Neuroendocrine Tumors

A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (pNETs), present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. Our goal was to determine whether urinary matrix metalloproteases (uMMPs) and/or their endogenous inhibitors, urinary tissue inhibitor of metalloproteases (uTIMPs), could be detected in the urine of patients with pancreatic malignancies and whether they may serve as independent predictors of disease status. Retrospective analyses of urine samples (n=139) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary MMP-2 and uTIMP-1 levels were determined using ELISA and zymography. Biomarker expression in tumour and normal pancreatic tissues was analysed via immunohistochemistry (IHC). Multivariable logistic regression analyses indicated that, when c...

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

This guideline summarizes the views of the Oncology Committee of the EANM and reflects recommendations for which the EANM cannot be held responsible. The recommendations should be taken in the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.

The purpose of this study was to evaluate by a retrospective analysis of 53 patients the efficacy of chemotherapy combining etoposide and cisplatin in the treatment of neuroendocrine tumours. The regimen was a combination of etoposide 100 mg m(-2) day(-1) for 3 days and cisplatin 100 mg m(-2) on day 1, given by 2-h intravenous infusion, administered every 21 days. Twelve patients had a well-differentiated and 41 a poorly differentiated neuroendocrine tumour. Toxicity of treatment was assessed in 50 patients and efficacy in 52 patients. Among the 11 patients with a well-differentiated tumour evaluable for tumoural response, only one (9.4%) had a partial response for 8.5 months. Forty-one patients with a poorly differentiated tumour showed an objective response rate of 41.5% (four complete and 13 partial responses); the median duration of response was 9.2 months, the median overall survival 15 months and the median progression-free survival 8.9 months. Haematological grade 3-4 toxicit...

We have recently observed an increased interest in gastro-entero-pancreatic neuroendocrine tumors (GEP NET). They are rare cancer types and therefore collaborative effort of specialists in various disciplines of medicine is necessary to work out the ...

A neuroendokrin daganatok kezelésében a hagyományos terápiás lehetőségek mellett ma már egyre nagyobb szerepet kap a peptid-receptor endoradioterápia. A kezelés alapjául a neuroendokrin daganatok jellegzetes szomatosztatinreceptor-expressziója és a ligand (szomatosztatin, illetve analógjai) kötődése után a szomatosztatinreceptor internalizálódása szolgál. Ezeket a jellegzetességeket kihasználva lehetőség nyílt a szomatosztatinanalógokhoz kapcsolt radioaktív izotópok terápiás célú felhasználására. Az endoradioterápiában a szomatosztatinanalóghoz kelátot kapcsolnak, ami stabilan köti a sugárzó izotópot. Neuroendokrin daganatok kezelésére a leggyakrabban használt izotópok a β-sugárzó ittrium-90 ( 90 Y) és a β+γ-sugárzó lutécium-177 ( 177 Lu). A szomatosztatinreceptor-endoradioterápia indikációja ma leginkább a sebészileg nem megoldható, progresszív, szomatosztatinreceptort erősen expresszáló neuroendokrin tumoros betegek esetében áll fenn. A nemzetközi irodalom szerint a kezeltek 25%-ában 50%-nál nagyobb tumor méret-csökkenés érhető el. Bár hazánkban jelenleg ez a kezelési lehetőség nem áll rendelkezésre, 2005 óta az Or szágos Egészségbiztosítási Pénztár támogatásával hazai betegek számára is lehetőség nyílt a bázeli Nuklearmedicina Intézettel történő együttműködés révén a kezelésre. Az elmúlt 5 évben a Semmelweis Egyetem II. Belgyógyászati Klinikáján keresztül 51 beteg részesült ilyen kezelésben. Az összefoglaló röviden áttekinti a szomatosztatinreceptor-endoradioterápia alapjait, felhasználási területeit, a nemzetközi irodalomban közölt eredményeit, mellékhatását, valamint elsőként mutatja be a bázeli intézettel kooperációban kezelt hazai betegekkel szerzett tapasztalatokat. Orv. Hetil., 2011, 152, 392-397.

