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 ∼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.
Background & Aims Individuals with hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) have a high risk for developing colorectal cancer (CRC). We evaluated the efficacy of annual ...surveillance colonoscopies to detect adenomas and CRCs. Methods In a prospective, multicenter cohort study, 1126 individuals underwent 3474 colonoscopies. We considered individuals from 3 groups of HNPCC families: those with a pathogenic germline mutation in a mismatch repair gene (MUT group), those without a mutation but with microsatellite instability (MSI group), and those who fufilled the Amsterdam criteria without microsatellite instability (MSS group). Results Compliance to annual intervals was good, with 81% of colonoscopies completed within 15 months. Ninety-nine CRC events were observed in 90 patients. Seventeen CRCs (17%) were detected through symptoms (8 before baseline colonoscopy, 8 at intervals >15 months to the preceding colonoscopy, and 1 interval cancer). Only 2 of 43 CRCs detected by follow-up colonoscopy were regionally advanced. Tumor stages were significantly lower among CRCs detected by follow-up colonoscopies compared with CRCs detected by symptoms ( P = .01). Cumulative CRC risk at the age of 60 years was similar in the MUT and MSI groups (23.0% combined; 95% confidence interval CI, 14.8%–31.2%) but considerably lower in the MSS group (1.8%; 95% CI, 0.0%–5.1%). Adenomas at baseline colonoscopy predicted an earlier occurrence of subsequent adenoma (hazard ratio, 2.6; 95% CI, 1.7–4.0) and CRC (hazard ratio, 3.9; 95% CI, 1.7–8.5), providing information about interindividual heterogeneity of adenomas and kinetics of CRC formation. Conclusions Annual colonoscopic surveillance is recommended for individuals with HNPCC. Less intense surveillance might be appropriate for MSS families.
To determine whether circular plastic wound edge protectors (CWEPs) significantly reduce the rate of surgical site infections (SSIs) in comparison to standard surgical towels in patients undergoing ...laparotomy.
SSIs cause substantial morbidity, prolonged hospitalization, and costs and remain one of the most frequent surgical complications. CWEPs have been proposed as a measure to reduce the incidence of SSIs.
In this randomized controlled, multicenter, 2-arm, parallel-group design, patient- and observer-blinded trial patients undergoing open elective abdominal surgery were assigned to either intraoperative wound coverage with a CWEP or standard coverage with surgical towels. Primary endpoint was superiority of intervention over control in terms of the incidence of SSIs within a 30-day postoperative period.
Between September 2010 and November 2012, 608 patients undergoing laparotomy were randomized at 16 centers across Germany. Three patients in the device group and 11 patients in the control group did not undergo laparotomy. Patients' and procedural characteristics were well balanced between the 2 groups. Forty-eight patients discontinued the study prematurely, mainly because of relaparotomy (control, n=9; intervention, n=9) and death (control, n=4; intervention, n=7). A total of 79 patients experienced SSIs within 30 days of surgery, 27 of 274 (9.9%) in the device group and 52 of 272 (19.1%) in the control group (odds ratio=0.462, 95% confidence interval: 0.281-0.762; P=0.002). Subgroup analyses indicate that the effect could be more pronounced in colorectal surgery, and in clean-contaminated/contaminated surgeries.
Our trial shows that CWEPs are effective at reducing the incidence of SSIs in elective and clean or clean-contaminated open abdominal surgery.
We analyzed a group of gastric carcinomas treated with a cisplatin-based
neoadjuvant chemotherapy regimen for microsatellite instability (MSI)
and loss of heterozygosity (LOH) to determine whether ...there is any
relation between microsatellite alterations and therapy response.
Pretherapeutic endoscopic biopsies of 37 patients were studied at 11
microsatellite loci. Thirteen (35%) had a complete or partial clinical
response (responders), and 24 (65%) had only a minor or no response
(nonresponders). High-grade MSI was found in two tumors, both
nonresponders, whereas low-grade MSI was found in five biopsies,
including three nonresponders and two responders. Regarding LOH, the
most obvious differences between the groups were observed on chromosome
17p13, the location of the p53 gene, with 7 of 12 (58%)
and 3 of 20 (15%) of the informative tumors exhibiting LOH in
responders and nonresponders, respectively ( P =
0.018). A statistically significant difference was also observed in the
fractional allelic loss (FAL) ratio of the groups. Among the 13
responding patients, 7 (54%) tumors exhibited high FAL (>0.5–0.75),
2 (15%) showed medium FAL (>0.25–0.5), and 4 (31%) demonstrated low
FAL values (0–0.25), whereas among the 22 nonresponding patients, 2
(9%) tumors showed high FAL, 5 (23%) showed medium FAL, and 15 (68%)
showed low FAL ( P = 0.020).
le;1.5q>These data suggest that LOH at chromosome 17p13 is associated
with a good clinical response to cisplatin-based chemotherapy,
suggesting that altered p53 function might render cells more sensitive
to therapy. Furthermore, the association of FAL with therapy response
indicates that gastric carcinomas with a high level of chromosomal
alteration may be more sensitive to this type of chemotherapy.
