Intraoperative oliguria predicts acute kidney injury after major abdominal surgery.

Background: The threshold of intraoperative urine output below which the risk of acute kidney injury (AKI) increases is unclear. The aim of this retrospective cohort study was to investigate the relationship between intraoperative urine output during major abdominal surgery and the development of postoperative AKI and to identify an optimal threshold for predicting the differential risk of AKI. Methods: Perioperative data were collected retrospectively on 3560 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or oesophageal resection) at Kyoto University Hospital. We evaluated the relationship between intraoperative urine output and the development of postoperative AKI as defined by recent guidelines. Logistic regression analysis was performed to adjust for patient and operative variables, and the minimum P -value approach was used to determine the threshold of intraoperative urine output that independently altered the risk of AKI. Results: The overall incidence of AKI in the study population was 6.3%. Using the minimum P -value approach, a threshold of 0.3 ml kg -1 h -1 was identified, below which there was an increased risk of AKI (adjusted odds ratio, 2.65; 95% confidence interval, 1.77-3.97; P <0.001). The addition of oliguria <0.3 ml kg -1 h -1 to a model with conventional risk factors significantly improved risk stratification for AKI (net reclassification improvement, 0.159; 95% confidence interval, 0.049-0.270; P =0.005). Conclusions: Among patients undergoing major abdominal surgery, intraoperative oliguria <0.3 ml kg -1 h -1 was significantly associated with increased risk of postoperative AKI.

MELD and Child-Pugh Scores Are Related to Immune Status of Intrahepatic Natural Killer Cells in Liver Transplant Candidates.

BACKGROUND: The role and phenotypic alterations of intrahepatic natural killer (NK) cells in liver disease were investigated. Although intrahepatic NK cells reportedly functionally deteriorate in the fibrotic liver, it remains unclear how the clinical severity of liver disease affects intrahepatic NK cells in patients with advanced liver failure. METHODS: We analyzed the phenotypic properties of intrahepatic NK cells by using mononuclear cells extracted from ex vivo liver perfusate effluents from patients who underwent liver transplantation. The relationship between the clinical severity of liver disease and the phenotype of intrahepatic NK cells in these patients was also evaluated. To estimate the immunological responsiveness of intrahepatic NK cells, phenotypic enhancement after interleukin-2 stimulation was analyzed. RESULTS: Intrahepatic NK cells from patients with advanced liver failure exhibited down-regulated monomodal expression of NKp46, a major activating molecule. Notably, the expression level of NKp46 decreased depending on the severity of liver disease, Model for End-Stage Liver Disease score, and Child-Pugh score rather than the etiology. After in vitro recombinant interleukin-2 stimulation, the enhancement of expression of cytotoxic molecules, NKp44, and tumor necrosis factor-related apoptosis-inducing ligand was significantly impaired in intrahepatic NK cells from patients with liver failure, concurrently with decreased expression of CD122 and interleukin-2 receptor beta. CONCLUSIONS: Our results suggest that terminal deterioration of liver environments by chronic liver disease impairs the potential of local NK cells, depending on the severity of the deterioration. These influences of advanced liver failure on intrahepatic NK cells may be attributed to multicentric carcinogenesis in patients with liver failure.

Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells.

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.

Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial.

BACKGROUND: Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC. PATIENTS AND METHODS: We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5-7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m2, day 1, every 4-6 weeks) or Sor (400 mg bid). The primary end point was overall survival. RESULTS: A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38-0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated. CONCLUSION: SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC. CLINICAL TRIAL REGISTRATION: UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

A genome-wide association study of periodontitis in a Japanese population.

