Socio-economic factors and medical conditions affecting regular stomach cancer screening in Korea: a retrospective longitudinal study using national public health data for 11 years.

OBJECTIVE: This study aimed to explore socio-economic factors and medical conditions that affect regular stomach cancer (SC) screening among Korean adults. STUDY DESIGN: This was a retrospective observational study. METHODS: Study subjects were 5545 adults aged ≥40 years who participated in the 2007-2012 Korean National Health and Nutrition Examination Survey and were followed up to year 2017 based on data linking to the Korean National Health Insurance Service and Korean Health Insurance Review and Assessment. Socio-economic factors included sex, age, residential area, education, occupation, marital status, disability, public and private health insurance, service through local public health organizations, history of cancer except for SC, and family history of SC. Medical factors included six gastric lesions with the possibility of facilitating SC screening, including benign gastric neoplasm, chronic atrophic gastritis, gastric polyp, Helicobacter pylori infection, intestinal metaplasia, and peptic ulcers. The outcome was adherence to SC screening, which was divided into non-adherence, irregular adherence, and regular adherence. RESULTS: After adjusting for the effects of socio-economic factors, multivariate ordinal logistic regression revealed that participants with a history of four types of gastric lesions were more likely to regularly participate in SC screening: chronic atrophic gastritis (odds ratio [OR] 1.567; 95% confidence interval [CI] = 1.276-1.923), gastric polyps (OR 1.565; 95% CI = 1.223-2.003), H. pylori infection (OR 1.637; 95% CI = 1.338-2.003), and peptic ulcer (OR 2.226; 95% CI 1.750-2.831). CONCLUSIONS: To improve participation in SC screening, it is necessary to implement personalized strategies for individuals at risk for gastric cancer in addition to population-based strategies for vulnerable groups.

Food for all? Wildfire ash fuels growth of diverse eukaryotic plankton.

In December 2017, one of the largest wildfires in California history, the Thomas Fire, created a large smoke and ash plume that extended over the northeastern Pacific Ocean. Here, we explore the impact of Thomas Fire ash deposition on seawater chemistry and the growth and composition of natural microbial communities. Experiments conducted in coastal California waters during the Thomas Fire revealed that leaching of ash in seawater resulted in significant additions of dissolved nutrients including inorganic nitrogen (nitrate, nitrite and ammonium), silicic acid, metals (iron, nickel, cobalt and copper), organic nitrogen and organic carbon. After exposure to ash leachate at high (0.25 g ash l-1) and low (0.08 g ash l-1) concentrations for 4 days, natural microbial communities had 59-154% higher particulate organic carbon concentrations than communities without ash leachate additions. Additionally, a diverse assemblage of eukaryotic microbes (protists) responded to the ash leachate with taxa from 11 different taxonomic divisions increasing in relative abundance compared with control treatments. Our results suggest that large fire events can be important atmospheric sources of nutrients (particularly nitrogen) to coastal marine systems, where, through leaching of various nutrients, ash may act as a 'food for all' in protist communities.

Hemorrhagic morbidity in nulliparous patients with placenta previa without placenta accrete spectrum disorders.

Background: Placental adhesion spectrum (PAS) is a disease in which the trophoblast invades the myometrium, and is a well-known high-risk condition associated with placental previa. Aim: The morbidity of nulliparous women with placenta previa without PAS disorders is unknown. Patients and Methods: The data from nulliparous women who underwent cesarean delivery were collected retrospectively. The women were dichotomized into malpresentation (MP) and placenta previa groups. The placenta previa group was categorized into previa (PS) and low-lying (LL) groups. When the placenta covers the internal cervical os, it is called placenta previa, when the placenta is near the cervical os, it is called the low-lying placenta. Their maternal hemorrhagic morbidity and neonatal outcomes were analyzed and adjusted using multivariate analysis based on univariate analysis. Results: A total of 1269 women were enrolled: 781 women in the MP group and 488 women in the PP-LL group. Regarding packed red blood cell transfusion, PP and LL had adjusted odds ratio (aOR) of 14.7 (95% confidence interval (CI): 6.6 - 32.5), and 11.3 (95% CI: 4.9 - 26) during admission, and 51.2 (95% CI: 22.1 - 122.7) and 10.3 (95% CI: 3.9 - 26.6) during operation, respectively. For intensive care unit admission, PS and LL had aOR of 15.9 (95% CI: 6.5 - 39.1) and 3.5 (95% CI: 1.1 - 10.9), respectively. No women had cesarean hysterectomy, major surgical complications, or maternal death. Conclusion: Despite placenta previa without PAS disorders, maternal hemorrhagic morbidity was significantly increased. Thus, our results highlight the need for resources for those women with evidence of placenta previa including a low-lying placenta, even if those women do not meet PAS disorder criteria. In addition, placenta previa without PAS disorder was not associated with critical maternal complications.

