Safety and efficacy of trastuzumab biosimilar plus irinotecan or gemcitabine in patients with previously treated HER2 (ERBB2)-positive non-breast/non-gastric solid tumors: a phase II basket trial with circulating tumor DNA analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) (ERBB2)-directed agents are standard treatments for patients with HER2-positive breast and gastric cancer. Herein, we report the results of an open-label, single-center, phase II basket trial to investigate the efficacy and safety of trastuzumab biosimilar (Samfenet®) plus treatment of physician's choice for patients with previously treated HER2-positive advanced solid tumors, along with biomarker analysis employing circulating tumor DNA (ctDNA) sequencing. METHODS: Patients with HER2-positive unresectable or metastatic non-breast, non-gastric solid tumors who failed at least one prior treatment were included in this study conducted at Asan Medical Center, Seoul, Korea. Patients received trastuzumab combined with irinotecan or gemcitabine at the treating physicians' discretion. The primary endpoint was the objective response rate as per RECIST version 1.1. Plasma samples were collected at baseline and at the time of disease progression for ctDNA analysis. RESULTS: Twenty-three patients were screened from 31 December 2019 to 17 September 2021, and 20 were enrolled in this study. Their median age was 64 years (30-84 years), and 13 patients (65.0%) were male. The most common primary tumor was hepatobiliary cancer (seven patients, 35.0%), followed by colorectal cancer (six patients, 30.0%). Among 18 patients with an available response evaluation, the objective response rate was 11.1% (95% confidence interval 3.1% to 32.8%). ERBB2 amplification was detected from ctDNA analysis of baseline plasma samples in 85% of patients (n = 17), and the ERBB2 copy number from ctDNA analysis showed a significant correlation with the results from tissue sequencing. Among 16 patients with post-progression ctDNA analysis, 7 (43.8%) developed new alterations. None of the patients discontinued the study due to adverse events. CONCLUSIONS: Trastuzumab plus irinotecan or gemcitabine was safe and feasible for patients with previously treated HER2-positive advanced solid tumors with modest efficacy outcomes, and ctDNA analysis was useful for detecting HER2 amplification.

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Tumor immune-gene expression profiles and peripheral immune phenotypes associated with clinical outcomes of locally advanced pancreatic cancer following FOLFIRINOX.

BACKGROUND: A comprehensive analysis of peripheral immune cell phenotypes and tumor immune-gene expression profiles in locally advanced pancreatic cancer patients treated with neoadjuvant chemotherapy in a phase II clinical trial was carried out. METHODS: Patients were treated with neoadjuvant modified folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin (mFOLFIRINOX) followed by surgery and adjuvant gemcitabine at the Asan Medical Center. Correlations between survival outcomes and baseline peripheral immune cells and their changes during preoperative chemotherapy were analyzed. Patients who had surgery were divided into two groups according to achievement of disease-free survival >10 months (achieved versus failed). Differential expression and pathway analysis of immune-related genes were carried out using the Nanostring platform, and immune cells within the tumor microenvironment were compared by immunohistochemistry. RESULTS: Forty-four patients were treated in the phase II clinical trial. Higher baseline CD14+CD11c+HLA-DR+ monocytes (P = 0.044) and lower Foxp3+CD4+ T cells (P = 0.02) were associated with poor progression-free survival of neoadjuvant mFOLFIRINOX. During the preoperative chemotherapy, PD-1 T cells significantly decreased (P = 0.0110). Differential expression and pathway analysis of immune-genes from the resected tumor after neoadjuvant treatment revealed transforming growth factor-ß pathway enrichment and higher expression of MARCO (adjusted P < 0.05) associated with early recurrence. Enrichment of the Th1 pathway and higher peritumoral CD8+ T cells (P = 0.0103) were associated with durable disease-free survival from surgery (>10 months) following neoadjuvant mFOLFIRINOX. CONCLUSIONS: Our results identify potential immune biomarkers for locally advanced pancreatic cancer and provide insights into pancreatic cancer immunity.

Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study.

