The evolving treatment of anal cancer: How are we doing?

HYPOTHESIS: The adaptation of new techniques in treatment of epidermoid carcinoma of the anal canal during the past 3 decades has improved clinical outcomes. DESIGN: Retrospective consecutive case review. SETTING: A university hospital and Veterans Affairs medical center. PATIENTS: Medical records of 76 consecutive patients treated for invasive epidermoid cancer of the anal canal between 1970 and 1999 were reviewed. Twenty-one patients were excluded because of inadequate staging information and/or follow-up of less than 12 months. MAIN OUTCOME MEASURES: Locoregional recurrence, survival, colostomy-free survival, and morbidity. RESULTS: Fifty-five patients composed the study population. Ten were treated during decade 1 (1970-1979), 16 in decade 2 (1980-1989), and 29 in decade 3 (1990-1999). Mean age and sex distributions were similar. The prevailing primary treatment modality changed during the course of the study from sequential treatment (chemotherapy then radiation therapy then radical surgery) to concurrent chemoradiation (70% and 0% of cases, respectively, in decade 1 to 7% and 76% of cases, respectively, in decade 3). Locoregional control (50%, 81%, and 93%; P =.01), crude survival (median, 28, 30, and 76 months), and colostomy-free survival (mean, 13, 90, and 80 months) improved during the 3 decades. There were no differences in major complications during the 3 decades (40%, 56%, and 41%). CONCLUSION: Primary treatment with concurrent chemoradiation has improved the local recurrence, survival, and colostomy-free survival rates in patients with invasive epidermoid carcinoma of the anal canal without increasing major morbidity.

Identification of a functional Ca2+-sensing receptor in normal human gastric mucous epithelial cells.

The purpose of the present study was to determine whether human gastric mucous epithelial cells express a functional Ca2+-sensing receptor (CaR). Human gastric mucous epithelial cells were isolated from surgical tissues and cultured on glass coverslips, plastic dishes, or porous membrane filters. Cell growth was assessed by the MTT assay, CaR localization was detected by immunohistochemistry and confocal microscopy, CaR protein expression was assessed by Western immunoblotting, and intracellular Ca2+ concentration ([Ca2+]i) was determined by fura 2 spectrofluorometry. In paraffin sections of whole stomach, we found strong CaR immunohistochemical staining at the basolateral membrane, with weak CaR-staining at the apical membrane in mucous epithelial cells. Confocal microscopy of human gastric mucous epithelial cell cultures showed abundant CaR immunofluorescence at the basolateral membrane and little to no CaR immunoreactivity at the apical membrane. Western immunoblot detection of CaR protein in cell culture lysates showed two significant immunoreactive bands of 140 and 120 kDa. Addition of extracellular Ca2+ to preconfluent cultures of human gastric mucous epithelial cells produced a significant proliferative response. Changes in [Ca2+]i were also observed in response to graded doses of extracellular Ca2+ and Gd3+. The phospholipase C inhibitor U-73122 specifically inhibited Gd3+-induced changes in [Ca2+]i in the gastric mucous epithelial cell cultures. In conclusion, we have identified the localization of a functional CaR in human gastric mucous epithelial cells.

Effects of paclitaxel on the growth of normal, polyposis, and cancerous human colonic epithelial cells.

BACKGROUND: The specific paclitaxel dose or time course in the treatment of colon carcinoma without the disruption of normal colonic cell proliferation is currently not known. The aim of this study was to determine the effects of paclitaxel on the growth of human colonic epithelial cells using cultures of normal, polyposis, and cancerous cells. METHODS: Normal, polyposis, and cancerous human colonic cells (Caco-2, T-84, and LoVo cell lines) were cultured, then treated with paclitaxel (10(-9)-10(-5) M) for 0-7 days.[AU: Please verify all dosages throughout.] Cell proliferation was assayed using either a Coulter-Counter or MTT-growth assay. Immunofluorescence and Western immunoblotting measured P-glycoprotein. RESULTS: Low paclitaxel doses (1 x 10(-9)-10(-8) M) were more effective than higher paclitaxel doses (>1 x 10(-8) M) in the growth inhibition of polyposis, Caco-2, and LoVo cancer (but not T-84) cell lines. Low paclitaxel doses had little effect on normal colonic cell growth over 7 days. Higher paclitaxel doses (>1 x 10(-8)-10(-5) M) produced a dose-dependent inhibitory effect on the growth of normal human colonic epithelial cells over 7 days but had no effect on the growth of polyposis, Caco-2, and LoVo cells over 3-7 days of treatment. Immunofluorescence and Western immunoblotting of cultures showed that 1 x 10(-6) M paclitaxel increased P-glycoprotein expression in Caco-2 and LoVo cells. There was no effect of paclitaxel on P-glycoprotein expression in T-84 cancer cells, which were found to have high endogenous basal levels of P-glycoprotein. P-glycoprotein expression in Caco-2 cells was found on plasma membranes and in perinuclear areas. CONCLUSIONS: Lower paclitaxel doses are more effective over time for the growth inhibition of polyposis and cancerous colonic cells, with minimal effects on the growth of normal colonic epithelial cells. Increased P-glycoprotein expression appears to be correlated with paclitaxel resistance in polyposis and cancerous colonic cells.

