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To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing.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.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.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.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.

Standard therapy for locally advanced rectal cancer includes neoadjuvant chemoradiation and surgery. Complete response (CR) rates after chemoradiation can be as high as 29%, suggesting that nonoperative management (NOM) may be reasonable with appropriately selected patients. We sought to identify potential NOM candidates.Using the Veterans Administration Central Cancer Registry, patients with stage II to III rectal cancer receiving chemoradiation with or without subsequent surgery were identified. Clinical CR (cCR) was assessed by physical examination, endoscopy, or imaging. Kaplan-Meier and log-rank tests were used to assess survival; multivariate analysis was performed using Cox proportional hazards.A total of 1313 patients were identified. Of these, 313 received chemoradiation alone (CRT cohort); 1000 received chemoradiation followed by surgery (CRT + S cohort). Median follow-up was 67.2 months. Median overall survival (OS) was 68.5 months. Median OS was 30.6 months for CRT and 89.3 months for CRT + S (P .001). Median disease-specific survival (DSS) was 44.8 months for CRT and not reached (NR) for CRT + S (P .001). Sixty-five CRT patients (20.8%) had a cCR. Median OS for CRT cCR patients was 73.5 months (P = .128 vs CRT + S); median DSS was NR (P = .161 vs CRT + S). One hundred thirty-seven (10.5%) CRT + S patients had a pathologic CR (pCR). Median OS with pCR was 133.7 months (P .001 vs CRT cCR), and median DSS was NR (P = .276 vs CRT cCR).CRT patients with cCR had similar OS and DSS versus CRT + S patients and similar DSS versus CRT + S patients with a pCR. This suggests that patients with locally advanced rectal cancer with a cCR to CRT have an excellent prognosis and may be candidates for organ preservation.

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.

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. 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). 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 =

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.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).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.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.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.

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.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.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.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.

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.

HIV status may affect outcomes after definitive chemoradiotherapy for anal cancer.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.This was a retrospective chart review.The study was conducted at an outpatient oncology clinic at large academic center.A total of 107 patients were reviewed, 39 HIV positive and 68 HIV negative. All of the patients underwent definitive chemoradiation for anal cancer.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.Median follow-up was 15 months. HIV-positive patients were younger (median, 52 vs 64 years; p0.001) 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.This study was limited by its retrospective design and small patient numbers.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.

Background Excess use of intravenous fluid can increase post-operative complications. We examined the influence of intra-operative crystalloid (IOC) administration on complications following pancreaticodudenectomy (PD) for pancreatic adenocarcinoma. Methods We categorized 188 patients who underwent PD for adenocarcinoma (1990–2009) into two groups: Group I received

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.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.The follow-up was 14.9 months (range, 0.7-94.8 months). Public hospital patients presented with significantly higher clinical T stage (P0.05) and clinical stage group (P0.05), had significantly longer radiotherapy delays (P0.05) and radiotherapy duration (P0.05), and had more frequent radiation therapy (RT) breaks ≥10 days (P0.05). 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.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.

Familial adenomatous polyposis, caused by mutations in the adenomatous polyposis coli gene located at chromosome 5q21, is an autosomal dominant syndrome characterized by polyposis of the colon and rectum and nearly 100 percent progression to colorectal cancer. We report a case of familial adenomatous polyposis and mental retardation caused by a chromosomal deletion at 5q15-q22. Chromosomal analysis is considered part of the evaluation of children with mental retardation and developmental delay. The resulting karyotypes from high-resolution chromosomal analysis can help characterize large deletions, some of which involve known tumor suppressor genes. Because familial adenomatous polyposis may arise from de novo chromosomal deletions involving the adenomatous polyposis coli gene locus, individuals with chromosomal deletions involving 5q21 should be considered at-risk for familial adenomatous polyposis and offered standard screening with flexible sigmoidoscopy by 10 to 12 years of age.

