Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database.

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).

Thyroid transcription factor-1 expression in lung neuroendocrine tumours: a gender-related biomarker?

PURPOSE: Thyroid transcription factor-1 (TTF-1) assessed by immunohistochemistry (IHC) is a specific biomarker for lung adenocarcinoma, and is commonly used to confirm the pulmonary origin of neuroendocrine tumours (NET). The majority of the available data suggest that TTF-1 is favourable prognostic biomarker for lung adenocarcinomas, whereas its role is more conflicting for lung NET. The main aim of this multicenter retrospective study was to investigate the potentially relevant associations between TTF-1 biomarker and clinical and pathological features of the study population, as well as determine TTF-1 prognostic effect on the clinical outcome of the patients. METHODS: A multicentre retrospective study was conducted on 155 surgically-removed lung NET, with available IHC TTF-1 assessment. RESULTS: Median age was 59.5 years (range 13-86), 97 patients (62.6%) were females, 31 cases (20%) were atypical carcinoids, 4 (2.6%) had TNM stage IV. Mitotic count ≥2 per 10 high-power field was found in 35 (22.6%) subjects, whereas necrosis was detected in 20 patients (12.9%). TTF-1 was positive in 78 cases (50.3%). The median overall survival was 46.9 months (range 0.6-323) and the median progression-free survival was 39.1 months (range 0.6-323). Statistically significant associations were found between (1) TTF-1 positivity and female sex (p = 0.007); and among (2) TTF-1 positivity and the absence of necrosis (p = 0.018). CONCLUSIONS: This study highlights that TTF-1 positivity differs according to sex in lung NET, with a more common TTF-1 positive staining in female. Moreover, TTF-1 positivity correlated with the absence of necrosis. These data suggest that TTF-1 could potentially represent a gender-related biomarker for lung NET.

Predictive Factors of Response to Streptozotocin in Neuroendocrine Pancreatic Neoplasms.

Pancreatic neuroendocrine neoplasms (Pan-NENs) may exhibit a heterogeneous clinical course, ranging from indolent to progressive/metastatic behavior. In the latter scenario, streptozocin (STZ) is considered the cornerstone of systemic treatment; however, response to STZ-based chemotherapy may vary among individuals. In this narrative review, we aimed to identify the predictive factors of response to STZ in advanced Pan-NENs. We performed an extensive search in international online databases for published studies and ongoing clinical trials evaluating STZ in Pan-NENs. We found 11 pertinent studies evaluating 17 patient-, tumor-, or treatment-related factors. Age, CgA blood levels, tumor grade, Ki-67% index, anatomical location of the primary tumor, tumor stage, site of metastasis origin, liver tumor burden, extrahepatic spread, functional status, O6-methylguanine-methyltransferase (MGMT) status, line of therapy, and response to previous treatments were all statistically associated with radiological response and/or survival. The identified predictors may help clinicians make appropriate treatment decisions, in this way improving clinical outcomes in patients with advanced Pan-NENs.

Association of Helicobacter pylori Infection with Autoimmune Thyroid Disease in the Female Sex.

BACKGROUND: Helicobacter pylori infection has been associated with an increased risk of thyroid diseases (TDs), although scientific evidence is conflicting. In the present study the relationship between TDs, including both autoimmune (AI) and non-autoimmune TD, and H. pylori infection was investigated. METHODS: Data from records of patients undergoing upper endoscopy and histologically evaluated for H. pylori infection were retrieved. In addition to demographic information, the features of gastritis based on non-targeted biopsies collected from the antrum, angulus, and corpus were analyzed. The presence of H. pylori infection and atrophy and/or metaplasia and/or dysplasia in at least one gastric specimen was defined as a long-lasting H. pylori infection and the presence of a chronic-active gastritis as a current infection. Hashimoto's and Graves' diseases were included in the AITD group, and thyroid nodules, goiter, iatrogenic thyroid hypo/hyper function, and thyroidectomy in the non-autoimmune TD group. RESULTS: A total of 8322 records from adult patients from Northern Sardinia, characterized by a similar genetic background, was analyzed. Participants were aged 18-93 years (females 5339, 64.1%), and more specifically, 562 (6.7%) had a diagnosis of AITD and 448 (5.4%) of non-autoimmune TD. A significant association between long-lasting H. pylori and AITD (OR 1.34; 95%CI 1.13-1.60) was found, irrespective of age, sex, body mass index, and smoking status, while it was not associated with non-autoimmune TD. Current H. pylori infection did not show significant ORs for AITD (OR 0.99; 95%CI 0.64-1.57) and non-autoimmune TD (OR 0.86; 95%CI 0.66-1.15). The association with long-lasting H. pylori infection was confirmed to be significant for both Hashimoto's thyroiditis and Graves' disease by multivariable regression analysis. Stratification according to sex revealed a significant association only for females (OR 1.39; 95%CI 1.12-1.72). CONCLUSIONS: Our results indicate that long-lasting H. pylori infection is associated with AITD in the female adult population of Northern Sardinia.

