Efficacy and Toxicity Analysis of mFOLFIRINOX in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

BACKGROUND: High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs. PATIENTS AND METHODS: We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX. RESULTS: A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities. CONCLUSIONS: mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.

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).

Assessment of bone turnover markers and DXA parameters to predict bone metastasis progression during zoledronate treatment: a single-center experience.

Bone metastases (BM) are a serious cancer complication, potentially causing substantial morbidity. Among the clinical issues related to BM, there is the lack of specific tools for early diagnosis and prognosis. We explored whether combining bone turnover markers (BTM) with dual-energy X-ray absorptiometry (DXA) assessment could identify early BM progression and risk of skeletal-related events (SREs) during zoledronate treatment. Before the initiation of zoledronate (T0) and after six months of treatment (T1), serum levels of five BTM were measured, and patients (N = 47) underwent DXA evaluation. Standard radiological imaging was performed to assess bone tumor response to medical anti-cancer treatment. High tumor burden in bone correlated with higher serum CTX (p = 0.007) and NTX (p = 0.005) at baseline. Low concentrations of OPG at T0 predicted BM progression with a sensitivity and specificity of 63% and 77%, respectively, when a cutoff of 5.2 pmol/l was used; such a predictive meaning was stronger in patients with lytic BM (sensitivity: 88%, specificity: 80%; p = 0.0006). As for the risk of SREs, we observed an association between low baseline OC (p = 0.04) and OPG (p = 0.08) and the onset of any-time SREs, whereas an increase in OPG over time was associated with reduced risk of on-study events (p = 0.03). Moreover, a statistically significant correlation emerged between low baseline lumbar T-score and femur BMD and on-study SREs (p < 0.001 in both instances). These findings suggest that addition of DXA to BTM dosage could help stratifying the risk of SREs at the time of BM diagnosis but does not enhance our capability of detecting bone progression, during zoledronate treatment.

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives.

Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.

Adamantinoma-like Ewing sarcoma of the salivary glands: a case report and systematic literature review.

Adamantinoma-like Ewing sarcoma (ALES) of the salivary glands is an exceedingly rare malignancy defined by the t(11,22) EWSR1::FLI1 fusion, with complex epithelial differentiation. To identify features that can allow for better recognition of this disease entity, we reviewed all published reports of molecularly confirmed ALES of the salivary glands and explored epidemiological, clinical, radiological, pathological, and therapeutic characteristics of a population of 21 patients including a single newly reported patient from our group. We searched the English-language literature indexed in PubMed, Medline, Scopus, and Web of Science using the keyword 'Adamantinoma-like Ewing sarcoma' published up to June 2022. The median age at diagnosis was 46 years, and a slight female sex predilection was observed. Most tumors originated in the parotid gland (86%) and presented as a painless palpable mass with a median diameter of 3.6 cm. Metastatic dissemination was reported only in one patient (5%), and after a median follow-up of 13 months the 1-year overall survival rate was 92%. Salivary gland ALES were frequently misdiagnosed at presentation (62% of cases) and were pathologically characterized by the presence of highly monomorphic small round blue cells with infiltrative pattern and positive immunostaining for CD99 and high- and low-molecular weight cytokeratins. Epidemiological and clinical features of salivary gland ALES raise questions on the incorporation of this malignancy in the Ewing sarcoma family tumor group.

An update on Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cancer of the skin characterized by a neuroendocrine phenotype and an aggressive clinical behavior. It frequently originates in sun-exposed body areas, and its incidence has steadily increased in the last three decades. Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) radiation exposure are the main causative agents of MCC, and distinct molecular features have been documented in virus-positive and virus-negative malignancies. Surgery remains the cornerstone of treatment for localized tumors, but even when integrated with adjuvant radiotherapy is able to definitively cure only a fraction of MCC patients. While characterized by a high objective response rate, chemotherapy is associated with a short-lasting benefit of approximately 3 months. On the other hand, immune checkpoint inhibitors including avelumab and pembrolizumab have demonstrated durable antitumor activity in patients with stage IV MCC, and investigations on their use in the neoadjuvant or adjuvant setting are currently underway. Addressing the needs of those patients who do not persistently benefit from immunotherapy is currently one of the most compelling unmet needs in the field, and multiple clinical trials of new tyrosine kinase inhibitors (TKIs), peptide receptor radionuclide therapy (PRRT), therapeutic vaccines, immunocytokines as well as innovative forms of adoptive cellular immunotherapies are under clinical scrutiny at present.

Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications.

Neuroendocrine neoplasms (NENs) are highly vascularized malignancies arising from cells of the diffuse neuroendocrine system. An intricated cross-talk exists between NEN cells and the tumor microenvironment, and three main molecular circuits (VEGF/VEGFR pathway, FGF-dependent signaling and PDGF/PDGFR axis) have been shown to regulate angiogenesis in these neoplasms. Multiple randomized trials have investigated antiangiogenic agents over the past two decades, and sunitinib is currently approved for the treatment of advanced, progressive, G1/G2 pancreatic NENs. In recent years, two phase III clinical trials have demonstrated the efficacy and safety of surufatinib, a multi-tyrosine kinase angioimmune inhibitor, in patients with well-differentiated pancreatic and extrapancreatic NENs, and two studies of this agent are currently underway in Europe and US. The HIF-2α inhibitor belzutifan has recently received regulatory approval for the treatment of tumors arising in the context of Von-Hippel Lindau syndrome including pancreatic NENs, and a study of this drug in patients with sporadic tumors is presently ongoing. Combinations of antiangiogenic agents with chemotherapeutics and targeted drugs have been tested, with accumulating toxicities being a matter of concern. The potential of antiangiogenic agents in fine-tuning the immune microenvironment of NENs to enhance the activity of immune checkpoint inhibitors has been only partially elucidated, and further research should be carried out at this regard. Here, we review the current understanding of the biology of angiogenesis in NENs and provide a summary of the latest clinical investigations on antiangiogenic drugs in this malignancy.

Correlation between targeted RNAseq signature of breast cancer CTCs and onset of bone-only metastases.

BACKGROUND: Bone is the most frequent site of metastases from breast cancer (BC), but no biomarkers are yet available to predict skeletal dissemination. METHODS: We attempted to identify a gene signature correlated with bone metastasis (BM) onset in circulating tumour cells (CTCs), isolated by a DEPArray-based protocol from 40 metastatic BC patients and grouped according to metastasis sites, namely "BM" (bone-only), "ES" (extra-skeletal) or BM + ES (bone + extra-skeletal). RESULTS: A 134-gene panel was first validated through targeted RNA sequencing (RNAseq) on sub-clones of the MDA-MB-231 BC cell line with variable organotropism, which successfully shaped their clustering. The panel was then applied to CTC groups and, in particular, the "BM" vs "ES" CTC comparison revealed 31 differentially expressed genes, including MAF, CAPG, GIPC1 and IL1B, playing key prognostic roles in BC. CONCLUSION: Such evidence confirms that CTCs are suitable biological sources for organotropism investigation through targeted RNAseq and might deserve future applications in wide-scale prospective studies.

The psychological impact of COVID-19 pandemic on patients with neuroendocrine tumors: Between resilience and vulnerability.

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.

Cerebellar ataxia and exercise intolerance in Erdheim-Chester disease.

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.

Insights From Molecular Characterization of Adult Patients of Families With Multigenerational Diabetes.

Multigenerational diabetes of adulthood is a mostly overlooked entity, simplistically lumped into the large pool of type 2 diabetes. The general aim of our research in the past few years is to unravel the genetic causes of this form of diabetes. Identifying among families with multigenerational diabetes those who carry mutations in known monogenic diabetes genes is the first step to then allow us to concentrate on remaining pedigrees in which to unravel new diabetes genes. Targeted next-generation sequencing of 27 monogenic diabetes genes was carried out in 55 family probands and identified mutations verified among their relatives by Sanger sequencing. Nine variants (in eight probands) survived our filtering/prioritization strategy. After likelihood of causality assessment by established guidelines, six variants were classified as "pathogenetic/likely pathogenetic" and two as "of uncertain significance." Combining present results with our previous data on the six genes causing the most common forms of maturity-onset diabetes of the young allows us to infer that 23.6% of families with multigenerational diabetes of adulthood carry mutations in known monogenic diabetes genes. Our findings indicate that the genetic background of hyperglycemia is unrecognized in the vast majority of families with multigenerational diabetes of adulthood. These families now become the object of further research aimed at unraveling new diabetes genes.