Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats.

Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.

Cell-free DNA is abundant in ascites and represents a liquid biopsy of ovarian cancer.

OBJECTIVE: Malignant ascites is a common clinical feature of ovarian cancer and represents a readily accessible sample of tumour cells and tumour DNA. This study aimed to characterise the cell-free DNA (cfDNA) in ascites in terms of its size profile, stability and cell-free tumour DNA (cftDNA) content. METHODS: Cell spheroids, loose cells and cell-free fluid was collected from ascites from 18 patients with ovarian cancer. cfDNA was isolated and assessed for size by electrophoresis, concentration by fluorometry,cftDNA content by methylation specific qPCR of HOXA9 and IFFO1 promoter regions and by targeted sequencing. Stability was assessed after ascites fluid was stored at 4 °C for 24 and 72 h before fractionating. RESULTS: The concentration of cfDNA in ascites ranged from 6.6 to 300 ng/mL. cfDNA size distribution resembled blood plasma-derived cfDNA, with major peaks corresponding to mono- and di-nucleosome DNA fragments. High molecular weight cfDNA was observed in 7 of 18 patients and appeared to be associated with extracellular vesicles. IFFO1 and HOXA9 methylation was proportionately higher in cfDNA than spheroid- and loose-cell fractions and was not observed in healthy primary cells. Variant allele frequency was highest in cfDNA compared to single cells and spheroids from ascites. Though cancer cell numbers in ascites declined to near zero in recurrent ascites from one patient undertaking chemotherapy, cftDNA could still be sampled. cfDNA size, concentration and tumour content was stable over 72 h. CONCLUSION: cfDNA in ovarian cancer ascites demonstrates inter-patient variability, yet is consistently a rich source of cftDNA, which is a stable substrate. This supports the wider clinical use of ascites in the molecular analysis of ovarian cancer.

Amomum subulatum Induces Apoptosis in Tumor Cells and Reduces Tumor Burden in Experimental Animals via Modulating Pro-Inflammatory Cytokines.

This study investigates the anticancer potential of methanolic extract of A. subulatum dry fruits (MEAS) in Dalton's Lymphoma Ascites (DLA) cells in vitro and on DLA induced ascitic and solid tumor-bearing mice. MEAS induced apoptosis in DLA cells and MEAS administration effectively reduced tumor burden, and increased life span via modulating pro-inflammatory cytokines and regulating NF-κB pathway. MEAS seemed to be much safer than the standard drug cyclophosphamide, as the latter was associated with adverse effects such as body weight loss, depletion of hemoglobin level and hepatotoxicity, suggesting A. subulatum as a potential nutraceutical against cancer.

Randomised clinical trial: palliative long-term abdominal drains vs large-volume paracentesis in refractory ascites due to cirrhosis.

BACKGROUND: Palliative care remains suboptimal in end-stage liver disease. AIM: To inform a definitive study, we assessed palliative long-term abdominal drains in end-stage liver disease to determine recruitment, attrition, safety/potential effectiveness, questionnaires/interview uptake/completion and make a preliminary cost comparison. METHODS: A 12-week feasibility nonblinded randomised controlled trial comparing large-volume paracentesis vs long-term abdominal drains in refractory ascites due to end-stage liver disease with fortnightly home visits for clinical/questionnaire-based assessments. Study success criteria were attrition not >50%, <10% long-term abdominal drain removal due to complications, the long-term abdominal drain group to spend <50% ascites-related study time in hospital vs large-volume paracentesis group and 80% questionnaire/interview uptake/completion. RESULTS: Of 59 eligible patients, 36 (61%) were randomised, 17 to long-term abdominal drain and 19 to large-volume paracentesis. Following randomisation, median number (IQR) of hospital ascitic drains (long-term abdominal drain group vs large-volume paracentesis group) were 0 (0-1) vs 4 (3-7); week 12 serum albumin (g/L) and serum creatinine (µmol/L) were 29 (26.5-32.5) vs 30 (25-35) and 104.5 (81-115.5) vs 127 (63-158) respectively. Total attrition was 42% (long-term abdominal drain group 47%, large-volume paracentesis group 37%). Median (IQR) fortnightly community/hospital/social care ascites-related costs and percentage study time in hospital were lower in the long-term abdominal drain group, £329 (253-580) vs £843 (603-1060) and 0% (0-0.74) vs 2.75% (2.35-3.84) respectively. Self-limiting cellulitis/leakage occurred in 41% (7/17) in the long-term abdominal drain group vs 11% (2/19) in the large-volume paracentesis group; peritonitis incidence was 6% (1/17) vs 11% (2/19) respectively. Questionnaires/interview uptake/completion were ≥80%; interviews indicated that long-term abdominal drains could transform the care pathway. CONCLUSIONS: The REDUCe study demonstrates feasibility with preliminary evidence of long-term abdominal drain acceptability/effectiveness/safety and reduction in health resource utilisation. TRIAL REGISTRATION: ISRCTN30697116, date assigned: 07/10/2015.

