Bruton tyrosine kinase inhibitor monotherapy in B-cell lymphoma and risk of infection: A systematic review and meta-analysis of randomized controlled trials.

Bruton's tyrosine kinase (BTK) inhibitors are important therapeutic advances with promising efficacy outcomes in the treatment of patients with chronic lymphocytic leukemia and other B-cell lymphoma subtypes. However, the utility of BTK inhibitors can be limited by adverse events such as infections. In this systematic review and meta-analysis, we aim to determine the risk of various infections associated with BTK inhibitor monotherapy in B-cell lymphoma patients. A comprehensive search was conducted in MEDLINE/PubMed, Embase, and Web of Science databases from their inception until October 2023. ClinicalTrials.gov, bibliographies, and relevant conference abstracts were also searched for additional records. Randomized controlled trials that included any B-cell lymphoma patients treated with BTK inhibitor monotherapy and reported infection were included. Meta-analysis was performed to calculate risk ratio (RR) using a random-effects model in R Statistical Software, version 4.3.2. Of 3292 studies retrieved, we included 12 studies in this systematic review and meta-analysis. The median age of patients across the study arms ranged between 64 and 73 years. The overall pooled RR for any grade upper respiratory tract infections (URTI) associated with BTK inhibitor treatment was 1.55 (95% Confidence Interval (CI) 1.22-1.97). The RR of grade ≥3 URTI was reported in 14 out of 1046 patients, yielding an RR of 1.46 (95% CI 0.61-3.54), which was not statistically significant. The pooled RR of any grade pneumonia was 1.20 (95% CI 0.68-2.10) and grade ≥3 pneumonia was 1.12 (95% CI 0.67-1.85), both of which were not statistically significant. Patients with B-cell lymphoma who are undergoing BTK inhibitor monotherapy face an elevated risk of developing URTI. Clinicians prescribing BTK inhibitors should be aware of the potential infectious events that may occur. Close monitoring and the implementation of effective prophylactic measures are essential for managing these patients.

Rasburicase induced methemoglobinemia: A systematic review of descriptive studies.

PURPOSE: There is an increased number of reports being published on rasburicase-induced methemoglobinemia recently. We aimed to identify and critically evaluate all the descriptive studies that described the rasburicase-induced methemoglobinemia, its treatment approach, and their outcomes. METHODOLOGY: PubMed, Scopus and grey literature databases were searched from inception to January 2022 using search terms "rasburicase" and "methemoglobinemia" without any language and date restriction. A bibliographic search was also done to find additional studies. Only descriptive studies on Rasburicase-induced methemoglobinemia were included for our review. Two contributors worked independently on study selection, data abstraction, and quality assessment, and any disagreements were resolved by consensus or discussion with a third reviewer. RESULT: A total of 24 reports including 27 patients (23 male, 3 female patients, and 1 study did not specify the gender of the patient) aged from 5 to 75 years were included in the review. Immediate withdrawal of the drug and administering methylene blue, ascorbic acid, blood transfusion, and supportive oxygen therapy are the cornerstone in the management of rasburicase-induced methemoglobinemia. CONCLUSION: Rasburicase administration should be followed by careful monitoring of patients for any severe complication and treat it as early as possible appropriately. In a patient who presents with rasburicase-induced haemolysis or methemoglobinemia, it is often important to expect a diagnosis of G6PD deficiency unless otherwise confirmed and to avoid administering methylene blue, even though the patient is from a low-risk ethnicity for G6PDD.

Efficacy and Effectiveness Outcomes of Treatments for Double-Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review.

BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax-treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double-exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double-exposed CLL patients. METHODS: PubMed, Embase, and Web of Science databases were searched until December 2023. RESULTS: We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T-cell therapy. CONCLUSION: This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.

Efficacy of antidepressants in functional dyspepsia: Systematic review and meta-analysis with trial sequential analysis of randomized controlled trials.

