The Dose-Dependent Efficacy of Cefepime in the Empiric Management of Febrile Neutropenia: A Systematic Review and Meta-Analysis

Abstract Background Despite reports questioning its efficacy, cefepime remains a first-line option in febrile neutropenia. We aimed to re-evaluate the role of cefepime in this setting. Methods We searched the PubMed and EMBASE databases to identify randomized comparisons of (1) cefepime vs alternative monotherapy or (2) cefepime plus aminoglycoside vs alternative monotherapy plus aminoglycoside, published until November 28, 2016. Results Thirty-two trials, reporting on 5724 patients, were included. Clinical efficacy was similar between study arms (P = .698), but overall mortality was greater among cefepime-treated patients (risk ratio [RR] = 1.321; 95% confidence interval [CI], 1.035–1.686; P = .025). Also of note, this effect seemed to stem from trials using low-dose (2 grams/12 hours, 100 mg/kg per day) cefepime monotherapy (RR = 1.682; 95% CI, 1.038–2.727; P = .035). Cefepime was also associated with increased mortality compared with carbapenems (RR = 1.668; 95% CI, 1.089–2.555; P = .019), a finding possibly influenced by cefepime dose, because carbapenems were compared with low-dose cefepime monotherapy in 5 of 9 trials. Treatment failure in clinically documented infections was also more frequent with cefepime (RR = 1.143; 95% CI, 1.004–1.300; P = .043). Toxicity-related treatment discontinuation was more common among patients that received high-dose cefepime (P = .026), whereas low-dose cefepime monotherapy resulted in fewer adverse events, compared with alternative monotherapy (P = .009). Conclusions Cefepime demonstrated increased mortality compared with carbapenems, reduced efficacy in clinically documented infections, and higher rates of toxicity-related treatment discontinuation. The impact of cefepime dosing on these outcomes is important, because low-dose regimens were associated with lower toxicity at the expense of higher mortality.

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Do adjuvants add to the efficacy and tolerance of bowel preparations? A meta-analysis of randomized trials

Endoscopy ◽

10.1055/s-0043-119638 ◽

2017 ◽

Vol 50 (02) ◽

pp. 159-176 ◽

Cited By ~ 3

Author(s):

Sophie Restellini ◽

Omar Kherad ◽

Charles Menard ◽

Myriam Martel ◽

Alan Barkun

Keyword(s):

Randomized Trials ◽

Low Dose ◽

Meta Analysis ◽

High Dose ◽

Detection Rates ◽

Adenoma Detection ◽

Adenoma Detection Rates ◽

Split Dosing ◽

Bowel Preparations ◽

The Impact

Abstract Background and study aims Recommendations on adjuvant use with bowel preparations remain disparate. We performed a meta-analysis determining the clinical impact of adding an adjuvant to polyethylene glycol (PEG), sodium phosphate, picosulfate (PICO), or oral sulfate solutions (OSS)-based regimens. Methods Systematic searches were made of MEDLINE, EMBASE, Scopus, CENTRAL and ISI Web of knowledge for randomized trials from January 1980 to April 2016 that assessed preparations with or without adjuvants, given in split and non-split dosing, and PEG high- (> 3 L) or low-dose (≤ 2 L) regimens. Bowel cleansing efficacy was the primary outcome. Secondary outcomes included patient willingness to repeat the procedure, and polyp and adenoma detection rates. Results Of 3093 citations, 77 trials fulfilled the inclusion criteria. Overall, addition of an adjuvant compared with no adjuvant, irrespective of the type of preparation and mode of administration, yielded improvements in bowel cleanliness (odds ratio [OR] 1.23 [1.01 – 1.51]) without greater willingness to repeat (OR 1.40 [0.91 – 2.15]). Adjuvants combined with high-dose PEG significantly improved colon cleansing (OR 1.96 [1.32 – 2.94]). The odds for achieving adequate preparation with low-dose PEG with an adjuvant were not different to high-dose PEG alone (OR 0.95 [0.73 – 1.22]), but yielded improved tolerance (OR 3.22 [1.85 – 5.55]). However, split high-dose PEG yielded superior cleanliness to low-dose PEG with adjuvants (OR 2.53 [1.25 – 5.13]). No differences were noted for OSS and PICO comparisons, or for any products regarding polyp or adenoma detection rates. Conclusions Critical heterogeneity precludes firm conclusion on the impact of adjuvants with existing bowel preparations. Additional research is required to better characterize the methods of administration and resulting roles of adjuvants in an era of split-dosing.

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European MCL Network: An Update on Current First Line Trials.

