The effect of hyaluronic acid in embryo transfer media in donor oocyte cycles and autologous oocyte cycles: a systematic review and meta-analysis.

STUDY QUESTION: Does the addition of hyaluronic acid (HA) to embryo transfer medium improve pregnancy outcomes in both autologous and oocyte donation IVF cycles? SUMMARY ANSWER: The best available evidence indicates that the addition of HA to embryo transfer medium is clinically beneficial in cycles with autologous oocytes. WHAT IS KNOWN ALREADY: There is a known clinical benefit of HA addition to embryo transfer media but it is not known if HA affects donor and autologous oocyte cycles differently. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was performed. The Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL via Cochrane Register of Studies Online (CRSO), MEDLINE, Embase and PsycINFO electronic databases (until 8 January 2020) were searched for randomized controlled trials (RCTs) examining the effect of HA in embryo transfer medium on pregnancy outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: RCTs with separate donor and autologous oocyte data that compared embryo transfer medium with functional HA concentrations (0.5 mg/ml) to those containing no or low HA concentrations (0.125 mg/ml) were included. Two review authors independently selected trials for inclusion, extracted data and assessed the included studies using the Cochrane risk of bias assessment tool. Pooled risk ratios and 95% CIs were calculated. A summary of findings table was generated using Grading of Recommendations, Assessment, Development and Evaluation criteria. Judgements about evidence quality were justified and incorporated into the reported results for each outcome. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen studies, totalling 4686 participants, were analysed. In autologous oocyte cycles, live birth increased from 32% to 39% when embryo transfer media contained functional HA concentrations (risk ratio (RR) 1.22, 95% CI 1.11-1.34; nine studies, 3215 participants, I2 = 39%, moderate-quality evidence (number needed to treat (NNT) 14). HA-enriched media increased clinical pregnancy and multiple pregnancy rates by 5% and 8%, respectively (RR 1.11, 95% CI 1.04-1.18; 13 studies, 4014 participants, I2 = 0%, moderate-quality evidence, NNT 21) and (RR 1.49, 95% CI 1.27-1.76; 5 studies, 2400 participants, I2 = 21%, moderate-quality evidence, number needed to harm 13). Conversely, in donor oocyte cycles, HA addition showed little effect on live birth and clinical pregnancy (RR 1.12 95% CI 0.86-1.44; two studies, 317 participants, I2 = 50%, low-quality evidence) and (RR 1.06, 95% CI 0.97-1.28; three studies, 351 participants, I2 = 23%, low-quality evidence). There was insufficient available information on multiple pregnancy in donor oocyte cycles and on total adverse effects in both groups to draw conclusions. LIMITATIONS, REASONS FOR CAUTION: There were limited studies with separate data on donor oocyte cycles and limited information on oocyte quality. Additionally, one-third of the included studies did not include the main outcome, live birth rate. WIDER IMPLICATIONS OF THE FINDINGS: There is a moderate level of evidence to suggest that functional HA concentration in embryo transfer medium increases clinical pregnancy, live birth and multiple pregnancy rates in IVF cycles using autologous oocytes. This effect was not seen in donor oocyte cycles, indicating either intrinsic differences between donor and autologous oocytes or lack of statistical power. The combination of HA addition to transfer media in cycles using autologous oocytes and a single embryo transfer policy might yield the best combination, with higher clinical pregnancy and live birth rates without increasing the chance of multiple pregnancies. STUDY FUNDING/COMPETING INTEREST(S): No financial assistance was received. The authors have no competing interests. REGISTRATION NUMBER: N/A.

Hyaluronic acid in embryo transfer media for assisted reproductive technologies.

