Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Coculture With Ischemia/Reperfusion-Preconditioned Hepatocytes Improves Islet Function and Survival.

In clinical islet transplantation, hepatic ischemia and insufficient neovascularization of transplanted islets are barriers to islet survival and function. However, hepatocytes have a potency to protect themselves against ischemia. We hypothesized that ischemia/reperfusion preconditioning (IRP) of hepatocytes might beneficially affect islet cells in a coculture system. Primary islets were cocultured with primary hepatocytes, and hepatocyte IRP was conducted by subjecting cells to hypoxic conditions for single 15-minute/30-minute hypoxia, or 2 tandem 15-minute/30-minute hypoxic treatments (hypoxic-normoxic-hypoxic). We show that gene expression levels of insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor-α (TGF-α), and TGF-ß1 in hepatocytes were increased by IRP. IRP hepatocytes secreted hepatocyte growth factor and insulin-like growth factor-1. Coculture of islets with IRP hepatocytes enhanced islet insulin secretion in glucose challenge test and expression of the survival-related gene Bcl-2 and the regenerating gene-1α (Reg-1α). Islets cocultured with the 30-minute double-IRP hepatocytes displayed significantly higher viability in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase dUTP nick end labeling stain compared with that of islets subjected to 30 minutes of hypoxia. These results suggest that islet coculture with IRP hepatocytes can improve islet survival and insulin secretion.

VDJ Gene Usage of B Cell Receptors in Peripheral Blood of ABO-incompatible Kidney Transplantation Patients.

INTRODUCTION: B cell subtypes and immunoglobulin variable (V), diversity (D), joining (J) gene segment usage of B cell receptors in ABO-incompatible (ABOi) kidney transplantation (KT) in comparison to ABO-compatible KT have not been studied. The aims of this study were to analyze the VDJ gene segment usages of B cell receptors in peripheral blood of ABOi KT recipients. METHODS: Eighteen ABOi KT patients with accommodation (ABOiA), 10 ABO-compatible stable KT patients (ABOcS), and 10 ABOi KT patients with biopsy-proven acute antibody-mediated rejection (ABOiR) at day 10 after transplantation were selected. Complete transcriptomes of their peripheral blood samples were sequenced and analyzed through RNA sequencing. RESULTS: By family, immunoglobulin heavy chain variable 3 (IGHV3), immunoglobulin light kappa chain variable 1 (IGKV1), immunoglobulin light lambda chain variable 2 (IGLV2), and immunoglobulin light lambda chain joining 3 (IGLJ3) gene segments were most frequently used in all groups, and their usage was not statistically different among the three groups except for IGHV3 and IGKV1. IGKV1 was more frequently used in the ABOiA group than in the ABOcS group. According to individual gene segments, IGHV3-7, IGHV3-15, IGHV4-59, IGKV3-11, IGLV1-44, IGLV2-14, IGLV4-69, and IGLV7-46 were more frequently used in the ABOcS group than other groups, and IGKV3-7 was more frequently used in the ABOiR group than other groups. IGLV5-52 and IGLV7-43 were more frequently used in the ABOiA group than in ABOcS group. CONCLUSIONS: Our findings suggest that RNA sequencing transcriptomic analyses of peripheral blood can provide information on the VDJ gene usage of B cell receptors and the mechanisms of accommodation and immune reaction in ABOi KT.

Erratum to: The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections.

[This corrects the article DOI: 10.1186/s13017-017-0141-6.].

Reduction of Slit Diaphragm-associated Molecules by Sirolimus: Is it Enough to Induce Proteinuria?

Sirolimus (SRL), a mammalian target of rapamycin inhibitor, is widely used in transplantation, but the mechanisms whereby it induces adverse effects, such as proteinuria and edema, remain unclear. To determine whether isolated SRL induces proteinuria or not, the authors intraperitoneally injected C57BL/6 mice with different doses of SRL (0 mg/[kg·d], 3 mg/[kg·d], 10 mg/[kg·d], or 30 mg/[kg·d]) for 24 days. Urinary albumin excretion was then quantified using a double-sandwich enzyme-linked immunosorbent assay, and serum creatinine levels were measured using a single dry-film chemistry auto-analyzer. The mRNA expression levels of various genes were also measured by polymerase chain reaction. Urinary albumin was not detected in the SRL-treated mice, but serum creatinine levels were found to increase dose-dependently and were significantly higher in the animals treated with 30 mg/kg of SRL than in untreated controls. Glomerular mRNA expression profiling showed down-regulations of podocyte-related genes (Wilms tumor 1, synaptopodin, nephrin, CD2-associated protein, and podocin) and of transforming growth factor-beta (a marker of fibrosis) in sirolimus-treated mice. In addition, expressions of the antiapoptotic genes Bcl-2 and Bcl-xL were also down-regulated. Furthermore, the protein levels of these genes in mice kidney were also decreased by sirolimus. Although sirolimus treatment reduced the expressions of slit diaphragm-associated molecules and increased serum creatinine levels, it failed to induce proteinuria. Our findings indicate that proteinuria is not induced by isolated SRL treatment. Further studies are required to identify conditions in which sirolimus induces proteinuria.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Capsaicin attenuates spermatogenic cell death induced by scrotal hyperthermia through its antioxidative and anti-apoptotic activities.

