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A chronological overview of the various staging systems for colorectal cancer is presented in an effort to demonstrate the reason for the current state of confusion. The Dukes 1932 system is considered to be the gold standard because of its simplicity and accuracy and is the system most often referred to in the literature. Number of positive nodes and depth of invasion are two variables that have been found to be predictors of survival. In the future, other prognostic factors such as nuclear morphology, flow cytometric characteristics, histological grade, and vascular or lymphatic invasion may also be entered into the staging equation. Use of the TNM system at this time is recommended since it most completely describes appropriate prognostic factors and allows conversion of other staging systems into a common format. Future modifications could logically evolve from the TNM system.

Colonic diverticular disease is responsible for over 300,000 admissions and expenditures exceeding $2.7 billion/year. There is recent evidence that rates of treatment for diverticulitis have increased in the United States over the last decade. We hypothesize that these national trends of increasing rates of hospitalizations for diverticulitis would be found in an analysis of a single-state discharge database. Data from the Office of Statewide Health Planning and Development were used to analyze treatment for diverticulitis in California from 1995 to 2006. For each hospitalization, surgical care was determined based on procedure codes for left colon resection and/or colostomy. Overall numbers of admissions for acute diverticulitis increased throughout the 12-year study period with an estimated annual percentage of change (EAPC) of 2.1 per cent (P0.001). Rates of admissions increased most rapidly in patients 20 to 34-years-old (EAPC = 8.6%, P0.001) and 35 to 49 years old (EAPC = 5.7%, P0.001). Elective colectomies had an EAPC of 2.1 per cent (P0.001), which was also most dramatic in younger age groups. Between 1995 and 2006 we found significant increases in both the rates of hospitalization for diverticulitis and rates of elective surgical treatment in California. These increases are entirely due to higher rates of care for younger patients.

The treatment costs for patients in the United States with inflammatory bowel disease (IBD) exceed 1.7 billion dollars/year. Infliximab, an antibody to tumor necrosis factor-alpha has been extensively used to treat IBD, with 390,000 IBD patients receiving the drug since its FDA approval in 1998. We sought to determine the impact of infliximab on population-based rates of hospitalizations and surgical care for patients with IBD in the United States. We used data from the Nationwide Inpatient Sample to analyze patterns of hospital-based treatment provided to patients with IBD between 1998 and 2005. Data from this analysis were combined with census data to calculate trends in population-based rates of treatment. Overall rates of hospitalization for patients with Crohn's disease and ulcerative colitis increased significantly between 1998 and 2005 (5.1%/year and 3.4%/year respectively, P0.001 for each). During the same time period there were no changes in the overall rates of surgical care. The expanding use of infliximab has not significantly impacted the use of surgical procedures for patients with either ulcerative colitis or Crohn's disease, and rates of nonsurgical hospitalizations have actually increased. Even in the era of infliximab, surgical care remains a mainstay in the treatment of IBD.

With the baby boomers entering retirement age, the United States population is seeing a dramatic increase in the number of elderly individuals. We hypothesized that as a result, during the next 20 years, the demand for colorectal procedures will grow rapidly.We used the 2005 Nationwide Inpatient Sample and the Florida State Ambulatory Surgery Database as source data. From these two data sources, we identified commonly performed inpatient and outpatient colorectal procedures, as well as associated diagnoses. These data were combined with census projections to generate projected volumes for the selected procedures and diagnoses.Between 2005 and 2025, the United States population is expected to grow by 18 percent, with disproportionate growth in individuals aged 65 to 74 years (92 percent) and those aged 75+ years (54 percent). We forecast that growth in outpatient procedures and inpatient procedures will be 21.3 percent and 40.6 percent, respectively. Inpatient operations for colon cancer and rectal cancer show the greatest growth.During the next two decades, demographic changes in the United States population will lead to a marked increase in the use of colorectal surgical services, especially inpatient and oncologic procedures. The ability of the surgical workforce to meet this projected growth in demand should be assessed.

The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein–binding protein (CBP) over p300 by the Wnt/β-catenin pathway is known to suppress differentiation and increase proliferation. We show that the β-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the β-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand–mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage. [Cancer Res 2009;69(9):3736–45]

Diverticular disease imposes an impressive clinical burden to the United States population, with over 300,000 admissions and 1.5 million days of inpatient care annually. Consensus regarding the treatment of diverticulitis has evolved over time, with increasing advocacy of primary anastomosis for acute diverticulitis, and nonoperative treatment of recurrent mild/moderate diverticulitis. We analyzed whether these changes are reflected in patterns of practice in a nationally-representative patient cohort.We used the 1998 to 2005 nationwide inpatient sample to analyze the care received by 267,000 patients admitted with acute diverticulitis, and 33,500 patients operated electively for diverticulitis. Census data were used to calculate population-based incidence rates of disease and surgical treatment. Weighted logistic regression with cluster adjustment at the hospital level was used for hypothesis testing.Overall annual age-adjusted admissions for acute diverticulitis increased from 120,500 in 1998 to 151,900 in 2005 (26% increase). Rates of admission increased more rapidly within patients aged 18 to 44 years (82%) and 45 to 74 years (36%). Elective operations for diverticulitis rose from 16,100 to 22,500 per year during the same time period (29%), also with a more rapid increase (73%) in rates of surgery for individuals aged 18 to 44 years. Multivariate analysis found no evidence that primary anastomosis is becoming more commonly used.We are the first to report dramatic changes in rates of treatment for diverticulitis in the United States. The causes of this emerging disease pattern are unknown, but certainly deserve further investigation. For patients undergoing surgery for acute diverticulitis, there was little change over time in the likelihood of a primary anastomosis.

This study evaluated combined 5-fluorouracil (5FU) and doxorubicin as postoperative adjuvant chemotherapy for patients who had undergone potentially curative resection of a primary gastric adenocarcinoma. One hundred twenty-five eligible and evaluable patients were stratified according to extent of surgical resection, location of the primary tumor within the stomach, and lymph node status. They were then randomized to either receive three cycles of chemotherapy or be observed. The median time from patient entry was 7 years. Results showed no significant difference in time to recurrence. The 5-year survival rate was 33% for the observation arm and 32% for the adjuvant therapy arm. The data excluded a 16% improvement in the 5-year survival rate for patients receiving chemotherapy with a P value less than 0.05. There were two drug-related fatalities due to sepsis. These results demonstrate no substantive benefit for this chemotherapy regimen as postoperative adjuvant treatment of resected gastric cancer.

