Changes in thoracic radio density after living donor liver transplantation.

BACKGROUND: The outcomes after liver transplantation have greatly improved, which has resulted in greater focus on improving non-hepatic outcomes of liver transplantation. The present study aimed to evaluate thoracic spine radio density in children and adolescents after liver transplantation. METHODS: A total of 116 patients who underwent living donor liver transplantation were retrospectively analyzed. The radio density at the eleventh thoracic vertebra was measured using computed tomography scan performed preoperatively then annually for 5 years postoperatively and subsequently every 2 or 3 years. RESULTS: The mean thoracic radio density of male recipients of male grafts had the lowest values during the study. The radio density of patients receiving a graft from a female donor was higher than in recipients with grafts from males. Total mean radio density decreased for first 5 years postoperatively and then increased. Changes in radio density were equally distributed in both steroid withdrawal and no steroid withdrawal groups for 5 years, after which patients with steroid withdrawal had a greater increase. Changes in radio density were equally distributed in both the steroid withdrawal and no steroid withdrawal groups up to age 20, after which patients in the steroid withdrawal group had a greater increase. CONCLUSIONS: Gender differences may affect the outcome of radio density changes after transplantation. Given the moderate association between thoracic radio density and bone mineral density in skeletally mature adults and further studies are needed to validate this relationship between thoracic radio density and bone mineral density changes in pediatric liver transplantation.

Successful living donor liver transplantation for liver failure due to maternal T cell engraftment following cord blood transplantation in X-linked severe combined immunodeficiency disease: Case report.

Maternal T cells from perinatal transplacental passage have been identified in up to 40% of patients with severe combined immunodeficiency (SCID). Although engrafted maternal T cells sometimes injure newborn tissue, liver failure due to maternal T cells has not been reported. We rescued a boy with X-linked SCID who developed liver failure due to engrafted maternal T cell invasion following living donor liver transplantation (LDLT) following unrelated umbilical cord blood transplantation (UCBT). After developing respiratory failure 3 weeks postpartum, he was diagnosed with X-linked SCID. Pathological findings showed maternal T cells engrafted in his liver and hepatic fibrosis gradually progressed. He underwent UCBT at 6 months, but hepatic function did not recover and liver failure progressed. Therefore, he underwent LDLT using an S2 monosegment graft at age 1.3 years. The patient had a leak at the Roux-en-Y anastomosis, which was repaired. Despite occasional episodes of pneumonia and otitis media, he is generally doing well 6 years after LDLT with continued immunosuppression agents. In conclusion, the combination of hematopoietic stem cell transplantation (HSCT) and liver transplantation may be efficacious, and HSCT should precede liver transplantation for children with X-linked SCID and liver failure.

High and low estimated glomerular filtration rates are associated with adverse outcomes in patients undergoing surgery for gastrointestinal malignancies.

BACKGROUND: Abnormally high estimated glomerular filtration rates (eGFRs) are associated with endothelial dysfunction and frailty. Previous studies have shown that low eGFR is associated with increased morbidity, but few reports address high eGFR. The purpose of this study is to evaluate the association of high eGFR with surgical outcomes in patients undergoing surgery for gastrointestinal malignancies. METHODS: We identified patients who underwent elective surgery for gastrointestinal malignancies from 2005 to 2015 in the American College of Surgeons National Surgical Quality Improvement Program database. We evaluated associations of eGFR with surgical outcomes by Cox or logistic models with restricted cubic spline functions, adjusting for case mix variables (i.e. age, gender, race and diabetes). RESULTS: The median eGFR is 83 (interquartile range 67-96) mL/min/1.73 m2. Thirty-day mortality was 1.9% (2555/136 896). There is a U-shaped relationship between eGFR and 30-day mortality. The adjusted hazard ratios (95% confidence intervals) for eGFRs of 30, 60, 105 and 120 mL/min/1.73 m2 (versus 90 mL/min/1.73 m2) are 1.73 (1.52-1.97), 1.00 (0.89-1.11), 1.42 (1.31-1.55) and 2.20 (1.79-2.70), respectively. Similar associations are shown for other surgical outcomes, including return to the operating room and postoperative pneumonia. Subgroup analyses show that eGFRs both higher and lower than the respective medians are consistently associated with a higher risk of adverse outcomes across age, gender and race. CONCLUSIONS: High and low eGFRs are associated with more adverse surgical outcomes in patients undergoing surgery for gastrointestinal malignancies. The eGFR associated with the lowest postoperative risk is approximately at the median eGFR of a given population.

