Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan

Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (¹¹¹In-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required.

     

The clinical significance of somatostatin in pancreatic diseases

The aim of the study was to provide knowledge on somatostatin and its action on the body, particularly the pancreas – in physiological and pathological conditions. In order to get to know the properties of somatostatin, a hormone discovered over forty years ago, many studies that define its structure and the mechanisms by which it operates have been conducted. The properties of somatostatin receptors and the effect of somatostatin on the body – both a healthy one and in various disease stages – were determined. It was proven that the somatostatin had an inhibitive effect on the endo- and exocrine secretion of this organ, which allowed a hypothesis that it might play an important role in the pathophysiology of diabetes. In patients with severe acute pancreatitis, both somatostatin and octreotide appear to reduce the mortality rate significantly, without any effect on the incidence of complications. Nevertheless, somatostatin analogues may be the cause of acute pancreatitis. With regard to severe chronic pancreatitis, refractory to other forms of therapy, it was demonstrated that octreotide significantly alleviated pain in many patients. A similar risk of death, and generally a lower risk of complications were found in the group of somatostatin-treated patients with chronic pancreatitis when compared to those receiving placebo or untreated. The occurrence of hyperglycemia after the application of somatostatin analogues, and in particular after pasireotide, is disturbing. Somatostatin analogues have found application in the treatment of cancers. They may improve symptoms in patients with gastroenteropancreatic neuroendocrine tumors (NETs) and stabilize the tumor growth (PROMID study). However, the optimal hormone dose sizes and frequencies necessary to ensure a full therapeutic effect in selected diseases of the pancreas have not been completely determined.     

Gastrointestinal neuroendocrine tumor with unresectable liver metastases: an example of multimodal therapeutic approach

Gastrointestinal neuroendocrine tumors (NET) frequently present with unresectable hepatic metastases, which poses a barrier for curative treatment. Resection of the primary tumor and subsequent orthotopic liver transplantation (OLT) has been proposed as a treatment approach but available data in this regard is limited. We present a clinical case of an otherwise asymptomatic 44-yo man complaining of abdominal pain and dyspepsia that was diagnosed of a 10 cm duodenal tumor with multiple hepatic metastases. A CT-guided biopsy confirmed a NET. He underwent first a Whipple’s procedure, and then was listed for liver transplantation. During the waiting time a multimodal therapeutic approach was used including the use of radioactive ¹⁷⁷lutetium-labeled somatostatin analogues, long-acting somastostatin analogues and antiangiogenic antibodies (bevacizumab) in order to keep neoplastic disease under control. Two years after Whipple’s procedure and given disease stability he underwent OLT with an uneventful postoperative evolution. Patient condition and graft function are optimal after a 4-year follow-up period with no evidence of recurrence. This case report underscores how a multimodal approach involving careful patient selection, resective surgery as well as use of somatostatin analogues and antiangiogenic biological therapy followed by liver transplantation can achieve excellent long-term results in this difficult patient population.     

Limited role of Chromogranin A as clinical biomarker for pancreatic neuroendocrine tumors

BackgroundSerum Chromogranin A (CgA) is widely used as a biomarker for pancreatic neuroendocrine tumors (PanNETs). The aim of this study was to investigate the value of CgA as a diagnostic and prognostic marker for well-differentiated PanNETs.MethodsPatients with well-differentiated PanNET and a baseline CgA measurement, between 2011 and 2016 were reviewed. The diagnostic value was determined by comparing CgA values from patients with PanNETs to those with other pancreatic neoplasms and healthy controls. The Kaplan–Meier method was used to investigate the CgA prognostic significance.ResultsNinety-nine patients met inclusion criteria. As a diagnostic marker, CgA had a sensitivity of 66%, specificity of 95%, and overall accuracy of 71%. The use of PPIs was associated with a higher CgA level (p = 0.015). When excluding patients on PPIs, CgA accuracy in distinguishing PanNETs from other pancreatic neoplasms was 66%, the sensitivity and specificity were 60% and 75% respectively. Elevated CgA (p = 0.004), Ki67% (p < 0.001), tumor grade (p < 0.001) and stage of disease (p = 0.036) were associated with disease-specific survival.ConclusionCgA has a limited role as a diagnostic biomarker for well-differentiated PanNETs. An elevated CgA level may have prognostic value but its role should be further investigated with respect to other known pathological factors.     

