Phase I/II investigation of paclitaxel, ifosfamide and carboplatin for advanced non-small-cell lung cancer.

BACKGROUND: The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen. PATIENTS AND METHODS: Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m(2) as a 1-h infusion on day 1 with carboplatin at an area under the concentration-time curve (AUC) of 6 mg.min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m(2) on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m(2) on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg.ml/min. Therapy for dose levels I and III included filgrastim support (5 micro g/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/ micro l. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimen's activity and tolerability. RESULTS: Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively. CONCLUSIONS: The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.     

Open thumb forceps. An unusual foreign body in the urethra: technique of its removal

A great variety of foreign bodies in the urethra have been reported in the literature. Mostly, these cases were reported to emphasize the unusual nature of the objects requiring technical modifications for their removal. We report an interesting case of self introduced open thumb forceps into the urethra and technique of its retrieval.     

In-hospital mortality after transurethral resection of the prostate in Victorian public hospitals

BACKGROUND: The purpose of the present paper was (i) to identify trends in in-hospital mortality after transurethral resection of the prostate (TURP) in Victorian public hospitals; and (ii) to explore associations between in-hospital mortality after TURP and age, adverse events, type of admission (emergency/planned), location of the hospital (metropolitan/rural), teaching status of the hospital and length of stay. METHODS: Trends in in-hospital mortality after TURP and the associations between in-hospital mortality and the aforementioned variables were studied using International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) coded Victorian hospital morbidity data from public hospitals between 1987-88 and 1994-95. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were based on univariate and multivariate logistic regression, respectively. RESULTS: After adjustment for age, comorbidity, and other confounding variables, the trend in mortality reduction over time was highly significant (P for trend < 0.0001, 95% CI for trend: 0.84-0.95). Highly significant associations with mortality were observed for emergency admissions (OR = 1.99, P < 0.0001), presence of adverse events (OR = 2.69, P < 0.0001), length of hospital stay (P for trend < 0.0001, 95% for trend: 1.88-2.15) and age (P for trend < 0.0001; 95% CI for trend: 1.26-1.48). CONCLUSIONS: Routinely collected data from hospitals can provide tentative evidence of improved effectiveness of a surgical treatment, provided analysis takes careful account of potential sources of bias, especially those related to possible changes in case selection over time. These kinds of data should stimulate a joint effort between clinicians, quality assurance experts and epidemiologists to confirm this attribution, and to locate the causative factors.     

Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.     

Exploring the anticancer activities of novel bioactive compounds derived from endophytic fungi: mechanisms of action,current challenges and future perspectives

Cancer is the second leading cause of death all around the world. The natural compounds derived from the endophytic flora of fungi are possible solutions to cancer treatment because they are safe for health, cost-effective, biocompatible and have fewer toxicity issues. The active ingredients in endophytic fungi that are responsible for anti-cancer activities are alkaloids, terpenoids, glycosides, saponin, peptides, steroids, phenols, quinones, and flavonoids. This review highlights the anti-cancer activities of entophytic fungus against human papillary thyroid carcinoma (IHH4), human pancreatic (PANC-1), ovarian (OVCAR-3), hepatic (HepG2), lung (A-549), human lymphoma (U937), human skin carcinoma (A431), breast (MCF-7), and Kaposi’s sarcoma. The emerging evidence suggested that bioactive compounds isolated from endophytic fungi showed their anti-cancer activities by revealing the disturbance of the microtubule network caused by increased levels of Bax and Bcl-2 proteins that triggers cell cycle arrest at the G2-M phase, by inhibiting the DNA replication via binding with topoisomerase II, by regulating the activity of extracellular signal-regulated kinase and NF-kB, by evaluating the levels of p21, p27, and cyclins B/D1/E that led to cell death by apoptosis and cell cycle arrest. This review will assist readers in better comprehending bioactive chemicals and the beneficial interaction between the fungal endophytes and medicinal plants.     

