ACTH-secreting pancreatic neuroendocrine neoplasms: A case-series.

Ectopic Cushing's syndrome (CS) occurs rarely in patients with pancreatic neuroendocrine neoplasms. Early recognition of symptoms is critical given the high morbidity and mortality associated with CS. A database of pancreatic neuroendocrine neoplasms (NENs) seen at the Moffitt Cancer Center between 1/2008 and 4/2022 was reviewed and cases of ectopic CS were identified. Information was extracted on tumor characteristics, clinical signs and symptoms, therapies, and outcomes. Thirteen cases were identified, ranging in age from 16 to 65 years at the initial time of diagnosis (median 42). Twelve of 13 patients had metastatic tumors at presentation. All were well-differentiated at diagnosis although two were described as transformed to poorly differentiated on rebiopsy. A total of 4 patients also experienced Zollinger-Ellison syndrome. Three patients underwent bilateral adrenalectomy to manage uncontrolled CS. Median overall survival of was 56 months from the time of initial cancer diagnosis but only 18 months from diagnosis of CS. Our study showed that ectopic CS is a highly morbid condition when occurring in pancreatic NENs and is associated with aggressive disease. Bilateral adrenalectomy can be considered for syndrome control. To our knowledge, this is the largest institutional case-series of ACTH-secreting metastatic pancreatic NEN.

Belzutifan in a Patient With VHL-Associated Metastatic Pancreatic Neuroendocrine Tumor.

von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease characterized by mutation of the VHL gene. This gene encodes for the VHL protein, which regulates the activity of HIF-α, a transcription factor involved in the cellular response to hypoxia. Mutations in VHL lead to the accumulation of HIF-α and, consequently, the engagement of hypoxia-sensitive genes with tumorigenic effects. VHL disease is associated with the development of tumors in multiple organs, including pancreatic neuroendocrine tumors (pNETs). Belzutifan is an HIF-α inhibitor; however, it has not been previously evaluated in patients with metastatic or treatment-refractory pNETs. This report presents a 43-year-old woman with VHL-associated metastatic pNET treated with belzutifan after progression on multiple systemic therapies. She began treatment with belzutifan and experienced partial radiographic response within 1 month of treatment. Other than asymptomatic anemia, no adverse effects developed during 5 months of ongoing therapy. Belzutifan is an inhibitor of HIF-2α that targets the underlying pathophysiology of VHL-associated pNETs. Our case report describes exceptional activity in a metastatic pNET arising from VHL.

γδ T Cell-Based Adoptive Cell Therapies Against Solid Epithelial Tumors.

ABSTRACT: Conventionally, adoptive cell therapies have been developed and optimized using αß T cells. However, the understudied and less abundant γδ T cells offer unique advantages to the immunotherapy field especially for therapies against solid tumors. Recently, γδ T-cell potential against a broad spectrum of malignant cells has been demonstrated in the preclinical setting. In the clinic, γδ T-cell-based immunotherapies have proven to be safe; however, their efficacy needs improvement. Considering the growing body of literature reflecting the increasing interest in γδ T cells, we sought to capture the current topics of discussion in the field, pertaining to their use in adoptive immunotherapy. We aimed to compile information about γδ T-cell enhancement in terms of expansion, phenotype, and inhibitory receptors, in addition to the latest advances in preclinical and clinical research using γδ T cells specifically against solid epithelial tumors.

Development of anti-somatostatin receptors CAR T cells for treatment of neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors (NETs) overexpress somatostatin receptors (SSTRs). METHODS: We developed a second-generation, ligand-based, anti-SSTR chimeric antigen receptor (CAR) incorporating the somatostatin analog octreotide in its extracellular moiety. RESULTS: Anti-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. CONCLUSIONS: Taken 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.

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.

Adoptive T-cell immunotherapy in digestive tract malignancies: Current challenges and future perspectives.

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.

Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms.

BACKGROUND: The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors. METHODS: We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM. RESULTS: A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed. CONCLUSIONS: The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.

Comparison of Nausea and Vomiting Associated With Amino Acid Formulations Coinfused With Peptide Receptor Radionuclide Therapy: Commercial Parenteral Nutrition Formulas Versus Compounded Arginine/Lysine.

