A pharmacogically guided phase I study of carboplatin in combination with methotrexate and vinblastine in advanced urothelial cancer

 Carboplatin is an alternative for cisplatin in the treatment of urothelial cancers. A pharmacologically guided phase I study of carboplatin in combination with methotrexate (30 mg/m²) and vinblastine (4 mg/m²) was conducted in ten patients by increment of the area under the plasma concentration versus time curve (AUC) for ultrafilterable carboplatin using the Calvert formula. The maximal tolerated AUC was 5 mg ml^-1 min, with neutropenia being the dose-limiting toxicity. There was a significant linear correlation between the percentage of decrease in neutrophil count and the carboplatin AUC. Determination of the glomerular filtration rate by the isotopic method allowed us to adapt the dose of carboplatin given to patients suffering from urothelial cancer, who frequently have impaired renal function. The recommended AUC for phase II study is 4 mg ml^-1 min. Received: 9 May 1994/Accepted: 16 August 1994     

Mechanism of interaction between cisplatin and human recombinant interferon gamma in human ovarian-cancer cell lines

Human ovarian carcinoma cells (2008 and its cisplatin-resistant sub-line 2008/C13*) were sensitized to cisplatin by treatment with human recombinant gamma interferon (IFNγ). IFNγ produced no significant change in the uptake of CDDP. Exposure of 2008 and 2008/C13* cells to IFNγ resulted in a time-dependent decrease of cellular glutathione and total glutathione-S-transferase activity, principally the π isoform. By contrast, the treatment of 2008 and 2008/C13* cell lines with IFNγ induced rather than suppressed metallothionein II_A mRNA levels. IFNγ changed neither the formation of total platinum-DNA adducts, nor DNA repair. A significant decrease in c-erbB-2 expression was observed both in sensitive and in resistant cell lines after treatment with IFNγ, and this decrease was dose-dependent. Our results indicate that the mechanism of IFNγ-induced sensitization in human ovarian-cancer cell lines is multifactorial. © 1995 Wiley-Liss, Inc.     

Intermediate neurological development of 60 neonates weighing 1500 grams or less at birth. Predictive value of initial findings (clinical aspects, electroencephalograms and brain imaging)

60 low birthweight (less than or equal to 1,500 g) are distributed according to existence or not, and intensity of brain disturbances, during the neonatal period; appreciated by neurological examinations, early EEG and brain imaging during the second month of life. At 18 months, at least, neurological outcome is normal for 46 children (but 6 had transient neuromotor anomalies), 14 have sequelae (7 mild, 7 major). All children with clinical neurological examination carried out during the neonatal period are normal at follow up. It is true also for the children without EEG anomaly and normal brain imaging. The early prediction of neurological outcome can be made easily with consideration of these three data. Standardised test are proposed, during the neonatal period, for these low birth weight infants.     

Indications for hepatic ultrasonography in breast cancer staging and follow-up

Retrospective analysis of the medical records of 6649 breast cancer patients seen over an 11-year period found 438 patients (6.6%) with liver metastases (LM) and 432 patients (6.5%) with benign liver lesions (BLL). Liver ultrasonography (LUS) and liver function tests had been performed for all patients. LM were the first manifestation of metastatic spread in 20.1% of the 438 patients; median survival was related to the presence (6.7 mo.) or absence (12.2 mo.) of extrahepatic metastases (EHM). Liver function tests were normal in 20.5% of the patients in whom LM were first diagnosed by LUS. Most LM were hypoechoic (70.9%). BLL corresponded to cysts, hemangiomas, calcifications, and focal fatty infiltration. LUS appears indicated for (i) pretherapy disease staging, and in particular for detection of BLL, and (ii) follow-up of patients without EHM for early diagnosis of LM.     

Pulmonary thromboembolism in beta-thalassemia intermedia: are we aware of this complication?

We describe a case of pulmonary thromboembolism in a 61-year-old woman with beta-thalassemia intermedia and no other risk factors for thrombosis. Thromboembolism was documented by perfusion lung scan. We review the literature on this uncommon complication of thalassemia intermedia and discuss the pathogenesis and treatment options. A significant relationship between pulmonary thromboembolism and pulmonary hypertension in these patients was noted.     