En este texto se ofrecen conceptos generales sobre las hormonas y sus funciones, mecanismos de acción y regulación endocrina y neuroendocrina. Estos contenidos sientan la base sobre la cual se desarrolla la especialización en Endocrinología.

a b s t r a c t [ 131 I]-metaiodobenzylguanidine (mIBG) is a known radiopharmaceutical used for the treatment of neuroendocrine tumors. The development of therapeutic [ 131 I]-mIBG doses at production level is highly challenging due to rapid product degradation and high radiation exposures to the production plant personnel. In the present work, a working module for the production of 10 doses (100 mCi each) in a single operation was developed following copper (I) assisted isotope exchange. The labeled product complies with the pharmaceutical specifications suitable for in-vivo patient use.

Neuroendocrine neoplasms (NENs) have variable biological behaviour​ but the majority exhibits a slow progression. Metastatic bone disease (mBD) in NENs is relatively uncommon and not well described albeit associated with an increased mortality.

Abundant expression of somatostatin receptors (SSTR) is frequently identified in differentiated neuroendocrine tumors and may serve as potential target for diagnostic imaging and treatment. This article discusses the &quot;theranostic approach&quot; of SSTR-targeting compounds including an overview of its role for diagnosis, staging and restaging, discussing its way to being established in clinical routine, and giving an outlook about further potentially relevant developments.

Patients with neuroendocrine tumors (NETs) often have metastatic spread at the time of diagnosis. NETs frequently express somatostatin receptors (SSTR) that can be targeted by radiolabeled somatostatin analogs (e.g. 177Lu-octreotate). Despite being highly effective in animal models (e.g. the human small intestine NET GOT1 transplanted to nude mice), 177Lu-octreotate-based therapies have shown low cure rates in clinical studies. The cellular processes that underlie positive treatment response to 177Lu-octreotate are largely unknown.
The aim of this work was to study the possibilities to optimize the therapeutic effects of 177Lu-octreotate in the GOT1 model in nude mice.
A literature study of available data on radiolabeled somatostatin analogs on NETs in animal models was performed, to identify strategies for treatment optimization. To test these strategies, GOT1-bearing BALB/c nude mice were treated with non-curative amounts of 177Lu-octreotate in different treatment schedules including single administrations, priming (fractionated) administrations and combination treatment with hedgehog inhibitor sonidegib. Biodistribution and dosimetry studies were performed and anti-tumor effects were monitored by measuring tumor volume. Global transcriptional and proteomic responses in tumor samples were evaluated using RNA microarray and liquid chromatography mass spectrometry, respectively.
177Lu-octreotate therapy of GOT1 tumors xenotransplanted in nude mice resulted in tumor volume reduction. Priming administration resulted in increased anti-tumor effects and increased therapeutic window. Combination therapy using sonidegib and 177Lu-octreotate resulted in prolonged time to progression. The global transcriptional and proteomic analyses of 177Lu-octreotate treated tumor samples revealed time-specific responses in terms of affected biological functions.
In conclusion, time-dependent changes in p53-related cell cycle regulation and apoptosis, angiogenesis, endoplasmic reticulum stress, and oxidative stress-related processes suggest possible niches for combination therapy at different time-points after radionuclide therapy. Priming 177Lu-octreotate therapy and combination therapy using sonidegib and 177Lu-octreotate could be beneficial to patients with NE-tumors.

Gastroenteropancreatic neuroendocrine tumors have been
increasing in frequency over the past decades. The goal of
this paper is to provide a concise overview of various treatment
options based mainly on consensus guidelines. The
only curative therapy for these tumors is timely surgical
intervention including endoscopic removal of early stage
neuroendocrine tumors. Since at initial diagnosis about half
of these patients present with advanced disease, systemic
drug and non-drug treatments are discussed in details.
Therapeutic approaches of advanced stages include surgical,
medical, interventional radiological and nuclear medicine
strategies. The aims of treatment are to provide an
appropriate antisecretory and antiproliferative effect. Optimization
of diverse treatment strategies is best achieved by
multidisciplinary approaches.