Background The lifetime risk of intra-abdominal surgery is unknown. The objectives of this study were to derive this information from our local population, and to consider the role of incidental surgery. Methods Over an 8-year period, 2648 autopsy and clinical records from a public and private hospital were reviewed for evidence of intra-abdominal surgery. Results 2262 (85%) cases were from the public hospital and 386 (15%) from the private hospital. The adjusted intra-abdominal surgical rate was 43.8% in those over the age of 60. With the exception of the age group 21-40, there were no statistical significant differences in operative rates between hospitals. The intra-abdominal surgical rate over the age of 60 was used as an estimate of the lifetime risk of intra-abdominal surgery. Conclusions The lifetime risk of intra-abdominal surgery can be used to assess the utilization of healthcare among ethnic groups and in considering the role of incidental surgery.

Despite consensus regarding the benefits of chemotherapy for stage III colon cancer, multiple reports have found significant variations in rates of use. In the current study, the authors attempted to systematically review reports of the community rates at which chemotherapy is administered for stage III colon cancer in the US, and in so doing plan strategies for improving rates of use. A systematic search strategy was undertaken using MEDLINE, Web of Science, and bibliographies to find reports of the rates at which patients with stage III colon cancer receive chemotherapy. A total of 22 studies published since 1990 were identified, with rates of chemotherapy use ranging from 39% to 71%. Age and comorbidity were found to be the most significant patient factors, but studies also found racial/ethnic and socioeconomic disparities in the rates of chemotherapy. Patients treated at teaching hospitals did not clearly receive chemotherapy more often. Oncologists and surgeons who treat a higher volume of colorectal cancer patients were more likely to have chemotherapy initiated in their patients. The authors developed a conceptual model of the process pathway experienced by patients with stage III colon cancer to demonstrate areas of potential underuse of chemotherapy. Nearly half of patients with stage III chemotherapy in the US do not receive chemotherapy. Although many patients are too old or frail to benefit appropriately, for many patients chemotherapy is simply not initiated. Attention needs to be focused on systematic approaches to prevent systems failures that result in underuse. Guidelines regarding chemotherapy use in elderly patients are especially important.

Surgical treatment of extensive and confluent anal condylomata results in large open wounds, which in other contexts of anorectal surgery (e.g., hemorrhoidectomy), have been associated with a relevant risk of stricture formation. The aim of our study was therefore to revisit the issue and assess this risk and the general morbidity in patients undergoing extensive excision and fulguration of anal warts.Records of 41 consecutive patients undergoing with excision/fulguration of extensive, i.e.,50% confluent anal condylomata were retrospectively reviewed. Excluded were patients with a lesser degree of warts and patients lost to follow-up before complete wound healing. Data recorded included patient characteristics and evolution of the local area after the surgery.Forty-one patients (40 males and one female) underwent excision and fulguration of a large anal condyloma with an average follow-up of 6 months (range, 1-36 months). The majority of patients (97.6%) were HIV-positive with 80% taking antiretroviral medication. Half of the patients had not received any previous medical or surgical treatment, whereas one fourth had undergone surgical excisions or fulgurations before. Recurrent warts developed in 19 patients (46.3%). The surgical morbidity after the extensive excision consisted of bleeding (22%). However, none of the patients showed any evidence or complaints of postoperative stricturing and anal stenosis at follow-up.Excision of extensive anal condylomata has a known high probability of recurrences, but the risk of developing anal stenosis is low. Careful primary excision of even confluent warts can therefore be safely performed without major primary flap reconstructions.

Between April 1981 and July 1984, 51 patients received intraoperative radiation therapy (IORT) as a component of therapy for the management of primary or recurrent pelvic malignancies which were initially unresectable for cure. For these patients, curative surgical alternatives did not exist, or would have involved extensive procedures such as pelvic exenteration, distal sacrectomy, hemipelvectomy, or hemicorporectomy. The primary disease was colorectal in 38 patients. Treatment consisted of external beam radiation (range 3000 to 6890 cGy, median 5040 cGy), surgical debulking when feasible, and an intra-operative electron beam boost to the gross or microscopic residual disease (dose range 1000 to 2500 cGy, median 1750 cGy) utilizing 9–18 MeV electrons. The most common IORT associated toxicities were peripheral neuropathy and ureteral obstruction. None were life-threatening or fatal in severity. Of the 50 patients evaluable for neurotoxicity analysis, 16 (32%) developed peripheral neuropathy consisting of pain in 16 patients, numbness and tingling in 11, and weakness in 8. The pain, numbness and tingling resolved in about 40% of patients, while weakness resolved in only 1 of 8. Sixteen ureters were initially unobstructed by tumor at the time of IORT. Of these, 10 (63%) subsequently showed evidence of obstruction and hydronephrosis. The development of neurotoxicity was more common at IORT doses of 1500 cGy or more versus 1000 cGy. Ureteral obstruction with hydronephrosis occurred more frequently at IORT doses of 1250 cGy or more compared to 1000 cGy. There was no relationship between the likelihood of developing complications and the total external beam dose. The observed dependence of human nerve toxicity primarily on the IORT dose is consistent with data generated from animal experiments.

Cancer of the colon is the second most common cancer. Adherence to principles of screening, diagnosis, and management have the potential to substantially improve survival.

The 2007 Santa Monica Conference on Assessing and Treating Early-Stage Colon and Rectal Cancer, a multidisciplinary meeting of leaders in surgery, medical and radiation oncology, and pathology, was convened on January 12 to 13, 2007. The purpose of the meeting was to assess current data and issues in the field and to develop recommendations for advancing patient care and clinical research. Topics included pathologic assessment and staging, transanal versus laparoscopic versus open resection, adjuvant therapy, genetic testing and counseling, cooperative group strategies, and the use of biological therapies and novel agents. A review of the key issues discussed, as well as conclusions and recommendations considered significant to the field, is summarized below and presented at greater length in the individual manuscripts and accompanying discussion that comprise the full conference proceedings. Although the management of early-stage colon and rectal cancers remains a challenge for all of us, the development and use of new technologies and methods of assessment and treatment over the past several decades is yielding encouraging results. A variety of opportunities to further improve outcomes were addressed in this forum, including recommendations that specific protocols be adopted regarding surgical and pathologic dissection and reporting, particularly for stage II disease; the corollary need to increase active multidisciplinary collaboration; and the development of comprehensive consensus guidelines and recommendations to standardize care in early-stage colorectal cancer.