OBJECTIVES: Positively charged amino acids (AA) such as arginine/lysine are coinfused with radiolabeled somatostatin analogs to reduce rates of nephrotoxicity. In the phase 3 NETTER-1 trial, commercial AA formulations were used in association with 177Lu-DOTA-0-Tyr3-Octreotate (DOTATATE). These formulations were also used in an early-access program (EAP) before regulatory approval of 177Lu-DOTATATE. Our program transitioned to compounded l-arginine 2.5%/l-lysine 2.5% in 0.9% NaCl after commercial approval of 177Lu-DOTATATE. We sought to compare rates of nausea/vomiting with arginine/lysine versus commercial parenteral AA formulations. METHODS: Rates of nausea/vomiting of all 20 EAP patients who received commercial AAs (15% Clinisol) were compared with the first 29 patients to receive 177Lu-DOTATATE after commercial approval and coinfused with arginine/lysine. Other parameters reviewed included infusion rates, need for PRN nausea medications, and other toxicities. RESULTS: Seventeen percent of patients who received compounded arginine/lysine experienced nausea, compared with 100% of patients in the EAP group (P < 0.0001). Infusion-related reactions occurred in 3% of the arginine/lysine cohort versus 35% in the EAP group. Infusion durations were substantially shorter in the arginine/lysine cohort (reduced by 61%). CONCLUSIONS: Coinfusions of arginine/lysine with radiolabeled somatostatin analogs result in substantially lower rates of nausea/vomiting compared with commercial AA formulations designed for parenteral nutrition.

Somatostatin receptor radionuclide therapy in neuroendocrine tumors.

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

Desmoplastic mesenteric lesions do not respond radiographically to peptide receptor radionuclide therapy.

177 Lu-Dotatate treatment is indicated for progressive, well-differentiated, small bowel neuroendocrine tumours) NETs. These tumours often metastasise to mesenteric lymph nodes and produce a desmoplastic reaction, consisting of tumour cells interspersed with fibrotic tissue. We hypothesised that, in patients treated with 177 Lu-Dotatate, mesenteric tumours would remain stable even as liver tumour size changes were observed. We retrospectively reviewed the records of all patients treated with 177 Lu-Dotatate between April 2018 and December 2019. Among patients with desmoplastic mesenteric tumours and liver metastases, we evaluated changes in tumour size of mesenteric and liver lesions based on pre- and post-treatment anatomic scans. As a result of the infrequency of objective radiographic response, any reported changes in tumour size were considered significant. Twenty-one patients met the inclusion criteria: nine had evidence of shrinkage of liver lesion(s), one had mild progression of liver lesions, seven had stable hepatic disease and four had a mixed hepatic response. Two of the patients with hepatic tumour shrinkage met the criteria for a partial response via RECIST 1.1 (https://recist.eortc.org). Desmoplastic mesenteric lesions remained unchanged in size, regardless of the changes detected in liver lesions. In conclusion, 177 Lu-Dotatate does not impact desmoplastic mesenteric tumours which are typically associated with midgut NETs. Patients whose disease is predominantly confined to desmoplastic mesenteric lesions are unlikely to respond radiographically to peptide receptor radionuclide therapy. Moreover, the inclusion of desmoplastic mesenteric lesions as target lesions in RECIST measurements tends to increase rates of disease stability vs response or progression.

Risk of Bowel Obstruction in Patients with Mesenteric or Peritoneal Disease Receiving Peptide Receptor Radionuclide Therapy.

Although radiation-induced mesenteritis or peritonitis can potentially exacerbate the risk of bowel obstruction, there are no data in the literature on the incidence of intestinal obstruction related to peptide receptor radionuclide therapy. Methods: The records of all patients treated with 177Lu-DOTATATE at Moffitt Cancer Center between April 2018 and October 2019 were evaluated. The number of patients who developed bowel obstruction within 3 mo of a 177Lu-DOTATATE treatment was divided by the total number of patients with preexisting peritoneal or mesenteric disease. Management strategies and outcomes were evaluated. Results: Of a total of 159 patients treated, 81 had baseline mesenteric or peritoneal disease, among whom 5 (6%) experienced at least 1 episode of bowel obstruction within 3 mo of treatment. Two of the patients underwent surgical exploration during obstruction describing a "frozen abdomen." All 5 responded at least temporarily to high-dose corticosteroid treatment and regained bowel function, but 2 patients eventually succumbed to progressive peritoneal disease. Conclusion: Peptide receptor radionuclide therapy can lead to bowel obstruction in patients with mesenteric or peritoneal disease, likely by inducing inflammation. Corticosteroids can potentially play a role in treatment and prophylaxis.

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice.

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.

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

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.

Efficacy of FOLFOX in Patients with Aggressive Pancreatic Neuroendocrine Tumors After Prior Capecitabine/Temozolomide.