Effect of mechanical ventilation versus spontaneous breathing on abdominal edema and inflammation in ARDS: an experimental porcine model.

BACKGROUND: Mechanical ventilation (MV), compared to spontaneous breathing (SB), has been found to increase abdominal edema and inflammation in experimental sepsis. Our hypothesis was that in primary acute respiratory distress syndrome (ARDS) MV would enhance inflammation and edema in the abdomen. METHODS: Thirteen piglets were randomized into two groups (SB and MV) after the induction of ARDS by lung lavage and 1 h of injurious ventilation. 1. SB: continuous positive airway pressure 15 cmH2O, fraction of inspired oxygen (FIO2) 0.5 and respiratory rate (RR) maintained at about 40 cycles min- 1 by titrating remifentanil infusion. 2. MV: volume control, tidal volume 6 ml kg- 1, positive end-expiratory pressure 15 cmH2O, RR 40 cycles min- 1, FIO2 0.5. MAIN OUTCOMES: abdominal edema, assessed by tissues histopathology and wet-dry weight; abdominal inflammation, assessed by cytokine concentration in tissues, blood and ascites, and tissue histopathology. RESULTS: The groups did not show significant differences in hemodynamic or respiratory parameters. Moreover, edema and inflammation in the abdominal organs were similar. However, blood IL6 increased in the MV group in all vascular beds (p < 0.001). In addition, TNFα ratio in blood increased through the lungs in MV group (+ 26% ± 3) but decreased in the SB group (- 17% ± 3). CONCLUSIONS: There were no differences between the MV and SB group for abdominal edema or inflammation. However, the systemic increase in IL6 and the TNFα increase through the lungs suggest that MV, in this model, was harmful to the lungs.

Model for End-Stage Liver Disease Sodium as a Predictor of Surgical Risk in Cirrhotic Patients With Ascites.

BACKGROUND: The Model for End-Stage Liver Disease Sodium (MELD-Na) incorporates hyponatremia into the MELD score and has been shown to correlate with surgical outcomes. The pathophysiology of hyponatremia parallels that of ascites, which purports greater surgical risk. This study investigates whether MELD-Na accurately predicts morbidity and mortality in patients with ascites undergoing general surgery procedures. MATERIALS AND METHODS: We used the National Surgical Quality Improvement Program database (2005-2014) to examine the adjusted risk of morbidity and mortality of cirrhotic patients with and without ascites undergoing inguinal or ventral hernia repair, cholecystectomy, and lysis of adhesions for bowel obstruction. Patients were stratified by the MELD-Na score and ascites. Outcomes were compared between patients with and without ascites for each stratum using low MELD-Na and no ascites group as a reference. RESULTS: A total of 30,391 patients were analyzed. Within each MELD-Na stratum, patients with ascites had an increased risk of complications compared with the reference group (low MELD-Na and no ascites): low MELD-Na with ascites odds ratio (OR) 4.33 (95% confidence interval [CI] 1.96-9.59), moderate MELD-Na no ascites OR 1.70 (95% CI 1.52-1.9), moderate MELD-Na with ascites OR 3.69 (95% CI 2.49-5.46), high MELD-Na no ascites OR 3.51 (95% CI 3.07-4.01), and high MELD-Na ascites OR 7.18 (95% CI 5.33-9.67). Similarly, mortality risk was increased in patients with ascites compared with the reference: moderate MELD-Na no ascites OR 3.55 (95% CI 2.22-5.67), moderate MELD-Na ascites OR 13.80 (95% CI 5.65-33.71), high MELD-Na no ascites OR 8.34 (95% CI 5.15-13.51), and high MELD-Na ascites OR 43.97 (95% CI 23.76-81.39). CONCLUSIONS: MELD-Na underestimates morbidity and mortality risk for general surgery patients with ascites.

