Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective.

The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Key treatment questions in childhood acute lymphoblastic leukemia: results in 5 consecutive trials performed by the ALL-BFM study group from 1981 to 2000.

Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.

A historical perspective on the development of the cytarabine (7days) and daunorubicin (3days) treatment regimen for acute myelogenous leukemia: 2013 the 40th anniversary of 7+3.

This paper reviews the development of therapy for acute myelogenous leukemia that in 1973 led to the regimen of 7days of continuous intravenous arabinosylcytosine (cytarabine) and the first 3 concurrent days of intravenous daunorubicin, given the nickname "7+3." The state of leukemia treatment in the 1950s, 1960s and early 1970s is reviewed, the discovery of the two drugs in question described, and the introduction of clinical trials to reach an optimal regimen for their use delineated. During the 1950s, following World War Two and after a period of civil reconstitution, a national effort, facilitated by the U.S. Congress and federal investments in the National Cancer Institute, was initiated to enhance cancer therapy in the United States. The development of mouse models of leukemia and advances in understanding the structure and function of DNA and RNA and the process of cell proliferation provided new targets for drug development and new concepts for their use. The year, 2013, marks the 40th year that this protocol, 7+3, is the method of induction of remission for most patients with acute myelogenous leukemia. Its inadequacies also are made clear. Many patients with the disease die soon after diagnosis, and patients who have more unfavorable oncogenetic subtypes, intrinsically drug resistant cells, and greater intolerance to therapy make up the vast majority of the affected and few are cured. It is evident to all that new paradigms are needed if acute myelogenous leukemia is to be subdued in most patients with the disease.

The early history of chemical immunosuppression: 1900-1965.

This is a short review on chemical immunosuppression following the discovery of anaphylaxis by Charles Richet. The paper discusses the role of serendipity in the advent of 6-mercapthopurine (6-MP) therapy and the productivity in the field through Nobel Prize recipients.

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.