INTRODUCTION: The beneficial effects of using antidepressants in improving functional dyspepsia (FD) symptoms have been reported in previous meta-analyses; however, the results have not been conclusive. The aim was to perform an updated meta-analysis coupled with trial sequential analysis (TSA) to assess the efficacy of the use of any antidepressants in the treatment of FD in adults. METHODS: Electronic databases were searched up to March 2024 for randomized controlled trials (RCTs) recruiting adults with FD. Data of overall symptoms improved between the antidepressants and placebo groups was pooled to obtain risk ratio (RR) employing the random-effects model. The effect of random errors was evaluated with TSA. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence. Analyses were performed using STATA version 16.0. RESULTS: Nine RCTs with 924 patients met the eligible criteria. The RRs of FD symptoms improving with any antidepressants, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors were (n = 9, RR = 1.30 [95% CI, 1.02-1.67]), (n = 5, RR = 1.41 [95% CI, 1.07-1.85]) and (n = 2, RR = 0.97 [95% CI, 0.72-1.29]), respectively. TSA demonstrated conclusive evidence for the beneficial effect of TCAs. The number needed to treat (NNT) with any depressants and TCAs were 11 (95% CI, 7-36) and 6 (95% CI, 4-15), respectively. The certainty of the evidence for an effect of TCAs was that of moderate GRADE quality. The benefit, however, was limited to the western population (n = 3, RR = 1.43 [95% CI, 1.04-1.96]) and did not extend to the Asian population (n = 2, RR = 1.32 [95% CI, 0.75-2.32]). Conversely, antidepressant-using patients experienced adverse events more frequently. However, no statistically significant association was found between TCAs and any adverse events (n = 3; RR = 1.36 [95% CI, 0.91-2.04]). CONCLUSION: Evidence was obtained suggesting TCAs can be an effective alternative in the treatment of FD, but more evidence from high-quality large trials is required to support their use, especially in the Asian population.

Effectiveness of low to moderate potency topical corticosteroids for phimosis resolution in children: results of a network meta-analysis.

PURPOSE: The use of topical corticosteroids (TCSs) has become an efficient, less-invasive treatment for phimosis. Whether any significant difference in efficacy exists between TCSs based on their potency is unclear. METHODS: Electronic databases were searched up to March 2024 for randomised controlled trials (RCTs) comparing the use of any type or concentration of TCSs with placebo or no treatment in boys with any degree of physician diagnosed phimosis. A random-effects network meta-analysis (NMA) using a consistency model within a frequentist approach was employed. The primary outcome was partial or complete resolution of phimosis reported as a pooled risk ratio (RR) with 95% CI. Relative ranking was assessed with surface under the cumulative ranking curve (SUCRA) probabilities. RESULTS: Seventeen RCTs, containing 2057 participants were identified. NMA suggested that, compared with control, the high (RR 3.19 (95% CI 1.42 to 7.16), moderate (RR 2.68 (95% CI 1.87 to 3.83) and low (RR 3.05 (95% CI 1.63 to 5.71) potency TCSs statistically significantly increased complete or partial clinical resolution of phimosis. The SUCRA plot revealed that high potency (SUCRA = 0.76) was ranked first followed by low and moderate TCSs. When we assessed comparative efficacy among TCSs based on potency, none of the classes were superior to others. The certainty of the evidence for an effect of moderate potent TCSs was that of moderate GRADE quality. CONCLUSION: Moderate to low potency TCSs are of comparable therapeutic effect in the treatment of phimosis to that of highly potent formulations. More high-quality RCTs are warranted.

Metronidazole induced cutaneous adverse drug reaction- a systematic review of descriptive studies.

BACKGROUND: A substantial number of research studies on metronidazole-related cutaneous symptoms have recently been published. Our objective was to identify and evaluate descriptive studies that described metronidazole-related skin manifestations, therapeutic interventions, and consequences. METHODOLOGY: A comprehensive literature search was carried out in the PubMed, Scopus, and grey literature databases from inception to April 2022 without any constraints, as well as a snowball search in Google and a search in Google Scholar. Descriptive articles describing metronidazole-related cutaneous manifestations were considered for the review. Two distinct reviewers carried out the research selection, data extraction, and quality assessment; any discrepancies were resolved by consensus with the third reviewer. RESULTS: About 24 out of 4648 descriptive studies, including 26 patients (20 Female patients and 6 male patients), were included in this review. The included studies comprised a range of ages from 16 to 78 years old. Metronidazole was indicated for the treatment of bacterial vaginosis, trichomoniasis, sepsis, anti-infection therapy, perforated appendicitis, rosacea, vaginal discharge, dysentery, acne rosacea, trichomonal vaginitis, lichen planus, liver abscess, facial rosacea, intestinal amoebiasis, and gingivitis. Fixed drug eruption was the most common skin manifestation which was reported in 7 cases included in this review. Cutaneous manifestations were ameliorated by cessation of the offending drug and by apportioning antihistamines, topical steroids, parenteral corticosteroids, emollients, and topical moisturizers. CONCLUSION: Clinicians and healthcare professionals should be cognizant of the potential cutaneous adverse drug reactions (CADRs) induced by metronidazole to mitigate fatal circumstances. The management of the CADRs appears to respond effectively with immediate drug discontinuation and supportive therapy.

Antimicrobial Activities of Novel Bis-Piperidinium Compounds.

