Dimitrios C. Ziogas

Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (“waitlist”), placebo treatment alone (“limited”) and, placebo treatment “augmented” with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

Meta-analysis: the effects of placebo treatment on gastro-oesophageal reflux disease.

Aliment Pharmacol Ther 2010; 32: 29–42

MTHFR gene polymorphisms and response to chemotherapy in colorectal cancer: a meta-analysis

AIMS Pharmacogenetic studies investigating the relationship between MTHFR gene polymorphisms and response to fluorouracil-based chemotherapy in patients with colorectal cancer have produced inconclusive results. In an attempt to interpret these results, a meta-analysis of all eligible studies published up until January 2009 was carried out. MATERIALS & METHODS A total of ten studies relating MTHFR C677T and six studies relating MTHFR A1298C to the response to chemotherapy in patients with colorectal cancer were included in the meta-analysis and random effects pooled odds ratios were estimated. The heterogeneity between studies, the sources of potential bias and the consistency of genetic effects across ethnicities were explored. Cumulative and recursive cumulative meta-analyses were also performed. RESULTS For both the C677T and A1298C polymorphisms, the main analysis revealed nonsignificant heterogeneity and a lack of association under the allele contrast, the recessive and dominant models. The subgroup analysis by ethnicity did not change this pattern of results. The lack of stability of the relative change of odds ratio in the recursive cumulative meta-analysis for both polymorphisms indicated the need for more evidence to support a definite lack of association. There was no differential magnitude of the effect in large versus small studies. CONCLUSION The available evidence indicates that MTHFR C677T and A1298C gene polymorphisms cannot be considered as reliable predictors of response to fluorouracil-based chemotherapy in patients with colorectal cancer.

Analysis of the Quality of Reporting of Randomized Controlled Trials in Acute and Chronic Myeloid Leukemia, and Myelodysplastic Syndromes as Governed by the CONSORT Statement

PURPOSE Randomized controlled trials (RCTs) are the best tool to evaluate the effectiveness of clinical interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement is an evidence-based approach to improve the quality of RCTs. The aim of this study was to evaluate the reporting quality of published RCTs concerning myeloid hematologic malignancies according to the CONSORT statement. METHODS PubMed was searched for English-language RCTs involving patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS). Trials were considered eligible when participants were randomly assigned to at least two treatment arms and included patients with AML, CML or MDS. Quality of reporting was assessed using a 24-item questionnaire based on the CONSORT checklist. Reporting was assessed in one pre-CONSORT (1988-1995) and one post-CONSORT (1996-2008) period. The effect of CONSORT statement in high- and low-ranked journals, according to their impact factor, has also been evaluated. RESULTS The search identified 261 eligible articles for analysis. Only 13 of the 24 items of CONSORT statement were addressed in 75% or more of the studies. Most items concerning the methodological issues were reported by fewer than 50% of the studies. Significant improvements over time were seen for items that assessed the methodological quality, while RCTs published in high-ranked journals showed better quality of reporting. CONCLUSIONS Quality of reporting in RCTs focusing on myeloid malignancies remains unsatisfactory. Further improvement of reporting is necessary to assess the validity of clinical research.

Predicting the Outcome of Sjogren’s Syndrome-Associated Non-Hodgkin’s Lymphoma Patients

Background Non-Hodgkins lymphoma (NHL) development in Sjögren’s syndrome (SS) remains a potentially lethal complication and efforts should focus on the identification of predictors that could aid in appropriate therapeutic decisions. Methods In order to identify potential prognostic factors for outcome in SS-associated NHL, we retrospectively analyzed a cohort of 77 patients, diagnosed with NHL according to WHO classification criteria and meeting the American-European Consensus Classification (AECC) criteria for SS and examined the effect of SS-activity (defined as the EULAR SS disease activity index-ESSDAI) in the prognosis of SS-related NHLs, as defined in terms of overall and event-free survivals (OS and EFS). An event was defined as lymphoma relapse, treatment failure, disease progression, histological transformation or death. The effect of NHL clinical and laboratory characteristics was also investigated. Results MALT lymphomas constituted the majority (66.2%) of lymphomas. During the follow-up (median = 57.93 months), the 5-year OS was 90.91% (95% CI: 82.14–95.80%) and the EFS was 77.92% (95% CI: 67.37–85.82%). Patients with high ESSDAI score at lymphoma diagnosis had a greater risk for death (OR = 5.241, 95% CI: 1.034–26.568) or for event (OR = 4.317, 95% CI: 1.146–9.699, p = 0.008). These patients had also significantly worse EFS (HR = 4.541, 95% CI: 1.772–11.637) and OS (HR = 5.946, 95% CI: 1.259–28.077). In addition, post-chemotherapy ESSDAI improvement was significantly lower in patients who had experienced an event (p = 0.005). An unfavorable International prognostic index (IPI) score (high-intermediate/high) was associated with high risk of death and event (OR = 13.867, 95% CI: 2.656–72.387 and OR = 12.589, 95% CI: 3.911–40.526, respectively), worse EFS (log-rank p<0.001, HR = 8.718, 95% CI: 3.477–21.858), as well as with worse OS (log-rank p<0.001, HR = 11.414, 95% CI: 2.414–53.974). After adjustment for identified risk factors, IPI score retained a significant prognostic role following by a strong effect of ESSDAI in survival outcomes. Conclusions At the point of NHL diagnosis, IPI and ESSDAI might be proved useful predictive tools in SS-associated lymphoma prognosis, directing to a more patient-tailored approach.

