Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Correction to: Development of micro mechanical device having two-dimensional array of micro chambers for cell stretching.

The original article has been corrected. Instances of the character "µ" should be replaced by the term "micro".

Development of micro mechanical device having two-dimensional array of micro chambers for cell stretching.

This paper presents a novel cell stretching micro device having two-dimensional array of micro chambers. It enables an in situ time-lapse observation of stretched cell by using an optical microscope with high measurement efficiency. The presented device consists of a cell culture dish and the array of micro chambers made of silicone elastomer and extension structures made of photocurable resin, and is fabricated with MEMS technology. The fabrication process of the thin micro chamber array combines photoresist mold and lift-off process based on conventional photolithography. The fabricated device has 134micro chambers in 5µm or less thickness. It was demonstrated that the fabricated micro device could be used to make in-situ time-lapse observation of cell responses to stretching under optical microscopy. In addition, the influence of the chamber thickness to the quality of the microscope image observed was evaluated. It is confirmed that the proposed device having two-dimensional array of the thin micro chambers makes it possible to observe cell response for stretch stimuli with high quality and efficiency.

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Survey of patient exposure from general radiography and mammography in Japan in 2014.

With the objective of reducing patient exposure to radiation, we conducted a questionnaire survey regarding radiographic conditions in 2014. Here we report estimates of dose exposure in general radiography and mammography through an investigation and comparison of present patient exposure conditions. Questionnaires were sent to 3000 facilities nationwide in Japan. Surveys asked questions on a total of 16 items related to general radiography, including the chest, abdomen, and breast. Output data from x-ray tubes measured in the Chubu area of Japan were used as the mean in these estimates. The index of patient exposure was adopted as the entrance skin dose (ESD) for general radiography and as the mean glandular dose (MGD) for mammography. The response rate for this survey was 21.9%. Our results showed that doses received through the use of flat-panel detector (FPD) devices were lower than those received through computed radiography devices, except for the ankle joint (e.g. in chest examination, the dose from FPD and CR was 0.24 mGy, 0.31 mGy on the average, respectively). These results suggest that more widespread use of FPD devices could lead to decreases in the ESD and MGD, thereby reducing patient exposure.

Results of a 2011 national questionnaire for investigation of mean glandular dose from mammography in Japan.

Diagnostic reference levels (DRLs) for mammography have yet to be created in Japan. A national questionnaire investigation into radiographic conditions in Japan was carried out for the purpose of creating DRLs. Items investigated included the following: tube voltage; tube current; current-time product; source-image distance; craniocaudal view; automatic exposure control (AEC) settings; name of mammography unit; image receptor system (computed radiography (CR), flat panel detector (FPD), or film/screen (F/S)); and supported or unsupported monitor diagnosis (including monitor resolution). Estimation of the mean glandular dose (MGD) for mammography was performed and compared with previous investigations. The MGD was 1.58(0.48) mGy, which did not significantly differ from a 2007 investigation. In relation to image receptors, although no difference in average MGD values was observed between CR and FPD systems, F/S systems had a significantly decreased value compared to both CR and FPDs. Concerning digital systems (FPDs), the MGD value of the direct conversion system was significantly higher than the indirect conversion system. No significant difference in MGD value was evident concerning type of monitor diagnosis for either the CR or the FPD digital systems; however, hard copies were used more often in CR. No significant difference in the MGD value was found in relation to monitor resolution. This report suggests ways to lower the doses patients undergoing mammography receive in Japan, and serves as reference data for 4.2 cm compressed breast tissue of 50% composition DRLs. Furthermore, our findings suggest that further optimisation of FPD settings can promote a reduction in the MGD value.

Epidemiology of Physeal Fractures and Clinically Significant Growth Disturbances Affecting the Distal Tibia, Proximal Tibia, and Distal Femur: A Retrospective Cohort Study.