This study was performed to examine whether capsaicin, the main pungent ingredient of red peppers, exerts protective effects against testicular injuries induced by transient scrotal hyperthermia. Capsaicin (0.33 mg kg-1 ) was administered subcutaneously to mice one hour before heat stress (HS) in a 43°C water bath for 20 min. After 7 days, mice exposed to HS showed low testicular weight, severe vacuolisation of seminiferous tubules followed by loss of spermatogenic cells, and appearance of multinucleated giant cells and remarkable TUNEL-positive apoptotic cells, as well as weak immunoreactivity of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in spermatogenic cells. Levels of lipid peroxidation and heat shock 70-kDa protein 1 (Hsp72) and BCL2-associated X protein (Bax) mRNA were greatly increased, but PHGPx, manganese superoxide dismutase (MnSOD), and B-cell lymphoma-extra large (Bcl-xL) mRNAs were significantly diminished in the testes by HS. However, capsaicin pre-treatment significantly suppressed the spermatogenic cell death, oxidative stress (levels of MDA, PHGPx immunoreactivity, and Hsp72, PHGPx, and MnSOD mRNA) and apoptosis (levels of TUNEL-positive cells, and Bcl-xL and Bax mRNA) in testes by HS. These suggest that capsaicin has a protective effect against spermatogenic cell death induced by scrotal hyperthermia through its antioxidative and anti-apoptotic activities.

Role of Thalidomide on the Expression of OX40, 4-1BB, and GITR in T Cell Subsets.

BACKGROUND: Thalidomide (TM) is known to have anti-cancer and anti-inflammatory properties; however, its mechanism on T cells is still unclear. We previously showed the immune modulatory effect of TM on T cells and its therapeutic effect on lupus nephritis models. Here we examined the changes in the expression of tumor necrosis factor receptor superfamilies (TNFRSFs), including OX40, 4-1BB, and glucocorticoid-induced TNFR-related protein (GITR) in T cell subsets by TM treatments. METHODS: Splenic naïve T cells (Tnaives) from C57BL/6 mice were sort-purified and cultured for CD4(+) T cell proliferation and regulatory T cells (Tregs) conversion with TM treatments. All samples were analyzed by flow cytometry after stained with anti-mouse CD4, Foxp3, OX40, 4-1BB, or GITR antibodies. RESULTS: Expressions of OX40, 4-1BB, and GITR on CD4(+) T cells showed a decreasing tendency by TM treatments. Especially, downregulation of these molecules on CD4(+)CFSE(low) T cells was significant in TM treatment groups. On the condition of Treg conversion, OX40 was downregulated significantly. In contrast, the expression of GITR was increased, and that of 4-1BB had shown no particular change under the condition of Treg. CONCLUSION: Considering these results, TM may have an immune modulatory role through the T cell subset-specific change of OX40, 4-1BB, and GITR expression. Further study is required to elucidate the effect of thalidomide on T cells.

The Introduction of Human Heme Oxygenase-1 and Soluble Tumor Necrosis Factor-α Receptor Type I With Human IgG1 Fc in Porcine Islets Prolongs Islet Xenograft Survival in Humanized Mice.

Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase-1 (HO-1) or soluble tumor necrosis factor-α receptor type I with human IgG1 Fc (sTNF-αR-Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO-1, sTNF-αR-Fc, sTNF-αR-Fc/HO-1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood-derived CD34(+) stem cells into NOD-scid-IL-2Rγ(null) mice. Both HO-1 and sTNF-αR-Fc reduced islet apoptosis under in vitro hypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig-to-humanized mice transplantation. The sTNF-αR-Fc/HO-1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor-α and IL-6 in treatment groups; however, frequency of pig-specific interferon-γ-producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO-1 or sTNF-αR-Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO-1 or sTNF-αR-Fc transgenic pigs have potential for islet xenotransplantation.