Neuroendocrine tumors. Peptide receptor radionuclide therapy

Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues is an emerging and convincing treatment modality for patients with unresectable, somatostatin-receptor-positive neuroendocrine tumours. Using radiolabelled somatostatin analogues for imaging became the gold standard for staging of neuroendocrine tumours. The somatostatin receptor is strongly over-expressed in most tumours, resulting in high tumour-to-background ratios. Consequently, the next step was to try to treat these patients by increasing the radioactivity of the administered radiolabelled somatostatin analogue in an attempt to bring about tumour cure. Many patients have been treated successfully with this approach, roughly 25% of them achieving objective tumour shrinkage >50%. Serious side-effects have been rare. This article reviews the effectiveness and safety of the different radiolabelled somatostatin analogues used. Furthermore, clinical issues--including indication and timing of therapy--are discussed. Finally, important directions for future research are mentioned to illustrate new strategies for increasing therapy efficacy.     

Advancements in pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PanNETs) have increased in incidence in the USA over the last 20 years. Although PanNETs are often misconceived as being indolent tumors as they have a far more favorable prognosis over pancreatic adenocarcinoma, roughly 60–70% of patients have metastatic disease at the time of diagnosis due to presentation late in the disease process. While improvements in imaging modalities allow for early detection and better tumor localization, recent advancements in basic science, as well as surgical and medical management of PanNETs have further improved the prognosis. The mainstay of therapy for localized PanNETs is surgical intervention, which has become safer and is slowly shifting towards a more minimally invasive approach. However, the prognosis still remains relatively bleak for patients with unresectable disease. Fortunately, novel molecular targeted therapies, such as everolimus and sunitinib, have recently come into the limelight and have shown significant promise for the treatment of locally advanced and metastatic disease.     

Biotherapies for GEP-NETs

Biological treatment for GI neuroendocrine tumours (NETs) includes treatment with somatostatin analogues and alpha interferons. Both of these therapies were developed in the early 1980's and initially for treatment of a carcinoid syndrome in patients with small intestinal NETs. Later on tumour biology studies indicated that well differentiated NETs (G1-tumours) benefit from treatment with somatostatin analogues and alpha interferons. Both agents give symptomatic improvement in patients with functioning tumours in 40–60% of the patients, biochemical responses in 50–70% of the patients and significant tumour shrinkage in 5–10% of the patients. Combination therapy with somatostatin analogues and alpha interferon has demonstrated some clinical benefit.In conclusion: Somatostatin analogues and alpha interferons are still playing an important role and considered to be first-line treatment in functioning and in non-functioning well-differentiated NETs, (G1-tumours) and somatostatin analogues might also be applied to control clinical symptoms in G2-tumours with higher proliferation.     

New treatment strategies in advanced neuroendocrine tumours

Malignant well-differentiated neuroendocrine tumours of the pancreas and the gastrointestinal tract are rare and clinically challenging heterogeneous neoplasms. This review focuses on neuroendocrine tumours grade 1 and grade 2 (new WHO classification 2010), in comparison to the neuroendocrine tumours grade 3 group, corresponding to poorly differentiated neuroendocrine carcinomas. Surgical resection of the primary and metastases remains the only curative treatment, however many patients with neuroendocrine tumours are diagnosed once unresectable metastases have occurred; management of functioning syndromes with somatostatin analogues remains the priority. Pasireotide, a new somatostatin analogue, is currently undergoing evaluation for carcinoid syndrome. Treatment options for advanced neuroendocrine tumours differ from pancreatic gastrointestinal tract neuroendocrine tumours: (a) in pancreatic neuroendocrine tumours, streptozotocin-based chemotherapies are challenged by other cytotoxic agents (dacarbazine, temozolomide and oxaliplatin); two randomized, placebo-controlled phase III studies have demonstrated that everolimus and sunitinib significantly improved progression-free-survival; (b) in midgut neuroendocrine tumours, octreotide improved time-to-progression in patients with a low proliferation index and low liver burden; preliminary data suggesting efficacy of bevacizumab are still to be confirmed; the effect of everolimus associated with octreotide was almost significant on progression-free-survival in a phase III trial. Liver-directed therapies are effective in both tumour types. New techniques of embolization need further evaluation and must be formally compared to other therapies. Finally, peptide receptor radionuclide therapy has shown promising activity in non-comparative studies in advanced neuroendocrine tumours.     