Compared with surgery alone, preoperative radiotherapy and 5-fluorouracil-based chemotherapy (combined-modality therapy; CMT) improves outcomes in patients with locally advanced rectal cancer. Although numerous studies have focused on identifying molecular markers of prognosis in the primary rectal cancer before CMT, our aim was to identify markers of prognosis in residual rectal cancer after preoperative CMT.Sixty-seven patients with locally advanced (T3-4 and/or N1) rectal cancer were treated with preoperative radiotherapy (median, 5040 cGy) with or without 5-fluorouracil-based chemotherapy. Residual tumor in the resected specimen, available for 52 patients, was analyzed for tumor-node-metastasis stage, lymphovascular and/or perineural invasion, and immunohistochemical expression of p27, p21, p53, Ki-67, retinoblastoma gene, cyclin D1, and bcl-2. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared by the log-rank test.With a median follow-up of 69 months, the overall 5-year RFS was 74%. RFS was significantly worse for patients with positive p27 expression (P = .005), T3-4 tumors (P = .02), and positive lymph nodes (P = .04) in the irradiated specimen. On multivariate analysis, positive p27 expression remained an independent negative prognostic factor for RFS (P = .04). None of the other proteins was significantly associated with RFS.Our results indicate that positive p27 expression in rectal cancer after preoperative chemoradiation is an independent negative predictor of RFS. Expression of p27 in the residual rectal cancer may therefore identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches should be strongly considered.

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 (ΔSUV max ) was 69% for patients free from recurrence and 37% for patients with recurrence (p = 0.004). ΔSUV max ≥ 62.5 and δTLG ≥ 69.5 were the best predictors of no-evidence-of-disease status and freedom from recurrence. Patients with ΔSUV max ≥ 62.5 and δTLG ≥ 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.

Recent data suggest a favorable prognosis for rectal cancer patients with a pathologic complete response to preoperative combined modality therapy. Prolongation of the interval between preoperative combined modality therapy and surgery (RT-surgery interval) as a means of increasing pathologic complete response rate has not been fully examined. One hundred and fifty-five rectal cancer patients undergoing preoperative pelvic external beam radiation therapy and 5-fluorouracil-based chemotherapy followed by rectal resection were identified. All patients had endorectal ultrasound prior to combined modality therapy. Final pathology reports were reviewed for ypT and ypN stage and margin status. Medical records were reviewed for sphincter preservation, operative time, estimated blood loss, hospital stay, and morbidity (overall, anastomotic, and perineal). A pathologic complete response (ypT0N0) occurred in 24 patients (15 percent). Median RT-surgery interval was 44 (range, 15-206) days. A pathologic complete response occurred in 19 percent of patients with an interval >44 days, vs. 12 percent in those with an interval ≤44 days (P = 0.27). Downstaging by three stages occurred more frequently in the long-interval group (15 percent vs. 6 percent, P = 0.11). The rates of sphincter preservation, positive margins, estimated blood loss, and operative time were not significantly different. Overall morbidity was similar between groups. Our results demonstrate a trend toward increased pathologic complete response rate and downstaging with increased RT-surgery interval. However, sphincter preservation is not increased. Until prospective analyses are conducted assessing the impact of prolonged RT-surgery interval on long-term outcome, the benefit of a prolonged interval between the completion of preoperative combined modality therapy and surgery remains unclear.

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 (P0.05) 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 responseor = 95% seemed to fare better than those with a treatment response95% (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.

