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Background: The aim of this article is to familiarize the reader with one system's approach to creating an aligned academic health system that facilitates delivery of academic health care in community hospitals., Methods: A wide variety of approaches to this challenge include viewing the community facilities as strictly feeders to the academic centers with no shared governance, to viewing them as branding opportunities with aligned governance, to a more integrated model such as ours, and to creating exclusive centers of excellence in the community facilities by consolidating services initially dispersed across competing hospitals into one center., Results: We leveraged service lines and domains to standardize care across all hospital settings which facilitated delivery of complex tertiary care in community hospitals, thus increasing capacity in the Academic Medical Center for complex quarternary care., Conclusion: Through creating a more completely integrated, patient centric health system that leverages the community partners we minimized the need for people to travel from their community hospitals to the Academic Medical Center while still ensuring they received the expertise of a leading academic institution., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Surgical site infections (SSIs) remain a morbid and costly complication in abdominal surgery. Topical antibiotic delivery via intraoperative irrigation and barrier wound protection are strategies for preventing SSI. We tested the safety and efficacy of a novel wound protector device with an integrated fluid irrigation platform in a porcine model., Methods: A simulated colorectal resection model was designed and performed on adult female pigs with a standardized concentration of 10 9 colony-forming units (CFU) of Escherichia coli administered to the wound site in 10 mL of normal saline (n = 7). The device was tested intraoperatively with and without irrigation with gentamicin-containing irrigant solution. Swab and tissue samples were obtained in addition to peripheral blood samples. Quantitative culture analysis was performed in addition to histological and immunohistochemical analysis and gentamicin concentration measurements., Results: There were no adverse events observed in the animals. Tissue protected by the device yielded exponentially lower levels of E. coli growth compared to exposed tissue, with a mean 1 × 10 2 CFU/swab. Use of the device, both with and without irrigation, was associated with an exponential reduction in quantitative bacterial load compared to the control wounds with no device, with limited growth after wound closure in the pigs receiving irrigation. Histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analysis revealed no significant damage to tissue. Serum gentamicin levels remained below the clinical threshold and decreased over time., Conclusions: This in vivo study suggests safety and efficacy of a novel device for the prevention of intraoperative wound contamination.

Objectives: The prognostic value of several hematologic parameters, including platelet, lymphocyte, and neutrophil counts, has been studied in a variety of solid tumors. In this study, we examined the significance of inflammatory markers and their prognostic implications in patients with colorectal cancer (CRC)., Materials and Methods: Patients with stage I-III CRC who underwent surgical resection at the Stanford Cancer Institute between 2005 and 2009 were included. Patients were excluded if they did not have preoperative complete blood counts performed within 1 month of surgical resection, underwent preoperative chemotherapy or radiation, had metastatic disease at diagnosis, or had another previous malignancy. We included 129 eligible patients with available preoperative complete blood counts in the final analysis., Results: A preoperative neutrophil-to-lymphocyte ratio of>3.3 was significantly associated with worse disease-free (DFS) and overall survival (OS) (P=0.009, 0.003), as was a preoperative lymphocyte-to-monocyte ratio of ≤2.6 (P=0.01, 0.002). Preoperative lymphopenia (P=0.002) was associated with worse OS but not DFS (P=0.09). In addition, preoperative thrombocytosis was associated with worse DFS (P=0.006) and OS (P=0.010). Preoperative leukocytosis was associated with worse OS (P=0.048) but not DFS (P=0.49). Preoperative hemoglobin was neither associated with OS (P=0.24) or DFS (P=0.15)., Conclusions: Pretreatment lymphopenia, thrombocytosis, a decreased lymphocyte-to-monocyte ratio, and an elevated neutrophil-to-lymphocyte ratio independently predict for worse OS in patients with CRC.

Objective: The incidence of anal cancer is higher in women than men in the general population and has been increasing for several decades. Similar to cervical cancer, most anal cancers are associated with human papillomavirus (HPV), and it is believed that anal cancers are preceded by anal high-grade squamous intraepithelial lesions (HSIL). Our goals were to summarize the literature on anal cancer, HSIL, and HPV infection in women and to provide screening recommendations in women., Methods: A group of experts convened by the American Society for Colposcopy and Cervical Pathology and the International Anal Neoplasia Society reviewed the literature on anal HPV infection, anal SIL, and anal cancer in women., Results: Anal HPV infection is common in women but is relatively transient in most. The risk of anal HSIL and cancer varies considerably by risk group, with human immunodeficiency virus-infected women and those with a history of lower genital tract neoplasia at highest risk compared with the general population., Conclusions: While there are no data yet to demonstrate that identification and treatment of anal HSIL leads to reduced risk of anal cancer, women in groups at the highest risk should be queried for anal cancer symptoms and required to have digital anorectal examinations to detect anal cancers. Human immunodeficiency virus-infected women and women with lower genital tract neoplasia may be considered for screening with anal cytology with triage to treatment if HSIL is diagnosed. Healthy women with no known risk factors or anal cancer symptoms do not need to be routinely screened for anal cancer or anal HSIL.

The incidence of anal cancer is elevated in human immunodeficiency virus (HIV)-infected men-who-have-sex-with-men (MSM) compared to the general population. Anal high-grade squamous intraepithelial lesions (HSIL) are common in HIV-infected MSM and the presumed precursors to anal squamous cell cancer; however, direct progression of HSIL to anal cancer has not been previously demonstrated. The medical records were reviewed of 138 HIV-infected MSM followed up at the University of California, San Francisco, who developed anal canal or perianal squamous cancer between 1997 and 2011. Men were followed up regularly with digital anorectal examination (DARE), high-resolution anoscopy (HRA) and HRA-guided biopsy. Although treatment for HSIL and follow-up were recommended, not all were treated and some were lost to follow-up. Prevalent cancer was found in 66 men. Seventy-two HIV-infected MSM developed anal cancer while under observation. In 27 men, anal cancer developed at a previously biopsied site of HSIL. An additional 45 men were not analyzed in this analysis due to inadequate documentation of HSIL in relation to cancer location. Of the 27 men with documented progression to cancer at the site of biopsy-proven HSIL, 20 men progressed from prevalent HSIL identified when first examined and seven men from incident HSIL. Prevalent HSIL progressed to cancer over an average of 57 months compared to 64 months for incident HSIL. Most men were asymptomatic, and cancers were detected by DARE. Anal HSIL has clear potential to progress to anal cancer in HIV-infected MSM. Early diagnosis is facilitated by careful follow-up. Carefully controlled studies evaluating efficacy of screening for and treatment of HSIL to prevent anal cancer are needed., (© 2013 UICC.)