Herbicide/pesticide effects on intestinal epithelial growth.

The purpose of the present study was to examine the effects of some common herbicides and pesticides on the growth of normal intestinal and colonic epithelial cells. Preconfluent cultures of normal rat intestinal cells (IEC-6 cell line) and normal human colonic epithelial cells were treated with 0.05-50 microM doses of atrazine, diazinon, and endosulfan. After 3 days of treatment, the change in cell proliferation was quantified by cell counting or the MTT growth assay. Both intestinal and colonic epithelial cell cultures had increases in cell growth when treated with as little as 1.0 microM atrazine, diazinon, or endosulfan. The observed changes in both cultured intestinal and colonic cell growth rates were not due to the influence of the vehicle control dimethyl sulfoxide (DMSO). That is, the treatment of the cell cultures with concentrations of DMSO as high as 0.5% for 3 days resulted in no change in cell growth compared with untreated control cultures. A consistent observation with all three of the compounds was that the highest doses (50 microM) had the least "proliferative potential" in stimulating either IEC-6 cell or human colonic epithelial cell growth. Within the concentration range used, none of the herbicides or pesticides caused a decrease in cell proliferation below that of the untreated control cultures. Overall, treatment of IEC-6 cell cultures with atrazine, diazinon, or endosulfan produced a biphasic growth response, whereas the same treatment in the human colonic epithelial cell cultures produced a more sustained level of growth over the same period. This culture system may provide the basis for an in vitro model to further study the cellular and molecular basis of the effects of herbicides and pesticides on intestinal epithelial proliferation.

Long-term outcome of completion gastrectomy for nonmalignant disease.

Between 1989 and 1995 we performed completion gastrectomy for non-malignant disease in 21 patients (11 men and 10 women, mean age 48.4 years). These patients had undergone a total of 48 prior gastric operations. Indications for completion gastrectomy in this group were anastomotic ulceration with stricture in eight patients, alkaline reflux gastritis and/or esophagitis in eight, postsurgical gastroparesis in two, gastroesophageal necrosis in two, and gastrocutaneous fistula in one. Major preoperative symptoms included nausea and vomiting in 16 cases, abdominal pain in 15, dysphagia in 14, heartburn in seven, and weight loss in five. Following completion gastrectomy, five patients (24%) had serious complications and there was one postoperative death (5%). Five patients were lost to follow-up. For the remaining 15 patients, mean follow-up has been 30 months with a range of 1 to 70 months. These patients were all interviewed and eight (53%) report significant improvement, two (13%) report moderate improvement, and four (27%) report no improvement; one patient (7%) has had worsening of symptoms since undergoing completion gastrectomy. The average body weight index was essentially unchanged after completion gastrectomy. We conclude that completion gastrectomy with Roux-en-Y esophagojejunostomy results in a favorable outcome in the majority of selected patients with diseases of the foregut who are unresponsive to less radical treatment.

Establishment of human colonic epithelial cells in long-term culture.

Study of normal colonic function is important in understanding the cellular mechanisms of carcinogenesis and other diseases of the colon. However, colonic pathophysiological studies have been limited due to the lack of long-term cultures of normal human colonic epithelial cells. The purpose of the present study was to develop methods of isolating viable human colonic epithelial cells for the establishment of nontransformed colonic epithelial cell lines. Human colonic epithelial cells were isolated from surgically resected normal human colons. We found that the use of a short enzymatic digestion gave a consistently higher number (>90%) of viable human colonic epithelial cells. These isolated colonocytes were grown on plastic, collagen-coated filters, or feeder layers using different media formulations. Those colonocytes from the initial primary cultures that were most "epithelial" in appearance were cloned and passaged to establish long-term cultures of nontransformed human colonic epithelial cells. The epithelial nature and secretory function of these established cell lines were confirmed by morphological criteria (light microscopy,, phase contrast microscopy, and electron microscopy). We found that the long-term cultures remained immunopositive to anti-cytokeratin antibodies and immunonegative to anti-vimentin antibodies. Using a soft agar assay we found that the colonocytes did not form colonies, suggesting that the long-term culturing did not cause these cells to become transformed. Under serum-free conditions, we found that epidermal growth factor and transforming growth factor-alpha were equally potent in their mitogenic effects for these colonocytes. Some of the subcultured cells could be maintained for at least 8 months and still retain their epithelial characteristics. We believe that this methodology will serve as a valuable tool for the isolation and culturing of human colonic epithelial cells for studies of normal and malignant colonic disease processes.

