Clinical use of expanded prostate cancer index composite-based health-related quality of life outcomes after robot-assisted radical prostatectomy for localized prostate cancer.

Background: This study aimed to assess the longitudinal health-related quality of life (HRQOL) using the Expanded Prostate Cancer Index Composite (EPIC) and HRQOL change between the nerve-sparing technique in Japanese men treated with robot-assisted radical prostatectomy (RARP). Methods: A total of 573 patients who received RARP were included in this study. EPIC questionnaire was administered before treatment and up to 36 months after RARP. Clinical recovery was defined as half of the standard deviation of the baseline score for each domain. We divided all patients into recovery group or nonrecovery group. The time from survey to each domain recovery was calculated using the Kaplan-Meier method. We compared the sexual and urinary score change between groups using analysis of variance to confirm the effect of nerve-sparing technique. Results: The median age was 67 years (interquartile range, 62-71 years). The mean score of all urinary domains worsened noticeably after 1 month. All postoperative urinary summary, function, and incontinence scores were significantly lower than preoperative scores up to 3 years post-RARP. Postoperative sexual summary and functional scores were significantly lower than preoperative score at all follow-up times throughout the 36 months. The recovery rate for the urinary incontinence domain was the lowest (44.5%), whereas the recovery rate for the urinary irritative-obstructive domain was the highest (73.7%). In the sexual domain, the bother domain had a higher recovery rate (73.0%) than the functional domain (29.7%). Although the recovery of sexual domains was slower compared with other domains, by 36 months after RARP, almost all values had recovered. Compared with other technique groups, bilateral intrafascial nerve-sparing group showed significantly decreased change in subscale scores before and after RARP in several sexual and urinary domain. Conclusion: The time course and extent of functional and bother domain recovery documented in this study may prove useful for RARP patient selection in Japan.

Topical administration of a ROCK inhibitor prevents anterior subcapsular cataract induced by UV-B irradiation.

The deposition of extracellular matrix (ECM)-which is mainly composed of type I collagen-in anterior subcapsular cataracts (ASCs) during epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs) decreases visual function. Transforming growth factor (TGF)-ß is a key factor in the induction of EMT in LECs. Although Rho kinase (ROCK) plays an important role in EMT induced by TGF-ß, it is unknown whether ROCK inhibition affects type I collagen expression in TGF-ß-stimulated LECs and ASC formation. This was investigated in the present study both in vitro using human lens epithelium (HLE)-B3 cells and in vivo using mice with ultraviolet radiation (UVR)-B-induced cataracts. We found that TGF-ß2 increased type I collagen mRNA expression in HLE-B3 cells; this was inhibited in a dose-dependent manner by treatment with the ROCK inhibitor Y-27632. UVR-B exposure caused ASC formation in mice. A histopathological examination revealed that LECs in the anterior subcapsular area were flattened and multi-layered, and had a spindle shape in cross section. Immunohistochemical analysis revealed the presence of α-smooth muscle actin and type I collagen around these flattened LECs; these opacities were reduced by topical instillation of Y-27632. These findings suggest that suppression of TGF-ß signaling in LECs by topical application of a ROCK inhibitor can prevent the formation of ASCs.

Monitored anesthesia care with dexmedetomidine of a patient with severe pulmonary arterial hypertension for inguinal hernioplasty.

The presence of severe pulmonary arterial hypertension (PAH) is a significant risk factor of major perioperative cardiovascular complications in patients undergoing even non-cardiac surgery under anesthetic management. The most important aspect of perioperative care of PAH patients is to avoid pulmonary hypertensive crisis, which can be induced by alveolar hypoxia, hypoxemia, hypercarbia, metabolic acidosis, airway manipulations, and activation of the sympathetic nervous system by noxious stimuli. We report a case of successful monitored anesthesia care supplemented by dexmedetomidine for inguinal hernioplasty of a patient with severe PAH secondary to congenital heart disease.