Large Volume Fluid Resuscitation for Severe Acute Pancreatitis is Associated With Reduced Mortality: A Multicenter Retrospective Study.

BACKGROUND AND AIMS: Although fluid resuscitation is critical in acute pancreatitis, the optimal fluid volume is unknown. The aim of this study is to evaluate the association between the volume of fluid administered and clinical outcomes in patients with severe acute pancreatitis (SAP). METHODS: We conducted a multicenter retrospective study at 44 institutions in Japan. Inclusion criteria were age 18 years or older, and diagnosed with SAP from 2009 to 2013. Patients were stratified into 2 groups: administered fluid volume <6000 and ≥6000 mL in the first 24 hours. We evaluated the association between the 2 groups and clinical outcomes using multivariable logistic regression analysis. The primary outcome was in-hospital mortality. Secondary outcomes included the incidence of pancreatic infection and the need for surgical intervention. RESULTS: We analyzed 1097 patients, and the mean fluid volume administered was 5618±3018 mL (mean±SD), with 708 and 389 patients stratified into the fluid <6000 mL and fluid ≥6000 mL groups, respectively. Overall in-hospital mortality was 12.3%. The fluid ≥6000 mL group had significantly higher mortality than the fluid <6000 mL group (univariable analysis, 15.9% vs. 10.3%; P<0.05). In multivariable logistic regression analysis, administration of ≥6000 mL of fluid within the first 24 hours was significantly associated with reduced mortality (odds ratio, 0.58; P<0.05). No significant association was found between the administered fluid volume and pancreatic infection, or between the volume administered and the need for surgical intervention. CONCLUSIONS: In patients with SAP, administration of a large fluid volume within the first 24 hours is associated with decreased mortality.

Suvorexant is associated with a low incidence of delirium in critically ill patients: a retrospective cohort study.

BACKGROUND: Benzodiazepine use is a risk factor for the development of delirium in adult intensive care unit (ICU) patients. Suvorexant is an alternative to benzodiazepines to induce sleep, but the incidence of delirium in critically ill patients is unknown. We undertook this retrospective study to investigate the incidence of delirium in patients who receive suvorexant in the ICU. METHODS: This retrospective cohort study was conducted in a closed 12-bed ICU at a tertiary teaching hospital. Patients admitted to the ICU for 72 h or longer between January and June 2015 were evaluated for delirium using the Confusion Assessment Method for the Intensive Care Unit tool. We evaluated the incidence of delirium in patients who received suvorexant and those who did not. To adjust for confounding factors, multivariable logistic regression analysis was conducted. RESULTS: Study subjects included 118 patients, with a median age of 72 years and a median Acute Physiology and Chronic Health Evaluation II score of 18 points. Eighty-two patients (69.5%) were admitted after cardiovascular surgery. In the suvorexant group, there were fewer post-cardiovascular surgical patients and more medical patients. The duration of mechanical ventilation during ICU stay was longer in the suvorexant group, and sedatives and sleep inducers other than suvorexant were used more frequently in the suvorexant group. The incidence of delirium was 43.8% in the suvorexant group and 58.8% in the non-suvorexant group (P = 0.149). After adjustment for risk factors using multivariable logistic regression analysis, suvorexant was associated with a lower incidence of delirium (odds ratio = 0.23, 95% confidence interval: 0.07-0.73; P = 0.012). CONCLUSIONS: Suvorexant was associated with decreased odds of transitioning to delirium in critically ill patients. The use of suvorexant may lower the incidence of delirium in ICU patients. Future prospective studies are warranted.

