Is Laparoscopic CME Right Hemicolectomy an Optimal Indication for NET of the Right Colon and Terminal Ileum?

PURPOSE: Since lymphadenectomy is crucial in midgut neuroendocrine tumor (NET) surgery, we adopted laparoscopic CME right hemicolectomy (LRH-CME) for the treatment of right colon and terminal ileum NETs. In this report, we present a series of nine cases of terminal midgut NETs (TM-NETs) treated by LRH-CME with a video demonstrating oncological principles and the surgical technique. METHODS: From September 2014 to November 2019, nine patients affected by TM-NETs underwent LRH-CME at the Unit of General and Hepatobiliary Surgery, University of Verona Hospital Trust, ENETS Center of Excellence. Clinicopathological data, post-operative and oncological outcomes were prospectively collected and analyzed. RESULTS: Tumors were in ileocecal valve or terminal ileum (5 cases), right colon (3 cases), and appendix (one case). Surgery had a curative intent (R0 resection) in 7 cases. Surgical debulking was required in 2 metastatic cases. Mean surgical time was 212 + 41 min and blood loss 47 + 24 mL. No postoperative mortality was observed. Post-operative course was uneventful in all except one case (Clavien-Dindo III). Median number of harvested lymph nodes was 21 (range, 11-31) and eight out of 9 patients were node positive (median 3, range 0-6). At a median follow-up of 18 months (range, 6-50), none of the patients suffered from mesenteric locoregional recurrence and all R0 resected patients were disease-free. CONCLUSIONS: Terminal midgut NETs represent an optimal indication for LRH-CME which increases the chance of complete resection and allows optimal lymphadenectomy. In expert hands, laparoscopic approach should be favored in consideration of good short-term outcomes.

Impact of visceral obesity and sarcobesity on surgical outcomes and recovery after laparoscopic resection for colorectal cancer.

BACKGROUND & AIMS: Studies analyzing the impact of visceral fat excess on surgical outcomes after resection for colorectal cancer (CRC) have yielded conflicting results. Visceral obesity (VO) and sarcobesity (SO) have been recently addressed as risk factors for poor short-term results while no data are available for recovery goals after surgery. No data are available on the protective effect of ERAS in VO and SO patients. The aim of this study was to assess clinical implications of computed tomography (CT) assessed VO and SO on surgical and recovery outcomes after minimally invasive resection for CRC before and after ERAS protocol implementation. METHODS: Visceral adipose tissue (VAT) and skeletal muscle area (SMA) were retrospectively assessed using pre-operative CT studies of 261 patients who underwent laparoscopic resection for CRC between January 2012 and April 2019; ERAS protocol was adopted in 160 patients operated on after March 2014. Patients' surgical and recovery outcomes were compared according to BMI categories, VO and SO which was defined using the VAT/SMA ratio (Sarcobesity Index). Predictive factors for poor surgical and recovery outcomes were evaluated by univariate and multivariate analyses. RESULTS: Of the 261 patients, 12.6% were BMI obese while 68.6% presented visceral obesity. BMI was not associated to any of the outcomes considered. No differences in intra-operative results were found except for a lower number of retrieved lymph nodes both in VO and SO patients. While VO showed no impact on post-operative course, SO resulted an independent risk factor for cardiac complications and prolonged post-operative ileus (PPOI) at logistic regression analysis. Furthermore, sarcobese patients showed delayed recovery after surgery. Patients enrolled in the ERAS protocol showed improved recovery outcomes for both VO and SO groups, although ERAS did not result to be a protective factor for cardiac complications and PPOI. CONCLUSIONS: A high Sarcobesity Index is a risk factor for developing cardiac complications and PPOI after laparoscopic resection for CRC. A reduced number of lymph nodes retrieved is associated to VO and SO. These conditions should then be considered in clinical practice for the risk of down staging the N stage. Effect of VO and SO on recovery items after surgery should be further investigated. ERAS protocol application should be implemented to improve recovery outcomes in VO and SO patients undergoing laparoscopic colorectal resection.

Mid-transverse colon cancer and extended versus transverse colectomy: Results of the Italian society of surgical oncology colorectal cancer network (SICO CCN) multicenter collaborative study.

