Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

Summary Diaziquone, a new alkylating agent which crosses the blood brain barrier, has shown a 20% response rate in phase II studies in heavily pretreated patients. We have treated 23 patients at our institution as part of a multicentric phase II European trial of diaziquone. All had histologically proven malignant glioma unequivocally progressing on CT scan. Prior therapy had consisted of surgical excision (13 patients), cobalt radiotherapy to CNS (13 patients), and chemotherapy with nitrosourea derivatives (11 patients). Six patients had no prior therapy. Median age was 42 years (range 22–69) and performance status was 3+ or better. They were treated with monthly courses of diaziquone 5.5 mg/m² I.V. (10 min.) × 5 days. Dosage adjustments were made according to leucocyte and platelet nadirs. Thrombocytopenia was the dose limiting toxicity. Very mild gastrointestinal toxicity was observed. One patient developed hemolytic anemia. One complete response (clinical and CT scan), 7 partial clinical responses (3: > 50%, 4: 25–50%), and 1 disease stabilization (<25%) were documented. The longest response has now lasted over 26 months. These preliminary results show that chemotherapy with diaziquone can achieve a response rate as high as 35% in malignant glioma even in patients previously treated with a chemotherapy regimen including a nitrosourea (four of the seven objective responses were seen in such patients). Diaziquone is well tolerated and deserves further study in the management of malignant glioma. Address for offprints: Dr J Maral, Medical Oncology Service, Hôpital de la Salpetriere, 75651 Paris Cedex 13, France     

Analysis of VH genes used by neoplastic B cells in endemic Burkitt's lymphoma shows somatic hypermutation and intraclonal heterogeneity

Tumor cell lines from six typical cases of endemic Epstein-Barr virus (EBV) genome-positive Burkitt's lymphoma (BL) have been investigated for usage and mutational pattern of Ig VH genes. The neoplastic cells all had a t(8;14) (q24;q32) translocation involving the c-myc protooncogene. The VH genes were derived from VH1, VH3 and VH4, and both the IgM-positive (four cases) and IgG-positive (two cases) were extensively mutated from germline sequence. In two cases, early and late passage tumor cells were available, and the VH nucleotide sequences were identical, indicating that mutations had not accumulated in vitro. In a further case, there was evidence of sequence heterogeneity, which appeared to have been generated in vivo, indicating that the tumor cell VH gene was able to undergo posttranslocation somatic hypermutation. Analysis of the relatively nonpolymorphic VH4 genes for the pattern of replacement or silent mutations did not show a role for antigen selection in the expressed sequences.     

针刺对肾性高血压大鼠6-酮-前列腺素F1及血栓素B2影响的研究

目的：探讨针刺治疗高血压的机理。方法：选用大鼠制备肾性高血压模型，以传统针刺治疗，观察了针刺对肾性高血压大鼠的血压、6-酮-前列腺素Fl(6-Keto-PGF1)、血栓素B2(TXB2)及6-Keto-PGF1／TXB2的影响。结果：针刺能够明显降低肾血管性高血压大鼠的血压并能明显升高6-Keto-PGF1左血浆中的含量及6-Keto-PGFl／TXB2比值。结论：针刺能增加6-Keto-PGF1的含量及它与TXB2的比值，以达到持续而稳定的降压效果。     

一个在小鼠头部特异表达的新基因BSG1 cDNA的克隆及研究

目的 克隆小鼠头部发育过程中特异表达的新基因并对新基因可能的功能进行初步分析。方法 采用消减差异筛选的方法筛选小鼠头部特异表达的新基因，并用生物信息学的方法对克隆到的新基因进行序列分析和蛋白结构域的预测。同时，还采用了小鼠胚胎原位杂交、小鼠脑部切片的原位杂交以及鸡胚的原位杂交方法研究BS61基因的表达情况。结果 克隆到1个与小鼠头部发育相关的新基因BSG1(brain specific gene 1)，其Gen Bank的登录号为AY210402。该基因包含1个2133bp的完整阅读编码框，编码1个710aa的C2H2型锌指蛋白。它与人的KIAA0441基因在氨基酸水平上有82.8％的同源性。该基因定位在小鼠的第10号染色体上，含7个外显子，6个内含子。BSG1主要在小鼠胚胎、鸡胚的头部表达，并且BSG1在小鼠头部表达的部位局限在海马、齿状回和小脑。结论 BSG1是1个可能的转录因子，在脑部特异表达。对其研究有助于进一步揭示大脑发育的分子机理。     