At present, several modalities exist for the preoperative staging of rectal lesions, including computed tomography (CT), body coil or endorectal coil magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS) done by rigid or flexible probes, and positron emission tomography (PET). Staging accuracy for CT ranges from 53% to 94% for T-stage accuracy and from 54% to 70% for N-stage accuracy. Improved CT accuracy is observed at higher disease stages. Body coil MRI has shown T- and N-stage accuracy ranging from 59% to 95% and 39% to 95%, respectively. Endorectal coil MRI has shown improved T- and N-stage accuracy, with rates of 66% to 91% and 72% to 79%, respectively. The development of phased-array MRI, combining high spatial resolution with a larger field of view, offers promise to improve on these rates. EUS, considered the current gold standard, has shown T-stage accuracy ranging from 75% to 95%, with N-stage accuracy ranging from 65% to 80%. Flexible EUS probes have the advantage of being able to access and sample iliac nodes. Recent studies also suggest that three-dimensional EUS may provide greater accuracy than conventional two-dimensional EUS. Limited studies exist on the use of PET in primary tumor staging. PET may upstage disease in 8% to 24% of patients and has also been used in posttreatment restaging and surveillance. Postradiation edema, necrosis, and fibrosis seem to decrease restaging accuracy in all modalities. This article reviews the current literature about the staging accuracy of the various modalities and suggests a staging algorithm for rectal cancer.

National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation.Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided.Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P.0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm.Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.

Contains fulltext : 50472.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Although Seprafilm has been demonstrated to reduce adhesion formation, it is not known whether its usage would translate into a reduction in adhesive small-bowel obstruction. METHODS: This was a prospective, randomized, multicenter, multinational, single-blind, controlled study. This report focuses on those patients who underwent intestinal resection (n = 1,701). Before closure of the abdomen, patients were randomized to receive Seprafilm or no treatment. Seprafilm was applied to adhesiogenic tissues throughout the abdomen. The incidence and type of bowel obstruction was compared between the two groups. Time to first adhesive small-bowel obstruction was compared during the course of the study by using survival analysis methods. The mean follow-up time for the occurrence of adhesive small-bowel obstruction was 3.5 years. RESULTS: There was no difference between the treatment and control group in overall rate of bowel obstruction. The incidence of adhesive small-bowel obstruction requiring reoperation was significantly lower for Seprafilm patients compared with no-treatment patients: 1.8 vs. 3.4 percent (P < 0.05). This finding represents an absolute reduction in adhesive small-bowel obstruction requiring reoperation of 1.6 percent and a relative reduction of 47 percent. In addition, a stepwise multivariate analysis indicated that the use of Seprafilm was the only predictive factor for reducing adhesive small-bowel obstruction requiring reoperation. In both groups, 50 percent of first adhesive small-bowel obstruction episodes occurred within 6 months after the initial surgery with nearly 30 percent occurring within the first 30 days. Additionally no first adhesive small-bowel obstruction events were reported in Years 4 and 5 of follow-up. CONCLUSIONS: The overall bowel obstruction rate was unchanged; however, adhesive small-bowel obstruction requiring reoperation was significantly reduced by the use of Seprafilm, which was the only factor that predicted this outcome.

PURPOSE: Locally recurrent rectal cancer is associated with poor quality of life and has justified aggressive surgical and adjuvant approaches to control the disease. This study was designed to evaluate if the use of brachytherapy in association with wide surgical excision (debulking operation) can offer reasonable palliation for patients with locally recurrent rectal cancer. MATERIALS AND METHODS: Patients with biopsy-proven locally recurrent rectal cancer who were not candidates for intraoperative radiation therapy and who were previously considered as having unresectable tumors were included in the study and were followed-up from May 1981 to November 1990. All of them had undergone laparotomy and had either radical or debulking surgical resection performed. At the same time, brachytherapy was used with temporary or permanent implant of seeds of iridium-192 or iodine-125. RESULTS: Thirty patients were included. Patients ranged in age from 28 to 74 years, and 16 patients were female. No mortality was observed, and morbidity was low (small-bowel obstruction (1 patient), intestinal fistula (1 patient), and urinary fistula (1 patient). Histologic examination of the specimen showed gross residual disease in 67 percent of patients and microscopic disease in 25 percent of patients. Long-term follow-up was possible in 28 patients. Mean follow-up and local control were, respectively, 26.5 months and 37.5 percent for gross residual disease and 34 months and 66 percent for microscopic residual disease. Eighteen patients (64 percent) had locally recurrent rectal cancer under control at the time of the last follow-up, with seven patients (25 percent) having no evidence of local or distant recurrence. CONCLUSION: This is the first report of brachytherapy for locally recurrent rectal cancer. This appears to offer a therapeutic alternative to patients who are not candidates for intraoperative radiation therapy. Surgical morbidity and mortality are acceptable. Local control in 18 patients (64 percent) is comparable with intraoperative radiation therapy or more morbid surgical alternatives. Cancer-related deaths are most often related to disseminated disease, which suggests the need for systemic therapy in addition to brachytherapy.

Background The management of locally recurrent rectal cancer should achieve local tumor control and potentially improving disease-free and overall survival. Radical pelvic resection has traditionally been associated with permanent fecal and urinary diversion. However, as advanced techniques have evolved to allow restoration of intestinal and urinary continence, we reviewed the use of these techniques in patients with recurrent rectal cancer. Methods Patients with recurrent rectal cancer who underwent a resection at Norris Comprehensive Cancer Center between 1993 and 1999 were retrospectively reviewed. Data collected included demographic data, surgical and oncological history, patterns of recurrence, treatment modalities, and outcome. Follow-up data was obtained from the last clinic visit and/or tumor registry. Results Sixty-seven patients with locally recurrent rectal cancer (male/female 45/22, age 32–81 years) were included in the analysis. Continence was re-established in 22 (33%) patients, urinary continence was restored in 12 patients, and intestinal continuity in 14 patients (both in 4 patients). A temporary diverting ostomy was necessary in 5 out of 14 (36%) patients. Mortality was zero and morbidity was low and included two urinary leaks and one fecal leak all of which could be managed non-operatively. At a median follow-up of 16 months (range 5–55), 11 (50%) patients were still alive, 7 (31%) without evidence of disease. Comparison of the groups of patients either with or without continence preservation showed no statistically significant difference in disease-free survival and overall survival rates. High quality of life was achieved with restoration of continuity, no patient with restored continuity expressed a desire for a diversion. Conclusion If an oncologically adequate resection of the recurrent rectal cancer can be performed without impairment of the pelvic floor integrity, continence preservation is feasible and results in good functional and oncological outcome. J. Surg. Oncol. 2005;92:76–81. © 2005 Wiley-Liss, Inc.

