A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.

Neoadjuvant long-course chemoradiation remains strongly favored over short-course radiotherapy by radiation oncologists in the United States.

BACKGROUND: Short-course radiotherapy (SC-RT) and long-course chemoradiotherapy (LC-CRT) are accepted neoadjuvant treatments of rectal cancer. In the current study, the authors surveyed US radiation oncologists to assess practice patterns and attitudes regarding SC-RT and LC-CRT for patients with rectal cancer. METHODS: The authors distributed a survey to 1701 radiation oncologists regarding treatment of neoadjuvant rectal cancer. Respondents were asked questions regarding the number of patients with rectal cancer treated, preference for SC-RT versus LC-CRT, and factors influencing regimen choice. RESULTS: Of 1659 contactable physicians, 182 responses (11%) were received. Approximately 83% treated at least 5 patients with rectal cancer annually. The majority of responding radiation oncologists (96%) preferred neoadjuvant LC-CRT for the treatment of patients with locally advanced rectal cancer and 44% never used SC-RT. Among radiation oncologists using SC-RT, respondents indicated they would not recommend this regimen for patients with low (74%) or bulky tumors (70%) and/or concern for a positive circumferential surgical resection margin (69%). The most frequent reasons for not offering SC-RT were insufficient downstaging for sphincter preservation (53%) and a desire for longer follow-up (45%). Many radiation oncologists indicated they would prescribe SC-RT for patients not receiving chemotherapy (62%) or patients with a geographic barrier to receiving LC-CRT (82%). Patient comorbidities appeared to influence regimen preferences for 79% of respondents. Approximately 20% of respondents indicated that altered oncology care reimbursement using capitated payment by diagnosis would impact their consideration of SC-RT. CONCLUSIONS: US radiation oncologists rarely use neoadjuvant SC-RT despite 3 randomized controlled trials demonstrating no significant differences in outcome compared with LC-CRT. Further research is necessary to determine whether longer follow-up coupled with the benefits of lower cost, increased patient convenience, and lower acute toxicity will increase the adoption of SC-RT by radiation oncologists in the United States. Cancer 2017;123:1434-1441. © 2016 American Cancer Society.

HIV Infection Is Associated With Poor Outcomes for Patients With Anal Cancer in the Highly Active Antiretroviral Therapy Era.

BACKGROUND: HIV status may affect outcomes after definitive chemoradiotherapy for anal cancer. OBJECTIVE: Here, we report a large series in the highly active antiretroviral therapy era comparing outcomes between HIV-positive and HIV-negative patients with anal cancer. DESIGN: This was a retrospective chart review. SETTINGS: The study was conducted at an outpatient oncology clinic at large academic center. PATIENTS: A total of 107 patients were reviewed, 39 HIV positive and 68 HIV negative. All of the patients underwent definitive chemoradiation for anal cancer. MAIN OUTCOME MEASURES: Data on patient characteristics, treatment, toxicity, and outcomes were collected. Overall survival, colostomy-free survival, local recurrence-free survival, and distant metastasis-free survival were analyzed. RESULTS: Median follow-up was 15 months. HIV-positive patients were younger (median, 52 vs 64 years; p < 0.001) and predominantly men (82% men vs 49% men; p = 0.001). There were no significant differences in T, N, or stage groups. HIV-positive patients had a significantly longer duration from biopsy to start of chemoradiation (mean number of days, 82 vs 54; p = 0.042). There were no differences in rates of acute toxicities including diarrhea, fatigue, or dermatitis. HIV-positive patients had significantly higher rates of hospitalization (33% vs 15%; p = 0.024). The 3-year overall survival rate was 42% in HIV-positive and 76% in HIV-negative patients (p = 0.037; HR, 2.335 (95% CI, 1.032-5.283)). Three-year colostomy-free survival was 67% in HIV-positive and 88% in HIV-negative patients (p = 0.036; HR, 3.231 (95% CI, 1.014-10.299)). Differences in overall survival rates were not significant on multivariate analysis. LIMITATIONS: This study was limited by its retrospective design and small patient numbers. CONCLUSIONS: In this cohort, HIV-positive patients had significantly worse overall and colostomy-free survival rates than HIV-negative patients. However, differences in survival were not significant on multivariate analysis. Additional studies are necessary to establish the etiology of this difference.

Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report.

BACKGROUND: MLH1 is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future. CASE PRESENTATION: We report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in MLH1. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in MSH2 and rarely with mutations in MLH1. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon. CONCLUSION: Our case demonstrates that HNPCC patients with MLH1 mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.

Disparity of Colon Cancer Outcomes in Rural America: Making the Case to Travel the Extra Mile.

OBJECTIVES: Rural patients experience disparities in cancer care compared to urban patients. We hypothesized that rural patients with colon cancer who traveled to high-volume centers for treatment have similar survival compared to urban patients who also traveled to high-volume centers to seek treatment for colon cancer. METHODS: The National Cancer Database was interrogated for patients treated for stage I-III colon cancer (2004-2015). Travel distance to treatment centers and annual hospital volume were divided into quartiles. Two groups of patients were identified and compared: (1) rural patients who traveled to high-volume hospitals and (2) urban patients who also traveled to high-volume centers. The primary outcome was overall survival (OS). RESULTS: Of 647,949 patients, 634, 447 were urban and 13,502 were rural. Rural patients were more likely to be Caucasian, with lower income, more comorbidities, and be treated at non-academic centers. In multivariable analysis, rural patients had worse OS compared to urban patients (hazard ratio [HR] 1.08; 95% confidence interval [CI] 1.04-1.12; p = < 0.001). There were 46,781 (7%) urban patients and 1276 (9%) rural patients who traveled a long distance (median 40 and 108 miles, respectively) to high-volume centers. There was no difference in adjusted OS between urban and rural patients who traveled to high-volume centers for treatment (HR 1.06; 95%CI 0.94-1.20; p = 0.36). CONCLUSIONS: This nationwide analysis suggests that rural patients with colon cancer experience worse survival than urban patients, but that this disparity might be mitigated by rural patients traveling to high-volume centers for treatment.

Clinical examination following preoperative chemoradiation for rectal cancer is not a reliable surrogate end point.

PURPOSE: Clinical assessment of rectal cancer response to preoperative combined-modality therapy (CMT) using digital rectal examination (DRE) has been proposed as a means of assessing efficacy of therapy. However, because the accuracy of this approach has not been established, we conducted a prospective analysis to determine the operating surgeon's ability to assess response using DRE. PATIENTS AND METHODS: Ninety-four prospectively accrued patients with locally advanced rectal cancer (T3/4 or N1) were evaluated with DRE and sigmoidoscopy in order to determine the following tumor characteristics: size, location, mobility, morphology, and circumference. Following preoperative CMT (50.40 Gy with fluorouracil-based chemotherapy) and under general anesthesia, the same surgeon estimated tumor response based on changes in these tumor characteristics, assessed via DRE. Percent pathologic tumor response was determined prospectively by a single pathologist using whole mount sections of the resected cancer. RESULTS: Clinical assessment using DRE underestimated pathologic response in 73 cases (78%). In addition, DRE was able to identify only 3 of 14 cases (21%) with a pathologic complete response. There were no clinical overestimates of response. None of the clinicopathologic tumor characteristics examined had a significant impact on DRE estimation of response. CONCLUSION: Clinical examination underestimates the extent of rectal cancer response to preoperative CMT. Given the inaccuracy of DRE following preoperative CMT, it should not be used as a sole means of assessing efficacy of therapy nor for selecting patients following CMT for local surgical therapies.

Predictors of Complete Response and Disease Recurrence Following Chemoradiation for Rectal Cancer.

