Clinical and genetic factors involved in Porto-sinusoidal vascular disorder after oxaliplatin exposure.

BACKGROUND AND AIMS: Oxaliplatin (OX) has been described as a potential etiologic agent for porto-sinusoidal vascular disorder (PSVD). Our aim was to describe the natural history of PSVD due to OX in colon cancer (CRC) and identify risk factors for its development. METHODS: We made a multicenter retrospective case-control (ratio 1:3) study with patients diagnosed of PSVD-OX. Baseline data, end of treatment, years of follow-up and diagnosis of PSVD were collected and compared to controls (without PSVD). Besides, 16 different SNPs were selected from bibliography and analyzed by genotyping in the case group to identify potential genetic risk factors. RESULTS: 41 cases were identified, with a median time to PSVD diagnosis after the end of OX of 34 months. Spleen diameter was the strongest predictor of PSVD during treatment (OR 43.94 (14.48-133.336); p < 0.0001). Additionally, thrombocytopenia (<150 × 10^9) at one year was a significant disease risk marker (OR 9.35; 95% CI: 3.71-23.58; p = 0.001). We could not establish any significant association between the selected SNPs and PSVD diagnosis. CONCLUSION: The increase of spleen diameter is the strongest predictor of PSVD in patients treated with OX for CRC. These patients could be candidates for a specific follow-up of portal hypertension-related complications.

Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Are liver contour and bone fusion comparable to fiducials for IGRT in liver SBRT?

Introduction: Liver stereotactic body radiotherapy (SBRT) is increasingly being used to treat tumours. The purpose of this study was to compare the differences in patient positioning when using implanted fiducials as surrogates compared to alternative methods based on liver contour or bone registration. Material and methods: Eighteen patients treated with SBRT who underwent a fiducial placement procedure were included. Fiducial guidance was our gold standard to guide treatment in this study. After recording the displacements, when fusing the planning CT and CBCT performed in the treatment unit using fiducials, liver contour and bone reference, the differences between fiducials and liver contour and bone reference were calculated. Data from 88 CBCT were analyzed. The correlation between the displacements found with fiducials and those performed based on the liver contour and the nearest bone structure as references was determined. The mean, median, variance, range and standard deviation of the displacements with each of the fusion methods were obtained. µ, Æ©, and σ values and margins were obtained. Results: Lateral displacements of less than 3 mm with respect to the gold standard in 92% vs. 62.5% of cases using liver contour and bone references, respectively, with 93.2% vs. 65.9% in the AP axis and SI movement in 69.3% vs. 51.1%. The errors µ, σ and Æ© of the fusions with hepatic contour and bone reference in SI were 0.26 mm, 4 mm and 3 mm, and 0.8 mm, 5 mm and 3 mm respectively. Conclusion: Our study showed that displacements were smaller with the use of hepatic contour compared to bone reference and comparable to those obtained with the use of fiducials in the lateral, AP and SI motion axes. This would justify that hepatic contouring can be a guide in the treatment of patients in the absence of fiducials.

Pre-surgical risk assessment in patients with cirrhosis.

Over the last decades, significant improvements in the clini- cal management of patients with cirrhosis have increased their life expectancy. Thus, indications for surgical procedures other than liver transplantation are becoming more frequent. However, patients with advanced liver disease are at high risk of perioperative morbidity and mortality. This is the consequence of multiple factors that include the presence of portal hypertension, alterations on hemostasis and coagulation, the immune dysfunction that entails an increased risk of infections, and the impaired synthesis of proteins that impacts on the nutritional status and the wound healing. Surgical outcomes are not only determined by the severity of the liver disease, but also by the type of surgery and the presence of other comorbidities. Different models to predict mortality have been proposed, including the MELD score, the Child-Pugh classification, the hepatic venous pressure gradient, and the Mayo postoperative mortality risk calculator, among others. Multidisciplinary committees including surgeons, anesthesiologists, hepatologists, critical care physicians and other specialties involved in each case, should assess individually the risk-benefit of the surgical procedure, also considering patient`s expectations and will.

Current management of acute idiopathic pancreatitis and acute recurrent pancreatitis. / Manejo actual de la pancreatitis aguda idiopática y la pancreatitis aguda recurrente.

