A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39-73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2-5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.     

Phase II trial of docetaxel, cisplatin and fluorouracil followed by carboplatin and radiotherapy in locally advanced oesophageal cancer

This study was performed to assess the efficacy and safety of docetaxel, cisplatin and fluorouracil combination in patients with unresectable locally advanced oesophageal squamous cell carcinoma. Treatment consisted of docetaxel 60 mg m(-2), cisplatin 75 mg m(-2) on day 1 and fluorouracil 750 mg m(-2) day(-1) on days 2-5, repeated every 3 weeks for three cycles, followed by carboplatin 100 mg m(-2) week(-1) for 5 weeks and concurrent radiotherapy (45 Gy in 25 fractions, 5 days week(-1)). After radiotherapy, eligible patients either underwent an oesophagectomy or received high dose rate endoluminal brachytherapy (HDR-EBT). Thirty-one out of 37 enrolled patients completed the planned chemotherapy and 30 completed chemoradiation. After completion of chemotherapy, 49% (95% CI: 32.2-66.2) had a clinical response. Twelve patients (32%) underwent a resection, which was radical in 60% (postoperative mortality: 0%). A pathological complete response was documented in four patients (11% of enrolled, 30% of resected). The median survival was 10.8 months (95% CI: 8.1-12.4), and the 1- and 2-year survival rates were 35.1 and 18.9%, respectively. Grade 3-4 toxicities were neutropoenia 32%, anaemia 11%, non-neutropoenic infections 18%, diarrhoea 6% and oesophagitis 5%. Nine patients (24%) developed a tracheo-oesophageal fistula during treatment. Even if the addition of docetaxel to cisplatin and 5-fluorouracil (5-FU) seems to be more active than the cisplatin and 5-FU combination, an incremental improvement in survival is not seen, and the toxicity observed in this study population is of concern. In order to improve the prognosis of these patients, new drugs, combinations and strategies with a better therapeutic index need to be identified.     

Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia

BACKGROUND: Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP). METHODS: Patients received decitabine 15 mg/m(2) intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing. RESULTS: Twenty-eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% +/- 0.9% (mean +/- standard error of the mean) to 60.4% +/- 2.0% on Day 5, 60.5% +/- 1.8% on Day 12, and returned to 68.8% +/- 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in nonresponders than in responders on Days 5 and 12. CONCLUSIONS: Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.     

Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesothelioma

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rapidly progressive lethal tumor. Treatment options remain limited and the outcome in recurrent disease is poor. METHODS: A Phase II open-label noncomparative study was conducted to assess the safety and efficacy of the triplet combination irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in untreated patients and in those with previous exposure to chemotherapy. RESULTS: In 62 patients an objective response rate of 25% was observed. In the first-line setting progression-free survival measured 6.4 months (95% confidence interval [CI]: 4.5-7.3) and overall survival was 10.8 months (95% CI: 7.9-13.7). In the second-line setting progression-free survival was 7.3 months (95% CI: 3.4-11.2) and overall survival was also 7.3 months (95% CI: 4.8-9.8). Psychosocial well-being improved during chemotherapy and the main toxicity observed was neutropenia (40%). CONCLUSIONS: IPM appeared to have a reasonable response rate with an acceptable toxicity profile in the first- and second-line treatment of MPM.     

Irinotecan and cisplatin with concurrent split-course radiotherapy in locally advanced nonsmall-cell lung cancer: a multiinstitutional phase 2 study

BACKGROUND: The purpose was to determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy (TRT) in locally advanced nonsmall-cell lung cancer. METHODS: Fifty patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naive, good performance status (PS, 0-2), age <75, stage III, and adequate organ function. The patients received irinotecan 60 mg/m(2) intravenously on Days 1, 8, and 15, and cisplatin 80 mg/m(2) intravenously on Day 1 in the first group. The doses were reduced to 50 and 60 mg/m(2), respectively, in the second group. Two cycles of chemotherapy were repeated every 4 weeks. Split-course thoracic radiotherapy of 2 Gy/day commenced on Day 2 of each chemotherapy cycle, with 28 and 32 Gy administered in the first and second cycles, respectively. RESULTS: Fifty patients were eligible and 48 (16 in the first, 32 in the second group) patients were assessable for response, toxicity, and survival. The overall response was 83% (95% confidence interval [CI], 70%-93%). Grade 4 leukopenia, neutropenia, grade 3 or 4 diarrhea, pneumonitis, esophagitis, and fatigue occurred in 21%, 48%, 19%, 10%, and 19%, respectively. The median time to progression was 8.2 months. The median overall survival time and the 2- and 5-year survival rates were 20.1 months, 47.1%, and 17.1%, respectively. In subgroup analysis, grade 4 neutropenia, grade 3 or 4 diarrhea, the overall response, and the median survival times of the first/second groups were 63%/41%, 19%/19%, 75%/88%, and 13.1/33.4 months, respectively. CONCLUSIONS: This combined modality of irinotecan and cisplatin with concurrent TRT is active and further investigations are warranted at the second group dose level.     

