Clorinda Ciafardini

Plasma chromogranin a in patients with inflammatory bowel disease.

Background: Circulating chromogranin A (CgA) levels, a marker for neuroendocrine tumors including carcinoids, have recently been found elevated in some patients with inflammatory bowel disease (IBD), although their significance is unclear. Therefore, we aimed to evaluate CgA levels and their possible relationship with clinical and biochemical disease activity indexes in 119 IBD patients. Methods: The study groups comprised 75 patients with ulcerative colitis, 44 with Crohns disease, in both active and quiescent phases, and 85 controls. Results: Mean CgA levels were significantly higher in IBD patients than in controls (20.4 ± 14.0 [SD] versus 11.3 ± 4.3 U/L, P < 0.001), without any statistical significant difference among the IBD subgroups. However, CgA levels were above the normal range (20 U/L) in 25/45 patients with active IBD (55%; 95% confidence interval [CI]: 40%–70%) and in 18/74 patients with remission IBD (24%; 95% CI: 15%–36%) (P < 0.001, Fishers test). Among biochemical parameters, CgA correlated with serum TNF‐&agr; levels (rs = 0.398, P < 0.001). Conclusions: High CgA levels can occur in IBD. The disease activity and TNF‐&agr; levels seem to influence the CgA pattern, which could reflect the neuroendocrine system activation in response to inflammation. From a clinical point of view, the possibility of high CgA levels in IBD should be taken into consideration when a carcinoid is suspected in such patients, since this event seems to be more frequent than previously considered. Indeed, revision of our 83 patients with gastrointestinal carcinoids, studied between 1997 and 2006, showed that 4 patients had IBD, with a prevalence of 4.8%, which is markedly higher than that of the general population.

Plasma Chromogranin A Response to Octreotide Test: Prognostic Value for Clinical Outcome in Endocrine Digestive Tumors

OBJECTIVES:Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) expressing somatostatin receptors may be treated with somatostatin analogs (SSAs). Selection criteria are a positive Octreoscan or a >50% hormone level decrease after octreotide subcutaneous (s.c.) injection (octreotide test) (OT). Plasma chromogranin A (CgA) is the best general GEP-NET marker, but data on CgA response to OT are scanty. Thus, we evaluated whether plasma CgA response to OT could predict the clinical response to SSAs.METHODS:At diagnosis, 38 GEP-NET patients received octreotide 200 μg s.c., with plasma CgA determination at 0, 3, and 6 h. Long-term SSA treatment was then given by monitoring symptomatic, biochemical, and objective responses, and survival.RESULTS:Basal plasma CgA levels were significantly higher in patients with functioning than non-functioning tumors (median (range): 220 (18–2,230) vs. 46 (25–8,610) U/l, P=0.03) and in those with than without metastases (171 (18–8,610) vs. 43 (28–220) U/l, P=0.04). CgA levels significantly correlated with WHO classification, clinical TNM staging, and Ki-67 proliferative index. After OT, CgA levels decreased from 146 (18–8,610) to 61 (10–8,535) U/l (basal and nadir values), P<0.001. In patients responsive to OT, a successful objective response occurred in 21/31 patients (68%). Successful symptomatic response occurred in 13/18 patients (72%), biochemical response in 25/31 (81%), and objective response in 21/31 (68%). In the remaining seven unresponsive cases, with CgA decrement <30%, disease progressed to death in six (86%). Median survival from enrollment was 48 months (6–138) in responsive and 6 (6–30) in unresponsive patients (P=0.0005).CONCLUSIONS:In GEP-NETs, plasma CgA is a reliable marker, and a >30% decrease after OT has a relevant prognostic meaning allowing the identification of the subgroup of patients most likely to be responsive to chronic SSAs.

Chromogranin A in diagnosing and monitoring patients with gastroenteropancreatic neuroendocrine neoplasms: a large series from a single institution.

