Neurotoxicity of antibodies in cancer therapy: A review.

The objective of this manuscript is to identify the neurological side effect profile associated with different classes of antibodies used in cancer pharmacotherapy and to estimate the frequency in which these neurotoxicity occurs. A systematic review of the literature was conducted using OVID MEDLINE and EMBASE databases for articles written between January of 2010 till August of 2018. The spectrum of neurotoxicity was searched using expanded terminology, medical subject headings, truncation, spelling variations and database specific controlled vocabulary. 2134 citations were retrieved that were narrowed down to 151 when SORT 1 or SORT 2 critical appraisal tool was applied to articles with human subjects. Meta-analysis using random effect model was done to estimate the prevalence of neurological symptoms per class of antibody described in SORT1 and SORT2 articles. It was found that the most common neurotoxicity per antibody class are as follows; Bi-specific T-cell engagers was headache 38% [35-40%; I2 0%]; anti-CD20, neuropathy, 16% [7-24%, I2 65%]; anti-CD30, neuropathy 57% [46-68%, I2 72%]; anti-CD52, neuropathy 5-15%; anti-CTL4, headache 12% [7-16%, I2 49%]; anti-EGFR, headache 25% [11-38%, I2 92%]; anti-Her2, neuropathy 33% [18-49%, I2 98%]; anti-PD1 and PDL1, headache 3% [2-5%, I2 85%]; and anti-VEGF, headache 25% [16-35%, I2 73%]. Therefore, all classes of antibodies used in cancer pharmacotherapy have associated neurotoxicity with a wide spectrum of effects afflicting the nervous system as a whole. The specific side effects and the frequency at which they occur differ per class of antibody. Broader and more severe symptoms were noted to effect patients with preexisting brain lesions.

The impact of chlorhexidine bathing on hospital-acquired bloodstream infections: a systematic review and meta-analysis.

BACKGROUND: Chlorhexidine gluconate (CHG) bathing of hospitalized patients may have benefit in reducing hospital-acquired bloodstream infections (HABSIs). However, the magnitude of effect, implementation fidelity, and patient-centered outcomes are unclear. In this meta-analysis, we examined the effect of CHG bathing on prevention of HABSIs and assessed fidelity to implementation of this behavioral intervention. METHODS: We undertook a meta-analysis by searching Medline, EMBASE, CINAHL, Scopus, and Cochrane's CENTRAL registry from database inception through January 4, 2019 without language restrictions. We included randomized controlled trials, cluster randomized trials and quasi-experimental studies that evaluated the effect of CHG bathing versus a non-CHG comparator for prevention of HABSIs in any adult healthcare setting. Studies of pediatric patients, of pre-surgical CHG use, or without a non-CHG comparison arm were excluded. Outcomes of this study were HABSIs, patient-centered outcomes, such as patient comfort during the bath, and implementation fidelity assessed through five elements: adherence, exposure or dose, quality of the delivery, participant responsiveness, and program differentiation. Three authors independently extracted data and assessed study quality; a random-effects model was used. RESULTS: We included 26 studies with 861,546 patient-days and 5259 HABSIs. CHG bathing markedly reduced the risk of HABSIs (IRR = 0.59, 95% confidence interval [CI]: 0.52-0.68). The effect of CHG bathing was consistent within subgroups: randomized (0.67, 95% CI: 0.53-0.85) vs. non-randomized studies (0.54, 95% CI: 0.44-0.65), bundled (0.66, 95% CI: 0.62-0.70) vs. non-bundled interventions (0.51, 95% CI: 0.39-0.68), CHG impregnated wipes (0.63, 95% CI: 0.55-0.73) vs. CHG solution (0.41, 95% CI: 0.26-0.64), and intensive care unit (ICU) (0.58, 95% CI: 0.49-0.68) vs. non-ICU settings (0.56, 95% CI: 0.38-0.83). Only three studies reported all five measures of fidelity, and ten studies did not report any patient-centered outcomes. CONCLUSIONS: Patient bathing with CHG significantly reduced the incidence of HABSIs in both ICU and non-ICU settings. Many studies did not report fidelity to the intervention or patient-centered outcomes. For sustainability and replicability essential for effective implementation, fidelity assessment that goes beyond whether a patient received an intervention or not should be standard practice particularly for complex behavioral interventions such as CHG bathing. TRIAL REGISTRATION: Study registration with PROSPERO CRD42015032523 .

Accuracy of the magnetic resonance imaging pathway in the detection of prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Although magnetic resonance imaging and subsequent targeted biopsy ('MRI pathway') have been widely adopted in routine clinical practice, it is still a common practice to perform systematic biopsy concurrently, because the accuracy of the MRI pathway is yet to be fully defined. This systematic review of the literature assessed the sensitivity of the MRI pathway for detecting clinically significant prostate cancer. METHODS: Multiple databases were searched up to May 2017 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement for studies assessing the accuracy of MR-guided biopsy (MRGB) compared to a reference standard which consisted of both MRGB and systematic biopsy with at least 20-cores. The primary outcome was the sensitivity of detecting clinically significant prostate cancer defined as Gleason ≥7 disease. RESULTS: A total of 15 studies met the predefined inclusion criteria. Overall, studies were assessed to be of low quality with inadequate blinding of personnel, which could introduce performance and detection bias. The calculated summary sensitivity of the MRI pathway was 78.3% [95%CI 75.0-81.4%]. There was moderate heterogeneity between the included studies (I2 = 36%). Subgroup analysis was performed based on clinical setting, the strength of MRI magnet and mode of image fusion as factors but no interaction was identified between any of the subgroups. No publication bias was identified. CONCLUSION: The MRI pathway cannot yet be solely relied upon to diagnose clinically significant disease and hence additional systematic sampling should still be performed during the biopsy procedure.

