Department of Human Pathology and Oncology, Section of General Surgery and Surgical Oncology, Translational Research Laboratory, University of Siena, Italy
Abstract: BACKGROUND: The purpose of this study is to analyze the diagnostic accuracy of MSCT in the identification of para-aortic lymph node metastases from gastric cancer. METHODS: A total of 92 consecutive patients with primary gastric cancer were prospectively submitted to preoperative MSCT staging according to a standard protocol in the period 2003-2010. All diagnostic procedures were performed by dedicated radiologists who were unaware of the final pathological nodal status. Subsequently all patients underwent potentially curative (R0) resection with extended lymphadenectomy plus para-aortic nodal dissection. Lymph node mapping in different stations and retrieval of single lymph nodes were performed by the surgeon on the fresh specimen and then submitted for pathological examination. Clinical, radiological, and pathological data were prospectively stored on database. RESULTS: A median number of 47 (range: 18-114) total lymph nodes and 7 (range: 3-29) para-aortic lymph nodes were removed. In 13 of 92 included patients (14%), histological examination demonstrated para-aortic nodal metastases; MSCT was correctly positive in 11 of these cases (sensitivity: 85%). In 79 patients para-aortic nodes were not involved, and MSCT resulted correctly negative in 75 of these patients (specificity: 95%). Positive (PPV) and negative (NPV) predictive values were 73 and 97%, with a global accuracy of 93%. CONCLUSIONS: MSCT performed according to a standard protocol by dedicated radiologists demonstrated high accuracy in preoperative identification of para-aortic nodal metastases from gastric cancer. These results may be useful in planning surgical approach or during clinical staging before neoadjuvant chemotherapy.
Abstract: Microsatellite instability (MSI) is a major pathway involved in gastric carcinogenesis occurring in 20% of gastric cancer (GC). However, it is not clear whether MSI phenotype preferentially occurs in the sporadic or familial GC, when stringent inclusion criteria are used. The aim of this study was to compare the frequency of MSI and hypermethylation of MLH1 promoter in a large series of familial GC patients (non-HNPCC and non-CDH1-related) and sporadic cases. Additionally, we analysed the immunoexpression of MMR proteins in a fraction of cases. Overall, the frequency of familial GC was 7.1%, and the frequency of hereditary tumours was 4.6%. MSI phenotype and MLH1 hypermethylation frequencies were not statistical different between familial and sporadic GC settings. Further, the MSI phenotype was not associated with any clinico-pathological features studied in the familial GC setting, whereas in the sporadic setting, it was associated with older age, female gender and intestinal histotype. Using our stringent Amsterdam-based clinical criteria to select familial GC (number of cases, age of onset), we verified that sporadic and familial cases differed in gender but shared histopathological features. We verified that the frequency of MSI was similar in familial and sporadic GC settings, demonstrating that this molecular phenotype is not a hallmark of familial GC in contrast to what is verified in HNPCC. Moreover, we observed that the frequency of MLH1 hypermethylation is similar in sporadic and familial cases suggesting that in both settings MSI is not associated to MMR genetic alterations but in contrast to epigenetic deregulation.
Abstract: Mitogen-activated protein kinase (MAPK) cascade and phosphatidylinositol 3-kinase (PI3K) survival pathways are frequently activated in the progression of gastrointestinal malignancies. In this study, we aimed to determine the frequency of gene mutations in members of these pathways--Epithelial Growth Factor Receptor (EGFR), KRAS, BRAF, PIK3CA and MLK3 in a series of 63 gastric carcinomas with high levels of microsatellite instability (MSI).
Abstract: About 90% of gastric carcinoma presents a sporadic setting and only 10% shows a familial cluster; among this group, 1-3% are considered as hereditary syndromes, with a clear genetic pathway. The most important genetic mechanisms are associated with CDH1 germline mutations, causing the hereditary diffuse gastric cancer syndrome. Other inherited predispositions with gastric carcinoma are the hereditary nonpolyposis colorectal cancer, Li-Fraumeni and Peutz-Jeghers syndromes. In this brief update, we described these principal hereditary syndromes offering a simple management to physicians where are these diseases diagnosed.
Abstract: CDH1 germline alterations occur in about 40% of hereditary diffuse gastric cancer (HDGC) families. CDH1 germline mutations are also documented in few early onset diffuse gastric cancer patients (EODGC) without family history, but the real frequency in this setting in unknown. In these patients, the advanced stage at the time of diagnosis remains a clinical burden due to the poor long term survival.