BACKGROUND: Grade 3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) origin with Ki-67 indices <55% do not respond well to platinum-based chemotherapy. The combination of capecitabine and temozolomide (CAPTEM) has shown favorable responses in grade 1-2 NENs, but has rarely been studied in patients with grade 3 NENs. PATIENTS AND METHODS: This open-label, single-arm phase II trial included patients with unresectable or metastatic grade 3 NENs of GEP origin with Ki-67 indices <55% enrolled between June 2017 and July 2020. Patients received oral capecitabine 750 mg/m2 twice daily on days 1 to 14 and oral temozolomide 200 mg/m2 once daily on days 10 to 14 every 4 weeks. Histologic findings were centrally reviewed after the completion of enrollment. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Of the 30 patients included in the full analysis set, 1 (3.3%) achieved complete response, 8 (26.7%) had partial responses, and 14 (46.7%) had stable disease, making the overall response rate 30.0%. At a median follow-up of 19.2 months, the median PFS was 5.9 months and the median OS was not reached. Patients with well-differentiated NENs showed significantly better median PFS (9.3 months versus 3.5 months, P = 0.005) and median OS (not reached versus 6.2 months, P = 0.004) than patients with poorly differentiated tumors. Expression of O6-methyl-guanine methyltransferase protein did not correlate with clinical outcomes. The most common grade 3-4 adverse events were thrombocytopenia (10%), anemia (6.7%), and nausea (6.7%). CONCLUSIONS: CAPTEM was effective and well tolerated in patients with grade 3 GEP-NENs with Ki-67 indices <55%, with superior efficacy outcomes compared with the historical controls receiving platinum-based chemotherapy.

Strategy to enhance dendritic cell-mediated DNA vaccination in the lung.

We here introduce a new paradigm to promote pulmonary DNA vaccination. Specifically, we demonstrate that nanoparticles designed to rapidly penetrate airway mucus (mucus-penetrating particle or MPP) enhance the delivery of inhaled model DNA vaccine (i.e. ovalbumin-expressing plasmids) to pulmonary dendritic cells (DC), leading to robust and durable local and trans-mucosal immunity. In contrast, mucus-impermeable particles were poorly taken up by pulmonary DC following inhalation, despite their superior ability to mediate DC uptake in vitro compared to MPP. In addition to the enhanced immunity achieved in mucosal surfaces, inhaled MPP unexpectedly provided significantly greater systemic immune responses compared to gold-standard approaches applied in the clinic for systemic vaccination, including intradermal injection and intramuscular electroporation. We also showed here that inhaled MPP significantly enhanced the survival of an orthotopic mouse model of aggressive lung cancer compared to the gold-standard approaches. Importantly, we discovered that MPP-mediated pulmonary DNA vaccination induced memory T-cell immunity, particularly the ready-to-act effector memory-biased phenotype, both locally and systemically. The findings here underscore the importance of breaching the airway mucus barrier to facilitate DNA vaccine uptake by pulmonary DC and thus to initiate full-blown immune responses.

Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: a multicenter retrospective study of the Korean Cancer Study Group (KCSG).

BACKGROUND: There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. PATIENTS AND METHODS: From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. RESULTS: There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL. CONCLUSIONS: Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.

Comparison of two different S-1 plus cisplatin dosing schedules as first-line chemotherapy for metastatic and/or recurrent gastric cancer: a multicenter, randomized phase III trial (SOS).

BACKGROUND: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m(2)/day on days 1-14 and cisplatin 60 mg/m(2) on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m(2) on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). RESULTS: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68-0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81-1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3. CONCLUSIONS: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.

Redox signalling to nuclear regulatory proteins by reactive oxygen species contributes to oestrogen-induced growth of breast cancer cells.