The antimicrobial activity of two new series of bis-piperidinium compounds with alkyl chains of different lengths against bacterial (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis) and fungal strains (Aspergillus flavus, Aspergillus niger, Rhodolorula rubera, Lipomyces lopofera and Candida albicans), are described. Antimicrobial activities of the synthesized compounds were compared to that of dodecyltrimethylammonium chloride. Bis-piperidinium salts possessing 12-16 carbon side chains showed better antimicrobial properties as compared to the standard dodecyltrimethylammonium chloride.

Methotrexate related cutaneous adverse drug reactions: a systematic literature review.

OBJECTIVES: Recently, there is an increased number of reports being published on Methotrexate (MTX) related cutaneous manifestations. We aimed to identify and critically appraise descriptive studies describing the MTX related skin manifestations, treatment approach, and their outcomes. METHODOLOGY: An extensive literature search was performed in the PubMed, Embase, and Scopus databases from inception to April 2021 without any restrictions along with the bibliographic search of included studies, grey literature search, and a snowball search was performed in Google and Google Scholar to identify the relevant literature. Descriptive studies reporting MTX related cutaneous manifestations were considered for the review. The study selection, data extraction, and quality assessment were conducted by two independent reviewers and any disagreements were settled by consensus with the third reviewer. RESULTS: 31 out of 8,365 descriptive studies including 38 patients (22 females and 16 males) aged between 12 and 78 years prescribed for the management of rheumatoid arthritis, ankylosing spondylitis, and psoriasis were included in this review. Toxic epidermal necrolysis (TEN), papular eruption, vasculitis, erosions of psoriasis, ulcerated psoriatic plaques, local reactions, keratinocyte dystrophy, erythema multiforme, drug rash with eosinophilia and systemic symptoms, Steven Johnson syndrome and photosensitive dermatitis were the majority of MTX induced cutaneous reactions. Immediate withdrawal of MTX, providing appropriate care with anti-inflammatory, topical steroids, and supplementation with folic acid were reported to be effective for the management of the MTX related cutaneous manifestations. CONCLUSIONS: Clinicians and healthcare professionals should be aware of possible acute cutaneous drug reactions induced by MTX to avoid further consequences and fatal conditions. Immediate withdrawal of MTX and supportive care were reported as an efficacious therapeutic management of acute cutaneous drug reactions. PROSPERO REGISTRATION NUMBER: CRD42020220038.

Characterization of human adenovirus 35 and derivation of complex vectors.

BACKGROUND: Replication-deficient recombinant adenoviral vectors based on human serotype 35 (Ad35) are desirable due to the relatively low prevalence of neutralizing antibodies in the human population. The structure of the viral genome and life cycle of Ad35 differs from the better characterized Ad5 and these differences require differences in the strategies for the generation of vectors for gene delivery. RESULTS: Sequences essential for E1 and E4 function were identified and removed and the effects of the deletions on viral gene transcription were determined. In addition, the non-essential E3 region was deleted from rAd35 vectors and a sequence was found that did not have an effect on viability but reduced viral fitness. The packaging capacity of rAd35 was dependent on pIX and vectors were generated with stable genome sizes of up to 104% of the wild type genome size. These data were used to make an E1-, E3-, E4-deleted rAd35 vector. This rAd35 vector with multiple gene deletions has the advantages of multiple blocks to viral replication (i.e., E1 and E4 deletions) and a transgene packaging capacity of 7.6 Kb, comparable to rAd5 vectors. CONCLUSIONS: The results reported here allow the generation of larger capacity rAd35 vectors and will guide the derivation of adenovirus vectors from other serotypes.

Systematic Screening, Rational Development, and Initial Optimization of Efficacious RNA Silencing Agents for Human Rod Opsin Therapeutics.

PURPOSE: To systematically evaluate human rod opsin (hRHO) mRNA for potential target sites sensitive to posttranscriptional gene silencing (PTGS) by hammerhead ribozyme (hhRz) or RNA interference (RNAi) in human cells. To develop a comprehensive strategy to identify and optimize lead candidate agents for PTGS gene therapeutics. METHODS: In multidisciplinary RNA drug discovery, computational mRNA accessibility and in vitro experimental methods using reverse transcription-polymerase chain reaction (RT-PCR) were used to map accessibility in full-length hRHO transcripts. HhRzs targeted predicted accessible and inaccessible sites and were screened for cellular knockdown using a bicistronic reporter construct. Lead hhRz and RNAi PTGS agents were rationally optimized for target knockdown in human cells. RESULTS: Systematic screening of hRHO mRNA targeting agents resulted in lead candidate identification of a novel hhRz embedded in an RNA scaffold. Rational optimization strategies identified a minimal 725 hhRz as the most active agent. Recently identified tertiary accessory elements did not enhance activity. A 725-short-hairpin RNA (shRNA) agent exerts log-order knockdown. Silent modulation of the 725-hhRz target site in hRHO mRNA resulted in resistance to knockdown. CONCLUSIONS: Combining rational RNA drug design with cell-based screening allowed rapid identification of lead agents targeting hRHO. Optimization strategies identified the agent with highest intracellular activity. These agents have therapeutic potential in a mutation-independent strategy for adRP, or other degenerations where hRHO is a target. This approach can be broadly applied to any validated target mRNA, regardless of the disease. TRANSLATIONAL RELEVANCE: This work establishes a platform approach to develop RNA biologicals for the treatment of human disease.

