Predictors of permanent stoma creation in patients with mid or low rectal cancer: results of a multicentre cohort study with preoperative evaluation of anal function.

AIM: Preoperative factors predictive of permanent stoma creation were investigated in a long-term follow-up of patients with mid or low rectal cancer. METHOD: We included patients who underwent radical resection for mid or low rectal cancer with available data for preoperative anal function measured by manometry and Faecal Incontinence Severity Index questionnaire between January 2005 and December 2015 in three tertiary referral hospitals. A permanent stoma was defined as a stoma present until the patient's last follow-up visit or death. Preoperative factors that predicted permanent stoma creation were analysed. RESULTS: Over a median follow-up of 57.4 months (range 12-143 months), a permanent stoma was created in 144/577 (25.0%) patients, including 89 (15.4%) who underwent abdominoperineal resection, one (0.2%) who underwent Hartmann's operation without reversal, 15 (2.6%) with a diverting ileostomy at the time of initial sphincter-preserving surgery without undergoing stoma reversal, and 39 (6.8%) who underwent permanent ileostomy formation after sphincter-preserving surgery. Patients with permanent stoma creation had a shorter tumour distance from the anal verge (P < 0.001), larger tumour size (P = 0.020) and higher preoperative Faecal Incontinence Severity Index score (P = 0.020). On multivariable analysis, tumour distance from the anal verge predicted permanent stoma formation (relative risk 0.53 per centimetre increase; 95% confidence interval 0.46-0.60; P < 0.001) but preoperative anal function did not. CONCLUSION: Tumour distance from the anal verge was the only preoperative determinant of permanent stoma creation in rectal cancer patients. These data may help mid and low rectal cancer patients understand the need for permanent stoma.

Temporal patterns of patient-reported trismus and associated mouth-opening distances in radiotherapy for head and neck cancer: A prospective cohort study.

OBJECTIVES: To identify temporal patterns of patient-reported trismus during the first year post-radiotherapy, and to study their associations with maximal interincisal opening distances (MIOs). DESIGN: Single institution case series. SETTING: University hospital ENT clinic. PARTICIPANTS: One hundred and ninety-six subjects who received radiotherapy (RT) for head and neck cancer (HNC) with or without chemotherapy in 2007-2012 to a total dose of 64.6/68 Gy in 38/34 fractions, respectively. All subjects were prospectively assessed for mouth-opening ability (Gothenburg Trismus Questionnaire (GTQ), European Organization for Research and Treatment of Cancer quality of life Questionnaire (EORTC QLQ-H&N35), and MIO) pre-RT and at 3, 6 and 12 months after RT. MAIN OUTCOME MEASURES: Correlations between temporally robust GTQ symptoms and MIO as given by Pearson's correlation coefficients (Pr ); temporally robust GTQ-symptom domains as given by factor analysis; rates of trismus with respect to baseline by risk ratios (RRs). RESULTS: Four temporally robust domains were identified: Eating (3-7 symptoms), Jaw (3-7), Pain (2-5) and Quality of Life (QoL, 2-5), and included 2-3 persistent symptoms across all post-RT assessments. The median RR for a moderate/severe (>2/>3) cut-off was the highest for Jaw (3.7/3.6) and QoL (3.2/2.9). The median Pr between temporally robust symptoms and MIO post-radiotherapy was 0.25-0.35/0.34-0.43/0.24-0.31/0.34-0.50 for Eating/Jaw/Pain/QoL, respectively. CONCLUSIONS: Mouth-opening distances in patients with HNC post-RT can be understood in terms of associated patient-reported outcomes on trismus-related difficulties. Our data suggest that a reduction in MIO can be expected as patients communicate their mouth-opening status to interfere with private/social life, a clinical warning signal for emerging or worsening trismus as patients are being followed after RT.

Cardiovascular risk in fire academy instructors during live-fire simulation activity.