A Network Meta-analysis of Randomized Controlled Trials of Induction Treatments in Acute Myeloid Leukemia in the Elderly

BACKGROUND The optimal induction treatment of acute myeloid leukemia (AML) in the clinically and biologically heterogeneous group of elderly patients is not well-defined since direct comparisons between treatments is limited. OBJECTIVE The aim of this study was to estimate the relative effectiveness of induction treatments in AML elderly patients. METHODS A network of multiple treatments meta-analysis was performed by combining direct and indirect evidence from published randomized controlled trials (RCTs). The complete remission (CR) was considered as the outcome of interest. We systematically searched PubMed, EMBASE, and Cochrane Library until September 30, 2010, to identify all RCTs published in English that compared diverse induction chemotherapies in elderly AML patients. Our search strategy focused on RCTs that included AML patients >60 years, considering, however, that age stratification was varied between countries and over time and studies were not necessarily designed to compare elderly patients. Regimens were grouped a priori into 42 different types of induction treatment. Prognostic parameters (age, performance status, unfavorable cytogenetics, antecedent malignancy), AML outcomes (median disease-free, overall survival, CR, induction deaths), and myelotoxicity parameters (median duration until neutrophil recovery [>1.0 × 10(9)/L], platelet recovery [>100 × 10(9)/L], hospitalization duration) were evaluated for each induction type. In combining direct and indirect evidence, we calculated the odds ratio (OR) for each therapy relative to the most commonly used combination of standard-dose daunorubicin (30-60 mg/m(2) for 3 days) and standard-dose cytarabine (100 mg/m(2) for 7-10 days) that was set as the reference induction treatment. RESULTS We identified 65 RCTs (15,110 patients) that described 64 direct comparisons of induction treatments, but only 14 of them showed significant differences in CR after random effects meta-analyses. Median age of included patients was 68, 18.0% had secondary AML, 21.1 % had poor performance status, 26.7% displayed unfavorable cytogenetics, and 49.3% finally achieved CR. No significant differences were observed in the recorded induction toxicity parameters among the treatment arms. Through the network meta-analysis, the addition of all-trans retinoic acids or lomustine to the combination of idarubicin plus cytarabine showed significantly higher CR rate (OR = 1.93 [1.06-3.49] and 1.76 [1.08-2.88], respectively), whereas no treatment, clofarabine, daunorubicin plus topotecan, and the 2 different schedules of gemtuzumab ozogamicin (at 1, 3, and 5 days and at 1 and 8 days) showed a significantly lower CR rate (OR = 0.01 [0.001-0.19], 0.15 [0.04-0.58], 0.03 [0.002-0.64], 0.06 [0.01-0.51], and 0.05 [0.01-0.32], respectively) than that of the reference induction. Median overall survival showed no difference between treatments (P = 0.150) but was significantly increased during the last 30 years (P < 0.001), presumably reflecting advances in AML management. CONCLUSIONS Compared with the reference induction, significant differences were found for specific induction regimens, although most compared regimens appeared to have similar efficacy profiles. These results, however, should be interpreted with caution because the network was dominated by indirect comparisons. Data from large RCTs that make direct comparisons between treatments are needed to detect the optimal induction regimen for elderly AML patients.

Serum correlates of the placebo effect in irritable bowel syndrome.

Background  In diseases defined primarily by the subjective nature of patient self‐report, placebo effects can overwhelm the capacity of randomized controlled trials to detect medication‐placebo differences. Moreover, it is unclear whether such placebo effects represent genuine psychobiological phenomena or just shifts in selective attention. Knowledge of predictors of the placebo response could improve the design of clinical trials and the delivery of personalized medical care.

Bortezomib‐based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis

Renal failure (RF) is a common and severe complication of symptomatic myeloma, associated with significant morbidity and mortality. Such patients are commonly excluded from clinical trials. Bortezomib/dexamethasone (VD)‐based regimens are the backbone of the treatment of newly diagnosed MM patients who present with severe RF even those requiring dialysis. We analyzed the outcomes of 83 consecutive bortezomib‐treated patients with severe RF (eGFR < 30 ml/min/1.73 m2), of which 31 (37%) required dialysis. By IMWG renal response criteria, 54 (65%) patients achieved at least MRrenal, including CRrenal in 35% and PRrenal in 12%. Triplet combinations (i.e., VD plus a third agent) versus VD alone were associated with higher rates of renal responses (72 vs. 50%; P = 0.06). Fifteen of the 31 (48%) patients became dialysis independent within a median of 217 days (range 11–724). Triplets were associated with a higher probability of dialysis discontinuation (57 vs. 35%). Serum free light chain (sFLC) level ≥11,550 mg/L was associated with lower rates of major renal response, longer time to major renal response, lower probability, and longer time to dialysis discontinuation. Rapid myeloma response (≥PR within the first month) was also associated with higher rates of renal response. Patients who became dialysis‐independent had longer survival than those remaining on dialysis. In conclusion, VD‐based triplets are associated with a significant probability of renal response and dialysis discontinuation, improving the survival of patients who became dialysis independent. Rapid disease response is important for renal recovery and sFLCs are predictive of the probability and of the time required for renal response. Am. J. Hematol. 91:499–502, 2016.

Evaluation of the Revised International Staging System (R-ISS) in an independent cohort of unselected patients with multiple myeloma

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P<0.001). The R-ISS could identify three groups with distinct outcomes among patients treated with or without autologous stem cell transplantation, among those treated with either bortezomib-based or immunomodulatory drug-based primary therapy and in patients ≤65, 66–75 or >75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma.

Cardiac and renal complications of carfilzomib in patients with multiple myeloma

Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; P = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR <60 mL/min/1.73 m2. Further investigation is needed to elucidate the underlying mechanisms of carfilzomib-related cardiorenal toxicity.