Periodontitis is a multifactorial disease in which bacterial, lifestyle, and genetic factors are involved. Although previous genetic association studies identified several susceptibility genes for periodontitis in European populations, there is little information for Asian populations. Here, we conducted a genome-wide association study and a replication study consisting of 2,760 Japanese periodontitis patients and 15,158 Japanese controls. Although single-nucleotide polymorphisms that surpassed a stringent genome-wide significance threshold (P < 5 × 10(-8)) were not identified, we found 2 suggestive loci for periodontitis: KCNQ5 on chromosome 6q13 (rs9446777, P = 4.83 × 10(-6), odds ratio = 0.82) and GPR141-NME8 at chromosome 7p14.1 (rs2392510, P = 4.17 × 10(-6), odds ratio = 0.87). A stratified analysis indicated that the GPR141-NME8 locus had a strong genetic effect on the susceptibility to generalized periodontitis in Japanese individuals with a history of smoking. In conclusion, this study identified 2 suggestive loci for periodontitis in a Japanese population. This study should contribute to a further understanding of genetic factors for enhanced susceptibility to periodontitis.

Clinical study of tympanostomy tube placement for patients with intractable Ménière's disease.

OBJECTIVE: To evaluate the effectiveness of tympanostomy tube placement in controlling symptoms of intractable Ménière's disease. METHODS: Fifteen patients with intractable Ménière's disease underwent tympanostomy tube placement in the affected ear. Post-operative changes in vertigo attacks and hearing level were recorded, and were evaluated according to American Academy of Otolaryngology-Head and Neck Surgery criteria. RESULTS: At 12 months after treatment, 3 patients (20 per cent) showed complete control of vertigo, 7 (47 per cent) showed substantial control and 2 (13 per cent) showed limited control; 3 patients (20 per cent) required other treatment. At 24 months after treatment, 7 patients (47 per cent) showed complete control of vertigo, 3 (20 per cent) showed substantial control and 1 (7 per cent) showed limited control; 1 patient required other treatment 15 months after tympanostomy tube placement. CONCLUSION: There is no definite pathophysiological explanation for the effect of tympanostomy tube placement in reducing vertigo attacks. This treatment is not effective for all patients with intractable Ménière's disease. However, tympanostomy tube placement might be an additional surgical therapeutic option to consider prior to contemplating other, more invasive treatments.

Preliminary analysis for integration of spot-scanning proton beam therapy and real-time imaging and gating.

PURPOSE: Spot-scanning proton beam therapy (PBT) can create good dose distribution for static targets. However, there exists larger uncertainty for tumors that move due to respiration, bowel gas or other internal circumstances within the patients. We have developed a real-time tumor-tracking radiation therapy (RTRT) system that uses an X-ray linear accelerator gated to the motion of internal fiducial markers introduced in the late 1990s. Relying on more than 10 years of clinical experience and big log data, we established a real-time image gated proton beam therapy system dedicated to spot scanning. MATERIALS AND METHODS: Using log data and clinical outcomes derived from the clinical usage of the RTRT system since 1999, we have established a library to be used for in-house simulation for tumor targeting and evaluation. Factors considered to be the dominant causes of the interplay effects related to the spot scanning dedicated proton therapy system are listed and discussed. RESULTS/CONCLUSIONS: Total facility design, synchrotron operation cycle, and gating windows were listed as the important factors causing the interplay effects contributing to the irradiation time and motion-induced dose error. Fiducial markers that we have developed and used for the RTRT in X-ray therapy were suggested to have the capacity to improve dose distribution. Accumulated internal motion data in the RTRT system enable us to improve the operation and function of a Spot-scanning proton beam therapy (SSPT) system. A real-time-image gated SSPT system can increase accuracy for treating moving tumors. The system will start clinical service in early 2014.

Bile CXC motif chemokine 10 levels correlate with anti-donor cytotoxic T cell responses after liver transplantation.

