Kamran Idrees

CpG Island Methylator Phenotype Associates with Low-Degree Chromosomal Abnormalities in Colorectal Cancer

Purpose: Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers. Experimental Design: We determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays. Results: The identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively). Conclusion: CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.

Effect of blood transfusion on outcome after pancreaticoduodenectomy for exocrine tumour of the pancreas

Blood transfusion is thought to have an immunosuppressive effect. The aims of this study were to examine survival in patients with pancreatic cancer receiving blood transfusion in association with pancreaticoduodenectomy, and to define preoperative risk factors for subsequent transfusion.

Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.

Loss of imprinting (LOI) of insulin‐like growth factor 2 (IGF2) is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation have not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumors and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through 2 different forms of aberrant gene expression.

Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study

Importance Pancreatic mucinous cystic neoplasms (MCNs) harbor malignant potential, and current guidelines recommend resection. However, data are limited on preoperative risk factors for malignancy (adenocarcinoma or high-grade dysplasia) occurring in the setting of an MCN. Objectives To examine the preoperative risk factors for malignancy in resected MCNs and to assess outcomes of MCN-associated adenocarcinoma. Design, Setting, and Participants Patients who underwent pancreatic resection of MCNs at the 8 academic centers of the Central Pancreas Consortium from January 1, 2000, through December 31, 2014, were retrospectively identified. Preoperative factors of patients with and without malignant tumors were compared. Survival analyses were conducted for patients with adenocarcinoma. Main Outcomes and Measures Binary logistic regression models were used to determine the association of preoperative factors with the presence of MCN-associated malignancy. Results A total of 1667 patients underwent resection of pancreatic cystic lesions, and 349 (20.9%) had an MCN (310 women [88.8%]; mean (SD) age, 53.3 [14.7] years). Male sex (odds ratio [OR], 3.72; 95% CI, 1.21-11.44; P = .02), pancreatic head and neck location (OR, 3.93; 95% CI, 1.43-10.81; P = .01), increased radiographic size of the MCN (OR, 1.17; 95% CI, 1.08-1.27; P < .001), presence of a solid component or mural nodule (OR, 4.54; 95% CI, 1.95-10.57; P < .001), and duct dilation (OR, 4.17; 95% CI, 1.63-10.64; P = .003) were independently associated with malignancy. Malignancy was not associated with presence of radiographic septations or preoperative cyst fluid analysis (carcinoembryonic antigen, amylase, or mucin presence). The median serum CA19-9 level for patients with malignant neoplasms was 210 vs 15 U/mL for those without (P = .001). In the 44 patients with adenocarcinoma, 41 (93.2%) had lymph nodes harvested, with nodal metastases in only 14 (34.1%). Median follow-up for patients with adenocarcinoma was 27 months. Adenocarcinoma recurred in 11 patients (25%), with a 64% recurrence-free survival and 59% overall survival at 3 years. Conclusions and Relevance Adenocarcinoma or high-grade dysplasia is present in 14.9% of resected pancreatic MCNs for which risks include male sex, pancreatic head and neck location, larger MCN, solid component or mural nodule, and duct dilation. Mucinous cystic neoplasm–associated adenocarcinoma appears to have decreased nodal involvement at the time of resection and increased survival compared with typical pancreatic ductal adenocarcinoma. Indications for resection of MCNs should be revisited.

The Impact of Health Literacy on Surgical Outcomes Following Radical Cystectomy

Health literacy is the ability to obtain, comprehend, and act on medical information and is an independent predictor of health outcomes in patients with chronic health conditions. However, little has been reported regarding the potential association of health literacy and surgical outcomes. We hypothesized that patient complications after radical cystectomy would be associated with health literacy. In a sample of 368 patients, we found that higher health literacy scores (as determined by the Brief Health Literacy Screen) were associated with decreased odds of developing minor complications (odds ratio = 0.90, 95% confidence interval [0.83, 0.97]). Health literacy should be considered when caring for patients undergoing radical cystectomy and should serve as a potential indicator of the need for additional resources to improve postoperative outcomes.