Abstract: Microsatellite instability (MSI) occurs in about 15% of gastrointestinal cancers and it is associated with specific clinic, pathologic, and molecular features of the tumors. MSI-high (MSI-H) carcinomas also follow specific tumor development pathways. This review is focused on the molecular profile of alterations in members of the KRAS signaling pathway (EGFR, KRAS, BRAF, PIK3CA, RASSF1A, and MLK3 genes) in MSI gastrointestinal carcinomas. Alterations in these genes characterize more than half of gastrointestinal cancers and frequently occur simultaneously in the same tumor, pinpointing the KRAS signaling pathway as one of the most frequently altered pathways in this subset of cancers. Nowadays, many and novel inhibitors targeting molecules of this signaling pathway are being described; therefore, it is worthwhile to test their efficacy in MSI gastrointestinal cancers in order to develop new and more directed targeted therapies for patients affected by this disease.
Abstract: Gastric cancer occurs in some familial diseases with inherited cancer predisposition. Genetic factors have been correlated with the hereditary diffuse gastric cancer and other familial gastric cancer conditions as hereditary non-polyposis colorectal cancer and Li-Fraumeni syndrome. The present study was aimed at searching for germ line mutations of TP53 gene in familial gastric cancer with cluster for Li-Fraumeni syndrome or Li-Fraumeni-like syndrome. Twenty-three pedigrees with characteristics for Li-Fraumeni-like syndrome were identified. DNA of the proband was sequenced using polymerase chain reaction/single-strand conformation polymorphism. Among these 23 cases, no germ line mutation of TP53 was identified, while two single-nucleotide polymorphisms were identified in four patients. In our area, in which a high rate of familial aggregation was demonstrated, the lack of germ line mutation of TP53 together with the infrequency of mutation of E-cadherin gene seem to limit the role of genetic predisposition in the development of gastric cancer.
Abstract: The aim of this study was to evaluate the prognostic value of the ratio of metastatic to examined lymph nodes (N ratio) in gastric cancer patients who underwent limited lymphadenectomy and had a small number (< or =15) of analyzed nodes.
Abstract: Other than in childhood, intussusception is unusual and nearly always caused by a structural and well demonstrable lesion. In contrast with the colon tract, the incidence of primary malignancies in the small bowel is very low. We report the case of a 51-year-old man presenting with jejunal intussusception due to a primary adenocarcinoma. To our knowledge, only a few similar cases have been reported in the literature to date. The patient was referred to our division for bowel obstruction. A CT scan showed a jejunal intussusception and surgical exploration was hence considered. At laparotomy, jejunal intussusception located just after the ligament of Treitz due to a polypoid lesion was confirmed and resection of the first jejunal loop was carried out. Histological examination of the specimen resulted in a diagnosis of a primary adenocarcinoma of the small bowel. In adult intestinal intussusception, resection without reduction is considered the optimal management if an underlying primary malignancy cannot be excluded.
Abstract: To evaluate the clinical impact of D-dimer (DD) as a tumor marker in patients with colorectal cancer (CRC). The prognostic value of preoperative DD measurement was assessed in relation to carcinoembryonic antigen (CEA) levels.
Abstract: To analyze our experience with D3 lymphadenectomy in the treatment of advanced GC with specific reference to post-operative morbidity and mortality, incidence of para-aortic node (PAN) metastases, and long-term prognosis.
Abstract: Germline CDH1 point or small frameshift mutations can be identified in 30-50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT-PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is approximately 46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families.
Abstract: The objective of this study was to find out whether C-160A single nucleotide polymorphism of the promoter region of the E-cadherin gene might be a potential genetic marker for identifying individuals at risk for gastric cancer (GC). To test this hypothesis, 412 GC patients and 408 controls were analyzed statistically. A PCR-restriction fragment length polymorphism assay was adopted for C-160A single nucleotide polymorphism detection. No statistical differences were found among CC, CA, and AA genotypes and the risk of GC, even stratifying according to age, sex, and area of residence. Similarly, genotype was not associated with intestinal or diffuse histotypes, or with cardia or noncardia carcinomas. In conclusion, the C-160A polymorphism is not associated with GC risk in the Italian population.