BACKGROUND: 17ß-Oestradiol (E2)-induced reactive oxygen species (ROS) have been implicated in regulating the growth of breast cancer cells. However, the underlying mechanism of this is not clear. Here we show how ROS through a novel redox signalling pathway involving nuclear respiratory factor-1 (NRF-1) and p27 contribute to E2-induced growth of MCF-7 breast cancer cells. METHODS: Chromatin immunoprecipitation, qPCR, mass spectrometry, redox western blot, colony formation, cell proliferation, ROS assay, and immunofluorescence microscopy were used to study the role of NRF-1. RESULTS: The major novel finding of this study is the demonstration of oxidative modification of phosphatases PTEN and CDC25A by E2-generated ROS along with the subsequent activation of AKT and ERK pathways that culminated in the activation of NRF-1 leading to the upregulation of cell cycle genes. 17ß-Oestradiol-induced ROS by influencing nuclear proteins p27 and Jab1 also contributed to the growth of MCF-7 cells. CONCLUSIONS: Taken together, our results present evidence in the support of E2-induced ROS-mediated AKT signalling leading to the activation of NRF-1-regulated cell cycle genes as well as the impairment of p27 activity, which is presumably necessary for the growth of MCF-7 cells. These observations are important because they provide a new paradigm by which oestrogen may contribute to the growth of breast cancer.

Intrastromal delivery of bevacizumab using microneedles to treat corneal neovascularization.

PURPOSE: This study tested the hypothesis that highly targeted intrastromal delivery of bevacizumab using coated microneedles allows dramatic dose sparing compared with subconjunctival and topical delivery for treatment of corneal neovascularization. METHODS: Stainless steel microneedles 400 µm in length were coated with bevacizumab. A silk suture was placed in the cornea approximately 1 mm from the limbus to induce corneal neovascularization in the eyes of New Zealand white rabbits that were divided into different groups: untreated, microneedle delivery, topical eye drop, and subconjunctival injection of bevacizumab. All drug treatments were initiated 4 days after suture placement and area of neovascularization was measured daily by digital photography for 18 days. RESULTS: Eyes treated once with 4.4 µg bevacizumab using microneedles reduced neovascularization compared with untreated eyes by 44% (day 18). Eyes treated once with 2500 µg bevacizumab using subconjunctival injection gave similar results to microneedle-treated eyes. Eyes treated once with 4.4 µg subconjunctival bevacizumab showed no significant effect compared with untreated eyes. Eyes treated with 52,500 µg bevacizumab by eye drops three times per day for 14 days reduced the neovascularization area compared with untreated eyes by 6% (day 18), which was significantly less effective than the single microneedle treatment. Visual exam and histological analysis showed no observable effect of microneedle treatment on corneal transparency or microanatomical structure. CONCLUSIONS: This study shows that microneedles can target drug delivery to corneal stroma in a minimally invasive way and demonstrates effective suppression of corneal neovascularization after suture-induced injury using a much lower dose compared with conventional methods.

Analysis of serum protein biomarkers, circulating tumor DNA, and dovitinib activity in patients with tyrosine kinase inhibitor-refractory gastrointestinal stromal tumors.

BACKGROUND: An exploratory translational analysis was conducted as part of a phase II study of dovitinib to assess the relevance of soluble serum proteins and circulating tumor (ct) DNA (ctDNA) as biomarkers in patients with tyrosine kinase inhibitor (TKI)-refractory gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: Predose serum samples were collected from 30 patients on day 1 of cycle 1 and cycle 2. Serum levels of angiogenesis-related proteins were assessed by enzyme-linked immunosorbent assay, and Beads, emulsions, amplification, and magnetics (BEAMing) assays were carried out to detect mutations in serum ctDNA. RESULTS: Dovitinib increased vascular endothelial growth factor (VEGF)165 (1.26-fold, P = 0.006), VEGF-A (1.27-fold, P = 0.004), placental growth factor (6.0-fold, P = 0.002), fibroblast growth factor 23 (1.45-fold, P = 0.02), and interleukin 8 (1.75-fold, P = 0.04) levels, and decreased soluble vascular endothelial growth factor receptor (sVEGFR)-2 levels (0.8-fold, P = 0.001). The changes in sVEGFR-2 were significantly associated with metabolic response determined by positron emission tomography (P = 0.02) and progression-free survival (PFS; P = 0.02). Secondary kinase mutations were identified in the ctDNA of 11 patients (41%), and these patients all had mutations involving KIT exon 17. Patients with secondary KIT mutations had significantly worse overall survival {median, 5.5 months [95% confidence interval (CI) 3.8-7.2 months]} than those with no detectable secondary mutations [9.8 months (95% CI 9.6-10.0 months); hazard ratio = 2.7 (95% CI 1.0-7.3); P = 0.047]. CONCLUSIONS: Changes in sVEGFR-2 levels were associated with dovitinib-mediated antitumor activity. Genotyping of serum ctDNA with BEAMing is useful for the identification of resistant mutations potentially associated with poor prognosis in patients with GISTs.