Differential characteristics of pediatric sinusitis in patients who underwent endoscopic sinus surgery: children vs. adolescents.

OBJECTIVES: We hypothesised that paediatric chronic sinusitis patients might have various clinical characteristics, depending on age, compared symptoms, physical findings and clinical features in younger children and older adolescent patients who underwent endoscopic sinus surgery. DESIGN: A retrospective review of medical records. SETTING: A total of 195 paediatric patients who underwent Endoscopic sinus surgery were enrolled and medical records were reviewed. PARTICIPANTS: The subjects were divided into children (age < 12 years, n = 70, mean age = 9.6 years) and adolescents (age ≥ 12 years, n = 125, mean age = 14.7 years). MAIN OUTCOME MEASURES: Subjective symptoms, physical findings, CT images and clinical features were compared in children and adolescent groups. RESULTS: Cough and nasal obstruction were more common in adolescents, and sleep disturbance was more common in children. Nasal mucosal injection was more common in adolescents, whereas tonsils were larger in children. Septal deviation was a more common finding in adolescents, and total CT score and serum total IgE levels were higher in children. There was no statistical difference in rate of recurrence after endoscopic sinus surgery. CONCLUSION: The clinical features of paediatric chronic sinusitis differed between the younger and older groups. Symptomatic, anatomical and clinical differences between these two groups suggest that further study of paediatric chronic sinusitis should stratify patients by age to better understand the effects of treatment on each age group.

Expression of nerve growth factor, its TrkA receptor, and several neuropeptides in porcine esophagus. Implications for interactions between neural, vascular and epithelial components of the esophagus.

UNLABELLED: This study was aimed to determine the expression and localization of nerve growth factor (NGF) and several neural peptides in porcine esophagus. Transmural esophageal specimens were obtained from euthanized pigs. STUDIES: 1) histologic evaluation, 2) expressions of NGF and its tropomyosin receptor kinase A (TrkA) receptor, calcitonin generelated peptide (CGRP), neuronal nitric oxide synthase (nNOS), and neuronal enolase using immunostaining and quantification of signal distribution and intensity. Immunostaining for NGF, CGRP, nNOS and neuronal specific enolase (NSE) showed their strong and differential expression and localization in the neuronal network. NGF was strongly expressed in the majority of neurons and nerves, distribution of TrkA was complementary; its signal was 1.5-fold weaker P < 0.001 than NGF). Quantitatively the signal intensity was: CGRP > nNOS > NGF > NES > TrkA. In addition to neural structures, nNOS, NGF and TrkA were expressed in keratinocyte progenitor cells of esophageal mucosa and in endothelial cells of blood vessels. We conclude that a strong expression of NGF in majority of esophageal neurons and nerves indicates important, but previously unrecognized regulatory roles in the esophagus; 2) This study showed expression of NGF and some of the neuropeptides in neural elements, keratinocyte progenitor cells and endothelial cells of blood vessels, which indicates local interactions between neural, epithelial and endothelial cells.

Clinical implications of angiotensin II type 1 receptor antibodies in antibody-mediated rejection without detectable donor-specific HLA antibodies after renal transplantation.

BACKGROUND: Solid-phase immunoassays have improved detection sensitivity for donor-specific HLA antibody (DSHA) and permitted the accurate diagnosis of antibody-mediated rejection (AMR). However, DSHA is not always sufficient to explain the cause of AMR. Consequently, a means of assessing non-HLA antibodies is required to determine the cause of AMR. The aim of the present study was to evaluate the clinical implications of antibodies (Abs) targeting angiotensin II type I receptor (AT1R) in recipients with AMR but without serum DSHA. METHODS: Non-HLA AMR cases diagnosed between January 2011 and June 2014 were included. Levels of anti-AT1R Abs (U/mL) were quantified by using AT1R assay kits (One Lambda, Calif, United States) with collected sera pretransplantation and at biopsy (cut-off value: 15 U/mL). RESULTS: Seventy-two patients were diagnosed with AMR during the above-mentioned period. Of them, 12 recipients (16.7%) had no DSHA. The sera of these 12 patients were tested (2 patients were only checked at time of biopsy). Nine patients (9/10) were presensitized for anti-AT1R Abs (median, 25.0 U/mL; range, 12.9 to 50.0 U/mL). Ten patients (10/12) were anti-AT1R- positive at time of biopsy (median, 23.2 U/mL; range, 11.4 to 50.0 U/mL). The mean time from transplantation to biopsy was 73 months. Eight patients experienced acute AMR, and 4 developed chronic AMR. Four patients showed negative C4d staining in peritubular capillaries (4/12). Patients were treated with plasmapheresis, low-dose intravenous immunoglobulin, and/or rituximab. CONCLUSIONS: AT1R Abs may play a significant role in AMR without detectable DSHA. Pretransplantation detection of AT1R Abs may be helpful for assessing the risk for non-HLA AMR.

