Chi Mei Medical Center

Abstract We herein present an overview of the upcoming 5 th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4 th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5 th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

BACKGROUND: Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS: A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. RESULTS: At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). CONCLUSIONS: Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .).

OBJECTIVE: To evaluate our experience with the diagnosis and treatment of Cesarean scar pregnancy. METHODS: During a 6-year period, 12 cases of Cesarean scar pregnancy were diagnosed using transvaginal color Doppler sonography and treated conservatively to preserve fertility. Incidence, gestational age, sonographic findings, beta-human chorionic gonadotropin ( beta-hCG) levels, flow profiles of transvaginal color Doppler ultrasound, and methods of treatment were recorded. RESULTS: The incidence of Cesarean scar pregnancy was 1:2216 and its rate was 6.1% in women with an ectopic pregnancy and at least one previous Cesarean section. Gestational age at diagnosis ranged from 5 + 0 to 12 + 4 weeks. The time interval from the last Cesarean section to the diagnosis of Cesarean scar pregnancy ranged from 6 months to 12 years. High-velocity and low-impedance subtrophoblastic flow (resistance index, 0.38) persisted until beta-hCG declined to normal. Patients were treated as follows: transvaginal ultrasound-guided injection of methotrexate into the embryo or gestational sac (n = 3), transabdominal ultrasound-guided injection of methotrexate (n = 2), transabdominal ultrasound-guided injection of methotrexate followed by systemic methotrexate administration (n = 2), systemic methotrexate administration alone (n = 2), dilatation and curettage (n = 2), or local resection of the gestation mass (n = 1). Eleven of the 12 patients preserved their reproductive capacity; the remaining patient, treated by dilatation and curettage, underwent a hysterectomy because of profuse vaginal bleeding. The Cesarean scar mass regressed from 2 months to as long as 1 year after treatment. Uterine rupture occurred in one patient during the following pregnancy at 38 + 3 weeks' gestational age. CONCLUSION: Ultrasound-guided methotrexate injection emerges as the treatment of choice to terminate Cesarean scar pregnancy. Surgical or invasive techniques, including dilatation and curettage are not recommended for Cesarean scar pregnancy due to high morbidity and poor prognosis.

The purpose of this study was to examine the most frequently used criteria to define treatment success in implant dentistry. An electronic MEDLINE/PubMED search was conducted to identify randomized controlled trials and prospective studies reporting on outcomes of implant dentistry. Only studies conducted with roughened surface implants and at least five-year follow-up were included. Data were analyzed for success at the implant level, peri-implant soft tissue, prosthetics, and patient satisfaction. Most frequently reported criteria for success at the implant level were mobility, pain, radiolucency, and peri-implant bone loss (> 1.5 mm), and for success at the peri-implant soft-tissue level, suppuration, and bleeding. The criteria for success at the prosthetic level were the occurrence of technical complications/prosthetic maintenance, adequate function, and esthetics during the five-year period. The criteria at patient satisfaction level were discomfort and paresthesia, satisfaction with appearance, and ability to chew/taste. Success in implant dentistry should ideally evaluate a long-term primary outcome of an implant-prosthetic complex as a whole.

MicroRNAs (miRs) are a class of single-stranded RNA molecules of 15-27 nucleotides in length that regulate gene expression at the post-translational level. miR-21 is one of the earliest identified cancer-promoting 'oncomiRs', targeting numerous tumor suppressor genes associated with proliferation, apoptosis and invasion. The regulation of miR-21 and its role in carcinogenesis have been extensively investigated. Recent studies have focused on the diagnostic and prognostic value of miR-21 as well as its implication in the drug resistance of human malignancies. The further use of miR-21 as a biomarker and target for cancer treatments is likely to improve the outcome for patients with cancer. The present review highlights recent findings associated with the importance of miR-21 in hematological and non-hematological malignancies.

Go for gold: As-prepared insulin–Au nanoclusters (NCs) show intense red fluorescence, excellent biocompatibility, and preservation of natural insulin bioactivity in lowering the blood-glucose level. Their versatility in applications is demonstrated by fluorescence imaging, X-ray computed tomography, and insulin–inhibitor interactions (see picture; IDE=insulin-degrading enzyme).