Short- and long-term effect of a long-acting somatostatin analogue, lanreotide (SR-L) on metastatic gastrinoma

Medical treatment is the elective therapy for patients with gastrinoma when the tumor is not found at surgery or is unresectable or when there is a metastatic disease. H2-blockers and omeprazol are able to control gastric acid secretion and, in addition, somatostatin analogues decrease gastrin levels. A new long-acting and slow release formulation of a somatostatin analogue (lanreotide, SR-L) has been developed. We treated two patients suffering from gastrinoma, total gastrectomy and hepatic metastases with 30 mg intramuscular injections of SR-L every 15 and 10 days, respectively, for a seven-month period. After the treatment, gastrin levels decreased from 35,494 and 15,086 ng/l to 3,211 and 167 ng/l (92 and 98% below pre-treatment levels) in case 1 and 2 respectively, with a relief of symptoms and no side effects.     

Therapeutic options for gastrointestinal carcinoids.

Although wide surgical resection is the optimal curative therapy for carcinoid tumors, in most patients the presence of metastatic disease at diagnosis usually renders excision a palliative procedure. This nevertheless decreases tumor burden, facilitates symptom control, and prevents complications caused by bleeding, perforation, or bowel obstruction resulting from fibrosis. In the stomach (types I and II) and rectum endoscopic excision may be adequate provided the lesion(s) are local. Long-term therapy is focused on symptom alleviation and improvement of quality of life using somatostatin analogues, particularly in a subcutaneous depot formulation. In some instances interferons may have a role but their usage often is associated with substantial adverse events. Conventional chemotherapy and external radiotherapy either alone or in a variety of permutations are of minimal efficacy and should be balanced against the decrease in quality of life often engendered by such agents. Hepatic metastases may be amenable to surgery, radiofrequency ablation, or embolization either alone or in combination with chemotherapeutic agents or isotopically loaded microspheres. Rarely hepatic transplantation may be of benefit although controversy exists as to its actual use. Peptide-receptor-targeted radiotherapy for advanced disease using radiolabeled octapeptide analogs (111In/90Yt/177Lu-octreotide) appear promising but data are limited and its status remains investigational. A variety of antiangiogenesis and growth factor-targeted agents have been evaluated, but as yet have shown little promise. The keystone of current therapy remains the long-acting somatostatin analogues that alleviate symptomatology and substantially improve quality of life with minimal adverse effects.     

The current strategy for managing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an inherited autosomal dominant disease presenting with pancreatic neuroendocrine tumors (pNETs), parathyroid tumors, or pituitary tumors. Using the PubMed database, we reviewed the literature on information regarding the proper diagnosis and treatment of MEN1-associated pNET. Many cases of MEN1-associated pNET are functioning pNETs. Gastrinomas and insulinomas tend to occur frequently in the duodenum and pancreas, respectively. In addition to diagnostic imaging, the selective arterial secretagogue injection test (SASI test) is useful for localizing functioning pNET. The standard treatment is surgical resection. However, in the case of a functioning pNET, the tumor should first be accurately located using the SASI test before an appropriate surgical method is selected. In cases of a MEN1-associated non-functioning pNET that exceeds 2 cm in diameter, the incidence of distant metastasis is significantly increased, and surgery is recommended. In cases of unresectable pNET, a somatostatin analog has been shown to demonstrate antitumor effects and is considered to be a promising treatment. In addition, molecular-targeted drugs have recently been found to be effective in phase III clinical trials.     

Combined-modality therapy in the nonsurgical management of unresectable stage III non-small cell lung cancer.

Combined chemotherapy and radiation for patients with unresectable non-small cell lung cancer has recently been associated with a survival advantage compared with radiation alone; however, despite this apparent improvement in survival, the optimal strategy to combine these two modalities has not yet been defined. Both local tumor control and distant micrometastatic disease remain problems, limiting the curative ability of current combined-modality programs. Over the past year, accelerated radiation schedules have been shown to improve both local tumor control and survival in a selected patient population compared with standard radiotherapy. Some work has centered on the incorporation of novel chemotherapy agents into combined-modality regimens, with encouraging results from phases I and II. Finally, although the benefit for combined-modality therapy has generally been limited to good performance status of patients with minimal weight loss, some data have shown the feasibility of the combined approach in high-risk patient populations. Several ongoing cooperative group phase III trials will help to better define the optimal approach to manage this high-risk patient population.     