Background: Previous work suggests hospitals serving high percentages of patients with Medicaid are associated with worse colon cancer survival. It is unclear if practice patterns in these settings explain differential outcomes., Hypothesis: High Medicaid hospitals (HMH) have lower compliance with evidence-based care processes (examining 12 or more lymph nodes (LN) during surgical staging and providing appropriate chemo-therapy)., Methods: Retrospective analysis of stage I-III colon cancers from California Cancer Registry (1996-2006) linked to discharge abstracts and hospital profiles predicted hospital compliance with guidelines and trends in compliance over time., Results: Cases (N=60,000) in 439 hospitals analyzed. High Medicaid hospital settings had lower odds of compliance with the 12 LN exam (OR(HMH)0.91, CI(HMH)[0.85, 0.98]) and with the delivery of appropriate chemotherapy (OR(HMH)0.76, CI(HMH)[0.67, 0.86])., Conclusions: High Medicaid hospital status is associated with poor performance on evidence-based colon cancer care. Policies to improve the quality of colon cancer care should target these settings.

Background: National quality initiatives have mandated the earlier removal of urinary catheters after surgery to decrease urinary tract infection rates. A potential unintended consequence is an increased postoperative urinary retention rate., Objective: The aim of this study was to determine the incidence and risk factors for postoperative urinary retention after colorectal surgery., Design: This was a prospective observational study., Settings: A colorectal unit within a single institution was the setting for this study., Patients: Adults undergoing elective colorectal operations were included., Interventions: Urinary catheters were removed on postoperative day 1 for patients undergoing abdominal operations, and on day 3 for patients undergoing pelvic operations. Postvoid residual and retention volumes were measured., Main Outcome Measures: The primary outcomes measured were urinary retention and urinary tract infection., Results: The overall urinary retention rate was 22.4% (22.8% in the abdominal group, 21.9% in the pelvic group) and was associated with longer operative time and increased perioperative fluid administration. Mean operative time for those with retention was 2.8 hours and, for those without retention, the mean operative time 2.2 hours (abdominal group 2 hours vs 1.4 hours, pelvic group 3.9 hours vs 3.1 hours, p ≤ 0.02). Patients with retention received a mean of 2.7L during the operation, whereas patients without retention received 1.8L (abdominal group 1.9L vs 1.4L, pelvic group 3.6L vs 2.2L, p < 0.01). In the abdominal group, patients with and without retention also received different fluid volumes on postoperative days 1 (2.2L vs 1.7L, p = 0.004) and 2 (1.6L vs 1L, p = 0.05). Laparoscopic abdominal group had a 40% retention rate in comparison with 12% in the open abdominal group (p = 0.004). Age, sex, preoperative radiation therapy, preoperative prostatism, preoperative diagnosis, and level of anastomosis were not associated with retention. The urinary tract infection rate was 4.9%., Limitation: The lack of documentation of preoperative urinary function was a limitation of this study., Conclusions: The practice of earlier urinary catheter removal must be balanced with operative time and fluid volume to avoid high urinary retention rates. Also important is increased vigilance for the early detection of retention.

Although the incidence of human papillomavirus (HPV)-associated anal neoplasia is increasing, interobserver and intraobserver reproducibility in the grading of biopsy specimens from this area remains unacceptably low. Attempts to produce a more reproducible grading scheme have led to the use of biomarkers for the detection of high-risk HPV (HR-HPV). We evaluated the performance of standard morphology and biomarkers p16, ProEx C, and Ki-67 in a set of 75 lesions [17 nondysplastic lesions, 23 low-grade squamous intraepithelial lesions (LSIL)/condyloma, 20 high-grade squamous intraepithelial lesions (HSIL), 15 invasive squamous cell carcinomas] from the anal and perianal region in 65 patients and correlated these findings with HPV subtype on the basis of a type-specific multiplex real-time polymerase chain reaction assay designed to detect HR-HPV. A subset of cases with amplifiable HPV DNA was also sequenced. HSIL was typically flat (15/20), and only a minority (4/20) had koilocytes. In contrast, only 1 LSIL was flat (1/23), and the remainder were exophytic. The majority of LSIL had areas of koilocytic change (20/23). HR-HPV DNA was detected in the majority (89%) of invasive carcinomas and HSIL biopsies, 86% and 97% of which were accurately labeled by strong and diffuse block-positive p16 and ProEx C, respectively. LSIL cases, however, only infrequently harbored HR-HPV (13%); most harbored low-risk HPV (LR-HPV) types 6 and 11. Within the LSIL group, p16 outperformed ProEx C, resulting in fewer false-positive cases (5% vs. 75%). Ki-67 was also increased in HR-HPV-positive lesions, although biopsies with increased inflammation and reactive changes also showed higher Ki-67 indices. These data suggest that strong and diffuse block-positive nuclear and cytoplasmic labeling with p16 is a highly specific biomarker for the presence of HR-HPV in anal biopsies and that this finding correlates with high-grade lesions.

Background: Locally advanced and recurrent colorectal cancers pose a significant therapeutic challenge. Orthovoltage intraoperative radiotherapy provides one potential means of improving disease control at the time of surgery., Objective: This study sought to analyze outcomes and identify prognostic factors of patients treated with orthovoltage intraoperative radiotherapy for locally advanced or recurrent colorectal cancer., Design and Setting: This study is a retrospective chart review conducted at a tertiary medical center., Patients: Between January 1990 and July 2009, 55 patients underwent intraoperative radiotherapy to a total of 61 sites for locally advanced (n = 14) or recurrent (n = 41) cancers of colon (n = 18) or rectum/rectosigmoid junction (n = 37)., Interventions: Median dose was 12 Gy (range, 7.5-20 Gy). Among locally advanced rectal/rectosigmoid cases, surgery included abdominoperineal resection (n = 3) or low anterior resection (n = 9). Seven treated sites had gross residual (R2) disease, 28 had pathologic or clinical microscopic residual disease (R1), and 15 were complete resections (R0). Treated sites included sacrum (n = 22), anterior pelvis/pelvic sidewall (19), sacrum and sidewall (n = 1), aortic bifurcation (n = 2), vaginal cuff (n = 2), psoas (n = 3), perivesicular region (n = 2), and other (n = 10)., Main Outcomes Measures: Outcomes measures included in-field local control, locoregional control, overall survival, and grade ≥3 toxicity., Results: At a median follow-up of 27 months (range, 4-237) among living patients, 2-year Kaplan-Meier estimates of in-field local control, locoregional control, and overall survival were 69%, 51%, and 59%. Margin status predicted for improved locoregional control (p = 0.01) and overall survival (p = 0.01). Seventeen patients (31%) developed a grade 3 to 5 toxicity following surgery with intraoperative radiotherapy., Limitations: This study was limited by its retrospective nature and relatively small sample size., Conclusions: Local control with intraoperative radiotherapy for locally advanced and recurrent colorectal cancers is good despite the high risk of residual disease. Among carefully selected patients, multimodality regimens including intraoperative radiotherapy may permit long-term survival.

