Cleary, Sean P.

Background and Objectives Patients with colorectal cancer with synchronous liver metastases may undergo a staged or a simultaneous resection. This study aimed to determine whether the time to adjuvant chemotherapy was delayed in patients undergoing a simultaneous resection. Methods A retrospective cohort study was conducted between 2005 and 2016. The primary outcome was time to adjuvant chemotherapy. A multivariate linear regression was conducted to ascertain the adjusted effect of a simultaneous versus a staged approach on time to adjuvant chemotherapy. Results A total of 155 patients were included. A total of 127 patients underwent a staged resection, whereas 28 patients underwent a simultaneous resection. Age, sex, and American Society of Anesthesiologists class as well tumor, node, metastasis stage, tumor location, and number and size of metastases were not significantly different between the groups. The median time to adjuvant chemotherapy was 70 and 63 days for the staged and simultaneous groups, respectively ( P = .27). Multivariate analysis did not demonstrate an increased propensity for prolonged time to chemotherapy after simultaneous resection (rate ratio: 0.97, 95% CI: 0.71‐1.32, P = .84). There were no significant differences in the length of stay, complications, overall survival, and disease‐free survival between the groups ( P > .05). Conclusions This study demonstrated that simultaneous resection does not result in significant delay of adjuvant chemotherapy compared with a staged approach.

BackgroundSimultaneous resection for colorectal cancer with synchronous liver metastases is an established alternative to a staged approach. This study aimed to compare these approaches with regards to economic parameters and short‐term outcomes.MethodsA retrospective cohort analysis was conducted between 2005 and 2016. The primary outcome was cost per episode of care. Secondary measures included 30‐day clinical outcomes. A multivariate analysis was performed to determine the adjusted effect of a simultaneous surgical approach on total cost of care.ResultsFifty‐three cases were identified; 27 in the staged approach, and 26 in the simultaneous group. Age (P = 0.49), sex (P = 0.20), BMI (P = 0.74), and ASA class (P = 0.44) were comparable between groups. Total cost ($20297 vs $27522), OR ($6830 vs $10376), PACU ($675 vs $1182), ward ($7586 vs $11603) and pharmacy costs ($728 vs $1075) were significantly less for the simultaneous group (P < 0.05). The adjusted rate ratio for total cost of care in the staged group compared to simultaneous group was 1.51 (95%CI: 1.16‐1.97, P < 0.05). The groups had comparable Clavien‐Dindo scores (P = 0.89), 30‐day readmissions (P = 0.44), morbidity (P = 0.50) and mortality (P = 1.00).ConclusionsOur study demonstrates that a simultaneous approach is associated with a significantly lower total cost while maintaining comparable short‐term outcomes.

Objective: Conventional management of pain following open liver resection involves intravenous, patient-controlled analgesia (IV PCA) or epidural analgesia. The objective of this trial was to assess the efficacy of a regional technique called Medial Open Transversus Abdominis Plane (MOTAP) catheter analgesia compared with IV PCA. Methods: This was a blinded, randomized, controlled parallel-arm trial conducted at 2 high-volume centers. Patients undergoing liver resection through a subcostal incision were enrolled. Using a standardized technique, 2 catheters were placed after resection: one in the plane between internal oblique and transversus abdominis and the other in the posterior rectus sheath. Patients were randomized to receive ropivacaine 0.2% (ROP) or saline (NS) through both catheters for 72 hours. All patients received IV PCA with hydromorphone as part of a multimodality analgesia program. Primary outcome was opioid use over the first 48 hours. Results: One hundred fifty-three patients were included in the analysis (71 ROP, 82 NS). Patients receiving ROP used significantly less opioid than patients with NS at 48 hours (median 39.6 mg morphine-equivalent vs 49.2 mg, P = 0.033) and at 72 hours (median 50.0 vs 66.4 mg, P = 0.046). Pain scores at rest and with coughing were significantly lower at all time points in patients who received ROP (P = 0.002). Median length of hospital stay was 5 days in patients receiving ROP and 6 days in patients who received NS (P = 0.035). There was no difference between groups in complications [ROP 20 (28.2%) vs NS 26 (31.7%), P = 0.63]. Conclusion: MOTAP catheter analgesia reduces opioid requirements, pain, and length of hospital stay compared with IV PCA following open liver resection with subcostal incisions.

