Pharmacokinetic study of pleural fluid penetration of carbapenem antibiotic agents in chemical pleurisy

SummaryStudy objectivesWe investigated pleural fluid penetration of carbapenem antibiotic agents [imipenem (IPM), panipenem (PAPM), meropenem (MEPM), and biapenem (BIPM)] using an experimental rabbit pleuritis model to clarify the usefulness of the carbapenem agents for the treatment of bacterial pleurisy or pyothorax.Measurements and resultsSerum and pleural fluid specimens were serially collected at 5, 10, 15, 30, 60, 90, 120, 180, 240, 300, and 360min after antibiotic administration for measurement of antibiotic levels. We investigated each agent alone as well as drug solutions containing each agent and a dehydropeptidase-I-specific inhibitor, cilastatin (CS), to remove the influence of dehydropeptidase-I-related hydrolysis. Groups of animals (n=3) received each carbapenem agent with or without CS. Serum and pleural fluid antibiotic levels were measured by high-performance liquid chromatography (HPLC). Because Cmax is not useful for evaluating the antimicrobial effects of carbapenem antibiotic agents due to their dose-dependent antimicrobial activity, we also investigated the AUC, which is correlated with the total drug levels in vivo.Among the drug solutions containing CS, MEPM/CS had the highest pleural fluid AUC0–360 (1594.8±510.3μgmin/ml), and the highest pleural fluid AUC0–360/plasma AUC0–360 ratio (0.79±0.04). BIPM/CS had the highest plasma AUC0–360 (3040.1±1525.9μgmin/ml). In pleural fluid AUC0–360/plasma AUC0–360 ratio MEPM/CS was significantly higher than those for the remaining agents. In pleural fluid AUC0–360 and plasma AUC0–360 there were no significant differences among these mixed solutions.ConclusionsMEPM had the most favorable pleural fluid penetration. Pleural fluid penetration should be examined in infection models and in clinical trials

A case of mucoepidermoid carcinoma arising in mature cystic teratoma

卵巣粘表皮癌は卵巣悪性腫瘍の中で極めてまれな組織型に分類される。今回、我々は成熟嚢胞性奇形種より発生した卵巣粘表皮癌の症例を経験したので報告する。症例は、69歳、女性、両側の成熟嚢胞性奇形腫を認めたが、SCC 高値とCT、MRI にて左側の腫瘍内に造影される充実性部分を認めたこと、小腸に浸潤を疑う所見を認めたこと、から悪性転化を疑い、手術を施行した。開腹時、両側卵巣腫瘍を認め、左卵巣腫瘍はS状結腸と強固に癒着していた。卵巣腫瘍充実性部分の迅速病理にて低分化癌と診断し、単純子宮全摘出術、両側付属器摘出術、S状結腸合併切除、骨盤リンパ節郭清術、大網切除術を施行した。病理組織学的には、左卵巣腫瘍の嚢胞壁肥厚部に皮膚付属器、脂肪織、軟骨組織、リンパ球集簇、卵巣間質を認め、充実成分に低分化な浸潤性扁平上皮癌を認めた。充実成分には、粘表皮癌に特徴的な、豊富な胞体粘液（PASおよびAlcian blue 染色陽性）を有する異型細胞が胞巣状~不完全な腺管状を呈する領域があり、成熟嚢胞性奇形腫より発生した卵巣粘表皮癌IIb期(pT2bN0M0)と診断した。術後補助化学療法としてDC（ドセタキセル、カルボプラチン）療法を施行し、術後1年8ヶ月現在、再発を認めない。雑誌掲載論

A Phase I/II Clinical Trial of Carbon-ion Therapy for patients with preoperative pancreas cancer (Protocol 9906, 16fractions/4weeks)

