Search

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

SARS-CoV-2; Carcinoids; Vaccination SARS-CoV-2; Carcinoides; Vacunación SARS-CoV-2; Carcinoides; Vacunació The COVID-19 outbreak has added complexity in the management of patients with neuroendocrine tumors (NETs). Little information is currently available regarding the real impact of the pandemic in current practice. The present study aimed to capture patients' and healthcare professionals' experiences on how the NET management has changed during the pandemic and how it should be modified in a foreseeable post-pandemic environment. Physicians and nurses working in ENETS Centers of Excellence or other hospitals with high volume of NET patients (n = 48), as well as NET patients residing worldwide (n = 353), were asked to respond to two online anonymous surveys addressing different aspects of NET care. Deferred diagnoses, delayed surveillance procedures and postponed elective surgeries were among the main negative consequences of the COVID-19 outbreak according to 40%, 54% and 46% of healthcare professionals (HPs) respectively. Somatostatin analogs were increasingly used as bridging strategy for delaying surgery based on the views of 31% of HPs and were self-injected or delivered by home care services more frequently than before the initiation of the pandemic (53% of patients during the pandemic vs. 44% before the pandemic). Multidisciplinary tumor boards kept their usual schedule according to 58% of HPs, but were held virtually in the 77% of cases. The contact with healthcare professionals was maintained by remote methods more often than in the past (69% of patients), but only 34% of patients (59% among subjects

BACKGROUND Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence. AIM To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey. METHODS Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. RESULTS Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). CONCLUSION Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.

Background Erdheim-Chester disease (ECD), a rare disorder of monocyte/macrophage lineage, has been related to cerebellar dysfunction. To increase the awareness of this rare, protean disease, an unusual, myasthenia-like onset of ECD is reported. Case presentation A 42-year-old man presented with a 6-year history of mild evening fatigability in his four limbs followed by motor and cognitive symptoms associated with cerebellar atrophy, dentate nuclei and dentato-thalamic pathway degeneration. Magnetic resonance imaging revealed hyperintense signals in T2 and fluid-attenuated inversion recovery sequences within the pons, cerebellar white matter, dentate nuclei and globi pallidi in the absence of any contrast enhancement. Whole-body bone scintigraphy with 99Technetium - methylene diphosphonate and fluorodeoxyglucose-positron emission tomography both revealed symmetric uptake in the lower extremities a finding suggestive of a diagnosis of ECD. Histological examination revealed diffuse infiltration of CD 68+ histiocytes with foamy cytoplasms in the presence of B-type of Rapidly Accelerated Fibrosarcoma protein kinase (BRAF)V600E activating mutation in tumor cells. Conclusion In patients with myasthenia-like symptoms who test negatively for myasthenia gravis, neurodegenerative diseases, and disorders of the hypothalamus, a diagnosis of ECD should be taken into consideration.

Background Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. Materials and Methods To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

The COVID‐19 pandemic has added another layer of complexity to the fears of patients with neuroendocrine tumors (NETs). Little is known regarding the psychological impact of the COVID‐19 outbreak on patients with gastroenteropancreatic or bronchopulmonary (BP) NETs. We longitudinally surveyed the mental symptoms and concerns of NET patients during the plateau phase of the first (W1) and second epidemic waves (W2) in Italy. Seven specific constructs (depression, anxiety, stress, health‐related quality of life, NET‐related quality of life, patient–physician relationship, psychological distress) were investigated using validated screening instruments, including DASS‐21, EORTC QLQ‐C30, EORTC QLQ GI.NET21, PDRQ9 and IES‐R. We enrolled 197 patients (98 males) with a median age of 62 years. The majority of the patients had G1/G2 neoplasms. Some 38% of the patients were on active treatment. At W1, the prevalence of depression, anxiety and stress was 32%, 36% and 26% respectively. The frequency of depression and anxiety increased to 38% and 41% at W2, whereas no modifications were recorded in the frequency of stress. Poor educational status was associated with higher levels of anxiety at both W1 (odds ratio [OR] = 1.33 ± 0.22; p = .07) and W2 (OR = 1.45 ± 0.26; p = .03). Notably, post‐traumatic stress symptoms were observed in the 58% of the patients, and both single marital status (OR = 0.16, 95% confidence interval [CI] = 0.06–0.48; p = .0009) and low levels of formal education (OR = 0.47, 95% CI = 0.23–0.99; p = .05) predicted their occurrence. No significant deteriorations of health‐related quality of life domains were observed from W1 to W2. High patient care satisfaction was documented despite the changes in health systems resource allocation. NET patients have an increased risk of developing post‐traumatic stress symptoms as result of the COVID‐19 pandemic. Specific screening measures and psychological interventions should be implemented in NET clinics to prevent, recognize and treat mental distress in this vulnerable population., NET patients have an increased risk of developing post‐traumatic stress symptoms as result of the COVID‐19 pandemic. Specific screening measures and psychological interventions should be implemented in NET clinics to prevent, recognize and treat mental distress in this vulnerable population.