Clostridium difficile colitis: an increasing hospital-acquired illness.

BACKGROUND: Colitis caused by Clostridium difficile is receiving increased attention as a nosocomial hospital-acquired infection. METHODS: To determine the incidence of C difficile colitis in our facility and the relative proportion of patients dying from the colitis or requiring colectomy for it, we retrospectively reviewed 201 cases of colitis caused by C difficile from 1984 to 1994. RESULTS: The incidence of C difficile colitis appears to be sharply increasing and is associated with the use of cephalosporins. Among patients who subsequently developed C difficile colitis, the most frequent indication for antibiotic use was perioperative prophylaxis; surgical patients comprised 55% of the total cases. Surgical intervention was required for 5% of patients with C difficile colitis, with an operative mortality of 30%. The overall mortality was 3.5% and was associated with a delay in diagnosis. The only discriminative factor between patients who died and those who survived was length of time from symptoms to treatment--5.43 days for survivors versus 10.7 days for those who died (P < 0.05). CONCLUSIONS: Most cases of C difficile colitis seen by surgeons have followed the use of perioperative prophylactic antibiotics. Strict guidelines for using perioperative antibiotics should be observed. Prompt recognition of C difficile colitis and aggressive therapy for it are essential for a favorable outcome.

The early experience with laparoscopic cholecystectomy in Oregon.

OBJECTIVE: To obtain a profile of laparoscopic cholecystectomy (LC) across the state of Oregon with regard to the safety of the procedure, use of intraoperative cholangiograms, and requirements for granting surgeons privileges to perform LC and other laparoscopic procedures. DESIGN: Single-mailing survey to surgeons and chiefs of surgery in Oregon. SETTING: The state of Oregon. STUDY PARTICIPANTS: Surgeons and chiefs of surgery in Oregon. INTERVENTION: None. MAIN OUTCOME MEASURE: Numbers of procedures performed, deaths, complications, and requirements for surgical privileges. RESULTS: Sixty-nine percent of surgeons returned the questionnaire, as did 53% of the chiefs of surgery. Four deaths (0.04%), 244 complications (2.5%), and 27 bile duct injuries (0.28%) were reported in 9597 patients undergoing LC. Most surgeons (55%) obtained intraoperative cholangiograms routinely. Requirements for the privilege to perform LC varied among hospitals. Although the accuracy of this self-reported survey is uncertain, the results agree with those of other reports published to date. CONCLUSION: Laparoscopic cholecystectomy is being performed with acceptable safety, although the process of granting surgeons the privilege to perform this and other "new" laparoscopic procedures should be standardized according to established guidelines.

Liver transplantation for severe Amanita phalloides mushroom poisoning.

Amanita phalloides mushroom poisoning is an increasingly common and potentially lethal problem for which liver transplantation offers definitive therapy in selected patients. When significant liver dysfunction appears, early transfer to a liver transplant center is important to identify appropriate candidates and to begin the search for a donor organ. The clinical course of five severely poisoned patients, four of whom underwent liver transplantation, is reviewed. Indications for transplantation included primarily a markedly prolonged prothrombin time that was only partially correctable and a constellation of findings including metabolic acidosis, hypoglycemia, hypofibrinogenemia, and increased serum ammonia, following a marked elevation in serum aminotransferase levels. Unlike viral fulminant hepatic failure, grade III or IV hepatic encephalopathy, marked elevation of the serum bilirubin level, and azotemia were not indications for transplantation. Resected livers demonstrated hepatocyte viability of 0% to 30%. Manifestations of Amanita poisoning complicating preoperative and/or postoperative care included severe diarrhea, gastrointestinal hemorrhage, hypophosphatemia, bowel edema, and marrow suppression with lymphopenia, thrombocytopenia, and neutropenia. All five patients are well 1 year later. This largest experience with liver transplantation for Amanita poisoning further defines the early clinical and laboratory indications for, and the unique complicating features of, transplantation in this setting.

Improved treatment of intra-abdominal abscess. A result of improved localization, drainage, and patient care, not technique.