Background: The purpose of this study was to compare outcomes in patients with anal canal squamous cell carcinoma (SCCA) who were treated with definitive chemoradiotherapy by either intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (CRT)., Methods: Forty-six patients who received definitive chemoradiotherapy from January 1993 to August 2009 were included. Forty-five patients received 5-fluorouracil with mitomycin C (n = 39) or cisplatin (n = 6). Seventeen (37%) were treated with CRT and 29 (63%) with IMRT. The median dose was 54 Gy in both groups. Median follow-up was 26 months (CRT) and 32 months (IMRT). T3-T4 stage (P = .18) and lymph node-positive disease (P = .6) were similar between groups., Results: The CRT group required longer treatment duration (57 days vs 40 days, P < .0001), more treatment breaks (88% vs 34.5%, P = .001), and longer breaks (12 days vs 1.5 days, P < .0001) than patients treated with IMRT. Eleven (65%) patients in the CRT group experienced grade >2 nonhematologic toxicity compared with 6 (21%) patients in the IMRT group (P = .003). The 3-year overall survival (OS), locoregional control (LRC), and progression-free survival were 87.8%, 91.9%, and 84.2%, respectively, for the IMRT groups and 51.8%, 56.7%, and 56.7%, respectively, for the CRT group (all P < .01). On multivariate analysis, T stage, use of IMRT, and treatment duration were associated with OS, and T stage and use of IMRT were associated with LRC., Conclusions: The use of IMRT was associated with less toxicity, reduced need for treatment breaks, and excellent LRC and OS compared with CRT in patients with SCCA of the anal canal., (Copyright © 2011 American Cancer Society.)

Objective: The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma., Method: Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT., Results: Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs 46 days vs 46 days vs

Anal squamous intraepithelial lesions include both low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) and are caused by chronic infection with the human papillomavirus (HPV). The disease is increasing in both incidence and prevalence, especially among patients with the following risk factors: homosexual men, acquired or iatrogenic immunosuppression, and presence of other HPV-related diseases. Although the natural history of the disease is unknown, there is significant evidence that untreated HSIL progresses to squamous cell carcinoma in 11% of patients and in up to 50% of patients with extensive disease and immunosuppression. Anal cytology and reflex HPV DNA testing are used to screen for disease, particularly among patients with the aforementioned risk factors. Evaluation of the patient should include physical examination and high-resolution anoscopy (HRA) to evaluate for disease above and below the dentate line. Intervention is warranted and this can be achieved in many ways. The treatment option associated with the best outcomes is ablation directed with HRA, which can be performed in the office or in the operating room with minimal morbidity. This strategy is effective in patients with both low-volume and high-volume disease and is associated with a malignant progression rate of 0.4% in patients with treated HSIL.

Introduction: Despite several meta-analyses and randomized controlled trials showing no benefit to patients, mechanical bowel preparation (MBP) remains the standard of practice for patients undergoing elective colorectal surgery., Methods: We performed a systematic review of the literature of trials that prospectively compared MBP with no MBP for patients undergoing elective colorectal resection. We searched MEDLINE, LILACS, and SCISEARCH, abstracts of pertinent scientific meetings and reference lists for each article found. Experts in the field were queried as to knowledge of additional reports. Outcomes abstracted were anastomotic leaks and wound infections. Meta-analysis was performed using Peto Odds ratio., Results: Of 4,601 patients (13 trials), 2,304 received MBP (Group 1) and 2,297 did not (Group 2). Anastomotic leaks occurred in 97(4.2%) patients in Group 1 and in 81(3.5%) patients in Group 2 (Peto OR = 1.214, CI 95%:0.899-1.64, P = 0.206). Wound infections occurred in 227(9.9%) patients in Group 1 and in 201(8.8%) patients in Group 2 (Peto OR = 1.156, CI 95%:0.946-1.413, P = 0.155)., Discussion: This meta-analysis demonstrates that MBP provides no benefit to patients undergoing elective colorectal surgery, thus, supporting elimination of routine MBP in elective colorectal surgery., Conclusion: In conclusion, MBP is of no benefit to patients undergoing elective colorectal resection and need not be recommended to meet "standard of care."

Anal squamous dysplasia is recognized as a spectrum of disease that ranges from low-grade intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) to invasive anal squamous cell carcinoma (SCC). Recent reports have shown a significant increase in both the incidence and prevalence of both HSIL and anal SCC, particularly in immunocompromised patients and in men who have sex with men. These lesions are associated with chronic infection with the human papillomavirus. The natural history is unknown, yet reports of untreated patients have shown progression rates of up to 50% in high risk patients. There are controversies as to the optimal management of patients with HSIL. However, there is evidence that screening of high-risk patients with anal cytology is useful in identifying those that require further evaluation. Examination of the anorectal region is enhanced with the use of high resolution anoscopy. Treatment modalities vary in terms of morbidity and success rates. Wide local excision is associated with significant morbidity. Newer therapies such as topical immunomodulation, photodynamic therapy and therapeutic vaccines have been proposed, but long-term follow-up is unavailable. High resolution anoscopy can be used in the office or in the operating room to direct therapy. Using a comprehensive approach of cytology and office-based and/or operating room procedures directed with high resolution anoscopy results in clearance of HSIL in up to 80% of patients, malignant progression in 1%, and less morbidity than wide local excision.

