Tayfur Toptas

Is alanine aminotransferase level a surrogate biomarker of hepatic apoptosis in nonalcoholic fatty liver disease

AIM To evaluate the serum alanine aminotransferase (ALT) variabilities in nonalcoholic fatty liver disease (NAFLD) and correlate it with hepatocyte apoptosis and oxidative stress parameters. METHODS 24 patients with NAFLD and normal ALT were compared with 26 subjects with NAFLD and elevated ALT. Liver oxidative stress was estimated on the basis of malondialdehyde, superoxide dismutase and glutathione. Immunohistochemistry was performed for activated caspase 3 and 8, nuclear factor-kappaB, antiapoptotic Bcl-2 protein and serum TNF receptor levels were measured. RESULTS The mean caspase 3 and 8 activity scores, oxidative stress parameters, necroinflammatory grade and prevalence of severe fibrosis were comparable across the groups with normal versus elevated ALT. Patients with nonalcoholic steatohepatitis had significantly higher caspase 3 and 8 activity (percentage of cells with positive staining per high power field), and serum malondialdehyde (mmol/l) levels than those with simple steatosis. ALT elevation was not a risk factor for advanced necroinflammatory grade and fibrosis. A receiver operating characteristic curve did not demonstrate sensitivity and specificity for discriminative power of ALT. CONCLUSION Apoptosis and oxidative stress are the main processes contributing to disease progression in NAFLD. ALT values do not correlate with the parameters of apoptosis and oxidative stress. The disease severity can only be determined by liver biopsy.

Validation of Biochemical Markers for the Prediction of Liver Fibrosis and Necroinflammatory Activity in Hemodialysis Patients with Chronic Hepatitis C

Background: Liver biopsy is an imperfect gold standard for assessing the disease severity in hemodialysis patients with chronic hepatitis C. Our purpose was to compare the accuracy of the FibroTest (FT) and ActiTest (AT) with liver biopsy and the AST-to-platelet ratio index (APRI) in determining hepatic fibrosis and necroinflammatory activity in hemodialysis patients with hepatitis C virus (HCV). Methods: The FT-AT index combining 6 biochemical markers was assessed in 33 hemodialysis patients with HCV. Liver fibrosis and necroinflammatory activity was staged and graded according to the METAVIR scoring system. Results: The accuracy of FT-AT versus biopsy was 0.46 for significant fibrosis and 0.36 for severe necroinflammatory activity. The FT index had a positive predictive value of 20% for scores greater than 0.6 and a negative predictive value of 45% for scores less than 0.2. Eleven of the 33 patients had scores ≤0.2, 6 had significant fibrosis on biopsy. Four out of 5 patients with FT scores >0.6 had mild fibrosis. APRI correlated well with the biopsy. Conclusion: The FT-AT test does not seem to be a reliable noninvasive marker for the prediction of necroinflammatory activity and fibrosis in hemodialysis patients with HCV and cannot be used as an alternative to either liver biopsy or APRI.

Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience

Background Reed-Sternberg cells of classical Hodgkins lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. Patients and methods We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. Results Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. Conclusions Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity.

Azacitidine versus decitabine in patients with refractory anemia with excess blast—Results of multicenter study

The present study aimed to compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndrome (MDS). A total of 88 patients diagnosed with refractory anemia with excess blast (RAEB) treated with azacitidine (n=57) or decitabine (n=31) were evaluated. Comparisons between azacitidine and decitabine groups were performed in the whole cohort, and in a 1:1 propensity score-matched cohort in order to reduce the simple selection bias. Patients who received azacitidine or decitabine had comparable overall response rates in both the unmatched (49.1% vs. 64.5%, p=0.166) and the propensity-matched cohorts (52% vs. 68%, p=0.248). The cumulative incidence of AML transformation at one year was comparable between azacitidine and decitabine in the unmatched (24.0% vs. 31.3%, p=0.26) and in the propensity-matched cohorts (18.7% vs. 31.5%, p=0.11). There was no difference in terms of transfusion requirement, febrile neutropenia episodes or the need for antifungal use during the treatment cycles in the propensity-matched cohort. The median overall survival was 20.4 months for azacitidine and 16.8 months for decitabine (p=0.59). Finally, we found that at least a four-cycle treatment with any HMA was a favorable factor. In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS-RAEB.