BACKGROUND: This is an update of a Cochrane Review first published in the Cochrane Library (2010, Issue 7). To increase the success rate of assisted reproductive technologies (ARTs), adherence compounds such as hyaluronic acid (HA) have been introduced into subfertility management. Adherence compounds are added to the embryo transfer medium to increase the likelihood of embryo implantation, with the potential for higher clinical pregnancy and live birth rates. OBJECTIVES: To determine whether adding adherence compounds to embryo transfer media could improve pregnancy outcomes, including improving live birth and decreasing miscarriage, in women undergoing assisted reproduction. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO electronic databases on 7 January 2020 for randomised controlled trials that examined the effects of adherence compounds in embryo transfer media on pregnancy outcomes. Furthermore, we communicated with experts in the field, searched trials registries, checked reference lists of relevant studies, and conference abstracts were handsearched. SELECTION CRITERIA: Only truly randomised controlled trials comparing embryo transfer media containing functional concentrations of adherence compounds to media with no or low adherence compound concentrations were included. DATA COLLECTION AND ANALYSIS: Two review authors selected trials for inclusion according to the above criteria, after which the same two review authors independently extracted data for subsequent analysis. Statistical analysis was performed according to the guidelines developed by Cochrane. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We used GRADE methods to assess the overall quality of evidence for the main comparisons. MAIN RESULTS: We analysed 26 studies with a total of 6704 participants. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity. Compared to embryos transferred in media containing no or low (0.125 mg/mL) HA, the addition of functional (0.5 mg/mL) HA concentrations to the transfer media probably increases the live birth rate (RR 1.21, 95% CI 1.1 to 1.31; 10 RCTs, N = 4066; I² = 33%; moderate-quality evidence). This suggests that if the chance of live birth following no HA addition in media is assumed to be 33%, the chance following HA addition would be between 37% and 44%. The addition of HA may slightly decrease miscarriage rates (RR 0.82, 95% CI 0.67 to 1.00; 7 RCTs, N = 3091; I² = 66%; low-quality evidence). Nevertheless, when only studies with low risk of bias were included in the analysis, there was no conclusive evidence of a difference in miscarriage rates (RR 0.96, 95% CI 0.75 to 1.23; N = 2219; I² = 36%). Adding HA to transfer media probably results in an increase in both clinical pregnancy (RR 1.16, 95% CI 1.09 to 1.23; 17 studies, N = 5247; I² = 40%; moderate-quality evidence) and multiple pregnancy rates (RR 1.45, 95% CI 1.24 to 1.70; 7 studies, N = 3337; I² = 36%; moderate-quality evidence). We are uncertain of the effect of HA added to transfer media on the rate of total adverse events (RR 0.86, 95% CI 0.40 to 1.84; 3 studies, N = 1487; I² = 0%; low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence shows improved clinical pregnancy and live birth rates with the addition of HA as an adherence compound in embryo transfer media in ART. Low-quality evidence suggests that adding HA may slightly decrease miscarriage rates, but when only studies at low risk of bias were included in the analysis, the results were inconclusive. HA had no clear effect on the rate of total adverse events. The increase in multiple pregnancy rates may be due to combining an adherence compound and transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.

Bendamustine for patients with indolent B cell lymphoproliferative malignancies including chronic lymphocytic leukaemia - an updated meta-analysis.

The question of which chemotherapy induction provides the best results for indolent lymphoma patients is yet unanswered. Different regimens have been compared, none of which has been shown to improve overall survival. The use of bendamustine is growing. A number of trials evaluated its efficacy for patients with indolent B-cell lymphoid neoplasms, including chronic lymphocytic leukaemia (CLL). To evaluate the efficacy of bendamustine in that population we performed a systematic review and meta-analysis of 9 randomised controlled trials (2726 patients). Bendamustine was compared to fludarabine-containing regimens, CVP (cyclophosphamide, vincristine, prednisolone), CHOP (CVP+ doxorubicin) and chlorambucil. Due to insufficient reported data, six of the nine trials were included in analysis of overall survival. Bendamustine was associated with a prolonged overall survival, (hazard ratio 0·79, 95% confidence interval 0·65-0·95). Data regarding quality of life was reported for two trials, therefore too scarce to pool. The risk of neutropenia was reduced with bendamustine treatment compared to other chemotherapy. Bendamustine induction is an efficacious option for patients with indolent lymphoma, and CLL. Maintenance therapy was not evaluated after bendamustine induction, and potentially there is an interaction between the two. Chemotherapy-free approach was shown to be efficacious for patients with CLL, while toxicity with that approach is not negligible.

The role of maintenance therapy in patients with diffuse large B cell lymphoma: A systematic review and meta-analysis.

