Activation of c-Ki-ras in human gastrointestinal dysplasias determined by direct sequencing of polymerase chain reaction products.

Activation of c-Ki-ras by point mutation within exon 1 was studied in 33 specimens of dysplastic gastrointestinal lesions or of cancers presumed to arise from dysplasia. Samples were obtained from patients with underlying ulcerative colitis or Barrett's esophagus, two diseases associated with dysplasia and increased rates of colonic or esophageal adenocarcinoma, respectively. Genomic DNA was amplified using primers bounding this exon in the polymerase chain reaction. Polymerase chain reaction products were analyzed by direct dideoxy sequencing. Three point mutations in codon 13 of c-Ki-ras were found, all in colonic specimens (two high-grade dysplasias and one adenocarcinoma arising in ulcerative colitis). No point mutations were observed in the second exon of c-Ki-ras or in and around codons 12, 13, and 61 of c-N-ras and C-Ha-ras in a partial sampling of the specimens. These data indicate that ras family protooncogene activation is an uncommon event at this level of malignant progression in these disease states. Carcinogenesis in ulcerative colitis and Barrett's esophagus may proceed via different pathways than in sporadic colon cancer, perhaps involving loss or inactivation of suppressor genes.

Growth retardation in children with ulcerative colitis: the effect of medical and surgical therapy.

The growth of 37 children with ulcerative colitis have been analyzed. While conventional growth charts showed only percentile changes in height, height data plotted on Tanner et al.'s growth charts showed increases and decreases in growth velocity. Growth retardation is a prominent complication of ulcerative colitis with onset on bowel symptoms. Both ulcerative colitis and "high-dose" steroid therapy (greater than 12 mg/sq m/day of cortisol) can hinder growth but in some instances there is a growth spurt after high-dose steroid therapy. "Low-dose" steroid therapy does not retard growth. Colectomy is more effective than high-dose steroid therapy in reversing the growth retardation caused by ulcerative colitis and is of greatest value if not delayed too long. Growth following subtotal colectomy with ileorectal anastomosis (Aylett procedure) is not likely to be as much as that after subtotal colectomy with ileostomy. Growth retardation is infrequently the only indication for surgical intervention but ileostomy and colectomy are appropriate for this complication of ulcertive colitis in itself when not improved by adequate medical treatment.

Intravenous corticotrophin vs. hydrocortisone in the treatment of hospitalized patients with Crohn's disease: a randomized double-blind study and follow-up.

Adrenocorticotrophic hormone (ACTH) and corticosteroids have no maintenance values for inflammatory bowel disease but serve to reduce the severity of disease. The effectiveness of intravenous corticotrophin versus hydrocortisone in ulcerative colitis has been determined including whether previous steroid therapy influenced the better response to one rather than the other, but no such studies have ever been done in Crohn's disease. Eighty-eight patients hospitalized with moderate-to-severe Crohn's disease (Present-Korelitz [P-K] Index -3 to -2 and the International Organisation for the Study of Inflammatory Bowel Disease-Crohn's & Colitis Foundation of America [IOIBD-CCFA] Index, mean 14, range 5-23) were treated in a prospective, randomized, double-blind clinical trial to receive either continuous intravenous infusion of 120 U/day of ACTH (44 patients) or hydrocortisone 300 mg/day (44 patients). Patients were also subdivided into those who received oral steroids during the 30 days prior to intravenous therapy and those who had not. Response was followed on a daily basis and tabulated at 3, 5, and 10 days. Patients were followed from 1-3 years to determine the later status. After 10 days of intravenous therapy 36 of 44 patients (82%) who received ACTH and 41 of 44 patients (93%) who received hydrocortisone fully responded (P-K index +3 and IOIBD-CCFA Index mean of 3). At the end of the study, response to intravenous ACTH and hydrocortisone was not statistically different whether or not patients received oral steroids during the 30 days prior to admission, although the response to IV ACTH tended to be faster at 3 days in those who had received previous steroid therapy. Intravenous ACTH and hydrocortisone are equally effective in achieving therapeutic goals in patients with Crohn's disease who have not achieved results with oral medications. Moreover the response rate was high (mean 88%), serving to buy time for establishment of successful maintenance programs of treatment with oral 5-ASA and immunosuppressive drugs for 69% of patients at 1-3 years.

