Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2.

In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58-97) and 49% (95% CI 31-77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.

A gastric neuroendocrine tumor after prolonged use of proton pump inhibitors.

We describe a case of a gastric neuroendocrine tumor (NET) in a patient with a history of long- term proton pump inhibitor (PPI) use. A 29- year- old man using PPI for the last 10 years due to gastroesophageal reflux disease developed progressive bouts of heartburn. Upper gastrointestinal endoscopy localized an elevated lesion with central depression in the greater curvature of gastric body. Lesion biopsies revealed a well- differentiated neuroendocrine tumor. Despite PPIs have a well- established safety profile, concerns have been raised about a potential relationship between PPI- induced hypergastrinemia and the development of neuroendocrine tumors.

Temozolomide duration and secondary hematological neoplasms: A literature review and implications for patients with neuroendocrine neoplasms.

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.

A Randomized Trial Evaluating Patient Experience and Preference Between Octreotide Long-Acting Release and Lanreotide for Treatment of Well-Differentiated Neuroendocrine Tumors.

PURPOSE: Somatostatin analogs octreotide long-acting release (octLAR) and lanreotide are equally acceptable in National Comprehensive Cancer Network guidelines for neuroendocrine tumors (NETs). Lanreotide is more expensive and given by deep subcutaneous injection, whereas octLAR is given intramuscularly. We evaluated patient preference between these agents in terms of injection site pain. MATERIALS AND METHODS: Randomized, single-blinded study. Patients with NETs received injections every 4 weeks. Arm 1: octLAR × 3, then lanreotide × 3; arm 2: reverse order. Self-reported injection site pain scores (range, 0-10) were obtained after each of the first three injections. Primary end point was comparison of mean pain scores over the first three injections. Secondary end points included patient-reported preference. RESULTS: Fifty-one patients enrolled (26 in arm 1 and 25 arm 2), all evaluable for primary end point. No significant difference was identified in the mean pain score over the first three injections (2.4 ± 1.9 v 1.9 ± 1.5, P = .5). Thirty-four of 51 (67%) patients (15 in arm 1 and 19 in arm 2) completed post-therapy questionnaires and were evaluable for secondary end points. Seven patients (47%) in arm 1 and eight patients (42%) in arm 2 indicated no drug preference at the end of treatment. In the other 19 patients, more patients indicated mild or strong preference for octLAR over lanreotide. CONCLUSION: We found minimal pain with octLAR and lanreotide and no significant pain score differences between the two. Patients indicating a drug preference trended toward favoring octLAR.

Gastric Neuroendocrine Tumors With Parietal Cell Atrophy in a Long-term Carcinogenicity Study in Rats.

Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.

Treatment of neuroendocrine tumours with 177 Lu-peptide receptor radionuclide therapy: Challenging clinical scenarios and their management.

Peptide receptor radionuclide therapy (PRRT) for the treatment of patients with neuroendocrine tumours is usually well tolerated, with selection based on existing guidelines. However, there are various scenarios where the risk-benefit analysis of PRRT needs to be evaluated to limit any complications associated with PRRT. This review looks at 11 key scenarios where the risk-benefit of PRRT needs to be closely evaluated.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship?

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin's effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers.

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.

Comparison of serum serotonin and serum 5-HIAA LC-MS/MS assays in the diagnosis of serotonin producing neuroendocrine neoplasms: A pilot study.

BACKGROUND: Serotonin (5-hydroxytyramine) is a mediator of gastrointestinal smooth muscle contraction, and is secreted by neuroendocrine neoplasms (NENs). We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for serum serotonin to be used in NEN diagnostics and follow-up. METHODS: We used serum samples from healthy volunteers (n = 31) and patients suspected or monitored for NEN (n = 98). Serotonin-D4 internal standard was added to samples before solid phase extraction (SPE) and quantification by LC-MS/MS. The effects of sample handling and preparation on serotonin stability were studied. Finally, we established a provisional reference range for serum serotonin and compared our assay with serum 5-hydroxyindoleacetic acid (5-HIAA) for detection of NENs. RESULTS: Our assay is sensitive and has a wide linear range (10-10,000 nmol/l). Serum serotonin is stable for 7 days at room temperature and for 3 months at -20 °C. Sampling temperature is not critical. Normal range for serum serotonin was 270-1490 nmol/l. We found that serum serotonin and 5-HIAA performed equally well as diagnostic tests for NENs. CONCLUSIONS: Our LC-MS/MS assay for serum serotonin is well suited for clinical research and patient diagnostics. Our results confirm that it can complement 5-HIAA in diagnosis of NENs.

Clinical and molecular features of treatment-related neuroendocrine prostate cancer.