Results of ABO-incompatible liver transplantation using a simplified protocol at a single institution.

BACKGROUND: Because of the development of various desensitization strategies, ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has become a feasible option for patients with end-stage liver disease. However, there has been no united desensitization protocol for ABOi LDLT. We analyzed the outcomes after establishment of simplified protocol without splenectomy, intravenous immunoglobulin, and local infusion therapy. METHODS: We analyzed 19 ABOi LDLT cases that had been performed between January 2012 and December 2013, without splenectomy and local infusion. We used a single dose of rituximab (375 mg/m(2)) 10 days before transplantation and several series of plasma exchange according to the recipients' iso-agglutinin titer-to-target titer ratio of 1:32. RESULTS: Nineteen recipients received ABOi LTs from living donors. The mean initial immunoglobulin (Ig) M and IgG anti-ABO titers were 76.63 ± 78.81 (range, 8∼256) and 162.53 ± 464.1 (0∼2048). We performed preoperative plasma exchange to 16 recipients (mean number of sessions, 3.58; range, 1-10). After surgery, 9 patients received plasma exchange (mean, 1.84; range 1∼14). One death occurred as the result of pneumonia (5.3%). There were 4 cases of acute rejections (21.1%), and all of them were treated successfully with steroid pulse or thymoglobulin. Antibody-mediated rejection and graft failure did not occur. Six cases of postoperative complications (31.6%) occurred, including 3 cases of infections. There were 2 cases of biliary anastomotic stricture (10.5%) and 1 case of portal vein stenosis (5.3%). CONCLUSIONS: ABOi LDLT with the use of simplified protocol can be safely performed without increased risk of antibody-mediated rejection and other complications.

Immune modulatory effect of thalidomide on T cells.

BACKGROUND: Thalidomide was originally used to alleviate morning sickness in pregnant women, but was banned due to severe adverse effects. Since the discovery of its anticancer and anti-inflammatory properties, it has regained research interest. However, its mechanism of action is still unknown. Therefore, we examined the effects of thalidomide on effector T (Teff) and regulatory T (Treg) cells in splenocytes of mice. METHODS: Splenic CD4(+), CD44(low), and CD62L(high) T lymphocytes (Tnaives) isolated from C57BL/6 mice were cultured for T-cell proliferation and Treg conversion. For T-cell proliferation, naive T cells (Tnaives) were cultured for 72 hours with anti-CD3 and anti-CD28 antibodies, and carboxyfluorescein succinimidyl ester (CFSE) labeling method was used. For Treg conversion, Tnaives were cultured for 72 hours with transforming growth factor-ß1 (TGF-ß1) and interleukin-2 (IL-2). Naïve T cells were plated at 1.5 × 10(5) cells on 96-well plates with 0, 1, 10, 50, or 100 µmol/L thalidomide. All samples were analyzed by flow cytometry after staining with CFSE, APC-conjugated anti-mouse CD4, and FITC-conjugated anti-mouse FoxP3. RESULTS: Thalidomide significantly decreased the proliferation of CD4(+) Teffs in a dose-dependent manner (P < .01). In contrast, conversion to CD4(+)FoxP3(+) Tregs tended to increase by thalidomide treatment, although the increase was not statistically significant. CONCLUSION: These findings suggest that thalidomide may have an immune modulatory effect by selectively suppressing CD4(+) Teff proliferation. Further studies will be needed to elucidate the underlying signaling pathway.

Rate and associated factors of solifenacin add-on after tamsulosin monotherapy in men with voiding and storage lower urinary tract symptoms.