OBJECTIVE: Approximately 10-40% of rectal patients have a complete response (CR) to neoadjuvant chemoradiation (CRT), and these patients have improved survival. Thus, non-operative management ("watch-and-wait" approach) may be an option for select patients. We aimed to identify clinical predictors of CR following CRT. METHODS: Patients treated with definitive CRT for T3-T4, locally unresectable T1-T2, low-lying T2, and/or node-positive rectal cancer from August 2004 to February 2015 were retrospectively reviewed. Most patients were treated with 50.4 Gy radiation and concurrent 5-fluoruracil or capecitabine. Patients were considered to have a CR if surgical pathology revealed ypT0N0M0 (operative management), or if they had no evidence of residual disease on clinical and radiographic assessment (non-operative management). Statistical analysis was carried out to determine predictors of CR and long-term outcomes. RESULTS: Complete records were available on 138 patients. The median follow-up was 24.5 months. Thirty-six patients (26.3%) achieved a CR; 30/123 operatively managed patients (24.5%) and 6/15 (40%) non-operatively managed patients. None of the 10 patients with mucinous adenocarcinoma achieved a CR. Carcinoembryonic antigen (CEA) ≥5 µg/L at diagnosis (OR 0.190, 95% CI 0.037-0.971, p = 0.046), tumor size ≥3 cm (OR 0.123, 95% CI 0.020-0.745, p = 0.023), distance of tumor from the anal verge ≥3 cm (OR 0.091, 95% CI 0.013-0.613, p = 0.014), clinically node-positive disease at diagnosis (OR 0.201, 95% CI 0.045-0.895, p = 0.035), and interval from CRT to surgery ≥8 weeks (OR 5.267, 95% CI 1.068-25.961, p = 0.041) were independent predictors of CR. The CR group had longer 3-year distant metastasis-free survival (DMFS) (93.7 vs. 63.7%, p = 0.016) and 3-year disease-free survival (DFS) (91.1 vs. 67.8%, p = 0.038). Three-year locoregional control (LRC) (96.6 vs. 81.3%, p = 0.103) and overall survival (97.2 vs. 87.5%, p = 0.125) were higher in the CR group but this did not achieve statistical significance. CR was not an independent predictor of LRC, DMFS, or DFS. CONCLUSION: CEA at diagnosis, tumor size, tumor distance from the anal verge, node positivity at diagnosis, and interval from CRT to surgery were predictors of CR. These clinical variables may offer insight into patient selection and timing of treatment response evaluation in the watch-and-wait approach.

Comparison of anal cancer outcomes in public and private hospital patients treated at a single radiation oncology center.

OBJECTIVE: To compare clinical and treatment characteristics and outcomes in locally advanced anal cancer, a potentially curable disease, in patients referred from a public or private hospital. METHODS: We retrospectively reviewed 112 anal cancer patients from a public and a private hospital who received definitive chemoradiotherapy at the same cancer center between 2004 and 2013. Tumor stage, radiotherapy delay, radiotherapy duration, and unplanned treatment breaks ≥10 days were compared using t-test and χ(2) test. Overall survival (OS), disease free survival (DFS), and colostomy free survival (CFS) were examined using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard models for OS and DFS were developed. RESULTS: The follow-up was 14.9 months (range, 0.7-94.8 months). Public hospital patients presented with significantly higher clinical T stage (P<0.05) and clinical stage group (P<0.05), had significantly longer radiotherapy delays (P<0.05) and radiotherapy duration (P<0.05), and had more frequent radiation therapy (RT) breaks ≥10 days (P<0.05). Three-year OS showed a marked trend in favor of private hospital patients for 3-year OS (72.8% vs. 48.9%; P=0.171), 3-year DFS (66.3% vs. 42.7%, P=0.352), and 3-year CFS (86.4% vs. 68.9%, P=0.299). Referral hospital was not predictive of OS or DFS on multivariate analysis. CONCLUSIONS: Public hospital patients presented at later stage and experienced more delays in initiating and completing radiotherapy, which may contribute to the trend in poorer DFS and OS. These findings emphasize the need for identifying clinical and treatment factors that contribute to decreased survival in low socioeconomic status (SES) populations.