Treatment-related neuroendocrine prostate cancer is a lethal form of prostate cancer that emerges in the later stages of castration-resistant prostate cancer treatment. Treatment-related neuroendocrine prostate cancer transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. The incidence of treatment-related neuroendocrine prostate cancer has been rising due to the increasing use of potent androgen receptor pathway inhibitors. Typically, treatment-related neuroendocrine prostate cancer is characterized by either low or absent androgen receptor expression, small cell carcinoma morphology and expression of neuroendocrine markers. Clinically, it manifests with predominantly visceral or lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels or a short response duration to androgen deprivation therapy. Furthermore, although the tumor initially responds to platinum-based chemotherapy, the duration of the response is short. Based on the poor prognosis, it is imperative to identify novel molecular targets for treatment-related neuroendocrine prostate cancer. Recent advances in genomic and molecular research, supported by novel in vivo models, have identified some of the key molecular characteristics of treatment-related neuroendocrine prostate cancer. The gain of MYCN and AURKA oncogenes, along with the loss of tumor suppressor genes TP53 and RB1 are key genomic alterations associated with treatment-related neuroendocrine prostate cancer. Androgen receptor repressed genes, such as BRN2 and PEG10, are also necessary for treatment-related neuroendocrine prostate cancer. These genetic changes converge on pathways upregulating genes, such as SOX2 and EZH2, that facilitate lineage plasticity and neuroendocrine differentiation. As a result, on potent androgen receptor pathway inhibition, castration-resistant prostate cancer transdifferentiates to treatment-related neuroendocrine prostate cancer in a clonally divergent manner. Further understanding of the disease biology is required to develop novel drugs and biomarkers that would help treat this aggressive prostate cancer variant.

[Neuroendocrine prostate cancer]. / Neuroendokrines Prostatakarzinom.

Neuroendocrine prostate cancer (NEPC) mostly occurs as a treatment-emergent adaptive response under the pressure of intensive androgen deprivation treatment (t-NEPC). Approximately 30-40% of patients with metastatic castration-resistant prostate cancer (mCRPC) also have neuroendocrine involvement. In contrast primary small cell prostate cancer is very rare (<1%). A t­NEPC should be clinically suspected in patients who have particularly aggressive mCRPC but a disproportionately low prostate-specific antigen (PSA) level and elevated neuroendocrine tumor markers, such as chromogranin A and neuron-specific enolase. The initial Gleason score was shown to be an independent factor correlated to the risk of development of t­NEPC. Treatment is oriented to that of small cell lung cancer. In patients with negative PSA levels, chemotherapy with cisplatin and etoposide is the first line treatment, for which response rates in the range of 30-60% with a median survival time of usually less than 1 year can be achieved. In patients with much higher serum PSA levels, chemotherapy with carboplatin plus docetaxel should be considered.

Neuroendocrine tumor of cecum in patient treated with imatinib mesylate for blastic phase of chronic myeloid leukemia.

Imatinib mesylate (IM), a tyrosine kinase inhibitor, is the treatment of choice in patients with chronic myeloid leukemia (CML). It is considered a very safe drug, with mostly mild and reversible side effects. Lately, it has been suggested that adverse events may occur after a long term. We report a case of a 72-year-old woman diagnosed with blastic phase of Philadelphia chromosome positive CML treated with IM for 28 months. The patient presented first with ascites as a side effect of the drug. When the ascites re-occurred, it was caused by neuroendocrine tumor (NET) with peritoneal carcinomatosis. We believe this is the first case of a NET as a secondary malignancy (SM) after IM treatment. SM have been described in patients on IM before. It is unclear whether these tumors are caused by imatinib or found more easily because of close follow-up.

Characterization of pancreatic islet cell tumors and renal tumors induced by a combined treatment of streptozotocin and nicotinamide in male SD rats.

We herein investigated the histopathological features, including proliferative activity and immunoexpression, of pancreatic islet cell tumors (ICTs) in male SD rats induced by streptozotocin (STZ) and nicotinamide (NA), and discussed their relevance to biological behaviors and prognoses. A total of 70 and 43% of rats developed ICTs 37-45 weeks after the treatment with STZ (50 or 75mg/kg, i.v.) and NA (350mg/kg, twice, p.o.), respectively. Among the islet tumors observed in the STZ/NA-treated groups, 75% were adenomas, while 25% were carcinomas. Most STZ/NA-induced carcinomas were characterized by well-differentiated tumor cells with/without local invasion into the surrounding tissues, and weak proliferative activity. No outcome such as distance metastasis and death was noted. All of the ICTs strongly expressed insulin, part of which had hormone productivity; however there were no hypoglycemia-related clinical signs such as convulsion in these rats 36 weeks after the treatment. These results suggested that rat ICTs induced STZ/NA have small impact on biological activity or prognosis. STZ/NA treatment significantly increased of focal proliferative lesions in the kidney, liver and adrenal glands other than pancreatic islets. Of the STZ/NA-induced kidney tumors, more than 60% were renal cell adenomas, and many of them were basophilic type. The incidence of eosinophilic or clear cell type of tumors was less than 10%, respectively. Immunohistochemical analyses revealed that many of the STZ/NA-induced basophilic type of renal tumors were derived from proximal tubules, whereas the clear cell and eosinophilic types were derived from collecting tubules.