Double Ki-67 and synaptophysin labeling in pancreatic neuroendocrine tumor biopsies

BackgroundPancreatic neuroendocrine tumors (PanNETs) are frequently detected on endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens. The conventional methods for evaluating the Ki-67 labeling index (Ki67LI) in EUS-FNAB specimens are laborious, and their results are difficult to interpret. More practical and easy methods for evaluating the Ki67LI in PanNETs from EUS-FNAB specimens is increasing in need.MethodsWe used double Ki-67 and synaptophysin (double Ki-Syn) antibody cocktail; Ki67LI, total Ki-67 positive cells, and total tumor cells were counted and compared with those detected on conventional single Ki-67 immunostaining (single Ki-67) of 96 PanNETs [Grade 1 (G1), 68 cases (71%); G2, 26 (27%); G3, 2 (2%)] from EUS-FNAB specimens.ResultsThe tumor grading between double Ki-Syn and single Ki-67 immunolabeling was highly concordant (correlation, 0.95; Fisher's exact test, P < 0.001). Seven EUS-FNAB specimens (7%) had discrepant results, of which 2 were removed through surgical resection and showed the same tumor grade as that detected on double Ki-Syn immunolabeling. Fifty-four specimens (56%) had higher Ki-67 positive tumor cell counts on single Ki-67 immunolabeling. Sixty-two specimens (65%) had higher total tumor cell counts on double Ki-Syn immunolabeling. The number of specimens with less than 500 total counted tumor cells were significantly reduced when double Ki-Syn immunolabeling was applied [P = 0.046; single Ki-67, 17 specimens (18%); double Ki-Syn, 9 specimens (9%)].ConclusionDouble Ki-Syn immunolabeling enables the accurate counting of the number of proliferating tumor cells without including inflammatory and contaminant epithelial cells compared with single Ki-67 immunolabeling in PanNETs from EUS-FNAB specimens.     

Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment

OBJECTIVE: Acromegaly is a syndrome with a high risk of impaired glucose tolerance (IGT) and diabetes mellitus (DM). Somatostatin analogues, which are used for medical treatment of acromegaly, may exert different hormonal effects on glucose homeostasis. Twenty-four active acromegalic patients were studied in order to determine the long-term effects of octreotide-LAR and SR-lanreotide on insulin sensitivity and carbohydrate metabolism. DESIGN: Prospective study. PATIENTS: We studied 24 patients with active acromegaly, 11 males and 13 females, aged 50.7 +/- 12.7 years, body mass index (BMI) 30.1 +/- 4.8 (kg/m2). MEASUREMENTS: All patients underwent an oral glucose tolerance test (OGTT) and 12 also had an euglycaemic hyperinsulinaemic clamp. All patients were evaluated at baseline and after 6 months of somatostatin analogues therapy. RESULTS: Acromegalic patients showed low M-values in respect to the control group at baseline (P<0.05), followed by a significant improvement after 6 months of therapy (P<0.005 vs. baseline). Serum glucose levels at 120 min during OGTT worsened (P<0.05) during somatostatin analogs therapy in patients with normal glucose tolerance, but not in those with impaired glucose tolerance or diabetes mellitus. This was associated with a reduced (P<0.05) and 30 min delayed insulin secretion during OGTT. Also, HbA1c significantly deteriorated in all subjects after treatment (4.7 +/- 0.6% and 5.1 +/- 0.5%, basal and after six months, respectively, P<0.005). CONCLUSION: In acromegalic patients, somatostatin analogues treatment reduces insulin resistance, and also impairs insulin secretion. This may suggest that the use of oral secretagogue hypoglycaemic agents and/or insulin therapy should be considered rather than insulin sensitizers, as the treatment of choice in acromegalic patients who develop frank hyperglycaemia during somatostatin analogues therapy.     