Patterns of morphologic alteration in residual rectal carcinoma following preoperative chemoradiation and their association with long-term outcome.

Preoperative radiation (RT) and chemotherapy improve outcome in patients with locally advanced rectal adenocarcinoma and, therefore, have been used increasingly in patient management. The histopathologic alterations in postirradiated rectal adenocarcinoma and their prognostic significance have not been fully characterized. In this study, detailed analyses of morphologic alterations of stromal and tumor cells were performed in a series of 66 posttreatment rectal carcinomas, and the pathologic findings were correlated with long-term outcome. All tumors were locally advanced, with a bulky and/or tethered tumor or endorectal ultrasound or magnetic resonance imaging evidence of T3-4 and / or N1 disease. All patients were treated at one institution with preoperative RT to the pelvis (at least 4500 cGy) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy 4 to 7 weeks prior to surgical resection. Pathologic assessment showed some treatment response in all patients. Nine patients (13.4%) had complete response, and 8 (11.9%) had near-complete response (> 95% of the tumor replaced by fibroinflammatory tissue). Salient morphologic features included marked fibrosis with or without prominent inflammatory cells replacing neoplastic glands; lack of active tumor necrosis; increased mucin production and mucin pools; marked cytoplasmic eosinophilia, often in combination with marked nuclear atypia but without active mitoses in tumor cells showing treatment effect; endocrine tumor phenotype; and retention of mucosal adenoma in the presence of tumor regression within the bowel wall. With a median follow-up of 69 months, the estimated 5-year recurrence-free survival (RFS) for the entire group was 79%. By univariate analysis, the residual tumor stage (P < 0.05) and reduction of pretreatment T stage (P = 0.002) significantly correlated with RFS, as did pN stage (P = 0.002) and lymphovascular invasion (P = 0.008). The extent of treatment response did not correlate with RFS (P = 0.4). However, patients with a treatment response > or = 95% seemed to fare better than those with a treatment response < 95% (marginally significant difference in RFS, P = 0.057). Univariate and multivariate analyses identified the following morphologic patterns that were significantly associated with a reduced RFS independent of other risk factors: a fibrotic-type stromal response with minimal inflammatory infiltrates (P = 0.001) and absence of surface ulceration (P = 0.026). Our study represents the first detailed morphologic assessment of rectal carcinomas that have been subjected to long course preoperative RT and chemotherapy. Our results demonstrate distinct morphologic features in treated rectal carcinomas that are prognostically relevant.

A636P testing in Ashkenazi Jews.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited colorectal cancer syndrome attributable to mutations in one of several DNA mismatch repair genes, most commonly MLH1 and MSH2 . In certain populations, founder mutations account for a substantial portion of HNPCC. In this report we summarize the literature and our personal experience testing for a specific founder mutation in the Ashkenazi Jewish population, MSH2*1906G > C , also known as A636P. Although rare in the general population, the A636P mutation is detected in up to 7% of Ashkenazi Jewish patients with early age-of-onset colorectal cancer, and may account for up to one third of HNPCC in the Ashkenazi Jewish population. In addition, we summarize our initial experience with a prospective A636P testing protocol aimed at Ashkenazi Jewish patients at high or intermediate risk for harboring the A636P mutation.

A case-controlled study of 18-fluorodeoxyglucose positron emission tomography in the detection of pelvic recurrence in previously irradiated rectal cancer patients.