[Brain MRI of reversible, recurrent white matter lesions in a patient with a 35-year history of neuro-Behçet disease].

Neuro-Behçet disease (NBD) can be categorized clinically as the acute type--characterized by meningoencephalitis--and the chronic progressive type- characterized by slowly progressive dementia, ataxia, and dysarthria. We describe a 35-year clinical course of NBD that was characterized by slowly progressive ataxia and dysarthria despite continued corticosteroid treatment. Because of difficulties in swallowing, which interrupted oral corticosteroid therapy, this case was characterized by recurrent manifestations of neurological symptoms and abnormal MRI findings. Resumption of corticosteroid therapy was effective. The patient was a 77-year-old woman who had presented with oral ulceration and dysarthria at the age of 42. She suffered from Entero-Behçet disease at the age of 52 and was treated with corticosteroids for 7 years. Oral corticosteroid therapy was resumed at the age of 64, but her neurological deficit slowly progressed and she developed paraplegia with dysphagia and dysarthria. Corticosteroids treatment was interrupted when she was 76; one year later, she was hospitalized in a state of somnolence. Brain MRI scans revealed new lesions with gadolinium enhancement. We diagnosed acute exacerbation of NBD attacks on the basis of positive findings for HLA-B51, protein elevation, and IL-6 in the cerebrospinal fluid. Corticosteroid treatment was effective. She became alert, and her MRI findings were no longer abnormal. Corticosteroids administration was continued via percutaneous endoscopic gastrostomy. Our case suggested that even if neurological exacertion is not obvious during the clinical course, immunosuppressive therapies should be continued for patients with chronic NBD to prevent acute aggravation.

Bovine serum albumin-sugar conjugates through the maillard reaction: effects on interfacial behavior and emulsifying ability.

Bovine serum albumin (BSA) was employed as a model protein emulsifier to conjugate with aldohexose (D-glucose (Glc) or D-allose (All)) and sugar fatty acid ester (6-O-octanoyl-D-glucose (GlcC8)) through the Maillard reaction. It was found during the reaction that rate of decrease of free amino groups in BSA was almost the same for the BSA-sugar mixtures whereas browning and protein aggregation developed in the following order: Glc < All < GlcC8. It was thought that the rate of degradation of the Amadori compound could have been influenced by the OH-group stereochemistry at the C3 position of aldohexose, while denaturation of BSA by GlcC8 enhanced the browning and protein aggregation. To understand the emulsifying ability of the BSA-sugar conjugates, hexadecane-water interfacial tension and the oil droplet size of emulsions prepared by homogenizing hexadecane and aqueous solution of the conjugates were examined. BSA-GlcC8 showed greater improvement in interfacial and emulsifying activity than did BSA-Glc and -All. However, no improvement in emulsion stability was observed for any of the BSA-sugar conjugates, suggesting the weakness of the film formed at the oil droplet interface.

Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients.

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015-0.042), more significantly to fluvoxamine. The -1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010-0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022-0.042), and more significantly in paroxetine-treated patients (p = 0.002-0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.

Novel structure of the CYP2D6 gene that confuses genotyping for the CYP2D6*5 allele.

We encountered DNA samples which showed a positive product using a long PCR-based method for the detection of CYP2D6*5, indicating deletion of the entire CYP2D6 gene, but the samples did not show a band related to CYP2D6*5 in either XbaI- or EcoRI-RFLP analysis. To achieve genotyping with accuracy, we performed a further genetic analysis to clarify the discrepancy. An unknown 1.6-kb insert was identified in a region downstream from the CYP2D6 stop codon where a specific primer was designed for long-PCR analysis for CYP2D6*5 genotyping. This finding suggested that the CYP2D6 gene might not be deleted in the samples even if a positive product was detected by the long-PCR method. Furthermore, the allelic frequency of this type was found to be approximately 0.3% (4 heterozygous/771 samples) in a Japanese population. In conclusion, we found a novel structure of the CYP2D6 gene, which might lead to incorrect genotyping for CYP2D6*5. Although the long PCR-based strategy for the detection of CYP2D6*5 has been widely used due to its usefulness and convenience, we recommend caution when adopting this method and propose re-evaluating the method for detecting CYP2D6*5.

Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism.

The present study aimed to compare the effects of two currently used selective serotonin reuptake inhibitors (SSRIs) in Japan taking the individual background in 5-HTT gene-linked polymorphic region (5HTTLPR) genotype into account. Clinical responses to paroxetine and fluvoxamine were evaluated by total and cluster depressive symptoms for 81 Japanese patients who were diagnosed with major depression. Patients with the l allele had a greater percentage reduction on the total score (P=0.059) and somatic anxiety items (P=0.026) of the 21-item Hamilton Depression Rating Scale (HAM-D) score compared to s/s genotype carriers. Paroxetine was significantly more effective than fluvoxamine in the s/s carriers, as evaluated on the percentage reduction in total score (P=0.012) and core (P=0.049) HAM-D after 4 weeks of medication, but not in the l/s carriers. These findings suggest that the genetic test may be useful in investigating the efficacy of the two SSRIs, and that normalization by the 5HTTLPR genotypes may lead to improvement of the precision of comparative analysis.

The frequency of candidate alleles for CYP2D6 genotyping in the Japanese population with an additional respect to the -1584C to G substitution.

The -1584C/G single nucleotide polymorphism (SNP) in the promoter region of CYP2D6 was suggested to have the potential to influence CYP2D6 activity. In this report, we demonstrated the frequencies of -1584C to G substitution-related alleles, such as CYP2D6*2, CYP2D6*21, CYP2D6*35 and CYP2D6*41, in the Japanese population. The frequencies of CYP2D6*2, *41 and *21 were 0.102, 0.026 and 0.005, respectively. We also showed a relationship between the SNP and other common alleles, CYP2D6*4, *5, *10, *14 and *18. Interestingly, the SNP was detected in all three subjects carrying CYP2D6*14. This finding suggests the -1584G is included in the CYP2D6*14 allele, which is a null-allele characteristic to the Japanese population. This report presents practical information on CYP2D6 alleles that should be considered in the pharmacokinetic study of CYP2D6 substrates in the Japanese population.

Expression of TH1/TH2-related chemokine receptors on peripheral T cells and correlation with clinical disease activity in patients with multiple sclerosis.

Th1 cells play an important role in the pathogenesis of multiple sclerosis (MS), a disease likely linked to an autoimmune process. We measured the levels of chemokines in serum or cerebrospinal fluid (CSF) samples by ELISA, and also studied the expression of Th1-related CXCR3/CCR5 chemokine receptors and Th2-related CCR4/CCR3 chemokine receptors on blood cells from MS patients using three-color flow cytometry. The Bonferroni correction was used for the statistical analysis. The levels of CXCL10, CCL3, and CCL5 in the CSF samples for the MS groups were significantly higher than those for the control group. However, the levels of CCL2 in both the CSF and serum samples for the remission group were significantly higher than those for the active group. The percentage of CXCR3-expressing CD4+ T cells in patients with MS was significantly elevated compared with the healthy controls. Moreover, MS patients in an active phase showed a more increased CD4+CXCR3+/CD4+CCR4+ ratio than patients in a remission phase. The increased percentage of CD4+CXCR3+ cells in the blood was associated with relapses in MS. This study suggested that the CD4+CXCR3+/CD4+CCR4+ ratio could be a sensitive maker of immune dysfunction in MS.

[A case of effective weekly paclitaxel administration for metastatic gastric cancer].

We report a case of long-term effectiveness of weekly paclitaxel (TXL) administration for metastatic gastric cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. A 61-year-old man was diagnosed as having gastric cancer with multiple liver metastases. He was treated with FP therapy and irinotecan/cisplatin administration and both therapies were assessed to result in progressive disease. We attempted weekly TXL administration and assessed a long period of no change after 6 courses. The treatment is ongoing. The toxic events were peripheral neuropathy and alopecia (grade 2), with no episodes of leukopenia, nausea and vomiting. The patient's quality of life was fair during the treatment. Weekly TXL administration is a useful treatment for metastatic gastric cancer.