Risks and Benefits of Stress Ulcer Prophylaxis for Patients With Severe Sepsis.

OBJECTIVES: The Surviving Sepsis Campaign Guidelines recommend stress ulcer prophylaxis for patients with severe sepsis who have bleeding risks. Although sepsis has been considered as a risk factor for gastrointestinal bleeding, the effect of stress ulcer prophylaxis has not been studied in patients with severe sepsis. Furthermore, stress ulcer prophylaxis may be associated with an increased risk of hospital-acquired pneumonia or Clostridium difficile infection. The aim of this study was to investigate the risks and benefits of stress ulcer prophylaxis for patients with severe sepsis. DESIGN: Retrospective cohort study. SETTING: Five hundred twenty-six acute care hospitals in Japan. PATIENTS: A total of 70,862 patients with severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-to-one propensity score matching created 15,651 pairs of patients who received stress ulcer prophylaxis within 2 days of admission and those who did not. Patient characteristics were well balanced between the two groups. No significant differences were seen between the stress ulcer prophylaxis group and the control group with regard to gastrointestinal bleeding requiring endoscopic hemostasis (0.6% vs 0.5%; p = 0.208), 30-day mortality (16.4% vs 16.9%; p = 0.249), and Clostridium difficile infection (1.4% vs 1.3%; p = 0.588). The stress ulcer prophylaxis group had a significantly higher proportion of hospital-acquired pneumonia (3.9% vs 3.3%; p = 0.012) compared with the control group. CONCLUSIONS: Since the rate of gastrointestinal bleeding requiring endoscopic hemostasis is not different comparing patients with and without stress ulcer prophylaxis, and the increase in hospital-acquired pneumonia is significant, routine stress ulcer prophylaxis for patients with severe sepsis may be unnecessary.

Efficacy and safety of endoscopic submucosal dissection for superficial colorectal tumors more than 50 mm in diameter.

BACKGROUND AND AIMS: The feasibility of endoscopic submucosal dissection (ESD) for large superficial colorectal tumors is undefined. The aim of this study was to assess the outcomes for patients undergoing ESD of superficial colorectal tumors larger than 50 mm. METHODS: A total of 472 patients who underwent ESD for superficial colorectal tumors from 2010 to 2014 were enrolled. We retrospectively reviewed their records. RESULTS: We compared patients with 20-mm to 50-mm lesions and those with lesions >50 mm regarding demographics, the ESD procedure, and histopathology. Among patients with lesions >50 mm, laterally spreading tumors nongranular and protruded types were uncommon. Histopathologically, deeply invasive (≥1000 µm) submucosal carcinomas were more frequent in lesions >50 mm (14% [10/70] vs 5% [20/402], P < .01). Technically, en bloc resection was successfully accomplished in 99% of patients (69/70). Although the total dissection time for lesions >50 mm was significantly longer than for lesions 20 mm to 50 mm (mean ± SD, 157 ± 114 minutes vs 68 ± 50 min; P < .01), dissection speed for lesions >50 mm was significantly faster than for lesions 20 mm to 50 mm (P < .01). There were no significant differences in en bloc R0 resection rate comparing both groups (>50 mm, 83% vs 20 mm to 50 mm, 87%; P = .31). No perforations or postoperative bleeding occurred in patients with lesions >50 mm. Post-ESD colorectal strictures requiring intervention did not develop in any patient. CONCLUSIONS: ESD for superficial colorectal tumors >50 mm is feasible. ESD of these lesions had a high R0 resection rate and a low adverse event rate. En bloc resection by ESD provides adequate pathological specimens and may limit the need for surgical intervention.

Gel immersion endoscopy: a novel method to secure the visual field during endoscopy in bleeding patients (with videos).