Anal squamous cell carcinoma and its precursor lesions are increasing in incidence in the United States and Europe. This trend predates human immunodeficiency virus/acquired immune deficiency syndrome and has been associated with persistent high-risk human papilloma virus (HPV) genotype infection, previous lower genital tract dysplasia/carcinoma, high frequency anoreceptive intercourse, heavy cigarette smoking, immunosuppression in solid organ transplant and immune disorders, and human immunodeficiency virus seropositivity. Screening protocols for at-risk patients are under active investigation and pathologists are often asked to assess anal canal and perianal biopsies for the presence of dysplasia and/or invasive carcinoma. Because underdiagnosis and overdiagnosis of anal cancer and precancer may lead to inappropriate treatment, it is important for the pathologist to be aware of current screening strategies, specific risk lesions, and the role of pathology in initial diagnosis and evaluation of anal biopsy and/or resection specimens. Standardized histologic criteria and uniform terminology should be used for reporting all anal canal and perianal squamous intraepithelial lesions. HPV subtyping, anal cytology, and recently identified biomarkers, such as p16 and Becton Dickinson ProEx C may provide additional information in problematic cases, but it is important to be aware of the limitations of these assays. HPV has been linked to all the major histologic subtypes of anal carcinoma (eg, basaloid, cloacogenic, transitional, etc.) and this association is strongest for anal canal lesions. With the possible exception of the microcystic pattern, histologic subtype does not seem to predict prognosis; and anal squamous cell carcinomas should be classified as either keratinizing or nonkeratinizing. Poorly differentiated squamous cell carcinomas have a worse prognosis and should be distinguished from poorly differentiated adenocarcinoma, melanoma, and neuroendocrine tumors. Very well differentiated squamous cell carcinoma with pushing margins (so-called giant condyloma of Buschke and Lowenstein) should be classified as verrucous carcinoma; this tumor shows aggressive local infiltration but does not metastasize. As all anal condylomata may harbor foci of high-grade dysplasia or invasive carcinoma, careful sectioning and complete histologic examination is required.

Purpose: This study was designed to determine whether high-resolution anoscopy and targeted surgical destruction of anal high-grade squamous intraepithelial lesions is effective in controlling high-grade squamous intraepithelial lesions while preserving normal tissues., Methods: Retrospective review of 246 patients with high-grade squamous intraepithelial lesions treated with high-resolution anoscopy-targeted surgical destruction from 1996 to 2006, with at least one follow-up at a minimum two months with physical examination, high-resolution anoscopy, cytology, and biopsy when indicated., Results: Lesions were extensive in 197 patients (81 percent); 207 (84 percent) were men, and 194 (79 percent) were immunocompromised (HIV or other). Persistent disease occurred in 46 patients (18.7 percent), requiring planned staged therapy; 10 required surgery. Recurrent high-grade squamous intraepithelial lesions occurred in 114 patients (57 percent) at an average 19 (range, 3-92) months; 26 of these required surgery. All other patients were retreated in-office with high-resolution anoscopy-directed therapies. Complications were seen in nine patients (4 percent). Despite treatment, three patients progressed to invasive cancer (1.2 percent). At their last visit, 192 patients (78 percent) had no evidence of high-grade squamous intraepithelial lesions., Conclusions: High-resolution anoscopy-targeted destruction combined with office-based surveillance and therapy is effective in controlling high-grade squamous intraepithelial lesions and is superior to reports of expectant management or traditional mapping procedures.

Anal dysplasia (low-grade squamous intraepithelial lesions, LSIL; high-grade squamous intraepithelial lesions, HSIL) is a challenging disease for the surgeon. We reviewed 42 patients that underwent high-resolution anoscopy (HRA)-targeted surgical therapy of anal dysplasia in the past 10 years. Patients were followed up in the Anal Neoplasia Clinic with physical examination, cytology, HRA, and biopsy if indicated. Patients with disease amenable to local therapy were treated with office-based HRA-directed therapies. There were 30 men (mean age 39 years, range 21-63) and 12 women (mean age 50 years, range 31-71) included in the study. HSIL was present in 33, with four undergoing planned staged treatment due to circumferential disease. HSIL recurred in 45%, and most were re-treated successfully in-office. Progression to HSIL was seen in one patient with LSIL and to squamous cell carcinoma in one patient with HSIL despite therapy. No patients with LSIL had dysplasia at last follow-up. Minor complications occurred in three patients. HRA-targeted surgical therapy coupled with surveillance and re-treatment with office-based therapies offered an effective method in controlling anal dysplasia in the immunocompetent patient. Morbidity is minimal, and our progression to cancer rate is low (2.4%).

Primary colorectal squamous cell carcinoma (SCC) and squamous dysplasia are uncommon and little is known about their pathogenesis. Most have been reported in association with ulcerative colitis and other chronic disease states. Although cervical and anal SCC have been strongly linked to human papillomavirus (HPV) infection, the role of HPV in rectal squamous carcinoma has not been well-examined. We evaluated 3 cases of primary rectal SCC for the presence of high-risk HPV by immunohistochemistry for p16(INK4A), in situ hybridization, and polymerase chain reaction. HPV type 16 was detected by polymerase chain reaction in all cases. In addition, all cases exhibited diffuse strong reactivity for p16(INK4A) and punctate nuclear staining by Ventana HPVIII in situ hybridization. The presence of HPV 16 in all three cases suggests that high-risk HPV infection is a risk factor for rectal SCC, particularly in patients with underlying chronic inflammatory disease processes or altered immune status. Further studies are warranted to determine if SCC occurring more proximal in the colon are also HPV-dependent or occur via another, HPV-independent pathway.

A number of surgical techniques have been described to treat rectovaginal fistulas. Recurrent or persistent fistulas after previous repair can be particularly difficult to treat. We report a novel technique used to successfully repair rectovaginal fistulas after failed mucosal advancement flap procedures using a transperineal-layered closure with an interposed graft of acellular cadaveric dermis (Alloderm).