All-cause mortality, cardiovascular mortality, and incidence of cardiovascular disease according to a screening program of cardiovascular risk in South Korea among young adults: a nationwide cohort study.

OBJECTIVES: We aimed to determine whether there are any differences in all-cause and cause-specific mortality with cardiovascular disease (CVD) risk between health screening attenders and non-attenders among young adults. STUDY DESIGN: We performed a retrospective cohort study using claim data from the Korean National Health Insurance Service database. METHODS: Individuals aged 20-39 years who had received health screening at least once between 2002 and 2005 were classified as attenders, and the others were classified as non-attenders. After propensity score matching according to attendance of health screening, 2,060,409 attenders and 2,060,409 non-attenders were included. We estimated adjusted hazard ratios (HRs) and 95% confidence interval (CI) for all-cause mortality, cause-specific mortality, and hospitalization of CVD from 2006 to 2015. RESULTS: Survival from all-cause mortality was greater among attenders than among non-attenders (log rank P < 0.001). Similarly, death from CVD (log rank P = 0.007) and CVD events (log rank P < 0.001) were less likely among attenders. The risk for all-cause mortality in attenders was significantly lower than that in non-attenders (HR = 0.83, 95% CI = 0.81 to 0.84). The risk for CVD mortality (HR = 0.80, 95% CI = 0.73 to 0.87) and hospitalization of CVD (HR = 0.92, 95% CI = 0.91 to 0.94) were lower in attenders. In stratified analyses, the risk for all-cause and cause-specific mortalities was lower among attenders regardless of insurance type. CONCLUSIONS: Among young adults, the risk for all-cause mortality, CVD mortality, and hospitalization of CVD were lower for those who underwent health screenings. Future studies that evaluate the cost-effectiveness of health screening with additional consideration of psychosocial aspects are needed.

Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): a multicentre, open-label randomised trial and meta-analysis.

OBJECTIVE: To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature. DESIGN: A multicentre, randomised, open-label, equivalence trial and a meta-analysis. SETTING: Tertiary referral hospitals in South Korea. POPULATION: Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm). METHODS: Eligible women were screened and randomised at 16-22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α-hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237). MAIN OUTCOME MEASURE: Preterm birth (PTB) before 37 weeks of gestation. RESULTS: A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention-to-treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI -7.6 to 13.8%), which was within the equivalence margin of 15%. The meta-analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments. CONCLUSION: Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length. TWEETABLE ABSTRACT: Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.

Survival of oral mucosal melanoma according to treatment, tumour resection margin, and metastases.

Because of the poor prognosis and of oral mucosal melanoma, and patients' short survival, large, randomised, clinical studies are difficult. We have investigated its demographic characteristics and analysed the effect of treatment, resection margins, and metastases on survival. We recorded age, sex, site of primary tumour, and types of treatment, survival, and metastases in 74 patients treated at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital. Survival was analysed based on bony invasion, depth of invasion, and resection margins, and we found that it varied depending on the primary site (p=0.002), and declined with liver (p=0.001) or brain (p=0.033) metastases. The two-year survival according to the primary site was as follows: palate 85% (n=32), anterior maxillary gingiva 53% (n=13), mandible 58% (n=13), and posterior maxillary gingival 74% (n=10) and buccal mucosa 50% (n=4). The two-year survival was 34% (n=8) in patients with liver metastases and 23% (n=7) in patients with brain metastases. In cases of bony invasion (p=0.005), depth of invasion (p=0.042), unclear resection margin (p=0.023), or higher T stages (p=0.009), the survival declined considerably. Neck dissection did not affect survival (p=0.343). Survival of the patients given chemotherapy was significantly lower (p=0.013) and the two-year survival was 54.0%. The patients given radiotherapy showed no significant difference in survival compared with those not given radiotherapy (p=0.107). In conclusion, primary site, bony invasion, resection margins, depth of invasion and systemic metastases were critical to predict prognosis and selection of treatment of oral mucosal melanoma.