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation.

Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.

Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology.

BACKGROUND: Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy. AIM: To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology. METHODS: A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology. RESULTS: A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found. CONCLUSIONS: Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.

Histopathological and Immunohistochemical Characterization of Methyl Eugenol-induced Nonneoplastic and Neoplastic Neuroendocrine Cell Lesions in Glandular Stomach of Rats.

Methyl eugenol induces neuroendocrine (NE) cell hyperplasia and tumors in F344/N rat stomach. Detailed histopathological and immunohistochemical (IHC) characterization of these tumors has not been previously reported. The objective of this study was to fill that data gap. Archived slides and paraffin blocks were retrieved from the National Toxicology Program Archives. NE hyperplasias and tumors were stained with chromogranin A, synaptophysin, amylase, gastrin, H(+)/K(+) adenosine triphosphatase (ATPase), pepsinogen, somatostatin, and cytokeratin 18 (CK18) antibodies. Many of the rats had gastric mucosal atrophy, due to loss of chief and parietal cells. The hyperplasias and tumors were confined to fundic stomach, and females were more affected than the males. Hyperplasia of NE cells was not observed in the pyloric region. Approximately one-third of the females with malignant NE tumors had areas of pancreatic acinar differentiation. The rate of metastasis was 21%, with liver being the most common site of metastasis. Immunohistochemically, the hyperplasias and tumors stained consistently with chromogranin A and synaptophysin. Neoplastic cells were also positive for amylase and CK18 and negative for gastrin, somatostatin, H(+)/K(+) ATPase, and pepsinogen. Metastatic neoplasms histologically similar to the primary neoplasm stained positively for chromogranin A and synaptophysin. Based on the histopathological and IHC features, the neoplasms appear to arise from enterochromaffin-like cells.

Evaluación y manejo de los insulinomas. Presentación de 4 casos y revisión de la literatura / Evaluation and management of the insulinomas. Report of four cases and review of the literature

Introducción: Los insulinomas son tumores neuroendocrinos poco frecuentes que habitualmente tienen buen pronóstico. El objetivo es la presentación y revisión de la literatura médica a propósito de 4 casos. Material y Métodos: Estudio descriptivo, observacional y retrospectivo de los pacientes diagnosticados e intervenidos en el Hospital Universitario de San Juan de Alicante de insulinomas, en un periodo de 18 años (1995-2013). Resultados: Nuestro grupo de estudio incluyó 4 pacientes, 1 caso en hombres (25%) y 3 en mujeres (75%), con una mediana de edad de años (rango 3; 72). La distribución de las lesiones fue : cuerpo (1 caso), proceso uncinado (1 caso), cabeza (1 caso), cola (1 caso). El diagnóstico preoperatorio se realizó mediante test del ayuno y Tac abdominal. La ecografía intraoperatoria se realizó en todos los casos. El procedimiento quirúrgico de elección fue la enucleación. Actualmente se encuentran libres de enfermedad en un seguimiento a 10 años. Conclusiones: Los insulinomas son tumores infrecuentes que presentan buen pronóstico a largo plazo. Su diagnóstico topográfico en ocasiones es complejo. El tratamiento de elección es la cirugía y el procedimiento quirúrgico empleado con mayor frecuencia es la enucleación

Background: Insulinomas are infrecuent neuroendocrine tumors that usually have a good prognosis. The goal is the presentation and review of the literature about 4 cases. Methods: A retrospective study of all patients diagnosed with insulinomas surgically managed at San Juan de Alicante Hospital during the period between 1995 and 2013 was performed. Results: We analyzed 4 patients, three females (75%) and one male (25%) with a range age (39 to 72 years). Distribution of the lesions were: body (1 case), uncinate process (1 case), head (1 case), tail (1 case). Preoperative diagnosis was made by fasting test and abdominal CT. In all cases, intraoperative ultraound was made. Surgical management of choice was enucleation. Currently, they are free of disease at 10 years of follow up. Conclusions: Insulinomas are infrecuent tumors with good long-term prognosis. Its topographic diagnosis is sometimes complex. The treatment of choice is surgery and the surgical procedure most often used is enucleation