Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients.

PURPOSE: To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Twenty-seven MBC patients received i.v. bevacizumab at 10 mg/kg on days 1 and 15 in combination with i.v. docetaxel 35 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Primary end points were to assess toxicity, overall response rate, and progression-free survival. A secondary end point was to assess the relationship between plasma endothelial and cell adhesion markers and clinical outcomes. RESULTS: One-hundred fifty-eight treatment cycles were administered with a median of six cycles (range 1-15 cycles) per patient. The most common grade 4 toxicities per patient were as follows: 2 (7%)-pulmonary embolus, 1 (4%)-febrile neutropenia, and 1 (4%)-infection; grade 3 toxicities were 4 (15%)-neutropenia, 4 (15%)-fatigue, 2 (7%)-neuropathy, 2 (7%)-athralgias, 2 (7%)-stomatitis, 1 (7%)-pleural effusion, and 1 (4%)-hypertension. The overall response rate was 52% [95% confidence interval (95% CI), 32-71%], median response duration was 6.0 months (95% CI, 4.6-6.5 months), and the median progression-free survival was 7.5 months (95% CI, 6.2-8.3 months). In hypothesis-generating univariate and limited multivariate analyses, E-selectin was statistically significantly associated with response to the combination. CONCLUSION: Bevazicumab in combination with weekly docetaxel is active with acceptable toxicities in MBC. Additional studies evaluating E-selectin as a marker of response to bevacizumab-containing chemotherapy are warranted.     

Continuous infusion of ceftazidime with a portable pump is as effective as thrice-a-day bolus in cystic fibrosis children

Continuous infusion (CI) of β-lactam antibiotics provides a stable concentration which may result in a better activity against gram-negative bacteria if exceeding the minimum inhibitory concentration (MIC). Treatment outcome after 24 h CI of ceftazidime (CAZ) in cystic fibrosis (CF) children was compared with the bolus administration regimen. Fourteen CF children with chronic Pseudomonas aeruginosa pulmonary infection were treated during 14 days with the conventional CAZ thrice-a-day bolus infusion (regimen A), and few months later with 24 h CI of CAZ (regimen B) using a portable pump. Amikacin was added to both regimens. Clinical efficacy of treatment was assessed using pulmonary, inflammatory and nutritional variables. Bacteriological analyses and CAZ concentrations in serum and sputum were also measured. All patients improved clinically with both regimens. Among the parameters used to compare both regimens, only prealbumin values improved (regimen A: +0.08 g/l versus regimen B: +0.11 g/l, P=0.015). No clinically significant side-effects were noted. In regimen A, the mean predose (trough level) CAZ concentration in serum was highly variable (range 2.2–45.4 μg/ml) with some values (32% of samples) below the MIC of P. aeruginosa isolates found in the sputum of the patients. In regimen B, the serum CAZ level achieved was 28.5 ± 8.4 μg/ml without any value below the MIC. The mean sputum levels were comparable in both regimens. No CAZ resistant strains of P. aeruginosa appeared between and directly after the treatments. Conclusion The clinical outcome of children with cystic fibrosis treated with 24 h continuous infusion of ceftazidime was no different from that achieved with the conventional bolus infusion regimen. Continuous infusion provided a sustained serum ceftazidime level well above the P. aeruginosa minimum inhibitory concentration. Continuous infusion was well tolerated and appreciated by the children and this may promote home therapy for cystic fibrosis children. Received: 12 February 2000 and in revised form: 26 May and 15 July 2000 / Accepted: 17 July 2000     

Why do preschool language abilities correlate with later reading? A twin study.

