Ronit Leiba

Strikingly high false positivity of surveillance FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era

Predictive value (PV) of surveillance fluorodeoxyglucose positron emission tomography (FDG‐PET) in patients with diffuse large B‐cell lymphoma (DLBCL) treated with chemotherapy‐rituximab (R) versus chemotherapy only, remains unclear. The aim of the current study was to compare the performance of surveillance PET in DLBCL patients receiving CHOP (cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone) alone versus CHOP‐R. Institutional database was retrospectively searched for adults with newly diagnosed DLBCL, receiving CHOP or CHOP‐R, who achieved complete remission and underwent surveillance PETs. Follow‐up (FU) PET was considered positive for recurrence in case of an uptake unrelated to physiological or known benign process. Results were confirmed by biopsy, imaging and clinical FU. One hundred nineteen patients, 35 receiving CHOP and 84 CHOP‐R, who underwent 422 FU‐PETs, were analyzed. At a median PET‐FU of 3.4 years, 31 patients relapsed (17 vs. 14, respectively; P = 0.02). PET detected all relapses, with no false‐negative studies. Specificity and positive PV (PPV) were significantly lower for patients receiving CHOP‐R vs. CHOP (84% vs. 87%, P = 0.023; 23% vs. 74%, P < 0.0001), reflecting a higher false‐positive (FP) rate in subjects receiving CHOP‐R (77% vs. 26%, P < 0.001). In the latter group, FP‐rate remained persistently high up to 3 years post‐therapy. Multivariate analysis confirmed rituximab to be the most significant predictor for FP‐PET. In conclusion, routine surveillance FDG‐PET is not recommended in DLBCL treated with rituximab; strict criteria identifying patients in whom FU‐PET is beneficial are required. Am. J. Hematol. 88:400–405, 2013.

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

Hypomethylating agents have become the standard therapy for patients with high‐risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA‐treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high‐risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29–92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130–134, 2013.

Modulation of systemic hemostatic parameters by enoxaparin during gestation in women with thrombophilia and pregnancy loss

Recurrent pregnancy loss (PL) is associated with maternal thrombophilia and prophylaxis with low molecular weight heparin (LMWH) can improve pregnancy outcome in this setting. The aim of this study was to investigate the modulation of systemic hemostatic parameters by enoxaparin in women with recurrent PL and to evaluate plasmatic parameters that would potentially enable monitoring LMWH prophylaxis effect during pregnancy. Study group included 87 women with thrombophilia and PL treated with enoxaparin 40 mg daily vs. 40 mg twice daily. The control group comprised 40 women with normal pregnancies. Blood samples have been collected throughout the period starting at 5-10 weeks of gestation until 6-10 weeks postpartum. The determined plasmatic markers included: anti-Xa activity, total and free tissue factor pathway inhibitor (TFPI), D-dimer, prothrombin fragment 1+2 (PT1+2), activated protein C resistance (APC-SR) and free protein S. Successful pregnancy outcome was recorded in 70 (80.5%) women treated with enoxaparin, without correlation to enoxaparin dosage. Seventeen women (19.5%) had pregnancy loss at 16+/-7 (6-32) weeks of gestation. Anti-Xa levels at 10-15 weeks of gestation were higher (0.39+/-0.38 u/ml) in the successful pregnancy outcome group compared to the abortion group (0.22+/-0.2 u/ml). Prophylactic anti-Xa activity levels (0.28+/-0.13 u/ml) were documented from 15 weeks of gestation until delivery in the successful pregnancy outcome group. Significant increase in anti-Xa, total TFPI and free TFPI levels (P<0.001) was achieved after beginning of LMWH prophylaxis in successful pregnancy outcome group but not in the abortion group. D-dimer and PT1+2 levels appeared to be significantly increased while APC-SR and free protein S levels gradually decreased during pregnancy, with no difference between study groups. These results suggest that LMWH prophylaxis during pregnancy enables modulation of systemic hemostatic parameters via inhibition of factor Xa and increase in plasmatic total and free TFPI levels.

Bortezomib-cyclophosphamide-dexamethasone (VCD) versus bortezomib-thalidomide-dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis.

Three‐drug induction regimens have become the standard of care in newly diagnosed transplant‐eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms ‘VTD’ or ‘VCD’ and ‘induction regimens for newly diagnosed multiple myeloma’. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3–4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3–4 adverse events was found in the VCD‐treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.

Effect of Sildenafil on Middle-Aged Sexually Active Males with No Erectile Complaints: A Randomized Placebo-Controlled Double-Blind Study