BACKGROUND: Although effective at detecting locally recurrent colorectal cancer, the accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting rectal cancer recurrence in an irradiated pelvis has not been systematically studied. STUDY DESIGN: Records of surgically resected rectal cancer patients who underwent FDG-PET imaging at least 6 months after external beam radiation therapy (EBRT) were reviewed. Cases (n = 19) were defined as scans from patients in whom a pelvic recurrence was confirmed (histologically, n = 14, radiologic followup, n = 5). Controls (n = 41), defined as scans from patients without clinical or radiologic evidence of pelvic recurrence, were compared with cases for the time interval between completion of EBRT and FDG-PET imaging (RT/PET interval, mean 25.1 months versus 27.5 months, respectively), as well as EBRT dose (mean 5,084 cGy versus 5,062 cGy, respectively). All 60 FDG-PET scans were iteratively reconstructed and reinterpreted by a single nuclear medicine physician blinded to original FDG-PET interpretation and disease status. Certainty of disease was scored on a five-point scale (1 to 5), with scores greater than or equal to 4 considered positive. RESULTS: FDG-PET correctly identified 16 of 19 recurrences, for a sensitivity of 84% and specificity of 88%. Overall accuracy was 87%. Positive predictive value was 76% and negative predictive value was 92%. Positive predictive value and accuracy improved in scans performed more than 12 months after EBRT. CONCLUSIONS: Our preliminary data suggest that FDG-PET is an accurate modality for detecting pelvic recurrence of rectal cancer after full-dose EBRT. Its reliability appears to improve with time, perhaps because of resolution of early postradiation inflammation.

Sequential preoperative fluorodeoxyglucose-positron emission tomography assessment of response to preoperative chemoradiation: a means for determining longterm outcomes of rectal cancer.

BACKGROUND: We have previously demonstrated that fluorodeoxyglucose-positron emission tomography (FDG-PET) can assess extent of pathologic response of primary rectal cancer to preoperative chemoradiation. Our goal was to determine the prognostic significance of FDG-PET assessment of rectal cancer response to preoperative chemoradiation. STUDY DESIGN: Fifteen patients with locally advanced primary rectal cancer (clinically bulky or tethered, or ultrasound evidence of T3-4 disease, N1 disease, or both) deemed eligible for preoperative radiation and 5-FU-based chemotherapy (5,040 cGy to the pelvis and 2 cycles of bolus 5-FU/leucovorin) were prospectively enrolled from May 1997 to September 1998. FDG-PET was performed before and 4 to 5 weeks after completion of preoperative chemoradiation. FDG-PET parameters included maximum standard uptake value (SUV(max)), total lesion glycolysis (TLG), and visual response score. Patients were prospectively followed after operation, and disease status was determined. RESULTS: All patients demonstrated some degree of response to preoperative therapy based on pathologic examination. At a median followup of 42 months (range 23 to 54 months), 11 patients had no evidence of disease and 4 had died of disease. The mean percentage decrease in SUV(max) (DeltaSUV(max)) was 69% for patients free from recurrence and 37% for patients with recurrence (p = 0.004). DeltaSUV(max) >or= 62.5 and deltaTLG >or= 69.5 were the best predictors of no-evidence-of-disease status and freedom from recurrence. Patients with DeltaSUV(max) >or= 62.5 and deltaTLG >or= 69.5 had significantly improved disease-specific and recurrence-free survival (p = 0.08, 0.02 and p = 0.03, 0.01, respectively). CONCLUSIONS: Our results indicate that FDG-PET assessment of locally-advanced rectal cancer response to preoperative chemoradiation may predict longterm outcomes.

Local therapy for rectal cancer.