Although the standard of care for T3 and/or N1-2 rectal cancers includes adjuvant chemoradiation, it is unclear whether T3 N0 patients with limited microscopic perirectal fat invasion warrant further therapy. Our aim was to determine the prognostic significance of gross perirectal fat invasion, or depth of microscopic perirectal fat invasion, in T3 N0 rectal cancers following sharp mesorectal excision and no adjuvant therapy.Utilizing a prospective database, the medical records of 108 patients who underwent a potentially curative resection for T3 N0 rectal cancer between June 1986 and December 1994 were analyzed. All pathological specimens were re-reviewed by a single pathologist, and extent of perirectal fat invasion was measured in millimeters. Patients who received either preoperative or postoperative adjuvant therapy were excluded.Macroscopic perirectal fat invasion (T3 gross) was present in 49 cases, absent in 40 cases (T3 microscopic), and not reported in 19 cases. Rectal cancers were stratified by extent of measured perirectal fat invasion into 3 mm or less and more than 3 mm. Five-year overall and local recurrence rates for the entire group were 19% and 8%, respectively. The disease-free survival, disease-specific survival, and overall recurrence for rectal cancers with 3 mm or less invasion vs. more than 3 mm invasion, or T3 gross vs. T3 microscopic, were not statistically different.Our data suggest that the extent of gross, or microscopic perirectal fat invasion (defined as3 or/=3 mm), determined in the resected specimen, does not predict outcome in select T3 N0 rectal cancers.

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.

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.

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.

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.

Colorectal cancer (CRC) is a disease with a major worldwide burden. It is the fourth most frequently diagnosed malignancy in men and third most common in women, with almost one million people developing CRC annually.1 In the world, CRC is the third most common cause of cancer death, responsible for 639,000 deaths annually.2 In the USA, CRC is the third most common cancer in men and women and the second most common cause of cancer death overall, accounting for 11% of cancers diagnosed.3 It was estimated that 147,000 cases were diagnosed in the USA in 2009 and that there were 50,000 deaths from the disease.3

614 Background: NACR followed by total mesorectal excision (TME) is standard of care for LARC. However, only 10-20% of patients achieve complete pathologic response with associated optimal clinical outcome. No predictive biomarker is currently available. Aberrant DNA methylation is well known for its key role in the pathogenesis of colorectal cancer. Previous rectal cancer methylation studies were conducted in patients without NACR or inconclusive. We hypothesized a correlation between methylation status and pathologic outcome following NACR. Methods: This is an IRB approved, retrospective, translational study of patients with LARC who received identical NACR before TME at New York University hospitals. Ten micron sections from FFPE tissue blocks underwent laser capture microdissection (LCM) followed by genome DNA isolation. Illumina Infinium 450k methylation array was used to assess 485,000 methylation sites. Methylation profiles and copy number changes were analyzed using in-house bioinformatics. Histone H3K27me, a global methylation marker, was assessed using immunohistochemistry (IHC) and expression quantified in carcinoma cells, normal epithelium, inflammatory cells, stromal cells and endothelial cells. Results: Tumor specimens from 52 patients were collected. Analyzed specimens of stromal and cancer cells showed distinct methylation profiles pre- and post- therapy. The histone H3K27me3 mark was markedly increased in carcinoma compared to normal epithelium and strong trimethyl mark expression persisted in invasive carcinoma after the therapy including single cells. We obtained adequate DNA to demonstrate differences between pre- and post- NACR specimens and tissue sites. Full data set, including the known clinical and pathologic results, is to be presented. Conclusions: This is the first study to combine LCM and high throughput quantitative methylation profiling in rectal cancer to correlate with NACR outcome. Histone H3K27me3 IHC can be used to identify high-grade and invasive carcinoma with high specificity. Data from our annotated clinical cohort and correlative molecular results can inform a future prospective trial.

BackgroundA pancreaticoduodenectomy (PD) offers the only chance of a cure for pancreatic cancer and can be performed with low mortality and morbidity. However, little is known about outcomes of a PD in octogenarians.MethodsDifferences in two groups of patients (Group Y, 2: 71% vs. 47%). The two groups were similar in underlying co-morbidities, operative time, rates of portal vein resection, intra-operative complications, blood loss, pathological stage and status of resection margins. Octogenarians had a longer post-operative stay (20 vs. 14 days) and higher overall morbidity (68% vs. 44%). There was a single death in each group. At a median follow-up of 13 months median survival appeared similar in the two groups (17 vs. 13 months).ConclusionsAs 30-day mortality and survival are similar to those observed in younger patients, a PD can be offered to carefully selected octogenarians.

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.