Outcome in patients with abdominal abscesses treated at the University of Pennsylvania, Philadelphia, between 1973 and 1978 (group 1) was compared with that in patients treated between 1981 and 1986 (group 2). Mortality was less in group 2 patients (21% vs 39% in group 1). The decrease in mortality in group 2 was accompanied by a greater percentage of successful predrainage localization (74% vs 55% in group 1), successful initial drainage (76% vs 55% in group 1), and decreased predrainage organ failure (23% vs 52% in group 1). Because failure of initial drainage and predrainage organ failure were associated with increased mortality, improvement in both of these criteria contributed substantially to the lower mortality in group 2 patients. There were no differences in mortality, in initial success in drainage, or in length of hospital stay when 29 group 2 patients who underwent percutaneous drainage were compared with 37 patients who underwent surgical drainage. Mortality (22% vs 21%) and initial success (78% vs 72%) were similar for patients who underwent surgical and percutaneous drainage, respectively. We conclude that initial success in localization and drainage of the abscess is more important than whether drainage is surgical or percutaneous.

Zollinger-Ellison syndrome (gastrinoma). Current diagnosis and treatment.

Zollinger-Ellison syndrome is being detected at an earlier stage through liberal use of serum gastrin testing and application of secretin provocative tests if needed. The peptic ulcer disease of patients with Zollinger-Ellison syndrome can usually be controlled by large doses of one of the new potent gastric acid inhibitors. A battery of preoperative localizing tests can then be applied to guide exploratory laparotomy in non-MEN I patients. The tumor should be resected if possible, and continued low gastrin levels after operation provide evidence of a complete resection. It is reasonable to perform a parietal cell vagotomy at celiotomy because it will facilitate control of acid secretion if tumor resection is not successful. The only need for total gastrectomy is in a few patients whose acid secretion cannot be controlled with H2 receptor antagonists or who cannot comply with medical therapy. When no tumor is found at celiotomy, the prognosis for long-term tumor-free survival is excellent. Unfortunately, if unresectable hepatic metastases are present at operation, the patient is likely to die from metastatic tumor.

Routine colonoscopy in the management of colorectal carcinoma.

A prospective study of the role of preoperative and routine follow-up colonoscopy in 75 patients with colon and rectal carcinoma disclosed that additional premalignant or malignant lesions were detected and successfully treated in 44 percent of patients. These included four synchronous and three metachronous carcinomas. Timely diagnosis and treatment of such tumors and secondary prevention of metachronous carcinomas by polypectomy is a major identifiable benefit of close follow-up examinations of these patients. No other test compares favorably with colonoscopy in this regard. These data support the conclusion that colonoscopy should be performed routinely preoperatively and every 6 to 12 months after colectomy for carcinoma.

Medical treatment of peptic ulcers.

Since duodenal ulcer can be treated effectively with several drugs (H2 receptor antagonists, sucralfate, colloidal bismuth or antacids) the choice of drug should be determined by cost, ease of administration, and lack of side effects. The H2 receptor antagonists and sucralfate cost about the same and have few side effects. They should both be considered first-line drugs for treatment of duodenal ulcer. Colloidal bismuth is not available for use in the United States, but should be otherwise included in this group. Antacids must be taken more often than H2 receptor antagonists; the liquid antacids are messy, will produce diarrhea in many patients, and have several other side effects that make them a second-choice drug. Although the tricyclic selective anticholinergic pirenzepine has been effective in treating duodenal ulcer, it is not approved in the United States and its role in the treatment of duodenal ulcer is not yet well defined. The only role for pirenzepine presently is as a second drug with the H2 receptor antagonists in the treatment of acid hypersecretion in the Zollinger-Ellison syndrome. The same principles apply in the treatment of gastric ulcers as in duodenal ulcers, with a few exceptions. Gastric ulcers probably respond less to antacids than to H2 receptor antagonists or coating agents such as sucralfate, and preliminary data suggest that long-term maintenance therapy with H2 receptor antagonists to prevent ulcer recurrence is not as effective with gastric ulcers as it is with duodenal ulcers. Several compounds will promote the healing of duodenal and gastric ulcers. These compounds have minimal side effects and are well tolerated by patients. They are without question highly effective acutely, but when discontinued they have no lasting influence on the chronic nature of peptic ulcer disease, and their role in the long-term treatment of peptic ulcer disease is unclear. Thus, whether or not these drugs will actually reduce the need for surgical treatment of peptic ulcer disease remains to be determined.

Follow-up of patients with colorectal cancer.