INTRODUCTION: Childhood fractures involving the physis potentially result in premature physeal closure that can lead to growth disturbances. Growth disturbances are challenging to treat with associated complications. Current literature focusing on physeal injuries to lower extremity long bones and risk factors for growth disturbance development is limited. The purpose of this study was to provide a review of growth disturbances among proximal tibial, distal tibial, and distal femoral physeal fractures. METHODS: Data were retrospectively collected from patients undergoing fracture treatment at a level I pediatric trauma center between 2008 and 2018. The study was limited to patients 0.5 to 18.9 years with a tibial or distal femoral physeal fracture, injury radiograph, and appropriate follow-up for determination of fracture healing. The cumulative incidence of clinically significant growth disturbance (CSGD) (a growth disturbance requiring subsequent physeal bar resection, osteotomy, and/or epiphysiodesis) was estimated, and descriptive statistics were used to summarize demographics and clinical characteristics among patients with and without CSGD. RESULTS: A total of 1,585 patients met the inclusion criteria. The incidence of CSGD was 5.0% (95% confidence interval, 3.8% to 6.6%). All cases of growth disturbance occurred within 2 years of initial injury. The risk of CSGD peaked at 10.2 years for males and 9.1 years for females. Complex fractures that required surgical treatment, distal femoral and proximal tibial fractures, age, and initial treatment at an outside hospital were significantly associated with an increased risk of a CSGD. DISCUSSION: All CSGDs occurred within 2 years of injury, indicating that these injuries should be followed for a period of at least 2 years. Patients with distal femoral or proximal tibial physeal fractures that undergo surgical treatment are at highest risk for developing a CSGD. LEVEL OF EVIDENCE: Level III Retrospective Cohort Study.

Feasibility of delta-shaped anastomoses in totally laparoscopic distal gastrectomy.

BACKGROUND: Delta-shaped (DS) anastomosis is a new reconstruction method for totally laparoscopic distal gastrectomy (TLDG) using a linear stapler. We evaluated the feasibility of using this method for TLDG. METHODS: A retrospective analysis was performed in 114 patients who underwent TLDG with DS anastomosis. Twenty-four patients reconstructed with a Roux-en-Y (RY) anastomosis during the same period were analyzed as control subjects. RESULTS: The patient characteristics of DS and RY anastomoses were slightly different in terms of tumor location and extent of lymph node dissection, since this was not a prospective comparative study. Blood loss, postoperative complication rate and postoperative hospital stay were not different between the two groups. There was only 1 case of anastomotic leakage, and no case of anastomotic stricture after DS anastomosis. The length of the operation using DS anastomosis was significantly shorter than for RY anastomosis. The rates of body weight loss were not significantly different at 1 year after the operation. CONCLUSIONS: Although this was a small retrospective analysis, DS anastomosis was feasible, required a shorter operation time, and had no associated complications. This method can therefore be recommended as a standard procedure for TLDG.

Hypertrophic obstructive cardiomyopathy with Schmidt's syndrome: report of a case.

Schmidt's syndrome is an autoimmune disease, which can present as a complication of idiopathic Addison's disease and chronic thyroiditis (Hashimoto's disease), and may cause acute adrenal insufficiency in the presence of stress such as surgery. In this study, we report a patient with hypertrophic obstructive cardiomyopathy (HOCM) complicated by Schmidt's syndrome who did not develop any complications after surgery.

Efficacy of neutrophil elastase inhibitor on type A acute aortic dissection.

BACKGROUND: Surgery for type A acute aortic dissection (AAD) is associated with a high mortality and incidence of postoperative complications, including acute respiratory failure and coagulopathy. Aim of the study was to investigate the effects of sivelestat on pulmonary function and coagulopathy in patients undergoing surgery for AAD. METHODS: Sixty patients undergoing emergency ascending replacement for AAD were divided into two groups. Group I was administered sivelestat intravenously from the beginning of surgery until extubation. Group II was not treated with sivelestat. The platelet count, antithrombin III (AT III) level, leukocyte count, C-reactive protein (CRP) level, prothrombin time (PT), activated partial thrombin time (APTT), and prothrombin time-international normalized ratio (PT-INR) were measured. RESULTS: The postoperative decrease of AT III and the platelet count on admission to the intensive care unit (ICU) and 3 hours later were significantly less in group I. The leukocyte count and the values of CRP, PT, APTT, and PT-INR did not differ significantly between the groups. The duration of mechanical ventilation after surgery tended to be shorter in group I. CONCLUSIONS: Sivelestat significantly reduced the postoperative decreases in AT III and platelet count in patients undergoing emergency surgery for AAD.

