the liver lesion, however, showed no malignancy, but did reveal a necrotic infection due to Enterobius vermicularis. This parasite is frequently found in the intestines, but only rarely infects the liver. The patient was subsequently treated with the anthelmintic drug mebendazole 100 mg once a week for 2 weeks. Histopathological assessment of the rectal specimen showed complete regression after neoadjuvant chemoradiotherapy without evidence of remaining E. vermicularis, suggesting pinworm eradication. The patient recovered promptly after both surgical procedures., (2015 BMJ Publishing Group Ltd.)

Bisphosphonates (BPs) are approved as standard therapy in breast cancer for the treatment of bone metastases, since they were demonstrated to reduce the prevalence of skeletal-related events including fractures and hypercalcemia. In the adjuvant setting, BPs can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. In this article we will review the mechanisms through which BPs have been demonstrated to prevent premetastatic niche formation and cell proliferation in bone lesions. Moreover, preclinical evidence of antitumoral effects of BPs will be presented and results from the most important clinical trials will be described critically. BPs may clearly play a clinically important role in early breast cancer in a postmenopausal adjuvant setting.

Background: The European Association for the Study of the Liver (EASL) criteria and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) are currently adopted to evaluate radiological response in patients affected by HCC and treated with loco-regional procedures. Several studies explored the validity of these measurements in predicting survival but definitive data are still lacking., Aim: To conduct a systematic review of studies exploring mRECIST and EASL criteria usefulness in predictive radiological response in HCC undergoing loco-regional therapies and their validity in predicting survival., Methods: A comprehensive search of the literature was performed in electronic databases EMBASE, MEDLINE, COCHRANE LIBRARY, ASCO conferences and EASL conferences up to June 10, 2014. Our overall search strategy included terms for HCC, mRECIST, and EASL. Loco-regional procedures included transarterial embolization (TAE), transarterial chemoembolization (TACE) and cryoablation. Inter-method agreement between EASL and mRECIST was assessed using the k coefficient. For each criteria, overall survival was described in responders vs. non-responders patients, considering all target lesions response., Results: Among 18 initially found publications, 7 reports including 1357 patients were considered eligible. All studies were published as full-text articles. Proportion of responders according to mRECIST and EASL criteria was 62.4% and 61.3%, respectively. In the pooled population, 1286 agreements were observed between the two methods (kappa statistics 0.928, 95% confidence interval 0.912-0.944). HR for overall survival (responders versus non responders) according to mRECIST and EASL was 0.39 (95% confidence interval 0.26-0.61, p<0.0001) and 0.38 (95% confidence interval 0.24-0.61, p<0.0001), respectively., Conclusion: In this literature-based meta-analysis, mRECIST and EASL criteria showed very good concordance in HCC patients undergoing loco-regional treatments. Objective response according to both criteria confirms a strong prognostic value in terms of overall survival. This prognostic value appears to be very similar between the two criteria.

Aim: Tobacco smoke contains many chemicals that are harmful and cause carcinogenesis. The aim of this study was to confirm the relationship between smoking and changes in respiratory functional and laboratory parameters comparing, in particular, smoking-cessation treatment's outcomes between smokers who reduce tobacco consumption (reducers) and smokers who quit completely (quitters)., Materials & Methods: A total of 181 current smokers were prospectively enrolled. All of the participants completed a sociodemographic questionnaire and underwent 3 months of varenicline plus nicotine-replacement therapy combined with basic counseling. Laboratory tests and clinical and lung-function parameters were evaluated at entry and after 3 months of therapy. After 3 months of smoking-cessation treatment, subjects were sorted into two subgroups: quitters and reducers., Results: After 3 months of combined therapy, 56% of the subjects (101 patients) stopped smoking; the remaining patients reduced. Significant improvements in pulmonary-function tests (especially in the 25-75% forced expiratory volume testing) were recorded. The most significant improvements were obtained in quitters: carboxyhemoglobin was reduced by 1.06%, the average expiratory flow between 25 and 75% of vital capacity increased by 16% from predicted, mean serum CEA level decreased by 1.83 ng/ml, heart rate decreased by approximately 16 beats/min on average and forced 1 s expiratory flow increased by 2.57% from predicted. The Fagerström scores showed a positive correlation with the corresponding blood carboxyhemoglobin levels., Conclusion: Just 3 months of smoking-cessation treatment achieved significant improvements in lung-function parameters and a decrease in serum CEA, mostly in subjects who totally quit smoking. This result confirms the effectiveness of our smoking-cessation treatment and suggests the utility of the selected parameters as tools to motivate and monitor patients.

Purpose: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration., Methods: One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded., Results: Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population., Conclusions: Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.