Purpose: The purpose of this video is to illustrate the use of high resolution anoscopy in the diagnosis and treatment of anal high-grade squamous intraepithelial lesions., Methods: Five patients with anal dysplasia were examined in the operating room with acetic acid and the operative microscope. Lugol's solution was used selectively. Acetic acid is generously applied to aide in the recognition of high-grade squamous intraepithelial lesions. Acetowhite regions are examined under the operative microscope to further distinguish lesions as either low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions. Acetowhite lesions with specific vascular characteristics like punctuate vessels or honeycomb patterns are highly suggestive of high-grade disease. These lesions are selectively destroyed under direct visualization with an effort to maintain normal mucosa and skin to prevent stenosis. Some pigmented lesions contain high-grade squamous intraepithelial lesions; the operative microscope is used in this setting to look for the vascular characteristics of high-grade disease., Results: The video reports five male patients treated for high-grade squamous intraepithelial lesions with the aide of high resolution anoscopy. There were no intraoperative or postoperative complications. All lesions suspicious for high-grade squamous intraepithelial lesions based on observed vascular patterns were confirmed as such with permanent histopathology., Conclusion: The use of acetic acid and the operative microscope with selective use of Lugol's solution accentuates the visual characteristics of high-grade lesions, enhancing the surgeon's ability to target treatment to high-grade squamous intraepithelial lesions. High resolution anoscopy is useful in the targeted treatment of high-grade squamous intraepithelial lesions.

Men who have sex with men have special health-care issues and are at high risk for sexually transmitted infections. In managing their anorectal health it is important to modify the history and physical and handle patients in a nonjudgmental fashion. It is important to understand behavioral patterns including recreational drug use, unprotected sex, and HIV infection. Screening and counseling play important roles in effective management of these patients.

Genital human papillomavirus (HPV) infection is an increasingly common sexually transmitted disease. This virus causes condylomata acuminata and is associated with anal neoplasia. Management options are discussed.

The anatomic definitions for anal cancer (canal versus margin) are made based on the relationship of the tumor to the anal verge. This method had led to confusion for some providers. A modification in the terminology is proposed that includes intra-anal, perianal, and skin as categories. The cause of anal carcinoma remains to be fully elucidated, and HPV seems to play a central role in this process. The incidence of anal cancers has increased, which is related to the evolution of HIV and AIDS, and their treatment. The accurate pathologic analysis of anal tumors is complex and is significantly aided by close communication between clinician and pathologist.

Anal cancer is an increasing problem among HIV-infected persons. Although patients are living longer and with better quality of life because of treatment with HAART, they remain at risk for invasive anal cancer and its precursor, anal HSIL. Given the substantial numbers of patients with anal HSIL, further studies need to be done to determine the efficacy and optimal mode of treatment of HSIL, to define the optimal method for screening patients at risk, to define the best way to follow up patients with documented HSIL to ensure early detection, to define prognostic factors for progression to invasive cancer, and to determine the progression rate of HSIL to invasive cancer. Although patients with good functional status and immunologic function seem to do relatively well with standard CMT for anal cancer, there are less fortunate patients who experience substantial morbidity from therapy and have a poorer outcome. It is difficult to draw definitive conclusions about the therapy of HIV-positive patients with anal cancer based on the available literature because of the retrospective nature of the analyses, the small number of patients, and the heterogeneity of the patients reported with regard to tumor size, pretreatment immunologic status, and the variety of treatments received by patients in some series. Identifying patients who develop invasive anal cancer as early as possible will improve results to some degree, but prospective, controlled, multi-institutional trials evaluating the treatment of anal cancer in HIV-infected persons are required to accurately define ways to improve outcome with less morbidity. The results of ongoing therapeutic HPV vaccine trials are eagerly awaited. Improvement may come by the following, determining ways to more accurately stage patients, such as endoanal ultrasound, sentinel lymph node sampling, or positron emission tomography scans; defining the role of cisplatin and whether it is indeed less toxic and equally or more effective; consideration of continuous protracted infusion of low-dose 5-FU; the optimum use of growth factors; and an evaluation of the role of conformal radiotherapy or the use of radio-protectants, such as amifostine. Meanwhile, the best way to treat anal cancer in HIV-infected persons may be to prevent it from occurring by screening persons at risk and treating HSIL, or at a minimum, following up patients carefully and detecting cancers, if they occur, at the earliest possible time.

Normal human colonic microvascular endothelial cells (HUCMEC) have been isolated from surgical specimens by their adherence to Ulex europaeus agglutinin bound to magnetic dynabeads that bind alpha-L-fucosyl residues on the endothelial cell membrane. Immunocytochemistry demonstrated the presence of a range of endothelial-specific markers on HUCMEC, including the von Willebrand factor, Ulex europaeus agglutinin, and platelet endothelial cell adhesion molecule-1. The growing cells form monolayers with the characteristic cobblestone morphology of endothelial cells and eventually form tube-like structures. HUCMEC produce vascular endothelial growth factor (VEGF) and express the receptors, kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase, through which VEGF mediates its actions in the endothelium. VEGF induces the tyrosine phosphorylation of KDR and a proliferative response from HUCMEC comparable to that elicited from human umbilical vein endothelial cells (HUVEC). On binding to HUCMEC or HUVEC, (125)I-labeled VEGF internalizes or dissociates to the medium. Once internalized, (125)I-labeled VEGF is degraded and no evidence of ligand recycling was observed. However, significantly less VEGF is internalized, and more is released to the medium from HUCMEC than HUVEC. Angiogenesis results from the proliferation and migration of microvascular, not large-vessel, endothelial cells. The demonstration that microvascular endothelial cells degrade less and release more VEGF to the medium than large-vessel endothelial cells identifies a mechanism permissive of the role of microvascular cells in angiogenesis.

