[show abstract][hide abstract] ABSTRACT: There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC).
HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes.
Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P < 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene.
Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.
[show abstract][hide abstract] ABSTRACT: Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.
[show abstract][hide abstract] ABSTRACT: Background International consensus diagnostic criteria (ICDC) have been proposed to classify autoimmune pancreatitis (AIP) in type 1, type 2, or not otherwise specified.
United European Gastroenterology Journal. 08/2013; 1(4):276-284.
[show abstract][hide abstract] ABSTRACT: To describe MR imaging features of non-hyperfunctioning neuroendocrine pancreatic tumours by comparing them to histopathology and to determine the accuracy of MR imaging in predicting biological behaviour.
After institutional review board approval, we retrospectively reviewed 45 patients with pathologically proven NF-NET of the pancreas and ≥1 preoperative MR/MRCP examinations. Of the NF-NETS, 29/45 (64.4 %) were G1 and 16/45 (35.5 %) were G2. Image analysis included the lesion maximum diameter, vascular encasement, extrapancreatic spread, signal intensity on T1- and T2-weighted, contrast enhancement features, and presence of metastases. Tumour vessel density was calculated on the histological specimen using a grid.
The median maximum diameter of NF-NETs was 20 mm (range 5-200 mm). Eighty per cent of the NF-NETs were hypointense on T1-weighted images, 82.2 % were hyperintense on T2-weighted images, and 75.6 % were hypervascular. Overall MRI accuracy showed a mean AUC of 0.86 compared to pathology. Lesions with a maximum diameter of 30 mm irregular margins, absence of a cleavage plane with the main pancreatic duct, vascular encasement, extrapancreatic spread and abdominal metastases were significantly associated with malignant NF-NETs. No correlation was found between the tumour vessel density and contrast-enhanced MR imaging pattern.
Hyperintensity on T2-weighted images and iso-/hypervascularity occurred in 27/45 (60.0 %) of NF-NETs. MRI identifies malignant NF-NETs with a sensitivity of 93.3 % and a specificity of 76.9 % (AUC = 0.85).
• Non-hyperfunctioning neuroendocrine pancreatic tumours (NF-NET) pose a difficult diagnostic challenge. • On T2-weighted MRI, 82.2 % of neuroendocrine tumours appeared hyperintense. • MR imaging showed 0.94 sensitivity and 0.77 specificity in predicting biological behaviour. • The hyper-/isointensity during dynamic MRI did not correlate with vessel density at pathology.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The aim of the present study was to determine the optimal number of lymph nodes (LN) examined to stage pN0 tumors after surgery for ampulla of Vater carcinoma (AVC). METHODS: We reviewed retrospectively 127 patients with AVC who underwent pancreaticoduodenectomy (1990-2008). Univariate and multivariate analysis was performed. RESULTS: Fifty-nine patients (46.5 %) were pN0, whereas 68 patients (53.5 %) were pN1. The 5-year disease-specific survival (DSS) was worse for pN1 patients than for pN0 patients (46 vs. 77 %; P < 0.0001). In the pN0 cohort, the optimal cut-off number of LN analyzed was found to be 12. The 5-year DSS for patients with ≤12 LN was 50 %, compared with 89 % in those with >12 LN (P = 0.001). By multivariate analysis, a LN count >12 was the only independent predictor associated with improved survival (HR 0.16, P = 0.003) among pN0 patients. Among pN1 patients, a LN count >12 was associated with a significantly better 5-year DSS (59 vs. 22 %; P = 0.027). Patients with a lymph node ratio (LNR) >0.20 had a 5-year DSS of 24 %, compared with 58 % in those with 0 < LNR ≤ 0.20 (P = 0.038). CONCLUSIONS: Removal of more than 12 LN for examination is associated with improved survival rate after surgery for AVC in both pN0 and pN1 patients.
World Journal of Surgery 04/2013; · 2.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatocellular carcinoma is one leading cause of cancer-related death and surgical resection is still one of the major curative therapies. Recently, there has been a major effort to find mechanisms involved in carcinogenesis and early relapse. c-myc gene abnormality is found in hepatocarcinogenesis. Our aim was to analyze the role of c-myc as prognostic factor in terms of overall survival and disease-free survival and to investigate if c-myc may be an important target for therapy. We studied sixty-five hepatocellular carcinomas submitted to surgical resection with curative intent. Size, macro-microvascular invasion, necrosis, number of nodules, grading and serum alfa-fetoprotein level were registered for all cases. We evaluated the c-myc aberrations by using break-apart FISH probes. Probes specific for the centromeric part of chromosome 8 and for the locus specific c-myc gene (8q24) were used to assess disomy, gains of chromosomes (polysomy due to polyploidy) and amplification. c-myc gene amplification was scored as 8q24/CEP8 > 2. Statistical analysis for disease-free survival and overall survival were performed. At molecular level, c-myc was amplified in 19% of hepatocellular carcinoma, whereas showed gains in 55% and set wild in 26% of cases. The 1- and 3-year disease-free survival and overall survival for disomic, polysomic and amplified groups were significantly different (p=0.020 and p=.018 respectively). Multivariate analysis verified that the AFP and c-myc status (amplified vs. not amplified) were significant prognostic factors for overall patients survival. c-myc gene amplification is significantly correlated with disease-free survival and overall survival in patients with hepatocellular carcinoma after surgical resection and this model identifies patients with risk of early relapse (≤12 months). We suggest that c-myc assessment may be introduced in the clinical practice for improving prognostication (high and low risk of relapse) routinely and may have be proposed as biomarker of efficacy to anti-c-myc targeted drugs in clinical trials.