Background: Ibrutinib is an orally administered inhibitor of Bruton’s tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited within neuroendocrine neoplasms (NENs) where they stimulate angiogenesis and tumor growth. Ibrutinib inhibits mast cell degranulation and has been associated with regression of tumors in a mouse insulinoma model. Methods: A prospective, phase II trial evaluated patients with advanced gastrointestinal (GI)/lung NENs and pancreatic NENs (pNENs) who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560 mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. The primary endpoint was objective response rate. Results: Twenty patients were enrolled on protocol from November 2015 to December 2017 (15 advanced GI/lung NENs and 5 pNENs). No patient reached an objective response. Median PFS was 3.0 months. A total of 44 drug-related adverse events (AEs) were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs, and 1 patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment. Conclusions: Ibrutinib does not show significant evidence of activity in well-differentiated gastroenteropancreatic and lung NENs.

Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30–49%) and 14/102 (14%; 95% CI, 8–22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25–44%), mild to moderate in 46/102 samples (45%, 95% CI, 35–55%), intense in 21/102 tumors (21%, 95% CI, 13–30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11–26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.

BackgroundNeuroendocrine tumors (NETs) overexpress somatostatin receptors (SSTRs).MethodsWe developed a second-generation, ligand-based, anti-SSTR chimeric antigen receptor (CAR) incorporating the somatostatin analog octreotide in its extracellular moiety.ResultsAnti-SSTR CAR T cells exerted antitumor activity against SSTR+NET cell linesin vitro. The killing activity was highly specific, as demonstrated by the lack of CAR T cell reactivity against NET cells engineered to express mutated variants of SSTR2/5 by CRISPR/Cas9. When adoptively transferred in NSG mice, anti-SSTR CAR T cells induced significant antitumor activity against human NET xenografts. Although anti-SSTR CAR T cells could recognize the murine SSTRs as shown by their killing ability against murine NET cells, no obvious deleterious effects on SSTR-expressing organs such as the brain or the pancreas were observed in mice.ConclusionsTaken together, our results establish anti-SSTR CAR T cells as a potential candidate for early phase clinical investigations in patients with NETs. More broadly, the demonstration that a known peptide drug can direct CAR T cell targeting may streamline the potential utility of multiple peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers.

Multiple systemic treatments are currently available for advanced cancers of the digestive tract, but none of them is curative. Adoptive T-cell immunotherapy refers to the extraction, modification and re-infusion of autologous or allogenic T lymphocytes for therapeutic purposes. A number of clinical trials have investigated either non-engineered T cells (i.e., lymphokine-activated killer cells, cytokine induced killer cells, or tumor-infiltrating lymphocytes) or engineered T cells (T cell receptor-redirected T cells or chimeric antigen receptor T cells) in patients with digestive tract malignancies over the past two decades, with variable degrees of success. While the majority of completed trials have been primarily aimed at assessing the safety of T-cell transfer strategies, a new generation of studies is being designed to formally evaluate the antitumor potential of adoptive T-cell immunotherapy in both the metastatic and adjuvant settings. In this review, we provide an overview of completed and ongoing clinical trials of passive T-cell immunotherapy in patients with cancers of the digestive tract, focusing on present obstacles and future strategies for achieving potential success.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with rising incidence and prevalence. Outcome and therapy of small bowel neuroendocrine tumours (SBNETs) is variable, depending on the grade, differentiation, tumour burden, as well as the site of the tumour origin. Because of this, multidisciplinary approach is essential. Large randomized clinical trials, with somatostatin analogues (PROMID, CLARINET) or with peptide receptor radionuclide therapy (PRRT) with 177-lutetium (NETTER-1 trial) as well as the mammalian target of rapamycin inhibitor (mTOR) everolimus (RADIANT trials), represent milestones for the medical management of unresectable grade 1 and 2 SBNETS over the last decade. Novel therapies, such as tyrosine kinase inhibitors (TKI), are on the cutting edge. However, multiple unsolved questions remain. This review provides a comprehensive review of the main systemic therapeutic options for advanced SBNETs and discusses the latest guideline recommendations for palliative treatment.