Pulmonary embolism with myomatous erythrocytosis syndrome and extreme obesity.

We here report a case of a 53-year-old woman requiring pulmonary embolectomy for acute massive pulmonary embolism caused by a huge uterine myoma compressing veins in the pelvis and extreme obesity. She was also diagnosed as having myomatous erythrocytosis syndrome, a rare disease associated with secondary polycythemia. The polycythemia improved after a hysterectomy which was performed after pulmonary embolectomy.

[Approaches and results in video-assisted thoracic surgery lobectomy for the patient with primary lung cancer].

Video-assisted thoracic surgery (VATS) lobectomy is defined as a video-assisted procedure using anatomic dissection with individual ligation of the vessels and bronchi. VATS lobectomy can offer several advantages, including decreased pain, and decreased inflammatory response. The patient is placed in the lateral decubitus position. A 12-mm port is inserted in the 7th intercostal space at the midaxillary line. A 8-cm utility incision is created in the axilla at the 4th intercostal space for upper or middle lobectomy. For lower lobectomy, a 8-cm utility incision is created in the auscultatory triangle at the 5th intercostal space. A 12-mm incision is frequently placed near the utility incision in the 6th intercostal space, particularly when using retraction for improved exposure or for insertion of added instrumentation. We performed the hilar vessel ligation using endoscopic ligation forceps SAITO model (Japan patent no. 4148324). We reported approaches and techniques in our hospital for the patients who underwent VATS lobectomy based on the surgical databases from the Division of Thoracic Surgery at the Kansai Medical University Hirakata Hospital during the period from January 5, 2006 through August 31, 2008.

[Does aortic cusp repair influence the outcome of valve sparing aortic root replacement?].

BACKGROUND: Outcome of the patients who underwent aortic root replacement with valve sparing procedure concomitant with cusp repair was evaluated. METHODS: Between October 1999 and April 2009, valve sparing aortic root replacement were performed in 62 patients. Isolated valve sparing procedure was performed in 38 patients (control) and concomitant cusp repair was performed in 24 patients (aortic valve plasty: AVP). Cusp prolapse was corrected by plication of Arantius body (n = 13), cusp perforations were closed by pericardial patch (n = 6) or reinforcement of free margin (n = 6). RESULTS: No patient died during the hospital stay and no thromboembolic events occurred in the follow up. Pre-operative grade of aortic insufficiency was 3.0 +/- 0.9 in AVP group vs. 2.5 +/- 1.3 in control (NS). There was no significant difference between both groups regarding age, cardiac function and preoperative aortic root diameter. However, eccentric jet by preoperative transesophageal echocardiography (TEE) was more often in group AVP than in control (p<0.01). Five patients underwent reoperation because of recurrent aortic regurgitation (AR) or hemolysis. Postoperative AR grade were similar in both groups (0.9 +/- 0.5 vs 0.5 +/- 0.6). During follow up, the 5 year freedom from re-operation (aortic valve replacement: AVR) was 85.1+/- 8.2% in AVP and 94.0 +/- 4.1% in control (NS). 5-year-survival was 100% and 95.0 +/- 4.9% (NS), respectively. CONCLUSIONS: Valve sparing aortic root replacement with concomitant cusp repair provided satisfactory midterm result.

ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis.

Glucose-responsive (GR) neurons in the hypothalamus are thought to be critical in glucose homeostasis, but it is not known how they function in this context. Kir6.2 is the pore-forming subunit of K(ATP) channels in many cell types, including pancreatic beta-cells and heart. Here we show the complete absence of both functional ATP-sensitive K+ (K(ATP)) channels and glucose responsiveness in the neurons of the ventromedial hypothalamus (VMH) in Kir6.2-/- mice. Although pancreatic alpha-cells were functional in Kir6.2-/-, the mice exhibited a severe defect in glucagon secretion in response to systemic hypoglycemia. In addition, they showed a complete loss of glucagon secretion, together with reduced food intake in response to neuroglycopenia. Thus, our results demonstrate that KATP channels are important in glucose sensing in VMH GR neurons, and are essential for the maintenance of glucose homeostasis.