Mucosal-cell counts in ulcerative and granulomatous colitis.

Epithelial and connective-tissue cells were counted in rectal mucosal biopsies from 215 patients with ulcerative colitis, 98 patients with granulomatous colitis, and 50 controls. The results were analyzed statistically. Significantly decreased mucous goblet cells were found both in sigmoidoscopically abnormal ulcerative colitis and in granulomatous colitis, and they increased during the healing process. More pyknotic and karyorrhectic epithelial cells occurred in active ulcerative colitis than in granulomatous colitis. Inactive ulcerative colitis still manifested histologic evidence of acute and chronic inflammation, while sigmoidoscopically normal granulomatous colitis biopsies after previous gross rectal disease showed significantly increased macrophages in the lamina propria. Cell counts were valuable for differential diagnosis after the sigmoidoscopic appearance became normal. The acute inflammation of ulcerative colitis, as indicated by neutrophils, was decreased most notably following therapy with prednisone or 6-mercaptopurine. Chronic inflammation associated with fewer plasma cells was decreased after salicylazosulfapyridine as well as either of the other two drugs; macrophages, indicators of healing, increased most after 6-mercaptopurine combined with another anti-inflammatory agent.

Microgranulomas in grossly normal rectal mucosa in Crohn's disease.

Rectal biopsies of sigmoidoscopically normal mucosa from 99 patients with Crohn's disease of the ileum, colon, or both were studied histologically, with particular reference to the presence of granulomas. Among the 14 cases of granulomas, some were of the usual sarcoid type and could easily be detected. Other microgranulomas were less well defined and were found only by mid- or high-power microscopic screening of serial sections. The morphologic characteristics, the relationship to ordinary Crohn's-disease granulomas and the possible significance of microgranulomas are discussed.

Anorectal Crohn's disease: surgical and medical management.

In some patients with Crohn's disease the anorectal complications are the major cause of symptoms and morbidity. Anorectal Crohn's disease may be present in patients with intestinal Crohn's disease, may be the initial manifestation of the disease, or rarely occurs without involvement of Crohn's disease elsewhere in the intestinal tract. The pathogenesis of these anorectal complications remains to be clarified. The anorectal examination is very important in the assessment of patients with suspected or documented inflammatory bowel disease. Meticulous physical examination, examination under anaesthesia and radiological imaging modalities may be utilised to specifically identify the location of abscesses and fistulae. Treatment strategy should be directed toward symptomatic relief; the most important symptom is pain. In most patients this pain will be attributable to an incompletely drained rectal abscess. Simple incision and drainage procedures are often all that is required as initial treatment of anorectal abscesses. Treatment of the anorectal fistulae that occur secondary to Crohn's disease requires combined medical and surgical therapy. Drug therapy is more often initiated for Crohn's disease that involves other areas of the gastrointestinal tract. The anorectal manifestations often respond to these same medications. Lay-open procedures (fistulotomies) are often all that is required surgically for simple (low) anorectal fistulae. High (complex) fistulae that involve large portions of the anorectal muscular ring are more difficult to treat. Patients with these fistulae must be treated on an individual basis, usually local surgical therapy combined with a medical regimen. Many surgical procedures are performed and many classes of medications are utilised on patients with these complex anorectal fistulae. Choosing the appropriate surgical and medical interventions is often quite difficult. Although sulfasalazine, mesalazine and corticosteroids have no lasting or maintenance value for fistulae, the immunosuppressive agents mercaptopurine, azathioprine and cyclosporin, the antibacterial metronidazole and the anti-tumour necrosis factor-alpha monoclonal antibody infliximab have varying degrees of effect. The goal of the combined regimen is to cure the fistula, or at least make it minimally symptomatic, without altering the patient's continence.