Selective pancreatic toxicity of palmitoylpentachlorophenol

Palmitoylpentachlorophenol (PPCP), which is a lipid conjugate of a xenobiotic compound, has been found in human fat. To study the toxicity associated with PPCP, rats were given 100 mg/kg PPCP and sacrificed at 4, 8 and 12 days. The target organ identified was the exocrine pancreas; no other major organs examined showed any gross or histopathological abnormality. At 4 and 8 days after treatment, focal, spotty vacuolation, and loss of pancreatic acini was observed. Acute inflammatory infiltrate was also observed in parenchyma at all time points and the loss of acinar tissue was resolved through fibrous tissue formation by 12 days. The present study indicates that PPCP has a specific target organ toxicity.     

Phase II trial of daily oral etoposide in patients with advanced non-small cell lung cancer

Forty-six previously untreated patients with advanced non-small cell lung cancer (NSCLC) were entered into a Hoosier Oncology Group phase II trial of daily oral etoposide 50 mg/m²/d. The dose limiting toxicity was granulocytopenia. The non-hematologic toxicity was mild, with only 19% of patients developing Grade 3 or 4 leukopenia. Two partial responses of 10 and 16 weeks duration were seen in 43 evaluable patients, for an overall response rate of 4%. We conclude that daily oral etoposide has minimal activity in advanced NSCLC, and does not improve response rates over conventional 1–5 day intravenous etoposide administration.from the Hoosier Oncology Group, the Walther Cancer Institute, Indianapolis, IN; Department of Medicine, Indiana University, Indianapolis, IN, USADr. Einhorn is the Walther American Cancer Society Professor of Clinical Oncology.     

Role of second-line systemic treatment post-docetaxel in metastatic castrate resistant prostate cancer- current strategies and future directions

Treatment of metastatic castrate resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy is a challenging clinical scenario with limited availability of treatment options. Re-treatment with docetaxel, either as monotherapy or in combination with other cytotoxics or targeted agents has shown durable responses. However, most docetaxel re-treatment studies have been either retrospective or early phase non-randomised studies which have not formally assessed Quality of life or survival gain with re-treatment. Despite limited evidence for efficacy of mitoxantrone in the second-line, it continues to remain widely used, largely due to lack of available suitable alternatives. Cabazitaxel in combination with prednisolone is the only chemotherapy to have shown a significant survival benefit and receive approval by the U.S. Food and Drug Administration for patients with mCRPC previously treated with a docetaxel-based regimen. Abiraterone acetate has recently demonstrated a significant improvement in survival when compared to placebo in patients with docetaxel-treated mCRPC. This review aims to summarize the current evidence and discuss future strategies for treatment of mCRPC patients following failure of docetaxel chemotherapy.     

4-羟基壬烯醛在糖尿病大鼠白内障中的代谢及发病中的作用

目的 研究脂质过氧化代谢产物4-羟基壬烯醛(HNE)在糖尿病性白内障中的代谢过程以及发病中的作用.方法 实验研究.采用两因素析因设计:处理因素为两水平(正常对照组和糖尿病组),时间因素为三水平(30、45、70 d).对于不同时期的正常与糖尿病大鼠晶状体采用下列方法进行处理:(1)使用一定晕的带有放射活性的HNE与这些晶状体一起培养,测定HNE在晶状体的代谢;(2)分光光度计法测定醛脱氢酶(ALDH)活性;(3)免疫印迹法检测ALDH和HNE-蛋白质加合物的表达.采用两因素析因设计定量资料方差分析对资料进行统计学处理.结果 HNE在正常对照组的晶状体的代谢主要是与谷胱甘肽(GSH)结合形成GS-HNE(约45%),其次为经ALDH氧化成HNA(约9.1%);但糖尿病组晶状体的HNE与GSH结合径路受到抑制,GS-HNE形成减少,与正常组相比30 d时减少约64%(F=49.59,P＜0.001);而糖尿病组晶状体的ALDH氧化径路代偿增强,HNA形成增多,70 d比30 d增多约1.7倍(F=11.51,P=0.0442).糖尿病组的晶状体ALDH活性增高,免疫印迹法显示ALDH较正常对照组增多,HNE-蛋白质加合物较对照组减少.结论糖尿病性白内障中HNE与GSH的结合径路受到抑制,而氧化径路代偿性增强,揭示了结合径路的损伤可能与白内障发生有密切关系,氧化径路的代偿增强可能对防止糖尿病性白内障的发生有一定的意义.(中华眼科杂志,2009,45:248-253)