长龙通注射液对纤维蛋白溶解酶活性的影响

长龙通注射液对家兔、豚鼠增加纤维蛋白溶解酶活性，给药后20min,50min时最显著，90min后作用明显减弱或恢复正常，在家兔连续多次给药实验中，测定给药20min时纤维蛋白溶解酶活性显著增加（P＜0．01），凡给药24h后测定，纤维蛋白溶解酶活性均不见明显增强，说明长龙通注射液中增加纤维蛋白溶解酶活性的有效成分在体内没有蓄 积作用，有效作用时间短。     

Humoral and cell-mediated immunity to MSP3 peptides in adults immunized with MSP3 in malaria endemic area, Burkina Faso

We performed a single-blind, randomized phase 1 trial of the long synthetic peptide (LSP) of merozoite surface protein-3 (MSP3) in adults living in Burkina Faso. Thirty eligible volunteers were randomized to receive either the MSP3-LSP candidate vaccine or tetanus toxoid vaccine as a control. A dose of each vaccine was administered on days 0, 28 and 112 and the vaccine was formulated with aluminium hydroxide. Humoral immune responses were assessed by ELISA at days 0, 28, 56, 112, 140, 252 and 365 and cell-mediated immune responses by lymphoproliferation assay and by ELISA on days 0, 56 and 140. IgG responses to four peptides of MSP3 were similar in both vaccine groups. Higher IgG concentrations were recorded after the beginning of malaria high transmission season in both vaccine groups. The lymphocyte proliferation and the production of IFN-γ in response to stimulation with the four overlapping peptides increased following vaccination in the MSP3-LSP vaccine group, but did not change appreciably in the control group. In contrast to natural infection, MSP3-LSP did not boost humoral responses to the four overlapping peptides of MSP3 to any detectable degree in our semi-immune adult. MSP3-LSP may be more immunogenic in young children with little or no acquired immunity.     

Evaluation of oxidative stress in children with congenital heart defects

Background: A significant cause of death and chronic illness in childhood is caused by cardiovascular diseases, including congenital heart disease (CHD). This study aims to investigate the oxidative stress status and to establish its association with CHD in children. Methods: The study involves measurements of malondialdehyde (MDA), protein carbonyl (PCO), total anti‐oxidant capacity, high‐sensitive C‐reactive protein (hs‐CRP), fibrinogen and cytokine (interleukin [IL‐6] and tumor necrosis factor‐α) levels in 43 children with CHD and 30 healthy age‐matched children. Results: MDA, PCO, hs‐CRP, fibrinogen, IL‐6 and tumor necrosis factor‐α were significantly elevated while total anti‐oxidant capacity was significantly declined in patients compared with the controls. MDA was positively correlated with PCO, hs‐CRP, Qp/Qs and systolic pulmonary artery pressure. PCO was positively correlated with hs‐CRP, fibrinogen, IL‐6 and systolic pulmonary artery pressure. Conclusion: Oxidative stress and its association with other markers in children with CHD was established. To the best of our knowledge, this is the first time that PCO has been used as a biomarker in CHD and it may be employed as a new diagnostic biomarker in CHD and in the assessment of its severity.     

Susceptibility mapping in the human brain using threshold‐based k‐space division

A method for calculating quantitative three‐dimensional susceptibility maps from field measurements acquired using gradient echo imaging at high field is presented. This method is based on division of the three‐dimensional Fourier transforms of high‐pass‐filtered field maps by a simple function that is the Fourier transform of the convolution kernel linking field and susceptibility, and uses k‐space masking to avoid noise enhancement in regions where this function is small. Simulations were used to show that the method can be applied to data acquired from objects that are oriented at one angle or multiple angles with respect to the applied field and that the use of multiple orientations improves the quality of the calculated susceptibility maps. As part of this work, we developed an improved approach for high‐pass filtering of field maps, based on using an arrangement of dipoles to model the fields generated by external structures. This approach was tested on simulated field maps from the substantia nigra and red nuclei. Susceptibility mapping was successfully applied to experimental measurements on a structured phantom and then used to make measurements of the susceptibility of the red nuclei and substantia nigra in healthy subjects at 3 and 7 T. Magn Reson Med 63:1292–1304, 2010. © 2010 Wiley‐Liss, Inc.