[Two cases of effective weekly paclitaxel administration and concurrent radiation for metastatic breast cancer].

We report two cases in which weekly paclitaxel (TXL) administration and concurrent radiation was effective for metastatic breast cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication. Case 1: A 50-year-old woman was found to have atelectasis of the middle lobe after treatment for brain metastasis. She was diagnosed with hilar, mediastinal and supraclavicular lymph nodes metastases. She received weekly TXL administration and concurrent radiation to the mediastinum and supraclavicular fossa. The metastatic lymph nodes had disappeared one month after the treatment. Case 2: A 31-year-old woman was diagnosed with advanced breast cancer with lung, pleural, bone and orbital metastases. She received weekly TXL administration and concurrent radiation to the orbit. The lung and pleural metastases had disappeared and the orbital metastasis was decreased by 75% one month after the treatment, and the case was assessed as a partial response. Leukopenia and other major adverse effects were not observed in either of the two cases.

[A case of effective weekly paclitaxel administration for metastatic gastric cancer].

We report a case of effective weekly paclitaxel (TXL) administration for metastatic gastric cancer. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. A 74-year-old man was diagnosed with recurrence 49 months after surgery for gastric cancer. He was treated with 5-fluorouracil and cisplatin, and thrombocytopenia (grade 3) and creatinin elevation (grade 1) were observed and assessed as progressive disease 2 months after the treatment. We attempted weekly TXL administration and after 5 courses assessed the patient as having a partial response. The treatment is ongoing. The toxic event was leukopenia (grade 2), with no episode of thrombocytopenia. The patient did not complain of nausea or vomiting, and his quality of life was fair during the treatment. Weekly TXL administration is a useful treatment for metastatic gastric cancer.

[A case of effective paclitaxel therapy for adriamycin resistant metastatic breast cancer with brain metastases].

A 36-year-old woman was referred to our hospital because of a right breast lump. Chest computed tomography revealed pulmonary metastases with lymphangitis carcinomatosa. Additional examination revealed liver metastases and axillary and cervical lymph node metastases. The patient was started on CA therapy (cyclophosphamide 900 mg, adriamycin 90 mg). A minor response was observed in the pulmonary metastases after two courses but new brain metastases were detected. We then tried paclitaxel administration (260 mg). A partial response was observed in the brain and pulmonary metastases. Thus, paclitaxel administration was continued on a weekly basis (120 mg) and the brain and pulmonary metastases continued to diminish. The primary breast cancer, liver metastases and axillary and cervical lymph node metastases were disappeared. Whole brain radiation was done with weekly paclitaxel administration and the brain metastases were diminished even more. Paclitaxel is as a radiosensitizer and seems to have a strong antineoplastic effect with concurrent radiation.

[Weekly paclitaxel therapy for metastatic breast cancer].

We treated 12 patients with metastatic breast cancer with weekly paclitaxel therapy. Paclitaxel was administrated by 1 hour infusion at a dose of 80 mg/m2 after short premedication every week on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. All patients had received prior metastatic chemotherapy, and prior anthracycline therapy was done in 66.7% of the patients. Partial responses were observed in 66.7% of the patients and progressive disease in 33.3%. The response rate was 66.7%. Responses were observed in 62.5% of the patients with prior anthracycline therapy. Grade 3/4 leukopenia and neutropenia occurred in 25% of the patients, respectively, and no grade 3/4 peripheral neuropathy was observed. Dyspnea occurred in 25% of the patients and was grade 3 in 16.7%. Dyspnea is thought to be one of the adverse events requiring caution with weekly paclitaxel administration. Weekly paclitaxel therapy is effective and well tolerated in patients with metastatic breast cancer.