INTRODUCTION: Transverse colon cancer (TCC) is poorly studied, and TCC cases are often excluded from large prospective randomized trials because of their complexity and their potentially high complication rate. The best surgical approach for TCC has yet to be established. The aim of this large retrospective multicenter Italian series is to investigate the advantages and disadvantages of both hemicolectomy and transverse colectomy in order to identify the best surgical approach. MATERIALS AND METHODS: This was a retrospective cohort study of patients with mid-transverse colon cancer treated with a segmental colon resection or an extended hemicolectomy (right or left) between 2006 and 2016 in 28 high-volume (more than 70 procedures/year) Italian referral centers for colorectal surgery. RESULTS: The study included 1529 patients, 388 of whom underwent a segmental resection while 1141 underwent an extended resection. A higher number of complications has been reported in the segmental group than in the extended group (30.1% versus 23.6%; p 0.010). In 42 cases the main complication was the anastomotic leak (4.4% versus 2.2%; p 0.020). Recovery outcomes also showed statistical differences: time to first flatus (p 0.014), time to first mobilization (p 0.040), and overall hospital stay (p < 0.001) were significantly shorter in the extended group. Even if overall survival were similar between the groups (95.1% versus 97%; p 0.384), 3-year disease-free survival worsened after segmental resection (78.1% versus 86.2%; p 0.001). CONCLUSIONS: According to our results, an extended right colon resection for TCC seems to be surgically safer and more oncologically valid.

Prognostic value of thrombocytosis in patients undergoing surgery for colorectal cancer with synchronous liver metastases.

PURPOSE: The purpose of this study was to evaluate the prognostic role of thrombocytosis in patients with synchronous colorectal liver metastases (CRLM). METHODS: Retrospective analysis of patients who underwent surgery for colorectal cancer with synchronous CRLM at the Division of General and Hepatobiliary Surgery, University of Verona Hospital Trust between 2005 and 2016. RESULTS: One hundred and ninety-six patients met the inclusion criteria. High platelet count (H-PC) was found in 32%, and it was associated with a higher rate of palliative surgery (p < 0.001), extra-hepatic metastases (p < 0.001), bilobar liver disease (p = 0.007), presence of more than three metastases (p = 0.005), biggest metastasis larger than 5 cm (p < 0.001), and CEA level higher than 200 ng/mL (p = 0.035). H-PC was significantly associated with poorer 5-year overall survival (14.3% vs. 34.3%; p = 0.001). At the multivariate analysis on R0-1 cases, platelet count resulted the only independent predictor of survival (HR 2.07, p = 0.036). CONCLUSION: H-PC correlates with the main negative clinical-pathological factors in patients with synchronous CRLM, as well as with overall survival. Moreover, it was the only independent prognostic factor in those who underwent curative surgery.

What is the most accurate lymph node staging method for perihilar cholangiocarcinoma? Comparison of UICC/AJCC pN stage, number of metastatic lymph nodes, lymph node ratio, and log odds of metastatic lymph nodes.

BACKGROUND: We compared the prognostic performance of the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) 7th edition pN stage, number of metastatic LNs (MLNs), LN ratio (LNR), and log odds of MLNs (LODDS) in patients with perihilar cholangiocarcinoma (PCC) undergoing curative surgery in order to identify the best LN staging method. METHODS: Ninety-nine patients who underwent surgery with curative intent for PCC in a single tertiary hepatobiliary referral center were included in the study. Two approaches were used to evaluate and compare the predictive power of the different LN staging methods: one based on the estimation of variable importance with prediction error rate and the other based on the calculation of the receiver operating characteristic (ROC) curve. RESULTS: LN dissection was performed in 92 (92.9%) patients; 49 were UICC/AJCC pN0 (49.5%), 33 pN1 (33.3%), and 10 pN2 (10.1%). The median number of LNs retrieved was 8. The prediction error rate ranged from 42.7% for LODDS to 47.1% for UICC/AJCC pN stage. Moreover, LODDS was the variable with the highest area under the ROC curve (AUC) for prediction of 3-year survival (AUC = 0.71), followed by LNR (AUC = 0.60), number of MLNs (AUC = 0.59), and UICC/AJCC pN stage (AUC = 0.54). CONCLUSIONS: The number of MLNs, LNR, and LODDS appear to better predict survival than the UICC/AJCC pN stage in patients undergoing curative surgery for PCC. Moreover, LODDS seems to be the most accurate and predictive LN staging method.

Factors influencing survival after hepatectomy for metastases from gastric cancer.