Background Methylation at certain human CpG rich sequences increases with age. The mechanisms underlying such age-related changes are unclear, but methylation may accumulate slowly in a clock-like manner from birth and record lifetime numbers of stem cell divisions. Alternatively, methylation may fluctuate in response to environmental stimuli. The relative stability of methylation patterns may be inferred through serial observations of the same colon. Case presentation A 22 year-old male with attenuated familial adenomatous polyposis received neo-adjuvant chemotherapy and radiation prior to surgery for rectal adenocarcinoma. Colon crypt methylation patterns before and after neo-adjuvant therapy (62 days apart) were essentially identical with respect to percent methylation and diversity. Consistent with previous studies, methylation patterns recorded no evidence for enhanced colon crypt stem cell survival with a germline mutation (codon 215) proximal to the mutation cluster region of APC. Conclusion The inability of neo-adjuvant therapy to significantly alter crypt methylation patterns suggests stem cells are relatively protected from transient environmental changes. Age-related methylation appears to primarily reflect epigenetic errors in stem cells that slowly accumulate in a clock-like manner from birth. Therefore, life-long human stem cell histories are potentially written within and may be read from somatic cell epigenomes.

Background Despite clinical evidence showing that steps can be taken perioperatively to enhance postoperative recovery and decrease morbidity in colonic operation patients, there is no comprehensive information on how widespread such practices are, or the combination of such steps into effective multimodal rehabilitation (fast-track) colonic surgery programs to decrease hospital stay. This survey investigated clinical practice around colonic operations across Europe and the United States. Methods The survey was conducted in 295 hospitals in the United Kingdom, France, Germany, Italy, Spain, and the United States. Details of perioperative care and postoperative recovery were recorded for 1,082 patients who had undergone elective colonic operations and who were discharged (or died) over a 2-week period (United States: up to 4 weeks). Results Preoperative bowel clearance was used in >85% of patients. A nasogastric tube was left in situ postoperatively in 40% versus 66% of patients in the United States and Europe, respectively, and was removed about 3 days postoperatively. It took 3 to 4 days until 50% of the patients first tolerated liquids and 4 to 5 days until 50% of patients were eating and having a bowel movement. Postoperative ileus was found to persist for over 5 days in approximately 45% of patients. Mean length of postoperative hospital stay was over 10 days in the United Kingdom, France, Germany, Italy, and Spain, and 7 days in the United States, compared with 2 to 5 days reported in trials of fast-track colonic surgery programs. Conclusions Strategies that can contribute to improved recovery and reduced complications after colonic operations do not appear to be applied optimally in clinical practice across Europe and the United States. These findings indicate a potential for major improvements in outcomes and reduction of costs if peri- and postoperative care can be adjusted to be in line with published evidence.

Evidence-based medicine suggests that in the management of chronic anal fissure (CAF), lateral internal sphincterotomy (LIS) is far more effective than medical treatment in lowering the anal sphincter tone and curing the fissure. In the current study, we developed a treatment algorithm from topical nitroglycerin (NTG) to botulinum toxin type A (Botox [BTX]) to LIS and analyzed its cost benefit by calculating the effective and potential costs based on the treatment success and the rate of avoided surgeries. Patients presenting between November 2003 and December 2004 with CAF and symptoms for greater than 3 months were prospectively treated according to a treatment algorithm which started with (1) topical NTG, in case of failure (2) injection of BTX, thus limiting (3) surgery to those who failed both nonsurgical options or at any point chose the surgical approach. Based on the primary end points of fissure healing or surgery, we calculated the true cost (algorithm) and the potential incremental cost (BTX plus surgery or surgery in all patients, respectively). Sixty-seven patients with CAF (25 men and 42 women; median duration of symptoms, 16 weeks) were treated according to the algorithm. NTG alone was successful in fissure healing in 31 of 67 patients (46.2%). Two developed a recurrent fissure and then received BTX as part of the protocol. Of the 36 patients who failed NTG trial, 3 requested surgery; the others were treated with BTX, which was successful in 84.8%. Five patients (15.2%) failed BTX and subsequently required surgery. The overall surgery rate in the whole study group was 11.9%, whereas CAF healed in 88.1% of our patients with medical treatment alone. Cost for NTG is $10; for 100 units BTX, $528; and for outpatient surgery, $1119. The total cost for these 67 patients therefore was $33,252 ($290 for NTG, $20,580 for NTG plus BTX, $3,357 for NTG plus LIS, and $9,025 for NTG plus BTX plus LIS). If all patients had received BTX with a 15% failure rate, the total cost would have been $56,688 (70.3% cost increase). If all patients had undergone surgery as initial/only treatment, the total cost would have been $74,973 (125% cost increase). Our treatment algorithm for CAF with stepwise escalation can avoid surgery in 88% of the patients. It is highly cost-efficient and resulted in savings of 41% (compared with BTX plus LIS) and up to 70% (compared with surgery in all patients), respectively.

Objective Postoperative ileus (POI) can negatively affect patient recovery and morbidity, yet the lack of an internationally accepted definition and clinical management pathway for this condition suggest POI may be under-recognized as a clinical problem. The purpose of this survey was therefore to assess current attitudes of surgeons towards the clinical impact and management of POI. Subjects and methods Telephone interviews were conducted with 230 surgeons from hospitals in the UK, France, Germany, Italy and Spain. Results Across Europe, there are differences in the terms surgeons use to refer to delayed recovery of gastrointestinal (GI) function and the symptoms, concerns and risks they associate with this condition. Furthermore, there is marked variation in the attitudes of European surgeons towards minimizing the risk of delayed recovery of GI function and in the strategies to manage POI. Additionally, some of the measures applied most commonly by European surgeons are in contrast to evidence in the literature indicating that they have no benefit for quicker resolution of GI function. Conclusion The results suggest that there is a need for clearer definition of the factors that constitute POI, increased recognition of the impact of this condition and improved understanding of the most effective peri-/postoperative care for surgical patients.