Acute pancreatitis is an entity of notable importance due to its high incidence and its non-negligible morbidity and mortality. Idiopathic acute pancreatitis is that in which the cause of the clinical condition cannot be determined after an initial basic study. Understanding the underlying aetiology enables clinicians to propose a targeted treatment to reduce the risk of recurrence. Endoscopic ultrasonography and magnetic resonance cholangiopancreatography are the tests of choice to deepen the aetiological study. The main cause is undiagnosed lithiasic disease in the initial study, whose treatment of choice is cholecystectomy. Moreover, recurrent acute pancreatitis is diagnosed after 2 or more episodes of acute pancreatitis. The objective of this review is to provide an updated approach for these 2 entities, reviewing aspects of their epidemiology, diagnosis and available alternative therapies.

Initial immunosuppression with or without basiliximab: a comparative study.

BACKGROUND: Following liver transplantation, acute kidney injury (AKI) and chronic kidney disease occur in 20%-50% and 30%-90% of patients, respectively. Basiliximab, a chimeric monoclonal antibody, is highly effective to prevent rejection in organ transplant recipients, particularly among patients with renal dysfunction who benefit from delayed introduction of calcineurin inhibitors. OBJECTIVE: The objective of this study was to measure the immunosuppressive effect of basiliximab and its impact on renal failure, lengths of hospital and intensive care unit (ICU) stays and prevalence of infection. METHODS: From January 2010 through December 2011, we performed a controlled, nonrandomized study comparing two different immunosuppressive regimens: Group I, 36 transplantation on 34 patients, tacrolimus and corticosteroids de novo with mycophenolate mofetil in cases of renal failure; and Group II, 33 transplantation in 33 patients, corticosteriods and mycophenolate mofetil de novo with basiliximab on day 0 and day 4, and inception of tacrolimus on day 3. RESULTS: Basiliximab patients (Group II) showed a significantly lower incidence of renal failure requiring replacement therapy (3.03% vs 25%; P = .014). The incidence of acute cellular rejection episodes treated with corticosteriod boluses was also significantly lower (3.03% vs 25%; P = .014). Bacterial, fungal, and cytomegalovirus infection rates were lower in Group II, although the differences were not significant. Similarly, Group II patients had an insignificantly shorter average stay in the hospital (25.9 vs 40.06 days) and the ICU (5.9 vs 8.17 days). CONCLUSIONS: Basiliximab administration with delayed introduction of calcineurin inhibitors may be an effective strategy to reduce post-liver transplantation AKI requiring renal replacement therapy.

Endoscopic follow-up of gastric ulcer in a population at intermediate risk for gastric cancer.

OBJECTIVES: Primary: to assess the necessity of a second endoscopy with a pathology study to confirm the healing of all gastric ulcers previously diagnosed through endoscopy in a population at intermediate risk for gastric cancer. Secondary: to assess correlation between endoscopic findings and pathology diagnosis. PATIENTS AND METHODS: a prospective analysis of patients diagnosed with gastric ulcer through endoscopy at Hospital General de Ciudad Real (Spain) over three years. We collected demographic, clinical, endoscopic, and pathological data for the first and subsequent endoscopies. We collected at least six biopsies obtained from ulcer margins, and assessed H. pylori infection. RESULTS: Three hundred and two patients were included in this study. H. pylori infection was diagnosed in 173 (57%), and 113 (37%) patients had used NSAIDs. The positive and negative predictive value for malignancy of endoscopic diagnosis regarding ulcer fold, base, and margins were 34 and 97%, respectively. Only one patient was diagnosed with a tumor during the second endoscopy. At the end of follow-up, the etiology of the ulcer was considered as peptic in 276 patients; Crohn s disease-related in one, and neoplastic in 25 patients (21 adenocarcinomas, 4 lymphomas). CONCLUSIONS: in an intermediate-risk population for gastric cancer a second endoscopy is not justified for gastric ulcer patients when endoscopy and biopsy results do not suggest malignancy.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes METHODS: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4-6 weeks on medical therapy. RESULTS: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction >or=20% or

[Hepatitis C virus in populations at risk for infection. Venezuela]. / Virus de hepatitis C en poblaciones de riesgo a adquirir la infección. Venezuela.