Neuroendocrine tumours (NETs) of the head and neck are rare neoplasms and can be of epithelial or non-epithelial differentiation. Although the natural history of NETs is variable, it is crucial to establish an early diagnosis of these tumours as they can be potentially curable. Conventional anatomical imaging and functional imaging using radionuclide scintigraphy and positron emission tomography/computed tomography can be complementary for the diagnosis, staging and monitoring of treatment response. This article describes and illustrates the imaging features of head and neck NETs, discusses the potential future role of novel positron-emitting tracers that are emerging into clinical practice and reviews contemporary management of these tumours. Familiarity with the choice of imaging techniques and the variety of imaging patterns and treatment options should help guide radiologists in the management of this rare but important subgroup of head and neck neoplasms.

In-pentetreotide. Forty-five patients were evaluated for carcinoid, 15 for islet cell tumour, seven for metastatic NE tumour, four for medullary thyroid carcinoma, and one patient had ophthalmopathy. SPECT/CT induced improvement in the interpretation of SPECT and conventional CT and resultant clinical management changes were recorded.

Introduction Recent studies have suggested that PET imaging with Ga-68-labelled DOTA-somatostatin analogues such as octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both computed tomography and planar and SPECT somatostatin receptor scintigraphy.

Neuroendocrine tumors (NETs) are malignant solid tumors originating from neuroendocrine cells dispersed throughout the body. Differentiated NETs overexpress somatostatin receptors (SSTRs), which enable the diagnosis using radiolabeled somatostatin analogues. Internalization and retention within the tumor cell are important for peptide receptor radionuclide therapy (PRRT). Use of the same DOTA peptide for SSTR PET/CT using 68 Ga and for PRRT using therapeutic radionuclides like 177 Lu and 90 Y offers a unique theranostic advantage. This forms the basis for the role of 68 Ga-SSTR PET/CT not only in patient selection for PRRT but also for prognostication, assessment of therapeutic response, and long-term follow-up after PRRT.

Zystische Tumoren des Pankreas werden mit zunehmender Häufigkeit in der Schnittbildgebung entdeckt. In den letzten Jahren hat sich ein differenziertes Verständnis der Pathologie und des natürlichen Verlaufs bei diesen Tumoren ausgebildet. Voraussetzung für die Differenzierung dieser zystischen Veränderungen ist eine gute Kenntnis der Makropathologie. Daneben spielen Faktoren wie klinisches Bild, Alter und Geschlecht eine ganz wesentliche Rolle, um diese Tumoren richtig zu klassifizieren. Da sich in dieser Gruppe von Tumoren benigne, prämaligne und maligne Formen finden, ist es ein Ziel der Diagnostik, die therapeutischen Konsequenzen je nach Tumortyp, Alter und Risiko eines operativen Eingriffs zu differenzieren.

Peptide receptor radionuclide therapy (PRRT) consists in the systemic administration of a synthetic peptide, labelled with a suitable beta-emitting radionuclide, able to irradiate tumours and their metastases via the internalization through a specific receptor, overexpressed on the cell membrane. After 15 years of experience, we can state that PRRT with 90 Y-labelled peptides is generally well tolerated. Acute side effects are usually mild, some of which are related to the co-administration of amino acids, such as nausea. Others are related to the radiopeptide, such as fatigue or the exacerbation of an endocrine syndrome, which rarely occurs in functioning tumours. Chronic and permanent effects on target organs, particularly the kidneys and the bone marrow, are generally mild if the necessary precautions are taken. Currently, the potential risk to kidney and red marrow limits the amount of radioactivity that may be administered. However, when tumour masses are irradiated with adequate doses, volume reduction may be observed. 90 Y-octreotide has been the most widely used radiopeptide in the first 8-10 years of experience. Unfortunately, all of the published results derive from different and inhomogeneous phase I/II studies. Hence, a direct comparison is virtually impossible to date. Nevertheless, even with these limitations, objective responses are registered in 10-34% of patients. The optimal timing of 90 Y-DOTATOC in the management of somatostatin receptor (SSTR)-positive tumours and the way in which it should be integrated with other treatments have yet to be defined, and prospective phase II/III trials comparing the efficacy and toxicity of different schemes of 90 Y-DOTATOC administration are still warranted.

