Integrative analysis of hereditary nonpolyposis colorectal cancer: The contribution of allele-specific expression and other assays to diagnostic algorithms

The identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC) is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS). Here we describe the results of integrative molecular analyses in 132 HNPCC patients providing evidences for improved genetic testing of HNPCC with traditional or next generation methods. Patients were screened for: germline allele-specific expression (ASE), nucleotide variants, rearrangements and promoter methylation of mismatch repair (MMR) genes; germline EPCAM rearrangements; tumor microsatellite instability (MSI) and immunohistochemical (IHC) MMR protein expression. Probands negative for pathogenic variants of MMR genes were screened for germline APC and MUTYH sequence variants. Most germline defects identified were sequence variants and rearrangements of MMR genes. Remarkably, altered germline ASE of MMR genes was detected in 8/22 (36.5%) probands analyzed, including 3 cases negative at other screenings. Moreover, ASE provided evidence for the pathogenic role and guided the characterization of a VUS shared by 2 additional probands. No germline MMR gene promoter methylation was observed and only one EPCAM rearrangement was detected. In several cases, tumor IHC and MSI diverged from germline screening results. Notably, APC or biallelic MUTYH germline defects were identified in 2/19 probands negative for pathogenic variants of MMR genes. Our results show that ASE complements gDNA-based analyses in the identification of MMR defects and in the characterization of VUS affecting gene expression, increasing the number of germline alterations detected. An appreciable fraction of probands negative for MMR gene variants harbors APC or MUTYH variants. These results indicate that germline ASE analysis and screening for APC and MUTYH defects should be included in HNPCC diagnostic algorithms

Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients

<p>Abstract</p> <p>Background</p> <p>Patients with hereditary non-poliposys colorectal cancer (HNPCC) have better prognosis than sporadic colorectal cancer (CRC). Aim of our retrospective study was to compare the overall survival between sporadic CRC and HNPCC patients.</p> <p>Methods</p> <p>We analyzed a cohort of 40 (25 males and 15 females) HNPCC cases with a hospital consecutive series of 573 (312 males and 261 females) sporadic CRC observed during the period 1970–1993. In 15 HNPCC patients we performed mutational analysis for microsatellite instability. Survival rates were calculated by Kaplan-Meier method and compared with log rank test.</p> <p>Results</p> <p>The median age at diagnosis of the primary CRC was 46.8 years in the HNPCC series versus 61 years in sporadic CRC group. In HNPCC group 85% had a right cancer location, vs. 57% in the sporadic cancer group. In the sporadic cancer group 61.6% were early-stages cancer (Dukes' A and B) vs. 70% in the HNPCC group (p = ns). The crude 5-years cumulative survival after the primary CRC was 94.2% in HNPCC patients vs. 75.3% in sporadic cancer patients (p < 0.0001).</p> <p>Conclusion</p> <p>Our results show that overall survival of colorectal cancer in patients with HNPCC is better than sporadic CRC patients. The different outcome probably relates to the specific tumorigenesis involving DNA mismatch repair dysfunction.</p

The application of pancreatitis activity score system in clinical practice: an italian experience

The improvement of the management strategies in acute pancreatitis (AP) is mainly limited by the lack of early and quickly accepted methods to measure disease activity. The identification of patients that will develop severe AP at the time of hospitalization allows for the selection of patients that could benefit from specific invasive interventions

Desmoid Tumors Characteristics, Clinical Management, Active Surveillance, and Description of Our FAP Case Series

(1) Background: desmoid tumors (DTs) are common in patients with familial adenomatous polyposis (FAP). An active surveillance approach has been recently proposed as a valuable alternative to immediate treatment in some patients. However, no clear indication exists on which patients are suitable for active surveillance, how to establish the cut-off for an active treatment, and which imaging technique or predictive factors should be used during the surveillance period. (2) Results: we retrospectively analyzed 13 FAP patients with DTs. A surveillance protocol consisting of scheduled follow-up evaluations depending on tumor location and tissue thickening, abdominal computed tomography (CT) scan/Magnetic resonance imaging (MRI) allowed prompt intervention in 3/11 aggressive intra-abdominal DTs, while sparing further interventions in the remaining cases, despite worrisome features detected in three patients. Moreover, we identified a possible predictive marker of tumor aggressiveness, i.e., the &ldquo;average monthly growth rate&rdquo; (AMGR), which could distinguish patients with very aggressive/life-threatening tumor behavior (AMGR &gt; 0.5) who need immediate active treatment, from those with stable DTs (AMGR &lt; 0.1) in whom follow-up assessments could be delayed. (3) Conclusion: surveillance protocols may be a useful approach for DTs. Further studies on larger series are needed to confirm the usefulness of periodic CT scan/MRI and the value of AMGR as a prognostic tool to guide treatment strategies

Two Cases, Too Little, Too Late: Surveillance for Gastric Cancer in Patients with FAP

Familial adenomatous polyposis is an autosomal dominant disease due to a mutation in the adenomatous polyposis coli (APC) gene. The disease, characterized by the development of adenomas throughout the colon and rectum, is also associated with extracolonic manifestations including gastric fundic polyps and cancer. In this report, we describe two patients with FAP with advanced gastric adenocarcinoma who received systemic chemotherapy. We reviewed the literature published over the past two decades on gastric cancer in FAP patients to assess the clinical course of this disease. Due to its recent increased incidence in Western countries, close endoscopic surveillance to detect early gastric neoplastic lesions is recommended

Tumor Regression Grade After Neoadjuvant Chemoradiation and Surgery for Low Rectal Cancer Evaluated by Multiple Correspondence Analysis: Ten Years as Minimum Follow-up

The tumor regression grade (TRG) role was investigated by multiple correspondence analysis (MCA) in 174 low rectal cancer patients undergone neoadjuvant chemoradiation and radical surgery, with a minimum follow-up of 10 years. The TRG 1 and 2 showed better survival than TRG 4 and 5 subgroups. MCA allocated TRG 3 together with other prognostic variables better than multivariate analysis. Background: The role of Mandard's tumor regression grade (TRG) classification is still controversial in defining the prognostic role of patients who have undergone neoadjuvant chemoradiation (CRT) and total mesorectal excision. The present study evaluated multiple correspondence analysis (MCA) as a tool to better cluster variables, including TRG, for a homogeneous prognosis. Patients and Methods: A total of 174 patients with a minimum follow-up period of 10 years were stratified into 2 groups: group A (TRG 1-3) and group B (TRG 4-5) using Mandard's classification. Overall survival and disease-free survival were analyzed using univariate and multivariate analysis. Subsequently, MCA was used to analyze TRG plus the other prognostic variables. Results: The overall response to CRT was 55.7%, including 13.2% with a pathologic complete response. TRG group A correlated strictly with pN status (P =.0001) and had better overall and disease-free survival than group B (85.1% and 75.6% vs. 71.1% and 67.3%; P =.06 and P =.04, respectively). The TRG 3 subset (about one third of our series) showed prognostically heterogeneous behavior. In addition to multivariate analysis, MCA separated TRG 1 and TRG 2 versus TRG 4 and TRG 5 well and also allocated TRG 3 patients close to the unfavorable prognostic variables. Conclusion: TRG classification should be used in all pathologic reports after neoadjuvant CRT and radical surgery to enrich the prognostic profile of patients with an intermediate risk of relapse and to identify patients eligible for more conservative treatment. Thus, MCA could provide added value