Purpose: The prevalence of anal squamous intraepithelial lesions is high among human immunodeficiency virus-positive homosexual males and, to a lesser extent, among human immunodeficiency virus-negative homosexual males. Furthermore, the incidence of high-grade squamous intraepithelial lesions, the putative precursor lesion to invasive cancer, is also high. We report the first prospective study of high-resolution anoscopy-directed surgical treatment of high-grade squamous intraepithelial lesions., Methods: A prospective study of patients undergoing surgical treatment of high-grade squamous intraepithelial lesions (excision/cauterization of lesions visualized with high-resolution anoscopy) was performed. Follow-up anoscopy with biopsy and Papanicolaou smear was performed every three to six months., Results: Patients diagnosed with high-grade squamous intraepithelial lesions during the course of their participation in a prospective cohort study of anal squamous intraepithelial lesions were identified. From this group, 37 patients who were treated surgically between 1995 and 1999 were studied. Of these, 29 had tested positive for human immunodeficiency virus and 8 were negative for the virus. Mean patient age was 45 +/- 8 years. Mean duration of follow-up was 32.3 +/- 20.6 months in the human immunodeficiency virus-negative group and 28.6 +/- 12.9 months in the human immunodeficiency virus-positive group. No human immunodeficiency virus-negative patient developed recurrent high-grade squamous intraepithelial lesions. Twenty-three of 29 human immunodeficiency virus-positive patients had persistent or recurrent high-grade squamous intraepithelial lesions (P = 0.003; mean time to recurrence, 12 months). Six patients underwent reoperation for high-grade squamous intraepithelial lesions (4 recurred by 6 months). No patients developed incontinence, stenosis, postoperative infection, or significant bleeding after surgical treatment., Conclusions: Surgical intervention directed by high-resolution anoscopy is safe and eliminates high-grade squamous intraepithelial lesions in human immunodeficiency virus-negative patients. The high persistence or recurrence rate in human immunodeficiency virus-positive patients suggests that multiple staged procedures and continued surveillance may be necessary.

In selected patients with early rectal cancer, local therapy is an effective alternative to radical resection and offers minimal morbidity and the avoidance of a colostomy. Several techniques are described: transanal excision, dorsal approaches (York-Mason or Kraske procedures), transanal endoscopic microsurgery, endocavitary radiation, and transanal fulguration. Among these, transanal excision is favored for the low rate of complications, promising outcomes, and ability to secure tissue for pathology. Patients with T1 lesions with favorable histologic features may undergo local excision alone, while those with T2 lesions require adjuvant chemoradiation. The data currently available do not support the use of local therapy with curative intent for tumors that are advanced (T3 or T4), poorly differentiated, or have other negative pathologic characteristics. In carefully selected patients for local excision, local recurrence and survival rates are similar to traditional radical resection. Following local excision, patients require close observation for recurrence. Most patients with local recurrence can be salvaged by radical resection, though the long-term outcome is unknown.

Purpose: Management of anal high-grade squamous intraepithelial lesions is controversial. Anal and cervical high-grade squamous intraepithelial lesions are similar in that they occur in transitional squamous epithelium, are associated with human papilloma virus infection, and have increased incidence in the immunocompromised population. Ablation of cervical high-grade squamous intraepithelial lesions is preferred, but similar ablation or excision of anal high-grade squamous intraepithelial lesions may compromise bowel control; thus, there is a need to define the malignant potential of anal high-grade squamous intraepithelial lesions., Methods: We analyzed 50 paraffin sections of normal anoderm, anal low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and anal squamous-cell carcinoma. Microvessels were detected immunohistochemically with von Willebrand factor and counted manually along the epithelial-stromal junction. Proliferation and apoptosis were determined in the epithelial cells with MIB-1 antibody immunostaining and the terminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end labeling, respectively., Results: Microvascular density was significantly greater in anal high-grade squamous intraepithelial lesions (mean, 0.50 vessels/cm) vs. normal anoderm (mean, 0.21 vessels/cm; P = 0.0017, Mann-Whitney U test). The proliferative percentages were greater in low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and squamous-cell carcinoma (mean, 20.4, 21.8, and 23.6 percent) vs. normal anoderm (mean, 14.4 percent), although not significantly (P = 0.06, Kruskal-Wallis statistic). Although the mean proliferative proportions were similar in low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions, the apoptotic proportion was lower for high-grade squamous intraepithelial lesions than low-grade squamous intraepithelial lesions (10.13 vs. 19.96 percent, respectively; P = NS, Mann-Whitney U test)., Conclusions: Angiogenesis, increased proliferation, and decreased apoptosis occur in anal high-grade squamous intraepithelial lesions as they do in the cervix before the development of malignancy. These biologic markers support the importance of anal high-grade squamous intraepithelial lesions as a potential premalignant lesion warranting surgical intervention.

In awake dogs, meal ingestion stimulates the absorption of water and electrolytes from neurovascularly intact jejunal Thiry-Vella loops, even though these loops are isolated from the remainder of the gut. This study was designed to investigate the role of Na+-glucose cotransport in mediating this event. Meal ingestion enhanced absorption when the jejunal lumen was perfused with an isotonic solution containing D-glucose, D-galactose, or 3-O-methylglucose. This response was absent when the perfusate contained mannitol or when phlorizin was added to the D-glucose solution. Mucosa from the jejunal loops was serially biopsied and assayed for brush-border Na+-glucose cotransporter (SGLT1) mRNA and protein expression. Although no changes in SGLT1 mRNA levels were observed, protein levels significantly increased within 30 min following meal ingestion. The time course of SGLT1 protein expression corresponded with that of increased Na+ and water absorption. These results suggest that meal-stimulated jejunal absorption may be mediated through an induction of mucosal SGLT1.

The long-term results of the continent ileostomy are controversial. Durability and patient satisfaction were evaluated by analyzing the outcome in 129 consecutive patients who had a continent ileostomy performed by one surgeon at the University of California, San Francisco, between 1975 and 1995. A quality-of-life questionnaire was sent to all patients for whom addresses were available (n = 121). Late outcome data could be obtained for 85 (66%) of the 129 patients. Three of the 85 patients died with their continent ileostomies but of unrelated causes. Fifty-one (60%) of 85 patients currently have the continent ileostomy (group A) (mean 15.1 years, range 2.7 to 21.7 years), whereas 31 (36%) of 85 have undergone conversion of continent ileostomy to conventional ileostomy (group B) (mean 5.4 years, range 0.2 to 20.4 years). Patients in group A underwent fewer major postoperative revisions (mean 0.7, range 0 to 4) than patients in group B (mean 1.3, range 0 to 8) (t test, P = 0. 088). The indications for pouch removal included valve dysfunction (42%), refractory pouchitis (23%), multiple fistulas (26%), Crohn's disease (6%), and other (16%) (four patients had two indications). Eighty-seven percent of survey respondents in group A considered their present state of health to be better than before their continent ileostomies. Fifty-seven percent and 82% of respondents in group A were not limited at all in regard to vigorous or moderate activity, respectively. Although in approximately one third of patients the pouch had to be removed, 97% of the remaining two thirds have a good to excellent outcome.

