Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer.

We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non-small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.     

Micafungin Does Not Influence the Concentration of Tacrolimus in Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Background

Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs.

Objective

To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation.

Results

The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 ± 306, 653 ± 328, 699 ± 340 and 671 ± 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 ± 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%.

Conclusion

We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients.     

CCAAT/enhancer-binding protein-d is induced in mesangial area during the early stages of anti-Thy1.1 glomerulonephritis and regulates cell proliferation and inflammatory gene expression in cultured rat mesangial cells

Background Interleukin (IL)-6, cyclooxygenase (COX)-2, and monocyte chemoattractant protein (MCP)-1 contribute to renal injury. The promoter regions of these genes contain CCAAT/enhancer-binding protein (C/EBP)-binding sites. In this study, we investigated the role of C/EBP-δ in mesangial cells (MCs). Methods In an in vivo study, anti-Thy 1.1 glomerulonephritis rats were generated and C/EBP-δ, IL-6, COX-2, and MCP-1 expressions were assessed by immunohistochemistry. In an in vitro study, cultured MCs were transfected with non-silencing (NS) short interfering RNA (siRNA) or C/EBP-δ siRNA. Subsequently, after stimulation with IL-1β, C/EBP-δ, IL-6, COX-2, and MCP-1 mRNA expression levels were evaluated using real-time polymerase chain reaction (PCR). IL-6 concentration in the culture medium was determined by enzyme-linked immunosorbent assay. In addition, cell proliferative activity against IL-1β or platelet-derived growth factor-BB was assessed by bromodeoxyuridine incorporation. Results In the in vivo study, C/EBP-δ, IL-6, COX-2, and MCP-1 were expressed in the mesangial region of anti-Thy 1.1 glomerulonephritis rats on day 1. In the in vitro study, IL-1β increased C/EBP-δ mRNA levels in NS siRNA-transfected MCs (7.3-fold), but no increase was evident in C/EBP-δ siRNA-transfected MCs. IL-6, COX-2, and MCP-1 mRNA levels in C/EBP-δ siRNA-transfected MCs were all lower than those in NS siRNA-transfected MCs (decreases of 57.7%, 85.7%, and 69.3%, respectively). The IL-6 concentration in the culture medium from C/EBP-δ siRNA transfected MCs (7.37 ± 4.3 pg/ml) was also lower than that in the culture medium from NS siRNA-transfected MCs (25.2 ± 3.4 pg/ml). Cell proliferative activity in C/EBP-δ siRNA-transfected MCs was lower than that in NS siRNA transfected MCs. Conclusions C/EBP-δ was induced in the mesangial region during the early stages of anti-Thy1.1 glomerulonephritis. C/EBP-δ contributes to inflammatory gene expression and MC proliferation.     

Preoperative assessment and surgical indication for malignant pleural mesothelioma

The standard surgical procedure for patients with malignant pleural mesothelioma (MPM) is extrapleural pneumonectomy (EPP). However, high morbidity and mortality rates have been reported in patients who received EPP, whereas survival rates after EPP remain unsatisfactory. Thus, a carefully and precise preoperative assessment to select appropriate candidates for EPP is essential in patients with MPM, and we conducted a surgical staging with laparoscopy, mediastinoscopy and contralateral thoracoscopy for potentially resectable MPM patients. Among 5 consective patients who received the preoperative surgical staging during past 10 months, 1 patient was judged not to be a surgical candidate due to the presence of contralateral pleural metastasis. In conclusion, this surgical staging is a useful preoperative evaluation to prevent an unnecessary operation.     

A case of well controlled renal small cell carcinoma with metastasis treated by intensive therapy

A 18-year-old male visited hospital with macroscopic hematuria. Computed tomography showed slightly enhanced left renal tumor that was uncharacteristic for clear cell carcinoma, and radical nephrectomy was performed. Operative specimen revealed primary small cell carcinoma of the kidney. 18 months after operation, bone metastases were diagnosed. Chemotherapy including cisplatinum, etoposide and bleomycin and external irradiation was performed. This intensive therapy was effective for metastatic lesion. He is still alive for 55 months after diagnosis, and is the best controlled case around the world. To our knowledge, this is the 14th case as primary renal small cell carcinoma in the world literature.     

Efficacy of temozolomide combined with capecitabine (CAPTEM) on refractory prolactinomas as assessed using an ex vivo 3D spheroid assay

Pituitary - Refractory prolactinomas resistant to dopamine agonists (DAs) pose a clinical challenge. Temozolomide (TMZ) is a recommended treatment option, but its effects are difficult to predict,...     

Development of a valve type semi-closed extracorporeal circulation system

Journal of Artificial Organs - In Japan, perfusionists who work on other clinical tasks are involved in cardiopulmonary bypass. Moreover, the number of cases they can perform is limited. In view of...     

Echocardiographic changes in diastolic filling and stroke volume during postural alterations and ankle exercise in a patient with congenital defect of the pericardium

Journal of Echocardiography -     

Luteinizing hormone induces progesterone receptor gene expression in cultured porcine granulosa cells.

We have examined the effect of LH on the regulation of the progesterone receptor (PR) in cultured porcine granulosa cells. In this study we used the RNase protection assay to evaluate the PR mRNA levels with a porcine cDNA clone isolated by the polymerase chain reaction (PCR) method. This clone was regarded as part of the porcine PR cDNA because of its 98.3% and 95.7% homology to the hormone-binding domain of human PR cDNA in amino acid and nucleotide sequences, respectively. Treatment with LH (500 ng/ml) increased porcine PR mRNA to a maximum level of 8.6 +/- 1.1-fold (mean +/- SE) after 3-h exposure. This induction was mimicked by (Bu)2cAMP as well as by FSH and hCG, and the increased PR caused by LH and (Bu)2cAMP occurred in a dose-dependent manner. Basal and LH-induced PR mRNA levels were not affected by progesterone (100 ng/ml), estrogen (100 ng/ml), and RU 486 (10 ng/ml) at 3 h. The mechanism of the increased PR mRNA levels was studied in the presence of actinomycin-D and cycloheximide. While inhibition of RNA synthesis with actinomycin-D blocked LH-induced PR mRNA expression, inhibition of protein synthesis with cycloheximide increased basal and LH-induced PR mRNA levels. These results indicate that the expression of PR mRNA is positively regulated by LH, and this induction does not require ongoing protein synthesis. There may be a cycloheximide-sensitive mechanism that modulates PR mRNA stability. From our results we suspect that progesterone modulates ovarian function through LH-induced PR in granulosa cells.