In our follow-up study of 65 patients after curative surgery for colorectal cancer, tests other than history and physical examination detected only two cases of potentially curable recurrent colorectal cancer. As a routine follow-up test, carcinoembryonic antigen determination is preferable to computerized tomographic scanning, since the sensitivity and specificity of carcinoembryonic antigen and computerized tomographic scanning were found to be equivalent and carcinoembryonic antigen is much less expensive. There was no benefit to the routine use of liver function tests or chest roentgenograms during follow-up. Since barium enema contributed little to what colonoscopy accomplished with greater comfort to the patient, barium enemas should be used only when colonoscopy is not totally successful in reaching the cecum. The most beneficial aspect of the follow-up of these patients is probably the elimination of future metachronous lesions by removal of small, benign polyps.

Resection of gastrinomas.

Exploratory laparotomy and a search for gastrinomas was performed in 52 patients with the Zollinger-Ellison syndrome (ZES). Gastrinoma tissue was resected in 11 patients (21%), 6 (12%) of whom appear to have been cured. After surgery, serum gastrin levels in these six patients have remained normal from 10 months to 10 years. In the 46 other patients, tumor was unresectable because of metastases or multiple primary tumors (21 patients; 40%) or inability to find the tumor at laparotomy (21 patients; 40%). Multiple pancreatic islet cell adenomata were found in six of seven patients with multiple endocrine neoplasia (MEN), indicating that patients with this condition usually have diffuse involvement of the pancreas. The results of CT scans correlated with findings at laparotomy in 13 of 16 patients. The smallest tumor detected by CT scans was 1 cm in diameter. CT technology is more accurate in finding gastrinomas now than in the past and has a useful role in preoperative evaluation. The possibility of resection should be seriously considered in every patient with Zollinger-Ellison syndrome. Abdominal CT scans, transhepatic portal venous sampling, and laparotomy should be used to find the tumor and to determine whether it is resectable. Using presently available methods, it should be possible to cure about 25% of patients with gastrinomas who do not have MEN and over 70% of those without MEN who appear to have a solitary tumor. Total pancreatectomy may be necessary to cure some patients with MEN, but that operation is rarely justified. The morbidity and mortality of surgical attempts at curing this disease have become minimal; we have had no deaths or serious complications following such operations in over 10 yrs. Total gastrectomy and indefinite use of H2-receptor blocking agents are the therapeutic options for patients with unresectable gastrinomas. Because H2-receptor blocking agents fail to control acid secretion in many patients after several yrs of therapy, total gastrectomy is indicated in a large proportion of patients whose tumors cannot be resected. Total gastrectomy in patients with ZES is also safe using current techniques; our last death following this operation for ZES occurred 15 yrs ago.

Factors influencing survival after therapeutic shunts. Results of a discriminant function and linear logistic regressions analysis.

Data on 100 consecutive patients undergoing portasystemic shunt at three hospitals of the University of California, San Francisco, were analyzed retrospectively to look for variables portending poor immediate and long-term outcome. As a determinant of early mortality after portacaval shunt, the Child's classification of the patient remains the single most important factor. If the patient is in Child's class C and has a hematocrit of less than 32 percent, he is even less likely to survive 30 days. The malnourished male patient who resumes drinking postoperatively is least likely to survive 1 year. Though short- and long-term mortality did not correlate with type of shunt, the prosthetic interposition mesocaval shunt was associated with an unacceptably high thrombosis rate of 20 percent in our institutions, and represented a technical failure to achieve the goal of preventing further variceal bleeding. No matter what type of shunt was performed, however, the 30 day mortality of Child's class C patients exceeded 50 percent. In the latter patients methods of treatment other than portasystemic shunts should be evaluated.

Effect of different absorbable sutures on healing of gastrointestinal anastomoses.

Studies were performed in dogs to determine whether the newer absorbable sutures would be preferable to catgut in the gastrointestinal tract. Dissolution times of plain and chromic catgut were compared with those of polyglycolic acid (Dexon) and polyglactin 910 (Vicryl) sutures exposed to gastrointestinal contents in vitro and in vivo. Strength and healing of gastric, jejunal, and colonic anastomoses performed with each suture were compared in dogs. Catgut sutures proved susceptible to rapid proteolytic digestion throughout the gastrointestinal tract, whereas Dexon and Vicryl were invulnerable. Type of suture did not affect microscopic healing in the stomach jejunum, or colon. However, gastric anastomoses of Dexon were stronger at four and seven days and jejunal anastomoses of Dexon and Vicryl were stronger at seven days than anastomoses of catgut. Dexon and Vicryl may be superior to catgut for use in gastrointestinal anastomoses.