PURPOSE: To investigate clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. METHODS: Retrospective multi-center chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: One hundred and five patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting of the disease. In 89 cases a R0 resection was achieved, while in 16 a R+ hepatic resection was performed. Adjuvant chemotherapy was administered to 29 patients. Surgical mortality was 1% and morbidity 13.3%. Median disease-free survival was 10 months, median overall survival was 14.6 months. Overall 1, 3, and 5-year survival rates were 58.2%, 20.3%, and 13.1%, respectively. Survival was influenced independently by the factor T of the gastric primary (p < 0.001), by the curativity of surgical procedure (p = 0.001), by the timing of hepatic involvement (p < 0.001) and by adjuvant chemotherapy (p < 0.001). T4 gastric cancer, R+ resection, synchronous metastases, and abstention from adjuvant chemotherapy were associated with a worse prognosis; T4 gastric cancer and R+ resections displayed a cumulative effect (p < 0.001). CONCLUSIONS: Our data show that R0 resection must be pursued whenever possible. Furthermore, in the synchronous setting, the coexistence of T4 gastric primaries and R+ resections suggests prudence and probably abstention from hepatectomy. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.

Role of surgery in the treatment of intrahepatic cholangiocarcinoma.

Intrahepatic Cholangiocarcinoma (ICC) is the second most common primary liver cancer, accounting for 10% to 15% of primary hepatic malignancy, and its incidence is increasing in Western Countries. Surgery with curative intent is the only treatment that offers a chance of long-term survival, with a reported 5-year overall survival rate ranging from 17% to 48%. In the most of recent series postoperative mortality is lower than 5% and morbidity varied from 6% to 66%. The macroscopic classification of ICC, proposed by Liver Cancer Study Group of Japan (LCSGJ), reflects different biologic behaviours, pattern of tumor growth and clinicopathological findings. The most important prognostic factors after resection are positive resection margins, lymph-node metastases, tumor size, presence of macrovascular invasion and intrahepatic metastases. Unfortunately, recurrence is still frequent and it is the leading cause of death. The treatment of the recurrence varied according to the location and extension of the disease. Recently, expression of several genes found to be related with the carcinogenesis of ICC. These molecular findings are helpful to differentiate the biological behaviour and will provide evidence for the development of new target therapies.

Changing clinical and pathological features of gastric cancer over time.

BACKGROUND: The aim of the present multicentre observational study was to evaluate potential changes in clinical and pathological features of patients with gastric cancer (GC) treated in a 15-year interval. METHODS: A centralized prospective database including clinical, surgical, pathological and follow-up data from 2822 patients who had resection of a primary GC was analysed. The analysis focused on three periods: 1991-1995 (period 1), 1996-2000 (period 2) and 2001-2005 (period 3). Surgical procedure, pathological classification and follow-up were standardized among centres. RESULTS: The number of resections decreased from 1024 in period 1 to 955 and 843 in periods 2 and 3 respectively. More advanced stages and a smaller number of intestinal-type tumours of the distal third were observed over time. Five-year survival rates after R0 resection (2320 patients) did not change over time (overall: 56·6 and 51·2 per cent in periods 1 and 3; disease-free: 66·8 and 61·1 per cent respectively). Decreases in survival in more recent years were related particularly to more advanced stage, distal tumours and tumours in women. Multivariable analysis showed a lower probability of overall and disease-free survival in the most recent interval: hazard ratio 1·22 (95 per cent confidence interval 1·06 to 1·40) and 1·29 (1·06 to 1·58) respectively compared with period 1. Recurrent tumours were more frequently peritoneal rather than locoregional. CONCLUSION: Overall and disease-free survival rates after R0 resection of GC were unchanged over time.

[Treatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. / Trattamento della carcinosi peritoneale mediante citoriduzione chirurgica e chemioipertermia intraperitoneale.

Pinto Peritoneal carcinomatosis (PC) had for long been regarded as a terminal disease, characterized by a very poor survival and worthy of being treated with palliative therapy only. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising additional treatment option for patients with peritoneal carcinomatosis, resulting in recently published series enable to obtain long-term survival. In spite of the need for more high quality studies, there is now a consensus among many international experts about the use of this new strategy as gold standard for treating with intent of cure selected patients with PC. We summarized the present status and possible future progress of this treatment modality, in particular outlining its rationale, current practice and general outcomes.

Super-extended (D3) lymphadenectomy in advanced gastric cancer.

PURPOSE: 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. METHODS: Short- and long-term results of D3 lymphadenectomy were analyzed in 286 patients with advanced GC. RESULTS: PAN metastases were demonstrated in 37 patients. PAN involvement was significantly higher in upper third tumours (29%) compared to middle and lower third (7%; P < 0.001). Eighty patients developed post-operative complications, being pulmonary disorders (6%), abdominal abscesses (4.5%) and pancreatic fistulas (3%) the most frequently observed. In-hospital mortality was 2%. Overall 5-year survival rate for R0 pT2-4 patients was 52%. When considering survival in relation to nodal involvement, both pN3 and non-regional lymph node metastases (M1a) patients showed a chance of long-term survival: 5-year survival was 31% for pN3 and 17% for M1a cases. Furthermore, the 5-year survival rate was remarkably high (about 60%) even in pN2 and pN3 subsets when no serosal invasion (pT2) was demonstrated. CONCLUSIONS: D3 lymphadenectomy could be further explored in specialized centers for curative surgery of advanced GC, especially for upper third tumours, providing that an acceptable morbidity and no increase in mortality can be offered.