Imaging can take advantage of developments in "omics" approaches and go from routine individual biomarkers to multiple-scale biomarker profiles. Imaging structural, functional, metabolic, cellular, and molecular changes will be made possible by multimodality hybrid techniques, such as positron emission tomography-magnetic resonance imaging. Imaging should predict treatment response, look at stratification for specific treatment modalities, and look at the "omic" characterization of an individual patient or a specific tumor. This should lead to the development of "personalized" medicine. In cancer radiotherapy, patient responses should be accurately predicted. In specific cases, proton and hadrontherapy will be further enhanced by the irradiation dose delivered to the tumors. For disseminated or metastatic disease, targeted radionuclide therapy is an effective addition to the arsenal against cancer. The clinical efficacy of radiolabeled antibodies has been clearly demonstrated in lymphoma as well as that of radiolabeled peptides derived from somatostatin in the treatment of neuroendocrine tumors. Preliminary studies now show interesting results in solid tumors, too. Even if the number of objective clinical responses based on tumor shrinkage is small, targeted radionuclide therapy increases progression-free survival or overall survival in some specific cases where tumor burden is small. Avenues for further improvement are multiple and include combination with other therapeutic modalities, development of new approaches (e.g., small molecules, pretargeting, and antibody alternatives). Using alpha-emitting radionuclides is another possibility for specific diseases, such as leukemias, multiple myeloma, or brain tumor remnants.

Galio (68Ga) edotreótida está indicada para la obtención de imágenes mediante tomografía por emisión de positrones (PET) de la sobreexpresión de receptores de somatostatina en pacientes adultos con confirmación o sospecha de tumores neuroendocrinos gastroenteropancreáticos (TNEGEP) bien diferenciados para la localización de tumores primarios y sus metástasis. La 68Ga edotreótida se une con alta afinidad a los receptores de la somatostatina (SSTR), principalmente al receptor SSTR2 y en menor al SSTR5. En términos de rendimiento técnico, tiene la ventaja técnica frente a (111In) pentetreótida de su mejor resolución espacial, que facilita el escaneo de todo el cuerpo en poco tiempo y el valor agregado de imágenes de fusión usando un escáner híbrido PET/CT. El isótopo de galio (68Ga) tiene la ventaja de ser producido a partir de un generador que está disponible en departamentos de hospitales, sin necesidad de un ciclotrón. Para los pacientes, la principal ventaja es un tiempo de escaneo más corto con menos exposición a la radiación.

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with 111 In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and g-emitter 111 In-diethylenetriaminepenta-acetic acid (DTPA) 0 ,octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with 90 Y, a pure b-emitter, 90 Y-1,4,7,10-tetraazacyclododecane-N,N 0 ,N 00 ,N 000 -tetraacetic acid (DOTA) 0 ,Tyr 3 ,octreotide ( 90 Y-DOTATOC, OctreoTher), was associated with 10-30% objective tumour response rates, and appears to be particularly effective in larger tumours. 111 In-and 90 Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with 177 Lu-DOTA 0 ,Tyr 3 octreotate ( 177 Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both 90 Y-DOTATOC and 177 Lu-DOTA 0 ,Tyr 3 octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on 111 In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.

Purpose 18F-FDG positron emission tomography (PET) value for the assessment of neuro-endocrine tumours (NET) is limited. Preliminary studies indicate that 18F-DOPA and 68Ga-DOTA-NOC are more accurate for disease assessment and 68Ga-DOTA peptides provide additional data on receptor status that are crucial for targeted radionuclide therapy. At present, there are no comparative studies investigating their role in NET. Aim The aim of this study was to compare 68Ga-DOTA-NOC and 18F-DOPA for the evaluation of gastro-entero-pancreatic and lung neuro-endocrine tumours. Materials and methods Thirteen patients with biopsy-proven NET (gastro-entero-pancreatic or pulmonary) were prospectively enrolled and scheduled for 18F-DOPA and 68Ga-DOTA-NOC PET. PET results obtained with both tracers were compared with each other, with other conventional diagnostic procedures (CT, ultrasound) and with follow-up (clinical, imaging). Results The most common primary tumour site was the pancreas (8/13) followed by the ileum (2/13), the lung (2/13) and the duodenum (1/13). The carcinoma was well differentiated in 10/13 and poorly differentiated in 3/13 cases. 68Ga-DOTA-NOC PET was positive, showing at least one lesion, in 13/13 cases while 18F-DOPA PET was positive in 9/13. On a lesions basis, 68Ga-DOTA-NOC identified more lesions than 18F-DOPA (71 vs 45), especially at liver, lung and lymph node level. 68Ga-DOTA-NOC correctly identified the primary site in six of eight non-operated cases (in five cases, the primary was surgically removed before PET), while 18F-DOPA identified the primary only in two of eight cases. Conclusions Although the patients studied are few and heterogeneous, our data show that 68Ga-DOTA-NOC is accurate for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours in either the primary or metastatic site and that it offers several advantages over 18F-DOPA.