OBJECTIVE: The aim of this study was to establish the prevalence of hepatitis C virus infection in different populations at risk for infection. METHODS: This was a descriptive, transversal study whose variables were evaluated by Pearson s correlation analysis. Different populations were selected: 100 drug users, 47 sex workers, and 50 hemodialysis patients for a total of 197 individuals. The only inclusion criterion was the apparent risk of acquiring this viral infection. The presence of antibodies against virus was examined by ELISA IV (Innotest HCV Ab IV). Reactive samples were then tested using a recombinant assay (INNO-LIA HCV Ab III), both from Innogenetics N. V. (Belgium). The presence of viral RNA was determined in all ELISA and immunoblot-reactive samples by a nested polymerase chain reaction method (HCV-fast of Pharma Gen). RESULTS: A prevalence of 1% was found in drug users, and absence of infection or previous contact with the virus in sex workers and hemodialysis patients. CONCLUSIONS: This study shows a very low prevalence of infection with hepatitis C virus in populations at risk for acquiring the infection, and considered that this infection is not a public health problem in these populations in Maracaibo, Venezuela.

[Serological and genetic markers in the diagnosis and follow-up of coeliac disease]. / Marcadores serológicos y genéticos en el diagnóstico y seguimiento de la enfermedad celíaca.

INTRODUCTION: Understanding of celiac disease has changed with the advent of serological markers (antigliadin IgA, anti-endomysial IgA and anti-transglutaminase IgA antibodies) and with the identification of major susceptibility genes (HLA-DQA1*05-DQB1*02). Reports of the efficacy of these diagnostic tests have varied, depending on the methodology used and the population investigated. OBJECTIVES: To determine the clinical utility of genetic and serological markers in the diagnosis of celiac disease, their relationship with histological lesions and their changes during treatment, in order to establish an optimal diagnostic algorithm in our environment. PATIENTS AND METHODS: We performed a retrospective study of 590 patients from the health area of Badajoz referred to the Immunology Laboratory for screening or follow-up of celiac disease. The results of intestinal histology, serological markers (antigliadin IgA, anti-endomysial IgA and anti-transglutaminase IgA antibodies), and genomic typing (HLA-DQA1*05-DQB1*02) were analyzed. RESULTS: The sensitivity and specificity of serological tests were greater than 90 %, with a negative predictive value of 98-100 %. HLA-DQA1*05-DQB1*02 was detected in 97 % of celiac patients, with a very high negative predictive value (99 %). On biopsy, 95 % of the patients with some grade of intestinal lesion were positive for antigliadin and/or anti-endomysial antibodies. CONCLUSION: To avoid missed diagnoses, the diagnostic algorithm of celiac disease should include at least two serological markers (antigliadin antibodies and anti-endomysial and/or anti-transglutaminase antibodies) and IgA quantification. Genomic typing should be carried out if one or more markers are positive or if the subject belongs to any of the risk groups. The physician should decide on the advisability of intestinal biopsy on the basis of the patient's clinical and immunological history.

Mitochondrial calcium sequestration and protein kinase C cooperate in the regulation of cortical F-actin disassembly and secretion in bovine chromaffin cells.

Mitochondria play an important role in the homeostasis of intracellular Ca(2+) and regulate its availability for exocytosis. Inhibitors of mitochondria Ca(2+) uptake such as protonophore CCCP potentiate the secretory response to a depolarizing pulse of K(+). Exposure of cells to agents that directly (cytochalasin D, latrunculin B) or indirectly (PMA) disrupt cortical F-actin networks also potentiate the secretory response to high K(+). The effects of cytochalasin D and CCCP on secretion were additive whereas those of PMA and CCCP were not; this suggests different mechanisms for cytochalasin D and CCCP and a similar mechanism for PMA and CCCP. Mitochondria were the site of action of CCCP, because the potentiation of secretion by CCCP was observed even after depletion of Ca(2+) from the endoplasmic reticulum. CCCP induced a small increase in the cytosolic Ca(2+) concentration ([Ca(2+)](c)) that was not modified by the protein kinase C (PKC) inhibitor chelerythrine. Both CCCP and PMA induced cortical F-actin disassembly, an effect abolished by chelerythrine. In addition, rotenone and oligomycin A, two other mitochondrial inhibitors, also evoked cortical F-actin disassembly and potentiated secretion; again, these effects were blocked by chelerythrine. CCCP also enhanced the phosphorylation of PKC and myristoylated alanine-rich C kinase substance (MARCKS), and these were also inhibited by chelerythrine. The results suggest that the rapid sequestration of Ca(2+) by mitochondria would protect the cell from an enhanced PKC activation and cortical F-actin disassembly, thereby limiting the magnitude of the secretory response.

Multicenter randomized controlled trial comparing different schedules of somatostatin in the treatment of acute variceal bleeding.