Background & aims:
The risk for small bowel cancer (SBC) is significantly increased in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC-associated SBCs are poorly characterized.
Methods:
...Thirty-two SBCs were characterized according to clinical, pathologic, and germline mutation data. Histomorphologic characteristics, microsatellite instability (MSI) testing, mismatch repair (MMR) protein expression, and frameshift mutations of 7 coding mononucleotide repeats were investigated in 17 SBCs.
Results:
Median age at diagnosis was 39 years. Fifty percent of SBCs were located in the duodenum. The Amsterdam criteria were fulfilled in 50% of patients; 45% of patients had no personal history of previous malignancies. Two patients had a positive family history for SBC. Pathogenic germline mutations were identified in 81%; high MSI was detected in 95% and loss of MMR protein expression in 89% of cases.
TGFBR2,
BAX,
MSH3,
MSH6,
ACVR2,
AIM2, and
SEC63 frameshift mutations were detected in 69%, 59%, 59%, 35%, 82%, 56%, and 56%, respectively. An expansive growth pattern of the tumor border and an intense intratumoral lymphocytic infiltrate were present in 75%, respectively.
Conclusions:
HNPCC-associated SBC often manifests at a young age and may be the first disease manifestation. Endoscopy may detect 50% of tumors. Considering recent data on gastric cancer, we propose endoscopic screening of mutation carriers starting at 30 years of age because clinical criteria cannot define a high-risk group. In addition, our study shows that histopathologic criteria, MSI, and MMR immunohistochemistry are often similar to these features in HNPCC.
E-Cadherin alterations have been reported frequently in sporadic diffuse type gastric and lobular breast carcinomas. Germline mutations of this gene have been identified recently in several gastric ...cancer families. We analyzed seven patients with a family history of the disease who had diffuse type gastric cancer diagnosed before the age of 45 for germline mutations in
CDH1, the gene encoding the E-cadherin protein. We identified a frameshift mutation in exon 3 in one patient with a strong family history of gastric cancer. The same germline mutation was found in the patient's mother, who had metachronous development of lobular breast and diffuse type gastric carcinomas. Immunohistochemistry for E-cadherin protein expression revealed an abnormal staining pattern in both of these tumors, suggesting complete inactivation of the cell adhesion molecule. Thus, our finding suggests that besides diffuse type gastric cancer, lobular breast carcinomas may be associated with germline
CDH1 mutations.
The prognostic impact of the proteolytic factors urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) was evaluated in 76 completely resected gastric cancer ...patients enrolled in a prospective study. All patients underwent macroscopically and microscopically residual tumor-free resection (category R0, Union International Contre Cancer, 1987). uPA and PAI-1 levels were quantified in detergent-extracted (Triton X-100) specimens of primary gastric tumors by enzyme-linked immunosorbent assays. Median values of 1.57 ng uPA/mg protein were determined in tumor tissue extracts compared to 0.14 ng uPA/mg protein in normal mucosa. For PAI-1, 0.93 ng PAI-1/mg protein versus 0.09 ng PAI-1/mg protein was calculated. uPA levels in tumor tissue extracts were significantly correlated with vascular invasion, Laurén classification, and WHO classification, whereas PAI-1 levels showed a significant correlation with advanced lymph node involvement, depth of invasion, tumor stage, site of tumor, and the Laurén, Borrmann, and WHO classifications. Elevated uPA and PAI-1 levels were found to be associated with poor prognosis. The optimal cutoff values indicating a group of patients with shorter survival were 1.5 ng uPA/mg protein and 1.25 ng PAI-1/mg protein, respectively (Classification and Regression Tree analysis). Patients with either high uPA or PAI-1 values were significantly associated with decreased survival (median time of survival was 23 months (high) versus 44 months (low). By univariate Cox regression analysis, it was shown that TNM categories, WHO classification, size of tumor, uPA and PAI-1 levels were all significantly associated with survival. However, in multivariate Cox regression analysis of these grouped variables, nodal status, PAI-1 levels, and WHO classification were the only independent prognostic factors. The relative risks of failure were 5-, 2.9-, and 2.4-fold, respectively. We conclude that PAI-1 and uPA positivity may serve as new prognostic factors in gastric cancer, predicting shorter survival even in clinically important subgroups of patients.
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