Randomized trials of maintenance therapy (MT) in diffuse large B cell lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta-analysis. Systematic review and meta-analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first-line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression-free survival, event-free survival, or disease-free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70 years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78-1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65-0.89) and improved disease control, OR 0.74 (95% CI 0.65-0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47-0.79) and in the subgroup of R-CHOP induction studies OR 0.77 (95% CI 0.67-0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR = 1.69 (95% CI 1.29-2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.

Spontaneous Regression of Hodgkin Lymphoma: Case Report and Review of the Literature.

Spontaneous regression of Hodgkin lymphoma (HL) is a rare event. We describe a 32-year-old woman with spontaneous regression of HL and review the literature. The patient presented with cervical lymphadenopathy and was diagnosed with stage IIA classical HL. The patient refused to receive any treatment for her disease. Positron emission tomography/computed tomography carried out 2 years later showed complete regression of the lymphadenopathy, without pathological uptake of fluorodeoxyglucose. At the last follow-up, 3.5 years after the initial presentation, the patient is with no evidence of disease. During workup for the HL, concomitant papillary thyroid carcinoma was diagnosed, for which the patient refused treatment as well. The thyroid malignancy has remained stable throughout the follow-up.

PET-adapted therapy for advanced Hodgkin lymphoma - systematic review.

INTRODUCTION: Positron emission tomography-computed tomography (PET-CT) performed after two chemotherapy cycles (PET-2) has become an accepted prognostic tool in Hodgkin lymphoma (HL). We evaluated the effect of PET-adapted strategy on outcome in advanced stage HL. METHODS: In August 2017, we searched electronic databases, conference proceedings and ongoing trials. We included all studies in which treatment modification for advanced HL was performed based on the results of the interim PET scan. The primary analysis included randomized controlled trials (RCTs). Outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: We identified 13 studies (4 RCTs, 7 phase II and 2 retrospective studies), conducted between 1999 and 2014, including 6856 patients. Of the four RCTS: one used therapy escalation, one did de-escalation and two trials performed both. Outcomes were assessed at different time point between 2 and 5 years. Three RCTs for de-escalating therapy, obtained similar outcomes despite reducing therapy, with a 2-year PFS of 88-92% (6 escalated BEACOPP (EB) vs. 4 ABVD cycles), a 5-year PFS of 91-92% (6/8 EB vs. 4 EB cycles) and a 5-year PFS of 80-82% (6 ABVD vs. omitting bleomycin after two successful ABVD cycles). Two RCTs implemented escalation. The randomization was between adding rituximab or not. In both trials, it did not affect outcome, with a 4-year PFS of 68-69% (addition of rituximab to BEACOPP after 2 ABVD cycles) and 5-year PFS of 88-90% (addition of rituximab to EB after 2 EB cycles). Performing true randomization between PET-adapted and a standard ABVD control arm was not feasible, given historical data. CONCLUSIONS: This systematic review of PET-adapted therapy, mainly based on RCTs, suggests that a change to the treatment paradigm is appropriate in advanced HL.

Bendamustine-associated infections-systematic review and meta-analysis of randomized controlled trials.

Data in the literature are lacking regarding the infection-related adverse events of bendamustine-containing regimens. Therefore, we aimed to assess this risk. We conducted a systematic review and meta-analysis of all randomized controlled trials including bendamustine-containing regimens and those administered for any lymphoproliferative disorder or plasma cell dyscrasia compared with any other regimens. A comprehensive search was conducted until December 2015. Two reviewers appraised the quality of trials and extracted data. Primary outcomes were any infections, grade 3 to 4 infections; secondary outcomes were grade 3 to 4 neutropenia and grade 3 to 4 lymphopenia. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool data unless there was significant heterogeneity, in which case a random-effects model was used. Nine trials published between 2006 and 2016 and randomizing 2620 patients were included. There was no statistically significant effect for bendamustine on the rate of any infection (RR 1.09 [95% CI, 0.87-1.36]) or on the rate of grade 3 to 4 infections (RR 1.04 [95% CI, 0.64-1.71]). There was no increase in the rate of grade 3 to 4 neutropenia in the bendamustine arm (RR 0.84 [95% CI, 0.63-1.12]). Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared with either alkylating agents or fludarabine. Thus, bendamustine remains a safe therapeutic option.

Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.