Objective The objective of this study was to assess the accuracy of gadoxetic acid hepatic enhancement indices in predicting posthepatectomy liver failure (PHLF) and other major complications (OMCs). Methods Sixty-five patients underwent prehepatectomy gadoxetic acid–enhanced magnetic resonance imaging. Enhancement indices were calculated by obtaining regions of interest on magnetic resonance images and segmented volumes of the liver and spleen. Multivariate regression analysis was performed to predict PHLF and OMC as a function of the indices, and areas under the receiver operator characteristic (AUROC) curves were calculated. Results Areas under the receiver operator characteristic values varied from 0.412 to 0.681 and 0.462 to 0.738 in predicting PHLF and OMC, respectively. The most accurate indices in predicting PHLF were the region of interest–based, fat-normalized relative liver enhancement and liver enhancement index (AUROC, 0.681). The most accurate index in predicting OMC was the volumetric least-squares regression slope of a pharmacokinetic model (K hep_V, AUROC, 0.738). Conclusions Indices of gadoxetic acid liver enhancement demonstrate variable performance in predicting PHLF and OMC.

Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian‐predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan‐Meier curves, and log‐rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM‐741 or BRM‐1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM‐741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89‐11.54 and BRM‐1321 per variant allele aHR 4.09, 95%CI 2.22‐7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45‐fold increase in risk of death when compared to those who were double wild‐type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Abstract Background: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. Methods: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. Results: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2; HR, 1.10; 95% CI, 1.06–1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98). Conclusions: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. Cancer Epidemiol Biomarkers Prev; 24(8); 1229–38. ©2015 AACR.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

Abstract Background: Tumor features such as stage, grade, and microsatellite instability (MSI) status have relevance for colorectal cancer survival whereas the prognostic role of body mass index (BMI) is unclear. We assessed the association of BMI and adult weight gain on colorectal cancer survival, overall and by strata of sex and MSI. Methods: Participants were identified from a multi-center cohort that includes 6,763 colorectal cancer patients with invasive colorectal cancer who were enrolled into the Colon Cancer Family Registry from 1997 to 2008. Vital status was updated through direct contact with patients/next-of-kin and/or linkage with mortality records. BMI 2 years before diagnosis, BMI at age 20 years, and adult weight gain were derived from self-reports of height and weight (i.e., weight 2 years before diagnosis and weight at age 20 years). Tumor MSI status was available for 4,987 patients. Multivariable, two-sided hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models, controlling for age at diagnosis, TNM summary stage (i.e., I, II, III, IV or missing), smoking (current, former, never), and study center. Results: After a maximum of 13.7 years of follow-up from enrollment to end-of-study (median: 5.3 years), 2,335 patients had died. Higher BMI 2 years before cancer diagnosis (per 5-kg/m2) was associated with higher risk of all-cause mortality overall (HR, 1.10; 95% CI, 1.05 to 1.14), with similar associations when stratified by sex (men: HR, 1.07; 95% CI, 1.02 to 1.14; women: HR, 1.11: 95% CI, 1.05 to 1.17; p-interaction: 0.18) and MSI status (MS-stable/MSI-low: HR, 1.08; 95% CI, 1.03 to 1.14; MSI-high, HR: 1.19; 95% CI, 1.02 to 1.40; p-interaction: 0.88). In joint models, with MS-stable/MSI-low and normal BMI as the referent group, risk of death was lower for those with MSI-high and normal BMI (HR: 0.77; 95% CI: 0.59 to 1.00), higher for MS-stable/MSI-low and high (≥30) BMI (HR: 1.23; 95% CI: 1.07 to 1.42), and essentially the same for MSI-high and high BMI (HR: 0.97; 95% CI: 0.72 to 1.30). Similar patterns of association were observed for BMI at age 20 years and when the outcome was colorectal cancer-specific mortality, although not all associations remained statistically significant for some of the smaller sub-group analyses. After controlling for BMI at age 20 years, adult weight gain was only modestly associated with all-cause mortality (per 5 kg HR: 1.01; 95% CI: 1.00 to 1.02; p-trend: 0.07). Conclusion: High pre-diagnosis BMI was associated with increased mortality after colorectal cancer diagnosis; this association was consistent for men and women and by tumor MSI status. These results also suggest that obesity attenuates the survival advantage observed with MSI-high tumors. Citation Format: Peter T. Campbell, Christina Newton, Polly A. Newcomb, Dennis Ahnen, John Baron, Sean Cleary, Michelle Cotterchio, A. Brad Farris, Jane Figueiredo, Roger C. Green, Loic Le Marchand, John McLaughlin, Amanda Phipps, John D. Potter, Andrew Renehan, Aung Ko Win, Noralane Lindor, Paul Limburg. Prospective study of body mass index and adult weight change with colorectal cancer survival, overall and by tumor microsatellite instability status. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-276. doi:10.1158/1538-7445.AM2014-LB-276