Analysis of relative effectiveness of high-dose versus standard-dose influenza vaccines using an instrumental variable method

Background

Observational studies of the relative effectiveness of influenza vaccines are essential for public health decision making. Their estimates, however, are subject to bias due to unmeasured confounders. Instrumental variable (IV) methods can control for observed and unobserved confounders.

Malignant lymphoma. Pathology, diagnosis, therapy

Summary Malignant lymphomas can be subdivided into Hodgkin's disease and low- or high-grade non-Hodgkin's lymphoma (NHL). The principal therapeutic options are polychemotherapy and radiotherapy. Besides the histological classification, staging of the disease with particular regard to risk factors is an essential prerequisite for the therapeutic decision. Diagnostic imaging modalities such as computer tomography, magnetic resonance imaging, and ultrasonography have improved the accuracy of clinical staging such that invasive pathological staging is only necessary in exceptional cases. A novel therapeutic approach is high-dose chemotherapy with autologous haematopoietic stem-cell support. This treatment improves the survival of patients with relapsed high-grade NHL. The place of high-dose therapy as the primary therapeutic option in malignant lymphoma is now being assessed in prospective studies following encouraging results from single-centre studies, including those involving the treatment of low-grade lymphoma. The effects of antibodies directed against lymphatic cells are currently being examined in experimental treatments. An assessment of the viability and rate of proliferation of lymphoma tissue on completion of therapy using sensitive radiological and nuclear medical methods is an important aim for the future. Eingegangen am 5. November 1996 Angenommen am 12. November 1996     

Marked improvement of delayed methotrexate-induced leukoencephalopathy treated with high-dose folinic acid

We report the case of a patient with delayed methotrexate (MTX)-induced leukoencephalopathy who showed a marked improvement both in clinical and neuroimaging findings after a high-dose of the active form of folinic acid (leucovorin) treatment. The patient developed progressive affective impairment accompanied by headache, nausea and vomiting after treatment with MTX during the chemotherapy for acute lymphoblastic leukemia, and diagnosed as delayed type MTX-induced leukoencephalopathy. After an intravenous injection of high-dose folinic acid (total 1920 mg), neurological deficits and white matter changes dramatically improved in a few weeks. Although delayed MTX-induced leukoencephalopathy may cause irreversible brain damage, an early treatment with high dose leucovorin may thus facilitate the marked improvement of clinical findings and white matter abnormalities.     

Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma

Summary The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice — 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) — gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.Abbreviations 5FU 5-fluorouracil - LV leucovorin (folinic acid, 5-formyl-tetrahydrofolate) - FdUMP 5-fluoro 2-deoxyuridine 5monophosphate - TS thymidylate synthase - CH2-THF 5-10 methylenetetrahydrofolate - UR uridine - GDF growth delay factor - TD tumor doubling time - MTD maximum tolerated dose - T/C mean tumor volume of treated mice divided by mean tumor volume of control mice     

High dose gammaglobulin therapy in adults with idiopathic thrombocytopenic purpura (ITP) clinical effects

Summary This study of the effect of high-dose intravenous gammaglobulins with one or two courses of therapy in 18 adults with idiopathic thrombocytopenia purpura showed a platelet rise in thirteen patients. The highest response rates were seen in splenectomized adults. In chronic patients the response was transient only. If therapy was effective, increased values of platelet-associated IgG were reduced, while shortened platelet survival times were prolonged. There was no influence of high-dose gammaglobulins on platelet function. Different 7S-preparations such as -propiolactone modified Ig, pH 4 treated Ig and reduced and alkylated Ig have comparable effects.Supported by the Deutsche Forschungsgemeinschaft (Mu 277/9-4)     

Pharmacokinetic study of methotrexate,folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue

Summary The pharmacokinetics of methotrexate (MTX), 7-hydroxymethotrexate (7-OHMTX), 2,4-diaminomethylpteroic acid (APA), folinic acid, and 5-methyltetrahydrofolate (5-MTHF) have been studied during 21 high-dose MTX (HDMTX) infusions (5 g·m^–2 in 24 h) with leucovorin (LCV) rescue, a component of the therapy of 5 children with acute lymphoblastic leukemia (ALL).The median steady-state concentration of MTX was 66 mol·l^–1. Three elimination half-lifes were determined for MTX: 1.8 h, 6.4 h and a terminal 15 h. The median systemic MTX clearance was 110 mg·m^–2·min^–1.The 7-OHMTX level increased during each infusion and a C_max of 19 mol·l^–1 was achieved at the end. Its initial half-life was 5 h and the terminal half-life was 12 h. Thus, the peak serum concentration ratio of 7-OHMTX to MTX was reached 24 h after the end of the infusion at a median ratio of 8.The MTX metabolite APA was detected in concentrations less than 0.06 mol·l^–1. The median folinic acid level during rescue, 48 h after starting the infusion, was 7.0 mol·l^–1 and 18 h following the last dose of LCV it was 0.44 mol·l^–1, leading to ratios of folinic acid to MTX of 31 and 6, respectively. The median 5-MTHF level during rescue was 0.44 mol·l^–1 with a median ratio of 5-MTHF to MTX of 2.Twenty infusions with 48 h MTX levels of less than 0.5 mol·l^–1 were without marked toxicity. Only one patient with a 48 h MTX concentration of 5.5 mol·l^–1 and a ratio of 5-MTHF to MTX of 0.08 suffered from ulcerating mucositis and septicaemia despite increased and prolonged LCV rescue.     

高剂量与常规剂量表阿霉素联合化疗初治非小细胞肺癌对比研究

目的本实验为一前瞻性随机化对照研究,以高剂量表阿霉素-丝裂霉素-顺铂,常规剂量表阿霉素-丝裂霉素-顺铂作比较,初治非小细胞肺癌(NSCLC),评价其疗效及毒副作用.方法治疗NSCLC共40例.分高剂量组和常规剂量组(A、B)各20例.男性25例,女性15例.病理类型以腺癌为主(26例),Ⅲa期4例,Ⅲb期17例,Ⅳ期19例.全部为初治病人.结果高剂量组(A)总有效率(65%)高于常规剂量组(B)(45%),中位缓解期A组3.1个月,B组2.2个月;中位生存期A组8.7个月,B组7.1个月.表阿霉素的剂量限制毒性为心脏毒性和骨髓抑制,心脏毒性发生率A、B两组均为5%(1例),骨髓抑制A组较B组稍高,白细胞下降率各为65.0%和55.0%.结论高剂量表阿霉素为主的联合化疗治疗NSCLC的有效率比常规剂量组高,毒性相似,可以耐受,是值得推荐的高效低毒的一种给药途径.     

5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial.

BACKGROUND: Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrences and improves survival. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in a long-term follow-up study in comparison with the effects of 5-FU plus levamisole in the prospective multicenter trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively resected stage III (International Union Against Cancer) colon cancer were stratified according to tumor, node and grading category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days, plus leucovorin 100 mg/m2, 12 cycles (arm A), or 5-FU plus levamisole (Moertel scheme; arm B). RESULTS: Six hundred and eighty (96.9%) of 702 patients enrolled into this study were eligible. To date, 261 patients have died, 117 on arm A and 144 on arm B (P = 0.007). After a median follow-up time of 82 months, the 5-FU plus leucovorin combination significantly improved disease-free survival [79.8 months in arm A versus 69.3 months in arm B (P = 0.012)] and significantly increased median overall survival (88.9 months in arm A versus 78.6 months in arm B; P = 0.003). Adjuvant treatment with 5-FU plus levamisole as well as 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities. CONCLUSIONS: After curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated. This long-term follow-up study demonstrates that adjuvant treatment with 5-FU plus leucovorin given for 12 cycles is significantly more effective than 5-FU plus levamisole (Moertel scheme) in reducing tumor relapse and improving survival.