Hypothesis: Selected clinicopathologic characteristics of locally treated rectal cancers are predictive of recurrence., Design: Case series review with median follow-up of 6 years., Setting: University medical center., Patients: Fifty-eight patients with rectal cancer who underwent local excisions from February 1, 1982, to December 31, 1998., Main Outcome Measures: Local and distant recurrence rates and overall survival., Results: Overall local recurrence rate was 14% (8 patients). There were no local recurrences among patients treated with chemotherapy or radiation. Of patients not treated, local recurrence rates were 33%, 5%, 45%, and 25% for T0, T1, T2, and T3 tumors, respectively. No clinicopathologic factor predicted local recurrence. Two patients developed distant recurrence. Overall survival was 98%, 93%, and 84% at 1, 3, and 5 years, respectively., Conclusion: In selected patients, outcomes for local excision combined with additional therapy may be equivalent to those for radical resection.

Context: Homosexual and bisexual men infected with human immunodeficiency virus (HIV) are at increased risk for human papillomavirus-related anal neoplasia and anal squamous cell carcinoma (SCC)., Objective: To estimate the clinical benefits and cost-effectiveness of screening HIV-positive homosexual and bisexual men foranal squamous intraepithelial lesions (ASIL) and anal SCC., Design: Cost-effectiveness analysis performed from a societal perspective that used reference case recommendations from the Panel on Cost-Effectiveness in Health and Medicine. A state-transition Markov model was developed to calculate lifetime costs, life expectancy, and quality-adjusted life expectancy for no screening vs several screening strategies for ASIL and anal SCC using anal Papanicolaou (Pap) testing at different intervals. Values for incidence, progression, and regression of anal neoplasia; efficacy of screening and treatment; natural history of HIV; health-related quality of life; and costs were obtained from the literature., Setting and Participants: Hypothetical cohort of homosexual and bisexual HIV-positive men living in the United States., Main Outcome Measures: Life expectancy, quality-adjusted life expectancy, quality-adjusted years of life saved, lifetime costs, and incremental cost-effectiveness ratio., Results: Screening for ASIL increased quality-adjusted life expectancy at all stages of HIV disease. Screening with anal Pap tests every 2 years, beginning in early HIV disease (CD4 cell count >0.50 x 10(9)/L), resulted in a 2.7-month gain in quality-adjusted life expectancy for an incremental cost-effectiveness ratio of $13,000 per quality-adjusted life year saved. Screening with anal Pap tests yearly provided additional benefit at an incremental cost of $16,600 per quality-adjusted life year saved. If screening was not initiated until later in the course of HIV disease (CD4 cell count <0.50 x 10(9)/L), then yearly Pap test screening was preferred due to the greater amount of prevalent anal disease (cost-effectiveness ratio of less than $25,000 per quality-adjusted life year saved compared with no screening). Screening every 6 months provided little additional benefit over that of yearly screening. Results were most sensitive to the rate of progression of ASIL to anal SCC and the effectiveness of treatment of precancerous lesions., Conclusions: Screening HIV-positive homosexual and bisexual men for ASIL and anal SCC with anal Pap tests offers quality-adjusted life expectancy benefits at a cost comparable with other accepted clinical preventive interventions.

Purpose: To assess the outcome and tolerance of HIV-positive patients with anal cancer to standard therapy based on their pretreatment CD4 count., Methods and Materials: Between 1991 and 1997, 17 HIV-positive patients with anal cancer and documented pretreatment CD4 counts were treated at the University of California, San Francisco or its affiliated hospitals with either concurrent chemotherapy and radiation or radiation alone. The outcome and complications of treatment were correlated with the patients' pretreatment CD4 count., Results: Disease for all 9 patients with pretreatment CD4 counts > or = 200 was controlled with chemoradiation. Although four required a treatment break of 2 weeks because of toxicity, none required hospitalization. Of the 8 patients with pretreatment CD4 counts < 200, 4 experienced decreased counts, intractable diarrhea, or moist desquamation requiring hospitalization. Additionally, 4 of these 8 ultimately required a colostomy either for a therapy-related complication or for salvage. Nevertheless, 6/7 in this group who received concurrent chemotherapy and radiation had their disease controlled, whereas the patient treated with radiation alone failed and required a colostomy for salvage., Conclusion: Patients with CD4 > or = 200 had excellent disease control with acceptable morbidity. Patients with CD4 < 200 had markedly increased morbidity; however, disease was ultimately controlled in 7/8 patients.

Perianal complications of Crohn's disease are common, and surgical management has been controversial. Over the last 10 years, improved outcomes have defined a more prominent role for operative interventions, especially with respect to management of focal perineal sepsis and fistulas. Liberal placement of drainage catheters and noncutting setons, advancement flap closure of perineal fistulas, and selective construction of diverting stomas have good results when combined with optimal medical therapy to induce remission of inflammation. Proctectomy, which is infrequently required, can often be postponed for several years when complementary surgical and medical treatments are provided.

Background: The pathophysiology of inflammatory bowel disease remains elusive primarily because of the limitations of the models available for study in the basic science laboratories. We propose a new model for the study of inflammatory bowel disease., Data Sources: Research and review articles published in the English literature., Conclusions: The human colonic microvascular endothelial cell in culture is a legitimate model for the study of the human colon in the normal and diseased states.

Normal pelvic floor function involves a set of learned and reflex responses that are essential for the normal control and evacuation of stool. A variety of functional disturbances of the pelvic floor, including incontinence and constipation, are not life threatening, but can cause significant distress to affected patients. Understanding the normal anatomy and physiology of the pelvic floor is essential to understanding and treating these disorders of defecation. This article describes the normal function of the pelvic floor, the diagnostic tools available to investigate pelvic floor dysfunction, and the etiology, diagnosis, and management of the functional pelvic floor disorders that lead to incontinence and constipation.

Objective: To define the role of biofeedback in fecal incontinence and constipation., Design: A case series of patients with fecal incontinence or constipation with pelvic floor dysfunction., Setting: Tertiary care center with an anorectal physiology laboratory., Patients: Patients with 1 of the following: (1) chronic or acute fecal incontinence, (2) fecal incontinence and neurologic injury, or (3) constipation with pelvic floor dysfunction., Intervention: Electromyogram-guided biofeedback retraining of the pelvic floor., Main Outcome Measures: Resolution of electromyographic abnormalities and subjective resolution of fecal incontinence or constipation., Results: Of the patients with fecal incontinence, 92% experienced significant improvement with biofeedback without significant improvement in electromyographic values. Of the patients with constipation and pelvic floor dysfunction 80% experienced improvement with biofeedback without significant change in electromyographic values., Conclusion: Biofeedback is effective in selected patients with fecal incontinence and constipation with pelvic floor dysfunction.