Purpose: We examined the effect of preoperative carbon ion therapy in terms of reducing the rate of local recurrence in patients undergoing resection for adenocarcinoma of the pancreas.Patients and Methods: Between July 2000 and December 2002, 22 patients with preoperative pancreas cancer were enrolled into this trial. Median age was 63 years. Carbon ion therapy was given once daily, 4 days a week, for a fixed 16 fractions in 4 weeks. The dose was set to 44.8GyE and escalated to 48.0GyE at 5% increments. Results:All patients completed the scheduled treatment course. Three grade3 acute reactions and two grade3 late reactions occurred among 16 of the patients treated with a dose of 48.0GyE. Two grade 3 late reactions of them were estimated to be caused by carbon ion therapy. Of 22 patients, 15(68%) had resection. All tumor specimens pathologically revealed evidence of grade 2 treatment effects with significant fibrosis, hyalinization, and necrosis (Pathological grade2 is defined as a less than 33% active cancer cells.). Remarkable antitumor effects were observed. The overall local control rates were 100% and 87% at 1 year and at 2 years of follow-up respectively. No local failure was observed in any of the 22 enrolled patients.Conclusion: Carbon ion radiotherapy seems to be a safe and effective modality in the management of resectable pancreatic carcinoma, providing good local control and offering a survival advantage without unacceptable morbidity.2010 Gastrointestinal Cancers Symposiu

A PHASE I/II CLINICAL TRIAL OF CARBON ION THERAPY FOR PATIENTS WITH LOCALLY ADVANCED PANCREAS CANCER (Protocol 0204, 12 fractions/3 weeks)

Purpose: We examined the maximum-tolerated dose and effect of carbon ion therapy alone for locally advanced pancreas cancer.Patients and Methods: Between April 2003 and February 2007, 46 patients with locally advanced pancreas cancer were eligible for this analysis. Patients eligible for study entry had histologically or cytologically confirmed with pancreas ductal adenocarcinoma. Carbon ion therapy was given once daily, 4 days a week, for fixed 12 fractions in 3 weeks. The dose was set at 38.4 GyE and escalated to 52.8 GyE at 5% increments. Results: Seven grade 3 acute and two grade 3 late toxicities were observed. Six of 7 grade 3 acute toxicities were anorexia. The maximum acute reaction of the grade 3 was observed in two-thirds of the patients (67%) on the 52.8 GyE. CR was observed in one lesion, PR in 7, SD in 37. The local control rate at one year in the all patients and in the patients receiving 45.6 GyE or more was 76% and 95% and the overall survival rate was 44% and 73%, respectively.Conclusion: Carbon ion radiotherapy seems to be a safe and effective modality in the management of locally advanced pancreas cancer, providing good local control and offering a survival advantage without unacceptable morbidity.40ｔｈ Anniversary Meeting of APA and JP

Genome-wide localization of pre-RC sites and identification of replication origins in fission yeast

DNA replication of eukaryotic chromosomes initiates at a number of discrete loci, called replication origins. Distribution and regulation of origins are important for complete duplication of the genome. Here, we determined locations of Orc1 and Mcm6, components of pre-replicative complex (pre-RC), on the whole genome of Schizosaccharomyces pombe using a high-resolution tiling array. Pre-RC sites were identified in 460 intergenic regions, where Orc1 and Mcm6 colocalized. By mapping of 5-bromo-2′-deoxyuridine (BrdU)-incorporated DNA in the presence of hydroxyurea (HU), 307 pre-RC sites were identified as early-firing origins. In contrast, 153 pre-RC sites without BrdU incorporation were considered to be late and/or inefficient origins. Inactivation of replication checkpoint by Cds1 deletion resulted in BrdU incorporation with HU specifically at the late origins. Early and late origins tend to distribute separately in large chromosome regions. Interestingly, pericentromeric heterochromatin and the silent mating-type locus replicated in the presence of HU, whereas the inner centromere or subtelomeric heterochromatin did not. Notably, MCM did not bind to inner centromeres where origin recognition complex was located. Thus, replication is differentially regulated in chromosome domains