Karamjit S. Khanduja

Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer

PURPOSE Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups. PATIENTS AND METHODS MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed. RESULTS Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations. CONCLUSION One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.

Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Importance Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. Main Outcomes and Measures Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. Results In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. Conclusions and Relevance Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Reconstruction of rectovaginal fistula with sphincter disruption by combining rectal mucosal advancement flap and anal sphincteroplasty

PURPOSE: This study evaluated the effectiveness of combining advancement flap with sphincteroplasty in patients symptomatic with rectovaginal fistula and anal sphincter disruption. METHODS: Twenty patients with rectovaginal fistulas and anal sphincter disruptions after vaginal deliveries underwent combined rectal mucosal advancement flap and anal sphincteroplasty between July 1986 and July 1993. The mean age of the patients was 30 (range, 18–40) years and the mean duration of symptoms was 54.8 weeks (range, 7 weeks to 6 years). In addition to mucosal advancement flap repair, 13 patients underwent two-layer repair of anal sphincters (with reapproximation of the puborectalis in 8 of the patients); 6 patients underwent one-layer overlap repair of anal sphincters (with reapproximation of the puborectalis in 2 of the patients); and 1 patient underwent reapproximation of internal anal sphincter alone because squeeze pressures were adequate, as determined by anal manometry. RESULTS: Postoperatively, vaginal discharge of stool and flatus was eliminated entirely in all 20 patients. Perfect anal continence of stool and flatus was restored in 14 patients (70 percent). Incontinence was improved but not eliminated in six patients (4 incontinent to liquid stool and 2 to flatus), and two patients required perineal pads. Subjectively, 19 patients (95 percent) reported the result as excellent or good. There were no complications. CONCLUSION: The combination of mucosal advancement flap and anal sphincteroplasty is a safe and highly effective procedure for correcting rectovaginal fistula with sphincter disruption after obstetrical injuries.

A new silicone prosthesis in the modified Thiersch operation

Experience with a new silicone prosthesis in the modified Thiersch operation for rectal procidentia in 16 extremely poor-risk patients is presented. The technique of implantation, structural details of the prosthesis, and the clinical results are described. The use of a new silicone prosthesis in the modified Thiersch procedure is a viable alternative in this group of patients. Surgical technique is a primary determining factor in preventing complications.

Intubation of the ileocecal valve made easy

Intubation of the ileocecal valve and terminal ileoscopy is useful clinically, especially in conjunction with diagnostic colonoscopy in patients with suspected or established inflammatory bowel disease or lower gastrointestinal tract bleeding. We describe a simple method of successful intubation of the ileocecal valve to facilitate ileoscopy. This method also confirms successful completion of colonoscopy, because the ileocecal valve is the most relevant endoscopic landmark of the cecum.

Efficient technique for retrieving small polyps from the colon and rectum following snare polypectomy

The use of a 4-×4-inch gauze pad at the suction port during snare colonoscopic polypectomy facilitates the retrieval of polyps. This technique is a simple, rapid, and cost-effective method of retrieving small polyps for pathologic evaluation.

Revised technique for retrieving small polyps from the colon and rectum after snare polypectomy.

Use of a nylon tissue biopsy bag at the suction port during snare colonoscopic polypectomy refines our previously reported technique in which we used a 4-inch × 4-inch gauze pad. The nylon tissue biopsy bag results in superior pathologic specimens, maintains simplicity of the technique, and is cost effective.

Use of simethicone during colonoscopy.

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