Firefighting is an extreme occupation with a risk of cardiovascular disease and sudden cardiac death due to strenuous physical exertion and psychological stress during fire suppression activity. This study aimed to investigate the vital signs (hemodynamic status) and biomarkers related to cardiac disease during live firefighting activity. In this pilot case-controlled study, seven firefighting training instructors performed a live-fire simulation for 40 min in a multi-storey training tower at the Gyenoggi-do Fire Service Academy Institute. Seven participants in the control group undertook similar exercises while wearing personal protective equipment. Cardiovascular evaluation, including vital signs and related biomarkers, was done before and after simulation until 24 h later. Nonparametric statistics were used to compare between the two groups and within the simulation group. After live-fire simulation, pulse pressure, heart rate (HR) and body temperature (BT) in the simulation group were higher than in the control group (pulse pressure 74.6 mmHg vs. 53.3 mmHg, HR 110 beats per minute (bpm) vs. 77 bpm, and BT 37.6 °C vs. 36.0 °C, P < 0.05 for all). Inflammatory cytokines (IL- 6), coagulation protein (fibrinogen), and stress hormones (cortisol, adrenocorticotrophic hormone) were elevated immediately after live-fire simulation, and IL-6 and fibrinogen remained elevated until 24 h after the simulation (all P < 0.05). Our exploratory analysis found increased altered hemodynamic status and stress-related biomarkers in live-fire firefighting simulations compared to controls. These markers have the potential to be used to decrease cardiovascular risk for firefighters, and warrant further investigation.

L'attaque de feu est une activité épuisante physiquement et psychologiquement stressante augmentant le risque cardio-vasculaire dont la mort subite. Cette étude pilote cas-témoin avait pour but d'étudier l'état hémodynamique et les biomarqueurs de pathologie cardiaque pendant l'attaque de feu. Elle a été menée sur 7 instructeurs de l'institut de formation du service d'incendie de la province de Gyenoggi-do, pendant un exercice de 40 mn en conditions réelles dans la tour d'entraînement. Le groupe contrôle effectuait un effort similaire, avec la même tenue, hors incendie. Les évaluations clinique et biologique étaient réalisées préalablement puis pendant 24 h. Des tests non paramétriques ont été utilisés pour les comparaisons entre groupes et au sein des groupes. En conditions réelles, la température corporelle (37,6/36°C), la PAM (74,6/53,3) et la fréquence cardiaque (110/77) étaient statistiquement plus élevées (p<0,05) que dans le groupe contrôle. De la même manière, IL6, fibrinogène, cortisol et ACTH étaient plus élevées en conditions réelles, IL6 et fibrinogène restant élevés à h24. L'élévation de ces marqueurs cliniques et biologiques de risque cardio-vasculaire et de stress nécessitent une étude plus poussée avant leur utilisation éventuelle pour évaluer la prévention.

Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient-derived induced pluripotent stem cells.

AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harbouring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PD patient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs). To unravel the gene and signalling networks associated with LK2GS, we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology (GO) and pathway analyses. RESULTS: The expression profiles of LK2GS were distinct from those of wild-type controls in hNESs and hIOs. The most represented GO biological process in hNESs and hIOs was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD. The results were further validated in four independent PD-specific hNESs and hIOs by microarray and qRT-PCR analysis. CONCLUSION: We provide the first evidence that LK2GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PD patients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.

Neutrophil pyroptosis mediates pathology of P. aeruginosa lung infection in the absence of the NADPH oxidase NOX2.

Nod-like receptor family, CARD domain-containing 4 (NLRC4) inflammasome activation is required for efficient clearance of intracellular pathogens through caspsase-1-dependent pyroptosis in macrophages. Although neutrophils have a critical role in protection from Pseudomonas aeruginosa infection, the mechanisms regulating inflammasome-mediated pyroptosis in neutrophils and its physiological role are largely unknown. We sought to determine the specific mechanisms regulating neutrophil pyroptosis in P. aeruginosa strain PAO1 (PAO1) lung infection and to identify the pathological role of this process. Nox2-/- models with reduced neutrophil antibacterial activity exhibited increased neutrophil pyroptosis, which was mediated by flagellin, a pathogenic PAO1 component. We also demonstrate that PAO1-induced pyroptosis depended on NLRC4 and Toll-like receptor 5 (TLR5) in neutrophils generated from Nlrc4-/- or Tlr5-/- mice. Our study reveals previously unknown mechanisms and physiological role of neutrophil pyroptosis during P. aeruginosa lung infection. Furthermore, our findings regarding neutrophil pyroptosis in the context of neutrophil dysfunction may explain the causes of acute and/or chronic infectious diseases discovered in immune-compromised patients.

ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition.

High-mobility group box 1 (HMGB1) mediates various functions according to the location. We tried to investigate the role of HMGB1 in upper airway under hypoxic conditions. We cultured primary normal human nasal epithelium (NHNE) cells under hypoxic conditions and evaluated the movement of HMGB1 by western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level was evaluated to estimate the translocation mechanism of HMGB1. The role of secreted HMGB1 was evaluated by ELISA assay. Furthermore, we collected human nasal mucosa samples and nasal lavage fluids from patients conditioned under hypoxic and non-hypoxic environment, and compared the expression of HMGB1 in human nasal mucosa samples by immunohistochemistry and the levels of HMGB1 in lavage fluids using ELISA assay. Hypoxia induced translocation of HMGB1 into the extracellular area and it was dependent on ROS produced by dual oxidase 2. Secreted HMGB1 was involved in the upregulation of interleukin (IL)-8. In human samples, HMGB1 was translocated from nucleus to the cytoplasm in hypoxic-conditioned nasal mucosa. HMGB1 was increased in nasal lavage samples of chronic rhinosinusitis patients, whose sinus mucosa was supposed to be hypoxic as compared with controls. We suggest that HMGB1 is secreted in hypoxic condition via ROS-dependent mechanism and secreted HMGB1 participates in IL-8 upregulation mediating inflammatory response.

Suprascapular neuropathy in massive rotator cuff tears with severe fatty degeneration in the infraspinatus muscle.

AIMS: Our aim was to describe the atypical pattern of increased fatty degeneration in the infraspinatus muscle compared with the supraspinatus in patients with a massive rotator cuff tear. We also wished to describe the nerve conduction and electromyography findings in these patients. PATIENTS AND METHODS: A cohort of patients undergoing surgery for a massive rotator cuff tear was identified and their clinical records obtained. Their MRI images were reviewed to ascertain the degree of retraction of the torn infraspinatus and supraspinatus muscles, and the degree of fatty degeneration in both muscles was recorded. Nerve conduction studies were also performed in those patients who showed more degeneration in the infraspinatus than in the supraspinatus. RESULTS: Out of a total of 396 patients who underwent surgery for a massive rotator cuff tear between 2006 and 2015, 35 who had more severe fatty degeneration in the infraspinatus than in the supraspinatus were identified. There were 13 men and 22 women. Their mean age was 67.2 years (56 to 81). A total of 20 (57%) had grade 4 fatty degeneration as classified by Fuchs et al, in the infraspinatus. Patte grade 3 muscle retraction was seen in 25 patients (71%). In all, eight patients (23%) had abnormal nerve conduction studies. The mean retraction of the infraspinatus was 3.6 cm (2.1 to 4.8) in patients with more severe fatty degeneration in the infraspinatus, versus 3.0 cm (1.7 to 5.5) in those with more severe degeneration in the supraspinatus (p = 0.003). The retraction ratios were 0.98 (0.61 to 1.57) and 0.77 (0.38 to 1.92), respectively (p < 0.001). CONCLUSION: Fatty degeneration affecting the infraspinatus more than the supraspinatus may be, in the context of a massive rotator cuff tear, due to entrapment of the suprascapular nerve at the spinoglenoid notch. Cite this article: Bone Joint J 2016;98-B:1505-9.

Lymph node size is not a reliable criterion for predicting nodal metastasis in rectal neuroendocrine tumours.

AIM: The study was designed to assess the correlation between lymph node (LN) size and LN metastasis in patients with rectal neuroendocrine tumours (NETs). METHOD: Forty patients who underwent curative resection with lymphadenectomy for a rectal NET between January 2007 and December 2012 were included. The short and long diameters of entire nodes were microscopically measured using a slide gauge. RESULTS: In all, 1052 LNs were collected from the 40 patients, with 49 (4.7%) showing evidence of metastasis. Metastasis-positive LNs had significantly greater long and short diameters (P < 0.001) than metastasis-negative LNs. Of the 49 metastatic LNs, 29 (59.2%) were ≤ 5 mm in largest diameter. In five patients, the largest metastatic LN was only 2-3 mm in diameter. In clinically node-negative (cN0) patients, 18 (51.4%) patients had metastatic LNs (pN1). CONCLUSION: The size of LNs containing metastasis varied widely, with some being very small. LN size alone is therefore not a sufficient predictor of tumour metastasis in rectal NETs. Radical surgery with lymphadenectomy should be considered for patients with rectal NETs with high risk factors for LN metastasis, even those without LN enlargement.

Cytokine-release kinetics of platelet-rich plasma according to various activation protocols.

OBJECTIVES: This study was conducted to evaluate the cytokine-release kinetics of platelet-rich plasma (PRP) according to different activation protocols. METHODS: Two manual preparation procedures (single-spin (SS) at 900 g for five minutes; double-spin (DS) at 900 g for five minutes and then 1500 g for 15 minutes) were performed for each of 14 healthy subjects. Both preparations were tested for platelet activation by one of three activation protocols: no activation, activation with calcium (Ca) only, or calcium with a low dose (50 IU per 1 ml PRP) of thrombin. Each preparation was divided into four aliquots and incubated for one hour, 24 hours, 72 hours, and seven days. The cytokine-release kinetics were evaluated by assessing PDGF, TGF, VEGF, FGF, IL-1, and MMP-9 concentrations with bead-based sandwich immunoassay. RESULTS: The concentration of cytokine released from PRP varied over time and was influenced by various activation protocols. Ca-only activation had a significant effect on the DS PRPs (where the VEGF, FGF, and IL-1 concentrations were sustained) while Ca/thrombin activation had effects on both SS and DS PRPs (where the PDGF and VEGF concentrations were sustained and the TGF and FGF concentrations were short). The IL-1 content showed a significant increase with Ca-only or Ca/thrombin activation while these activations did not increase the MMP-9 concentration. CONCLUSION: The SS and DS methods differed in their effect on cytokine release, and this effect varied among the cytokines analysed. In addition, low dose of thrombin/calcium activation increased the overall cytokine release of the PRP preparations over seven days, relative to that with a calcium-only supplement or non-activation.Cite this article: Professor J. H. Oh. Cytokine-release kinetics of platelet-rich plasma according to various activation protocols. Bone Joint Res 2016;5:37-45. doi: 10.1302/2046-3758.52.2000540.

A phantom model study to identify the most effective manual aspiration thrombectomy for acute deep-vein thrombosis of the lower extremity.

AIM: To identify the most effective manual aspiration thrombectomy (MAT) method for the initial endovascular management of acute deep-vein thrombosis (DVT) in the lower extremity using a phantom model. MATERIALS AND METHODS: An acute DVT phantom model was created by infusing a bovine acute thrombus in a 20-mm diameter, 120-cm long plastic tube with banding of the distal portion. A total of 32 types of aspiration methods using combinations of two aspiration catheters (8 and 10 Fr), four syringes (10, 20, 40, and 50 ml), and four different aspiration methods (I, II, III, and IV) were performed. Each method was performed 10 times. The total weight of the aspirated thrombus was measured and compared among the 32 aspiration methods. The aspiration methods were classified based on the length of the dynamic catheter withdrawal (0 cm [method I], 15 cm [II], 30 cm [III], or >45 cm [IV]) while maintaining continuous negative pressure using a syringe. Analysis of variance and Student's t-test were used for statistical analysis. RESULTS: There were no statistically significant differences in the total amount of aspirated thrombus among the various types of aspiration catheters and syringes; however, different aspiration methods showed significantly different results. Acute thrombus was most effectively aspirated by method IV irrespective of the catheter and syringe used. The longer the length of dynamic catheter withdrawal, the greater the amount of total thrombi that could be aspirated, irrespective of the type of aspiration catheter and syringe used (IV > III > II > I; p<0.05). CONCLUSION: MAT can be performed most effectively using method IV. Effective MAT relies on the length of the dynamic catheter withdrawal while maintaining continuous negative pressure using a syringe in the initial endovascular management of acute DVT in the lower extremity.

Cognitive impairments associated with morphological changes in cortical and subcortical structures in multiple system atrophy of the cerebellar type.

BACKGROUND AND PURPOSE: Patients with the cerebellar variant of multiple system atrophy (MSA-C) often show cognitive deficits in various cognitive domains. The association between morphometric changes in cortical and subcortical structures and cognitive impairments in MSA-C were investigated to explore the neural correlates responsible for cognitive deficits in MSA-C patients. METHODS: Using surface-based morphometry, region-of-interest cortical thickness and the volumes and shapes of subcortical structures were examined in 18 patients who fulfilled the criteria of probable MSA-C and were compared to 50 healthy controls. The association between regional changes and cognitive functions in MSA-C were investigated by applying linear regression analyses after controlling for confounding factors. RESULTS: Compared with controls, the patients with MSA-C showed significant cortical thinning in the fronto-temporo-parietal regions and volume reduction in subcortical structures with shape changes. Cerebellar volume had no significant effect on cortical and subcortical volumes. The severity of atrophic changes in the bilateral thalamus, the left cerebellum and the left pericalcarine gyrus were significantly correlated with attentional, executive and visuospatial dysfunctions. CONCLUSION: Cognitive impairment in MSA-C might result from functional disruption of the corticostriatal and pontocerebellar circuit mediated by primary cortical, cerebellar or thalamic pathology.

Long-term outcomes of locally or radically resected T1 colorectal cancer.

AIM: Little is known about the long-term outcome of T1 colorectal cancer (CRC) following curative resection. The present study addressed the long-term outcome of locally or radically resected T1 CRCs. METHOD: A total of 430 patients with T1 CRC who underwent local or radical resection were considered. Unfavourable histological factors were defined as positive resection margin, deep submucosal invasion, vascular invasion, Grade 3 and budding. The patients were classified as low-risk (unfavourable histological factor negative, n = 65) or high-risk (unfavourable histological factor positive, n = 365). RESULTS: Over a median follow-up of 78.4 months, disease recurred in 16 (3.7%) patients in the high-risk group, and no recurrence in the low-risk group. Resection type and vascular invasion were significantly associated with recurrence. In the vascular invasion (+) high-risk group, both 5-year disease-free survival rate and 5-year overall survival rate were significantly associated with resection type (radical 94.6%, local 43.8%, P < 0.001, and radical 99.1%, local 66.7%, P < 0.001). In the vascular invasion (-) high-risk group, 5-year disease-free survival rate was also significantly associated with resection type (radical 98.9%, local 84.7%, P = 0.001). However, 5-year overall survival rate was not associated with resection type (radical 98.9%, local 95.2%, P = 0.816). CONCLUSION: Local resection may be effective and oncologically safe in low-risk T1 CRC. Although additional surgery should be recommended for the locally resected high-risk T1 CRC cases, intensive surveillance without additional surgery and timely salvage operation may offer another treatment option, if vascular invasion is negative.

The measurement of bone mineral density of bilateral proximal humeri using DXA in patients with unilateral rotator cuff tear.

UNLABELLED: We propose that the measurement of the bone mineral density (BMD) of the proximal humerus be standardized using the dual energy X-ray absorptiometry (DXA) in patients supposed to undergo rotator cuff repair surgery as well as those with the fracture of the proximal humerus as the BMD of the proximal humerus is decreased in these patients. INTRODUCTION: We propose that the measurement of the BMD of the proximal humerus be standardized using the DXA in patients who are supposed to undergo rotator cuff repair surgery as well as those with the fracture of the proximal humerus. METHODS: We conducted the prospective study in 213 patients with unilateral rotator cuff tear but without contralateral shoulder pain or disease. In these patients, we preoperatively measured the BMD of the bilateral proximal humeri with a repeat measurement in 20 patients. We predefined three regions of interest (ROIs) in the proximal humerus with the consideration of the rotator cuff repair surgery as well as proximal humeral fractures. RESULTS: The measurement of the BMD of the proximal humerus using the DXA showed excellent reliability (intraclass correlation coefficient > .90). BMD values of all three ROIs in the affected shoulder were significantly lower than those in asymptomatic shoulder (all p < 0.05). In female patients, the BMD values of ROIs in bilateral shoulder were significantly lower than those in male patients (all p < 0.001). In multiple regressions, however, there were no significant correlations between other clinical characteristics, except for the gender, and the BMD of GT in the affected shoulder. CONCLUSIONS: It is imperative that the bone quality of the proximal humerus be accurately evaluated prior to surgery in patients who are supposed to undergo rotator cuff repair using suture anchors as well as in those with proximal humeral fractures. This is because the BMD of the proximal humerus is decreased in these patients.

Effects of Rashba and Dresselhaus spin-orbit interactions on the ground state of two-dimensional localized spins.

Starting with the indirect exchange model influenced by the Rashba and the Dresselhaus spin-orbit interactions, we derive the Dzyaloshinskii-Moriya interaction of localized spins. The strength of the Dzyaloshinskii-Moriya interaction is compared with that of the Heisenberg exchange term as a function of atomic distance. Using the calculated interaction strengths, we discuss the formation of various atomic ground states as a function of temperature and external magnetic field. By plotting the magnetic field-temperature phase diagram, we present approximate phase boundaries between the spiral, Skyrmion and ferromagnetic states of the two-dimensional weak ferromagnetic system.

Dopaminergic manipulations and its effects on neurogenesis and motor function in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder that is classically defined by a triad of movement and cognitive and psychiatric abnormalities with a well-established pathology that affects the dopaminergic systems of the brain. This has classically been described in terms of an early loss of dopamine D2 receptors (D2R), although interestingly the treatments most effectively used to treat patients with HD block these same receptors. We therefore sought to examine the dopaminergic system in HD not only in terms of striatal function but also at extrastriatal sites especially the hippocampus, given that transgenic (Tg) mice also exhibit deficits in hippocampal-dependent cognitive tests and a reduction in adult hippocampal neurogenesis. We showed that there was an early reduction of D2R in both the striatum and dentate gyrus (DG) of the hippocampus in the R6/1 transgenic HD mouse ahead of any overt motor signs and before striatal neuronal loss. Despite downregulation of D2Rs in these sites, further reduction of the dopaminergic input to these sites by either medial forebrain bundle lesions or receptor blockade using sulpiride was able to improve both deficits in motor performance and adult hippocampal neurogenesis. In contrast, a reduction in dopaminergic innervation of the neurogenic niches resulted in impaired neurogenesis in healthy WT mice. This study therefore provides evidence that D2R blockade improves hippocampal and striatal deficits in HD mice although the underlying mechanism for this is unclear, and suggests that agents working within this network may have greater effects than previously thought.

Antitumor activity of IL-32ß through the activation of lymphocytes, and the inactivation of NF-κB and STAT3 signals.