Pembrolizumab monotherapy versus chemotherapy for treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy. A Cochrane Rapid Review.

BACKGROUND: The use of systemic immunotherapy targets is emerging as an important treatment option for metastatic urothelial carcinoma, particularly for patients who cannot tolerate or who fail cisplatin-based chemotherapy. One such target is the inhibition of the checkpoint protein programmed cell death-1 (PD-1) receptor and its ligand (PD-L1) by monoclonal antibodies. OBJECTIVES: To assess the effects of pembrolizumab monotherapy versus chemotherapy for treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy. SEARCH METHODS: We performed a Cochrane Rapid Review, limiting our search to published studies in the English language. We searched databases of the medical literature, including the Cochrane Central Register of Controlled Trials and MEDLINE, as well as trial registries including ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). Our search extended from January 2000 to June 2018. SELECTION CRITERIA: We included randomised controlled trials except cross-over trials and cluster randomised trials. We excluded all other study designs. Participants included had locally advanced or metastatic urothelial carcinoma of the bladder, with disease progression during or following platinum-containing chemotherapy (synonymous with second-/third-/fourth-line therapy). This review focused on pembrolizumab (synonyms: MK-3475, lambrolizumab, Keytruda). DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included study. The certainty of evidence was rated according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified one randomised controlled trial that included 542 participants, which compared the use of pembrolizumab monotherapy versus chemotherapy for the treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy. Results were reported after a median follow-up of 14.1 months (range 9.9 to 22.1 months).Primary outcomesPembrolizumab probably reduces the risk of death from any cause (hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59 to 0.90; moderate certainty evidence). This corresponds to 115 fewer deaths (191 fewer to 38 fewer) per 1000 participants with pembrolizumab at 12 months. We downgraded the certainty of evidence one level for imprecision.Pembrolizumab may slightly improve quality of life (change from baseline to week 15 assessed with the Core Quality of Life Questionnaire; higher value reflects better quality of life; scale 0 to 100) with a mean difference (MD) of 9.05, 95% CI 4.61 to 13.50; low certainty evidence). We downgraded the certainty of evidence two levels for study limitations and imprecision.Secondary outcomesPembrolizumab may have little or no effect on disease progression (HR 0.98, 95% CI 0.81 to 1.19; low certainty evidence). This corresponds to three fewer patients (42 fewer to 24 more) whose disease progressed per 1000 participants at 12 months. We downgraded the certainty of evidence two levels for study limitations and imprecision.Pembrolizumab probably improves treatment response (based on complete or partial radiologic response) with a risk ratio (RR) of 1.85, 95% CI 1.24 to 2.77; moderate certainty evidence). This corresponds to 97 more respondents (27 more to 202 more) per 1000 participants with pembrolizumab. We downgraded the certainty of evidence one level for imprecision.Pembrolizumab may have little or no effect on treatment-related mortality (RR 0.96, 95% CI 0.24 to 3.79; low certainty evidence). This corresponds to one fewer (12 fewer to 44 more) treatment-related deaths per 1000 participants with pembrolizumab. We downgraded the certainty of evidence two levels for study limitations and imprecision.Pembrolizumab may have little or no effect on discontinuations due to adverse events (RR 0.66, 95% CI 0.39 to 1.10). This corresponds to 54 fewer discontinuations per 1000 participants (95% CI 79 fewer to 7 more). We downgraded the certainty of evidence for study limitations and imprecision.Pembrolizumab may reduce serious adverse events (RR 0.83, 95 CI 0.72 to 0.97; low certainty evidence). This corresponds to 107 fewer serious averse events per 1000 participants (95% CI 19 fewer to 176 fewer). We downgraded two levels for study limitations and imprecision. AUTHORS' CONCLUSIONS: The use of pembrolizumab in men with advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy probably improves overall survival when compared with chemotherapy alone. At 12 months follow-up about 70% of those in the chemotherapy group had died, compared with 59% of those treated with pembrolizumab. We are very uncertain about the effects of pembolizumab on quality of life. Pembolizumab may also improve treatment response rates, and reduce the risk of serious adverse events, but may make little or no difference to discontinuations of treatment due to adverse events. These conclusions are based on a single trial that was sponsored by the producer of pembrolizumab.

Management of giant omphaloceles: A systematic review of methods of staged surgical vs. nonoperative delayed closure.

PURPOSE: Despite the numerous methods of closure for giant omphaloceles, uncertainty persists regarding the most effective option. Our purpose was to review the literature to clarify the current methods being used and to determine superiority of either staged surgical procedures or nonoperative delayed closure in order to recommend a standard of care for the management of the giant omphalocele. METHODS: Our initial database search resulted in 378 articles. After de-duplification and review, we requested 32 articles relevant to our topic that partially met our inclusion criteria. We found that 14 articles met our criteria; these 14 studies were included in our analysis. 10 studies met the inclusion criteria for nonoperative delayed closure, and 4 studies met the inclusion criteria for staged surgical management. RESULTS: Numerous methods for managing giant omphaloceles have been described. Many studies use topical therapy secondarily to failed surgical management. Primary nonoperative delayed management had a cumulative mortality of 21.8% vs. 23.4% in the staged surgical group. Time to initiation of full enteric feedings was lower in the nonoperative delayed group at 14.6days vs 23.5days. CONCLUSION: Despite advances in medical and surgical therapies, giant omphaloceles are still associated with a high mortality rate and numerous morbidities. In our analysis, we found that nonoperative delayed management with silver therapy was associated with lower mortality and shorter duration to full enteric feeding. We recommend that nonoperative delayed management be utilized as the primary therapy for the newborn with a giant omphalocele.

Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons. METHODS: We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function ≥32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. RESULTS: We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons. CONCLUSIONS: In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality.