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Biomedicines Sep 2023This umbrella review aimed to determine the various drugs used to treat trigeminal neuralgia (TN) and to evaluate their efficacies as well as side effects by surveying... (Review)
Review
This umbrella review aimed to determine the various drugs used to treat trigeminal neuralgia (TN) and to evaluate their efficacies as well as side effects by surveying previously published reviews. An online search was conducted using PubMed, CRD, EBSCO, Web of Science, Scopus, and the Cochrane Library with no limits on publication date or patients' gender, age, and ethnicity. Reviews and meta-analyses of randomized controlled trials pertaining to drug therapy for TN, and other relevant review articles added from their reference lists, were evaluated. Rapid reviews, reviews published in languages other than English, and reviews of laboratory studies, case reports, and series were excluded. A total of 588 articles were initially collected; 127 full-text articles were evaluated after removing the duplicates and screening the titles and abstracts, and 11 articles were finally included in this study. Except for carbamazepine, most of the drugs had been inadequately studied. Carbamazepine and oxcarbazepine continue to be the first choice for medication for classical TN. Lamotrigine and baclofen can be regarded as second-line drugs to treat patients not responding to first-line medication or for patients having intolerable side effects from carbamazepine. Drug combinations using carbamazepine, baclofen, gabapentin, ropivacaine, tizanidine, and pimozide can yield satisfactory results and improve the tolerance to the treatment. Intravenous lidocaine can be used to treat acute exaggerations and botulinum toxin-A can be used in refractory cases. Proparacaine, dextromethorphan, and tocainide were reported to be inappropriate for treating TN. Anticonvulsants are successful in managing trigeminal neuralgia; nevertheless, there have been few studies with high levels of proof, making it challenging to compare or even combine their results in a statistically useful way. New research on other drugs, combination therapies, and newer formulations, such as vixotrigine, is awaited. There is conclusive evidence for the efficacy of pharmacological drugs in the treatment of TN.
PubMed: 37892981
DOI: 10.3390/biomedicines11102606 -
International Journal of Radiation... Jan 2024Radiation necrosis (RN) secondary to stereotactic radiosurgery is a significant cause of morbidity. The optimal management of corticosteroid-refractory brain RN remains... (Review)
Review
A Systematic Review Informing the Management of Symptomatic Brain Radiation Necrosis After Stereotactic Radiosurgery and International Stereotactic Radiosurgery Society Recommendations.
Radiation necrosis (RN) secondary to stereotactic radiosurgery is a significant cause of morbidity. The optimal management of corticosteroid-refractory brain RN remains unclear. Our objective was to summarize the literature specific to efficacy and toxicity of treatment paradigms for patients with symptomatic corticosteroid-refractory RN and to provide consensus guidelines for grading and management of RN on behalf of the International Stereotactic Radiosurgery Society. A systematic review of articles pertaining to treatment of RN with bevacizumab, laser interstitial thermal therapy (LITT), surgical resection, or hyperbaric oxygen therapy was performed. The primary composite outcome was clinical and/or radiologic stability/improvement (ie, proportion of patients achieving improvement or stability with the given intervention). Proportions of patients achieving the primary outcome were pooled using random weighted-effects analysis but not directly compared between interventions. Twenty-one articles were included, of which only 2 were prospective studies. Thirteen reports were relevant for bevacizumab, 5 for LITT, 5 for surgical resection and 1 for hyperbaric oxygen therapy. Weighted effects analysis revealed that bevacizumab had a pooled symptom improvement/stability rate of 86% (95% CI 77%-92%), pooled T2 imaging improvement/stability rate of 93% (95% CI 87%-98%), and pooled T1 postcontrast improvement/stability rate of 94% (95% CI 87%-98%). Subgroup analysis showed a statistically significant improvement favoring treatment with low-dose (below median, ≤7.5 mg/kg every 3 weeks) versus high-dose bevacizumab with regards to symptom improvement/stability rate (P = .02) but not for radiologic T1 or T2 changes. The pooled T1 postcontrast improvement/stability rate for LITT was 88% (95% CI 82%-93%), and pooled symptom improvement/stability rate for surgery was 89% (95% CI 81%-96%). Toxicity was inconsistently reported but was generally low for all treatment paradigms. Corticosteroid-refractory RN that does not require urgent surgical intervention, with sufficient noninvasive diagnostic testing that favors RN, can be treated medically with bevacizumab in carefully selected patients as a strong recommendation. The role of LITT is evolving as a less invasive image guided surgical modality; however, the overall evidence for each modality is of low quality. Prospective head-to-head comparisons are needed to evaluate the relative efficacy and toxicity profile among treatment approaches.