Cytokine and activation of lymphocytes are critical for tumor growth. We investigated whether interleukin (IL)-32ß overexpression changes other cytokine levels and activates cytotoxic lymphocyte, and thus modify tumor growth. Herein, IL-32ß inhibited B16 melanoma growth in IL-32ß-overexpressing transgenic mice (IL-32ß mice), and downregulated the expressions of anti-apoptotic proteins (bcl-2, IAP, and XIAP) and cell growth regulatory proteins (Ki-67 antigen (Ki-67) and proliferating cell nuclear antigen (PCNA)), but upregulated the expressions of pro-apoptotic proteins (bax, cleaved caspase-3, and cleaved caspase-9). IL-32ß also inhibited colon and prostate tumor growth in athymic nude mice inoculated with IL-32ß-transfected SW620 colon or PC3 prostate cancer cells. The forced expression of IL-32ß also inhibited cell growth in cultured colon and prostate cancer cells, and these inhibitory effects were abolished by IL-32 small interfering RNA (siRNA). IL-10 levels were elevated, but IL-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) levels were reduced in the tumor tissues and spleens of IL-32ß mice, and athymic nude mice. The number of cytotoxic T (CD8(+)) and natural killer (NK) cells in tumor tissues, spleen, and blood was significantly elevated in IL-32ß mice and athymic nude mice inoculated with IL-32ß-transfected cancer cells. Constituted activated NF-κB and STAT3 levels were reduced in the tumor tissues of IL-32ß mice and athymic nude mice, as well as in IL-32ß-transfected cultured cancer cells. These findings suggest that IL-32ß inhibits tumor growth by increasing cytotoxic lymphocyte numbers, and by inactivating the NF-κB and STAT3 pathways through changing of cytokine levels in tumor tissues.

Clinicopathological characteristics of T1 colorectal cancer without background adenoma.

AIM: Background adenoma (BGA) is defined as benign adenomatous tissue contiguous to resected carcinomas, and the absence of BGA in a tumour is considered a histological criterion of de novo cancers. The present study aimed to identify the clinicopathological characteristics of T1 colorectal cancer (CRC) without BGA. METHOD: A retrospective review was carried out of prospectively collected data from two centres: the National Cancer Center, Korea; and Chonnam National University Hwasun Hospital, Korea. A total of 590 patients with T1 CRC, treated by endoscopic or surgical resection between January 2001 and August 2011, were enrolled. Details regarding gender, age, tumour location, endoscopic gross type, tumour size, depth of submucosal (SM) invasion, angiolymphatic invasion, tumour grade, budding and lymph node (LN) metastasis were evaluated with regard to the presence or absence of BGA. RESULTS: BGA was absent in 197 (33.4%) patients. Tumour size <20 mm, flat or depressed type, deep SM depth and tumour budding were associated with the absence of BGA in univariate and multivariate analyses (P < 0.05). In surgically resected patients, LN metastases were significantly associated with the absence of BGA (P = 0.022). CONCLUSION: T1 CRC without BGA presented several characteristics of small size (<20 mm), flat or depressed type, deep SM depth (SM 2/3), LN metastasis and tumour budding. These results indicate that de novo cancers may have a more invasive potential.

4-O-methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21-mediated suppression of NF-κB activity.

BACKGROUND AND PURPOSE: The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACH: The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTS: MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATION: MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.

The clinical characteristics of gastroesophageal reflux disease in patients with laryngeal symptoms who are referred to gastroenterology.

The prevalence of gastroesophageal reflux disease (GERD) has increased recently in Asia-Pacific countries. However, little is known about its prevalence and clinical characteristics in GERD patients with atypical symptoms in Asia. The aim of this study was to investigate the clinical characteristics of GERD in patients who had laryngeal symptoms in Korea. Data were gathered retrospectively from patients who presented with atypical symptoms, such as throat discomfort, globus pharyngeus, hoarseness, and chronic cough. They underwent a 24-hour ambulatory intraesophageal pH monitoring and filled in a validated reflux questionnaire. Overall, 128 patients (36 men and 92 women) with laryngeal symptoms were included. Of these 128, 43 patients (34%) had erosive esophagitis or pathological reflux from 24-hour ambulatory pH monitoring, and 24 (19%) had a positive Bernstein test or positive symptom index from 24-hour pH monitoring. Sixty-one patients (48%) had no evidence of reflux esophagitis on upper endoscopy and pathological acid reflux on 24-hour pH monitoring. Fifty-six patients (44%) had weekly heartburn or regurgitation. Typical symptoms and dyspepsia were significantly more common in patients with GERD who had laryngeal symptoms than non-GERD. Fifty-two percent of patients had laryngeal symptoms that were associated with GERD. The presence of typical reflux symptoms and dyspepsia are risk factors for GERD in patients who present with laryngeal symptoms.