Local procedures for carefully selected distal rectal cancer offer significant advantages such as sphincter preservation and avoidance of radical surgery. However, since preoperative selection criteria including current imaging modalities are unable to definitively stage regional lymph node status, local therapies for rectal cancer have the inherent potential disadvantage of undertreating a fraction of patients due to unresected mesorectal/regional lymph node disease. Current available data suggests that the local approach may be appropriate only for carefully selected T1 tumors with favorable pathologic features. Inferior local control and survival reported for T2 tumors and T1 tumors with unfavorable features, despite the addition of chemoradiation, outweigh the advantages of the local approach. Patients with unfavorable tumors who are unable to tolerate radical resection or who refuse surgery may be treated with local excision with or without adjuvant chemoradiation. Other modalities, such as electrocoagulation and endocavitary radiation, may also be valuable in this setting, as well as preoperative chemoradiation followed by local excision. Regardless of the approach used, all patients undergoing local therapy of a rectal cancer require careful long-term follow-up, because these patients remain at significant risk for local recurrence and distant failure.

Anal neoplasms.

A common theme in most anal neoplasms appears to be a delay in diagnosis due to confusion with more common, benign conditions. Thus, the clinician must maintain a high index of suspicion when evaluating lesions of the anal canal and margin. The use of primary chemoradiation for SCC of the anal canal has resulted in equivalent, if not superior, local control and survival compared with radical surgery, and results in sphincter preservation in over two thirds of cases. Nevertheless, abdominoperineal resection still plays an important role in salvage of treatment failures, and also for patients who are unlikely to tolerate chemoradiation or have pre-existing impaired continence. Recent studies indicate that variations in chemotherapeutic agents and radiation technique might potentially produce even better results. The prognosis for anorectal melanoma, as well as for small cell and undifferentiated tumors, continues to be poor. Fortunately, these are relatively rare tumors.

Multimodality management of locally advanced rectal cancer.

Despite the routine use of adjuvant chemoradiation for curatively resected stage II and III rectal cancer a significant percentage of patients ultimately fail locally and/or distally; this underscores the need for continued improvement in the efficacy of combined-modality therapy and quality of rectal cancer resection. The recognition of the significance of lateral or circumferential margins of resection has paralleled the widespread use of total mesorectal excision. In addition to facilitating negative margins of resection and local control, sharp mesorectal techniques also facilitate identification and preservation of pelvic autonomic nerves thereby greatly reducing the incidence of urinary and sexual dysfunction following radical resection. Lastly, restorative options can result in excellent bowel function in carefully selected patients undergoing a "very low" anterior resection. Efforts are currently directed at identifying the subset of locally advanced rectal cancer patients who may be adequately treated with a resection alone thereby avoiding the added morbidity of adjuvant radiation and chemotherapy.

Patients with colorectal and renal cell carcinoma diagnoses appear to be at risk for additional malignancies.

UNLABELLED: Patients with colorectal cancer (CRC) and renal cell carcinoma (RCC) may be at risk for additional primary malignancies. A review of 101 patients with these concurrent diagnoses was performed. Forty-two percent of patients had 1 or more additional malignancies; none appeared to be associated with Lynch syndrome (LS). This suggests the need for careful follow-up in these patients and further study. BACKGROUND: Small studies have demonstrated that patients who have both colorectal and renal cell carcinoma may be at increased risk for the development of additional malignancies. A possible genetic basis has been suggested. Our study describes the clinicopathologic features of these patients and clarifies the relationship of this cohort with Lynch syndrome (LS). METHODS: Patients with primary CRC and RCC treated at our institution were identified. Medical records were reviewed for demographic and clinical information. Immunohistochemical staining for mismatch repair (MMR) proteins was performed on tumor tissue when possible. RESULTS: During the study period, 24,642 patients were treated for CRC and 7,366 were treated for RCC at our institution. One hundred seventy-nine patients had both diagnoses, with 101 patients eligible for inclusion in our cohort. Tumors were typically early stage. The 2 cancers presented as synchronous lesions in 42% of patients. Thirty-two patients had 1 additional primary malignancy, 7 patients had 2 additional primary malignancies, and 3 patients had 3 additional primary malignancies. No patient had a family history that met the Amsterdam II criteria (AC) for LS, but 50% had family members with 1 malignancy. One of 10 colorectal tumors analyzed for the absence of MMR protein expression demonstrated the absence of MSH6, but the corresponding RCC demonstrated intact expression of all 4 MMR proteins. CONCLUSION: It is rare for patients to be diagnosed with both CRC and RCC. The clinicopathologic features of this cohort and the results of immunohistochemical analysis performed on a sample of these patients do not suggest LS. However, the high rate of additional carcinomas suggests a need for careful follow-up. Multicenter longitudinal studies are warranted to further understand the natural history and possible genetic basis for this entity.