Inflammation and immune response play an important role in the pathogenesis of atherosclerosis. In this prospective study we tested the hypothesis of whether polymorphic variations in the NOD2/CARD15 gene may influence the risk of developing clinically evident coronary artery disease (CAD). ARG702TRP, GLY908ARG, and Leu1007fsinsC NOD2/CARD15 polymorphisms were analyzed in 109 consecutive patients with angiographically documented CAD and in 109 age- and sex-matched healthy controls. The ARG702TRP, GLY908ARG, and Leu1007fsinsC polymorphisms were analyzed by polymerase chain reaction followed by restriction digestion. The prevalence of the Leu1007fsinsC polymorphism was significantly increased in CAD patients compared with controls (11.9% vs 1.8%; odds ratios (OR) 7.2, 95% confidence interval (95% CI) 1.5-32.9; p = 0.01), especially in those presenting with an acute coronary syndrome (OR 5.7; 95% CI 1.1-39.7; p = 0.034 vs stable angina). In CAD patients the frequency of GLY908ARG polymorphism was significantly lower (1.8% vs 6.4% in controls; OR 0.05, 95% CI 0.01-0.69; p = 0.031, at multivariable analysis) and the prevalence of the ARG702TRP polymorphism was higher compared with controls (10.1% vs 3.7%; OR 2.9, 95% CI 0.91-9.6; p = 0.07). We report in a Caucasian population that NOD2/CARD15 polymorphisms influence the development of clinically evident and angiographically documented coronary artery disease. In particular, the Leu1007fsinsC polymorphism was associated with an increased risk of clinically evident and angiographically documented coronary atherosclerosis and clinical destabilization of coronary plaques, whereas the GLY908ARG polymorphism demonstrated a protective effect on coronary atherogenesis. These correlations were independent of cardiovascular risk factors at multivariable analysis. These findings may contribute to the identification of a novel genetic approach for the stratification of cardiovascular risk profile., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Nucleoside transporter proteins are specialized proteins that mediate the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a member of these proteins and mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. We investigated the immunohistochemical expression of hENT in tumor samples from 111 patients with resected gastric adenocarcinoma, correlating these data with clinical parameters and disease outcomes. None of the patients received chemotherapy or radiation therapy before or after surgery as a part of an adjuvant or neoadjuvant program. On univariate survival analysis, the hENT1 expression was associated with overall survival (OS) and disease free survival (DFS). Specifically, those patients with overexpression of hENT1 showed a shorter OS (P = 0.021) and a shorter DFS (P = 0.033). Considering only the node positive patients, higher hENT levels were associated with significantly shorter median DFS (21.7 months; 95% CI 11.1-32.4) compared with patients with low expression of hENT1. The hENT1 expression was defined, in the lymph-node positive patients, as an independent prognostic factor (P = 0.019). Furthermore, considering only patients with diffuse or mixed tumors and lymph-node positive, the expression of hENT1 was strongly related with DFS and OS. Immunohistochemistry for the hENT1 protein carries prognostic information in patients with resected gastric cancer and holds promise as a predictive factor in chemotherapy decisions.

In the present case-control study we investigated the potential role of CARD15 R702W, G908R, and 1007fs polymorphisms in Italian gastric cancer patients. The study population consisted of 170 gastric cancer patients and 156 controls. Unconditional regression (odds ratios and 95% confidence interval) was used to investigate the association of the studied polymorphisms with gastric cancer. Higher allele frequencies of R702W and 1007fs polymorphisms were observed in patients with gastric cancer compared with controls (8.53 vs 2.3 and 9.4 vs 0.7, respectively). CARD15 R702W and 1007fs polymorphisms were significantly correlated with gastric cancer incidence (p < 0.0001, p < 0.0001, respectively). No correlation was found upon analyzing the G908R single nucleotide polymorphism (SNP). Our study reports an increased susceptibility to gastric cancer in Italian populations when R702W and 1007fs polymorphisms in the coding region of CARD15 are present. The interaction between NOD-induced proinflammatory cytokines on gastric mucosa and environmental carcinogens could represent one of the mechanisms by which CARD15 polymorphisms increase the susceptibility to gastric cancer. Meta-analyses of these SNPs and further analyses of additional polymorphisms/haplotypes in NOD genes will help determine their role in carcinogenesis.

We investigated the clinical significance of tumour-infiltrating FOXP3-positive regulatory T cells (Tregs) in radically resected (R0) gastric cancer. From a single-institution database, tumors of 110 patients who underwent R0 resection for stage II-III disease were studied for FOXP3-positive Tregs by immunohistochemistry. The observed median number of FOXP3-positive Tregs was used as the cut-point in analyses (<6 versus >or=6 count). Tregs were significantly higher in gastric carcinomas than in normal tissue (P = 0.0001). Tregs count >or=6 was significantly associated with vascular/lymphatic/perineural invasion (VELIPI) in the tumour (P = 0.03). Multivariate analysis showed association between adverse relapse-free survival and grading 3, stage III, VELIPI and Tregs count >or=6 (P = 0.02). Adverse overall survival was associated with grading 3, stage III, VELIPI and Tregs count >or=6 (P = 0.006). FOXP3-positive Tregs may be a novel marker for identifying high-risk gastric cancer patients. Present findings deserve additional investigation as Tregs may also represent an innovative therapeutic target.