Considerations of surveillance, dysplasia, and carcinoma of the colon in the management of ulcerative colitis and Crohn's disease.

Patients with ulcerative colitis are at greater risk of developing carcinoma of the colon than the general population even if the exact risk cannot be determined. Thus, an effort must be made to find the carcinoma at its inception or better still before it occurs. Dysplasia serves as a premalignant marker in some cases, and a surveillance program serves to find either dysplasia or the carcinoma. Until more specific premalignant changes are identified, endoscopic surveillance with multiple biopsies offers the best protection for the patient with longstanding ulcerative colitis against carcinoma. There is now sufficient evidence that this also pertains to Crohn's disease of the colon.

Anorectal Crohn's disease: definitive surgery for fistulas and recurrent abscesses.

Twenty patients with anorectal Crohn's disease manifested by anal fistulas or recurrent perirectal abscesses underwent attempted definitive surgical eradication of that pathologic process. The role of Parks' partial internal anal sphincterectomy is discussed. The results are presented and correlated with the activity of the underlying Crohn's disease. The excellent results recommend this approach for recurrent perirectal abscess and intersphincteric abscess, even when occurring for the first time.

A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at The Mount Sinai Hospital.

Much of what we know about the role of immunopathologic mechanisms in causing Crohn's disease and ulcerative colitis originated from research at The Mount Sinai Hospital. The authors were privileged to have been able to share in this undertaking, along with many others, including Moschcowitz, Klemperer, Otani, Crohn, Ginzburg, Oppenheimer, Garlock, Lyons, Marshak, Janowitz, Aufses, Waye, Greenstein, Sachar, Meyers, Gelernt, Mayer, Lichtiger and Kornbluth. In medical history, elucidation of disease processes is often serendipitous. Transplant surgery was successful because of the discovery by Hitchings and Elion of 6-mercaptopurine (6-MP) and azathioprine, which inhibited rejection. And the concept of immunosuppression slowly evolved into possible treatment of any disease thought to be caused by autoimmunity. This includes those diseases of the bowel seen so frequently at The Mount Sinai Hospital: ileitis, granulomatous colitis, ileocolitis, and ulcerative colitis. This paper depicts the progressive role of immunosuppressive drugs, from corticosteroids to 6-mercaptopurine, cyclosporine and anti-tumor necrosis factor, in both the treatment and understanding of the pathogenesis of Crohn's disease and ulcerative colitis. Major contributions to these treatments have come from physicians and surgeons with roots at The Mount Sinai Hospital.

A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at the Mount Sinai Hospital.

If the cause of Crohn's disease and ulcerative colitis turns out to be some immunopathologic mechanism, many of the steps leading to such an understanding of their pathogenesis can be attributed to concepts that originated at The Mount Sinai Hospital. Perhaps immodestly, we can claim a role in the acceleration and the acceptance of these concepts; however, many contributions were made by others, including Moschkowitz, Klemperer, Otani, Crohn, Ginzburg, Oppenheimer, Marshak, and Janowitz. This does not mean that clinicians and researchers from other institutions did not contribute to this understanding. As happens so often in medical history, elucidation of many disease processes are serendipitous. The concept of autoimmune diseases was introduced when we were house officers at Mount Sinai. The early days of transplant surgery soon followed along with the introduction by Hitchings and Elion of azathioprine to inhibit rejection. The concept of immunosuppression slowly evolved into possible treatment of any disease thought to be caused by autoimmunity, including those diseases of the bowel, seen so frequently at The Mount Sinai Hospital: ileitis, granulomatous colitis, ileocolitis, and ulcerative colitis. Although most of the world called granulomatous disease of the bowel Crohn's disease, it was only after the deaths of Drs. Crohn, Ginzburg, and Oppenheimer that we accepted this single eponym. However, we will always pay tribute to all three Mount Sinai physicians who wrote the original paper that described the disease.