PURPOSE: Language acquisition is predictive of successful reading development, but the nature of this link is poorly understood. METHOD: A sample of 7,179 twin pairs was assessed on parent-report measures of syntax and vocabulary at ages 2, 3, and 4 years and on teacher assessments of reading achievement (RA) at ages 7, 9, and 10 years. These measures were used to construct latent factors of early language ability (LA) and RA in structural equation model-fitting analyses. RESULTS: The phenotypic correlation between LA and RA (r = .40) was primarily due to shared environmental influences that contribute to familial resemblance. These environmental influences on LA and RA overlapped substantially (rC = .62). Genetic influences made a significant but smaller contribution to the phenotypic correlation between LA and RA, and showed moderate overlap (rA = .36). There was also evidence for a direct causal influence of LA on RA. CONCLUSIONS: The association between early language and later reading is underpinned by common environmental and genetic influences. The effects of some risk factors on RA may be mediated by language. The results provide a foundation for more fine-grained studies that examine links between specific measures of language, reading, genes, and environments.     

Automated and quantitative immunocytochemical assays of Bcl-2 protein in breast carcinomas.

Expression of the bcl-2 gene was investigated in 218 human breast carcinomas by immunohistochemical analysis. Immunodetections were assessed using (1) frozen sections, (2) documented commercially available monoclonal antibody (bcl-2/124, Dako), (3) automation of immunoperoxidase technique (Ventana) and (4) quantitative evaluation of results by image analysis (SAMBA) and statistical analysis of quantitative data (BMDP software). Bcl-2 protein expression was correlated with current prognostic indicators and with molecular markers detected by the same procedure as for Bcl-2. It was shown that Bcl-2 expression is not related to patients'' age, tumour size and type or lymph node status, but an inverse relationship was observed between Bcl-2 and tumour grade (P < 0.0001). An inverse relationship was also observed between Bcl-2 expression and p53 (P < 0.0001), Ki67/MIB1 antigen- (P = 0.0012), and P-gp- (P = 0.002) positive immunoreactions. In contrast, anti-Bcl-2 positive reaction was significantly associated with ER-positive (P < 0.001) and with ER/PR-positive or ER/PR/pS2-positive immunoreactions (P < or = 0.005). Bcl-2 expression was independent of CD31 and cathepsin D expression. Thus, Bcl-2 protein, thought to be antiapoptotic, exhibits parodoxical expression in human breast carcinomas. It is strongly detected in low-grade tumours (well-differentiated) with low (MIB1) growth fraction, but is independent of the tumour progression (size, node status, CD31, and cathepsin D). Bcl-2 acting on apoptosis is related to p53 gene abnormalities in breast carcinomas. Bcl-2 protein expression may also be involved in response to endocrine therapy (associated to ER/PR/pS2 positive immunoreactions) and probably with chemoresistance mechanisms (inverse relationship with P-gp).     

Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia

Two children with acute lymphoblastic leukaemia (ALL) taking daily 6-mercaptopurine as part of a national UK therapeutic trial repeatedly developed profound myelosuppression on 25% of the standard protocol dose. Both were found to have undetectable intracellular activity of thiopurine methyltransferase (TPMT), an enzyme controlling one of the major alternative catabolic pathways of 6-mercaptopurine, and both produced higher concentrations of cytotoxic drug metabolites at 10-25% of the protocol dose than other patients taking 100%. It is supposed that these patients represent the 0.33% of the normal population constitutionally lacking TPMT. It is important to recognise such individuals both to avoid fatal bone marrow failure through inadvertent overdosage, and to be reassured that an adequate drug effect can be achieved at around 10% of the standard dose.     

Endometrial secretory proteins enhance early embryo development

Purpose To evaluate the role of endometrial stromal cells and their secretory proteins in early embryo development, two-celled CB6F1 mouse embryos were cultured alone or cocultured with human endometrial stromal cells in various culture conditions.Results The percentage of embryo blastocyst formation, hatching, and outgrowth was significantly greater in (1) coculture with endometrial stromal cells than in a cell-free control when both coculture and control were carried out in protein-free medium or in RPMI 1640 plus 10% fetal calf serum; (2) coculture with hormone (i.e., progesterone plus relaxin)-treated cells than in coculture with hormone-nontreated cells; and (3) media supplemented with isolated endometrial secretory proteins than in media supplemented with BSA (0.35%). Embryo development was not found to be significantly different in coculture and in media supplemented with endometrial secretory protein.Conclusion Our data provides credence to the theory that endometrial stromal cells enhance embryo development by secreting specific proteins that are beneficial to embryo growth in vitro.Presented at the 48th Annual Meeting of the American Fertility Society, New Orleans, Louisiana, October 31–November 5, 1992.     