Abstract: About 90% of gastric cancer (GC) cases appear in a sporadic setting. Nonetheless, in high incidence areas high familial aggregation rates have been recently described. Microsatellite instability (MSI) is thought to be an important molecular phenotype both in sporadic GC and in tumors of the HNPCC spectrum. The aim of this study was to assess the frequency of MSI in GC with familial aggregation. Five quasimonomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21 and NR-27) were analyzed in 250 GC patients. Seventy-five patients (30%) had at least one-first-degree family member affected by GC and 63 patients (25.2%) showed MSI. The frequency of MSI was significantly higher in patients with a positive family history of GC (38.7%) compared to patients with other tumor types within the family (15.7%) or with a negative oncological familial history (21.9%, P = 0.004). Within cases with a positive familial oncological history, the MSI frequency in families with GC only was similar to the one observed in families with GC and colon cancer (P = 0.96). Nonetheless, in families with GC and lung cancer, the frequency of MSI was significantly lower (5.6%, P = 0.007). MSI occurs in GCs with familial aggregation. Similar MSI rates have been observed in GC patients with other family members affected by GC or colon cancer. The same does not occur in families with other members affected by lung cancer. Our data seem to suggest that familial aggregation for either GC alone or gastric and colon cancer share common etiological factors in contrast to families with gastric and lung cancers.
Abstract: X-ray repair cross complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the bas-excision repair pathway. Several single-nucleotide polymorphisms in the XRCC1 gene are identified and related with increased cancer risk development. In particular, the -77T>C polymorphism located on the promoter region relates with lung cancer risk development. The aim of this study is to analyze the -77T>C allelic frequencies in a population composed of 456 primary gastric cancer patients (GC) and 507 blood donor controls.
Abstract: Recent studies have suggested that Helicobacter pylori (H. pylori) infection may be related to better prognosis in patients with gastric cancer, but to the authors' knowledge, this finding has not yet been validated. In the current study, the association between H. pylori status and clinical outcome was investigated in a large cohort of patients.
Abstract: Microsatellite instability (MSI) correlates with clinicopathologic characteristics and long-term prognosis in patients having gastric carcinoma.
Abstract: It has been demonstrated that polymorphisms within inflammation-related genes are associated with the risk of gastric carcinoma (GC) in people infected with Helicobacter pylori. Recently, polymorphisms in the gene encoding the interferon gamma receptor 1 (IFNGR1) were found to be associated with increased susceptibility to H pylori infection. We aimed to determine the association between polymorphisms in the IFNGR1 gene and development of chronic gastritis and GC.
Abstract: The purpose of this prospective observational study was to analyze the role of Mib-1 immunostaining as a proliferation index in breast cancer. Correlations between Mib-1 expression and clinico-pathological characteristics as well as its prognostic value have been studied in a series of 432 node negative breast cancers.
Abstract: Despite the decrease in incidence observed during the last decades, gastric adenocarcinoma remains the fourth most common cancer in the world and the second leading cause of cancer-related death. Radical surgical resection is the best treatment option, though the role of extended and super-extended lymphadenectomy remains debatable. This review examines the different issues related to the surgical treatment of early and advanced gastric adenocarcinoma as well as the most recent strategies for the treatment and prevention of peritoneal carcinomatosis.
Abstract: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer.
Abstract: Subtotal gastrectomy is considered the preferred treatment for gastric cancer with antral location. The aim of this study was to assess the incidence of early postoperative complications and late functional results in patients who underwent subtotal gastrectomy with Billroth II reconstruction for primary gastric adenocarcinoma. The results of 310 patients were analyzed with regard to postoperative complications and death rates. Functional results as they relate to the gastric resection were evaluated in 195 disease-free patients. Of the 310 patients, 77 developed postoperative general and surgical complications (24.8%) and 13 consequently died (in-hospital mortality: 4.2%). Although infrequent (6 cases, 1.9%), anastomotic leak was the most serious complication (4 cases died during the postoperative phase). Considering functional results, weight loss continued for the first trimester after surgery, after which it stabilized. Loss of appetite was rarely observed; early after the operation the majority of patients were consuming a normal diet and regularly consumed less than five meals per day (83.6%). Dumping syndrome was uncommon and usually resolved within one year (12.3% at three months, 9.5% after one year, 5.2% after two years). On the other hand, postprandial abdominal fullness was frequently observed (43.1% at three months, 36.1% after one year, 21.3% after three years, and 16.5% after five years). Billroth II reconstruction after subtotal gastrectomy is associated with a limited risk of anastomotic complications. Anastomotic leak, although infrequent, is a life-threatening complaint and requires prompt recognition and aggressive surgical treatment. The incidence of late complications was low and the majority of patients recovered from them within one year after surgery, although the occurrence of postprandial abdominal fullness was not completely irrelevant.