The molecular mechanisms involved in progression of squamous cell carcinoma of the anus (SCCA) are poorly elucidated, as well as the potential role of HIV infection. Loss of heterozygosity (LOH) is one of the mechanisms responsible for inactivation of tumor suppressor genes. We hypothesized that HIV-induced immunosuppression may contribute to an alternate molecular pathway in SCCA progression, through persistence of human papillomavirus infection within the anal canal. This study was undertaken to compare the molecular biology of SCCA in HIV-positive (HIV+) and HIV-negative (HIV-) patients. We retrieved tumor specimens from 18 HIV- and 10 HIV+ patients diagnosed with SCCA in two institutions. DNA from tumor and normal tissues was extracted and then amplified by polymerase chain reaction. LOH was investigated at 14 loci: three at 18q (DCC), two at 13q (Rb), three at 17p (p53), three at 11q, one at 2p, and two at 5q (APC). LOH was defined by a tumor DNA-to-normal tissue DNA ratio of >2. HIV+ patients were younger (36 ± 7 years versus 53 ± 13 years, P = 0.001) and showed a trend toward tumors of larger size (3.7 ± 1.6 cm versus 2.6 ± 1.5 cm, P = 0.09). The median CD4+ count in HIV+ patients at the time of diagnosis was 74 × 106/L (range, 5–900). The overall frequency of LOH was 17.3% (41 LOH of 236 informative loci). Tumors in HIV- patients were more likely to present LOH than were tumors in HIV+ patients (24.1% versus 6.6%, P = 0.0004). Differences between the two groups with regard to allelic losses were also observed at specific loci, such as 18q (41% [HIV-] versus 0% [HIV+], P = 0.05), 17p (43% versus 10%, P = 0.09), and 5q (33% versus 0%, P = 0.12). Consistent LOH on chromosomes 17p, 18q, 5q, and 11q were observed in HIV- patients with SCCA. By contrast, allelic losses at 17p, 5q, and 18q seem to be rare in tumors of HIV+ individuals. These data suggest that immunosuppression may promote SCCA progression through an alternate pathway and that persistence of HPV infection within the anal canal may play a central role in this process.

The incidence of colonoscopic perforation of colon is about 0.3 per cent. The incidence of colonoscopic bleeding is about 0.6 per cent. Many of those patients undergo unnecessary operations. In order to assess the outcome of nonoperative management of those patients with postcolonoscopic perforation and bleeding, the records of 5120 patients who underwent colonoscopies from September 1, 1988 to June 30, 2003 were retrospectively reviewed with attention paid to colonoscopic perforation and bleeding. Their symptoms, management, and outcome were reviewed. There were 2765 male and 2355 female patients. Ages ranged from 9 to 91 years. A total of 1902 patients (37.1%) had polyps removed. Six patients (0.1%) had colonoscopic perforation. All of them presented with abdominal pain 1 to 4 days after colonoscopic polypectomy. All had subphrenic free air or subcutaneous emphysema on the radiogram. All were treated nonoperatively with nothing by mouth and intravenous fluids and antibiotics in the hospital and recovered uneventfully. Six patients (0.1%) had colonic bleeding that occurred 1 to 14 days after colonoscopic polypectomy. All of them were managed by repeat colonoscopy with injection of epinephrine. All recovered without further bleeding. Therefore, postcolonoscopic perforation and bleeding can be treated nonoperatively. It is safe and cost effective. The mortality and morbidity are very low.

This review was designed to determine whether "high-dose" steroid therapy (> or =20 mg prednisone/day) increases the likelihood of anastomotic complications after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). The hospital records of 100 patients undergoing proctocolectomy with IPAA were reviewed. Patient characteristics were analyzed to determine what factors were associated with higher rates of anastomosis-related complications. Seventy-one of our patients were given diverting ileostomies, whereas the remaining 29 underwent a single-stage procedure. Fifty-four percent of the patients in our review were taking steroids preoperatively, 39 of whom were on high-dose therapy. The overall anastomosis-related complication rate was 14%. There was no significant difference in complication rates with respect to age, steroid use, steroid dose, use of a diverting ileostomy, type of anastomosis, duration of disease, or presence of backwash ileitis. A trend toward higher leakage rates was found in patients undergoing single-stage procedures (10.3% vs. 2.8%, P=0.14) as well as in patients undergoing single-stage procedures on high-dose steroids (22% vs. 5.0, P=0.22). Nevertheless, neither of these trends was found to be statistically significant, which was likely influenced by the small sample size. Our data suggest that there may be an increase in anastomotic leakage rates in patients on high-dose steroids undergoing a single-stage proctocolectomy with IPAA. Nevertheless, our rate was not as high as the rates seen by other investigators and did not reach statistical significance. During preoperative counseling, patients on high-dose steroids should be informed of this uncertain but real risk of anastomotic leakage.

A case of an 82-year-old woman is reported who developed a lower gastrointestinal hemorrhage secondary to metastatic ovarian carcinoma to the colon. The bleeding, associated with an incomplete obstruction of the large bowel, was successfully treated with the endoscopic insertion of two self-expanding metal stents. A technique of stent placement is presented which differs from that previously reported, where both stents were via colonoscopy and without the use of fluoroscopy.