Topics: Humans; Radiosurgery; Bevacizumab; Prospective Studies; Brain Neoplasms; Brain; Radiation Injuries; Necrosis; Adrenal Cortex Hormones; Retrospective Studies
PubMed: 37482137
DOI: 10.1016/j.ijrobp.2023.07.015 -
Blood Advances Oct 2023Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell... (Meta-Analysis)
Meta-Analysis
Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; B-Cell Maturation Antigen; Immunotherapy; T-Lymphocytes; CD3 Complex
PubMed: 37467036
DOI: 10.1182/bloodadvances.2023010539 -
EClinicalMedicine Aug 2023Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the...
BACKGROUND
Refractory chronic cough (RCC) has a significant impact on patient's health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC.
METHODS
A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940.
FINDINGS
19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887-2.387) and -11.042 (P = 0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P = 0.003) and -7.843 (P = 0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012-1.259), especially taste-related AEs (RR: 6.216, P < 0.05).
INTERPRETATION
In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough.
FUNDING
National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).
PubMed: 37538538
DOI: 10.1016/j.eclinm.2023.102100 -
Cancer Research and Treatment Jul 2023We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis. (Meta-Analysis)
Meta-Analysis
Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis.
PURPOSE
We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis.
MATERIALS AND METHODS
R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and chimeric antigen receptor (CAR) T-cell therapy was used as reference treatment.
RESULTS
Twenty-six ASCT-eligible cohorts from 17 studies comprising 2,924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3,617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval [CI], 0.15 to 0.65) for the CAR T-cell group and 0.34 (95% CI, 0.30 to 0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI, 0.35 to 0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI, 0.37 to 0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment.
CONCLUSION
Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Salvage Therapy; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Lymphoma, Large B-Cell, Diffuse
PubMed: 36915243
DOI: 10.4143/crt.2022.1658 -
JAMA Oct 2023Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough.
OBJECTIVE
To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough.
DATA SOURCES
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023.
STUDY SELECTION
Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID).
MAIN OUTCOMES AND MEASURES
Cough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events.
RESULTS
Nine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]).
CONCLUSIONS AND RELEVANCE
Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.
Topics: Adult; Humans; Cough; Pyrimidines; Quality of Life; Sulfonamides; Dose-Response Relationship, Drug; Treatment Outcome; Chronic Disease; Taste
PubMed: 37694849
DOI: 10.1001/jama.2023.18035 -
Clinical Medicine (London, England) Sep 2023Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease... (Meta-Analysis)
Meta-Analysis
Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research.
Topics: Humans; Adult; Hypercalcemia; Denosumab; Diphosphonates; Quality of Life; Neoplasms; Bone Density Conservation Agents
PubMed: 37775175
DOI: 10.7861/clinmed.2023-0227 -
Frontiers in Microbiology 2023Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs... (Review)
Review
Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs. Artemisinin derivatives, quercetin and baicalein, and anti-cyclooxygenase-2 are derived from natural molecules and are generally used for different indications. Although they have demonstrated indirect anti-CMV activity, few clinical studies were performed with these compounds. Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy. The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials.
PubMed: 38053548
DOI: 10.3389/fmicb.2023.1321116 -
RMD Open Dec 2023Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing...
OBJECTIVE
Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases.
METHODS
A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome.
RESULTS
38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%).
CONCLUSION
Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.
Topics: Humans; Antibodies, Monoclonal; Rituximab; Autoimmune Diseases; Autoantibodies
PubMed: 38101819
DOI: 10.1136/rmdopen-2023-003604 -
Transplantation and Cellular Therapy Jan 2024Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients... (Meta-Analysis)
Meta-Analysis
Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.
Topics: Humans; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Neurotoxicity Syndromes; Observational Studies as Topic; Pathologic Complete Response; Receptors, Chimeric Antigen; Retrospective Studies; T-Lymphocytes
PubMed: 37890589
DOI: 10.1016/j.jtct.2023.10.017