PLoS ONE 01/2013; 8(7):e68203. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute a heterogeneous group of neoplasms. In the last few decades, due to a substantial rise in incidence and prevalence, GEP-NETs have been included among the most common tumours of the gastrointestinal tract. Diagnosis could be challenging and a significant number of patients present with metastatic or unresectable disease. The development of appropriate tools for standardised prognostic stratification and the introduction of effective target therapies have opened new horizons for planning tailored surgical or medical management and follow-up programs for these complex neoplasms. An overview on the GEP-NETs' diagnostic and prognostic criteria proposed by the recently published WHO classification and ENETS and UICC TNM staging systems is presented, focussing on their impact on the clinical and therapeutical approaches.
Best practice & research. Clinical gastroenterology 12/2012; 26(6):705-17. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
[show abstract][hide abstract] ABSTRACT: Poorly differentiated, resectable pancreatic ductal adenocarcinoma is associated with early recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocarcinoma according to histologic grading.
A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma between 1990 and 2008 were analyzed via the use of different histologic grading.
Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients. Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%, respectively. Only the presence of symptoms was a significant clinical predictor of G3 status (P = .035). G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2, and G3 neoplasms (P < .0001). Median disease-free survival was 63, 14, and 9 months for G1, G2, and G3 pancreatic ductal adenocarcinoma (P < .0001). Adjuvant therapy improved disease-specific survival in G2 (P < .04) and G3 (P < .0001) pancreatic ductal adenocarcinoma, with a greater survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116).
G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3 PDAC can be considered as possible targets for neoadjuvant treatment.
Surgery 07/2012; 152(3 Suppl 1):S112-9. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ischemic colitis is a serious drug-induced adverse event. There are only few cases of immunosuppression-associated ischemic colitis described in the literature, but none with a pancolitis-like manifestation. We report the case of a 72-year-old female patient who developed a pancolitis with ischemic injury on immunosuppressive treatment with steroids and azathioprine for autoimmune hepatitis. The patient presented with massive rectal bleeding. Colonoscopy confirmed the diagnosis of pancolitis. The results of histological examination indicated drug-induced ischemic colitis involving the entire colon. This is the first case of ischemic pancolitis mimicking an inflammatory bowel disease (IBD) in a patient with immunosuppressive therapy.
Case reports in gastrointestinal medicine. 01/2012; 2012:698404.
[show abstract][hide abstract] ABSTRACT: To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas.
Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy.
Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs.
We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%).
The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.
Annals of surgery 12/2011; 255(2):326-33. · 7.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Malignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs.
The prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed.
Fifty-seven patients (male/female ratio=1) with a median age of 58 years (33-78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ≤0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR=2.75) and a value of Ki67 >5% (HR=3.39) were significant predictors of recurrence (P<0.02).
After resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.
European journal of cancer (Oxford, England: 1990) 11/2011; 48(11):1608-15. · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the ARFI ultrasound imaging with Virtual Touch tissue quantification in studying pancreatic cystic lesions, compared with phantom fluid models.
Different phantom fluids at different viscosity or density (water, iodinate contrast agent, and oil) were evaluated by two independent operators. From September to December 2008, 23 pancreatic cystic lesions were prospectively studied. All lesions were pathologically confirmed.
Non-numerical values on water and numerical values on other phantoms were obtained. Inter-observer evaluation revealed a perfect correlation (rs=1.00; p<0.0001) between all measurements achieved by both operators per each balloon and fluid. Among the pancreatic cystic lesions, 14 mucinous cystadenomas, 4 pseudocysts, 3 intraductal papillary-mucinous neoplasms and 2 serous cystadenomas were studied. The values obtained ranged from XXXX/0-4,85 m/s in mucinous cystadenomas, from XXXX/0-3,11 m/s in pseudocysts, from XXXX/0-4,57 m/s in intraductal papillary-mucinous neoplasms. In serous cystadenomas all values measured were XXXX/0m/s. Diagnostic accuracy in benign and non-benign differentiation of pancreatic cystic lesions was 78%.
Virtual Touch tissue quantification can be applied in the analysis of fluids and is potentially able to differentiate more complex (mucinous) from simple (serous) content in studying pancreatic cystic lesions.
European journal of radiology 11/2011; 80(2):241-4. · 2.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pancreatic tumors in children and adolescents are uncommon. The aim of the present paper was to analyze short- and long-term outcomes after surgical treatment of primary pancreatic neoplasms in children and adolescents at a single high-volume center for pancreatic diseases.