Neuroendocrine tumors (NETs) are malignant solid tumors originating from neuroendocrine cells dispersed throughout the body. Differentiated NETs overexpress somatostatin receptors (SSTRs), which enable the diagnosis using radiolabeled somatostatin analogues. Internalization and retention within the tumor cell are important for peptide receptor radionuclide therapy (PRRT). Use of the same DOTA peptide for SSTR PET/CT using 68 Ga and for PRRT using therapeutic radionuclides like 177 Lu and 90 Y offers a unique theranostic advantage. This forms the basis for the role of 68 Ga-SSTR PET/CT not only in patient selection for PRRT but also for prognostication, assessment of therapeutic response, and long-term follow-up after PRRT.

Purpose Peptide receptor radionuclide therapy (PRRT) has become an important treatment option in the management of advanced neuroendocrine tumours. Long-lasting responses are reported for a majority of treated patients, with good tolerability and a favourable impact on quality of life. The treatment is usually limited by the cumulative absorbed dose to the kidneys, where the radiopharmaceutical is reabsorbed and retained, or by evident haematological toxicity. The aim of this study was to evaluate how renal function affects (1) absorbed dose to the kidneys, and (2) the development of haematological toxicity during PRRT treatment. Methods The study included 51 patients with an advanced neuroendocrine tumour who received 177 Lu-DOTATATE treatment during 2006 -2011 at Sahlgrenska University Hospital in Gothenburg. An average activity of 7.5 GBq (3.5 -8.2 GBq) was given at intervals of 6 -8 weeks on one to five occasions. Patient baseline characteristics according to renal and bone marrow function, tumour burden and medical history including prior treatment were recorded. Renal and bone marrow function were then monitored during treatment. Renal dosimetry was performed according to the 177 Lu-DOTATATE treatment. The study confirms the tolerability of PRRT in patients with an advanced neuroendocrine tumour but indicates that patients with inferior renal function are at risk of being exposed to higher absorbed doses to normal tissue on treatment.

Background: Distinction of small cell lung carcinoma (SCLC) from non-small cell lung carcinoma (NSCLC) is critical because of the differences in prognosis and management. Patients with SCLC usually present with distant metastasis, and clinicians demand an accurate diagnosis in order to initiate appropriate therapy. Limited cytology material, occasionally with crush artifact, is not uncommon. Therefore, robust cytomorphologic features and a small immunostaining panel would be ideal to differentiate SCLC from NSCLC and other neuroendocrine neoplasms. We evaluated CD56 and the quantitative Ki-67 immunohistochemical panel in comparison to synaptophysin and chromogranin, along with cytomorphology to diagnose SCLC. Design: Eighty-eight cases of SCLC were retrieved from the cytology archives of The Johns Hopkins Hospital. Forty neuroendocrine neoplasms were used as control cases. Results: SCLCs included 33 lung cases and 55 metastatic lesions. The specimens were obtained by fine needle aspiration, thoracocentesis, bronchoalveolar lavage and abdominal paracentesis. CD56 was expressed in 98.9% of SCLCs, which is significantly more sensitive than synaptophysin and chromogranin. The Ki-67 labeling index was high (>70%) in all cases, which is a reliable marker to dif-

The diagnostic work-up and treatment of patients with neuroendocrine tumours has undergone a major change during the last decade. New diagnostic possibilities and treatment options have been developed. These Nordic guidelines, written by a group with a major interest in the subject, summarises our current view on how to diagnose and treat these patients. The guidelines are meant to be useful in the daily practice for clinicians handling patients with neuroendocrine tumours.