Synthesis, Characterization, and In Vivo Anti-Cancer Activity of New Metal Complexes Derived from Isatin-N(4)antipyrinethiosemicarbazone Ligand Against Ehrlich Ascites Carcinoma Cells.

The current study aimed to synthesize new metal coordination complexes with potential biomedical applications. Metal complexes were prepared via the reaction of isatin-N(4)anti- pyrinethiosemicarbazone ligand 1 with Cu(II), Ni(II), Co(II), Zn(II), and Fe(III) ions. The obtained metal complexes 2-12 were characterized using elemental, spectral (1H-NMR, EPR, Mass, IR, UV-Vis) and thermal (TGA) techniques, as well as magnetic moment and molar conductance measurements. In addition, their geometries were studied using EPR and UV-Vis spectroscopy. To evaluate the in vivo anti-cancer activities of these complexes, the ligand 1 and its metal complexes 2, 7 and 9 were tested against solid tumors. The solid tumors were induced by subcutaneous (SC) injection of Ehrlich ascites carcinoma (EAC) cells in mice. The impact of the selected complexes on the reduction of tumor volume was determined. Also, the expression levels of vascular endothelial growth factor (VEGF) and cysteine aspartyl-specific protease-7 (caspase-7) in tumor and liver tissues of mice bearing EAC tumor were determined. Moreover, their effects on alanine transaminase (ALT), aspartate transaminase (AST), albumin, and glucose levels were measured. The results revealed that the tested compounds, especially complex 9, reduced tumor volume, inhibited the expression of VEGF, and induced the expression of caspase-7. Additionally, they restored the levels of ALT, AST, albumin, and glucose close to their normal levels. Taken together, our newly synthesized metal complexes are promising anti-cancer agents against solid tumors induced by EAC cells as supported by the inhibition of VEGF and induction of caspase-7.

Metalloproteinases at the surface of small extrcellular vesicles in advanced ovarian cancer: Relationships with ascites volume and peritoneal canceromatosis index.

Metalloproteinases and their extracellular matrix metalloproteinase inducer (EMMPRIN) play an essential role in the regulation of signaling from growth factors receptors and adhesion molecules, cell motility and extracellular matrix degradation. The aim of the study was to evaluate the relationship between the levels of small extracellular vesicles (sEVs) metalloproteinases, such as ADAM10, ADAM17, MMP2, MMP9 and EMMPRIN and ascites volume and peritoneal canceromatosis index in advanced ovarian cancer patients (OCPs). The subpopulations of metalloproteinases at the surface of sEVs of borderline ovarian tumor patients (BOTPs) (n = 20, 36.5 ±â€¯2.5 years) and previously untreated advanced OCPs (n = 35, 56.5 ±â€¯2.5 years) were evaluated using flow cytometry. The metalloproteinase subpopulations of CD9-positive sEVs isolated from plasma of BOTPs and OCPs appeared to be quite similar. However, a significant difference in the expression of ADAM-metalloproteinases in ascites sEVs was found between BOTPs and OCPs. The level of sEVs metalloproteinases in OCPs significantly depended on the ascites volume. A statistically significant relationship between the level of ADAM10+/ADAM17- subpopulation in plasma sEVs and the peritoneal canceromatosis index was found (R = 0.66, p < .05). The levels of metalloproteinases and EMMPRIN in circulating sEVs, as well as the assessment of individual subpopulations may be promising approaches to OCPs managing.

Next-generation sequencing reveals mutational accordance between cell-free DNA from plasma, malignant pleural effusion and ascites and directs targeted therapy in a gastric cancer patient.