BACKGROUND AND AIMS: It is difficult to secure the visual field during endoscopy for GI bleeding or colonoscopy without preparation because the injected water is rapidly mixed with fresh blood or stool. We developed a novel method to secure the visual field in these situations. METHODS: Clear gel with the appropriate viscosity to prevent rapid mixing is injected through the accessory channel, instead of water. A vinyl tube was used as an in vitro GI bleeding model. After filling the lumen with indigo carmine dye, air insufflation and water injection are not effective for securing the visual field. However, after gel injection, the bleeding source is observed clearly in the space occupied by the gel. The efficacy of this method was evaluated subjectively in clinical use. From February 2014 until June 2015, gel immersion was used in 17 consecutive patients when the visual field could not be secured with routine insufflation. RESULTS: Of these 17 patients, gel injection was very effective in 10, effective in 5, slightly effective in 1, and not effective in 1. There were no adverse events associated with this method. CONCLUSION: Gel immersion endoscopy is safe and effective for securing the visual field, creating a space for endoscopic visualization and treatment in otherwise difficult situations.

Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons.

Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na(+),K(+)-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na(+) concentration in single ARC neurons that subsequently exhibited [Ca(2+)]i responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca(2+)]i in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca(2+)]i increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKAα3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes.

The Volume-Outcome Relationship in Critically Ill Patients in Relation to the ICU-to-Hospital Bed Ratio.

OBJECTIVES: A volume-outcome relationship in ICU patients has been suggested in recent studies. However, it is unclear whether the ICU-to-hospital bed ratio affects the volume-outcome relationship. The aim of this study is to investigate the relationship between hospital volume and in-hospital mortality of adult ICU patients in relation to the ratio of ICU beds to regular hospital beds. DESIGN: Retrospective cohort study. SETTING: Four hundred seventy-seven Japanese hospitals from 2007 to 2012 in the Japanese Diagnosis Procedure Combination database. PATIENTS: A total of 596,143 patients discharged from acute care hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data from 596,143 ICU patients from 2007 through 2012 using a nationwide administrative database. Patients were categorized into nine subgroups (the tertiles of hospital volume of ICU patients combined with the tertiles of ICU-to-hospital bed ratio). Multivariable logistic regression analyses were performed to examine the concurrent effects of hospital volume of ICU patients and ICU-to-hospital bed ratio on in-hospital mortality, with adjustment for patient and hospital characteristics. Higher hospital volume of ICU patients and a higher ICU-to-hospital bed ratio were independently associated with lower mortality. When patients were stratified by ICU-to-hospital bed ratio categories, in-hospital mortality was significantly lower in the high-volume subgroup (odds ratio, 0.74; 95% CI, 0.58-0.93) compared with the low-volume subgroup in hospitals with a high ICU-to-hospital bed ratio. However, these relationships were not significant in hospitals with low ICU-to-hospital bed ratios (odds ratio, 0.94; 95% CI, 0.59-1.50) or in hospitals with intermediate ICU-to-hospital bed ratios (odds ratio, 0.80; 95% CI, 0.71-1.08). CONCLUSIONS: An inverse relationship between hospital volume of ICU patients and mortality was seen only when the ICU-to-hospital bed ratio was sufficiently high. Regionalization and increasing the number of ICU beds in referral centers may improve patient outcomes.

The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma.