Multiple splenic infarctions in a dog with immune-mediated hemolytic anemia: therapeutic implications.

BACKGROUND: Splenic infarction (SI) is a rare clinical entity seldom encountered in veterinary medicine. Its most frequent causes include thromboembolic status, splenomegaly, and cardiac disease. Although thrombotic elements from the circulation provide the most common context for thromboembolic SIs, immune-mediated hemolytic anemia (IMHA) has not been reported as an underlying disease in canine SI. CASE DESCRIPTION: A 2-year-old, female spayed Dachshund, was referred with vomiting, hematochezia, and brown colored urine over the preceding 4 days. Physical examination revealed abnormalities including generalized weakness, jaundice, and splenomegaly; blood work showed pancytopenia and hyperbilirubinemia. Erythrocyte agglutination, polychromasia, and spherocytes on a peripheral blood smear were observed and IMHA concurrent with thrombocytopenia was diagnosed. FINDINGS/TREATMENT AND OUTCOME: Although erythrocyte agglutination and leukopenia disappeared after treatment, anemia and thrombocytopenia were unresponsive to oral immunosuppressive drugs and repeated transfusions. Further abdominal ultrasound identified an occlusive splenic vein thrombus. Splenic histopathology found marked multifocal to coalescing necrosis, and hemorrhage consistent with multiple SI. Symptoms resolved following splenectomy combined with 1 month of immunosuppressive medication, and the dog was healthy on follow-up evaluation after 2 years. CONCLUSION: Immune-mediated hemolytic anemia is an incompletely characterized cause of SI. This report establishes a potential and novel causal role for IMHA in canine SI. We believe it to be the first case report of SI in a dog with refractory IMHA and thrombocytopenia, successfully managed by splenectomy combined with short-term immunosuppressive therapy.

Three-percent sucrose acts as a thermostabilizer for cell-adapted foot-and-mouth disease virus without any negative effect on viral growth.

AIMS: As cell-adapted foot-and-mouth disease virus (FMDV) with H56R mutation in VP3 has reduced thermostability, this study aimed to investigate the effect of thermostabilizers on cell-adapted FMDV for vaccine production. METHODS AND RESULTS: We examined the effect of 3% sucrose, 10% (or 25%) glycerol or 10% FBS on cell-adapted FMDV O/SKR/JC/2014, containing H56R mutation in VP3, as vaccine seed virus at -80, 4, 25 or 37°C for 2, 4 or 7 days. The stabilizing effect of 3% sucrose on O/SKR/JC/2014 was observed at 25, 37°C, and after repeated freeze-thaw cycles. Additionally, we tested the effect of 3% sucrose on the growth of FMDV or cells and did not observe any decrease in either viral growth or cell viability. CONCLUSIONS: Our study showed the protective effect of 3% sucrose on FMDV infectivity at various temperatures; this virus stock in 3% sucrose could be used for infecting cells without the removal of sucrose. SIGNIFICANCE AND IMPACT OF THE STUDY: We suggest that 3% sucrose-containing medium could be beneficial for the stable storage and transport of cell-adapted FMDV.

Analysis of Damage and Wound Healing in the Retinal Pigmented Epithelium.

Previous studies of retinal pigment epithelium (RPE) morphology found cell-level and spatial patterning differences in many quantitative metrics in comparing normal and disease conditions. However, most of these studies examined eyes from deceased animals. Here we sought to compare noninvasively imaged RPE cells from live mice to histopathology. We describe changes to improve noninvasive imaging of RPE in the live mouse. In retinal diseases, there can be invasion by Iba1-positive cells, which can be detected by noninvasive imaging techniques. Here we can detect potential Iba1-positive cells at the level of the RPE noninvasively.

Salvage of failed osteosynthesis for an atypical subtrochanteric femoral fracture associated with long-term bisphosphonate treatment using a 95° angled blade plate.