Cell-free DNA (cfDNA) has been a research hotspot in molecular tumor profiling. In advanced gastric cancer patients, malignant pleural effusion (MPE) and ascites provide a wealth of tumor cells that can be investigated. Here we conducted next-generation sequencing (NGS) on matched cfDNA from plasma, MPE and ascites from a stage-IV gastric cancer patient to identify potential therapeutic targets. In all three samples, we detected an amplification in the cellular-mesenchymal to epithelial transition factor (MET) gene, a truncation mutation in SMAD3 (p.R368X), and four ataxia telangiectasia-mutated gene (ATM) variants, including a missense mutation (p.E2351A), an in-frame deletion (p.NPAVIM2353delinsK), a frame-shift deletion (p.D1758fs) and an ATM- BPI fold containing family B member 1 (BPIFB1) gene fusion. In contrast, we detected amplification of TEK only in malignant ascites. The patient was subjected to Crizotinib to counter MET amplification. Our study demonstrates high accordance in mutational spectra of matched cfDNA from plasma, MPE and ascites, and suggests that it is feasible to utilize these tumor sources in clinical decision-making.

Delayed diagnosis of spontaneous bladder rupture: a rare case report.

BACKGROUND: Bladder rupture caused by trauma or pelvic fracture is very common, and can be easily diagnosed. However, Spontaneous rupture of the bladder is rare. Reported by Peters PC. (Peters, Urol Clin N Am 16:279-82, 1989): The incidence of spontaneous bladder rupture is 1: 126000. During childbirth, the occurrence rate of this disease is lower than that of the former. It is very difficult to make an early diagnosis of the spontaneous rupture of the bladder during childbirth, which eventually results in high maternal mortality. Due to peritoneal reabsorption, the patient may show high levels of serum creatinine and potassium, and this would easily be misdiagnosed as acute renal failure. However, these patients have normal renal function, hence the diagnosis of renal failure is incorrect. CASE PRESENTATION: A 23 year-old female patient had her first pregnancy and delivered a full-term healthy baby girl. After delivery, the patient developed fever, oliguria, massive ascites, high serum creatinine and high serum potassium. The patient was initially diagnosed with acute renal failure, however treatment for her condition was ineffective. After further examination, the patient was diagnosed with intraperitoneal bladder rupture. The patient was treated for bladder rupture, made a full recovery and was discharged. CONCLUSIONS: Sudden onset of massive ascites and renal failure due to abnormal serum biochemical characteristics after delivery should be first diagnosed as spontaneous bladder rupture. However, bladder radiography may suggest a false negative result, hence cystoscopy should be performed to confirm the diagnosis. The ratio between ascites creatinine and serum creatinine would be helpful for early diagnosis and to determine the time of rupture. Conservative management or surgical repair should be used to treat bladder rupture.

Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis.

AIMS: The study aimed to evaluate the effects of tolvaptan treatment on survival of patients with decompensated liver cirrhosis with refractory ascites. METHODS: This multicenter, retrospective, observational study included patients with cirrhosis who were treated with tolvaptan for hepatic ascites refractory to conventional diuretics. Patients who could and could not decrease accompanying diuretics within 1 month after tolvaptan administration were defined as the "Decreased" and "Not-decreased" groups, respectively. RESULTS: Median body weight change 1 week after tolvaptan treatment was -1.95 kg, with the 50% of patients experiencing a 2 kg/week reduction. Spot urinary sodium was found to be a better predictor of tolvaptan response than liver function and liver fibrosis markers. Median survival was significantly longer (not reached versus 116 days, p = 0.005) and serum creatinine concentrations 12 weeks after tolvaptan administration significantly lower (0.99 vs. 1.55 mg/dL, p < 0.05) in the Decreased than in the Not-decreased group. Multivariate analysis showed that the presence of viable hepatocellular carcinoma (hazards ratio [HR] 2.14, p = 0.02) and a decrease in diuretics were independently prognostic of survival (HR 0.36, p < 0.01). CONCLUSIONS: The maintenance of renal function is essential in enhancing survival of patients with cirrhosis. Doses of diuretics should be adjusted appropriately during tolvaptan treatment.

Protective and recuperative effects of 3-bromopyruvate on immunological, hepatic and renal homeostasis in a murine host bearing ascitic lymphoma: Implication of niche dependent differential roles of macrophages.