In addition to regulating acid secretion, the gastric antral hormone gastrin regulates several important cellular processes in the gastric epithelium including proliferation, apoptosis, migration, invasion, tissue remodelling and angiogenesis. Elevated serum concentrations of this hormone are caused by many conditions, particularly hypochlorhydria (as a result of autoimmune or Helicobacter pylori (H pylori)-induced chronic atrophic gastritis or acid suppressing drugs) and gastrin producing tumors (gastrinomas). There is now accumulating evidence that altered local and plasma concentrations of gastrin may play a role during the development of various gastric tumors. In the absence of H pylori infection, marked hypergastrinemia frequently results in the development of gastric enterochromaffin cell-like neuroendocrine tumors and surgery to remove the cause of hypergastrinemia may lead to tumor resolution in this condition. In animal models such as transgenic INS-GAS mice, hypergastrine...

The incidence of pancreatic neuroendocrine tumors (panNETs) has increased worldwide in the last two decades. Given the indolent nature of these tumors, several patients are diagnosed with metastatic disease, which partially impairs the long-term efficacy of currently available treatments and reduces survival rates. The search for new therapeutic strategies for cancer patients has pushed towards the retrospective analysis of studies involving patients who concomitantly received other drugs together with standard anticancer agents. In this light, several retrospective analyses have shown that metformin use is associated with improved prognosis in patients with different tumor types treated with standard antitumor agents. Metformin, the cornerstone oral agent for the treatment of type 2 diabetes, plays a role in modulating glucose cell metabolism. Its potential ability to interfere with tumors may derive from the tight relationship between metabolic reprogramming in cancer cells and tumor progression. Indications for metformin use as an anticancer drug result from pre-clinical and clinical observations. In particular, metformin use in diabetic patients with advanced panNETs has been associated with better progression-free survival in patients treated with somatostatin analogues with or without metformin.

Pancreatic neuroendocrine tumors (pancreatic NETs) are rare, low-to intermediate-grade neoplasms thought to arise from the pancreatic islets. Recent advances in pathology and our understanding of the biological behavior of this group of tumors has resulted in changes in their nomenclature and how we treat them. This review puts into perspective our current understanding of pancreatic NETs in terms of their incidence, pathology, and management.

For patients with neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas (GEP) (GEP-NETs), excellent care should ideally be provided by a multidisciplinary team of skilled health care professionals. In these patients, a combination of nuclear medicine imaging and conventional radiological imaging techniques is usually mandatory for primary tumour visualisation, tumour staging and evaluation of treatment. In specific cases, as in patients with occult insulinomas, sampling procedures can provide a clue as to where to localise the insulin-hypersecreting pancreatic NETs. Recent developments in these fields have led to an increase in the detection rate of primary GEP-NETs and their metastatic deposits. Radiopharmaceuticals targeted at specific tumour cell properties and processes can be used to provide sensitive and specific whole-body imaging. Functional imaging also allows for patient selection for receptor-based therapies and prediction of the efficacy of such therapies. Positron emission tomography/computed tomography (CT) and single-photon emission CT/CT are used to map functional images with anatomical localisations. As a result, tumour imaging and tumour follow-up strategies can be optimised for every individual GEP-NET patient. In some cases, functional imaging might give indications with regard to future tumour behaviour and prognosis.

Abstract: This study was primarily conducted to investigate influencing factors for insurance companies specifically for private insurance operating in Ethiopia. To attain the objective both industry-specific and macro-economic factors include the ratio of liquidity, leverage, the volume of capital, age of the insurance, underwriting risk, premium growth, market share,  inflation, and economic growth. The study included ten insurance companies with operations from 2011 to 2020. Secondary data was collected from the Ethiopian central bank (National Bank of Ethiopia). An explanatory research design with a mixed approach was used for this study. Furthermore, this study employed OLS to estimate a multiple regression model constructed through E-views 10 software after all the necessary diagnostic tests were undertaken. The finding indicates liquidity, firm premium growth, the age of the company, and market share have significant positive effects on insurance profitability. Whereas,  underwriting risk, leverage, the volume of capital, and inflation reveal significant but adverse effects on insurance profitability.  The study suggests insurances companies adopt different techniques such as improving loss handling mechanisms, assessing
and gathering adequate information about the insured before selection, and marketing managers should pay a great deal of  attention to maximizing market share through the use of user-friendly information technology for both the insurance and it is
customers.
Keywords: Profitability, Private Insurance Company, Panel, Ethiopia