BACKGROUND: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. OBJECTIVES: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. SEARCH METHODS: For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible. MAIN RESULTS: Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate-quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low-quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low-quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram-positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram-positive superinfections. Resistant colonisation was not documented in the studies. AUTHORS' CONCLUSIONS: Based on very low- or low-quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.

First line treatment with newer tyrosine kinase inhibitors in chronic myeloid leukemia associated with deep and durable molecular response - systematic review and meta-analysis.

BACKGROUND: The choice of a specific tyrosine kinase inhibitor (TKI) as first line treatment in chronic myeloid leukemia (CML) is complex and influenced by multiple factors. We published a meta-analysis examining the role of newer TKIs as first line treatment in chronic phase CML. In view of the recently published data, we decided to update it. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing first line treatment with imatinib to the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib). We searched MEDLINE, conference proceedings and databases of ongoing trials up to August 2015. RESULTS: Our search yielded eight trials including 3554 patients. Treatment with the newer TKIs significantly improved major molecular response (MMR) at all time points and increased the rate of complete molecular response (CMR) at 12 and 24 months [relative risk (RR) 2.58, 95% CI 1.98-3.37, six trials and RR 2.05, 95% CI 1.63-2.58, three trials, respectively]. Early molecular response at three months was better with the newer TKIs (RR 1.33, 95% CI 1.26-1.40, six trials). Importantly, progression rate to accelerated or blastic phase was significantly lower with the newer TKIs at 12, 24 months and 5 years. Yet, there was no difference in all-cause mortality. The risk of adverse events requiring treatment discontinuation increased with the newer TKIs. CONCLUSIONS: With a longer follow-up, the newer TKIs remain more potent than imatinib, yet with no significant effect on survival. As CMR is a prerequisite for treatment discontinuation and cure, the newer TKIs favor treatment cessation.

CHOP-like-14 compared to CHOP-like-21 for patients with aggressive lymphoma--a meta-analysis of randomized controlled trials.

BACKGROUND: R-CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkin's lymphoma. It was suggested that decreasing the treatment interval from three weeks (CHOP-21) to two weeks (CHOP-14) may improve survival and disease control of patients with aggressive lymphoma. PURPOSE: To evaluate the effect of CHOP-like-14 (with or without rituximab) compared to standard CHOP-like -21 on overall survival (OS), disease control and toxicity of patients with aggressive non-Hodgkin lymphoma. METHODS: Systematic review and meta-analysis of RCTs. In October 2014 we searched The Cochrane Library, MEDLINE, LILACS, conference proceedings, and databases of ongoing trials. Authors were contacted for complementary data. The primary outcome was OS. RESULTS: We identified seven trials (4073 patients), conducted between the years 1999 and 2008. Trials were at low or unclear risk for selection bias, and at low or unclear risk of attrition bias. CHOP-like-14 improved OS of patients with aggressive lymphoma compared to the same regimen given every 21 days (all trials): HR of death 0.86, 95% confidence interval (CI) 0.77-0.97. There was no OS difference between rituximab-CHOP-like 14 to rituximab-CHOP-like-21 (3 trials): HR 0.93 95% CI 0.78-1.10. The rates of progression or death, complete response, treatment-related mortality, grade 3-4 infection, and discontinuation were similar between groups. CONCLUSION: R-CHOP-21 remains the standard of care for patient with aggressive B-cell lymphoma. CHOP-14 can be considered as in case rituximab is omitted.

Subcutaneous versus intravenous granulocyte colony stimulating factor for the treatment of neutropenia in hospitalized hemato-oncological patients: randomized controlled trial.