AIMS: The aim of this study was to evaluate the outcomes of a salvage procedure using a 95° angled blade plate for failed osteosynthesis of atypical subtrochanteric femoral fractures associated with the long-term use of bisphosphonates. These were compared with those for failed osteosynthesis of subtrochanteric fractures not associated with bisphosphonate treatment. PATIENTS AND METHODS: Between October 2008 and July 2016, 14 patients with failed osteosynthesis of an atypical subtrochanteric femoral fracture were treated with a blade plate (atypical group). Their mean age was 67.8 years (60 to 74); all were female. During the same period, 21 patients with failed osteosynthesis of a typical subtrochanteric fracture underwent restabilization using a blade plate (typical group). Outcome variables included the time of union, postoperative complications, Harris Hip Score, and Sanders functional rating scale. RESULTS: In the atypical group, union was achieved in 12 patients (85.7%) at a mean of 8.4 months (4 to 12). The mean follow-up was 31.2 months (12 to 92) The plate broke in one patient requiring further stabilization with a longer plate and strut-allograft. Another patient with failure of fixation and varus angulation at the fracture site declined further surgery. In the typical group, union was achieved in 18 patients (85.7%) at a mean of 7.9 months (4 to 12). There was no difference in the mean Harris Hip Score between the two groups (83.1 points vs 86.8 points; p = 0.522) at the time of final follow-up. Sanders functional rating scores were good or excellent in 78.6% of the atypical group and in 81.0% of the typical group. CONCLUSION: The 95° angled blade plate was shown to be an effective fixation modality for nonunion of atypical subtrochanteric fractures with a high rate of union and functional improvement, comparable to those after fractures not associated with bisphosphonate treatment. Cite this article: Bone Joint J 2018;100-B:1511-17.

Clinical and laboratory features of patients with osteomalacia initially presenting with neurological manifestations.

Patients with osteomalacia often visit the neurology department with conditions mimicking other myopathies. We analyzed clinical features of osteomalacia patients who visited the neurology department. These patients frequently presented with hypocalcemia, hypovitaminosis D, and pain with less severe weakness. Osteomalacia should be considered when patients present with pain and weakness. INTRODUCTION: Osteomalacia is a disease of bone metabolism; however, some patients with osteomalacia initially visit the neurology department. As these patients often complain of weakness and gait disturbance, osteomalacia can be confused with other myopathies. We analyzed the clinical features of patients with osteomalacia who visited the neurology department. METHODS: We retrospectively reviewed the medical records. Osteomalacia was diagnosed based on symptoms, laboratory features, and imaging results. We compared the characteristics of patients with osteomalacia who visited the neurology department with (1) those who did not visit the neurology department and (2) patients with idiopathic inflammatory myopathy. RESULTS: Eighteen patients with osteomalacia visited the neurology department (NR group). The common etiologies in the NR group included tumors or antiepileptic medication, whereas antiviral medication was the most common in patients who did not visit the neurology department (non-NR group). The NR group showed lower serum calcium (p = 0.004) and 25-hydroxyvitamin D (p = 0.006) levels than the non-NR group. When compared with patients with inflammatory myopathy, both groups showed proximal dominant weakness. However, pain was more common in osteomalacia than in myopathy (p = 0.008), and patients with osteomalacia showed brisk deep tendon reflex more often (p = 0.017). Serum calcium (p = 0.003) and phosphate (p < 0.001) levels were lower in osteomalacia than in myopathy. CONCLUSIONS: It was not uncommon for patients with osteomalacia to visit the neurology department. The clinical presentation of these patients can be more complex owing the superimposed neurological disease and accompanying hypocalcemia. Osteomalacia should be considered when patients present with pain and weakness.

Lysophosphatidylserine receptor P2Y10: A G protein-coupled receptor that mediates eosinophil degranulation.

