Roberta Elisa Rossi

BRAF V600E mutation analysis increases diagnostic accuracy for papillary thyroid carcinoma in fine needle aspiration biopsies

OBJECTIVE Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid cancers, presenting the V600E activating BRAF mutation in 29-83% of cases. The aim of our study is to analyze the influence of BRAF mutation analysis on the diagnostic accuracy of fine-needle aspiration biopsy (FNAB) in patients with suspected PTC. DESIGN AND METHODS Thyroid cytoaspirates from 469 nodules (size: 1.1+/-0.8 cm) with ultrasonographic features suspicious of malignant lesion, performed in 374 patients, were submitted to cytological evaluation and to biomolecular analysis, carried out after somatic DNA isolation, specific PCR amplification, and subsequent automated direct sequencing. All PCR fragments were also processed by specific enzyme restriction analysis. RESULTS BRAF V600E mutation was found in 48 samples, 41 of which were also cytologically diagnosed as PTC, with histologic confirmation after thyroidectomy. Total thyroidectomy was perfomed also in seven patients with negative cytology but positive BRAF mutation, with histological confirmation of PTC in all. Among the 429 BRAF-negative samples, 407 had negative cytology for PTC, while 22 were diagnosed as suspected PTC and underwent total thyroidectomy with histological diagnosis of PTC in 17 and benign lesion in five. The prevalence of BRAF V600E mutation among histologically diagnosed PTC patients was 64%. Biomolecular analysis significantly increased cytology sensitivity for PTC from 77.3 to 86.7% (P<0.01). CONCLUSIONS These data indicate that BRAF V600E mutation analysis can significantly improve FNAB diagnostic accuracy. However, biomolecular analysis is complementary to cytology, which should always be performed.

Nutritional deficiencies in inflammatory bowel disease: therapeutic approaches.

BACKGROUND & AIMS Malnutrition is common in inflammatory bowel diseases (IBD), mainly in Crohns disease (CD) because the small bowel is primarily affected. We reviewed the literature to highlight the importance of proper nutrition management. METHODS A PubMed search was performed for English-language publications from 1999 through 2012. Manuscripts comparing nutritional approaches for IBD patients were selected. RESULTS We identified 2025 manuscripts: six meta-analyses, 170 clinical-trials, 692 reviews. The study findings are discordant. In adult CD, enteral nutrition plays a supportive role, steroid therapy remaining the first choice treatment. In CD children enteral nutrition may represent the primary therapy. As regards parenteral nutrition, there are no large randomized studies, although mild improvements in morbidity have been described as a result of parenteral nutrition in malnourished surgical IBD patients. Specific micronutrient deficiencies are common in IBD. A number of factors may contribute to micronutrient deficiencies, and these include: dietary restriction, disease activity and surgery. The possible therapeutic roles of omega-3 fatty-acids, probiotics and prebiotics have been studied, but the results are still preliminary. CONCLUSION Protein-energy malnutrition and micronutrient depletion are clinical concerns in IBD patients. Enteral nutrition, parenteral nutrition and micronutrient supplementation are cornerstone of the multidisciplinary management of IBD patients.

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.

Cyclooxygenase-2 inhibitors prevent the development of chemoresistance phenotype in a breast cancer cell line by inhibiting glycoprotein p-170 expression

Breast cancer cells are usually sensitive to several chemotherapeutic regimens, but they can develop chemoresistance after prolonged exposure to cytotoxic drugs, acquiring a more aggressive phenotype. Drug resistance might involve the multi-drug resistance (MDR) 1 gene, encoding a transmembrane glycoprotein p-170 (P-gp), which antagonizes intracellular accumulation of cytotoxic agents, such as doxorubicin. We previously demonstrated that type 2 cyclooxygenase (COX-2) inhibitors can reverse the chemoresistance phenotype of a medullary thyroid carcinoma cell line by inhibiting P-gp expression and function. The aim of our study was to investigate the role of COX-2 inhibitors in modulating chemoresistance in a human breast cancer cell line, MCF7. MCF7 cells, expressing COX-2 but not MDR1, were treated with increasing doses of doxorubicin, and they became chemoresistant after 10 days of treatment, in association with MDR1 expression induction. This effect was reversed by doxorubicin withdrawal and prevented by co-incubation with N-[2-(cyclohexyloxy)4-nitrophenyl]-methanesulfonamide (NS-398), a selective COX-2 inhibitor. Treatment with NS-398 alone did not influence cell viability of a resistant MCF7 cell clone (rMCF7), but sensitized rMCF7 cells to the cytotoxic effects of doxorubicin. Moreover, treatment with NS-398 significantly reduced MDR1 expression in rMCF7 cells. Doxorubicin-induced membrane P-gp expression and function was also greatly impaired. Our data therefore support the hypothesis that COX-2 inhibitors can prevent or reduce the development of the chemoresistance phenotype in breast cancer cells by inhibiting P-gp expression and function.

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.

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.