Effect of inhalers on the development of haemoptysis in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: The association of inhaler use with haemoptysis has rarely been reported in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVE: To elucidate the effect of inhaler use on the development of haemoptysis in patients with non-CF bronchiectasis. METHODS: In a case-crossover study of 192 non-CF bronchiectasis patients with a history of haemoptysis and inhaler use, the risk of haemoptysis associated with the use of inhalers was elucidated. Two inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA), one long-acting muscarinic antagonist and one short-acting ß2-agonist (SABA) were evaluated. The case and control periods were defined respectively as 030 and 180210 days before haemoptysis. RESULTS: The risk of haemoptysis during the case period was 3.51 times higher than during the control period with any use of inhalers (95%CI 1.966.28). The results of clinically significant haemoptysis showed good agreement with those of total events. These associations were consistent with the sensitivity analyses. In the sub-analysis according to inhaler type, ICS/LABA and SABA were significantly associated with an increased risk of haemoptysis (aOR 2.62, 95%CI 1.255.45; aOR 2.51, 95%CI 2.235.15). CONCLUSIONS: In patients with non-CF bronchiectasis, the use of inhalers, especially including 2-agonist, was associated with an increased risk of haemoptysis.

Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib.

BACKGROUND: This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib. METHODS: Patients received oral dovitinib, 500 mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)-CT scans performed at baseline and after 4 weeks of treatment. RESULTS: Between September 2011 and April 2012, 30 patients were enrolled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3-12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5-3.7 months) and median overall survival was 9.7 months (95% CI, 6.0-13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification. CONCLUSION: Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.

Antiplatelet or anticoagulant therapy might not increase the risk of haemoptysis in patients with bronchiectasis.

The aim of this study was to assess whether the use of antiplatelets and anticoagulants increased haemoptysis in patients with bronchiectasis. Cases (n = 242) with a history of haemoptysis were compared with controls (n = 242) without a history of haemoptysis. Of the 242 case patients, 16.5% took antiplatelets compared with 19.8% of controls (P = 0.346). The proportion of warfarin users did not differ between cases and controls (3.3% vs. 2.5%, P = 0.588). The use of these agents might not be associated with increased risk of haemoptysis in patients with bronchiectasis.

Diagnostic accuracy of Xpert® MTB/RIF on bronchoscopy specimens in patients with suspected pulmonary tuberculosis.

OBJECTIVE: To determine the diagnostic accuracy of the Xpert® MTB/RIF assay using samples obtained through bronchoscopy in patients with suspected pulmonary tuberculosis (PTB). DESIGN: We retrospectively reviewed the records of patients with suspected PTB for whom the Xpert MTB/RIF assay was performed on bronchoscopy specimens. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of active PTB were calculated for acid-fast bacilli (AFB) smear microscopy and the Xpert assay using culture of Mycobacterium tuberculosis from sputum or bronchoscopy specimens as a reference standard. RESULTS: A total of 132 patients were included in the final analysis. Of these, 38 had culture-confirmed PTB. The sensitivity of the Xpert assay using bronchial washing or bronchoalveolar lavage (BAL) fluid for the diagnosis of PTB was 81.6%, and specificity was 100%. The PPV and NPV were 100% and 92.1%, respectively. The sensitivity and specificity of AFB smear microscopy were respectively 13.2% and 98.8%. CONCLUSION: The Xpert assay on bronchoscopy specimens provided an accurate diagnosis of PTB in patients who had a negative AFB smear or who could not produce sputum.