HISTOLOGICAL AND BIOCHEMICAL CHANGES IN NEONATAL THYROID TISSUES

ABSTRACT: Etling, N. and Larroche, J. C. (Unité Inserm 30, Hôpital des Enfants Malades, Centre de Recherches biologiques néonatales, Hôpital de Port Royal, Paris, France). Histological and biochemical changes in neonatal thyroid tissues. Acta Paediatr Scand 64:315, 1975.–The thyroid tissues of 17 infants who died between 3 hours and 46 days after birth were studied by histological and biochemical techniques. The morphological aspect and the iodine content of these tissues are not related to the gestational age of the neonates, but they are related to the survival time, There are dramatic events early after birth: desquamation of the epithelium and absence of colloid, low iodine content of tissue extract (less than 1 g127-I per mg of protein) and low percentage of thyroglobulin (less than 10 %). 24 hours after birth, the vesicles fill with colloid and the epithelium is cuboidal; the iodine content of the protein increases (between 1 and 2 g 127I per mg protein) as well as the thyroglobulin percentage (around 20 %). One week after birth, there is a maximum of colloid and flat epithelium; the iodine content of the protein extract is much higher (more than 2 g 127I per mg protein) as is thyroglobulin percentage (up to 40 %). Our studies of thyroid tissues of neonates suggest that a leakage of colloid, iodine and thyroglobulin takes place in the perinatal period, this phenomenon being followed by their rapid repletion.     

The role of small bowel radiology in the diagnosis and management of Crohn's disease

A total of 50 children with Crohn's disease were examined by barium follow-through and colonoscopy with ileoscopy, to determine the value of small bowel radiology. Of these children, 40 (80%) had evidence of small bowel Crohn's disease on ileoscopy and/or barium follow-through. Twenty-two (44%) had disease confined to the terminal ileum. Radiology diagnosed disease proximal to the terminal ileum in 18 cases (36%), including 5 children in whom the terminal ileum was normal. Ileoscopy was not possible in nine patients (18%), six of whom had small bowel disease on barium follow-through. Colonic involvement, demonstrated in 34 (68%), was the sole site of disease in 6 (12%). Fifteen (30%) children had surgery, which in six (12%) was determined by the radiological findings of complicated small bowel disease. As the terminal ileum may be uninvolved in the presence of proximal ileal disease, normal ileoscopy does not exclude small bowel Crohn's disease. Small bowel radiology remains necessary to assess the full extent of Crohn's disease in children.     

Proarrhythmia associated with cisapride in children

BACKGROUND: Cisapride is a prokinetic agent that facilitates gastrointestinal motility and is widely used for the treatment of gastroesophageal reflux disease (GERD) in adults and children. However, reports of ventricular proarrhythmia have been noted in patients taking cisapride, particularly in conjunction with other drugs that may inhibit hepatic metabolism of cisapride via the cytochrome P450 3A4 system. OBJECTIVE: We designed a prospective, blinded study to evaluate the effect of cisapride on ventricular repolarization in children with GERD. METHODS: We analyzed the electrocardiograms (ECGs) from 35 children (age 0.4 to 18 years, mean 5.2 years) including measurement of the resting QT interval (QTc), JT interval (JTc), as well as QT and JT interlead dispersion markers. Data from these patients were compared with ECGs from a control group of 1000 normal children. RESULTS: Eleven (31%) of 35 patients receiving cisapride had a prolonged QTc (> or = 450 ms). The JTc was prolonged > or = 360 ms in 16 of 35 patients (46%). The mean QTc in the cisapride group was 428 +/- 35 ms and mean JTc was 336 +/- 35 ms. An increased QT or JT dispersion (> 70 ms) was seen in only 3 of 35 children. Of the 11 children with QTc prolongation, 2 had documented torsades de pointes ventricular tachycardia. Both patients were taking cisapride concomitantly with a macrolide antibiotic. All other patients were treated with either cisapride alone or in conjunction with other GERD agents, such as ranitidine or omeprazole. CONCLUSIONS: Cisapride may cause prolongation of ventricular repolarization in children. There does not appear to be increased heterogeneity of repolarization or delayed depolarization in this small sample. The proarrhythmia may be exacerbated by medications that inhibit cytochrome P450 3A4 hepatic metabolism, overdosage, or mechanisms that result in decreased serum clearance. ECG intervals should be monitored in children maintained on cisapride, particularly when used in combination with other known QT-prolonging medications.