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

Introduction: Medullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients. Aim of the study: This review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC. Materials and methods: We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories. Results: Our search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials. Conclusion: We found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival.

Is Glucose-6-Phosphate Dehydrogenase Deficiency a Risk Factor for Autoimmune Thyroid Disease? A Retrospective Case-Control Study.

BACKGROUND: The risk of developing thyroid disorders (TDs) in subjects with inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. The aim of this study was to explore the association between autoimmune (AITD) and G6PD deficiency in Northern Sardinia, in a population with a high frequency of these two conditions. METHODS: In this retrospective single-center case-control study, demographic and clinical data were collected from patients examined in a tertiary referral Gastroenterology Section of a teaching hospital. RESULTS: In 8894 subjects examined (64.7% females), 1218 patients were diagnosed with TDs; more specifically, 767 were diagnosed with AITD and 451 were not (non-AITD). Overall, G6PD deficiency was more prevalent in TD patients compared with patients without TD (controls) (16.7% vs. 11.2%; p < 0.0001). Multivariable logistic regression analysis (after adjusting for age, sex, excess weight and smoking habits), confirmed a higher risk of AITD among G6PD deficient patients with an odds ratio (OR) of 1.36 and 95% confidence interval (CI) of 1.11-1.6, female patients (OR 1.33, 95% CI 1.07-1.65) and overweight patients (OR 1.22, 95% CI 1.03-1.44). CONCLUSIONS: The risk of AITD is increased in carriers of G6PD deficiency. A careful assessment of thyroid function is advisable in patients with inherited G6PD defects.

Autoimmune Thyroid Disorders Are More Prevalent in Patients with Celiac Disease: A Retrospective Case-Control Study.

Background. Among patients with celiac disease (CD), there is an increased incidence of autoimmune thyroid disorders (AITDs), with hypothyroidism being more frequent than hyperthyroidism. This retrospective case-control study aimed to explore the prevalence of TDs in a population of adult celiac patients from Northern Sardinia, a geographic area with a high prevalence of autoimmune disorders. Methods. Data were collected from consecutive patients with CD (cases) and without CD (controls) who were undergoing upper endoscopy and referred to a tertiary gastroenterology section of a teaching hospital (University of Sassari, Italy). Thyroid disorders were stratified as (i) autoimmune: including Hashimoto's disease in euthyroidism or with hypofunction, and Graves' disease; or (ii) non-autoimmune: thyroid nodules/goiter, iatrogenic thyroid hypo/hyperfunction, and thyroidectomy for any reason, including cancer. Results. Among a total of 8489 participants (females 5839, 64.7%) enrolled, there were 623 (7.3%) celiac patients and 7866 controls (92.7%). The overall frequency of TDs was 1177 (13.9%) and was higher (26.0%) in celiac patients than in controls (12.9%) (p < 0.001). The difference between AITDs (15.4% vs. 7.5%) and no-AITDs (2.7% vs. 1.1%) was statistically significant in CD patients compared with controls, respectively, and prevailed in the fifth and sixth decades. Hashimoto's thyroiditis was more commonly associated with gland hypofunction. Odds ratios with their 95% confidence intervals (CIs) for the presence of AITDs were calculated, adjusting for sex, age, body mass index, smoking habits, occupation, and residence, and they were 2.387 (95% CI 1.857−3.068, p < 0.001) in CD patients, 5.855 (95% CI 4.434−7.731, p < 0.001) for female sex, and 1.012 (95% CI, 1.007−1.017, p < 0.001) for age. Conclusion. These results suggest the need for surveillance for TDs in patients with CD at onset and during follow-up.

Association between High Normal TSH Levels and Obesity in Women with Anti-Thyroid Autoantibodies (ATAs).