BACKGROUND: Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors. DESIGN AND METHODS: The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms. RESULTS: SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt's lymphoma but not in any other mature lymphoid neoplasm. SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt's lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma. CONCLUSIONS: SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma.

AIM: To report several types of response of immature permanent teeth with infected necrotic pulp tissue and either apical periodontitis or abscess to revascularization procedures. METHODOLOGY: Twenty immature permanent teeth with infected necrotic pulp tissue and either apical periodontitis or abscesses from 20 patients were included. The teeth were isolated with rubber dam, and pulp chambers was accessed through the crowns. The canals were gently irrigated with 5.25% sodium hypochlorite with minimal mechanical debridement. Calcium hydroxide was used as an inter-appointment intracanal medicament and placed into the coronal half of the canal space. After resolution of clinical signs and symptoms, bleeding was induced into the canal space from the periapical tissues using K-files. The coronal canal space was sealed with a mixture of mineral trioxide aggregate (MTA) and saline solution. The access cavity was filled with composite resin. These immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscesses were followed up from 6 to 26 months. RESULTS: Five types of responses of these immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess to revascularization procedures were observed: type 1, increased thickening of the canal walls and continued root maturation; type 2, no significant continuation of root development with the root apex becoming blunt and closed; type 3, continued root development with the apical foramen remaining open; type 4, severe calcification (obliteration) of the canal space; type 5, a hard tissue barrier formed in the canal between the coronal MTA plug and the root apex. CONCLUSIONS: Based on this case series, the outcome of continued root development was not as predictable as increased thickening of the canal walls in human immature permanent teeth with infected necrotic pulp tissue and apical periodontitis/abscess after revascularization procedures. Continued root development of revascularized immature permanent necrotic teeth depends on whether the Hertwig's epithelial root sheath survives in case of apical periodontitis/abscess. Severe pulp canal calcification (obliteration) by hard tissue formation might be a complication of internal replacement resorption or union between the intracanal hard tissue and the apical bone (ankylosis) in revascularized immature permanent necrotic teeth.

BACKGROUND: The association of the magA gene with the hypermucoviscosity phenotype relevant to the pathogenesis of Klebsiella pneumoniae liver abscess has been reported in Taiwan. Similarly, the rmpA gene, known as a positive regulator of extracapsular polysaccharide synthesis that confers a mucoid phenotype, may be another candidate gene causing hypermucoviscosity. However, the association of rmpA with K. pneumoniae clinical syndromes is unreported. We aimed to investigate the clinical correlation between rmpA and primary Klebsiella abscess, focusing on sites other than the liver. METHODS: From July 2003 through December 2004, a total of 151 K. pneumoniae isolates recovered from 151 patients with bacteremia were collected from 2 large medical centers in southern Taiwan. Clinical data were collected from medical records. The genes rmpA and magA were amplified by polymerase chain reaction using specific primers. RESULTS: The prevalences of hypermucoviscosity, rmpA, and magA were 38%, 48%, and 17%, respectively. As determined by statistical multivariate analysis, strains carrying rmpA were significantly associated with the hypermucoviscosity phenotype, and there was a significant correlation with purulent tissue infections, such as liver abscess and lung, neck, psoas muscle, or other focal abscess. CONCLUSION: Our data support a statistical correlation between the rmpA gene and virulence in terms of abscess formation for these hypermucoviscous K. pneumoniae strains. Hypermucoviscosity associated with rmpA, together with a thorough physical examination, may be helpful as a guide to carry out appropriate diagnostic tests on patients with an initially unknown source of K. pneumoniae bacteremia, particularly when looking for the occurrence of an underlying abscess.

This study aimed to establish the psychometric properties of parent ratings on the Chinese version of the Swanson, Nolan, and Pelham IV scale (SNAP-IV) in a school-based sample of 3534 students in grades 1 to 8 from two cities and two suburbs in Taiwan and 189 children diagnosed with attention deficit/hyperactivity disorder (ADHD) (aged 6 to 15) consecutively recruited from a medical center in Taipei. Parents completed the Chinese versions of the SNAP-IV, Strengths and Difficulties Questionnaire, and Child Behavior Checklist. The Chinese SNAP-IV demonstrated similar three factor structure (Inattention, Hyperactivity/Impulsivity, and Oppositional) as its English version, and satisfactory test-retest reliability (intraclass correlation = 0.59 approximately 0.72), internal consistency (alpha = 0.88 approximately 0.90), concurrent validity (Pearson correlations = 0.56 approximately 0.72), and discriminant validity. Boys scored higher than girls across the eight school grade levels. The SNAP-IV clearly distinguished children with ADHD from school-based participants. Comorbidity with oppositional defiant disorder/conduct disorder predicted higher SNAP-IV scores among children with ADHD. Our findings suggest that the Chinese SNAP-IV is a reliable and valid instrument for rating ADHD-related symptoms in both clinical and community settings in Taiwan.

