Presentation, diagnostic features and glucose handling in a monocentric series of insulinomas.

BACKGROUND: New aspects have emerged in the clinical and diagnostic scenarios of insulinoma: current guidelines have lowered the diagnostic insulin threshold to 3 µU/ml in the presence of hypoglycemia (<55 mg/dl); post-prandial hypoglycemia has been reported as the only presenting symptom; preexisting diabetes mellitus (DM) was recognized in some patients. AIM: To evaluate clinical features, diagnostic criteria and glucose metabolic profile in a monocentric series of patients affected by insulinomas including two subgroups: sporadic and multiple endocrine neoplasia type-1 syndrome (MEN-1). SUBJECTS AND METHODS: Clinical, pathological and biochemical data regarding 33 patients were analyzed. RESULTS: following the current guidelines the 72-h fasting test was initially positive in all cases but one. In this case the test, initially negative, became positive after a 2-yr follow-up. Nadir insulin level was ≥ 3 µU/ml but <6 µU/ml in 3 patients and ≥ 6 µU/ml in the remaining 30 cases. At presentation, 27 patients (82%) reported only fasting symptoms, 3 (9%) only post-prandial and 3 (9%) both. Seven cases (21%) had previously been affected by type 2 DM or impaired glucose metabolism. CONCLUSIONS: In our series the new cut-off of insulin increased the sensitivity of the 72-h fasting test from 87% to 97%. The absence of hypoglycemia during the test cannot definitively rule out the diagnosis and the test should be repeated in every highly suspicious case. Post-prandial hypoglycemia can be the only presenting symptom. DM may be associated with the occurrence of insulinoma. So that a possible diagnosis of insulinoma must not be ignored if previous impaired glucose handling is evident.

Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases.

BACKGROUND: Surgery for small intestinal neuroendocrine tumours (SI-NETs) is limited by metastatic disease in most patients. However, resection of the primary lesion alone has been advocated in patients with unresectable liver metastases. The present systematic review investigated the value of surgical resection of the primary lesion in patients with unresectable metastatic disease. METHODS: MEDLINE was searched for studies reporting the outcome of patients with SI-NETs and unresectable liver metastases where there was an explicit comparison between resection of the primary lesion alone and no resection. The primary outcome was overall survival. Secondary outcomes were progression-free survival, treatment-related mortality and relief of symptoms. RESULTS: Meta-analysis was not possible, but six studies were analysed qualitatively to highlight useful information. Possible confounders in these studies were the inclusion of patients with other primary tumour sites, unknown primary tumour or non-metastatic disease. Bearing in mind these limitations, there was a clear trend towards longer survival in patients who underwent surgical resection in all studies; their median overall survival ranged from 75 to 139 months compared with 50-88 months in patients who did not have resection. The difference between the two groups was statistically significant in three studies. Data on symptomatic improvement were scarce and did not suggest a clear benefit of surgery. Surgery-related mortality seemed low. CONCLUSION: Available data suggest a possible benefit of resection of the primary lesion in patients with unresectable liver metastases, but the studies have several limitations and the results should therefore be considered with caution.

Impact of lymphadenectomy on survival after surgery for sporadic gastrinoma.

BACKGROUND: The study was undertaken to determine prognostic factors and the value of systematic lymphadenectomy on survival in sporadic gastrinoma. METHODS: Patients with sporadic gastrinoma who underwent initial surgery during a 21-year period in two tertiary referral centres were analysed retrospectively with respect to clinical characteristics, operative procedures and outcome. RESULTS: Forty-eight patients with a median age of 52 (range 22-73) years were analysed. Some 18 patients had pancreatic and 26 had duodenal gastrinomas, whereas the primary tumour remained unidentified in four patients. After a median postoperative follow-up of 83 (range 3-296) months, 20 patients had no evidence of disease, 13 patients were alive with disease, 11 patients had died from the disease and four had died from unrelated causes. In 41 patients who underwent potentially curative surgery, systematic lymphadenectomy with excision of more than ten lymph nodes resulted in a higher rate of biochemical cure after surgery than no or selective lymphadenectomy (13 of 13 versus 18 of 28 patients; P = 0·017), with a trend towards prolonged disease specific survival (P = 0·062) and disease-free survival (P = 0·120), and a reduced risk of death (0 of 13 versus 7 of 24 patients; P = 0·037). Negative prognostic factors for disease specific survival were pancreatic location (P = 0·029), tumour size equal to or larger than 25 mm (P = 0·003), Ki-67 index more than 5 per cent (P < 0·001), preoperative gastrin level 3000 pg/ml or more (P = 0·003) and liver metastases (P < 0·001). Sex, age, type of surgery and presence of lymph node metastases had no influence on disease free or disease specific survival. CONCLUSION: In sporadic gastrinoma, systematic lymphadenectomy during initial surgery may reduce the risk of persistent disease and improve survival.