Background/Aims: Plasma chromogranin A (CgA) is the most widely used biochemical biomarker in the diagnostic workup and follow-up of gastroenteropancreatic neuroendo- crine neoplasms (GEP-NENs). Herein, we assessed the clinical utility of CgA in diagnosing and monitoring a large series of GEP-NENs. Patients and Methods: A total of 181 GEP-NEN patients (87 males, 94 females) with pancreatic (n = 81) and gastrointestinal neoplasms (n = 100) were included; 99 patients had grade (G)1 NENs (Ki-67 ≤2%), 57 G2 NENs (Ki-67 3-20%) and 25 G3 NENs (Ki-67 >20%); 81 patients had tumor-node-metastasis (TNM) stage I, 14 stage II, 17 stage III and 69 stage IV cancer. For every patient, CgA values were assessed at diagnosis and during follow-up. Results: At diagnosis, the CgA values were above the upper reference limit in 148 patients (82%); the median CgA levels were significantly higher in functioning than in nonfunctioning tumors (295 vs. 43 U/l; p = 0.0001) as well as significantly higher in patients with metastases than in those without metastases (324.5 vs. 42 U/l; p = 0.0001). In logistic regression analysis, baseline CgA levels were significantly associated with Ki-67 index (p < 0.0001) and TNM stage (p < 0.0001) independently of the age and sex of the patient and the primary site of the tumor. The overall 5- and 10-year survival rates were 74 and 64.5%, respectively. A low Ki-67 index, the type of treatment and an early CgA decrease after treatment were positively correlated with the survival rate. After radical surgery, 15/95 patients relapsed, and an increase in CgA values anticipated the clinical and objective disease recurrence after a period of 9-12 months. Conclusions: In GEP-NENs, plasma CgA has a significant prognostic relevance.

Chromogranin A levels in chronic liver disease and hepatocellular carcinoma.

BACKGROUND Hepatocellular carcinoma (HCC) is the relevant cause of death in patients with compensated cirrhosis. Alpha-fetoprotein (AFP) is used for screening HCC, with limited success. AIM We evaluated plasma chromogranin A (CgA) as a marker of HCC. PATIENTS CgA plasma levels and AFP serum levels were prospectively measured in 30 patients with HCC, 14 with cirrhosis, 79 with chronic hepatitis and 65 controls. METHODS CgA was measured with an enzyme-linked immunosorbent assay (DAKO A/S Glostrup, Denmark). AFP was measured by electrochemiluminoimmunoassay (Elecsys, Roche S.p.A., Italy). RESULTS CgA levels were significantly higher in the three groups of patients than in controls and in patients with HCC they were significantly higher than in chronic hepatitis patients [median 44.5 (interquartile range 21-145.9)U/L vs. 15.3 (10.9-29.25)U/L, p<0.001]. AFP values were above the upper reference limit in 75% of patients with HCC, 50% of cirrhotic patients and 11% of chronic hepatitis patients (p<0.005). CgA values significantly correlated with AFP levels (r(s)=0.42, p<0.0001). The overall diagnostic accuracy of CgA was 75% (CI 66-82), with a sensitivity of 70% (CI 50.6-85.2) and a specificity of 67% (CI 55.9-76.3). CONCLUSIONS Despite the evidence of higher CgA levels in patients with HCC, this test has low-diagnostic accuracy. Its pathophysiological meaning remains unknown, even if it could suggest an endocrine phenotype of HCC.

Unusually aggressive type 1 gastric carcinoid: a case report with a review of the literature.

Gastric carcinoids are rare tumors of the stomach. Gastric carcinoid type 1 is associated with chronic atrophic gastritis, and because of a low metastatic potential, is the most benign type. Death from metastatic disease has been reported in only three patients in a review including 724 cases. The present report refers to a 60-year-old man who was affected by type 2 diabetes mellitus and pernicious anemia and died from metastatic gastric carcinoid type 1. In 1998, a well-differentiated 1.2 cm gastric neuroendocrine tumor, immunoreactive for chromogranin A, with a Ki-67 index less than 2% and with infiltration to the submucosal layer was diagnosed and enucleated. In 2002, a new well-differentiated gastric endocrine tumor 6 mm in size with a Ki-67 of approximately 2% was detected, and endoscopic ultrasound confirmed it to be limited to the submucosal layer. The patient refused antrectomy and started long-acting somatostatin analog (lanreotide) in 2005 when the Ki-67 index was 7%, but he stopped the treatment after 4 months. In 2007, despite previous endoscopic stability, endoscopic ultrasound showed an infiltrating gastric lesion of 7 cm. At surgery, the disease appeared to be extended to the liver and to the peritoneum (well-differentiated endocrine carcinoma, Ki-67 40%) with both hepatic and massive peritoneal metastases. A regimen of somatostatin analog was soon restarted; however, the disease continued to spread, and the patient died 6 months later. Overall, despite their generally benign course, type 1 gastric carcinoids may have malignant potential, a finding that should be considered when planning the medical workup of these patients.