Intravenous (IV) granulocyte colony stimulating factor (G-CSF) might be safer and more convenient than subcutaneous (SC) administration to hospitalized hemato-oncological patients receiving chemotherapy. To compare IV vs. SC G-CSF administration, we conducted a randomized, open-label trial. We included inpatients receiving chemotherapy for acute myeloid leukemia, acute lymphoblastic leukemia, lymphoma or multiple myeloma, and allogeneic or autologous hematopoietic cell transplantation (HCT). Patients were randomized to 5 mcg/kg single daily dose of IV bolus versus SC filgrastim given for its clinical indications. Patients were crossed-over to the alternate study arm on the subsequent chemotherapy course. The primary outcomes were time from initiation of filgrastim to recovery of stable neutrophil count of >500 cells/µL and a composite clinical outcome of infection or death assessed for the first course post-randomization. The study was stopped on the second interim analysis. Of 120 patients randomized, 118 were evaluated in the first treatment course. The mean time to neutropenia resolution was longer with IV G-CSF [7.9 days, 95% confidence interval (CI) 6.6-9.1] compared with SC G-CSF (5.4 days, 95% CI 4.6-6.2), log-rank P = 0.001. Longer neutropenia duration was observed in all patient subgroups, except for patients undergoing autologous HCT. There was no significant difference between groups in the occurrence of infection or death, but more deaths were observed with IV (4/57, 7%) versus SC (1/61, 1.6%) G-CSF administration, P = 0.196. Similar results were observed when all 158 courses following cross-over were analyzed. Patients reported similar pain and satisfaction scores in both groups. Bolus IV administration of G-CSF results in longer neutropenia duration than SC administration, with no difference in clinical or quality-of-life measures.

Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients.

BACKGROUND: Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality. OBJECTIVES: To assess the effectiveness of PCP prophylaxis among non-HIV immunocompromised patients; and to define the type of immunocompromised patient for whom evidence suggests a benefit for PCP prophylaxis. SEARCH METHODS: Electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE and EMBASE (to March 2014), LILACS (to March 2014), relevant conference proceedings; and references of identified trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing prophylaxis with an antibiotic effective against PCP versus placebo, no intervention, or antibiotic(s) with no activity against PCP; and trials comparing different antibiotics effective against PCP among immunocompromised non-HIV patients. We only included trials in which Pneumocystis infections were available as an outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias in each trial and extracted data from the included trials. We contacted authors of the included trials to obtain missing data. The primary outcome was documented PCP infections. Risk ratios (RR) with 95% confidence intervals (CI) were estimated and pooled using the random-effects model. MAIN RESULTS: Thirteen trials performed between the years 1974 and 2008 were included, involving 1412 patients. Four trials included 520 children with acute lymphoblastic leukemia and the remaining trials included adults with acute leukemia, solid organ transplantation or autologous bone marrow transplantation. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was an 85% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR of 0.15 (95% CI 0.04 to 0.62; 10 trials, 1000 patients). The evidence was graded as moderate due to possible risk of bias. PCP-related mortality was also significantly reduced, RR of 0.17 (95% CI 0.03 to 0.94; nine trials, 886 patients) (low quality of evidence due to possible risk of bias and imprecision), but in trials comparing PCP prophylaxis against placebo or no treatment there was no significant effect on all-cause mortality (low quality of evidence due to imprecision). Occurrence of leukopenia or neutropenia and their duration were not reported consistently. No significant differences in overall adverse events or events requiring discontinuation were seen comparing trimethoprim/sulfamethoxazole to no treatment or placebo (four trials, 470 patients, moderate quality evidence). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients). AUTHORS' CONCLUSIONS: Given an event rate of 6.2% in the control groups of the included trials, prophylaxis for PCP using trimethoprim/sulfamethoxazole is highly effective among non-HIV immunocompromised patients, with a number needed to treat to prevent PCP of 19 patients (95% CI 17 to 42). Prophylaxis should be considered for patients with a similar baseline risk of PCP.

Empirical antibiotics targeting Gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.

BACKGROUND: The pattern of infections among neutropenic cancer patients has shifted in the last decades to a predominance of Gram-positive infections. Some of these Gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. OBJECTIVES: To assess the effectiveness of empirical antiGram-positive (antiGP) antibiotic treatment for febrile neutropenic cancer patients in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 7), MEDLINE (1966 to 2013), EMBASE (1982 to 2013), LILACS (1982 to 2013), conference proceedings, and the references of the included studies. First authors of all included and potentially relevant trials were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing one antibiotic regimen to the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic cancer patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I(2) > 50%). Outcomes were extracted by intention to treat and the analysis was patient-based whenever possible. MAIN RESULTS: Thirteen trials and 2392 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 11 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Seven studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.82 (95% CI 0.56 to 1.20, 852 patients). Ten trials assessed failure, including modifications as failures, while six assessed overall failure disregarding treatment modifications. Failure with modifications was significantly reduced, RR of 0.76 (95% CI 0.68 to 0.85, 1779 patients) while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27, 943 patients). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Both mortality and failure did not differ significantly among patients with Gram-positive infections, but the number of studies in the comparisons was small. Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented Gram-positive superinfections. Resistant colonisation was not documented in the studies. AUTHORS' CONCLUSIONS: Current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.

Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis.

Second generation tyrosine kinase inhibitors have recently been introduced as first-line treatment for chronic phase chronic myelogenous leukemia. We aimed to evaluate the efficacy and safety of 2(nd) generation tyrosine kinase inhibitors versus imatinib as first-line treatment for these patients. We carried out a systematic review and meta-analysis of randomized controlled trials comparing 2(nd) generation tyrosine kinase inhibitors to imatinib as first-line treatment in chronic phase chronic myelogenous leukemia patients. Outcomes assessed were: complete cytogenetic response and major molecular response at 12, 18 and 24 months, all-cause mortality and progression to accelerated phase/blastic crisis at 12, 18 and 24 months, and chronic myelogenous leukemia related mortality and toxicity at last follow up. Relative risks were estimated and pooled using a fixed effect model. Our search yielded four trials including 2,120 patients. At 12 months, treatment with 2(nd) generation tyrosine kinase inhibitors significantly improved both complete cytogenetic response and major molecular response (relative risk 1.16, 95% CI: 1.09-1.23, and 1.68, 95% CI: 1.48-1.91, respectively). While major molecular response was improved at all time points, complete cytogenetic response improved at 18 months but not at 24 months. Importantly, rate of progression to accelerated phase/blastic crisis was significantly lower with the newer tyrosine kinase inhibitors throughout all time points. Second generation tyrosine kinase inhibitors improved chronic myelogenous leukemia related mortality without a statistically significant difference in all-cause mortality at 12, 18 and 24 months. We conclude that 2(nd) generation tyrosine kinase inhibitors can be added safely to the first-line treatment armamentarium of chronic phase chronic myelogenous leukemia patients. Although an advantage is suggested by surrogate parameters, longer follow up is necessary to see if this translates into superior overall survival.

Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: a retrospective 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.

Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Current guidelines are inconclusive regarding intravenous (IV) iron for treatment of chemotherapy-induced anaemia (CIA). MATERIAL AND METHODS: Systematic review and meta-analysis of randomised controlled trials comparing IV iron with no iron or oral iron for treatment of chemotherapy induced anaemia (CIA). PRIMARY OUTCOMES: haematopoietic response and red blood cell (RBC) transfusion requirements. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous data, weighted mean differences were calculated. RESULTS: Eleven trials included 1681 patients, the majority examining the addition of IV iron to erythropoiesis stimulating agents (ESA) (1562 patients, 92.9%). IV iron significantly increased haematopoietic response rate [RR 1.28 (95% CI 1.125-1.45), seven trials with ESA] and decreased the rate of blood transfusions both in trials with ESA [RR 0.76 (95% CI 0.61-0.95), seven trials] and without ESA [RR 0.52 (95% CI 0.34-0.80)]. The increase in haematopoietic response rate correlated with total IV iron dose, regardless of baseline iron status. Mortality and safety profile was comparable between groups. CONCLUSIONS: IV iron added to ESA results in an increase in haematopoietic response and reduction in the need for RBC transfusions, with no difference in mortality or adverse events.

Burkitt's lymphoma of the ovary: case report and review of the literature.

Primary Burkitt's lymphoma of the ovary is extremely rare. We report the case of a 39-year-old woman who presented with a 1-month history complaints of night sweats, abdominal pain and dyspnea. Physical examination demonstrated pleural effusions, ascites and an abdominal mass. Imaging showed enlargement of both ovaries extending to the surrounding tissue. Frozen sections on explorative laparotomy suggested granulosa cell tumor of the ovary, and thus extensive debulking was carried out. The final pathological report was compatible with Burkitt's lymphoma. A systematic literature review revealed another 16 cases of ovarian Burkitt's lymphoma. Characteristics predictive for the diagnosis of Burkitt's lymphoma were: younger age, bilateral ovarian involvement, a rapidly progressive course and high LDH levels.