Effects of duloxetine on pain and walking distance in neuropathic pain models via modulation of the spinal monoamine system.

BACKGROUND: Approximately 40% of patients with chronic low back pain have a neuropathic component. In this study, we assessed the effects of analgesics on tactile hypersensitivity and walking distance in the rat cauda equina compression (CEC) model of neuropathic low back pain. METHODS: The effects of analgesics on tactile hypersensitivity were examined using the von Frey test in CEC and partial sciatic nerve ligation (pSNL) models. Effects on walking distance were assessed using a treadmill test. Levels of α2δ1 subunit and ATF-3 mRNA in dorsal-root ganglion (DRG) neurons and those of α2δ1 subunit protein in the spinal cord were determined using quantitative RT-PCR and western blotting, respectively. Histological features were assessed using immunohistological methods. RESULTS: Histological changes indicating nerve damage (increase in ATF-3 mRNA, decrease in NF-200 and an increase in CD68 immunoreactivity) were observed in the CEC model. Duloxetine had analgesic effects in both models and improved walking distance in the CEC model. Pregabalin had analgesic effects in both models; however, the effect was weaker in the CEC model than in the pSNL model. α2δ1 subunit expression in DRG neurons and in the spinal cord was unchanged in the CEC model, but significantly increased in the pSNL model. Indomethacin had no analgesic effect in either model. Intrathecal yohimbine inhibited the effects of duloxetine with significant effects on depression. CONCLUSIONS: These findings suggest that the analgesic effects of duloxetine are mainly mediated by the spinal monoamine system, independent of the antidepressant effects of this agent. SIGNIFICANCE: The findings of this study suggest that duloxetine may be an effective treatment of broad neuropathic pain states, including neuropathic low back pain. The analgesic effects of duloxetine might be mediated by alterations of the descending pain modulatory pathways in the spinal cord, independent of the antidepressant effects.

Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury.

BACKGROUND: Hydrogen (H2) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I-R renal injury (composition of dual gas; N2: 77.8%; O2: 20.9%; H2: 1.30%; CO: 250 parts per million). METHODS: Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H2 gas alone inhalation (H2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. RESULTS: Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. CONCLUSIONS: Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury.

Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.

Post-rest contractile behavior of isolated myocardium indicates the capacity of the sarcoplasmic reticulum (SR) to store and release Ca2+. We investigated post-rest behavior in isolated muscle strips from nonfailing (NF) and endstage failing (dilated cardiomyopathy [DCM]) human hearts. At a basal stimulation frequency of 1 Hz, contractile parameters of the first twitch after increasing rest intervals (2-240 s) were evaluated. In NF (n = 9), steady state twitch tension was 13.7 +/- 1.8 mN/mm2. With increasing rest intervals, post-rest twitch tension continuously increased to maximally 29.9 +/- 4.1 mN/mm2 after 120s (P < 0.05) and to 26.7 +/- 4.5 mN after 240 s rest. In DCM (n = 22), basal twitch tension was 10.0 +/- 1.5 mN/mm2 and increased to maximally 13.6 +/- 2.2 mN/mm2 after 20 s rest (P < 0.05). With longer rest intervals, however, post-rest twitch tension continuously declined (rest decay) to 4.7 +/- 1.0 mN/mm2 at 240 s (P < 0.05). The rest-dependent changes in twitch tension were associated with parallel changes in intracellular Ca2- transients in NF and DCM (aequorin method). The relation between rest-induced changes in twitch tension and aequorin light emission was similar in NF and DCM, indicating preserved Ca(2-)-responsiveness of the myofilaments. Ryanodine (1 microM) completely abolished post-rest potentiation. Increasing basal stimulation frequency (2 Hz) augmented post-rest potentiation, but did not prevent rest decay after longer rest intervals in DCM. The altered post-rest behavior in failing human myocardium indicates disturbed intracellular Ca2- handling involving altered function of the SR.

A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling.

Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.