No dose-dependent tubulotoxicity of 5-aminosalicylic acid: a prospective study in patients with inflammatory bowel diseases

BACKGROUND AND AIMS: Elevated levels of renal tubular markers in the urine are found in 20-30% of patients with chronic inflammatory bowel diseases. We investigated whether this reflects a dose-dependent tubulotoxicity of 5-aminosalicylic acid (5-ASA). PATIENTS AND METHODS: In an open, prospective, multicenter study 18 patients with Crohn's disease and 29 with ulcerative colitis were treated with 3 g 5-ASA or more daily as the sole drug for 6 weeks. Clinical activity (CDAI, CAI) and renal tubular markers [beta-N-acetyl-D-glucosaminidase (beta-NAG) and other proteins in urine] were monitored. We examined whether the proportion of patients with elevated beta-NAG is more than 15% higher (absolute difference) than that prior to treatment. RESULTS: The proportion decreased from 19.2% to 12.8% in the intention-to-treat analysis (n=47) and from 24.3% to 13.5% in the per-protocol analysis (n=37), which was not more than 15% higher than at baseline. Mean CDAI decreased from 222 to 146 and mean CAI from 7.3 to 3.1 (intention-to-treat analysis). Response to therapy was shown by 61% of patients with Crohn's disease and 66% of patients with ulcerative colitis. The cumulative dose of 5-ASA was not correlated with beta-NAG level in the urine. CONCLUSION: This study largely rules out that 5-ASA at 3 g or higher per day for 6 weeks induces renal tubular damage. Elevated renal tubular markers reflect inflammatory activity or an extraintestinal manifestation of inflammatory bowel diseases.     

Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791

Objectives Hereditary medullary thyroid carcinoma (MTC) is caused by germ‐line mutations in the RET proto‐oncogene. Our study addresses the difference in development of MTC between rare mutations in RET codons 790, 791 and 804. Design We evaluated tumour stage, calcitonin levels, biochemical cure rates and associated endocrinopathies in 153 German/Austrian patients with RET 790 (n = 47), 791 (n = 56) and 804 mutations (n = 50), divided into index‐ and screening groups. Results Age at diagnosis in index‐patients did not differ significantly among the three codon groups (medians of 57, 61 and 53 years). Tumour stage at diagnosis was significantly less advanced with codon 791 (n = 22) than 790 (n = 16) and 804 (n = 16) mutations (P = 0·001). In screening patients, age at diagnosis did not differ significantly among the three groups (medians 19, 24 and 32 years). Tumour stage at diagnosis was also significantly less advanced with codon 791 (n = 34) than 790 (n = 31) and 804 (n = 34) (P = 0·032). Preoperative basal calcitonin levels were significantly lower in codon 791 carriers compared to codon 790 carriers, and cure rates were significantly higher in both index (75%vs. 31%; P = 0·03) and screening patients (100%vs. 75%; P = 0·015). Additional endocrinopathies were observed only with codon 791 carriers (four pheochromocytomas and two hyperparathyroidism). Conclusion There is a significant difference in MTC development with less extensive C‐cell disease, higher cure rate and more frequent additional endocrinopathies in carriers of RET codon 791 mutations compared with carriers of codons 790 and 804 mutations. This information should be considered when age of prophylactic thyroidectomy is discussed.     

Chemotherapy for mobilisation of Ph-negative progenitor cells from patients with CML: impact of different mobilisation regimens

Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/miniICE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-alpha. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/miniICE.     

Towards a pathogenesis-oriented therapy of acute myeloid leukemia

Genetic and molecular techniques have provided increasing insights into the biology of acute myeloid leukemia (AML). These investigations showed that AML is not a homogeneous disease but a heterogeneous group of biologically different subentities. These subentities are currently primarily defined by cytogenetics by which three main subgroups can be discriminated: AML with balanced translocations, AML with unbalanced aberrations and AML without cytogenetically detectable aberrations. Within the latter group molecular alterations are identified in more than half of cases such as NPM mutations, FLT3 mutations, MLL duplications and mutations of CEBP-alpha. The clinical meaning of these findings is illustrated by substantial differences in response to therapy and long-term outcome. As demonstrated by the recent multicenter trial of the German AML Cooperative Group (AMLCG) and other studies intensification of induction therapy may improve the results in distinct subtypes but fails to do so in others. Therefore, new strategies need to be explored which incorporate the knowledge about the biology of AML to develop biology adapted treatment strategies. This process has just begun and is predominantly determined by the availability of new agents and their evaluation in clinical phase I and II studies. A variety of targets are currently explored and some trials have yielded promising results already. The step towards a biology adapted treatment of AML is long and requires the combined efforts of researchers, clinicians and the pharmaceutical industry. The first steps towards this goal have been taken and give rise to the hope for more effective and more specific therapies of AML.     

Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin’s disease

Chemotherapy-treated patients with advanced Hodgkins disease (HD) differ considerably in acute hematotoxicity. Hematotoxicity may be indicative of pharmacological and metabolic heterogeneity. We hypothesized that low hematotoxicity might correlate with reduced systemic dose and thus reduced disease control. A total of 266 patients with advanced HD treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD) were analyzed (HD6 trial of the German Hodgkins Lymphoma Study Group). The reported WHO grade of leukocytopenia was averaged over chemotherapy cycles given and weighted with the reciprocal dose intensity of the corresponding cycle. The low and high toxicity groups were defined in retrospect as having had an averaged WHO grade of leukocytopenia 2.1 and >2.1, respectively. The independent impact of low hematological toxicity on freedom from treatment failure (FFTF) was assessed multivariately adjusting for the international prognostic score for advanced HD. The results were validated in two independent cohorts [181 patients treated with COPP-ABVD (HD9-trial) and 250 patients treated with COPP-ABV-ifosfamide, methotrexate, etoposide, and prednisone (IMEP) (HD6 trial)]. The 5-year FFTF rates were 68% for patients with high toxicity vs 47% for patients with low toxicity [multivariate relative risk (RR) 2.0, 95% confidence interval (CI) 1.4–3.0, p=0.0002]. Patients with low toxicity received significantly higher nominal dose (p=0.02) and dose intensity (p<0.0001). This finding was confirmed in both validation cohorts (multivariate RR 2.1, 95% CI 1.2–3.8, p=0.01 and RR 1.5, 95% CI 1.01–2.26, p=0.04, respectively). Patients with low hematotoxicity have significantly higher failure rates despite higher doses and dose intensity. Hematotoxicity is an independent prognostic factor for treatment outcome. This observation suggests a strategy of individualized dosing adapted to hematotoxicity.The authors listed above wrote this contribution on behalf of the German Hodgkins Lymphoma Study Group     

Isosorbide dinitrate spray as therapeutic strategy for treatment of chronic venous ulcers

Venous ulcers are the most common form of leg ulcers, which induce lesion because of the loss of substances deposited on the damaged skin. Isosorbide dinitrate is a vasodilator with effects on both arteries and veins and induces opening of vascular layers. The objective is to study the effects of isosorbide dinitrate-spray in patients with chronic venous ulcers. Forty-five patients of both sexes with chronic venous ulcers were randomized to receive isosorbide dinitrate or placebo sprays daily for 3 months. The ulcers were measured and clinical characteristics were taken every 15 days during the treatment. Patients treated with isosorbide dinitrate showed an improvement of the ulcerated area (71.29%) compared with patients treated with placebo (54.35%). The histopathological study indicated an increment in the number of hypertrophic and hyperplasic capillaries. Macroscopically, the isosorbide dinitrate-treatment showed the best results, but it was only during the first 6 weeks of treatment. Patients with chronic venous ulcer receiving isosorbide dinitrate spray showed improvement.     

Analysis of the therapeutic efficacy of different doses of budesonide in patients with active Crohn''s ileocolitis depending on disease activity and localization

Background and aims The nonsystemic steroid budesonide has been used to treat active ileocecal and ileocolonic Crohn's disease (CD). This study investigated the optimal budesonide dose using a pH-dependent release formulation. The goal of treatment was the remission of CD (CDAI <150) within 6 weeks of treatment.Patients and methods The study was of randomized, double-blind, dose-finding design. Patients with active CD ileocolitis without steroid pretreatment were treated with 3×2 mg (n=39), 3×3 mg (n=33), or 3×6 mg (n=32) oral pH-modified released budesonide daily.Results The remission rates after 6 weeks were 36% with 3×2 mg, 55% with 3×3 mg, and 66% with 3×6 mg. Significantly more patients were in remission while treated with 3× 6mg than with 3×2 mg budesonide/day. Subgroup analyses revealed that patients with high disease activity (CDAI 300) or ileocolonic disease with disease manifestation distal to the transverse colon responded better to the highest budesonide dose.Conclusion Oral pH-modified released budesonide shows a dose-dependent effectiveness in patients with active ileocolonic CD. In the majority of patients 9 mg budesonide per day is sufficient. However, in patients with highly active disease or ileal disease with distal colonic manifestation higher doses of budesonide could increase the therapeutic response     

Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM)

We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.     

Functional and reactive hyperemia are unaltered by homocysteine in conscious dogs

Summary The purpose of this study was to test the hypothesis that L-homocysteine thiolactone (L-HCTL), through its reaction with adenosine to formS-adenosylhomocysteine, may modulate myocardial functional and reactive hyperemic responses. Reactive hyperemic responses to 10-sec occlusions or 400-msec diastolic occlusions of the circumflex coronary artery and functional hyperemic responses to ventricular extra-activations were studied in a chronic heart-blocked dog preparation during a control period and following L-HCTL (40 mg/kg). In two additional dogs multiple venous blood samples and left ventricular myocardial biopsies were obtained following L-HCTL to measure changes in plasma homocysteine and tissueS-adenosylhomocysteine. Despite a 75-fold increase in peak plasma homocysteine and a 26-fold increase in tissueS-adenosylhomocysteine, L-HCTL did not alter myocardial functional and reactive hyperemic responses.The rapid increase in myocardialS-adenosylhomocysteine confirmed cellular entry of homocysteine and its reaction with endogenous adenosine. The failure of L-HCTL to alter functional and reactive hyperemic responses suggests that either such treatment does not affect myocardial release of adenosine or that adenosine is not an important regulator of coronary flow.Supported in part by the National Institutes of Health Grants HL 18468 and AM 12828 and the Medical Research Service of the Veterans Administration. Dr. Sadick is a recipient of an Overseas Research Fellowship from the Australian National Heart Foundation. Parts of this work were presented at the 56th Scientific Sessions, American Heart Association, Anaheim, California, November, 1983.