Blood ◽

10.1182/blood.v110.11.388.388 ◽

2007 ◽

Vol 110 (11) ◽

pp. 388-388 ◽

Cited By ~ 2

Author(s):

Martin H. Dreyling ◽

Eva Hoster ◽

Olivier Hermine ◽

J.C. Kluin-Nelemans ◽

Jan Walewski ◽

...

Keyword(s):

Overall Survival ◽

Febrile Neutropenia ◽

Elderly Patients ◽

Response Rate ◽

Response Rates ◽

High Dose ◽

High Dose Cytarabine ◽

The Impact ◽

Grade Iii

Abstract Background: Conventional chemotherapy achieves only short term remission despite high initial response rates of 70%–80%. In the current study generation, the European MCL Network investigates the impact of various combined immuno-chemotherapy regimens. Additionally, in elderly patients the role of rituximab maintenance is being evaluated, whereas in younger patients dose-intensified regimens with implementation of high dose cytarabine are investigated based on the excellent results of the HyperCVAD regimen. Methods: In MCL elderly, patients are initially randomized between 8 cycles of R-CHOP or 6 cycles of R-FC (experimental arm). Patients who achieve either an PR or CR, receive subsequently either interferon maintenance (standard arm) or a single rituximab dose every 2 months. In MCL younger, the standard arm (R-CHOP induction followed by myeloablative consolidation: 12 Gray TBI, 2x 60mg/kg cyclophosphamide) is compared to the implementation of high dose cytarabine into induction (R-CHOP/R-DHAP) and consolidation (10 Gray TBI, 4x1,5 g/m2 Ara-C, 140mg/m2 melphalan). Results: In MCL elderly, 222 of 263 patients were evaluable based on the annual interim analysis. Median age was 70 years with 66% of patients displaying an intermediate high/high risk IPI. Induction was well tolerated with mainly hematological toxicity (grade III/IV in R-CHOP/R-FC): Leukocytopenia 62/72%, thrombocytopenia 13%/40%, but only rare febrile neutropenia (23%/7%) or infections (19%/23%). Despite the poor risk profile, combined immuno-chemotherapy (total group) achieved a remarkable 84% response rate (51% CR/CRu). Although the impact of maintenance is not yet evaluable, both progression-free and overall survival were encouraging with 77% and 86% at 12 months, respectively. In MCL younger, 247 of 271 patients were evaluable. Again, toxicity (grade III/IV in R-CHOP/alternating R-DHAP) was mainly hematological: leukocytopenia 58/77%, thrombocytopenia 14%/74%, but only rare febrile neutropenia (11%/22%) or infections (5%/7%). Combined immuno-chemotherapy achieved a 93% response rate (60% CR/CRu) before subsequent high dose consolidation. Again, both progression-free and overall survival are remarkable with both 90% at 12 months, respectively. Discussion: Combined immuno-chemotherapy results in high response rates in two prospective international trials. Further recruitment and follow-up will determine the role of rituximab maintenance and high dose cytarabine in this distinct subtype of malignant lymphoma.

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SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis

European Respiratory Journal ◽

10.1183/13993003.00625-2020 ◽

2020 ◽

Vol 56 (3) ◽

pp. 2000625 ◽

Cited By ~ 6

Author(s):

Paola Rogliani ◽

Beatrice Ludovica Ritondo ◽

Josuel Ora ◽

Mario Cazzola ◽

Luigino Calzetta

Keyword(s):

Severe Asthma ◽

Treatment Option ◽

Low Dose ◽

Therapeutic Option ◽

Meta Analysis ◽

Specific Treatment ◽

High Dose ◽

Asthmatic Patients ◽

The Impact ◽

Medium Dose

To date, there are no network meta-analyses comparing the impact of as-needed treatments in asthma, including the single maintenance and reliever therapy (known as “SMART” or “MART”; for simplicity, SMART will be used hereafter) and the use of inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination exclusively on an as-needed basis. Therefore, we performed a systematic review and network meta-analysis concerning the efficacy and safety of SMART and as-needed therapies in asthma. Data from 32 096 asthmatic patients were extracted from 21 studies, lasting from 6 to 12 months. In adult mild-to-moderate asthmatic patients low-dose SMART and as-needed low-dose ICS/LABA combination were significantly (relative effect <0.78; p<0.05) more effective than the other as-needed therapies in reducing the risk of exacerbation, and both were ranked as the first treatment option reaching the first quartile of the surface under the cumulative ranking curve analysis (SUCRA). In adult moderate-to-severe asthmatic patients, low-dose to medium-dose SMART and high-dose ICS/LABA+as-needed short-acting β2-agonist were equally effective in reducing the risk of severe asthma exacerbation (p>0.05), although only low- to medium-dose SMART was ranked as the first treatment option (first SUCRA quartile). Overall, these treatments were well tolerated, and effective also on lung function and disease control. This study supports SMART and as-needed therapies as a suitable therapeutic option for asthma, by providing the most effective positioning of each specific treatment according to the disease severity.