Familial gastric cancer and Li-Fraumeni syndrome.

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.

Elastofibroma dorsi: three cases of personal experience.

Elastofibroma dorsi is a rare, slow growing, soft tissue lesion, which occurs mainly in elderly women, typical located in the infrascapular region. This lesion is characterized by a poorly defined solid mass of fibro-elastic and fatty tissue, enlarging into intermuscular spaces. Elastofibroma may simulate an aggressive behaviour, and differential diagnosis with malignant tumors is sometimes difficult. Surgical resection is generally recommended in symptomatic lesions or in the suspicion of malignancy. We report our experience of three cases of elastofibroma, two of which typically located in the infrascapular region and one located in the supra-clavicle fossa, atypical site never reported so far.

Surgical treatment of gastric cancer in Latvia: results of centralized experience.

BACKGROUND: Although the mortality for gastric cancer is decreasing in Western Europe and United States, it still remains high in Eastern Europe. This study was aimed at evaluating short- and long-term results of surgical treatment of gastric cancer performed in Latvia Oncology Center. METHODS: Retrospectively collected data from 461 patients who underwent gastrectomy with curative intent in Latvia Oncology Center from January 2001 to December 2005 were analyzed statistically. RESULTS: An average (range) of 92.2 (81-102) R0-R1 gastrectomies was performed each year. Post-operative complications occurred in 75 patients (16.3%); in-hospital mortality was 3.3%. The overall 5-year survival was 50.8%. In 444 cases (96.3%) there was histopathologic confirmation of R0-resection with a 5-year survival of 52.5% (P<0.001). Considering pT category, 5-year survival was 88.6% for pT1 patients, 65% for pT2, 42.3% for pT3 and 27% for pT4 (P<0.001). Considering pN category, 5-year survival was 67% for pN0 patients, 30% for pN1 and 29% for pN2-3 (P<0.001). CONCLUSIONS: Clinico-pathologic characteristics of patients who underwent resection with curative intent are comparable to other Western experiences. Short- as well as long-term results are also similar if not for pN+ patients where no difference between pN1 and pN2 cases was observed.

Resection line involvement after gastric cancer surgery: clinical outcome in nonsurgically retreated patients.

PURPOSE: Resection line infiltration (RLI) after surgical treatment represents an unfavorable prognostic factor in advanced gastric cancer. We performed a retrospective analysis of 89 patients with resection line involvement who did not undergo reoperation. METHODS: On behalf of the Italian Research Group for Gastric Cancer, we present the characteristics and outcome of 89 patients who were submitted to surgical resection for gastric cancer from 1988 to 2001 and did not undergo reoperation because of disease extension or associated pathologies. RESULTS: RLI was significantly higher in patients with T4 tumors and diffuse histological type. Anastomotic leakages were observed in 4.8% of infiltrated esophageal resection margins, whereas 1.9% of infiltrated duodenal resection lines showed duodenal fistulas. Five-year overall survival of patients with RLI was 29%. Prognosis was not affected by RLI in early forms (100% 5-year survival); however, 5-year survival in T2 and T3 stages was significantly lower with respect to the same stages without residual tumor. The influence of RLI on prognosis was confirmed in N0 as well as in N1 and N2 patients. RLI also was an independent prognostic at multivariate analysis (odds ratio = 1.5; 95% confidence interval, 1.08-2.08; P = 0.0144). CONCLUSIONS: RLI significantly affects long-term survival of advanced gastric cancer. The impact on prognosis is independent of lymph node involvement. Patients in good general condition for whom radical surgery is possible should be considered for reoperation.

The interferon gamma receptor 1 (IFNGR1) -56C/T gene polymorphism is associated with increased risk of early gastric carcinoma.