BACKGROUND/AIMS: The dose of somatostatin used for variceal bleeding (250 microg/h) is lower than that proven to effectively decrease portal pressure and azygos blood flow (500 microg/h). Moreover, i.v. somatostatin boluses have greater effects than continuous infusions. The aim of this study was to investigate whether higher doses of somatostatin and repeated boluses may increase its efficacy in controlling variceal bleeding. METHODS: A total of 174 patients with acute variceal bleeding were randomized to receive for 48 h: (A) one 250 microg bolus +250 microg/h infusion; (B) three 250 microg boluses +250 microg/h infusion; (C) three 250 microg boluses +500 microg/h infusion. RESULTS: The three schedules of somatostatin were equally effective in controlling variceal bleeding (73, 75 and 81%, respectively, NS). Multivariate analysis showed active bleeding at endoscopy (n=75) as the only predictor of failure to control bleeding. In these patients, the 500 microg/h infusion dose achieved a higher rate of control of bleeding (82 vs. 60%, P<0.05), less transfusions (3.7 +/- 2.7 vs. 2.5 +/- 2.3 UU, P=0.07) and better survival (93 vs. 70%, P<0.05) than schedules A/B. CONCLUSIONS: Somatostatin is highly effective in controlling variceal bleeding. Patients with active bleeding at emergency endoscopy may benefit from higher doses of somatostatin infusion.

Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers.

BACKGROUND & AIMS: Nonselective beta-blockers (beta-blockers) are very effective in preventing first variceal bleeding (FVB) in patients with cirrhosis. However, 15%-25% of patients have contraindications or develop severe side effects precluding its use. The present study evaluates whether isosorbide-5-mononitrate (Is-MN) effectively prevents variceal bleeding in patients with contraindications or who could not tolerate beta-blockers. METHODS: One hundred thirty-three consecutive cirrhotic patients with gastro-esophageal varices and contraindications or intolerance to beta-blockers were included in a multicenter, prospective, double-blind randomized controlled trial. Sixty-seven were randomized to receive Is-MN, and 66 to receive placebo. RESULTS: There were no significant differences in the 1- and 2-year actuarial probability of experiencing a FVB between the 2 treatment groups. Presence of variceal red signs at endoscopy was the only variable independently associated with an increased risk of variceal bleeding on follow-up (relative risk 3.4; P < 0.01). Survival and adverse events were similar in the 2 groups. There were no significant differences in the incidence of ascites or changes in renal function. CONCLUSIONS: Is-MN does not reduce the incidence of FVB in patients with cirrhosis and esophageal varices who cannot be treated with beta-blockers because contraindications or intolerance to these drugs, suggesting that Is-MN has no place in the primary prophylaxis of variceal bleeding.

Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis.

BACKGROUND & AIMS: It has been suggested that losartan, an angiotensin II (A-II) type 1 receptor blocker, may have a pronounced portal pressure reducing effect, far greater than that of propranolol. This randomized controlled trial compared the hemodynamic and renal effects of continued 6-week administration of losartan (n = 25) vs. propranolol (n = 15) in portal hypertensive patients with cirrhosis treated endoscopically after a variceal bleeding episode. METHODS: Hepatic venous pressure gradient (HVPG), systemic hemodynamics, renal function, and vasoactive factors were measured before and at 6 weeks of treatment. RESULTS: Losartan did not reduce HVPG (-2% +/- 12%, NS) but significantly decreased mean arterial pressure (MAP, -8% +/- 10%, P = 0.001). On the contrary, propranolol significantly reduced HVPG (-10% +/- 11%, P = 0.003) and cardiac output (-16% +/- 12%, P = 0.001) but did not modify MAP (2.5% +/- 10%, NS). Losartan increased A-II levels, reduced aldosterone, and decreased glomerular filtration rate (GFR) in Child B patients. Propranolol did not modify renal function. Adverse events related to therapy were mild and similar in both groups. CONCLUSIONS: Unlike propranolol, long-term losartan administration does not significantly reduce HVPG in patients with cirrhosis treated after a variceal bleeding episode, and it caused hypotension and reduced GFR in patients with moderate liver failure. Therefore, losartan is not an alternative to propranolol in preventing variceal rebleeding.

Control of secretion by mitochondria depends on the size of the local [Ca2+] after chromaffin cell stimulation.