Retrospective review of medical records and pathology reports of patients younger than 18 years who underwent surgery at Verona University Hospital from 1990 through 2010.
The study population consisted of 20 patients. Abdominal pain and palpable mass were the most common presenting symptoms. No patient had a locally advanced, unresectable or metastatic disease. Complete resection (R0) was achieved in 19 patients. There was no postoperative mortality, but postoperative complications occurred in 5 cases (25%). Histological examination showed 12 solid pseudopapillary tumors, 5 neuroendocrine tumors, 2 cystadenomas and 1 epithelial malignant tumor. At a median follow-up of 49.5 months (range: 7-234), there was no tumor recurrence. Postoperative diabetes was diagnosed in 1 patient and 4 other patients developed pancreatic exocrine insufficiency.
In the setting of a high-volume surgical center, radical resection of pancreatic tumors in children and adolescents is associated with acceptable postoperative morbidity and favorable long-term outcome.
[show abstract][hide abstract] ABSTRACT: Neoadjuvant treatment frequently is performed in unresectable/borderline resectable pancreatic cancer. The aim of this study was to retrospectively compare postoperative outcomes and survival of patients who underwent pancreatectomy after neoadjuvant treatment for locally advanced/borderline resectable pancreatic cancer (neoadjuvant treatment group) with those of patients with resectable disease who underwent upfront surgery.
Between 2000 and 2008, there were 403 patients who underwent pancreatic cancer resection, 41 (10.1%) patients after neoadjuvant treatment for initially unresectable tumors and 362 (89.9%) patients had upfront surgery. Univariate and multivariable analyses were performed.
Mortality/morbidity rates were similar in the 2 groups. Nodal metastases were significantly lower in the neoadjuvant treatment group (31.7% vs 86.2%; P < .001). A complete pathologic response was observed in 13.6% after neoadjuvant treatment. Median disease-specific survival from resection was 35 and 27 months in the neoadjuvant treatment and upfront groups, respectively (P = .74). In the neoadjuvant treatment group survival rates were similar in N0/N1 patients.
Postoperative mortality and morbidity do not significantly increase after neoadjuvant treatment. Neoadjuvant treatment in locally advanced pancreatic cancer can lead to an objective pathologic response, but this does not significantly improve survival after resection.
American journal of surgery 08/2011; 203(2):132-9. · 2.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Solid pseudopapillary tumors of the pancreas are rare exocrine pancreatic tumors. Through a review of pediatric cases in a single Institution, we present the clinical and surgical management of this neoplasm.
We retrospectively reviewed the clinical charts of patients treated at our unit between 1995 and 2009 for SPT. Clinical and surgical management were analyzed and reported.
During the study period 11 patients underwent surgery for pseudopapillary tumor. Five patients were treated with duodenum-preserving pancreatic head resection and six patients with splenopancreasectomy with a Roux-en-Y pancreatic jejunostomy. Patients did not show recurrence and are currently disease free. Blood tests, Ultrasound, Computed tomography and Magnetic Resonance Imaging were not useful to preoperatively identify the nature of the pancreatic masses.
Solid pseudopapillary tumor is a rare condition that should be taken into account for the differential diagnosis of pancreatic masses in pediatric age. Due to its favourable prognosis, surgical removal should be planned and done following the intraoperative findings.
Pediatric Surgery International 07/2011; 27(12):1271-5. · 1.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors.
All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed.
Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease.
A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally.
Surgery 07/2011; 150(1):75-82. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: The value of splenic vessels invasion (which identified T3 tumors) in prognosis after resection for pancreatic ductal adenocarcinoma (PDA) of the body and tail has not been extensively investigated. The goal of this study was to evaluate prognostic factors in PDA of the body/tail, emphasizing the role of splenic vessels infiltration.
Between 1990 and 2008, 87 patients who underwent distal pancreatectomy (DP) for histologically proven PDA of the body and tail were analyzed. Clinicopathological prognostic factors for survival were evaluated. Univariate and multivariable analyses were performed.
Postoperative morbidity was 31% with no mortality. The 1-, 3-, and 5-year overall survival rates were 77%, 48%, and 24.5%, respectively. Invasion of the splenic artery (SA) was observed in 19 patients (22%). Patients with SA invasion had a significantly poorer prognosis compared with those without SA invasion (median survival: 15 vs. 39 months, P = 0.014). On multivariable analysis, adjuvant therapy, poor differentiation (G3/G4), R2 resection, the presence of lymph node metastases, and SA invasion were independent predictors of survival.
Along with other well-known prognostic factors, invasion of SA is an independent predictor of poor survival in PDA of the body/tail. In case of the presence of SA infiltration, neoadjuvant treatment should be considered. SA infiltration might be reclassified from a T3 to T4 tumor.
Annals of Surgical Oncology 05/2011; 18(13):3608-14. · 4.12 Impact Factor