Short-term pre-surgical treatment with somatostatin analogues, octreotide and lanreotide, in acromegaly

Eighteen patients with symptoms of active acromegaly were treated with somatostatin analogues for 4 weeks before surgery. Both before and after the treatment, levels of growth hormone (GH), prolactin (PRL), insulin growth factor -I (IGF-I), luteotropin (LH), folliculostimulin (FSH) and subunit alpha of glycoprotein hormones were estimated. Glucose tolerance test, magnetic resonance imaging (MRI) examination, sight acuity and field of vision tests were also performed. The same tests were performed on ten control patients with clinically and biochemically active acromegaly, subjected to surgery but not treated with somatostatin analogues. In six patients treated with somatostatin analogues GH levels decreased significantly to less than 5 ng/ml and in two patients remained elevated while in 10 patients GH level decreased and ranged from 6.1 to 42.9 ng/ml. In 13 patients we observed a decrease in IGF-I to normal levels (<400 ng/dl) and in 3 patients we noted a decrease to levels slightly higher than normal. There was also a slight decrease in alpha subunit concentration. In the glucose inhibition test 4 patients demonstrated normalized GH levels. In patients with elevated PRL and TSH levels, treatment with somatostatin analogues induced their decrease. No changes were observed in levels of LH and FSH. After therapy MRI examination disclosed a decrease in tumor volume in two patients (by 20 and 25%, respectively) and no changes in tumor size in 16 patients. The two patients with a decreased tumor volume also showed normalized glucose tolerance tests. All patients manifested an improved clinical condition. Neurosurgeons disclosed a decreased tumor consistency which greatly facilitated surgical procedure. Our studies documented favourable effects of somatostatin analogues on the assayed hormone levels, and on the general condition of the patients as well as on the course of the surgical procedure itself.     

Do somatostatin-analogues have the same impact on postoperative morbidity and pancreatic fistula in patients after pancreaticoduodenectomy and distal pancreatectomy? – A systematic review with meta-analysis of randomized-controlled trials

ObjectivePostoperative pancreatic fistula/POPF is the most feared complication in pancreatic surgery. Although several systematic reviews investigated the impact of somatostatin analogues on POPF, no stratification was performed regarding type of pancreatic resection (pancreaticoduodenectomy/PD; distal pancreatectomy/DP) and different somatostatin analogues.MethodsThis study was planed according to the Preferred-Reporting-Items-for-Systematic –Review-and-Meta-Analysis/PRISMA-guidelines. After screening databases for randomized controlled trials/RCT, studies were stratified into pancreatic resection techniques and data were pooled in meta-analyses containing subgroups of octreotide, somatostatin, lanreotide, pasireotide and vapreotide.ResultsThe meta-analysis of studies with a mixed cohort of patients after pancreatic resection revealed a protective effect of somatostatin analogues for morbidity (RR: 0.71, p < .00001) but not for mortality (RR: 1.07, = 0.78) or intra-abdominal abscesses (RR: 1.00, p = 1.00). Moreover, no effect was visible for mortality (RR: 1.57, p = .15), morbidity (RR: 0.87, p = .15) and intra-abdominal abscesses (RR: 0.92, p = .48) after PD. The meta-analysis of patients after PD revealed no impact of somatostatin analogues on POPF (RR: 0.87, p = .19) and clinically relevant POPF (RR: 0.69, p = .30). However, treatment with somatostatin analogues in the mixed cohort showed less POPF (RR: 0.60, p < .00001) and clinically relevant POPF (RR: 0.47, p = .02), which was also the case after DP (RR: 0.41, p = .03).ConclusionSomatostatin analogues did not affect POPF and clinically relevant POPF after PD, but seemed to be associated with less POPF after DP. As no sufficiently powered RCT could be identified by the systematic review, further RCTs are urgently needed to investigate the effect of somatostatin analogues after DP.Study registrationCRD42018099808.     

Future aspects of somatostatin-receptor-mediated therapy

More than 30 years have passed since somatostatin was discovered and its hormonal function defined. The wide range of anatomical distribution and actions of somatostatin and its receptors have stimulated intense scientific and clinical interest. The development of somatostatin analogues helped define its usefulness in the treatment of endocrine diseases and cancer. The molecular cloning of five distinct subtypes of somatostatin receptors in the 1980s has significantly increased our insight into the biology of somatostatin and its receptor subtypes and has led to the design and development of subtype-selective peptides and nonpeptide agonists and antagonists. In the future, the development of somatostatin-receptor-mediated treatment will go along different lines. Tumor-targeted radioactive treatment based on somatostatin analogues will be further developed and improved. New somatostatin analogues will come into clinical practice, both receptor subtype-specific analogues, but also pan-receptor analogues. One is currently in clinical trial--SOM230--which is a cyclo-hexapeptide binding with high affinity to receptor type 1, 2, 3 and 5, but not 4. It has already shown activity both in acromegaly and in neuroendocrine gastrointestinal tumors. Preclinical studies on somatostatin analogues, coupled to cytotoxic agents, have shown rather promising results and will hopefully be further developed in clinical trials. Another interesting area is treatment of neuroendocrine gut tumors with ultra-high doses of somatostatin analogues, which has demonstrated significant clinical effects in patients resistant to standard-dose treatment with the same somatostatin analogue.     