Peri-operative risk factors for delayed gastric emptying after a pancreaticoduodenectomy

BACKGROUND Delayed gastric emptying (DGE) is a frequent cause of morbidity, prolonged hospital stay and readmission after a pancreaticoduodenectomy (PD). We sought to evaluate predictive peri-operative factors for DGE after a PD. METHODS Four hundred and sixteen consecutive patients who underwent a PD at our tertiary referral centre were identified. Univariate and multivariate (MV) logistic regression models were used to assess peri-operative factors associated with the development of clinically significant DGE and a post-operative pancreatic fistula (POPF). RESULTS DGE occurred in 24% of patients (n = 98) with Grades B and C occurring at 13.5% (n = 55) and 10.5% (n = 43), respectively. Using MV regression, a body mass index (BMI) ≥35 [odds ratio (OR) = 3.19], operating room (OR) length >5.5 h (OR = 2.72) and prophylactic octreotide use (OR = 2.04) were independently associated with an increased risk of DGE. DGE patients had a significantly longer median hospital stay (12 versus 7 days), higher 90-day readmission rates (32% versus 18%) and an increased incidence of a pancreatic fistula (59% versus 27%). When controlling for POPF, only OR length >5.5 h (OR 2.73) remained significantly associated with DGE. CONCLUSIONS DGE remains a significant cause of morbidity, increased hospital stay and readmission after PD. Our findings suggest patients with a BMI ≥35 or longer OR times have a higher risk of DGE either independently or through the development of POPF. These patients should be considered for possible enteral feeding tube placement along with limited octreotide use to decrease the potential risk and consequences of DGE.

Association of Optimal Time Interval to Re-resection for Incidental Gallbladder Cancer With Overall Survival: A Multi-Institution Analysis From the US Extrahepatic Biliary Malignancy Consortium

Importance The current recommendation is to perform re-resection for select patients with incidentally discovered gallbladder cancer. The optimal time interval for re-resection for both patient selection and long-term survival is not known. Objective To assess the association of time interval from the initial cholecystectomy to reoperation with overall survival. Design, Setting, and Participants This cohort study was conducted from January 1, 2000, to December 31, 2014 at 10 US academic institutions. A total of 207 patients with incidentally discovered gallbladder cancer who underwent reoperation and had available data on the date of their initial cholecystectomy were included. Exposures Time interval from the initial cholecystectomy to reoperation: group A: less than 4 weeks; group B: 4 to 8 weeks; and group C: greater than 8 weeks. Main Outcomes and Measures Primary outcome was overall survival. Results Of 449 patients with gallbladder cancer, 207 cases (46%) were discovered incidentally and underwent reoperation at 3 different time intervals from the date of the original cholecystectomy: group A: less than 4 weeks (25 patients, 12%); B: 4 to 8 weeks (91 patients, 44%); C: more than 8 weeks (91 patients, 44%). The mean (SD) ages of patients in groups A, B, and C were 65 (9), 64 (11), and 66 (12) years, respectively. All groups were similar for baseline demographics, extent of resection, presence of residual disease, T stage, resection margin status, lymph node involvement, and postoperative complications. Patients who underwent reoperation between 4 and 8 weeks had the longest median overall survival (group B: 40.4 months) compared with those who underwent early (group A: 17.4 months) or late (group C: 22.4 months) reoperation (log-rank P = .03). Group A and C time intervals (vs group B), presence of residual disease, an R2 resection, advanced T stage, and lymph node involvement were associated with decreased overall survival on univariable Cox regression. Only group A (hazard ratio, 2.63; 95% CI, 1.25-5.54) and group C (hazard ratio, 2.07; 95% CI, 1.17-3.66) time intervals (vs group B), R2 resection (hazard ratio, 2.69; 95% CI, 1.27-5.69), and advanced Tstage (hazard ratio, 1.85; 95% CI, 1.11-3.08) persisted on multivariable Cox regression analysis. Conclusions and Relevance The optimal time interval for re-resection for incidentally discovered gallbladder cancer appears to be between 4 and 8 weeks after the initial cholecystectomy.

Assessing the impact of common bile duct resection in the surgical management of gallbladder cancer.

Although radical re‐resection for gallbladder cancer (GBC) has been advocated, the optimal extent of re‐resection remains unknown. The current study aimed to assess the impact of common bile duct (CBD) resection on survival among patients undergoing surgery for GBC.

Genetic variants in germline TP53 and MDM2 SNP309 are not associated with early onset colorectal cancer.

Colorectal cancer (CRC) arising in patients under age 30 is a rare disease, and few cases have been reported within Li‐Fraumeni kindreds. To determine how often alterations in the p53 pathway genes contribute to disease susceptibility, we have evaluated patients with early onset CRC for the presence of germline variants in the p53 gene and MDM2 SNP309.

Advances in the Surgical Management of Resectable and Borderline Resectable Pancreas Cancer

Successful surgical resection offers the only chance for cure in patients with pancreatic cancer. However, pancreatic resection is feasible in less than 20% of the patients. In this review, the current state of surgical management of pancreatic cancer is discussed. The definition of resectability based on cross-sectional imaging and the technical aspects of surgery, including vascular resection and/or reconstruction, management of aberrant vascular anatomy and extent of lymphadenectomy, are appraised. Furthermore, common pancreatic resection-specific postoperative complications and their management are reviewed.