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).We previously described a founder mutation, MSH2*1906GC (A636P) that causes HNPCC in 8/1345 (0.59%) of Ashkenazim with colorectal cancer. The mutation was more common in Ashkenazim diagnosed ator=40 years (7%).Twenty-seven Ashkenazi probands at risk for HNPCC were ascertained. Single-amplicon A636P testing was performed on 21 by polymerase chain reaction of exon 12 of MSH2, followed by direct DNA sequencing. Mutational analysis of the entire open reading frame of MLH1 and MSH2 was performed on 7 by PCR of each exon, followed by heteroduplex analysis using denaturing high-performance liquid chromatography and direct sequencing of exons with variant chromatographs. One patient received both studies,The A636P mutation was detected in 3/21 (14%) prospectively evaluated patients using single amplicon testing. In 6 patients, the entire open reading frame of MLH1 and MSH2 was analyzed, and 1 additional A636P carrier and 2 carriers of previously unrecognized mutations were identified. The A636P mutation was present in 2 patients who met Amsterdam criteria and in 2 patients who did not.Although rare in the general population, A636P mutations are found at increased frequency in Ashkenazim with a personal or family history of colorectal or other HNPCC-associated cancers. This inexpensive and rapid approach may be useful preoperatively in helping determine the extent of colon resection for a subset of patients.

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.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.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.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%), bothor =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 verge5 cm) (P = 0.03).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.

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.

This study was designed to identify preoperative and intraoperative features of locally recurrent colorectal cancer that predict R0 resection in patients scheduled for attempted complete resection followed by intraoperative radiation therapy. Review of a prospective data base identified 119 patients brought to the intraoperative radiation therapy suite for planned complete resection of locally recurrent rectal (n = 101) and colon (n = 18) cancer between January 1994 and November 2000. R0 resection was achieved in 61 patients. This group was compared with patients in which an R1 (n = 38), R2 (n = 7), or palliative procedure (n = 13) was performed. Variables evaluated included: tumor location, features of the primary tumor, and preoperative findings on computed tomography, magnetic resonance imaging, and history/physical. Tumor location was established by review of operative/pathologic reports and classified as axial (anastomotic/perineal), anterior (bladder/genitourinary organs), posterior (presacral), or lateral (pelvic sidewall). When recurrence was confined to the axial location only, or axial and anterior locations, R0 resection was achieved significantly more often than when other locations were involved (P < 0.001, P = 0.003, respectively). When a lateral component was present, R0 resection was achieved significantly less often than when there was no lateral component (P = 0.002). For patients with available preoperative computed tomography and/or magnetic resonance imaging results (n = 70), the finding of lateral tumor involvement was associated with R0 resection significantly less often than when lateral disease was not identified (P = 0.004). Pelvic recurrences confined to the axial location, or axial and anterior locations, are more likely to be completely resectable (R0) than those involving the pelvic sidewall. Efforts to enhance preoperative identification and imaging of these patients are clearly justified.

Background: In order to evaluate the impact of preoperative radiation and chemotherapy (combined modality therapy, or CMT) on primary rectal cancer and mesorectal lymph nodes (MLNs), middle and lower third rectal cancers were resected with total mesorectal excision (TME) and assessed for frequency of MLN retrieval and residual MLN involvement. Methods: Between 1990 and 2001, 187 consecutive patients underwent abdominoperineal resection (APR) or low anterior resection (LAR) for locally advanced (endorectal ultrasound [ERUS] stage, T3–4) mid and distal rectal cancer following preoperative CMT. Sphincter preservation was possible in 150 patients (80%). The mean number of retrieved MLNs was 10.6. Pre-CMT ERUS stage was compared with final pathologic stage. Results: Comparison of pre-CMT ERUS stage with pathologic stage revealed a decrease in T stage in 93 patients (49%), as well as a decrease in the percentage of individuals with positive MLNs, from 54% to 27% (P < .0001). The overall incidence of positive MLN involvement was 27%, and incidence paralleled pathologic T stage (pT): pT0 = 7%, pT1 = 8%, pT2 = 22%, pT3 = 37%, and pT4 = 67%. Conclusions: Following preoperative CMT, the incidence of residual MLN involvement remains significant and parallels increasing pT stage. Therefore, the standard of care for locally advanced distal rectal cancer should continue to include formal rectal resection (TME).