BACKGROUND: P2Y10, along with GPR34 and GPR174, is a G protein-coupled receptor that is activated by an endogenous lipid mediator lysophosphatidylserine (LysoPS). Its expression pattern and its function are completely unknown. We have previously shown that P2Y10 is one of the highly up-regulated genes at the late differentiation stage during in vitro eosinophilopoiesis. OBJECTIVE: We explored the expression and functions of P2Y10 in human cord blood (CB)-derived and peripheral blood (PB) eosinophils. METHODS: Real-time PCR, FACS, Western blot, ELISA, and chemotaxis assays were performed to determine the expression and function of P2Y10. RESULTS: As CB cells differentiated towards eosinophils, P2Y10 mRNA and protein were abundantly expressed. P2Y10 was the most highly expressed in the granulocytes from PB, to a lesser extent in monocytes, and least in lymphocytes. Further fractionation of granulocytes revealed that eosinophils express P2Y10 much more strongly than do neutrophils. PB eosinophils solely expressed P2Y10 among the three LysoPS receptors, while PB neutrophils expressed the three at comparable levels. LysoPS activated both CB and PB eosinophils to induce a robust ERK phosphorylation. Importantly, LysoPS was capable of triggering degranulation of ECP in PB eosinophils. This response was significantly reduced by pharmacological inhibitors of TNF-alpha-converting enzyme (TACE), epidermal growth factor receptor (EGFR), and ERK1/2, which were known to be required in P2Y10-mediated signalling pathways. However, LysoPS had no effect on chemotaxis, differentiation, or eosinophil survival. CONCLUSIONS AND CLINICAL RELEVANCE: LysoPS provokes eosinophil degranulation through P2Y10. Therefore, P2Y10 is a potential therapeutic target to control eosinophil-associated diseases.

Severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) virus has a variety of central nervous system (CNS) manifestations. However, there are limited data regarding SFTS-associated encephalopathy/encephalitis (SFTSAE) and its mechanism. METHODS: All patients with confirmed SFTS who underwent cerebrospinal fluid (CSF) examination due to suspected acute encephalopathy were enrolled in three referral hospitals between January 2013 and October 2016. Real-time RT-PCR for SFTS virus and chemokine/cytokines levels from blood and CSF were analysed. RESULTS: Of 41 patients with confirmed SFTS by RT-PCR for SFTS virus using blood samples, 14 (34%) underwent CSF examination due to suspected SFTSAE. All 14 patients with SFTSE revealed normal protein and glucose levels in CSF, and CSF pleocytosis was uncommon (29%, 4/14). Of the eight patients whose CSF was available for further analysis, six (75%) yielded positive results for SFTS virus. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) level in CSF were significantly higher than those in serum (geometric mean 1889 pg/mL in CSF versus 264 pg/mL in serum for MCP-1, p = 0.01, and geometric mean 340 pg/mL in CSF versus 71 pg/mL in serum for IL-8, p = 0.004). CONCLUSIONS: The CNS manifestation of SFTS as acute encephalopathy/encephalitis is a common complication of SFTS. Although meningeal inflammation was infrequent in patients with SFTSAE, SFTS virus was frequently detected in CSF with elevated MCP-1 and IL-8. These findings indicate that possible direct invasion of the CNS by SFTS virus with the associated elevated cytokine levels in CSF may play an important role in the pathogenesis of SFTSAE.

Comparison of body surface area-based and weight-based dosing format for oral prednisolone administration in small and large-breed dogs.

This study compared the pharmacokinetics of Prednisolone (PDS) in small- and large breed dogs with a dosing format based on body surface area (BSA) or body weight (BW). The maximum concentration and area under the curve in large-breed dogs orally administered 2 mg/kg PDS were significantly greater than those in small-breed dogs given 2 mg/kg and in large-breed dogs given 40 mg/m2. The higher blood concentrations that result from BW-based dosing of oral PDS in large-breed dogs can be more than required for effect. Meanwhile, BSA dosing at 40 mg/m may be suboptimal. These findings confirm important differences between standard PDS dosing schemes in dogs while highlighting the need to further optimize PDS dosing in large-breed dogs.

Molecular epidemiology and environmental contamination during an outbreak of parainfluenza virus 3 in a haematology ward.