The impact of diet and nutrition in the prevention and progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. There is growing evidence for a chemopreventive role of nutrition in the development of HCC in at risk populations. Bibliographical searches were performed in PubMed for the terms ‘nutrition and hepatocellular carcinoma’, ‘nutrition and liver cancer’, ‘nutrition and hepatic cancer’, ‘diet and hepatocellular carcinoma’, ‘diet and liver cancer’. High dietary sugar intake should be discouraged in at risk populations. Coffee, polyphenols, vanadium, dietary fibre, fruits and vegetables show encouraging results in terms of chemoprevention. Red meat intake may be associated with increased risk of HCC. The evidence for fatty acids is inconclusive, but they might exert anti-cancer effects. Inconclusive results are available on vitamins, selenium probiotics and prebiotics. There is increasing evidence that diet may play an important role in the development of HCC, and may also have a chemopreventive role in at risk populations.

Differentiated Thyroid Cancers 11–20 mm in Diameter Have Clinical and Histopathologic Characteristics Suggesting Higher Aggressiveness than Those ≤10 mm

OBJECTIVE To compare characteristics and outcomes of differentiated thyroid cancers < or =10 mm with those 11-20 mm in diameter. DESIGN Retrospective chart review of 426 patients with thyroid carcinoma < or =20 mm diagnosed and treated between 1990 and 2004 in one university clinic. MAIN OUTCOMES Lymph node metastases were more frequent at diagnosis in 11-20 mm than in < or =10 mm cancers (p < 0.001). The prevalence of distant metastases did not differ between < or =10 mm and 11-20 mm cancers. One hundred and thirty-three patients (73%) with tumors 11-20 mm were disease free 2 years after 131I treatment, and no recurrence has been observed over 2-14 years of follow-up. Forty-one patients (22%) with cancers 11-20 mm (N1 or M1) required 2-4 years to become disease free. Neck lymph node recurrence was observed in nine patients (4.9%) 4 months to 14 years after surgery and (131)I therapy. Four patients (1.6%) with cancers < or =10 mm in diameter had cancer recurrence (p = 0.05 compared to the 11-20 mm cancers). Based on the presence of distant metastases at diagnosis and recurrence of disease during follow-up, cancers 11-20 mm in diameter seemed more aggressive than those < or =10 mm (p < 0.05). CONCLUSION Cancers 11-20 mm seem more aggressive than those < or =10 mm.

Primary sclerosing cholangitis associated with inflammatory bowel disease: an update.

Primary sclerosing cholangitis (PSC) is a chronic progressive disease, usually associated with underlying inflammatory bowel diseases (IBDs), with a prevalence of 60–80% in western countries. Herein, we review the current knowledge about the association between PSC and IBD in terms of clinical approach and long-term patient management. A PubMed search was conducted for English-language publications from 2000 through 2015 using the following keywords: primary sclerosing cholangitis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, diagnosis, therapy, follow-up, and epidemiology. In terms of diagnosis, liver function tests and histology are currently used. The medical treatment options for PSC associated with IBD do not differ from the cases of PSC alone, and include ursodeoxycholic acid and immunosuppressive agents. These treatments do not seem to improve survival, even if ursodeoxycholic acid given at low doses may be chemopreventive against colorectal cancer (CRC). Liver transplantation is the only potential curative therapy for PSC with reported survival rates of 85 and 70% at 5 and 10 years after transplant; however, there is a risk for PSC recurrence, worsening of IBD activity, and de-novo IBD occurrence after liver transplantation. PSC–IBD represents an important public health concern, especially in view of the increased risk for malignancy, including CRC. Long-life annual surveillance colonoscopy is usually recommended, although the exact timescale is still unclear. Further studies are required both to clarify whether annual colonoscopy is cost-effective, especially in younger patients, and to identify potential pharmaceutical agents and genetic targets that may retard disease progression and protect against CRC.

Diagnosis and treatment of nutritional deficiencies in alcoholic liver disease: Overview of available evidence and open issues

Malnutrition is common in alcoholic liver disease and is associated with high rates of complications and mortality. In this article, the current literature was reviewed to highlight the relevance of proper nutritional management providing levels of evidence, when available. A PubMed search was performed for English-language publications from 1980 through 2014 with the keywords: alcoholic liver disease, nutritional deficiencies, nutritional support, enteral nutrition, parenteral nutrition, and protein-energy malnutrition. Manuscripts focused on nutritional approach in patients with alcoholic liver disease were selected. Although nutritional support for malnourished patients improves the outcome of hospitalization, surgery, transplantation and reduces the complications of liver disease and the length of hospital stay, specific guidelines are scanty. Both enteral and parenteral nutrition appear to improve nutritional parameters and liver function; however data on survival is often conflicting. As micronutrient depletion is common in alcoholic liver disease and each deficiency produces specific sequelae, all cirrhotic patients should be screened at baseline for deficiencies of micronutrient and supplemented as needed. In summary, protein-energy malnutrition and micronutrient depletion are clinical concerns in alcoholic liver disease. Nutritional therapy, including enteral nutrition, parenteral nutrition and micronutrient supplementation should be part of the multidisciplinary management of these patients.