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Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3048 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3048-3048

Author(s):

Francesca Battaglin ◽

Shu Cao ◽

Fotios Loupakis ◽

Sebastian Stintzing ◽

Aparna Raj Parikh ◽

...

Keyword(s):

Multiple Testing ◽

Meta Analysis ◽

Critical Role ◽

Progression Free Survival ◽

Phase Iii ◽

P Value ◽

Nucleotide Polymorphisms ◽

First Line ◽

The Impact

3048 Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( PFDR= 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( PFDR= 0.056), and between SLC6A3 rs6347 and OS ( PFDR= 0.041) and SLC6A3 rs6876890 and TR ( PFDR= 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.

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Aspirin and Reducing Risk of Gastric Cancer: Systematic Review and Meta-Analysis of the Observational Studies

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld-818 ◽

2020 ◽

Vol 29 (2) ◽

pp. 191-198 ◽

Cited By ~ 1

Author(s):

Thin Thin Win ◽

Saint Nway Aye ◽

Joyce Lau Chui Fern ◽

Cheng Ong Fei

Keyword(s):

Gastric Cancer ◽

Systematic Review ◽

Observational Studies ◽

Fixed Effects ◽

Low Dose ◽

Meta Analysis ◽

High Dose ◽

Fixed Effects Model ◽

Dose Aspirin

Background and Aims: The latest meta-analysis on the role of aspirin on various cancers was published in early 2018. By including the latest and updated primary observational studies, we aimed to conduct this systematic review and meta-analysis to synthesize stronger evidence on the role of aspirin in reducing gastric cancer (GC) risk. Methods: The PubMed, Scopus, and MEDLINE databases were systematically searched up to December 2019 to identify relevant studies. Random-effects model was used to calculate summary ORs and 95%CI for I 2 >50%. If the heterogeneity is not significant, the fixed-effects model was used. Overall analysis of the studies, inverse variance weighting after transforming the estimates of each study into log OR and its standard error were used. Results: 21 studies were included in this meta-analysis. Results showed that aspirin significantly reduced the GC risk (OR=0.64, 95%CI=0.54-0.76) with substantial heterogeneity (I 2 =96%). Effect of GC risk reduction in low dose (OR=0.80, 95%CI=0.59-1.09) is slightly greater than high dose aspirin (OR=1.08, 95%CI=0.77-1.52). Protective effect of aspirin uses >5 years (OR=0.67, 95%CI=0.34-1.31) was greater than <5 years (OR=1.01, 95%CI=0.72-1.43) Conclusion: In conclusion, this meta-analysis showed that low dose aspirin with longer duration of more than 5 years were associated with a statistically significant reduction in GC risk. However, due to possible confounding variables and bias, these results should be cautiously treated.

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The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

International Journal of Molecular Sciences ◽

10.3390/ijms22052578 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2578

Author(s):

Trim Lajqi ◽

Christian Marx ◽

Hannes Hudalla ◽

Fabienne Haas ◽

Silke Große ◽

...

Keyword(s):

Oxygen Consumption ◽

Immune Tolerance ◽

Immune Cells ◽

Low Dose ◽

Innate Immune ◽

Immune Memory ◽

Innate Immune Cells ◽

Atp Production ◽

Dose Dependent

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

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Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy in Patients with Multinodular Goiters: A Meta-Analysis of Randomized Controlled Trials

Hormone and Metabolic Research ◽

10.1055/a-1240-5058 ◽

2020 ◽

Vol 52 (12) ◽

pp. 841-849

Author(s):

Chunmei Xu ◽

Ping Wang ◽

Huikai Miao ◽

Tianyue Xie ◽

Xiaojun Zhou ◽

...