Retrieval, Maturation, and Fertilization of Immature Oocytes Obtained from Unstimulated Patients with Polycystic Ovary Syndrome

Purpose: Our purpose was to determine whether immature oocytes could be retrieved under local anesthesia, whether these oocytes would mature and fertilize in vitro, and whether adequate endometrium development could be obtained after hormonal supplementation. Methods: Ovum pick-up was performed under local anesthesia. Immature oocytes were cultured and inseminated. To prepare the endometrium, estradiolvalerate was administered in combination with micronized progesterone. Results: Immature oocytes were obtained in all cases. Fifty-six percent (n = 30) of the oocytes developed into metaphase II (MII) after 48 hr of culture, and another 20% reached the MII stage by 72 hr. Normal fertilization was observed in only 10% of oocytes inseminated. No embryonic development occurred, and therefore embryo transfer was not performed in any of the patients. Endometrial microbiopsy was performed in all subjects and endometrial development was considered sufficient in eight patients. Conclusions: We collected immature oocytes from patients with polycystic ovary syndrome without general anesthesia. In vitro maturation of these oocytes seemed adequate but fertilization rates were poor. Sufficient endometrial quality was obtained after hormonal substitution.     

A difficult airway is not more prevalent in patients suffering from spasmodic torticollis: a case series

PURPOSE: We designed this retrospective study to assess the frequency of difficult airway and difficult intubation in patients with spasmodic torticollis and compare it to that of the general population. METHODS: After Institutional Review Board approval, data were collected from the charts of all the patients with spasmodic torticollis who underwent selective peripheral denervation at our institution between 1988 and 2001. The intubation grade was determined using the Cormack and Lehane laryngoscopic classification. The best laryngeal view was recorded. RESULTS: Data from 342 patients were available for analysis. Fourteen patients had a difficult airway. In two patients, intubation was difficult with three attempts at laryngoscopy in one patient and use of fibreoptic bronchoscopy in the other. Twelve (3.5%) patients presented with laryngoscopic grades of III or IV. The combined prevalence of laryngoscopic view grade III and IV and difficult intubation was 4.4%. CONCLUSIONS: This study assesses the frequency of difficult intubation in patients suffering from spasmodic torticollis. When compared to the general population, these patients do not appear to have a higher frequency of difficult airway or difficult intubation.     

Cloning of a cDNA encoding phosphoenolpyruvate carboxykinase from Haemonchus contortus.

Biochemical and metabolic data have led to the conclusion that the enzyme phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) contributes to a critical point of divergence in energy conservation pathways between mammals and nematodes. To facilitate the determination of the molecular basis for host vs parasite differences in PEPCK, we have cloned a cDNA encoding this enzyme from a parasitic nematode of ruminants, Haemonchus contortus. H. contortus PEPCK was cloned by functional complementation of a PEPCK, malic enzyme strain of Escherichia coli (E1786) using an egg stage H. contortus cDNA library in λZAPII. Selection was for growth on malate as the sole carbon source (malate phenotype). We isolated a plasmid, pPEPCK, which reproducibly confers a malate phenotype in E1786. The sequence of the 2.0-kb EcoRI insert of pPEPCK predicts a 612-amino acid protein which shows about 74% similarity to Drosophila melanogaster and chicken PEPCK. Extracts of E1786[pPEPCK], but not E1786, contain IDP- or GDP-dependent PEPCK enzyme activity. Sequence analysis revealed that the open reading frame (ORF) in pPEPCK lacked a 5′ initiation codon and was probably expressed as an in-frame fusion protein with β-galactosidase. A strategy combining library screening with PCR analysis of positive clones led to the identification of a clone encoding 6 additional NH₂-terminal amino acids, including a Met, which, by comparison with known PEPCK amino acid sequences, is likely to be the translation initiation site.