BACKGROUND: Although fomites or contaminated surfaces have been considered as transmission routes, the role of environmental contamination by human parainfluenza virus type 3 (hPIV-3) in healthcare settings is not established. AIM: To describe an hPIV-3 nosocomial outbreak and the results of environmental sampling to elucidate the source of nosocomial transmission and the role of environmental contamination. METHODS: During an hPIV-3 outbreak between May and June 2016, environmental surfaces in contact with clustered patients were swabbed and respiratory specimens used from infected patients and epidemiologically unlinked controls. The epidemiologic relatedness of hPIV-3 strains was investigated by sequencing of the haemagglutinin-neuraminidase and fusion protein genes. FINDINGS: Of 19 hPIV-3-infected patients, eight were haematopoietic stem cell recipients and one was a healthcare worker. In addition, four had upper and 12 had lower respiratory tract infections. Of the 19 patients, six (32%) were community-onset infections (symptom onset within <7 days of hospitalization) and 13 (68%) were hospital-onset infections (≥7 days of hospitalization). Phylogenetic analysis identified two major clusters: five patients, and three patients plus one healthcare worker. Therefore, seven (37%) were classified as nosocomial transmissions. hPIV-3 was detected in 21 (43%) of 49 environmental swabs up to 12 days after negative respiratory polymerase chain reaction conversion. CONCLUSION: At least one-third of a peak season nosocomial hPIV-3 outbreak originated from nosocomial transmission, with multiple importations of hPIV-3 from the community, providing experimental evidence for extensive environmental hPIV-3 contamination. Direct contact with the contaminated surfaces and fomites or indirect transmission from infected healthcare workers could be responsible for nosocomial transmission.

Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis.

The cellular prion protein (PrPC) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrPC degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrPC accumulation and tumorigenicity in vivo. PrPC was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrPC. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrPC, thereby increasing PrPC ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrPC, thereby revealing an essential mechanism that controls PrPC levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrPC accumulation during tumor progression.

Benefits of Intraoperative Continuous Renal Replacement Therapy During Liver Transplantation in Patients With Renal Dysfunction.

BACKGROUND: Comparative outcomes of continuous renal replacement therapy during liver transplantation have not been investigated. We retrospectively compared the outcomes of intraoperative continuous renal replacement therapy with those of non-dialytic conservative treatment in patients with pretransplant renal dysfunction. METHODS: We analyzed 240 transplantation patients with preoperative renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2). RESULTS: Compared with the non-dialytic conservative treatment group (n = 98), the intraoperative continuous renal replacement therapy group (n = 142) experienced more severe critical illness (as indicated by Model for End-Stage Liver Disease score) and more severe preoperative renal dysfunction, as well as more frequent hepatic encephalopathy, ventilatory care, and intensive care unit admission (P < .005). There were also worse outcomes regarding patient survival, graft survival, recovery of renal function, and postoperative complications. However, the intraoperative continuous renal replacement therapy group significantly escaped volume overload (adjusted odds ratio, 0.396; 95% confidence interval, 0.223-0.703; P = .002) and unnecessary changes in serum sodium concentration ≥10 mmol/L during surgery (adjusted odds ratio, 0.208; 95% confidence interval, 0.065-0.665; P = .008). CONCLUSIONS: Considering the more severe critical illness of the intraoperative continuous renal replacement therapy group but the low frequency of volume overload and serum sodium fluctuation, intraoperative continuous renal replacement therapy could be useful during liver transplantation in critically ill patients with renal dysfunction. Randomized, controlled studies that could demonstrate outcome benefits and indications of intraoperative continuous renal replacement therapy during liver transplantation are needed.

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

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

Polycystic ovary syndrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with polycystic ovary syndrome (PCOS). However, most studies investigated the prevalence of NAFLD in obese PCOS patients. AIM: To compare the prevalence of non-obese NAFLD in women with or without PCOS, and to assess an independent association between PCOS and NAFLD in a non-obese Asian cohort. METHODS: This was a case-control study using a prospective PCOS cohort. After subjects with other potential causes of chronic liver disease were excluded, 275 non-obese women with PCOS and 892 non-obese controls were enrolled. NAFLD was determined by hepatic ultrasonography. Main outcomes were the prevalence of NAFLD on hepatic ultrasonography between non-obese women with or without PCOS, and an independent association between non-obese NAFLD and PCOS. RESULTS: Non-obese women with PCOS had a significantly higher prevalence of NAFLD than those without PCOS (5.5% vs. 2.8%, P = 0.027). PCOS was associated with non-obese NAFLD (odds ratio: 2.62, 95% confidence intervals: 1.25-5.48) after adjustment for age and body mass index (BMI). In women with PCOS, the level of androgenicity represented by free testosterone or free androgen index was associated with NAFLD after adjustment for age, BMI, lipid profile, insulin resistance or glycaemic status. CONCLUSIONS: Non-obese NAFLD is more prevalent in women with polycystic ovary syndrome than in those without. In non-obese patients with polycystic ovary syndrome, hyperandrogenemia may be an independent risk factor for non-obese NAFLD.

Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition.

Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.