IL-10 is an immunosuppressive cytokine in the immune system. It was in clinical trial as an anti-inflammatory therapy for inflammatory bowel disease and various autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis. IL-19 belongs to the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiation-associated gene (MDA-7, IL-24), and AK155 (IL-26). Despite a partial homology in their amino acid sequences, they are dissimilar in their biologic functions. Little is known about the biologic function and gene regulation of IL-19. To understand the gene regulation of human IL-19, we identified a human IL-19 genomic clone and analyzed its promoter region. Five fusion genes containing different regions upstream of exon 1 linked to a luciferase reporter gene were expressed in the canine kidney epithelial-like Madin-Darby canine kidney cells. A fusion gene containing 394 bp showed luciferase activity 7- to 8-fold higher than the negative control of the promoterless fusion gene. We also isolated a full-length mouse cDNA clone. Mouse IL-19 shared 71% amino acid identity with human IL-19. Treatment of monocytes with mouse IL-19 induced the production of IL-6 and TNF-alpha. It also induced mouse monocyte apoptosis and the production of reactive oxygen species. Taken together, our results indicate that mouse IL-19 may play some important roles in inflammatory responses because it up-regulates IL-6 and TNF-alpha and induces apoptosis.

UNLABELLED: Lamivudine is effective to control hepatitis B virus (HBV) reactivation in HBV-carrying cancer patients who undergo chemotherapy, but the optimal treatment protocol remains undetermined. In this study, HBV carriers with newly diagnosed non-Hodgkin's lymphoma (NHL) who underwent chemotherapy were randomized to either prophylactic (P) or therapeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of the first course of chemotherapy and continued treatment until 2 months after completion of chemotherapy. Group T patients received chemotherapy alone and started lamivudine treatment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5-fold of the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation during the 12 months after starting chemotherapy. During chemotherapy, fewer group P patients had HBV reactivation (11.5% versus 56%, P = 0.001), HBV-related hepatitis (7.7% versus 48%, P = 0.001), or severe hepatitis (ALT more than 10-fold ULN) (0 versus 36%, P < 0.001). No hepatitis-related deaths occurred during protocol treatment. Prophylactic lamivudine use was the only independent predictor of HBV reactivation. After completion of chemotherapy, the incidence of HBV reactivation did not differ between the 2 groups. Two patients, both in group P, died of HBV reactivation-related hepatitis, 173 and 182 days, respectively, after completion of protocol treatment. When compared with an equivalent group of lamivudine-naïve lymphoma patients who underwent chemotherapy, therapeutic use of lamivudine neither reduced the severity of HBV-related hepatitis nor changed the patterns of HBV reactivation. CONCLUSION: Prophylactic lamivudine use, but not therapeutic use, reduces the incidence and severity of chemotherapy-related HBV reactivation in NHL patients.

Bone-marrow-derived human MSCs (mesenchymal stem cells) support repair when administered to animals with TBI (traumatic brain injury) in large part through secreted trophic factors. We directly tested the ability of the culture medium (or secretome) collected from human MSCs under normoxic or hypoxic conditions to protect neurons in a rat model of TBI. Concentrated conditioned medium from cultured human MSCs or control medium was infused through the tail vein of rats subjected to TBI. We have demonstrated that MSCs cultured in hypoxia were superior to those cultured in normoxia in inducing expression of both HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor) in the cultured medium. We showed further that rats treated with the secretome from both normoxic- and hypoxic-preconditioned MSCs performed significantly better than the controls in both motor and cognitive functional test. Subsequent post-mortem evaluation of brain damage at the 4-day time point confirmed that both normoxic- and hypoxic-preconditioned MSC secretome-treated rats had significantly greater numbers of newly forming neurons, but significantly less than the controls in brain damaged volume and apoptosis. The TBI rats treated with hypoxic-preconditioned MSC secretome performed significantly better in both motor and cognitive function tests and neurogenesis, and had significantly less brain damage than the TBI rats treated with the normoxic-preconditioned MSC secretome. Collectively, these findings suggest that MSCs secrete bioactive factors, including HGF and VEGF, that stimulate neurogenesis and improve outcomes of TBI in a rat model. Hypoxic preconditioning enhances the secretion of these bioactive factors from the MSCs and the therapeutic potential of the cultured MSC secretome in experimental TBI.