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.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.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 deltaTLGor= 69.5 were the best predictors of no-evidence-of-disease status and freedom from recurrence. Patients with DeltaSUV(max)or= 62.5 and deltaTLGor= 69.5 had significantly improved disease-specific and recurrence-free survival (p = 0.08, 0.02 and p = 0.03, 0.01, respectively).Our results indicate that FDG-PET assessment of locally-advanced rectal cancer response to preoperative chemoradiation may predict longterm outcomes.

Background: Preoperative combined-modality therapy (CMT) for rectal cancer allows a sphincter-sparing procedure in some individuals who would otherwise require an abdominoperineal resection. To further define the subset of rectal cancer patients suitable for this approach, we determined the adequacy of a distal margin of ≤1 cm in patients with locally advanced rectal cancer requiring preoperative CMT. Methods: Ninety-four consecutive patients, status post curative low anterior resection for rectal cancer after preoperative CMT, were identified from the prospective Colorectal Service Database. Distal margin length, tumor grade, tumor-node-metastasis stage, presence of lymphovascular and perineural invasion, and tumor distance from the anal verge were examined for their effect on recurrence and survival. Median follow-up was 44 months. Results: Distal margin length ranged from .1 to 9.5 cm (median, 2.0 cm) and did not correlate with local recurrence (hazard ratio, 1.1; P = .34) or recurrence-free survival (hazard ratio, 1.1; P = .29) by univariate analysis. Kaplan-Meier estimates of recurrence-free survival and local recurrence at 3 years for the ≤1 cm versus >1 cm and the ≤2 cm versus >2 cm groups were not significantly different. Groups were well matched for other clinicopathologic variables. Conclusions: Our data suggest that for patients with locally advanced rectal cancer undergoing resection and preoperative CMT, distal margins ≤1 cm do not seem to compromise oncological outcome.

PURPOSE: Familial adenomatous polyposis is a well-described, autosomal dominant, inherited syndrome characterized by diffuse polyposis of the colon and rectum as well as various upper gastrointestinal and extraintestinal manifestations. A subset of patients present with fewer colorectal polyps, later age of onset of polyps and cancer, and a predilection toward involvement of the proximal colon. This variant of familial adenomatous polyposis is known as attenuated familial adenomatous polyposis. The purpose of this review is to summarize current knowledge regarding this poorly understood entity and propose guidelines for diagnosis, surveillance, and surgical management. METHODS: The MEDLINE database was searched from 1985 onward using the keywords, “attenuated familial adenomatous polyposis,” “AFAP,” “adenomatous polyposis coli gene,” and “APC gene.” Additional articles were identified through the reference sections of retrieved papers. All papers that pertained to attenuated familial adenomatous polyposis or mutations in the APC gene producing an attenuated phenotype were included. RESULTS: Attenuated familial adenomatous polyposis is transmitted in an autosomal dominant fashion. Several distinct mutations within the APC gene have been associated with an attenuated phenotype, but variability of disease expression within kindreds possessing identical mutations makes classification difficult. Polyps are diagnosed at a mean age of 44 years, with cancer diagnosed at a mean of 56 years of age. Frequent involvement of the proximal colon necessitates the use of colonoscopy for surveillance, and infrequent involvement of the rectum supports the role of a total abdominal colectomy and ileorectal anastomosis. CONCLUSIONS: Although currently recognized as a distinct clinical entity, attenuated familial adenomatous polyposis may be part of a spectrum of disease that includes familial adenomatous polyposis and is caused by different mutations within the APC gene. Because of its unique characteristics, yet apparent overlap with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, increased awareness of attenuated familial adenomatous polyposis should improve diagnosis, surveillance, and treatment strategies in this unique subset of familial polyposis syndromes.

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.