A positive correlation between Thyroid-Stimulating Hormone (TSH) and Body Mass Index (BMI) has been reported in many studies, but data on this topic remain controversial, especially when TSH values are in the normal range. Moreover, few studies have evaluated the co-existence of thyroid autoimmunity. This study investigated the role of thyroid autoimmunity in the interconnection between TSH, BMI, and waist circumference (WC) in euthyroid patients with overweight or obesity. We enrolled 902 patients (213 males; mean age ± SD: 45 ± 14 years; mean BMI ± SD: 35.8 ± 6.5 kg/m2), with normal serum TSH concentration; anti-thyroid autoantibodies (ATAs) were evaluated in 752 patients (186 males). Patients were divided into four BMI classes, based on WHO criteria, and the relationship between BMI, WC, and TSH was evaluated in the whole sample and compared to ATAs positivity, observed in 235 patients (44 males). No significant difference was found between TSH levels in the BMI classes. A statistically significant correlation between TSH and BMI was found only in ATAs-positive females (N = 191, Spearman rho: 0.149; p-value: 0.040). However, this finding was not confirmed when considering the WC. Our study shows a positive correlation only between TSH and BMI in obese women with positive ATAs, suggesting that in these patients, the high normal levels of TSH could be attributed to a mild thyroid failure with a possible worsening obesity-related effect, and both need a careful evaluation.

Immunotherapy of Neuroendocrine Neoplasms: Any Role for the Chimeric Antigen Receptor T Cells?

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with variable clinical presentation and prognosis. Surgery, when feasible, is the most effective and often curative treatment. However, NENs are frequently locally advanced or already metastatic at diagnosis. Consequently, additional local or systemic therapeutic approaches are required. Immunotherapy, based on chimeric antigen receptor T cells (CAR-T), is showing impressive results in several cancer treatments. The aim of this narrative review is to analyze the available data about the use of CAR-T in NENs, including studies in both preclinical and clinical settings. We performed an extensive search for relevant data sources, comprising full-published articles, abstracts from international meetings, and worldwide registered clinical trials. Preclinical studies performed on both cell lines and animal models indicate a significant therapeutic effect of CAR-T cells in NENs. Ongoing and future clinical trials will clarify the possible role of these drugs in patients with highly aggressive NENs.

Immune Checkpoint Blockade in Lung Carcinoids with Aggressive Behaviour: One More Arrow in Our Quiver?

Lung carcinoids are well-differentiated and low-/intermediate-grade neuroendocrine neoplasms of the lung. Given their relative rarity, and the paucity of data available from prospective studies, no global consensus exists on the systemic treatment of these tumours. In recent years, immune checkpoint inhibitors have revolutionized cancer management and are under evaluation in patients with diverse types of neuroendocrine neoplasms. The aim of this narrative review is to analyse all available data for the use of approved immune checkpoint inhibitors in patients with lung carcinoids. We performed an extensive search for relevant data sources and found five published articles, one meeting abstract, and nine registered clinical trials indicating a growing interest of researchers in this field, and providing preliminary evidence of efficacy for combined nivolumab plus ipilimumab and durvalumab plus tremelimumab regimens in the treatment of advanced and/or metastatic lung carcinoids.

YouTube as a patient-information source for hypothyroidism.

INTRODUCTION: Hypothyroidism is a very common disease that requires life-long treatment. In our study, we analyze the quality of the YouTube videos concerning hypothyroidism as a "source of health information" for the patients, and the (possible) correlation between video quality and video popularity. METHODS: We included 96 YouTube videos obtained by using the following search terms: "hypothyroidism", "Hashimoto's disease", "thyroid insufficiency", and "low thyroid hormone". We evaluated video quality by using the DISCERN criteria, and video popularity by using the Video Power Index. RESULTS: The mean DISCERN score for both raters was 1.995, indicating poor YouTube videos' quality. Sixty-eight videos achieved a high score in the video power index (VPI). The mean popularity score for videos with misleading information was higher than the mean score for all evaluated videos. CONCLUSIONS: The overall quality of YouTube videos regarding hypothyroidism was poor. Videos frequently lack the source of information presented. Besides, content is often incomplete, and sometimes includes misleading statements. Physicians dealing with hypothyroid patients should be aware of the possibility that information and instruction they give to patients could be "modulated" by the availability of both low quality and popular alternative "sources of medical knowledge".

Immune Checkpoint Inhibitors: New Weapons Against Medullary Thyroid Cancer?

Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative approach. However, in most cases, the tumor recurs at locoregional or metastatic level. In this setting, the management remains challenging. In recent years, the immune checkpoint inhibitors have provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body's natural antitumor defenses. The aim of this review is to summarize and discuss available data on efficacy and safety of the Food and Drug Administration-approved immune checkpoint inhibitors in patients with medullary thyroid carcinoma. After an extensive search, we found 7 useful data sources (one single-case report, one short article with very preliminary data, five ongoing registered clinical trials). Despite the lack of published evidence regarding the use of immune check point inhibitors, it must be considered that all the ongoing registered clinical trials saw first light in the last three years, thus indicating a growing interest of researchers in this field. Results coming from these trials, and hopefully, in the next future, from additional trials, will help to clarify whether this class of drugs may represent a new weapon in favor of patients with medullary thyroid carcinoma.