PURPOSE: To compare the accuracy of digital and conventional impression techniques for completely edentulous patients and to determine the effect of different variables on the accuracy outcomes. MATERIALS AND METHODS: A stone cast of an edentulous mandible with five implants was fabricated to serve as master cast (control) for both implant- and abutment-level impressions. Digital impressions (n = 10) were taken with an intraoral optical scanner (TRIOS, 3shape, Denmark) after connecting polymer scan bodies. For the conventional polyether impressions of the master cast, a splinted and a non-splinted technique were used for implant-level and abutment-level impressions (4 cast groups, n = 10 each). Master casts and conventional impression casts were digitized with an extraoral high-resolution scanner (IScan D103i, Imetric, Courgenay, Switzerland) to obtain digital volumes. Standard tessellation language (STL) datasets from the five groups of digital and conventional impressions were superimposed with the STL dataset from the master cast to assess the 3D (global) deviations. To compare the master cast with digital and conventional impressions at the implant level, analysis of variance (ANOVA) and Scheffe's post hoc test was used, while Wilcoxon's rank-sum test was used for testing the difference between abutment-level conventional impressions. RESULTS: Significant 3D deviations (P < 0.001) were found between Group II (non-splinted, implant level) and control. No significant differences were found between Groups I (splinted, implant level), III (digital, implant level), IV (splinted, abutment level), and V (non-splinted, abutment level) compared with the control. Implant angulation up to 15° did not affect the 3D accuracy of implant impressions (P > 0.001). CONCLUSION: Digital implant impressions are as accurate as conventional implant impressions. The splinted, implant-level impression technique is more accurate than the non-splinted one for completely edentulous patients, whereas there was no difference in the accuracy at the abutment level. The implant angulation up to 15° did not affect the accuracy of implant impressions.

To assess the species distribution and epidemiologic trends of nontuberculous mycobacteria, we examined isolates from patients in Taiwan. During 2000-2008, the proportion increased significantly from 32.3% to 49.8%. Associated disease incidence increased from 2.7 to 10.2 cases per 100,000 patients. Mycobacterium avium complex and M. abscessus were most frequently isolated.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

BACKGROUND/PURPOSE: Current studies on pediatric coronavirus disease 2019 (COVID-19) are rare. The clinical characteristics and spectrum are still unknown. Facing this unknown and emerging pathogen, we aimed to collect current evidence about COVID-19 in children. METHODS: We performed a systematic review in PubMed and Embase to find relevant case series. Because some reports were published in Chinese journals, the journals and publications of the Chinese Medical Association related to COVID-19 were completely reviewed. A random effects model was used to pool clinical data in the meta-analysis. RESULTS: Nine case series were included. In the pooled data, most of patients (75%) had a household contact history. The disease severity was mainly mild to moderate (98%). Only 2 children (2%) received intensive care. Fever occurred in 59% of the patients, while cough in 46%. Gastrointestinal symptoms (12%) were uncommon. There are 26% children are asymptomatic. The most common radiographic finding was ground glass opacities (48%). Currently, there is no evidence of vertical transmission to neonates born to mothers with COVID-19. Compared with the most relevant virus, SARS-CoV, SARS-CoV-2 causes less severe disease. CONCLUSION: COVID-19 has distinct features in children. The disease severity is mild. Current diagnosis is based mainly on typical ground glass opacities on chest CT, epidemiological suspicion and contact tracing.