Background: COVID-19 pandemic has added a degree of complexity in the management of patients with NET. We have little information about the real impact of COVID-19 in current practice. The aim of this study is to capture if and how COVID-19 is changing the way in which healthcare professionals treat NET patients. Methods: NET CONNECT taskforce designed an online anonymous survey addressing different aspects of NET. Survey was sent to nurses and physicians working in ENETS Centers of Excellence (CoE) and other hospitals with high volume of NET between March 24th and April 27th 2021. Results: 47 health professionals (47% female, 19% nurses, 72% >20 years of experience) from 37 institutions (79% ENETS CoE, 55% >500 ongoing NET patients;51% EU, 38% UK, 11% US) completed the survey;70% of responders worked in areas of high COVID prevalence and 11% tested positive for COVID themselves. According to responders, pandemic affected their relationship with patients (49%). Telemedicine was widely used by 62% and included phone calls (96%), video conference (43%), telemedicine apps (19%) and email (51%). Tumor boards kept their usual schedule (60%), but were held virtually in 79%. Among main patient worries perceived by clinicians were the risk of COVID-19-related complications (64%), difficulties in the management of their disease (74%), or oncological medication (87%). Watch and wait strategies were used more commonly (34%), while surgery was often (55%) delayed. Somatostatin analogs (SSA) were increasingly used as bridging strategy for delaying surgery (32%), and were self-injected or delivered by home care service in 36% and 49% of cases respectively. Treatment breaks of targeted therapies (17%), PRRT (13%), or chemotherapy (9%) were also proposed. Patients with advanced NET were considered a priority group for vaccination (94%), but not those with resected NET (19%). Conclusions: COVID-19 pandemic paved the way towards telemedicine in many institutions. While systemic treatments were generally continued, surgical interventions were delayed in 55% of cases. Regarding SSA, home care service or self-injections have been used more frequently. As the pandemic evolves, new data will be needed to design future health policy measures. Legal entity responsible for the study: NET CONNECT Taskforce Group. Funding: Ipsen. Disclosure: All authors have declared no conflicts of interest.

Introduction The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. Methods A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 Results The main modification in the centers’ activity consisted of decreases in newly diagnosed NEN patients (− 76.8%), decreases in performed surgical procedures (− 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams’ activity (20.8%). A low proportion of centers (

Skeletal colonization is often regarded as a rare event in patients with neuroendocrine tumors (NETs) although both national registries and retrospective series report an incidence of bone metastases as high as 20% in subjects with advanced disease. While the biological mechanisms leading to bone metastatic colonization in NETs have been poorly investigated so far, key steps of osteotropic mechanisms, including the epithelial-to-mesenchymal transition, preparation of the premetastatic niche, migration of circulating tumor cells towards the bone marrow as well as the resulting alterations of the skeletal metabolism, are likely to operate also during the development of NET bone metastases. The skeleton involvement by NETs has a detrimental impact on both quality of life and patients’ prognosis, leading to pain in the majority of symptomatic subjects. While it is currently unclear whether or not the earlier recognition of bone involvement by PET/CT imaging techniques employing 68Ga-DOTA-conjugated peptides might improve outcomes through the exploitation of timely treatments, the management of bone-colonizing NETs is today based only on clinical experience from other osteotropic tumors. Here, we summarize the fundamental molecular mechanisms driving bone colonization and revisit both established and novel treatments for patients with bone metastatic NETs.

The clinical diagnosis of cancer emerges from the recognition of specific signs and symptoms, is corroborated by laboratory and imaging tests, and is eventually confirmed by pathology examination. While a comprehensive panel of laboratory tests may provide useful information in the diagnostic work-up of cancer patients, tumor markers should not be routinely investigated for diagnostic purposes, but their use should be confined to surveillance. CT and MRI scans represent the main radiologic techniques used for both anatomic diagnosis and staging of cancer, while 18F-FDG PET/CT allows the evaluation of the metabolic activity of tumor lesions. Innovative radiotracers including 11C-choline and 68Ga-DOTA compounds have been recently developed and show high specificity for detecting prostate cancer and neuroendocrine tumors, respectively. Novel biomarkers such as circulating tumor cells or circulating tumor DNA are on the horizon, and their clinical implementation is steadily undergoing. For the foreseeable future, the integration of next-generation sequencing technologies and high-resolution imaging modalities carries the promise of achieving earlier cancer diagnosis in the precision medicine era, as well as more accurate tumor staging and personalized tumor follow-up.