Colorectal cancer: what should patients and families be told to lower the risk of colorectal cancer?

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. CRC, however, is potentially preventable, and several strategies may be employed to decrease the incidence of and mortality from CRC. Understanding of individual risk and adherence to screening and surveillance recommendations undoubtedly will reduce CRC-associated deaths. Several natural and synthetic chemopreventive agents may prove effective for both primary and secondary CRC chemoprevention. Finally, dietary modifications (ie, increased dietary fiber, fruits and vegetables, and decreased red meat) and other lifestyle changes (i.e., increased physical activity, weight maintenance, avoidance of smoking, and moderation of alcohol intake) also may lower the risk of developing CRC.

A prospective pathologic analysis using whole-mount sections of rectal cancer following preoperative combined modality therapy: implications for sphincter preservation.

OBJECTIVE: The aims of this study were to use a comprehensive whole-mount pathologic analysis to characterize microscopic patterns of residual disease, as well as circumferential and distal resection margins, in rectal cancer treated with preoperative CMT; and to identify clinicopathologic factors associated with residual disease. SUMMARY BACKGROUND DATA: Recent studies have shown that preoperative combined modality therapy (CMT) for rectal cancer enhances rates of sphincter preservation. However, the efficacy of preoperative CMT in conjunction with a total mesorectal excision (TME)-based resection, in terms of resection margins using whole-mount sections, has not been reported. Furthermore, since patterns of residual disease and extent of distal spread following preoperative CMT are largely unknown, intraoperative determination of distal rectal transection remains a surgical challenge. METHODS: We prospectively accrued 109 patients with endorectal ultrasound (ERUS)-staged, locally advanced rectal cancer (T2-T4 and/or N1), located a median distance of 7 cm from the anal verge, requiring preoperative CMT, and undergoing a TME-based resection. Comprehensive whole-mount pathologic analysis was performed, with particular emphasis on extent of residual disease, margin status, and intramural tumor extension. Clinicopathologic factors associated with residual disease were identified. RESULTS: A sphincter-preserving resection was feasible in 87 patients (80%), and in all 109 patients, distal margins were negative (median, 2.1 cm; range, 0.4-10 cm). Intramural extension beyond the gross mucosal edge of residual tumor was observed in only 2 patients (1.8%), both < or =0.95 cm. There were no positive circumferential margins (median, 10 mm; range, 1-28 mm), although 6 were less than or equal to 1 mm. On multivariate analysis, residual disease was observed more frequently in distally located tumors (distance from anal verge <5 cm) (P = 0.03). CONCLUSION: Our comprehensive pathologic analysis suggests that, following preoperative CMT and a TME-based resection, distal margins of 1 cm may provide for complete removal of locally advanced rectal cancer. Although residual cancer following preoperative CMT was more likely in the setting of distally located tumors, occult tumor beneath the mucosal edge was rare and, when present, limited to less than 1 cm. Our results extend the indications for sphincter preservation, as distal resection margins of only 1 cm may be acceptable for rectal cancer treated with preoperative CMT.

Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: role in presurgical management.

OBJECTIVE: This study summarizes our initial experience with prospective, single-amplicon (mutation-specific) A636P testing in Ashkenazi Jewish patients at risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). SUMMARY BACKGROUND DATA: We previously described a founder mutation, MSH2*1906G >C (A636P) that causes HNPCC in 8/1345 (0.59%) of Ashkenazim with colorectal cancer. The mutation was more common in Ashkenazim diagnosed at