Pathological response after chemoradiation for T3 rectal cancer.

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

Controversies in the management of anal high-grade squamous intraepithelial lesions.

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.

Local therapy for rectal cancer.

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.

Role of Na+-glucose cotransport in jejunal meal-induced absorption.

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.

Angiogenesis, proliferation, and apoptosis in anal high-grade squamous intraepithelial lesions.

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.

The continent ileostomy: long-term durability and patient satisfaction.

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.

Local excision of rectal carcinoma.

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.

The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men.

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.

The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer.

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.

Surgical options in the management of perianal Crohn's disease.

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.

Human colonic microvascular endothelial cells is a model of inflammatory bowel disease.

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.

The pelvic floor in health and disease.

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.

Biofeedback is effective therapy for fecal 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.

Selective arterial embolization for the control of lower gastrointestinal bleeding.

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.

Retrospective review of colorectal cancer in ulcerative colitis at a tertiary center.

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.

Benign colorectal polyps. Endoscopic surveillance guidelines and effects on colorectal cancer risk.

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.

Surgical treatment of pancreatic cancer. The United States experience.

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.

Receptors for sensory neuropeptides in human inflammatory diseases: implications for the effector role of sensory neurons.

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.

Vasoactive intestinal polypeptide receptor binding sites in the human gastrointestinal tract: localization by autoradiography.

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.