BACKGROUND Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence. AIM To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey. METHODS Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. RESULTS Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). CONCLUSION Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.

Background: Erdheim-Chester disease (ECD), a rare disorder of monocyte/macrophage lineage, has been related to cerebellar dysfunction. To increase the awareness of this rare, protean disease, an unusual, myasthenia-like onset of ECD is reported.Case presentation: A 42-year-old man presented with a 6-year history of mild evening fatigability in his four limbs followed by motor and cognitive symptoms associated with cerebellar atrophy, dentate nuclei and dentato-thalamic pathway degeneration. Magnetic resonance imaging revealed hyperintense signals in T2 and fluid-attenuated inversion recovery sequences within the pons, cerebellar white matter, dentate nuclei and globi pallidi in the absence of any contrast enhancement. Whole-body bone scintigraphy with 99Technetium - methylene diphosphonate and fluorodeoxyglucose-positron emission tomography both revealed symmetric uptake in the lower extremities a finding suggestive of a diagnosis of ECD. Histological examination revealed diffuse infiltration of CD 68+ histiocytes with foamy cytoplasms in the presence of B-type of Rapidly Accelerated Fibrosarcoma protein kinase (BRAF)V600E activating mutation in tumor cells.Conclusion: In patients with myasthenia-like symptoms who test negatively for myasthenia gravis, neurodegenerative diseases, and disorders of the hypothalamus, a diagnosis of ECD should be taken into consideration.

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

In the “precision medicine” era, chemotherapy still remains the backbone for the treatment of many cancers, but no affordable predictors of response to the chemodrugs are available in clinical practice. Single nucleotide polymorphisms (SNPs) are gene sequence variations occurring in more than 1% of the full population, and account for approximately 80% of inter-individual genomic heterogeneity. A number of studies have investigated the predictive role of SNPs of genes enrolled in both pharmacodynamics and pharmacokinetics of chemotherapeutics, but the clinical implementation of related results has been modest so far. Among the examined germline polymorphic variants, several SNPs of dihydropyrimidine dehydrogenase (DPYD) and uridine diphosphate glucuronosyltransferases (UGT) have shown a robust role as predictors of toxicity following fluoropyrimidine- and/or irinotecan-based treatments respectively, and a few guidelines are mandatory in their detection before therapy initiation. Contrasting results, however, have been reported on the capability of variants of other genes as MTHFR, TYMS, ERCC1, XRCC1, GSTP1, CYP3A4/3A5 and ABCB1, in predicting either therapy efficacy or toxicity in patients undergoing treatment with pyrimidine antimetabolites, platinum derivatives, irinotecan and taxanes. While formal recommendations for routine testing of these SNPs cannot be drawn at this moment, therapeutic decisions may indeed benefit of germline genomic information, when available. Here, we summarize the clinical impact of germline genomic variants on the efficacy and toxicity of major chemodrugs, with the aim to facilitate the therapeutic expectance of clinicians in the odiern quicksand field of complex molecular biology concepts and controversial trial data interpretation.

Exosomes (Exo) are small vesicles produced by melanoma cells and the accessory cells of the tumor microenvironment. They emerge via both classical and direct pathways and actively participate in tumor colonisation of distant tissues. The proteins, nucleic acids, cytokines and growth factors engulfed by Exo are transferred to recipient cells, where they drive numerous functions required for the tumor escape from immune system control and tumor progression. By positively or negatively modulating immune cell properties, Exo provoke immune suppression and, in turn, defective dendritic cell (DC) functions. Together, these effects limit the cytotoxicity of T-cells and expand both T-regulatory and myeloid-derived suppressor populations. They also hinder perforin and granzyme production by natural killer cells. Finally, Exo also control the organotropism of melanoma cells. The distinct phenotypic properties of Exo can be exploited both for diagnostic purposes and in the early identification of melanoma patients likely to respond to immunotherapy. The potential therapeutic application of Exo derived from DCs has been demonstrated in vaccination trials, which showed an increase in anti-melanoma activity with respect to circulating tumor cells. However, additional studies are required before Exo can be effectively used in diagnostic and therapeutic applications in melanoma.