PURPOSE: Creation of a safe ileal pouch requires a tension-free anastomosis. The aim of this study was to evaluate a technical procedure that increases the length of the mesentery while preserving the blood supply to the ileal pouch. HYPOTHESIS: Preservation of the marginal vascular arcade (MVA) of the right colon will allow ligation of more mesenteric vessels and increase the mesenteric length. METHODS: Six fresh cadavers were dissected. Measurement of the apex of the terminal ileum was done in relation to the pubic symphysis. Measurements were taken after 1) complete mobilization of the terminal ileum, right colon, and hepatic flexure; 2) vascular ligation between colon wall and the MVA, preserving the latter from the right branch of the middle colic artery to the ileal branch of the ileocolic artery (ICA); 3) ligation of the distal third of the superior mesenteric artery; 4) ligation of the ICA at its origin; 5) ligation of the right colon artery; and 6) division of the terminal ileal mesentery. RESULTS: This technique enabled complete division of the terminal ileal mesentery, adding a mean additional 3.6 (range, 2.5–5.0) cm (36.5±16.5 percent) in length to the mesentery, compared with superior mesenteric artery, ICA, and right colic artery ligation. CONCLUSION: Patients who have a shorter mesentery and concern of excessive mesenteric tension should have colectomy performed, preserving the MVA from the middle colic artery to the ileal branch of the ICA. The preserved MVA can be a reliable alternative blood supply to the pouch if more mesenteric vessel ligations are necessary.

The purpose of this study was to evaluate the overexpression of cyclin G in colorectal neoplasia, which may be a more frequent event than cyclin D1 during the cell cycle and thus may have a more enhanced therapeutic potential in treating colorectal cancer. Ninety formalin-fixed, paraffin-embedded human colon and rectal specimens were obtained from the Pathology Department of Norris Cancer Center/University of Southern California. The tissues had been obtained after surgical resection between 1995 and 2001, and had been processed by routine clinical histopathologic methods. Ninety-one percent of colorectal tumors had cyclin G overexpression. These cyclin-positive patients were evenly distributed between men and women, and between tumor locations, that is, 36% rectal tumors and 34% right-sided tumors. Thirty-two percent were well differentiated, and 66% were moderately differentiated. Thirty patients (38%) had stage I disease, 16 (20%) had stage II disease, 25 (32%) had stage III, and seven (9%) had stage IV disease. Eight patients (10%) in this group had recurrent disease during follow-up. There was no correlation between cyclin G overexpression and clinical and pathologic characteristics. Cyclin D1 overexpression was found to be present in only 42% of colorectal adenocarcinomas. There was no correlation between cyclin D1 overexpression and clinical and pathologic characteristics. The present study demonstrates that cyclin G overexpression is a frequent event in colorectal cancer. This frequent event in colorectal carcinogenesis may facilitate new therapeutic approaches acting as a target for gene therapy, possibly directed at downregulating cyclin G in colorectal cancer.

The frequency of Internet use for self-directed medical care in different patient populations is increasing. We evaluated Internet use by patients presenting for bariatric surgery.Surveys were completed by 136 patients (109 women, 22 men) presenting to a private academic clinic for bariatric surgery. Data collected included age, gender, education level, household income, and pattern of Internet use. Comparisons were made with a group of 135 patients who visited a colorectal surgery clinic in the same institution.Bariatric patients who used the Internet were more likely than colorectal patients to inform themselves about their medical problem (76% versus 49%, p0.001) and tended to use the Internet more overall (85% versus 78%, p = ns). Use of the Internet to research bariatric surgery was associated with education level (p = 0.002) and household income (p = 0.01), but not with age or gender. Bariatric patients were more likely than colorectal patients to search our institution's Web site (40% versus 17%, p0.001) and to use the Internet to find out about their surgeon (47% versus 31%, p = 0.01). Only 9% of bariatric patients used a chat room. Ninety-six percent of bariatric patients found the information on the Internet easy to understand and 58% described it as very helpful.Bariatric patients are especially likely to use the Internet to gain information about their medical condition, possibly reflecting their limited mobility. This represents an educational opportunity for the surgical community.

Background and Objectives The goal of this study was to establish a reproducible nude mouse model of liver metastasis and investigate the potential of deploying targeted injectable retroviral vectors for metastatic gastrointestinal cancer. Methods Human cancer cells were injected into the portal vein via an indwelling catheter. The animals were sacrificed at specified time intervals, and the number of tumor nodules was counted in histologic sections of harvested livers. A group of animals received either an extracellular matrix-targeted or a nontargeted retroviral vector bearing a β-galactosidase gene by portal vein infusion. Results The number of tumor nodules increased progressively over time at ≤50 days post-infusion (r = 0.81; P

The hypothesis that the length of bowel and amount of mesentery resected with laparoscopically assisted colectomy are comparable to traditional open techniques was tested by means of a chart review of prospectively collected data of 22 laparoscopically assisted colectomies, 35 open colectomies performed by the same surgeon, and 39 other open colectomies performed at the same institution by other community surgeons. The average length of bowel resected in the laparoscopically assisted group was 21.7 cm, for the traditionally resected group, 31.4 cm, and for the other group, 26.7 cm. No statistically significant differences existed between the three evaluable groups. Although there was a trend toward greater length of bowel resected with the open technique, there was no statistically significant difference in this study. Follow-up at a mean of 24 months after resections shows no abdominal wall recurrences or any unusual patterns of recurrence. It is concluded that laparoscopically assisted colectomy can be performed in select groups to obtain adequate surgical resection for colorectal carcinoma. Further studies to generate larger numbers of patients with longer follow-up to determine the adequacy of resection as well as the comparability of cure rate will be necessary to confirm the findings of this preliminary study.

3603 Background: The two primary aims of NSABP R-04 were 1) Can the oral fluoropyrimidine, Cape be substituted for the standard of care in the curative setting of Stage II & III rectal cancer namely, CIV 5-FU, during neoadjuvant RT; and 2) Can the addition of Ox enhance the activity of fluoropyrimidine sensitized RT? Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without intravenous Ox (50mg/m2 /wk x 5) or oral Cape (825 mg/m2 BID 5 days/wk), with or without Ox (50mg/m2/wk x 5). The primary endpoint was local-regional (L-R) tumor control that included L-R tumor recurrence, less than a complete surgical resection, and no surgery for any reason. Results: From July 2004 to August 2010, 1,608 patients were randomly assigned and 99.2% were eligible for analysis. There were n...

