Low miR-10b-3p associated with sorafenib resistance in hepatocellular carcinoma.

BACKGROUND: Sorafenib is one of the standard first-line therapies for advanced hepatocellular carcinoma (HCC). Unfortunately, there are currently no appropriate biomarkers to predict the clinical efficacy of sorafenib in HCC patients. MicroRNAs (miRNAs) have been studied for their biological functions and clinical applications in human cancers. METHODS: In this study, we found that miR-10b-3p expression was suppressed in sorafenib-resistant HCC cell lines through miRNA microarray analysis. RESULTS: Sorafenib-induced apoptosis in HCC cells was significantly enhanced by miR-10b-3p overexpression and partially abrogated by miR-10b-3p depletion. Among 45 patients who received sorafenib for advanced HCC, those with high miR-10b-3p levels, compared to those with low levels, exhibited significantly longer overall survival (OS) (median, 13.9 vs. 3.5 months, p = 0.021), suggesting that high serum miR-10b-3p level in patients treated with sorafenib for advanced HCC serves as a biomarker for predicting sorafenib efficacy. Furthermore, we confirmed that cyclin E1, a known promoter of sorafenib resistance reported by our previous study, is the downstream target for miR-10b-3p in HCC cells. CONCLUSIONS: This study not only identified the molecular target for miR-10b-3p, but also provided evidence that circulating miR-10b-3p may be used as a biomarker for predicting sorafenib sensitivity in patients with HCC.

Combined hepatectomy and hepatic pedicle lymphadenectomy in colorectal liver metastases is justified.

BACKGROUND: The aim of this study was to describe the outcome of patients with colorectal liver metastases (CRLM) and radiological or clinical evidence of metastatic hepatic lymph node involvement who underwent combined hepatectomy and hepatic pedicle lymphadenectomy. METHODS: Retrospective analysis of a prospectively maintained audit of 2082 patients undergoing liver resection for CRLM between 1994 and 2014. Age, type of resection, CT/MRI/PET detection, location, disease recurrence and survival were analysed. RESULTS: Combined hepatectomy and hepatic pedicle lymphadenopathy was performed on 76 patients who met the inclusion criteria. 46% of enlarged lymph nodes were located in the hepatic ligament, with 38% retroportal, 38% common hepatic and 33% coeliac nodes. 50% of lymph node resections were positive for metastatic tumour. Pre-operative CT, MRI and CT/PET failed to detect histologically proven lymph node disease in 25/38 patients. Patients with negative nodal histology had a significant overall (44 vs 20 months, p = 0.008) and disease free (20 vs 11 months, p < 0.001) survival advantage. CONCLUSION: Combined hepatectomy and lymph node resection for CRLM in the setting of enlarged or suspicious lymphadenopathy is justified as imaging and operative findings are poor guides in determining positive lymph node disease.

Characterization and clinical course of 1000 patients with COVID-19 in New York: retrospective case series.

Objective: To characterize patients with coronavirus disease 2019 (COVID-19) in a large New York City (NYC) medical center and describe their clinical course across the emergency department (ED), inpatient wards, and intensive care units (ICUs). Design: Retrospective manual medical record review. Setting: NewYork-Presbyterian/Columbia University Irving Medical Center (NYP/CUIMC), a quaternary care academic medical center in NYC. Participants: The first 1000 consecutive patients with laboratory-confirmed COVID-19. Methods: We identified the first 1000 consecutive patients with a positive RT-SARS-CoV-2 PCR test who first presented to the ED or were hospitalized at NYP/CUIMC between March 1 and April 5, 2020. Patient data was manually abstracted from the electronic medical record. Main outcome measures: We describe patient characteristics including demographics, presenting symptoms, comorbidities on presentation, hospital course, time to intubation, complications, mortality, and disposition. Results: Among the first 1000 patients, 150 were ED patients, 614 were admitted without requiring ICU-level care, and 236 were admitted or transferred to the ICU. The most common presenting symptoms were cough (73.2%), fever (72.8%), and dyspnea (63.1%). Hospitalized patients, and ICU patients in particular, most commonly had baseline comorbidities including of hypertension, diabetes, and obesity. ICU patients were older, predominantly male (66.9%), and long lengths of stay (median 23 days; IQR 12 to 32 days); 78.0% developed AKI and 35.2% required dialysis. Notably, for patients who required mechanical ventilation, only 4.4% were first intubated more than 14 days after symptom onset. Time to intubation from symptom onset had a bimodal distribution, with modes at 3-4 and 9 days. As of April 30, 90 patients remained hospitalized and 211 had died in the hospital. Conclusions: Hospitalized patients with COVID-19 illness at this medical center faced significant morbidity and mortality, with high rates of AKI, dialysis, and a bimodal distribution in time to intubation from symptom onset.

Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.