Background: The COVID-19 pandemic has dramatically changed lifestyles and quality of life (QoL) of the global population. Little is known regarding the psychological impact of the COVID-19 outbreak on patients with gastroenteropancreatic (GEP) or bronchopulmonary (BP) neuroendocrine tumors (NETs). Methods: We prospectively evaluated seven specific constructs (depression, anxiety, stress, QoL, NET-related QoL, patient-physician relationship, psychological distress) by using validated screening instruments including the Depression anxiety stress scale-21 (DASS-21), the EORTC QLQ-C30, the EORTC QLQ GI.NET21, the patient doctor relationship questionnaire 9 (PDRQ9) and the Impact of event scale-revised (IES-R). Mental symptoms and concerns of patients with any stage, well-differentiated GEP or BP-NET were surveyed twice, during the plateau phase of the first (W1) and second epidemic waves (W2) in Italy. Results: We enrolled 197 patients (98 males) with a median age of 62 years (G1/G2: 96%;pancreas: 29%;small bowel: 25%;active treatment: 38%). At W1, the prevalence of depression, anxiety and stress was 32%, 36% and 26% respectively. The frequency of depression and anxiety increased to 38% and 41% at W2, with no modifications in the frequency of stress. By ordinal logistic regression analysis, female patients showed more severe forms of stress at W1 (OR=0.45±0.14;p=0.01), while the educational status was associated with the levels of anxiety at both W1 (OR=1.33±0.22;p=0.07) and W2 (OR=1.45±0.26;p=0.03). An improvement of the physical (p=0.03) and emotional functioning domains (p=0.001) was observed over time. Both nausea/vomiting (p=0.0002), appetite (p=0.02), treatment-related symptoms (p=0.005), disease-related worries (p=0.0006) and sexual function (p=0.02) improved between W1 and W2, suggesting that NET patients were able to cope with the perturbations caused by the pandemic. No difference was seen between W1 and W2 in the mean score (>4/5) of the PDRQ9. By IES-R, post-traumatic stress disorder was observed in 53% of patients at W2. Conclusions: The implementation of psychological interventions within NET clinics might favor functional coping strategies, attenuating the psychological distress caused by the COVID-19 pandemic. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background/aim Low-grade pancreatic neuroendocrine tumors (LG-PNETs) behave unpredictably. The aim of the study was to identify biomarkers that predict PNET metastasis to improve treatment selection. Patients and methods Five patients with primary non-metastatic LG-PNETs, six with primary LG-PNETs with synchronous or metachronous metastases (M-PNETs), and six metastatic to liver LG-PNETs (ML-PNETs) from the group of six M-PNET patients were selected. RNA data were normalized using iterative rank-order normalization. Student's t-test identified differentially-expressed genes in LG-PNETs versus M-PNETs. A 2-fold difference in expression was considered to be significant. Results were validated with an independent dataset of LG-PNETs and metastatic LG-PNETs. Results Overall, 195 genes had a >2-fold change (in either direction). A total of 29 genes were differentially overexpressed in M-PNETs. Erythrocyte membrane protein band 4.1-like 5 (EPB41L5) had a 2.07-fold change increase in M-PNETs and the smallest p-value. EPB41L5 was not statistically different between M-PNETs and ML-PNETs. EPB41L5 differential expression between primary and metastatic LG-PNETs was confirmed by immunohistochemistry. Conclusion These results support further investigation into whether EPB41L5 is a biomarker of PNETs with high risk for metastases.

Management of localized well-differentiated pancreatic neuroendocrine tumors (panNETs) is controversial and primarily dependent on tumor size. Upfront surgery is usually recommended for tumors larger than 2 cm in diameter since they frequently show metastatic potential, whereas smaller panNETs are generally characterized by an indolent clinical course, with a rate of relapse or metastasis below 15%. To explore whether increased tumor size is paralleled by genomic variations, we compared the rate and the mutational patterns of putative driver genes that are recurrently altered in these tumors by investigating differential cohorts of panNET surgical specimens smaller (n = 27) or larger than 2 cm (n = 29). We found that the cumulative number of mutations detected in panNETs >2 cm was significantly higher (p = 0.03) relative to smaller tumors, while mutations of DAXX were significantly more frequent in the cohort of larger tumors (p = 0.05). Moreover, mutations of DAXX were associated with features of malignancy including increased grade, nodal involvement and lymphovascular invasion, and independently predicted both relapse after surgery (p = 0.05) and reduced DFS in multivariable analysis (p = 0.02). Our data suggest that alterations of the DAXX/ATRX molecular machinery increase the malignant potential of panNETs, and that identification of mutations of DAXX/ATRX in small, nonfunctioning tumors can predict the malignant progression observed in a minority of them.