3-bromopyruvate (3-BP) possesses promising antineoplastic potential, however, its effects on immunological homeostasis vis a vis hepatic and renal functions in a tumor bearing host remain unclear. Therefore, the effect of 3-BP administration to a murine host bearing a progressively growing tumor of thymoma origin, designated as Dalton's lymphoma (DL), on immunological, renal and hepatic homeostasis was investigated. Administration of 3-BP (4 mg/kg) to the tumor bearing host reversed tumor growth associated thymic atrophy and splenomegaly, accompanied by altered cell survival and repertoire of splenic, bone marrow and tumor associated macrophages (TAM). TAM displayed augmented phagocytic, tumoricidal activities and production of IL-1 and TNF-α. 3-BP-induced activation of TAM was of indirect nature, mediated by IFN-γ. Blood count of T lymphocytes (CD4+ & CD8+) and NK cells showed a rise in 3-BP administered tumor bearing mice. Moreover, 3-BP administration triggered modulation of immunomodulatory cytokines in serum along with refurbished hepatic and renal functions. The study indicates the role of altered cytokines balance, site specific differential macrophage functions and myelopoiesis in restoration of lymphoid organ homeostasis in 3-BP administered tumor bearing host. These observations will have long lasting impact in understanding of alternate mechanisms underlying the antitumor action of 3-BP accompanying appraisal of safety issues for optimizing its antineoplastic actions.

Curcumin Attenuates Inflammation in a Severe Acute Pancreatitis Animal Model by Regulating TRAF1/ASK1 Signaling.

BACKGROUND Inflammation plays an important role in initiation and development of severe acute pancreatitis (SAP). Curcumin exerts potent anti-inflammatory effects in many diseases, including acute pancreatitis. However, the specific molecular mechanisms are not clear. MATERIAL AND METHODS Intra-biliopancreatic duct injection of taurocholate was used to establish an animal model of SAP. Curcumin was administrated to animals as pre-treatments. Concentrations of cytokines in serum and ascites were measured by enzyme-linked immunosorbent assay (ELISA). A colorimetric method was used to determine the amylase activity. Western blotting was used to examine the expression levels and phosphorylation levels of proteins. Immunoprecipitation was used to assess the molecular association between apoptosis signal- regulating kinase 1 (ASK1) and thioredoxin (Trx). RESULTS Pre-treatment with curcumin reduced the concentrations of interleukin (IL6) and tumor necrosis factor (TNFα) in serum and ascites, as well as the ascites volume and amylase activity in SAP rats. Pre-treatment with curcumin reduced the expression level of TNF receptor-associated factor 1 (TRAF1), IL6, and TNFa in pancreas in SAP rats. Moreover, the phosphorylation levels of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4), MKK7, and c-Jun NH(2)-terminal protein kinase (JNK) were reduced by curcumin pre-treatment. The molecular association between ASK1 and Trx was recovered by curcumin pre-treatment. As a result, the nuclear translocation of nuclear factor kappa B (NF-κB) was suppressed in pancreases from SAP rats. CONCLUSIONS Activation of the TRAF1/ASK1/JNK/NF-κB signaling pathway is involved in the inflammation of SAP. Curcumin exerts anti-inflammatory effects by suppressing this proinflammatory pathway.

Vitronectin (Vn) glycosylation patterned by lectin affinity assays-A potent glycoproteomic tool to discriminate plasma Vn from cancer ascites Vn.

Changes in glycosylation have been associated with human cancer, but their complexity poses an analytical challenge. Ovarian cancer is a major cause of death in women because of an often late diagnosis. At least one-third of patients presents ascites fluid at diagnosis, and almost all have ascites at recurrence. Vitronectin (Vn) is a multifunctional glycoprotein that is suggested to be implicated in ovarian cancer metastasis and is found within ascites. The present study evaluated the potential of using lectin affinity for characterizing the glycosylation pattern of Vn. Human Vn was purified from 1 sample of ovarian cancer ascites or a pool of plasma samples. Consistent findings were observed with both dot blot and lectin array assays. Based on a panel of 40 lectins, the lectin array revealed discriminant patterns of lectin binding to Vn glycans. Interestingly, almost all the highlighted interactions were found to be higher with Vn from ascites relative to the plasma counterpart. Also, the lectin array was able to discriminate profiles of lectin interactions (ConA, SNA-I, PHA-E, PHA-L) between Vn samples that were not evident using dot blot, indicating its high sensitivity. The model of ConA binding during thermal unfolding of Vn confirmed the higher accessibility of mannosylated glycans in Vn from ascites as monitored by turbidimetry. Thus, this study demonstrated the usefulness of lectins and the lectin array as a glycoproteomic tool for high throughput and sensitive analysis of glycosylation patterns. Our data provide novel insights concerning Vn glycosylation patterns in clinical specimens, paving the way for further investigations regarding their functional impact and clinical interest.