Efficacy and safety of the simultaneous administration of mirodenafil and an α-blocker in men with BPH-LUTS: a multicenter open-label prospective study.

We evaluated the clinical efficacy and safety of the coadministration of a PDE5 inhibitor and an α-adrenergic blocker in patients with both benign prostatic hyperplasia/lower urinary tract symptoms (BPH-LUTS) and ED using mirodenafil 50 mg (Mvixx) once daily (OD) in patients already receiving stable α-blocker therapy. This study was a prospective, multicenter, open-label trial. We selected 147 patients undergoing stable (longer than 4 weeks) α-blocker therapy for BPH-LUTS as recipients of the additive mirodenafil 50 mg OD for 8 weeks. The coprimary measures were the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5). The key secondary measures were peak flow rate (Qmax) and postvoiding residual (PVR) volume. Safety was assessed by evaluating cardiovascular parameters and the participant-reported treatment-emergent adverse events (TEAEs). The additional administration of mirodenafil 50 mg OD significantly improved IPSS results (18.70-14.30 at 4 weeks and 18.70-13.72 at 8 weeks; P<0.001). The IIEF-5 score was improved at 8 weeks (10.94-16.16; P<0.001). There was no significant change in systolic blood pressure/diastolic blood pressure (124.8 mm Hg/78.6 mm Hg-122.0 mm Hg/79.6 mm Hg; P=0.638) and heart rates (78.8 per min to 80.2 per min; P=0.452). The most common TEAEs were hot flashes (10.9%) and headache (8.1%). The combination of mirodenafil with an α-blocker did not significantly improve PVR; however, Qmax was improved at 8 weeks (14.51-16.80 ml s(-1); P=0.026). Mirodenafil 50 mg OD in combination with an α-blocker appeared to have few adverse effects, to improve BPH-LUTS and restore sexual function.

Metabolic syndrome is associated with increased risk of recurrent colorectal adenomas in Korean men.

OBJECTIVE: Because of the high incidence of recurrent colorectal adenomas, regular surveillance by colonoscopy is recommended. However, there is still a shortage of information on the factors that influence the incidence of recurrent colorectal adenomas in patients with a history of these lesions. The aim of this study was to determine the association between the development of recurrent colorectal adenomas, metabolic syndrome and obesity. SUBJECTS AND METHODS: The hospital-based cohort was composed of 193 patients who had recurrent colorectal adenomas removed between January 2002 and December 2003. The Cox proportional hazard model was used to determine hazard ratio (HR) and 95% confidence interval (CI) between obesity, metabolic syndrome and other factors, and the incidence of recurrent adenomatous polyps. RESULTS: The mean follow-up period was 4.8 person-years. In all, 78 of the patients (40.4%) had recurrent colorectal adenomas. In the overall recurrent adenoma group, significant associations between metabolic syndrome (HR, 1.33; 95% CI, 1.02-1.73), waist circumference (WC) ≥ 90 cm (HR, 1.42; 95% CI, 1.06-1.90) and waist-hip ratio (WHR) ≥ 0.9 (HR, 2.03; 95% CI, 1.55-2.68) were found. Moreover, advanced adenomas were significantly associated with metabolic syndrome (HR, 2.81; 95% CI, 1.86-4.25), body mass index ≥ 25 kg m(-2) (HR, 2.69; 95% CI, 1.64-4.42), WC (HR, 2.16; 95% CI, 1.31-3.54) and WHR (HR, 1.99; 95% CI, 1.28-3.11). In addition, current smoking (HR, 2.60; 95% CI, 1.09-6.25) and alcohol consumption (HR, 2.20; 95% CI, 1.10-4.39) were also significantly associated with recurrent advanced adenoma. CONCLUSION: Metabolic syndrome and obesity were significantly associated with the development of recurrent colorectal adenomas in Korean adult males. Furthermore, these associations were more strongly associated with advanced adenomas.