384 Background: Valentini, et al. (J Clin Oncol 29: 2011, 3163-72) developed nomograms for predicting overall survival (OS) based on clinical factors available after neoadjuvant therapy (tx). Pathologic T-stage (pT), N-stage (pN), and clinical T (cT) were the most important independent predictors of OS. We developed a neoadjuvant RC score (NAR score) using pN and downstaging of T (cT – pT) based on relative weights suggested by the nomograms. NSABP’s R-04 trial presents an opportunity for independent validation of the NAR score. Methods: Pts with clinical stage II/III RC undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540-1,080cGy in 3-6 daily fractions) were randomized to one of four regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without oxaliplatin (Ox) (50mg/m2 /wk x 5) or oral capecitabine (825 mg/m2 BID 5 days/wk), with or without Ox. The NAR score is computed as [5 pN – 3 (cT – pT) + 12]2/ 9.61 where: cT in {1, 2, 3, 4}, pT in {0, 1, 2, 3, 4}, and pN in {0, 1, 2}. The NAR score takes values from 0 to 100; higher scores indicate poorer prognosis. Analyses based on the score should be stratified by cT. NAR score is compared to pathologic complete response (ypCR) by Akaike’s information criterion (AIC) to determine the better predictor of OS. Results: 1,479 pts had data for the NAR score and follow-up for OS. Continuous NAR score was significantly associated with OS (HR/unit 1.04 95% CI 1.03-1.05, p

390 Background: The primary aims were to: 1) compare capecitabine (Cape) and continuous intravenous infusion (CVI) 5-FU combined with pelvic radiation therapy (RT) given preoperatively for patients (pts) with stage II or III rectal cancer; 2) determine whether the addition of oxaliplatin (Ox) would improve pt outcomes. Preliminary results focusing on pathologic complete response, sphincter-sparing surgery, surgical downstaging, and toxicity were presented at ASCO 2011 (Roh: J Clin Oncol 29: 2011 Ab 3503). Methods: Pts with clinical stage II or III rectal cancer undergoing preoperative RT (4,500cGy in 25 fractions over 5 wks + boost of 540cGy-1080cGy in 3-6 daily fractions) were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU (225mg/m2 5 days/wk), with or without intravenous Ox (50mg/m2 /wk x 5) or oral Cape (825 mg/m2 BID 5 days/wk), with or without Ox (50mg/m2/wk x 5). The primary endpoint of local-regional (L-R) tumor control included L-R tumor recurrence, less than an R0 resection (complete surgical resection), and no surgery. Results: From July 2004 to August 2010, 1608 patients were randomly assigned and 99.2% were eligible. There were no significant differences in L-R tumor control, DFS, or OS between regimens for either the 5-FU-Cape (L-R p=0.98) or the Ox-none (L-R p=0.70) comparisons. The addition of Ox was associated with significantly more grade 3-4 diarrhea (p80% of the ideal chemotherapy dose in combination with preoperative RT. Conclusions: CVI 5-FU or oral Cape combined with RT produced similar outcomes and toxicity profiles. Because use of oral Cape avoids the need for central venous catheters and ambulatory infusion pumps, it can be considered a new standard of care in this setting. The addition of Ox provided no improvement in outcomes but did add significant toxicity. Clinical trial information: NCT00058474.

Reports of metastatic spread of colon and rectal cancer to port sites after laparoscopic resection of potentially curable lesions has raised doubt regarding the efficacy and safety of laparoscopic technology in cancer surgery. Experimental study in animals has led us to believe that the mode of spread of these metastases is via the direct route. We hypothesized, therefore, that we could decrease the rate of trocar-site recurrences by treating the individual port sites with a topical tumoricidal agent.Male BD-IX rats weighing 240 to 360 g were injected with syngeneic colon cancer to simulate free intraperitoneal cancer spread to trocar sites. All rats were subjected to a sham laparoscopic operation after 2 x 10(5) viable cancer cells had been injected into their peritoneal cavities. Five-millimeter trocars were inserted into each rat after abdominal insufflation to 10 mm Hg. Pneumoperitoneum was maintained for 10 minutes before the trocars were removed simultaneously. Trocar sites were then subjected to one of three treatments, with each animal receiving a maximum of two different treatments. Sites were treated with 70% ethanol (N = 42), povidine/ iodine (N = 40), or no topical treatment (N = 46). Three weeks later, the animals were euthanized and autopsied. Subcutaneous tumors at trocar sites or tumors with50% volume within the wound were considered implants.Control sites revealed a metastasis rate of 41% (19/46). The tumor implant rate was 36% (15/42) at alcohol-treated sites and 20% (8/40) at sites treated with povidone-iodine (P0.05).Topical administration of povidone-iodine to trocar wounds after laparoscopic surgery can significantly reduce the incidence of port-site metastasis in a syngeneic animal model of colon cancer.

PURPOSE: The WAND™ is a computer-controlled local anesthetic delivery system. Its use has been proven to be more comfortable for dental patients. The purpose of this study is to explore its applicability to anal procedures. Our hypothesis is that the WAND™ will provide greater comfort during anesthesia delivery while achieving the same anesthetic effect as traditional syringe technique. METHODS: Twenty patients with painless anal pathology were randomized to receive anal anesthesia using either the WAND™ or traditional syringe technique to a randomly selected half of the anoderm (right or left). The opposite side was then anesthetized by the alternate method, allowing patients to act as their own control. Objective and subjective pain scores were obtained from the patient after each mode of delivery. An independent observer interpreted the patient's tolerance by giving a subjective pain score. The volume of anesthetic used was recorded. Adequacy of anesthesia was tested by a pinch test. RESULTS: Sixteen (80 percent) of the 20 patients preferred the use of the WAND™. Objective and subjective pain scores per the patients and subjective pain scores per the observer were significantly lower for the WAND™ than for traditional syringe technique (P

Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demonstrated that intravenous infusion of a matrix (i.e., collagen)-targeted retroviral vector provided efficacious gene delivery of a cytocidal mutant cyclin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mice. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted vector bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without associated toxicity. Kaplan-Meier survival studies were conducted in mice treated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-targeted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value for comparing all three groups simultaneously was 0.003, with a trend that was significant to a level of 0.004, indicating that the probability of long-term control of tumor growth was significantly greater with the matrix-targeted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS placebo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficiency, and (3) enhanced therapeutic gene delivery and long-term efficacy without eliciting appreciable toxicity.