Keyword(s):

Fixed Effects ◽

Dose Group ◽

Low Dose ◽

Radioiodine Therapy ◽

Meta Analysis ◽

High Dose Group ◽

High Dose ◽

Fixed Effects Model ◽

Recombinant Human Thyrotropin

AbstractA potential reduction of goiter volume (GV) of recombinant human thyrotropin (rhTSH) on multinodular goiters (MNG) was previously reported but controversial. Hence we conducted a meta-analysis to estimate the effect of rhTSH-stimulated radioiodine therapy in patients with MNG. PubMed, Cochrane, CNKI, VIP, and Wanfang databases were searched. Mean difference (MD) and odds ratios with 95% confidence intervals (95% CI) were derived by using an inverse variance random-effects model and fixed-effects model, respectively. Six studies (n=237) were involved in the analysis. For 12 months follow up, high dose (>0.1 mg) of rhTSH significantly reduced GV (MD=17.61; 95% CI=12.17 to 23.04; p<0.00001) compared with placebo. No effective pooled results of low dose of rhTSH (<0.1 mg) were applicable for only one study included. For 6 months follow up, the source of heterogeneity was determined by subgroup and sensitivity analysis. High dose group showed vast improvement in GV reduction (MD=16.62; 95% CI=1.34 to 31.90; p=0.03). The reduction of low dose group compared with placebo was inferior to high dose group. No available data were obtained to assess the influence of rhTSH after 36 months follow up for the only included study. Hypothyroidism incidence was higher for rhTSH group. No publication bias was seen. High dose of rhTSH treatment-stimulated radioactive 131I therapy after 6 months and 12 months follow up had a better effect in reducing GV, but with higher incidence of hypothyroidism. Owing to the limited methodological quality, more clinical researches are warranted in the future.

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Why Do Firms Participate in Voluntary Environmental Programs? A Meta-Analysis of the Role of Institutions, Resources, and Program Stringency

Organization & Environment ◽

10.1177/1086026621990063 ◽

2021 ◽

pp. 108602662199006

Author(s):

Peter Tashman ◽

Svetlana Flankova ◽

Marc van Essen ◽

Valentina Marano

Keyword(s):

Quality Management ◽

Prior Experience ◽

Meta Analysis ◽

Institutional Pressures ◽

Environmental Programs ◽

Voluntary Environmental Programs ◽

Management Standards ◽

Trade Offs ◽

The Impact

We meta-analyze research on why firms join voluntary environmental programs (VEPs) to assess the impact of program stringency, or the extent to which they have rigorous, enforceable standards on these decisions. Stringency creates trade-offs for firms by affecting programs’ effectiveness, legitimacy, and adoption costs. Most research considers singular programs and lacks cross program variation needed to analyze program stringency’s impact. Our meta-analysis addresses this by sampling 127 studies and 23 VEPs. We begin by identifying common institutional and resource-based drivers of participation in the literature, and then analyze how program stringency moderates their impacts. Our results suggest that strictly governed VEPs encourage participation among highly visible and profitable firms, and discourage it when informal institutional pressures are higher, and firms have prior experience with other VEPs or quality management standards. We demonstrate that VEP stringency has nuanced effects on firm participation based on the institutional and resource-based factors facing them.

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Dose dependence of efficacy but not of safety in sublingual immunotherapy

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2006.584 ◽

2016 ◽

Vol 65 (1) ◽

Author(s):

F. Frati ◽

C. Incorvaia ◽

F. Marcucci ◽

L. Sensi ◽

G. Di Cara ◽

...

Keyword(s):

Sublingual Immunotherapy ◽

Clinical Symptoms ◽

Meta Analysis ◽

Dose Dependence ◽

Subcutaneous Immunotherapy ◽

High Dose ◽

Systemic Reactions ◽

Significant Difference

Sublingual immunotherapy (SLIT) currently represents, as indicated by meta-analysis of its efficacy and safety, a valid option to the generally used traditional subcutaneous immunotherapy (SCIT) for treating respiratory allergy. Regarding efficacy, recent studies demonstrated that, similar to what has already been observed in SCIT as well as in experimental and clinical studies about the magnitudo of allergen exposure, the effectiveness on both clinical symptoms and immunologic changes depends on the amount of allergen administered during treatment. In addition, in vitro studies addressed with the role of dendritic cells, currently considered to be of pivotal importance in orienting toward tolerance the immune response to allergens, showed that the internalisation of allergen molecules, which is followed by tolerogenic presentation to T cells, depends on the amount of allergen. However, such dose dependence is not apparent concerning the safety. In fact, the comparison of studies respectively conducted with high and low allergen doses did not show differences in the rate of systemic reactions, which in any case never had the presentation of anaphylaxis, and instead a significant difference in the rate of local reactions, following the oral and gastrointestinal contact with the allergen extract, in favour of high dose studies.

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Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

Psychological Medicine ◽

10.1017/s0033291700000660 ◽

1987 ◽

Vol 17 (4) ◽

pp. 869-873 ◽

Cited By ~ 37

Author(s):

C. Schmauss ◽

J.-C. Krieg

Keyword(s):

Low Dose ◽

Matched Control ◽

Control Group ◽

High Dose ◽

Withdrawal Therapy ◽

The Mean ◽

Dose Dependent ◽

Dose Dependent Effect ◽

Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

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