Levofloxacin for the treatment of severe refractory BK virus‑associated hemorrhagic cystitis in hematopoietic stem cell transplantation recipients: A report of three cases

BK-virus (BKV) is an important etiological agent for late-onset hemorrhagic cystitis (HC) in patients undergoing hematopoietic stem cell transplantation. Late-onset HC causes significant morbidity among these patients. Therapeutic approaches remain predominantly symptomatic. Several treatment options have been used with variable success rates. Cidofovir has the highest specificity against BKV; however, its lack of availability in the majority of countries, high costs and potential nephrotoxic effects limit its use. The present study reports three cases of severe and prolonged BKV-associated HC (BKHC). HC was resolved in all three of the patients using oral levofloxacin. Thus, levofloxacin may be an effective treatment modality for achieving complete clinical and molecular response in patients with refractory, severe BKHC.

Reliability of caspase activity as a biomarker of hepatic apoptosis in nonalcoholic fatty liver disease

A letter in response to: Yilmaz Y, Kurt R, Kalayci C. Apoptosis in nonalcoholic steatohepatitis with normal aminotransferase values: zooming in on cytokeratin 18 fragments. Biomarkers Med. 4(5), 743–745 (2010).

Bortezomib in patients with renal impairment

Abstract Renal failure is a common manifestation of multiple myeloma (MM). Bortezomib is primarily metabolized by cytochrome p450 isoforms. It also has a cytochrome-independent metabolism by excretion through the bile and kidney. Based on our observations, we aimed to explore the efficacy and toxicity profiles of bortezomib in 56 patients with MM, 24 of which had moderate to severe renal failure. Overall response and complete response, as well as very good partial response rates, were comparable between patients with normal renal functions and renal impairment. The median overall survivals for patients with estimated glomerular filtration rates of <60 and ⩾60 ml/minute were similar. Although there was a tendency for shorter overall survival along lower estimated glomerular filtration rates, this difference did not reach a statistical significance. Overall and severe adverse events, and dose modification and treatment discontinuation rates were higher in patients with renal impairment. Patients with renal failure had more thrombocytopenia and diarrhea. While thrombocytopenia was mild to moderate and manageable, diarrhea, which led to serious adverse events, was more severe in patients with renal failure who received bortezomib as monotherapy. Bortezomib appears to be active; however, when used alone, it may cause more frequent and severe adverse events in patients with MM and renal failure.

Precursor B cell lymphoblastic lymphoma presenting as a solitary bone tumor: a case report and review of the literature

Precursor B cell lymphoblastic lymphoma (B-LBL) is quite uncommon and it usually manifests as an extranodal disease. Although B-LBL may present with bone involvement, it is a very rare manifestation of B-LBL as a primary solitary bone tumor. Here, we report a case of precursor B-LBL presenting with solitary bone tumor and a review of a total of seven adult patients reported previously in the literature. We described demographic and clinical characteristics of these patients with unique presentation and discussed treatment options. Unlike previous reports except one case, our patient underwent allogeneic stem cell transplantation (allo-SCT) due to refractory disease. She is alive without evidence of disease by the post-transplant 12th month. B-LBL has an aggressive clinical course in adult patients and allo-SCT may be the best treatment option.

Myelodysplastic syndrome with t(9;22)(p24;q11.2), a BCR-JAK2 fusion: case report and review of the literature

The human JAK2 gene is mainly targeted by two types of genetic lesions that play roles in the pathogenesis of hematologic malignancies: intragenic mutations and chromosomal translocations. Chromosomal translocations of JAK2 are typically associated with myeloid or lymphoid malignancies with an aggressive course and poor outcome. Here we report a t(9;22)(p24;q11.2) translocation, in a MDS patient and review results associated with BCR-JAK2 fusion reported in the literature.

Miliary Tuberculosis Induced Acute Liver Failure

Hepatobiliary tuberculosis is uncommon even in endemic countries. It is associated with a high mortality and is even diagnosed early in the disease course. Acute liver failure (ALF) caused by tuberculosis bacilli has been reported in only a few reports. All previous cases have been diagnosed by postmortem examination. Time to antituberculosis treatment is very critical. In case of suggestive findings on clinical and radiologic examination, antituberculosis treatment should be initiated immediately. Drug use can be a challenge in patients with ALF. However, as long as the other possible causes of ALF can be excluded and hepatotoxic drugs were avoided during the early course of treatment, such a highly fatal presentation of tuberculosis can be treated safely. Here, we report a case of acute liver failure as a presentation of miliary tuberculosis. He was treated successfully with antituberculosis treatment.