Injection drug use in North America

Injection drug use of psychotropic agents for nontherapeutic purposes is associated with some of the most pernicious infectious diseases seen in the United States. There is an inextricable link between infection, injection drug use (IDU) and other risk behaviors, especially those related to sexual activity. A number of national surveys now provide excellent databases to track the breadth, scope and impact of IDU across the United States. The prevalence of heroin use has increased over the past decade with larger numbers of users presenting for treatment of drug use disorders. A host of serious infections can result from IDU. Prevention and early intervention with evidence-based harm-reduction strategies are crucial to reducing and eliminating these odious consequences.     

Sequential development of Hodgkin's disease and CD30+ diffuse large B-cell lymphoma in a patient with MALT-type lymphoma: evidence of different clonal origin of single microdissected Reed-Sternberg cells

We observed in the same patient the development of a tonsil mucosa-associated lymphoid tissue-type lymphoma in 1994, a mediastinal Hodgkin's disease in 1998, and a colonic CD30+ anaplastic diffuse large B-cell lymphoma in 2000. A same-sized FR3-JH fragment was demonstrated by polymerase chain reaction, both at the level of total DNA and of single micromanipulated cells, showing monocytoid, Reed-Sternberg, or anaplastic morphology. Moreover, an identical IgH nucleotide sequence was detected in mucosa-associated lymphoid tissue-type lymphoma and colonic CD30+ anaplastic diffuse large B-cell lymphoma, whereas mediastinal Hodgkin's disease IgH rearrangement involved different VH and JH genes. CD30+ Reed-Sternberg and diffuse large B-cell lymphoma cells contained Epstein-Barr virus EBER sequences that were not observed at the level of mucosa-associated lymphoid tissue-type lymphoma. Therefore, Epstein-Barr virus infection may have played a role in diffuse large B-cell lymphoma transformation of mucosa-associated lymphoid tissue-type lymphoma and in the lymphomagenesis of Hodgkin's disease. In addition to their different clonal origin, Reed-Sternberg cells of Hodgkin's disease expressed a CD15+, CD20+ (rare cells), CD30+, Oct-2-, EBNA2-, LMP1+ phenotype, whereas anaplastic and Reed-Sternberg-like cells of diffuse large B-cell lymphoma were CD15-, CD20+, CD30+, Oct-2+, EBNA2+, and LMP1+. Interestingly, we also detected scattered CD30+ Epstein-Barr virus- large cells with prominent nucleoli in the initial tonsil mucosa-associated lymphoid tissue-type lymphoma, suggesting that these cells could be prone to Epstein-Barr virus infection and/or large cell transformation.     

Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study

PURPOSE: To assess the natural history of retinal manifestations in von Hippel-Lindau (VHL) disease and to study the genotype-phenotype correlation. METHODS: Data concerning 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations were extracted from the French VHL database. A retrospective study was performed by questionnaire. Patients were classified into three visual morbidity groups. Molecular analysis of the VHL gene was performed in 196 patients. RESULTS: The mean age of ocular manifestations detection was 24.8 years. In half of the cases, the ocular manifestations revealed the disease. Half of the cases had bilateral involvement. Visual morbidity was significantly associated with the retinal hemangioblastoma count but not with other ocular or general characteristics. One third of the patients were classified in the worst visual morbidity group at the end of follow-up. Mutations were detected in 81% of patients with retinal hemangioblastomas and in 71% of patients without retinal involvement. Using a Poisson model and a marginal approach, the number of hemangioblastomas, age-adjusted, was 2.1 times higher in patients who had a substitution than in patients with a truncation (95% CI, 1.05-4.44; P < 0.05). CONCLUSIONS: Visual loss remains one of the major complications of VHL disease, confirming the importance of early ophthalmologic screening. Visual morbidity was not related to the type of extraocular manifestation but appeared to be related to the type of germline mutation. However, only further genetic and clinical studies in a larger series of patients will clearly determine the genotype-phenotype relationship.