BACKGROUND: Although advanced esophageal squamous-cell carcinoma (ESCC) is treated using a multidisciplinary approach, outcomes remain unsatisfactory. The microenvironment of cancer cells has recently been shown to strongly influence the biologic properties of malignancies. We explored the effect of supernatant from esophageal fibroblasts on the cell growth and chemo-resistance of ESCC cell lines. METHODS: We used 22 ESCC cell lines, isolated primary human esophageal fibroblasts and immortalized fibroblasts. We first examined cell proliferation induced by fibroblast supernatant. The effect of supernatant was evaluated to determine whether paracrine signaling induced by fibroblasts can influence the proliferation of cancer cells. Next, we examined the effects of adding growth factors HGF, FGF1, FGF7, and FGF10, to the culture medium of cancer cells. These growth factors are assumed to be present in the culture supernatants of fibroblasts and may exert a paracrine effect on the proliferation of cancer cells. We also examined the intrinsic role of HGF/MET and FGFs/FGFR in ESCC proliferation. In addition, we examined the inhibitory effect of lapatinib on ESCC cell lines and studied whether the fibroblast supernatants affect the inhibitory effect of lapatinib on ESCC cell proliferation. Finally, we tested whether the FGFR inhibitor PD-173074 could eliminate the rescue effect against lapatinib that was induced by fibroblast supernatants. RESULTS: The addition of fibroblast supernatant induces cell proliferation in the majority of cell lines tested. The results of experiments to evaluate the effects of adding growth factors and kinase inhibitors suggests that the stimulating effect of fibroblasts was attributable in part to HGF/MET or FGF/FGFR. The results also indicate diversity in the degree of dependence on HGF/MET and FGF/FGFR among the cell lines. Though lapanitib at 1 µM inhibits cell proliferation by more than 50% in the majority of the ESCC cell lines, fibroblast supernatant can rescue the growth inhibition of ESCC cells. However, the rescue effect is abrogated by co-treatment with FGFR inhibitor. CONCLUSION: These results demonstrate that cell growth of ESCC depends on diverse receptor tyrosine kinase signaling, in both cell-autonomous and cell-non-autonomous manners. The combined inhibition of these signals may hold promise for the treatment of ESCC.

Carperitide Increases the Need for Renal Replacement Therapy After Cardiovascular Surgery.

OBJECTIVES: Acute kidney injury is a common complication after aortic surgery. Carperitide, a human atrial natriuretic peptide, was reported to be effective for preventing acute kidney injury after cardiac surgery. However, most studies were from single centers, and results of meta-analyses are subject to publication bias. The aim of the present study was to investigate whether carperitide preserved renal function in patients undergoing cardiovascular surgery. DESIGN: Retrospective cohort study. SETTING: Participating hospitals (N = 281) in a national database from 2010 to 2013. PARTICIPANTS: Adult patients (N = 47,032) who underwent cardiovascular surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main intervention variable investigated was the use of carperitide on the day of surgery. Assessed outcomes included receiving renal replacement therapy within 21 days of surgery and in-hospital mortality. Data were available for 47,032 patients, of whom 2,186 (4.6%) received carperitide on the day of surgery. Multivariate logistic regression analysis revealed that carperitide was significantly associated with a greater likelihood of receiving renal replacement therapy within 21 days of surgery, but not with in-hospital mortality. CONCLUSIONS: In patients undergoing cardiovascular surgery, carperitide significantly increased the odds of receiving renal replacement therapy within 21 days after surgery.

Telomere Attrition in Intraductal Papillary Mucinous Neoplasms of the Pancreas Associated With Carcinogenesis and Aging.

OBJECTIVES: It is challenging to preoperatively distinguish malignant and benign forms of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. The aims of this study were to investigate whether telomere length is associated with pathological grade of IPMNs and age and to clarify the utility of telomere length as a marker to identify malignant IPMNs. METHODS: Pancreas tissue was obtained from 28 patients after resection. We measured the telomere lengths of tumor cells in IPMNs and normal duct cells by quantitative fluorescence in situ hybridization. The association of normalized telomere-centromere ratio (NTCR) to pathological grade of IPMNs and age were determined. RESULTS: The NTCR showed a gradual decrease with increasing pathological grade of IPMNs. The NTCR in intermediate- and high-grade dysplasia and adenocarcinoma lesions was significantly shorter than in normal pancreatic ducts (P < 0.05). In multivariate analysis, telomere length was most associated with carcinogenesis. When the cutoff value of NTCR was set to 0.74, the sensitivity for detection of high-grade dysplasia and adenocarcinoma was 82.8%, with a specificity of 87.5%. CONCLUSIONS: Telomere shortening occurs with carcinogenesis and aging. A significant reduction of telomere length in IPMNs may be useful for surgical decision making.