OBJECTIVE: To characterize patients with coronavirus disease 2019 (covid-19) in a large New York City medical center and describe their clinical course across the emergency department, hospital wards, and intensive care units. DESIGN: Retrospective manual medical record review. SETTING: NewYork-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical center in New York City. PARTICIPANTS: The first 1000 consecutive patients with a positive result on the reverse transcriptase polymerase chain reaction assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented to the emergency department or were admitted to hospital between 1 March and 5 April 2020. Patient data were manually abstracted from electronic medical records. MAIN OUTCOME MEASURES: Characterization of patients, including demographics, presenting symptoms, comorbidities on presentation, hospital course, time to intubation, complications, mortality, and disposition. RESULTS: Of the first 1000 patients, 150 presented to the emergency department, 614 were admitted to hospital (not intensive care units), and 236 were admitted or transferred to intensive care units. The most common presenting symptoms were cough (732/1000), fever (728/1000), and dyspnea (631/1000). Patients in hospital, particularly those treated in intensive care units, often had baseline comorbidities including hypertension, diabetes, and obesity. Patients admitted to intensive care units were older, predominantly male (158/236, 66.9%), and had long lengths of stay (median 23 days, interquartile range 12-32 days); 78.0% (184/236) developed acute kidney injury and 35.2% (83/236) needed dialysis. Only 4.4% (6/136) of patients who required mechanical ventilation were first intubated more than 14 days after symptom onset. Time to intubation from symptom onset had a bimodal distribution, with modes at three to four days, and at nine days. As of 30 April, 90 patients remained in hospital and 211 had died in hospital. CONCLUSIONS: Patients admitted to hospital with covid-19 at this medical center faced major morbidity and mortality, with high rates of acute kidney injury and inpatient dialysis, prolonged intubations, and a bimodal distribution of time to intubation from symptom onset.

Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis.

De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways.

Late small bowel toxicity after aggressive abdominopelvic intensity modulated radiation therapy.

PURPOSE: We retrospectively analyzed late small bowel toxicity in patients who received abdominal or pelvic intensity modulated radiation therapy (IMRT) to the small bowel with a maximum dose greater than the generally accepted maximal tolerable dose of 45 Gy. METHODS AND MATERIALS: All patients (N = 94) who received IMRT with a point dose of at least 45 Gy to tightly contoured small bowel between 2005 and 2014 at our institution were included. The median prescribed treatment dose was 70.2 Gy. The median follow-up was 20.1 months. Late small bowel toxicity was assessed using the Common Terminology Criteria for Adverse Events Version 3.0. Dosimetric variables and clinical factors were assessed for their relationship to small bowel toxicity. RESULTS: The median maximal small bowel point dose (Dmax) was 6546.5 cGy. The estimated 5-year rates of freedom from at least grade 1, at least grade 2, and at least grade 3 late small bowel toxicity were 72.4% (95% confidence interval [CI], 60.7%-86.5%), 91.9% (95% CI, 84.1%-100%), and 93.6% (95% CI, 86.2%-100%), respectively. One patient (1.1%) developed grade 3 late toxicity, and 2 patients (2.1%) developed grade 4 late toxicity. Use of capecitabine/5-fluorouracil treatment was a significant predictor (P < 0.001) of at least grade 1 and at least grade 2 small bowel toxicity. No other clinical factors were associated with toxicity. None of the dose-volume parameters were significant predictors of small bowel toxicity. CONCLUSION: It may be possible with IMRT to deliver high doses to small volumes of small bowel with low rates of significant long-term complications. Further studies should explore tolerable dose-volume relationships in cases in which aggressive abdominal or pelvic treatment may be warranted to treat the underlying malignancy.

Fetal nutrition and muscle oxygen supply in childhood.

Fetal undernutrition may increase the risk of insulin resistance syndrome in adult life and low birth weight carries with it the risk of endothelial dysfunction. We studied 59 prepubertal and adolescent children whose birth weight exceeded 2.5 kg. We related their birth weight and ponderal index (PI) (weight/length(3)) at birth to muscle oxygen supply (assessed by near infrared spectroscopy [NIRS]) and to variables associated with increased risk of developing the insulin resistance syndrome (ie, abdominal subcutaneous and visceral fat volumes, percentage body fat, fasting leptin, insulin, and glucose levels). Birth weight was not associated with muscle oxygen supply or any other independent variable measured. In the prepubertal group, there was a significant inverse relation between PI and muscle reoxygenation half-time in both the male (R =.58, P =.03) and female (R =.72, P =.009) groups. This relationship was not present in either the male (R =.03, P =.90) or female (R =.09, P =.75) adolescent groups. In a population in which low birth weight subjects were excluded, low PI at birth is associated with poor muscle oxygen supply in early childhood, but this relationship is not present in adolescence.

Intramyocellular lipid, adiposity, and muscle oxygen supply in prepubertal type 1 diabetes.

BACKGROUND: In the non-diabetic population, intramyocellular lipid (IMCL) accumulation is associated with obesity and poor muscle oxygen supply. IMCL levels are increased in type 1 diabetes, but their significance is less clear. METHODS: We studied a group of 16 prepubertal boys (age 6.4-9.9 yr) with type 1 diabetes and a range of glycemic control [hemoglobin A1c (HbA1c) 6.4-10.2%]. Children's adiposity was assessed by anthropometry, muscle oxygen supply by near-infrared spectroscopy (NIRS), abdominal and IMCL content by magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS). RESULTS: IMCL content did not associate with muscle reoxygenation rate, abdominal adiposity, duration of diabetes, or recent glycemic control. Muscle reoxygenation rate correlated with percentage body fatness (r2 = 0.46, p = 0.004), visceral (r2 = 0.45, p = 0.007) and abdominal subcutaneous fat volume (r2 = 0.63, p = 0.0004), and dietary fat intake (r2 = 0.27, p = 0.03) but not with the duration of diabetes nor HbA1c. HbA1c was significantly related to dietary fat intake only (r2 = 0.28, p = 0.03). CONCLUSION: While causality cannot be inferred, interventions aimed at improving muscle oxygen supply, or preventing its deterioration, might reduce the development of adiposity in children with type 1 diabetes.