The role of maintenance therapy in acute promyelocytic leukemia in the first complete remission.

BACKGROUND: Acute promyelocytic leukemia (APL) is the most curable type of leukemia. A consensus exists regarding the need for administration of both induction and consolidation treatments, albeit using different approaches. However, there is conflicting evidence for the role of maintenance treatment in APL patients. OBJECTIVES: To examine the efficacy and safety of maintenance therapy in APL patients and to establish the optimal regimen for maintenance. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1966 to July 2012), LILACS (1982 to July 2012), relevant conference proceedings (2000 to 2012) and databases of ongoing and unpublished trials. SELECTION CRITERIA: Randomized controlled trials assessing maintenance treatment in patients with newly diagnosed APL in first complete remission (CR) following induction or induction and consolidation therapy. DATA COLLECTION AND ANALYSIS: Two review authors assessed the quality of trials and extracted data. We estimated and pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) using the fixed-effect model. If significant heterogeneity was present we explored potential causes for such heterogeneity and if not found we used also the random-effects model. MAIN RESULTS: We included 10 randomized controlled trials enrolling 2072 patients in the systematic review, and conducted meta-analysis on nine of them. There was no statistically significant effect on overall survival (OS) in the three main comparisons (HR for any maintenance treatment versus observation 0.79, 95% CI 0.49 to 1.27; HR for all-trans retinoic acid (ATRA)-based maintenance versus non-ATRA based maintenance 1.21, 95% CI 0.73 to 1.98; HR for ATRA alone maintenance versus ATRA and chemotherapy 0.99, 95% CI 0.69 to 1.43). However, disease free survival (DFS) was improved with any maintenance therapy compared to observation (HR 0.59, 95% CI 0.48 to 0.74; 5 trials, 1209 patients) and with ATRA and chemotherapy compared to ATRA alone maintenance (HR for ATRA alone compared to ATRA and chemotherapy 1.38, 95% CI 1.09 to 1.76; 4 trials, 1028 patients). DFS was not improved with ATRA-based regimens compared to non-ATRA based regimens (HR 0.72, 95% CI 0.51 to 1.01; 4 trials, 670 patients). Analysis of clinically relevant adverse events could not be conducted due to paucity of data. Yet, increased reports of grade 3/4 adverse events were noted for any maintenance versus observation and for combined ATRA and chemotherapy versus ATRA alone treatment. The major limitation of this review lies in the variability between the included trials in both maintenance and pre-maintenance parameters. We tried to address this variability and to reduce its potential biases by conducting three separate main comparisons, as outlined above, leaving less statistical power to the presented results. AUTHORS' CONCLUSIONS: Maintenance therapy compared to observation in APL patients improved DFS but not OS. Similarly, ATRA and chemotherapy compared to ATRA improved DFS but not OS. In contrast, ATRA based regimens compared to non-ATRA based regimens did not demonstrate a survival benefit. The significance of these findings is limited due to clinical heterogeneity between studies.

Anthracycline-containing regimens for treatment of follicular lymphoma in adults.