In chromaffin cells, plasma membrane calcium (Ca2+) channels and mitochondria constitute defined functional units controlling the availability of Ca2+ nearby exocytotic sites. We show here that, when L-/N-type Ca2+ channels were inhibited with nisoldipine and omega-conotoxin GVIA, cytosolic [Ca2+] ([Ca2+]c) peaks measured in fura-4F-loaded cells were reduced by 36%; however, mitochondrial Ca2+ uptake was unaffected and secretion was potentiated by protonophores as in control cells. By contrast, when non L-type Ca2+ channels were inhibited with omega-conotoxin MVIIC, [Ca2+]c peaks induced by high K+ were reduced by 73%, mitochondrial Ca2+ uptake was abolished, and secretion was not modified by protonophores. However, if Ca2+ entered only through L-type channels activated by FPL64176, high K+ stimulation induced fast mitochondrial Ca2+ uptake and catecholamine secretion was strongly increased and potentiated by protonophores. These results confirm the close association of catecholamine secretion to mitochondrial Ca2+ uptake, and indicate the sharp threshold of local [Ca2+]c (about 5 microM) required for triggering fast mitochondrial Ca2+ uptake that is able to modulate secretion. The entry of Ca2+ through L-type channels generated local [Ca2+]c increases just below that, inducing little mitochondrial Ca2+ uptake unless FPL64176 was present. By contrast, Ca2+ entry through P/Q-type channels fully activated mitochondrial Ca2+ uptake. Control of secretion by mitochondria therefore depends critically on the ability of the stimulus to create large local [Ca2+]c microdomains.

Mitochondrial Ca(2+)-induced Ca(2+) release mediated by the Ca(2+) uniporter.

We have reported that a population of chromaffin cell mitochondria takes up large amounts of Ca(2+) during cell stimulation. The present study focuses on the pathways for mitochondrial Ca(2+) efflux. Treatment with protonophores before cell stimulation abolished mitochondrial Ca(2+) uptake and increased the cytosolic [Ca(2+)] ([Ca(2+)](c)) peak induced by the stimulus. Instead, when protonophores were added after cell stimulation, they did not modify [Ca(2+)](c) kinetics and inhibited Ca(2+) release from Ca(2+)-loaded mitochondria. This effect was due to inhibition of mitochondrial Na(+)/Ca(2+) exchange, because blocking this system with CGP37157 produced no further effect. Increasing extramitochondrial [Ca(2+)](c) triggered fast Ca(2+) release from these depolarized Ca(2+)-loaded mitochondria, both in intact or permeabilized cells. These effects of protonophores were mimicked by valinomycin, but not by nigericin. The observed mitochondrial Ca(2+)-induced Ca(2+) release response was insensitive to cyclosporin A and CGP37157 but fully blocked by ruthenium red, suggesting that it may be mediated by reversal of the Ca(2+) uniporter. This novel kind of mitochondrial Ca(2+)-induced Ca(2+) release might contribute to Ca(2+) clearance from mitochondria that become depolarized during Ca(2+) overload.

Time course of serum hepatitis C virus-RNA during chronic hepatitis C treatment accurately predicts the type of response.

AIM: To establish the value of alanine aminotransferase normalization and hepatitis C virus-RNA clearance as predictors of sustained virological response in naïve and relapser chronic hepatitis C patients on mono or combination therapy. METHODS: A total of 282 hepatitis C patients were studied: 98 naïves on interferon, and 64 naïves and 75 relapsers on interferon plus oral ribavirin; 45 patients were excluded. Drugs were administered at standard doses for 12 months. Alanine aminotransferase and hepatitis C virus-RNA were determined at baseline and at weeks 4, 12, 24, 48, and at 72 and 96 weeks after completion of therapy. RESULTS: The rate of sustained response was greater (P < 0.05) in naïves and relapsers on combination therapy (33% and 48%, respectively) than in naïves on interferon alone (16%). Hepatitis C virus-RNA significantly decreased from baseline by week 4 in naïves on interferon and relapsers on combination therapy and by week 12 in naïves on combination therapy. Alanine aminotransferase levels paralleled viremic load in naïves on interferon, yet in patients on combination therapy, alanine aminotransferase normalized independently of the virological response. During treatment, the main factor associated with sustained response was hepatitis C virus-RNA clearance by week 4 in naïves on interferon and relapsers on combination therapy, and by week 24 in naïves on combination therapy. CONCLUSION: Clearance of viraemia constitutes the best predictor of a sustained response to therapy, but needs to be measured at patient-specific times.