Spatial Association between Gastric Cancer Mortality and Goiter in Sardinia.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. The incidence of GC varies between countries according to exposure to different risk factors. Hypothyroidism has been suggested as a potential GC risk factor. In Sardinia, Italy, the prevalence of endemic goiter is high and GC mortality is unevenly distributed. This ecological study aimed to investigate GC mortality and its relationship with hypothyroidism, adjusting for potential confounders. METHODS: The spatial association between GC mortality and goiter (a proxy of hypothyroidism), diet, stature and pastoralism (a proxy of Helicobacter pylori infection), available at the aggregated level, was modelled in the island's 377 municipalities, separately by sex, using geographically weighted regression (GWR). RESULTS: The GC standardized mortality ratio ranged from 0.0 to 10.4 across municipalities. A hotspot of GC mortality was detected in the central mountainous area of Sardinia among males, positively associated with goiter (GWR estimate 0.213 ± 0.122), and the practice of sheep‒rearing (GWR estimate 0.127 ± 0.080), whereas a negative association with the diet score (GWR estimate 0.032 ± 0.034), and null for stature were found. No significant associations were found in females. CONCLUSION: Within the limitations of ecological studies goiter prevalence was an independent predictor of GC mortality in males.

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.

Clinically relevant thyroid disorders and inflammatory bowel disease are inversely related: a retrospective case-control study.

OBJECTIVES: The risk of thyroid disorders (TDs) in inflammatory bowel disease (IBD) is still controversial. The aim of this retrospective, single-center, case-control study was to explore the association between clinically relevant functional TDs and IBD. METHODS: Consecutive individuals for a total of 313 IBD patients [90 Crohn's disease (CD); 223 ulcerative colitis (UC)], and 833 individuals undergoing colonoscopy for screening without IBD were collected. In the study, subject's information on thyroid status were retrieved. Thyroid disorders were classified, according to the functional status, as hypothyroidism or hyperthyroidism. Patients with TDs (cases) were compared with 941 without (controls) according to IBD exposure. Unadjusted and adjusted odds ratios (ORs) and their 95% confidence interval (CI) were calculated. RESULTS: Clinically relevant TDs were detected in 205 (17,9%) patients and the prevalence was significantly lower in IBD patients compared with subjects without (8.3% vs 12.9%; p = 0.029). After adjusting for potential confounders, a higher TDs risk was confirmed in female (OR 2.72; 95%CI 1.88‒3.92) and older subjects (OR 1.01; 95%CI 1.00‒1.03), and a lower risk in IBD (OR 0.51; 95%CI 0.34‒0.76), especially for hypothyroidism (OR 0.33; 95%CI 0.17‒0.66) in UC. Among four thyroid cancers, only one was detected in IBD patients. CONCLUSIONS: Overall, in our study, the risk of TDs was lower in IBD patients. To assess routinely hormones and/or thyroid gland imaging in the absence of clinical signs or symptoms seems unnecessary in IBD patients, at least in our geographic area.

Advances in the Management of Medullary Thyroid Carcinoma: Focus on Peptide Receptor Radionuclide Therapy.

Effective treatment options in advanced/progressive/metastatic medullary thyroid carcinoma (MTC) are currently limited. As in other neuroendocrine neoplasms (NENs), peptide receptor radionuclide therapy (PRRT) has been used as a therapeutic option in MTC. To date, however, there are no published reviews dealing with PRRT approaches. We performed an in-depth narrative review on the studies published in this field and collected information on registered clinical trials related to this topic. We identified 19 published studies, collectively involving more than 200 patients with MTC, and four registered clinical trials. Most cases of MTC were treated with PRRT with somatostatin analogues (SSAs) radiolabelled with 90 yttrium (90Y) and 177 lutetium (177Lu). These radiopharmaceuticals show efficacy in the treatment of patients with MTC, with a favourable radiological response (stable disease, partial response or complete response) in more than 60% of cases, coupled with low toxicity. As MTC specifically also expresses cholecystokinin receptors (CCK2Rs), PRRT with this target has also been tried, and some randomised trials are ongoing. Overall, PRRT seems to have an effective role and might be considered in the therapeutic strategy of advanced/progressive/metastatic MTC.

Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective.

PURPOSE: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs. METHODS: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis. RESULTS: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis. CONCLUSIONS: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.