Background: Transcatheter embolization is accepted as a safe method for treating acute bleeding from the upper gastrointestinal (GI) tract. Hesitancy persists using this technique below the ligament of Treitz, based on the belief that the risk of intestinal infarction is unacceptably high, despite mounting clinical evidence to the contrary., Methods: A series of 17 consecutive patients with angiographically demonstrated small intestinal or colonic bleeding was retrospectively reviewed. The success and complication rate of subselective embolization was assessed., Results: Bleeding was stopped in 13 of 14 patients (93%) in whom embolization was possible, and in 13 of 17 patients (76%) where there was an intention to treat. Sufficiently selective catheterization to permit embolization could not be achieved in 3 patients. No clinically apparent bowel infarctions were caused., Conclusion: Subselective embolization is a safe treatment option for lower GI bleeding, suitable for many patients and effective in most. Careful technique and a readiness to abandon embolization when a suitable catheter position cannot be achieved are important.

Objective: To review patient characteristics, surgical indications, operative procedures, and survival of patients with ulcerative colitis who develop colorectal cancer., Design: Retrospective medical record review., Setting: Tertiary referral center., Patients: Of 493 patients who underwent surgery for ulcerative colitis between 1978 and 1994, 25 patients had colorectal cancer., Intervention: All patients underwent surgical exploration and either a biopsy, segmental resection, total abdominal colectomy, or restorative proctocolectomy was performed., Main Outcome Measure: Duration of postoperative disease-free survival., Results: The average duration of illness prior to surgery was 18.5 years (range, 0.25-40 years). Surgical indications were intractability for 3 patients (12%); dysplasia as revealed by colonoscopic biopsy for 8 patients (32%); and preoperatively diagnosed cancer for 14 patients (56%). Three patients (12%) underwent exploratory laparotomy, 3 (12%) underwent right hemicolectomy, 5 (20%) underwent total proctocolectomy with ileostomy, 3 (12%) underwent total proctocolectomy with continent ileostomy, and 12 (48%) underwent restorative proctocolectomy. Pathological stage was carcinoma in situ for 3 patients (12%), stage I for 7 patients (28%), stage II for 4 patients (16%), stage III for 6 patients (25%), and stage IV for 5 patients (20%). Five-year survival was 100% (3/3) for patients with carcinoma in situ, 100% (4/4) for those with stage I disease, 50% (2/4) for those with stage II, 25% (1/4) for those with stage III, and 0% (0/5) for those with stage IV. Of the 12 patients treated with a restorative proctocolectomy, 6 are 5-year survivors, and 4 are alive at 24, 36, 38, and 48 months., Conclusions: Twelve percent of the patients in this series had no preoperative evidence of colorectal malignant neoplasms but had invasive cancer in the resected specimen. Therefore, duration of disease alone may be an indication for surgery. A restorative proctocolectomy is a satisfactory procedure in selected patients with malignant neoplasms.

In the past several years, there have been major advances in the understanding of colorectal cancer from both the clinical and basic science level. Although there are various techniques for colorectal cancer screening and surveillance, the most cost-effective approach has yet to be determined. As molecular biology techniques are improved and incorporated into clinical practice, identification of high-risk populations seems possible. With future advances in endoscopy and imaging, patient compliance can be improved. With the proper combination of both clinical and basic science techniques, it seems reasonable that a further reduction in the mortality from colorectal cancer can be accomplished.

About 28,000 new cases of pancreatic cancer are diagnosed yearly in the United States. The diagnosis is now made up to two months more quickly than just a few years ago, but this has had no impact on survival. In most institutions, 20-25% of patients have resectable lesions. The standard operation is still the Whipple pancreaticoduodenectomy, but many surgeons now use the pylorus preserving modification of that procedure. The operative mortality rate has fallen to less than 5%. The five-year survival rate after a resection for attempted cure is about 9%. Palliation requires cholecysto(docho)jejunostomy and gastrojejunostomy, which is often done prophylactically. The operative mortality rate in patients undergoing palliation is less than 10% (recent UCLA experience), and the average survival is seven months.

Vasoactive intestinal polypeptide (VIP) is a putative neurotransmitter in both the brain and peripheral tissues. To define possible target tissues of VIP we have used quantitative receptor autoradiography to localize and quantify the distribution of [125I]VIP receptor binding sites in histologically normal human surgical specimens. While the distribution of VIP binding sites was different for each gastrointestinal segment examined, specific vasoactive intestinal polypeptide binding sites were localized to the mucosa, the muscularis mucosa, the smooth muscle of submucosal arterioles, the circular and longitudinal smooth muscle of the muscularis externa, the myenteric plexus, and lymph nodules. In most segments, the mucosal layer expressed the highest concentration of VIP binding sites, with the duodenal and jejunal mucosa showing the highest density of receptors. These results identify putative VIP target tissues in the human gastrointestinal tract. In correlation with physiological data, VIP binding sites appear to be involved in the regulation of a variety of gastrointestinal functions including mucosal ion transport, gastric secretion, hemodynamic regulation, gastric and intestinal motility, neuronal excitability, and modulation of the immune system.

Glutamate and several neuropeptides are synthesized and released by subpopulations of primary afferent neurons. These sensory neurons play a role in regulating the inflammatory and immune responses in peripheral tissues. Using quantitative receptor autoradiography we have explored what changes occur in the location and concentration of receptor binding sites for sensory neurotransmitters in the colon in two human inflammatory diseases, ulcerative colitis and Crohn's disease. The sensory neurotransmitter receptors examined included bombesin, calcitonin gene related peptide-alpha, cholecystokinin, galanin, glutamate, somatostatin, neurokinin A (substance K), substance P, and vasoactive intestinal polypeptide. Of the nine receptor binding sites examined only substance P binding sites associated with arterioles, venules and lymph nodules were dramatically up-regulated in the inflamed tissue. These data suggest that substance P is involved in regulating the inflammatory and immune responses in human inflammatory diseases and indicate a specificity of efferent action for each sensory neurotransmitter in peripheral tissues.