Markers of Oxidative Stress and Inflammation in Ascites and Plasma in Patients with Platinum-Sensitive, Platinum-Resistant, and Platinum-Refractory Epithelial Ovarian Cancer.

Diverse proinflammatory biomarkers and oxidative stress are strongly associated with advanced epithelial ovarian cancer (EOC). Objective. To determine the behavior of markers of oxidative stress and inflammation in plasma and ascites fluid in patients with platinum-sensitive, platinum-resistant, and platinum-refractory EOC. Methods. A prospective cohort study. The colorimetric method was used to determine levels of the markers 8-isoprostanes (8-IP), lipid peroxidation products (LPO), and total antioxidant capacity (TAC) in plasma and ascites fluid; and with ELISA, the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were determined in patients with EOC. Results. In ascites fluid, a significant increase in 8-IP versus baseline plasma levels was found (p = 0.002). There was an important leakage of the TAC levels in ascites fluid versus baseline plasma levels (p < 0.001). The IL-6 was elevated in ascites fluid versus baseline plasma levels (p = 0.003), and there were diminished levels of TNF-α in ascites fluid versus baseline plasma levels (p = 0.001). Discussion. We hypothesize that the ascites fluid influences the behavior and dissemination of the tumor. Deregulation between oxidants, antioxidants, and the proinflammatory cytokines was found to vary among platinum-sensitive, platinum-resistant, and platinum-refractory patients.

Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology.

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating PIK3CA mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. Mol Cancer Ther; 16(5); 948-55. ©2017 AACR.

Risk Factors for Postoperative Ascites in Patients Undergoing Liver Resection for Hepatocellular Carcinoma.

BACKGROUND: Postoperative ascites is a common complication after liver resection. This study aimed to identify the risk factors for ascites in patients after liver resection and the relationship between postoperative ascites and other complications. METHODS: We retrospectively analyzed data that were obtained from 266 patients who underwent liver resection for treating hepatocellular carcinoma between 2008 and 2015. Postoperative ascites was defined as a daily ascitic fluid drainage exceeding 500 mL on postoperative day 3 or later. The participants were categorized and analyzed with respect to the presence or absence of postoperative ascites. RESULTS: Overall, 17 (6.4%) patients developed postoperative ascites. A multivariate analysis identified that three significant factors-serum albumin, platelet count, and operation duration-were associated with the development of postoperative ascites. Sixteen (94.1%) of the 17 patients with postoperative ascites experienced other associated complications. The patients with ascites had more pleural effusion (70.6 vs. 17.7%, P < 0.001) than the patients without ascites. Postoperative morbidity, except for pleural effusion, was similar between the groups. The postoperative hospital stay duration was significantly longer in patients with ascites than in those without ascites. CONCLUSIONS: Postoperative ascites frequently occurred in patients with decreased liver functional reserve. Moreover, the presence of ascites was associated with significantly increased pleural effusion rates, and postoperative hospital stay duration was significantly prolonged.

MicroRNA-155 is upregulated in ascites in patients with spontaneous bacterial peritonitis.

MircoRNA's (miR) have been recognised as important modulators of gene expression and potential biomarkers. However, they have been rarely investigated in bio fluids apart from blood. We investigated the association of miR-125b and miR-155 with complications of cirrhosis. Ascites was prospectively collected from patients with cirrhosis undergoing paracentesis at our department. miR's were determined in the supernatant using qPCR and normalized by SV-40. Clinical parameters were assessed at paracentesis and during follow-up. 76 specimens from 72 patients were analysed. MiR's were not associated to age, sex or aetiology of cirrhosis. MiR-125b levels differed between patients with low and high MELD score, and miR-125b levels showed an inverse correlation to serum creatinine (r2 = -0.23; p = 0.05). MiR-155 was elevated in patients with spontaneous bacterial peritonitis (SBP) (n = 10; p = 0.04). MiR-155 levels differed between patients with and without 30-day survival (p = 0.02). No association of ascites levels of investigated miR's to size of varices, episodes of gastrointestinal bleeding or hepatorenal syndrome was observed. While miR-125b levels in ascites seem to be associated with liver and renal dysfunction, miR-155 might be implicated in local immune response in SBP.