The impact of combined pulmonary fibrosis and emphysema on mortality.

SETTING: The impact on patient mortality of combined pulmonary fibrosis and emphysema (CPFE) compared with emphysema alone has never been investigated. OBJECTIVE: To elucidate whether CPFE has an impact on overall mortality over that of emphysema alone. DESIGN: We screened patients who underwent chest computed tomography (CT) scans during the period from 1 January 2001 to 31 December 2005 in a tertiary referral hospital. Patients who had both emphysema and pulmonary fibrosis, thus meeting the inclusion criteria, were defined as CPFE. Controls with emphysema alone who were matched for age, sex and the date of CT scan were randomly selected. Cox proportional regression analysis was performed to verify whether CPFE is associated with increased overall mortality. RESULTS: We found 135 CPFE cases. In the multivariable Cox regression stratified by the presence of comorbid malignancy, CPFE had five times higher mortality risk (adjusted HR 5.10, 95%CI 1.75-14.9) in non-malignant cases, and showed a statistically insignificant trend for higher mortality risk (adjusted HR 1.70, 95%CI 0.94-2.51) in the malignant cases after adjusting for forced vital capacity, height and hypertension. CONCLUSION: CPFE is not rare and CPFE patients had a higher overall mortality risk than emphysema-only patients.

Impact of antibiotic prophylaxis on postbronchoscopy fever: a randomised controlled study.

BACKGROUND: Postbronchoscopy fever can develop in 5-16% of adult patients. The microbiological contribution to postbronchoscopy fever is unclear. OBJECTIVE: To elucidate the effect of prophylactic antibiotics on the development of postbronchoscopy fever and pneumonia. DESIGN: Study patients were randomised to receive no treatment or oral amoxicillin/clavulanate 30 min before flexible bronchoscopy. The primary outcome variable was the frequency of postbronchoscopy fever and pneumonia. White blood cell counts, C-reactive protein and the serum pyrogenic cytokines interleukin (IL) 1ß, IL-6 and tumour necrosis factor-alpha were measured before and after bronchoscopy. RESULTS: Of 143 subjects enrolled in the study, the final analysis was performed among 67 subjects in the prophylaxis group and 64 in the control group. The frequency of postbronchoscopy fever did not differ between the groups (25.4% for the prophylaxis group vs. 26.6% for controls, P > 0.05). Pneumonia developed in 1.5% of the prophylaxis group and 4.7% of the controls. There was no bacteraemia in either group. Serum pyrogenic cytokines did not differ between the groups. CONCLUSIONS: Prophylactic antibiotics before bronchoscopy did not reduce the frequency of postbronchoscopy fever and did not affect serum levels of pyrogenic cytokines. These findings suggest that microbiological factors may not be responsible for the development of postbronchoscopy fever.

Optimal timing of G-CSF administration for effective autologous stem cell collection.

The best time of G-CSF administration for PBPC collection remains to be defined. We aimed to identify optimal G-CSF administration timing for efficient autologous stem cell collection. A total of 262 lymphoma or multiple myeloma patients, who underwent PBPC collection from January 2000 to March 2008, were included. PBPCs were mobilized with chemotherapy followed by lenograstim at 10 µg/kg/day. Patients received lenograstim at 2000 hours, about half a day before leukapheresis (PM group) before November 2004, and at 0600 hours, 3 h before apheresis (AM group) subsequently. In the AM group, the median number of total collected CD34+ cells/kg was greater over a shorter duration of apheresis, and the median number of collected CD34+ cells/kg at first leukapheresis was larger. Stem cell collection efficacy (ratio of total collected CD34+ cells/kg per number of leukapheresis procedures) was higher, and proportion of patients who yielded an optimum harvest was larger. The statistically significant between-group difference was observed only in patients with high-dose CY chemotherapy for stem cell mobilization in subgroup analysis. The present study showed that G-CSF injection 3 h before apheresis improved the efficacy of autologous stem cell collection.