BACKGROUND: Anthracycline-containing regimens (ACR) are the most prevalent regimens in the management of patients with advanced follicular lymphoma (FL). However, there is no proof that they are superior to non-anthracycline-containing regimens (non-ACR). OBJECTIVES: To compare the efficacy of ACRs to other chemotherapy regimens, in the treatment of FL. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), MEDLINE (January 1966 to April 2013), smaller databases, relevant conference proceedings (2004 to 2012) and the National Medical Library (April 2013). SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ACR with non-ACR for adult patients with FL. We excluded trials in which immunotherapy, radiotherapy alone or stem-cell transplantation were used in one arm alone. Our primary outcome was overall survival (OS). Secondary outcomes included disease control, as measured by progression-free survival (PFS) or remission duration (RD). DATA COLLECTION AND ANALYSIS: Two review authors assessed the quality of trials and extracted data. We contacted study authors for additional information. We analyzed trials separately according to resemblance of the chemotherapeutic regimens in study arms, other than the addition of anthracyclines ('same' versus 'different' chemotherapy). Hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) were estimated and pooled using the fixed-effect model. MAIN RESULTS: Eight RCTs, conducted between 1974 and 2011, and involving 2636 patients were included in this meta-analysis. All trials included therapy-naive patients. Rituximab was used in one trial only. Follow-up was between three and five years in most trials (range three to 18 years). All trials were published in peer-reviewed journals.Five trials compared similar chemotherapeutic regimens, except for the anthracycline. In three studies reporting overall survival specifically in FL patients, there was no statistically significant difference between ACR and non-ACR arms (HR 0.99; 95% CI 0.77 to 1.29; I(2) = 0%). ACR significantly improved disease control (HR 0.65; 95% CI 0.52 to 0.81; four trials). Progression or relapse at three years were reduced (RR 0.73; 95% CI 0.63 to 0.85). Anthracyclines did not significantly increase rates of complete response (RR 1.05; 95% CI 0.94 to 1.18) or overall response (RR 1.06; 95% CI 1.00 to 1.12), but heterogeneity was substantial.Overall, ACR were more often associated with cytopenias, but not with serious infections or death related to chemotherapy. Cardiotoxicity, albeit rare, was associated with anthracycline use (RR 4.55; 95% CI 0.92 to 22.49; four trials).Three trials added anthracycline to one arm of two different regimens. None showed benefit to ACR regarding OS, yet there was a trend in favor of anthracyclines for disease control. Results were heterogeneous.We judged the overall quality of these trials as moderate as all are unblinded, some are outdated and are not uniform in outcome definitions. AUTHORS' CONCLUSIONS: The use of anthracyclines in patients with FL has no demonstrable benefit on overall survival, although it may have been mitigated by the more intense regimens given in the control arms of three of five trials. ACR improved disease control, as measured by PFS and RD with an increased risk for side effects, notably cardiotoxicity. The current evidence on the added value of ACR in the management of FL is limited. Further studies involving immunotherapy during induction and maintenance may change conclusion.

Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients.

BACKGROUND: Fever occurring in a neutropenic patient remains a common life-threatening complication of cancer chemotherapy. The common practice is to admit the patient to hospital and treat him or her empirically with intravenous broad-spectrum antibiotics. Oral therapy could be an alternative approach for selected patients. OBJECTIVES: To compare the efficacy of oral antibiotics versus intravenous (IV) antibiotic therapy in febrile neutropenic cancer patients. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1) in The Cochrane Library, MEDLINE (1966 to January week 4, 2013), EMBASE (1980 to 2013 week 4) and LILACS (1982 to 2007). We searched several databases for ongoing trials. We checked the conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) (1995 to 2007), and all references of included studies and major reviews were scanned. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral antibiotic(s) to intravenous antibiotic(s) for the treatment of neutropenic cancer patients with fever. The comparison between the two could be started initially (initial oral) or following an initial course of intravenous antibiotic treatment (sequential). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and methodological quality and extracted data. Data concerning mortality, treatment failures and adverse events were extracted from the included studies assuming an 'intention-to-treat' basis for the outcome measures whenever possible. Risk ratios (RR) with 95% confidence intervals (CI) were estimated for dichotomous data. Risk of bias assessment was also made in line with methodology of The Cochrane Collaboration. MAIN RESULTS: Twenty-two trials (3142 episodes in 2372 patients) were included in the analyses. The mortality rate was similar when comparing oral to intravenous antibiotic treatment (RR 0.95, 95% CI 0.54 to 1.68, 9 trials, 1392 patients, median mortality 0, range 0% to 8.8%). Treatment failure rates were also similar (RR 0.96, 95% CI 0.86 to 1.06, all trials). No significant heterogeneity was shown for all comparisons but adverse events. The effect was stable in a wide range of patients. Quinolones alone or combined with another antibiotic were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics. AUTHORS' CONCLUSIONS: Based on the present data, oral treatment is an acceptable alternative to intravenous antibiotic treatment in febrile neutropenic cancer patients (excluding patients with acute leukaemia) who are haemodynamically stable, without organ failure, and do not have pneumonia, infection of a central line or a severe soft-tissue infection. The wide CI for mortality allows the present use of oral treatment in groups of patients with an expected low risk for mortality, and further research should be aimed at clarifying the definition of low risk patients.