Contrast-enhanced ultrasonography in evaluating hepatic metastases from neuroendocrine tumours

OBJECTIVES At presentation, gastroenteropancreatic neuroendocrine tumours (GEP NETs) frequently show prognostically negative hepatic involvement. The aim of this study was to characterise hepatic metastases of GEP NETs as revealed by contrast-enhanced ultrasonography (CEUS), which allows the fine definition of the microvascular system, and to correlate these findings to the biological behaviour of the tumour. METHODS Eighteen out of 62 GEP NET patients examined between January 2007 and September 2008 had histologically proven hepatic metastases from primary ileal (#6), gastric (#1) or rectal (#1) carcinoids, pancreatic tumours (#7), or primary duodenal (#2) or occult gastrinomas (#1), and all underwent low mechanical index real-time CEUS with SonoVue injection. RESULTS Strong early enhancement in the arterial phase was observed in 15 cases (83%), and a rapid wash-out in the portal venous phase in 14 (78%). In the late venous phase, the lesions were hypoechoic in 12 cases (67%), isoechoic in five (28%), and hyperechoic in one (0.05%). The time of arterial enhancement correlated with the Ki-67 proliferative index (r(s)=0.516; p=0.028). CONCLUSIONS Most of the neuroendocrine liver metastases showed increased arterial enhancement at CEUS, a behaviour that is similar to that of hepatocellular carcinomas and the opposite of that of other metastases. CEUS can be a useful diagnostic means of characterising such metastases.

Treatment of Liver Metastases in Patients with Digestive Neuroendocrine Tumors

BackgroundLiver metastases are a strong prognostic indicator in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Therapeutic options for metastatic NETs are expanding and not mutually exclusive.AimsThis paper reviews the literature relating to multidisciplinary approach towards GEP-NET metastases, to highlight advances in knowledge regarding these tumors, and to understand the interdisciplinary management of individual patients.MethodsA PubMed search was performed for English-language publications from 1995 through 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for GEP-NET-related liver metastases were selected.ResultsThere is considerable controversy regarding the optimal management of GEP-NET metastases. Although radical surgery still remains the gold standard, a variety of other therapeutic options are available for metastatic GEP-NETs, including loco-regional chemotherapy/radiotherapy, radioembolization, systemic peptide receptor radionuclide therapy, biotherapy, and chemotherapy. In selected patients, liver transplantation should also be considered. Systemic somatostatin analogues and/or interferon show anti-proliferative effects, representing an appropriate first-line treatment for most patients. In advanced metastatic NETs, recent options include targeted therapies (i.e., everolimus and sunitinib).ConclusionsIt is evident that multidisciplinary care and multimodality treatments remain the cornerstone of management of NET patients. Since NETs often show a more indolent behavior compared to other malignancies, physicians should aim to preserve a satisfactory quality of life for the patient by personalizing the therapeutic approach according to the tumor’s features and prognostic factors.

Chronic autoimmune atrophic gastritis associated with primary hyperparathyroidism: a transversal prospective study.