Quantum charge transport and conformational dynamics of macromolecules.

We study the dynamics of quantum excitations inside macromolecules which can undergo conformational transitions. In the first part of the paper, we use the path integral formalism to rigorously derive a set of coupled equations of motion which simultaneously describe the molecular and quantum transport dynamics, and obey the fluctuation/dissipation relationship. We also introduce an algorithm which yields the most probable molecular and quantum transport pathways in rare, thermally activated reactions. In the second part of the paper, we apply this formalism to simulate the propagation of a quantum charge during the collapse of a polymer from an initial stretched conformation to a final globular state. We find that the charge dynamics is quenched when the chain reaches a molten globule state. Using random matrix theory we show that this transition is due to an increase of quantum localization driven by dynamical disorder. We argue that collapsing conducting polymers may represent a physical realization of quantum small-world networks with dynamical rewiring probability.

TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study.

BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.

Imaging of neuroendocrine gastroenteropancreatic tumours.

The role of imaging in functioning endocrine tumours (FETs) is primarily to detect the tumour, that is, to verify lesion number and location. Radiological detection of carcinoid tumours is limited by typical tumour location throughout the gastrointestinal tract or appendix and is therefore dependent on the tumour being large enough to make it recognisable in that site. The most common FET is insulinoma, which is commonly characterised by the typical appearance of a hypervascular lesion at multidetector-row computed tomography and magnetic resonance imaging. A particularly important role is played by intraoperative ultrasound in defining the exact number of lesions, their relationship with adjacent vascular structures and the pancreatic duct for the purposes of correct surgical planning (enucleation or resection). In the setting of nonfunctioning endocrine tumours (NFETs), which manifest late as large masses causing compression symptoms or as incidental findings, imaging is not primarily aimed at tumour detection, as this is relatively easy given the large size of the lesions. Rather, its role is to characterise the tumour and, in particular, to differentiate pancreatic NFET from ductal adenocarcinoma, as in comparison, malignant NFETs have a more favourable prognosis (5-year survival rate 40% compared with 3%-5% for adenocarcinoma) and therefore require different treatment approaches. As NFET are often malignant, they also require accurate staging and appropriate follow-up. In 80% of cases, NFETs have a "typical" imaging appearance: location in the pancreatic head, large dimensions (diameter between 5 and 15 cm, >10 cm in 30% of cases), capsule, sharp and regular margins owing to the expansile and noninfiltrative growth pattern, solid density and arterial hypervascularity. Some 20% of NFETs display different imaging characteristics ("atypical" appearance) as a result of arterial hypovascularity due to the presence of abundant fibrous stroma. Lastly, a small percentage of NFETs has yet a different appearance ("unusual") due to the cystic nature and/or diffuse location throughout the pancreatic parenchyma.

Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas.

BACKGROUND: The role of debulking surgery in metastatic nonfunctioning pancreatic endocrine carcinomas (M-NF-PECs) with resectable primary tumour and unresectable liver metastases is debated. AIM: Aim of the study is to evaluate whether the resection of the primary tumour in metastatic nonfunctioning pancreatic endocrine carcinoma improves survival. PATIENTS AND METHODS: Fifty-one metastatic nonfunctioning pancreatic endocrine carcinoma patients with unresectable liver metastases were enrolled from 1990 to 2004 at the time of diagnosis. Nineteen patients underwent complete resection of the primary tumour whilst 32 were judged unresectable. All cases were classified according to the WHO 2000 classification. All clinico-pathological parameters, including grade of differentiation and the Ki-67 proliferation index were considered in univariate and multivariate models. RESULTS: Of the 19 resected patients, 14 (73.7%) underwent left-pancreatectomy and 5 (26.3%) pancreaticoduodenectomy. In the unresected group of 32 patients, 9 (28.1%) underwent surgical biliary and/or gastric by-pass. There was no postoperative mortality and the median survival was 54.3 months (95% CI: 25.7-82.9). No difference in survival was observed between the two groups [resected: median 54.3 months (95% CI: 25-83.6), unresected: median 39.5 months (95% CI: 5.4-73.6); p=0.74]. Upon multivariate analysis poor differentiation (HR 3.01; 95% CI 1.08-8.4; p=0.035) and a Ki-67 index > or = 10% (HR 4.4; 95% CI 1.2-16.1; p=0.023) were significant predictors of survival. CONCLUSIONS: Resection of the primary pancreatic tumour in metastatic nonfunctioning pancreatic endocrine carcinoma patients with unresectable liver metastases does not significantly improve survival. Resection can be considered as symptomatic palliative therapy in patients with well-differentiated endocrine carcinomas and a proliferative index lower than 10%.

Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.

BACKGROUND: Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis. PATIENTS AND METHODS: From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models. RESULTS: There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K(i)-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality. CONCLUSION: This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.