In the present study, the mature epidermal growth factor (EGF) protein was engineered to incorporate a high affinity collagen-binding domain (CBD) derived from co-agulation von Willebrand factor, to specifically target EGF to colonic lesions. The fusion protein was expressed in an E. coli bacterial expression system, purified by metal chelate chromatography, and renatured by oxidative refolding into a soluble biologically active growth factor. The EGF-CBD fusion protein bound tightly to collagen matrices under conditions in which native non-targeted EGF was washed away. In biologic assays, the EGF-CBD fusion protein stimulated NIH3T3 cell proliferation with near wild-type biological activity. In vivo binding studies showed that the collagen-targeted EGF, but not the non-targeted EGF, accumulated at areas of exposed collagen on the luminal surface of the inflamed colon. Finally, a single colonic instillation of the collagen-targeted EGF-induced a more rapid regeneration of intestinal crypts 24 h after treatment (no. of crypts = 89.2+/-8.1) compared to the non-targeted EGF (no. of crypts = 52.2+/-29.8; p=0.027), and the PBS control (no. of crypts = 24. 0+/-22.9; p=0.001). Taken together, these findings indicate that intracolonic delivery of collagen-targeted EGF represents a potentially effective therapeutic strategy for acute or chronic inflammatory bowel disease.

Neoplastic cells within solid tumors develop an intimate and complex relationship with nonneoplastic tissues, including vascular endothelial cells, stromal cells, and extracellular matrix (16). These histologic features of solid tumors, which make up more than 90% of all human cancers, taken together with the emerging mechanisms of angiogenesis that accompany tumor growth and metastasis (16, 27), have promoted the concept of targeting to tumor vasculature as a compelling therapeutic strategy (11, 18). Accordingly, antiangiogenic gene therapy directed against microvascular endothelial cells that have been recruited into the tumor beds has been developed (19) and employed (23, 58) with considerable success (7). Vascular endothelial growth factor (VEGF), a selective endothelial cell mitogen (13, 32, 59) and mediator of vascular permeability (53, 57), is an important factor in driving the growth, metastasis, and angiogenesis of solid tumors (12, 50). Within the tumor microenvironment, there is a reported up-regulation of both VEGF and its cognate receptor(s) on tumor vascular endothelium (8). Both oncogenic transformation and hypoxic conditions that are found in most solid tumors act synergistically to modulate VEGF expression (20, 40). Moreover, recent studies of VEGF expression in tumor stromal cells versus tumor cells have also focused on the importance of stromal fibroblasts as a source of VEGF and hence as a contributor to tumor angiogenesis (22). Additionally, both fibroblast growth factor type 2 exposure (46) and hypoxia (9, 61) serve to up-regulate the expression of the VEGF receptor(s) on endothelial cells. Thus, the VEGF-receptor complex is a highly specific marker of tumor endothelium (15, 33) and can be used for the targeting and/or imaging of tumor vasculature (8). In addition to expression of angiogenic growth factors, endothelial cells within the activated microvasculature of solid tumors express αv integrins, which are virtually absent from the cells of established blood vessels (10, 21, 26). Indeed, fundamental roles for inducible integrin receptors and extracellular matrix (ECM) proteins in angiogenesis are well established (57). The integrin αvβ3, for example, is expressed preferentially on vascular cells during the proliferative and invasive phases of angiogenesis and serves as a multifunctional adhesion receptor that binds to a number of ECM proteins which typically constitute a provisional matrix (including collagen, fibronectin, vitronectin, and fibrinogen) and which are reported to promote cell proliferation (1, 38). Normally undetectable in quiescent blood vessels, αvβ3 becomes highly expressed upon stimulation by angiogenic growth factors or tumor cell supernatant (10). Conversely, blockade of αvβ3 function by specific antibodies or peptide antagonists results in unscheduled apoptosis of proliferating endothelial cells (10), suggesting that the αvβ3 receptor system provides a critical survival signal that facilitates vascular cell proliferation (57). Endothelial cell apoptosis appears to be mediated by p53 and accompanied by induction of the cell cycle inhibitor p21WAF1/CIP1 (57). Thus, the interaction between the inducible αvβ3 adhesion receptor and the provisional ECM directly regulates growth arrest signals and promotes endothelial cell survival (57). Growth factor and/or adhesion receptors that are selectively expressed on the surface of activated endothelial cells provide an advantageous locus for targeting drugs and gene therapy vectors to angiogenic tissues. Molecular screens for high-affinity targeting motifs have been developed using designated panels of monoclonal antibodies (31) and random phage display peptide libraries (45). Remarkably, many of the peptide ligands isolated by random phage display technology, either (i) by panning for peptides that bind the integrin αvβ1 (34, 35) or αvβ3 (29) in vitro or (ii) by isolating peptides with homing specificity for tumor blood vessels in vivo (5), exhibit sequences that correspond to identifiable ligand-receptor contact points within the primary structure of fibronectin. Specifically, Asn-Gly-Arg (NGR)-containing sequences identified in vitro and in vivo bear striking similarities to the 9th type III repeat of fibronectin, while Arg-Gly-Asp (RGD) sequences correspond closely to the 10th type III repeat of fibronectin (5, 34, 35). From this point, we will use the term “tumor vasculature targeting motif” (TVTM) to concisely describe the tumor-homing and accumulation phenomenology of fibronectin-derived (NGR) congeners originally characterized by phage display technology (5). NGR motifs exhibit a greater homing ratio (tumor/control organs) than do comparable RGD motifs, and the two motifs have differential affinities for defined integrins and peptide competition kinetics, suggesting that NGR and RGD peptides bind to different cellular receptors (5). In the present study, we constructed a number of NGR-bearing peptide congeners displayed within the context of Moloney murine leukemia virus (MoMLV) envelope escort proteins. Escort proteins are defined as noninfectious Env proteins that accompany the infectious wild-type (WT) Env to provide a gain-in-function phenotype (i.e., targeting) to the composite vector. Escort proteins consist of ligands or peptides that replace the deleted receptor binding domains of the modified ecotropic Env construct, CEEC, which bears an amphotropic (CAE) instead of the ecotropic (CEE+) hinge region. The performance of these chimeric vectors was evaluated in terms of in vitro targeting and transduction of activated endothelial cells.

Increased attention to surgical indications and technique can minimize the risks of recurrent rectal cancer. In addition, the use of adjuvant chemoradiation therapy has been shown to further decrease the risks of recurrent rectal cancer. In the event a recurrence develops, surgical therapy, combined with radiation therapy, can result in local control in as many as 75% of patients and long term survival in 25% to 40% of patients.