BACKGROUND AND AIMS: 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. METHODS: In a case-control study including 733 controls, 213 patients with chronic gastritis and 393 patients with GC, the IFNGR1 -611*G/*A, -56*C/*T, +1004*A/*C and +1400*T/*C polymorphisms were genotyped. A second independent case-control study including 100 controls and 65 patients with GC was used for confirmation of the original results. The effect of the -56*C/*T promoter polymorphism in the level of expression of the IFNGR1 gene was evaluated by an IFNGR1 -56*C/*T allele specific luciferase reporter assay. RESULTS: In patients with early onset GC (defined as being less than 40 years of age at the time of diagnosis) we found a significant over-representation of the IFNGR1 -56*T/*T homozygous genotype with an odds ratio (OR) of 4.1 (95% confidence interval (CI) 1.6 to 10.6). This result was confirmed in a second independent case-control study. In the luciferase reporter assay we observed a 10-fold increase (p<0.001) in luciferase expression associated with the IFNGR1-56*T allele. CONCLUSIONS: Our results indicate that the IFNGR1 -56C/T polymorphism is a relevant host susceptibility factor for GC development. Our data also indicate that this genetic polymorphism is functionally relevant and may be related to the early development of GC.

Mayer-Rokitansky-Küster-Hauser syndrome presenting as vaginal atresia: report of two cases.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome) is characterized by Müllerian duct structures agenesis: the vagina atresia is the commonest variant. There can be some anomalies associated, such as renal, skeletal, spine malformations and others. Patients with MRKH can show different presentation from newborn period to adolescence. We report our experience in treatment of the vaginal atresia presenting in two young girls as a sign of MRKH syndrome.

Prognostic relevance of proliferative activity evaluated by Mib-1 immunostaining in node negative breast cancer.

AIM: 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. METHODS: Mib-1 expression was evaluated by immunohistochemistry. Tumor sections from highly cellular invasive areas of cancer were stained by monoclonal antibody Mib-1 (Dako) and cells whose nuclei stained positive were counted in 10 randomly chosen HPFs and expressed as percentages of all epithelial cells. A minimum of 400 cells were counted. Correlation between Mib-1 staining and clinico-pathological factors was investigated by means of univariate and multivariate analyses. The prognostic impact on actuarial disease free (DFS) and overall survival (OS) was evaluated by univariate analysis using the log-rank test and by multivariate analysis using Cox regression model. RESULTS: Tumors were considered as positive for Mib-1 expression when more than 15% of cells counted were stained. Mib-1 positivity was found in 190/432 cases and resulted in being significantly related to tumor grade, tumor size and absence of estrogen receptors at multivariate analysis. With a median follow-up of 66 months, Mib-1 positivity resulted in being the only independent predictor of OS (RR 2.92), and an independent predictor of DFS (RR 2.01) together with absence of estrogen receptors (RR 2.15). CONCLUSIONS: Mib-1 index of proliferative activity correlates well to other established prognostic factors of breast cancer. Mib-1 index may improve the tailoring of adjuvant therapy in early breast cancer, and our experience adds evidence to its effectiveness as prognostic factor. Efforts to reach uniformity in the methodology and in the scoring system should be done to warrant a standardized procedure and make Mib-1 determination definitively reliable in the current clinical practice.

A case of small-cell gastric carcinoma with an adenocarcinoma component and hepatic metastases: treatment with systemic and intra-hepatic chemotherapy.

Primary small-cell carcinoma (SmCC) of the stomach is a rare neoplasm with a poor prognosis and unclear histogenesis: to date, only 50 cases, including ours, have been reported in the literature. In the World Health Organization gastrointestinal tumours' classification, SmCC of the stomach has been recognized as an 'independent entity affecting the stomach'. In this paper, the authors present a clinical case and the surgical treatment of an adult with a SmCC of the stomach associated with gastric adenocarcinoma. After laparotomy, a large neoplasm with locoregional extension and multiple liver metastases were found. A palliative resection, subtotal gastrectomy, was performed, followed by systemic and intra-hepatic chemotherapy: computed tomography scan demonstrated a marked response, but the patient died 15 months after the operation. A review of the literature showed that the diagnosis of gastric SmCC is based on immunohistochemical findings. Our experience confirmed the high aggressiveness of this neoplasm, which is generally diagnosed in advanced stage and is unresponsive to chemotherapy, but the combined use of systemic and intra-hepatic chemotherapy shows an acceptable result in a palliative care perspective.

Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management.

AIM: 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. METHODS: Assessment of the P373L mutation effect was based on cell aggregation and invasion assays. LOH analysis at the E-cadherin locus, search for somatic E-cadherin mutations and for promoter hypermethylation were performed to identify the mechanism of inactivation of the E-cadherin wild-type allele in the tumour. RESULTS: In vitro the P373L germline mutation impaired the E-cadherin functions. E-cadherin promoter hypermethylation was observed in the tumour of the P373L mutation carrier. CONCLUSION: We conclude that the combination of clinical, in vitro and molecular genetic data is helpful for establishing an accurate analysis of HDGC-associated CDH1 germline missense mutations and subsequently for appropriate clinical management of asymptomatic mutation carriers.