Study of clinicopathological features,hormone immunoexpression,and loss of ATRX and DAXX expression in pancreatic neuroendocrine tumors

Objectives: Neuroendocrine tumors of the pancreas (PanNETs) are rare neoplasms, and not much is known about their pathogenesis. We aimed to evaluate ATRX/DAXX immunoexpression in PanNETs a cohort of well-characterized PanNETs. Methods: PanNETs diagnosed over a 10-year period were retrieved and clinicopathogical features reviewed. Immuohistochemistry for pancreatic hormones, and for ATRX and DAXX was performed. Results: Sixty-eight PanNETs were included (30 males and 38 females) with median age of 39 years. Histologically, there were 37 Grade 1 (54.4%), 27 Grade 2 (39.7%), and 4 Grade 3 (5.9%) cases. On immunostaining for hormones, insulin expression was most frequent (22 cases; 38.6%), followed by gastrin (7 cases; 12.3%); 25 cases (43.9%) were negative for all hormones. Loss of ATRX/DAXX immunoexpression was noted in 18 cases (39.1%), and was significantly more frequent in tumors larger than 5?cm. Lymphovascular invasion, infiltrative borders, and infiltration of adjacent organs were also more frequent in tumors with loss of ATRX/DAXX immunoreactivity. A little over half the tumors with ATRX/DAXX loss showed negative immunostaining for all hormones (55.6%). Conclusion: Loss of ATRX/DAXX expression is frequent in PanNETs, indicating a role in their pathogenesis. As ATRX/DAXX loss is more frequent in larger tumors, and in those with lymphovascular invasion, adjacent organ infiltration and infiltrative borders, this suggests that loss of ATRX/DAXX expression is a late event in pathogenesis and is associated with an aggressive phenotype. Immunohistochemical detection of ATRX/DAXX loss is a simple method for ATRX/DAXX evaluation and can easily be incorporated into routine pathological evaluation of PanNETs.     

New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors

Successful treatment of unresectable and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) requires the thoughtful choice of systemic therapy as a component of a multidisciplinary therapeutic approach. The role of somatostatin analogues is established in symptom relief, but the efficacy of interferon and radiopeptide targeted therapy is not clear. The utility of a variety of tyrosine kinase and antiangiogenic agents is variable and under investigation, whereas the role of cytotoxic chemotherapy in poorly differentiated GEP-NETs is accepted. Overall, the ideal treatment of more indolent tumors is less certain. Reassessments of the GEP-NET pathology classification has provided improved logic for the role of a variety of agents, whereas the precise positioning of many new agents that target molecular pathways of angiogenesis and proliferation is under examination. This article describes the current options for systemic therapy for GEP-NETs within the framework of the current World Health Organization classification system.     

Biliary palliation for unresectable pancreatic adenocarcinoma: surgical bypass or self-expanding metal stent?

BackgroundStandard of care guidelines endorse self-expanding metal stents (SEMS) rather than open surgical biliary bypass (OSBB) for biliary palliation in the setting of unresectable pancreatic ductal adenocarcinoma (PDAC). This study used competing risk analysis to compare short- and long-term morbidity and overall survival among patients undergoing SEMS or OSBB after unresectable or metastatic disease is identified at the time of exploration.MethodsSingle institution retrospective cohort study (n = 127) evaluating outcomes after OSBB and SEMS for biliary palliation in patients found to have unresectable PDAC at exploration. Short-term, long-term, and lifetime risk of biliary occlusion and survival were compared after adjustment for stage and comprehensive complication index (CCI).ResultsBaseline demographics and tumor characteristics were equivalent between cohorts. Short-term complications were more frequent after OSBB, whereas late complications were greater after SEMS. The cumulative incidence of recurrent biliary obstruction was greater after SEMS, but lifetime complication burden and median survival were equivalent.ConclusionOSBB was associated with longer hospital stays and more short-term complications, and SEMS was associated with a higher risk of recurrent biliary obstruction among surgical patients with unresectable PDAC. Patient preference should be defined pre-operatively in the case the unresectable disease is encountered during attempted resection.