BACKGROUND: CXC motif chemokine 10 (CXCL10), known as interferon-γ-induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-γ. CXCR3, the receptor of CXCL10, is predominantly expressed on activated T, B, natural killer, and dendritic cells, as well as macrophages. CXCR3 promotes chemotaxis upon binding CXCL10. Serum CXCL10 levels have recently attracted attention as a post-transplantation biomarker for graft rejection. However, the correlation between the degree of T cell response to allostimulation and CXCL10 levels remains unclear. In this study, we investigated the serum and bile CXCL10 levels of patients who underwent living donor liver transplantation (LDLT) and compared them with the T cell responses to allostimulation. PATIENTS AND METHODS: Between February 2009 and August 2012, 41 patients underwent LDLT at Hiroshima University Hospital. Serum and bile CXCL10 levels were measured weekly for 4 weeks after surgery, while the T cell responses to allostimulation were evaluated using a mixed lymphocyte reaction with an intracellular carboxyfluorescein diacetate succinimidyl ester-labeling technique that we regularly use to monitor the immune response to anti-donor and anti-third-party stimulation after liver transplantation. The stimulation index (SI) and CD25 expression of the CD4+ and CD8+ T cell subsets in response to allostimulation were then analyzed using flow cytometry. RESULTS: Serum CXCL10 levels were significantly correlated with the SI values for CD8+ T cells in response to both types of allostimulation. Bile CXCL10 levels were significantly correlated with CD25 expression of CD8+ T cell subsets, especially in response to anti-donor stimulation. Patients with higher bile CXCL10 levels suffered from severe acute cellular rejection that was refractory to steroid pulse. CONCLUSION: Measurements of bile CXCL10 levels could predict anti-donor cytotoxic T cell responses in liver transplant recipients.

Multiple hepatic vein reconstruction using an all-in-one sleeve patch graft technique in living donor liver transplantation: a case report.

Maintaining hepatic inflow and appropriate venous drainage is important for maximizing the capacity of the retrieved graft in liver transplantation. Here, we report a successful case of multiple hepatic vein (HV) reconstruction using an all-in-one sleeve patch graft of the autologous great saphenous vein to ensure adequate blood flow through the HV. A patient with hepatocellular carcinoma caused by hepatitis C virus-induced cirrhosis underwent living donor liver transplantation using a right lobe graft. A preoperative dynamic computed tomography scan and intraoperative findings revealed that the graft had three middle HV tributaries, a superficial vein, segment VIII HV (V8), and segment V HV (V5). The openings of the superficial vein and V8 were located very close to that of the right hepatic vein (RHV) in the cutting surface. Each HV had significant diameter and drainage territory requiring reconstruction. An autologous great saphenous vein was used to create a sleeve patch to incorporate the close-packed HV openings. The autologous sleeve patch graft was sutured to the openings of the RHV and the superficial vein and the hole created on the sleeve patch graft was anastomosed to the openings of V8 directly on the back table to create an all-in-one sleeve patch. For the V5 reconstruction, the recipient's intrahepatic portal vein graft was used to create an interpositional conduit from the recipient's V5 to the inferior vena cava. The postoperative course was uneventful and postoperative studies revealed good graft function with excellent blood flow in the HV.

Blocking of the ATP sensitive potassium channel ameliorates the ischaemia-reperfusion injury in the rat testis.

There is increasing evidence that the effects of administered ATP sensitive potassium (KATP ) channel openers or blockers during ischaemia are still controversial in many organs/tissues. Testicular torsion detorsion which causes ischaemia-reperfusion (IR) injury, cannot be predicted, thus an effective drug should be administered during or after the ischaemia. The aim of this study was to examine whether the administration of KATP channel openers or blockers during ischaemia ameliorates IR injury in the testis. Eight-week-old male Sprague-Dawley rats were subjected to 2 h right testicular ischaemia followed by 24 h reperfusion. The selective mitochondrial (mito) KATP channel blocker, 5-hydroxydecanoate (5-HD) (40 mg/kg), the non-selective KATP channel blocker glibenclamide (5 mg/kg), the selective mito KATP channel opener diazoxide (10 mg/kg) and the non-selective KATP channel opener cromakalim (300 µg/kg) were administered intraperitoneally 15 min prior to the ischaemia or 75 min after the induction of ischaemia. Tissue damage was evaluated by malondialdehyde concentration, myeloperoxidase activity, histological evaluation and TdT-mediated dUTP nick end labelling assay in the testis. There was a significant increase in oxidative stress, neutrophil infiltration, histological damage and apoptosis in the testicular IR model. A significant reduction in the testicular IR injury was observed with the administration of glibenclamide, but not 5-HD, diazoxide or cromakalim during ischaemia. The administration of non-selective KATP channel blocker glibenclamide ameliorated the testicular IR injury. On the other hand, the selective mito KATP channel blocker, 5-HD and KATP channel openers did not reduce the testicular IR injury. These data suggest that blocking of the membrane KATP channel may have a protective effect during the testicular ischaemia. Glibenclamide could be an effective drug to manage the post-ischaemic injury caused by the testicular torsion-detorsion.