Rescue and production of vaccine and therapeutic adenovirus vectors expressing inhibitory transgenes.

Expression of certain transgenes from an adenovirus vector can be deleterious to its own replication. This can result in the inhibition of virus rescue, reduced viral yields, or, in the worst case, make it impossible to construct a vector expressing the inhibiting transgene product. A gene regulation system based on the tet operon was used to allow the rescue and efficient growth of adenovectors that express transgenes to high levels. A key advantage to this system is that repression of transgene expression is mediated by the packaging cell line, thus, expression of regulatory products from the adenovector are not required. This provides a simple, broadly applicable system wherein transgene repression is constitutive during vector rescue and growth and there is no effect on adenovector-mediated expression of gene products in transduced cells. Several high-level expression vectors based on first- and second-generation adenovectors were rescued and produced to high titer that otherwise could not be grown. Yields of adenovectors expressing inhibitory transgene products were increased, and the overgrowth of cultures by adenovectors with nonfunctional expression cassettes was prevented. The gene regulation system is a significant advancement for the development of adenovirus vectors for vaccine and other gene transfer applications.

Adenovirus vector library: an approach to the discovery of gene and protein function.

A method was developed to generate a complex cDNA expression library within an adenovirus type 5 (Ad5)-based vector backbone, termed AdLibrary. Construction of the AdLibrary entailed the conversion of an Ad5 genome-containing cosmid to infectious virus particles. The Ad5 genome was modified by replacing the E1A and E1B genes with a Rous sarcoma virus-driven expression cassette. Conversion was accomplished by liberating the viral genome by restriction enzyme digestion and transfection in HEK 293 cells, which support the growth of E1A/E1B-deficient virus. A test AdLibrary demonstrated the possibility of converting and identifying a marker gene present at a frequency of 1/10(5) in the cosmid library. To demonstrate the utility of this technology, an AdLibrary was used to isolate a viral gene by its biological function. Virus growth was selected for with an AdLibrary on A549 cells, which do not complement for E1A/E1B function. The AdLibrary was generated with cDNAs derived from HeLa cells productively infected with Ad5. A cDNA corresponding to Ad5 E1A 13S was selected and isolated from the AdLibrary using this strategy. Since multiple genes are assayed simultaneously, this technology should expedite the discovery of genes affecting defined biological activities. This AdLibrary approach provides an opportunity to exploit the efficient gene delivery capabilities of adenovirus vectors for the rapid discovery of gene and protein function.

Rapid construction of adenoviral vectors by lambda phage genetics.

Continued improvements of adenoviral vectors require the investigation of novel genome configurations. Since adenovirus can be generated directly by transfecting packaging cell lines with viral genomes isolated from plasmid DNA, it is possible to separate genome construction from virus production. In this way failure to generate a virus is not associated with an inability to generate the desired genome. We have developed a novel lambda-based system that allows rapid modification of the viral genome by double homologous recombination in Escherichia coli. The recombination reaction and newly generated genome may reside in a recombination-deficient bacterial host for enhanced plasmid stability. Furthermore, the process is independent of any restriction endonucleases. The strategy relies on four main steps: (i) homologous recombination between an adenovirus cosmid and a donor plasmid (the donor plasmid carries the desired modification[s] and flanking regions of homology to direct its recombination into the viral genome); (ii) in vivo packaging of the recombinant adenoviral cosmids during a productive lambda infection; (iii) transducing a recombination-deficient E. coli lambda lysogen with the generated lysate (the lysogen inhibits the helper phage used to package the recombinant andenoviral cosmid from productively infecting and destroying the host bacteria); (iv) effectively selecting for the desired double-recombinant cosmid. Approximately 10,000 double-recombinant cosmids are recovered per reaction with essentially all of them being the correct double-recombinant molecule. This system was used to generate quickly and efficiently adenoviral genomes deficient in the E1/E3 and E1/E3/E4 regions. The basis of this technology allows any region of the viral genome to be readily modified for investigation of novel configurations.