Abstract: The prognosis of gastroesophageal junction adenocarcinoma is unquestionably related to the extent of nodal involvement; nonetheless, few studies deal with the pattern of lymph node spread and specifically analyze the prognostic value of the site of metastasis. The present study was aimed at evaluating these key aspects in advanced gastroesophageal junction adenocarcinoma.
Abstract: Very few studies from Western centers have compared D2 and D3 dissection in the surgical treatment of gastric cancer. The aim of the prospective observational study reported here was to analyze the postoperative outcome and potential risk factors for complications following D2 and D3 lymphadenectomy.
Abstract: Local recurrence occurs in 10%-20% of patients treated with breast-conserving surgery for stage I-II breast cancer. The aim of the present study was to investigate breast cancer local recurrence, potential risk factors, and prognostic impact.
Abstract: Germline mutation of the E-cadherin gene (CDH1) accounts for the Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Fourteen pedigrees with Diffuse Gastric Cancer that fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria were selected and screened for CDH1 germline mutations.
Abstract: Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by E-cadherin germline mutations. One-third of these mutations are of the missense type, representing a burden in genetic counselling. A new germline missense mutation (P373L) was recently identified in a HDGC Italian family. The present work aimed at addressing the disease-causative nature of the P373L mutant.
Abstract: Perforation is a rare complication of gastric carcinoma, accounting for less than 1% of all gastric cancer cases. The aim of the present study is to evaluate the prognostic value of perforation and to point out the surgical treatment options.
Abstract: Alterations in the mechanisms of apoptosis are responsible not only for the progression of breast cancer, but for different responses to treatment as well. Among the genes regulators of apoptosis, the tumor suppressor gene p53 and the bcl-2 gene have raised interest for their possible role as predictors of response to therapy and markers of prognosis. The purpose of our study was to prospectively analyze the prognostic value of the expression of p53 and bcl-2 genes in a series of 235 consecutive patients operated on for breast cancer at the Department of General Surgery and Surgical Oncology of the University of Siena, Italy.p53 and bcl-2 expression were evaluated by immunohistochemistry, their association with conventional clinicopathological factors was analyzed by univariate analysis and their prognostic impact was evaluated by multivariate analysis.p53 and bcl-2 were detected respectively in 15.7 and 75.7% of cases, and resulted significantly related to presence of estrogen receptors for p53 over-expression and presence of peritumor lymphovascular invasion (LVI) for bcl-2 expression. With a median follow-up of 79 months, an independent negative prognostic impact on disease free and overall survival was observed for presence of LVI, absence of bcl-2 expression and number of involved axillary lymphnodes. The expression of bcl-2 improved the prognosis of LVI positive tumors up to values similar to LVI negative cases, while its absence associated to presence of LVI resulted in a poor outcome with only 28% of patients alive at 8 years. These data may indicate that expression of bcl-2 is a marker of breast cancers with reduced capability of distant colonization, even in presence of LVI, and may be particularly useful in the clinical setting, allowing to identify a subset of patients with an high risk of relapse.
Abstract: We describe a case of duodenal, third portion, segmental resection for gastrointestinal stromal tumor. A 76-year-old man was referred for gastrointestinal bleeding, dyspnea and asthenia. Esophagogastroduodenoscopy showed a duodenal bleeding fistula. Computerized tomography demonstrated a retroperitoneal mass that compressed and displaced forward the third duodenal tract. Segmental resection of the third portion of the duodenum with a subtotal gastrectomy was performed. The patient was reconstructed with a termino-terminal duodenal anastomosis of the second and the fourth tract and with a Roux-en-Y gastrojejunum anastomosis. There were no postoperative complications. This duodenectomy procedure could be useful as a less extensive resection for duodenal gastrointestinal stromal tumor located in the third portion of the duodenum when the tumor is well capsulated, when the surrounding structures are not infiltrated and when there are no vascular difficulties. The technique reduces the morbidity and mortality correlated with duodenocefalopancreasectomy and improves postsurgical quality of life without worsening the risk of recurrence.