BACKGROUND: 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) has activity in pancreatic neuroendocrine tumors (pNETs), but its use is limited, partly because of toxicities. pNETs can often become aggressive over time. We evaluated the efficacy of FOLFOX in patients with aggressive pNETs who had progressed after capecitabine plus temozolomide (cap/tem) among other treatments. MATERIALS AND METHODS: This was a retrospective study of all patients with well-differentiated metastatic pNETs, treated at an academic cancer center between January 2008 and June 2019, who received FOLFOX and had received cap/tem in the past. The primary endpoint was objective response rate. RESULTS: Thirty-one patients met eligibility criteria. Twenty-five received FOLFOX, and six received FOLFOX with bevacizumab. Patients were heavily pretreated, having received a median of three prior lines of systemic therapy prior to FOLFOX (range, 1-8). Three (9.7%) patients had grade [G]1 tumors, 16 (51.6%) had G2, and 6 (19.4%) had G3, and grade was unspecified in 6 (19.4%) patients. Fourteen (45.2%) exhibited a best response of partial radiographic response per RECIST 1.1 criteria, 15 (48.4%) stable disease, and 2 (6.4%) progressive disease; overall response rate was 45.2% and disease control rate was 93.5%. Median progression-free survival was 6 months (95% confidence interval [CI], 5.0-7.0), and median overall survival was 16 months from onset of study treatment (95% CI, 11.3-20.7) and 67 months from date of diagnosis (95% CI, 49.8-84.2). Median duration of treatment was 3 months, and median duration of response was 2 months. Toxicity profile was consistent with known adverse events associated with this regimen. CONCLUSION: FOLFOX is active in aggressive, heavily pretreated pNETs that have progressed on prior cap/tem chemotherapy; response durations are relatively short. IMPLICATIONS FOR PRACTICE: FOLFOX chemotherapy has robust activity in patients with rapidly progressive, heavily pretreated pancreatic neuroendocrine tumors (NETs), a setting in which few, if any, other options are likely to be effective. Durations of response, however, are relatively short, and new treatments are urgently needed for patients with aggressive transformation of pancreatic NETs.

Emerging Treatment Options for Gastroenteropancreatic Neuroendocrine Tumors.

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.

DAXX mutations as potential genomic markers of malignant evolution in small nonfunctioning pancreatic neuroendocrine tumors.

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 Role of Cytotoxic Chemotherapy in Well-Differentiated Gastroenteropancreatic and Lung Neuroendocrine Tumors.

OPINION STATEMENT: The treatment landscape of well-differentiated neuroendocrine tumors (NETs) has considerably expanded in recent years, and both somatostatin analogs, radiolabeled somatostatin analogs, everolimus, and sunitinib have been incorporated within the therapeutic armamentarium against these malignancies. Even in the context of multiple treatment options available, cytotoxic chemotherapy plays a pivotal role in the management of pancreatic NETs (panNETs), while its activity in midgut carcinoids and lung NETs is still debated. High response rates, ranging from 30 to 70%, have been consistently reported in studies of panNETs investigating streptozotocin-, temozolomide-, or platinum-based regimens, and an unprecedented prolongation of progression-free survival has been recently demonstrated in a prospective, randomized trial of capecitabine and temozolomide in patients with progressive panNETs. As a general principle, cytotoxic chemotherapy appears particularly appropriate in patients with bulky, symptomatic, or rapidly progressing tumors, especially of pancreatic origin, or in the salvage setting of NET patients who have failed alternative therapeutic options. Emerging evidence has also shown the potential efficacy of induction chemotherapy in patients with locally advanced or oligometastatic panNET, but prospective validation is needed before implementation of this approach in routine clinical practice. At present, there is no consensus on adjuvant therapy in pulmonary NETs, and differences between guideline recommendations at this regard mainly stem from the lack of high-level evidence. In the future, the identification of molecular biomarkers of response to chemotherapy might allow better patient preselection, thus leading to improved outcomes.

The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications.

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 ß 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.

Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology.

Over the last decades, the concept of precision medicine has dramatically renewed the field of medical oncology; the introduction of patient-tailored therapies has significantly improved all measurable outcomes. Liquid biopsy is a revolutionary technique that is opening previously unexpected perspectives. It consists of the detection and isolation of circulating tumor cells, circulating tumor DNA and exosomes, as a source of genomic and proteomic information in patients with cancer. Many technical hurdles have been resolved thanks to newly developed techniques and next-generation sequencing analyses, allowing a broad application of liquid biopsy in a wide range of settings. Initially correlated to prognosis, liquid biopsy data are now being studied for cancer diagnosis, hopefully including screenings, and most importantly for the prediction of response or resistance to given treatments. In particular, the identification of specific mutations in target genes can aid in therapeutic decisions, both in the appropriateness of treatment and in the advanced identification of secondary resistance, aiming to early diagnose disease progression. Still application is far from reality but ongoing research is leading the way to a new era in oncology. This review summarizes the main techniques and applications of liquid biopsy in cancer.