Serum levels of IL-6 and IL-1ß can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer.

BACKGROUND: With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC). METHODS: Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively. RESULTS: Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1ß levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1ß level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1ß. CONCLUSION: The serum levels of IL-6 and IL-1ß predict the efficacy of GEM in patients with advanced PC.

Single-incision plus one port laparoscopic anterior resection for rectal cancer as a reduced port surgery.

BACKGROUND: Only limited data in the literature about single-incision laparoscopic rectal surgery, because the laparoscopic stapler does not allow low rectal transection without sufficient distal margins from the umbilicus port. We have developed single-incision plus one port laparoscopic anterior resection of the rectum (SILS+1-AR) as a reduced port surgery in which we can utilize the incision for drainage as an additional access route for laparoscopic procedures including the transection the lower rectum. METHODS: A Lap protector (LP) mini was inserted through a 2.5 cm transumbilical incision, and an EZ-access was mounted to LP and three 5-mm ports were placed in EZ-access. A 12 mm port was inserted in right lower quadrant. Almost all the procedures were performed with usual laparoscopic instruments, and the operative procedures were much the same as in usual laparoscopic low anterior resection of the rectum using a flexible 5mm scope. The rectum was transected normally using only one endoscopic linear stapler inserted from the right lower quadrant port. RESULTS: We underwent modified SILS+1-AR in 16 patients with advanced rectal cancer. In all cases, there was no need to extend the skin incision. We transected the lower rectum with one laparoscopic stapler in all six cases. Postoperative follow-up did not reveal any umbilical wound complications or recurrences. CONCLUSIONS: The safety and feasibility of SILS+1-AR for advanced rectal cancer was established in this study. However, further studies are needed to prove the advantages of this procedure to conventional laparoscopic law anterior resection.

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages.

Anti-apoptotic Bcl-2 family proteins, which inhibit the mitochondrial pathway of apoptosis, are involved in the survival of various hematopoietic lineages and are often dysregulated in hematopoietic malignancies. However, their involvement in the megakaryocytic lineage is not well understood. In the present paper, we describe the crucial anti-apoptotic role of Mcl-1 and Bcl-xL in this lineage at multistages. The megakaryocytic lineage-specific deletion of both, in sharp contrast to only one of them, caused apoptotic loss of mature megakaryocytes in the fetal liver and systemic hemorrhage, leading to embryonic lethality. ABT-737, a Bcl-xL/Bcl-2/Bcl-w inhibitor, only caused thrombocytopenia in adult wild-type mice, but further induced massive mature megakaryocyte apoptosis in the Mcl-1 knockout mice, leading to severe hemorrhagic anemia. All these phenotypes were fully restored if Bak and Bax, downstream apoptosis executioners, were also deficient. In-vitro study revealed that the Jak pathway maintained Mcl-1 and Bcl-xL expression levels, preventing megakaryoblastic cell apoptosis. Similarly, both were involved in reticulated platelet survival, whereas platelet survival was dependent on Bcl-xL due to rapid proteasomal degradation of Mcl-1. In conclusion, Mcl-1 and Bcl-xL regulate the survival of the megakaryocytic lineage, which is critically important for preventing lethal or severe hemorrhage in both developing and adult mice.