Occupational noise-induced hearing loss (ONIHL) is the most prevalent occupational disease in the world. The goal of this study was to review the epidemiology, pathogenesis, and preventive measures of ONIHL among workers and provide evidence for the implementation of control measures. Literature studies were identified from the MEDLINE, PubMed, Embase, Web of Science, and Google Scholar using the search terms "noise-induced hearing loss" "prevalence", "pathogenesis", and "preventive measures". The articles reviewed in this report were limited from 2000 to 2020. Articles that were not published in the English language, manuscripts without an abstract, and opinion articles were excluded. After a preliminary screening, all of the articles were reviewed and synthesized to provide an overview of the current status of ONIHL among workers. The mechanism of ONIHL among workers is a complex interaction between environmental and host factors (both genetic and acquired factors). The outcomes of noise exposure are different among individual subjects. Clinical trials are currently underway to evaluate the treatment effect of antioxidants on ONIHL. Noise exposure may contribute to temporary or permanent threshold shifts; however, even temporary threshold shifts may predispose an individual to eventual permanent hearing loss. Noise prevention programs are an important preventive measure in reducing the morbidity of ONIHL among workers.

BACKGROUND: Klebsiella pneumoniae, a Gram-negative bacillus usually forming glistening mucoid colonies with viscid consistency on the culture plate, is a common pathogen causing various clinical infection patterns. However, little is known about the clinical implications of this mucoid character. OBJECTIVE: The purposes of this study, therefore, were to investigate the frequency of hypermucoviscosity (HV) in bacteraemic isolates of K. pneumoniae, and determine the significance of any association between HV and various clinical manifestations. DESIGN: Retrospective observational study. PATIENTS: Patients diagnosed with K. pneumoniae bacteraemia at a community-based university hospital between June 1999 and June 2001 were enrolled in this analysis. MEASUREMENTS: Clinical data concerning comorbid diseases and infection patterns was collected. K. pneumoniae bacteraemic isolates were examined for the presence of HV using a modified string test. The clinical impact of HV and risk factors for the invasive syndrome were assessed using statistical analysis. Polymerase chain reaction (PCR) was performed to detect magA, a gene related to HV phenotype. RESULTS: Overall, 200 (64.9%) of the 308 cases of K. pneumoniae bacteraemia were community-acquired infections. Compared with hospital-acquired K. pneumoniae bacteraemia (HA-KpB), community-acquired K. pneumoniae bacteraemia (CA-KpB) was more likely to be monomicrobial in nature (83.5% vs. 64.8%; P < 0.001) and caused by HV strains (41.5% vs. 14.8%; P < 0.001). The prevalence rate of magA among HV phenotypical K. pneumoniae strains was 24.1%. Patients infected with HV-positive strains were more likely to have the distinctive invasive syndrome (i.e. liver abscess, meningitis, pleural empyaema or endophthalmitis) than those infected with HV-negative variants (37.3% vs. 6.8%; P < 0.001). Multivariate logistic regression analysis, adjusted for age, showed that HV phenotype in K. pneumoniae strains (OR 8.86; 95% CI, 3.70-21.25; P < 0.001) was positively associated with the development of the invasive syndrome in CA-KpB cases. CONCLUSIONS: The HV phenotype of K. pneumoniae bacteraemic isolates was associated with the development of a distinctive invasive syndrome. Identification of the HV phenotype should prompt clinicians to initiate aggressive investigations for invasive diseases.

Long noncoding RNAs (lncRNAs) have been implicated in hypoxia/HIF-1-associated cancer progression through largely unknown mechanisms. Here we identify MIR31HG as a hypoxia-inducible lncRNA and therefore we name it LncHIFCAR (long noncoding HIF-1α co-activating RNA); we describe its oncogenic role as a HIF-1α co-activator that regulates the HIF-1 transcriptional network, crucial for cancer development. Extensive analyses of clinical data indicate LncHIFCAR level is substantially upregulated in oral carcinoma, significantly associated with poor clinical outcomes and representing an independent prognostic predictor. Overexpression of LncHIFCAR induces pseudo-hypoxic gene signature, whereas knockdown of LncHIFCAR impairs the hypoxia-induced HIF-1α transactivation, sphere-forming ability, metabolic shift and metastatic potential in vitro and in vivo. Mechanistically, LncHIFCAR forms a complex with HIF-1α via direct binding and facilitates the recruitment of HIF-1α and p300 cofactor to the target promoters. Our results uncover an lncRNA-mediated mechanism for HIF-1 activation and establish the clinical values of LncHIFCAR in prognosis and potential therapeutic strategy for oral carcinoma.