AIM: To explore the rate of add-on therapy with solifenacin in men with voiding and storage lower urinary tract symptoms (LUTS) after tamsulosin monotherapy and to explore predictive factors for starting solifenacin add-on therapy. METHODS: Men aged ≥ 45 years with IPSS ≥ 12 and symptoms of OAB (OAB-V8 ≥ 8, micturition ≥ 8/24 h, urgency ≥ 2/24 h) were enrolled to receive tamsulosin 0.2 mg once daily. After 4 weeks, men with residual symptoms of OAB and reported 'dissatisfied' or 'a little satisfied' were received solifenacin 5 mg in combination with tamsulosin monotherapy. Subjects completed an IPSS, a Quality of life (QoL) index, OAB V8, and an International Consultation of Incontinence Questionnaire (ICIQ)-Male LUTS, and patient perception of bladder condition (PPBC) at baseline and week 4. RESULTS: Of a total of 305 patients, 254 patients completed 4 weeks of tamsulosin treatment. For 176 patients, solifenacin was added (69.3%). Significant predictive factors of solifenacin add-on therapy included long LUTS duration, high IPSS, number of micturitions per 24 h, more urgency episodes, high urgency severity score in a voiding diary and high OAB V8 score. Based on multivariable analysis, potential predictive factors of solifenacin add-on therapy included long LUTS duration (OR = 1.008, 95% CI: 1.001-1.014), high serum PSA (OR = 1.543, 95% CI: 1.136-2.095) and small prostate size (OR = 0.970, 95% CI: 0.947-0.994) (p < 0.05). IPSS, daytime micturitions and urgency episodes, OAB V8 scores, ICIQ and PPBC were improved after tamsulosin monotherapy. CONCLUSIONS: Two thirds of men with voiding and storage LUTS needed to add anticholinergics after 4 weeks of tamsulosin monotherapy. Patients with longer lasting symptoms and storage symptoms with small prostate volume may require the anticholinergic add-on.

Persistence with solifenacin add-on therapy in men with benign prostate obstruction and residual symptoms of overactive bladder after tamsulosin monotherapy.

AIMS: In spite of the reported efficacy and safety of antimuscarinics in men with OAB (overactive bladder) and BPO (benign prostatic obstruction), many patients do not persist with the treatment. We aimed to evaluate persistence and the reasons for the discontinuation of solifenacin add-on therapy in men with residual symptoms of OAB after tamsulosin monotherapy for BPO in a real clinical environment. METHODS: Men aged ≥ 45 years with IPSS ≥ 12 and symptoms of OAB (OAB-V8 ≥ 8, micturition ≥ 8/24 h, urgency ≥ 2/24 h) were prescribed tamsulosin 0.2 mg. After 4 weeks, men who had residual symptoms of OAB (OAB-V8 ≥ 8, micturition ≥ 8/24 h, urgency ≥ 1/24 h) and reported that they were 'dissatisfied' or 'a little satisfied' with the therapy were enrolled and prescribed solifenacin 5 mg in combination with tamsulosin. After 52 weeks, persistence and the reasons for the discontinuation of solifenacin were evaluated. Factors related to persistence were analysed. RESULTS: Of the 305 men who had been treated with tamsulosin, 176 were prescribed solifenacin. After 52 weeks, 44 (25%) remained on solifenacin therapy. Of the 132 who discontinued solifenacin, 85 were evaluated on the reason for discontinuation. The three most common reasons for discontinuation were adverse events (AEs) (35%), lack of efficacy (33%), and improvement in symptoms (16%). The aggravation of voiding symptoms was the most common AE leading to discontinuation. Retention was observed in 11 men. None of the demographical or clinical characteristics were significantly related to persistence. CONCLUSIONS: Only 25% men with OAB and BPO remained on antimuscarinic add-on therapy after 1 year, mostly because of AEs and lack of efficacy. Realistic data should be added to what is already known about antimuscarinic treatment in men by including patients who were excluded or who dropped out of well-designed clinical trials.

Removable esophageal stents have poor efficacy for the treatment of refractory benign esophageal strictures (RBES).

With the recent availability of removable esophageal stents, endoscopic stenting has been utilized to treat refractory benign esophageal strictures (RBES). The objective of this study was to review the feasibility and effectiveness of removable esophageal stents to treat RBES. Patients who received removable esophageal stents for the treatment of RBES at the institution between 2004-2010 using its stent implantation logs and endoscopic database were retrospectively identified. Patient demographics, stricture etiology and location, stent and procedure characteristics, and clinical outcomes were obtained. Twenty-five patients with a mean age of 70 (72% male) underwent initial stent placement; 24 were successful. Overall clinical success was achieved in five of the 19 patients (26%) ultimately undergoing stent removal. RBES etiologies included anastomotic (13), radiation (5), peptic (3), chemotherapy (1), scleroderma (1), and unknown (2). Alimaxx-E (Merit-Endotek, South Jordan, UT, USA) stents were placed in 20 patients and Polyflex (Boston Scientific, Natick, MA, USA) stents were used in five patients. Immediate complications included failed deployment (1) and chest pain (7). Five patients died prior to stent removal. Stent migration was found in 53% (10/19) of patients who underwent stent removal: nine required additional therapy and one had symptom resolution. Out of the nine patients without stent migration, five required additional therapy and four had symptom resolution. Although placement of removable esophageal stents for RBES is technically feasible, it is frequently complicated by stent migration and chest pain. In addition, few patients achieved long-term stricture resolution after initial stenting. In this study, most patients ultimately required repeated stenting and/or dilations to maintain relief of dysphagia.