BACKGROUND In clinical practice, we commonly encounter sexually healthy males who use phosphodiesterase type 5 (PDE5) inhibitors and report a beneficial effect to their sex life. OBJECTIVE In this study, we aimed to evaluate in a controlled manner the true effect of sildenafil 50 mg on the quality of sexual life (QSL) in a group of sexually active males who do not have erectile complaints. DESIGN, SETTING, AND PARTICIPANTS This prospective, placebo-controlled, double-blind, crossover study included sexually active middle-aged males who were never evaluated/treated for erectile dysfunction (ED) and who had an International Index of Erectile Function (IIEF) Erectile Function (EF) Domain score > or = 22. The study included four visits in which subjects randomly received six tablets of sildenafil 50mg or placebo in a crossover manner. MEASUREMENTS Assessment of efficacy was performed by subjects filling out the following QSL questionnaires: the Self-Esteem and Relationship Questionnaire (SEAR), the IIEF, the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), and additional questions regarding sexual performance (SAQ). RESULTS AND LIMITATIONS From a group of 65 screened subjects, 47 were eligible for analysis (28 without ED and 19 with mild ED). Average age was 52.1+/-10, mostly married (88%), with an IIEF-EF Domain score of 25.6+/-3.1. We found significant differences between the sildenafil vs placebo groups in the EDITS (70.8+/-18 vs 60.3+/-19, p=0.013), SEAR (57.6+/-1 vs 51+/-1. p<0.0001), and IIEF-EF Domain score (25.1+/-4.8 vs 23+/-5.3, p=0.013). All of our structured questionnaires showed significant improvement in the treated group. We did not find significant differences between the groups in the total IIEF score. We also performed individual analysis in the subgroup of subjects (mild ED vs normal EF), and no significant differences were demonstrated in the results of these groups with regard to total scores on all questionnaires employed. CONCLUSIONS This is the first placebo-controlled study performed on a selected group of individuals suggesting that middle-aged subjects without complaints of ED may have real benefit when using sildenafil. This study provides some preliminary data regarding the use of a phosphoesterase type 5 inhibitor (PDE5-I) in this unexplored population, but more data are needed in order to seriously consider extending their use in these males and perhaps in the younger population.

Higher Infection Rate After 7- Compared With 5-Day Cycle of Azacitidine in Patients With Higher-Risk Myelodysplastic Syndrome

INTRODUCTION Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patients age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.

Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the “3 + 7” induction regimen for acute myeloid leukemia

Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re‐induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re‐induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re‐induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to <5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3‐year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long‐term survivors than the Day 14th BM count (66% vs. 30%, P = 0.0001 and 48% vs. 37%, respectively, P = 0.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re‐induction based on such early evaluation should be prospectively studied. Am. J. Hematol. 90:1159–1164, 2015.

Sedation with the Combination of Ketamine and Propofol in a Pediatric ED: A Retrospective Case Series Analysis ☆ ☆☆ ★ ★★

BACKGROUND Literature to date has suggested advantages of sedation with the combination of ketamine and propofol over ketamine alone or propofol alone. However, there is a paucity of data regarding sedation with the combination of ketamine and propofol in pediatric emergency medicine. METHODS A retrospective case series analysis of children who underwent sedation with the combination of ketamine and propofol in a pediatric emergency department was conducted. Study covariates were extracted from the emergency department medical records. RESULTS Four hundred twenty-nine patients, 297 males and 132 females, with a median age of 6.8 years (interquartile range, 3.9-10.9 years), underwent sedation by pediatric emergency physicians. Serious adverse events during sedation (SAEDS) were recorded in 52 procedures (12.1%), which included 39 hypoxic events (9.1%), 12 apneic events (2.8%), and 1 laryngospasm (0.2%). All SAEDS were managed successfully, and no child underwent intubation because of an adverse reaction or required hospitalization. Multivariate logistic regression analysis did not reveal any association between age, weight, fasting time, analgesic medication provided before sedation, length of procedure, capnography use, dosages of medications, and the presence of SAEDS. CONCLUSIONS This is the largest reported series of sedation with the combination of ketamine and propofol in pediatric emergency medicine. Findings suggest that sedation with the combination of ketamine and propofol can be safely performed by a skilled emergency physician.

Anchoring the numerical pain scale changes pain intensity reports in patients with chronic- but not with acute-pain

Despite enormous differences between acute and chronic pain, the numeric pain scale (NRS) is commonly used in pain research and clinical practice for assessing the intensity of both acute and chronic pain. The use of this scale has been challenged as it may fail to accurately reflect the pure intensity of chronic pain.

Single dose oral midazolam for minor emergency department procedures in children: a retrospective cohort study

Background In the pediatric emergency department, patients are commonly treated with a single dose of oral midazolam for minor procedures. We sought to evaluate the effect of this treatment on procedure completion rates. Methods We conducted a single-center retrospective cohort study of all patients who were treated with pre-procedure oral midazolam between January 2011 and June 2016. The primary outcome was the procedure completion rate. Results During the study period, 1,504 patients were treated with oral midazolam as per department protocol; 1,467 received midazolam and 37 declined midazolam. Oral midazolam was used in 14 different types of emergency department procedures. The procedure completion rates in the treatment and non-treatment groups were 1,402/1,467 (95.6%) and 24/37 (64.8%), respectively (difference 30.7%; 95% confidence interval [CI] 17.3%–46.8%); p<0.0001. Treatment group patients had procedure completion rates of 25/33 (75.8%), 165/188 (87.8%%), 1,154/1,187 (97.2%), and 58/59 (98.3%), in the less than 0.3 mg/kg group, 0.3 to less than 0.5 mg/kg group, 0.5 to less than 0.7 mg/kg group, and 0.7 to less than 0.9 mg/kg group, respectively. Multivariate regression did not demonstrate an association between sex, ethnicity, dosage of 0.5 mg/kg or greater, type of procedure, and failure to complete procedure. Severe adverse events were not recorded. A dose of less than 0.3 mg/kg was significantly associated with an increased risk of failure to complete a procedure (adjusted odds ratio 8.34, 95% CI 3.32–20.9; p<0.0001). Conclusion The findings suggest that oral midazolam in a single dose of 0.5 mg/kg or greater is associated with successful completion of minor pediatric procedures.