The management of neuroendocrine tumors (NETs) has been rapidly evolving since the advent of the so-called “precision medicine” era. The availability of high-throughput sequencing technologies has substantially improved our ability to stratify NET patients based on their genomic, epigenomic, transcriptomic, or metabolomic profile. Although different molecular subgroups of NETs have been identified, prospective evaluation of their ability to predict prognosis, tumor clinical aggressiveness, and/or response to treatment is still lacking, thus hampering wide clinical application of such “-omic” profiles. Analysis of circulating NET transcripts as well as detection of changes in circulating tumor cells have been reported to predict response to treatment. If clinically validated in well-designed trials, liquid biopsy methodologies may be increasingly used in the future for both follow-up and treatment personalization. Molecular predictors of response to both somatostatin analogs, biologic agents, and chemotherapy have been intensely investigated, but no reliable biomarkers have been identified so far. An improved understanding of the complexity of pathway interactions through system biology approaches is required to advance further the NET field.

Purpose of review Neuroendocrine tumors (NETs) are a group of biologically and clinically heterogeneous neoplasms arising from the diffuse neuroendocrine system. In the last few years, advances in our understanding of the biology of these tumors have translated into an expansion of treatment options for patients with NETs. Current treatment modalities include somatostatin analogs (SSAs), radiolabeled SSAs, targeted agents, cytotoxic drugs and liver-directed therapies for the management of metastatic disease. Recent findings Recent studies have expanded the role of SSAs in gastroenteropancreatic (GEP)-NETs, and everolimus has shown robust antitumor activity across a broad range of NETs of the lung and GEP tract. The radiolobeled SSA Lu-DOTATATE has been investigated in a randomized phase III trial, and has demonstrated exceptional efficacy and tolerability in patients with progressive midgut NETs. The new serotonin inhibitor telotristat etiprate has shown significant activity in the palliation of symptoms of carcinoid syndrome, and its approval by regulatory authorities is expected soon. Summary The field of NETs has been transformed from one dominated by limited treatment options to one characterized by an increasing number of therapeutic agents and active clinical trials. Navigating the current therapeutic algorithm may be challenging, and requires an understanding both of the heterogeneity of NETs and of characteristics that are shared by NETs across tumor subtypes.

// Mauro Cives 1 , Valeria Simone 1 , Francesca Maria Rizzo 1 and Franco Silvestris 1 1 Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro”, Bari, Italy Correspondence to: Franco Silvestris, email: // Keywords : carcinoid tumors, DAXX, ATRX, MEN1, DNA methylation Received : April 06, 2016 Accepted : June 30, 2016 Published : July 13, 2016 Abstract High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications.

Treatment options for neuroendocrine tumors (NETs) and carcinomas (NECs) are expanding. Early-phase studies have shown preliminary evidence of the antitumor activity of alpha-emitting peptide receptor radionuclide therapy (PRRT), and novel radiopeptides incorporating somatostatin receptor antagonists (rather than agonists) have been developed. Several tyrosine kinase inhibitors (TKIs) with antiangiogenic potential have been evaluated in patients with NETs, including lenvatinib, axitinib, cabozantinib and pazopanib. Recently, two phase 3 clinical trials have demonstrated the efficacy and safety of surufatinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, fibroblast growth factor receptor (FGFR)-1 and colony stimulating factor-1 receptor (CSF-1R), in patients with pancreatic and extra-pancreatic NETs. Multiple clinical trials of combination immunotherapy have been recently completed, but interpretation of the results is hampered by small samples sizes and discordant outcomes. This review summarizes recent data on emerging treatments for neuroendocrine neoplasms.

Neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are a heterogeneous family of neoplasms. Well-differentiated tumors are often slow growing and characterized by low tumor mutational burden. Poorly differentiated NECs are aggressive, with an increased mutational burden and higher propensity to express PD-L1. While the therapeutic landscape for neuroendocrine neoplasms (NENs) has evolved substantially over the past decade, immunotherapy has been unexplored in NENs until recently. Checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 agents, bi-specific tumor-targeting antibodies, and chimeric antigen receptor (CAR) T-cell therapy are examples of treatments that have demonstrated efficacy in other cancers and have recently been investigated in NENs. This review examines the immune landscape of NENs in detail, summarizes recent clinical study results, and discusses potential future directions for immunotherapy.

Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor β primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs’ surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs’ microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.