Effects of a 1:1 inspiratory to expiratory ratio on respiratory mechanics and oxygenation during one-lung ventilation in the lateral decubitus position.

Prolonged inspiratory to expiratory (I:E) ratio ventilation may have both positive and negative effects on respiratory mechanics and oxygenation during one-lung ventilation (OLV), but definitive information is currently lacking. We therefore compared the effects of volume-controlled ventilation with I:E ratios of 1:1 and 1:2 on respiratory mechanics and oxygenation during OLV. Fifty-six patients undergoing thoracoscopic lobectomy were randomly assigned volume-controlled ventilation with an I:E ratio of 1:1 (group 1:1, n=28) or 1:2 (group 1:2, n=28) during OLV. Arterial and central venous blood gas analyses and respiratory variables were recorded 15 minutes into two-lung ventilation, at 30 and 60 minutes during OLV, and 15 minutes after two-lung ventilation was re-initiated. Peak and plateau airway pressures in cmH2O [standard deviation] during OLV were significantly lower in group 1:1 than in group 1:2 (P <0.01) (19 [3] and 23 [4]; 16 [3] and 19 [5], respectively). The arterial to end-tidal carbon dioxide tension difference was significantly lower in group 1:1 than in group 1:2 (P <0.01), (0.5 [0.3] and 1.1 [0.5]). There were no significant differences in PaO2 during OLV between the two groups (OLV30, P=0.856; OLV60, P=0.473). In summary, volume-controlled ventilation with an I:E ratio of 1:1 reduced peak and plateau airway pressures improved dynamic compliance and efficiency of alveolar ventilation, but it did not improve arterial oxygenation in a substantial manner. Furthermore, the associated increase in mean airway pressure might have reduced cardiac output, resulting in a lower central venous oxygen saturation.

Treatment satisfaction with low-dose tamsulosin for symptomatic benign prostatic hyperplasia: results from a multicentre cross-sectional survey.

AIMS: To evaluate the efficacy and treatment satisfaction with low-dose (0.2 mg) tamsulosin in patients with symptomatic benign prostatic hyperplasia (BPH), and to investigate individual lower urinary tract symptoms according to treatment satisfaction. METHODS: A cross-sectional study was conducted in a total sample of 2574 patients from multiple centres. International Prostate Symptom Score (IPSS), prostate volume, uroflowmetry and combined medications were reviewed. Detailed questionnaires were used to assess treatment satisfaction and IPSS 8 weeks after treatment with low-dose tamsulosin. RESULTS: After 8 weeks of treatment with low-dose tamsulosin, IPSS improved significantly. Among the 2574 patients, 1,630 (63.42%) were satisfied and 940 patients (36.50%) were dissatisfied with low-dose tamsulosin. The reasons for dissatisfaction included efficacy problems (84.66%) and side effects (3.72%). Treatment satisfaction was affected by symptom duration, baseline IPSS, and prostate size (p = 0.0441, < 0.001, < 0.009, respectively). IPSS voiding (IPSS-V) and IPSS storage (IPSS-S) after treatment differed significantly depending on the degree of satisfaction (p < 0.001). IPSS-V after treatment did not improve in patients who were 'not satisfied' or 'totally not satisfied' (p = 0.170, 0.240, respectively). All the individual IPSS items except urgency (p = 0.1436) varied significantly with the degree of satisfaction (p < 0.001). CONCLUSIONS: Treating symptomatic BPH with low-dose tamsulosin improved IPSS, but more than one-third of patients were dissatisfied with the treatment. The main reason for dissatisfaction was efficacy problems, and the degree of satisfaction was related to symptom duration, baseline IPSS, and prostate size, and also to IPSS-V. In patients with severe LUTS, the tamsulosin dose should be increased earlier.