DESIGN The coexistence of chronic autoimmune atrophic gastritis (CAAG) and primary hyperparathyroidism (PHPT) has been described previously, even if its extent and underlying mechanisms remain poorly understood. We therefore prospectively evaluated this association in two series of patients, one with CAAG and the other with sporadic PHPT. METHODS From January 2005 to March 2012, 107 histologically confirmed CAAG patients and 149 PHPT patients were consecutively enrolled. Routine laboratory assays included serum calcium, parathyroid hormone (PTH), plasma gastrin and chromogranin A (CgA). In CAAG patients with high PTH levels, ionized calcium and 25(OH)-vitamin D were evaluated. All CAAG and hypergastrinemic PHPT patients received an upper gastrointestinal endoscopy. Exclusion criteria were familial PHPT, MEN1 syndrome, treatment with proton pump inhibitor drugs, Helicobacter pylori infection and renal failure. RESULTS Of the 107 CAAG patients, nine (8.4%) had PHPT and 13 (12.1%) had secondary hyperparathyroidism stemming from vitamin D deficiency. Among the 149 PHPT patients, 11 (7.4%) had CAAG. Gastrin and CgA levels were similar in the CAAG patients with vs those without hyperparathyroidism (either primary or secondary), and calcium and PTH levels were similar in the PHPT patients with vs those without CAAG. CONCLUSIONS This study confirms a non-casual association between PHPT and CAAG. The prevalence of PHPT in CAAG patients is threefold that of the general population (8.4 vs 1-3%), and the prevalence of CAAG in PHPT patients is fourfold that of the general population (7.4 vs 2%). The mechanisms underlying this association remain unknown, but a potential role for autoimmunity is suggested.

A wait-and-watch approach to small pancreatic neuroendocrine tumors: prognosis and survival

Background Whether all the small (ø≤20mm) non-functional pancreatic neuroendocrine neoplasms (pNENs) should be routinely resected is unclear. Aim To assess the overall survival (OS) and progression-free survival (PFS) of patients with small pNENs, followed-up with different management options. Material and methods Between 2007-2014, 51 patients were newly diagnosed with pNEN. 15 patients with pNENs ø ≤20 mm underwent an intensive follow-up at 3-month intervals during the first year and then every 6 months (FU pNEN group). They were all at TNM stage I, except for one patient at stage IIA. 21 patients underwent surgical resection (SR pNEN group): 2 patients were at TNM stage I, 9 IIA, one IIIB, 9 IV. 15 patients received systemic therapy (ST pNEN group) due to advanced disease or contraindications to surgery: 5 were at stage IIA, 2 IIB, 8 IV. Results The median follow-up for the entire cohort was 50 months. Survival was similar in the FU and SR pNEN groups, but significantly worst in the ST pNEN patients (log-rank test P <0.05). The 4-year survival rate was 100% in the FU pNEN group, 90.5% among the SR pNEN patients, 61% for the ST pNEN ones (p <0.0001). The disease remained stable in all but one patient in the FU pNEN group, whereas six patients in the SR group and five in the ST group showed disease progression. Conclusions The “wait-and-watch” approach to early-stage small pNENs appears to be safe although further studies are needed to confirm these results in larger cohorts of patients.

Intermittent treatment of recurrent type-1 gastric carcinoids with somatostatin analogues in patients with chronic autoimmune atrophic gastritis

BACKGROUND Optimal management and treatment of type-1 gastric carcinoids is under debate. AIMS This prospective study evaluates the outcome of patients with recurrent type-1 gastric carcinoids treated with somatostatin analogues. METHODS From 2000 to 2013, among a population of 107 chronic atrophic gastritis patients, 25 (20% males, median age 62 years) developed type-1 gastric carcinoids and underwent regular clinical and endoscopic follow-up (median 77 months, range 6-165) after the initial treatment. Those patients showing recurrent disease were treated with somatostatin analogues until carcinoid disappearance. RESULTS 12/25 patients (33% males, median age 65 years) showed recurrent gastric carcinoids and were treated with somatostatin analogues for a median duration of 12 months. Median gastrin and chromogranin A levels, which were 802 pg/mL and 33 U/L, respectively, decreased to 299 pg/mL (p=0.002) and 15.6 U/L (p=0.001) at the end of the treatment. Gastric carcinoids disappeared after a median length of treatment of 12 months. After a median time of 19.5 months from somatostatin analogues discontinuation, 4/12 patients (25% males, median age 56 years) showed a further recurrence. A new cycle of treatment was performed successfully. CONCLUSIONS This study confirms that type-1 gastric carcinoids are a recurring disease and somatostatin analogues, administered on 12-month cycles, represent an effective treatment.