Non-randomized Clinical Trials Research Articles

Start low, go slow: A systematic review and meta-analysis of upfront tailored treatment dosing in older adults with advanced cancer.

1625 Background: Older adults aged ≥65 with advanced cancer are underrepresented in treatment trials. This gap limits informed decision-making regarding the dose and tolerability of proposed therapies. Standard chemotherapy is associated with >50% serious adverse event rate among older adults, with frequent dose reduction and early treatment discontinuation. A "start low, go slow" (SLGS) approach begins systemic therapy at lower-than-standard doses and increases the dose if well-tolerated. This alternative dosing strategy has shown value in minimizing adverse events and functional decline without compromising the overall effectiveness of treatments. We conducted the first systematic review and meta-analysis of SLGS effectiveness among older adults across advanced cancers. Methods: This review, was registered with PROSPERO and adhered to PRISMA criteria, covering PubMed, Journal of Geriatric Oncology and EMBASE from January 2000 until December 15, 2024. Eligible study designs were randomized controlled trials, retrospective trials, and non-randomized clinical trials with patients with advanced cancers who underwent systemic therapy. We reported all studies that studied the SLGS approach. Our studied outcomes were overall survival (OS), progression-free survival (PFS), treatment discontinuation, and toxicity. Data extraction included author, patient, cancer type, treatment, and survival outcomes. A meta-analysis using fixed effects and risk ratios (RR) was performed when sufficient data was available; significant outcomes had α<0.05. Results: Our search identified 13 studies testing SLGS strategies in oncology, including 3,508 patients, with a median age 63-78 years. The -represented cancers included colorectal (6 studies, 3059 patients total), lung (2 studies, 113 pts), chronic myeloid leukemia (2 studies, 127 pts), non-Hodgkin lymphoma (1 study, 45 pts), and prostate (2 studies, 164 pts) cancers. Ten (77%) studies assessed OS and PFS. Five studies (39%) compared SLGS against standard doses, finding no significant differences in PFS and OS across all trials. Dose escalation rates for SLGS ranged from 5% to 60%. The ability to complete planned cycles was higher with SLGS compared to standard dose (1 study, 43% vs 26%, p=0.04). Treatment discontinuation was not different for SLGL vs. standard dose (5 studies, meta-analysis RR 1.07, 95% CI 0.90-1.27, p=0.42). Toxicity ranged from 5% to 89% across studies; SLGS had lower grade ≥3 adverse events compared to standard dose (4 studies, meta-analysis RR 0.88, 95% CI 0.80-0.94, p < 0.001). Conclusions: This is the first systematic review and meta-analysis analyzing the SLGS approach to systemic therapy dosing in older adults with advanced cancer. Compared to standard-dose systemic therapy, older adults pursuing a SLGS strategy had greater completion of planned cycles, reduced toxicity, and similar survival.

Cosmeceuticals for antiaging: a systematic review of safety and efficacy.

Cosmeceuticals, the bridge between pharmaceuticals and cosmetics, contain biologically active ingredients that may improve the skin's overall appearance. As the market, accessibility, and popularity of cosmeceuticals increase, it is essential to understand the safety and efficacy of such products. This systematic review aims to examine published clinical studies involving the use of cosmeceuticals for antiaging to provide evidence-based recommendations based on available efficacy and safety data. PubMed, Embase, and Cochrane were systematically searched on January 1, 2023 using PRISMA guidelines. Strength of evidence was graded using the Oxford Centre for Evidence-Based Medicine guidelines. Clinical recommendations were made based on the quality of the existing literature. A total of 153 articles regarding the use of cosmeceuticals for treatment of antiaging were identified. After screening of titles, abstracts, and full text, 32 studies involving 1236 patients met inclusion criteria, including 20 randomized controlled trials (RCTs) and 12 non-randomized open-label clinical trials for Vitamin C, Retinol, Bakuchiol, Tetrahydrojasmonic acid, Growth Factors, Methyl Estradiolpropanoate, Timosaponin A-III (TA-III), Protocatechuic acid, Grammatophyllum speciosum, and Jasmine rice panicle extract. Retinol and vitamin C for antiaging received a Grade A for recommendation. Methyl estradiolpropanoate, bakuchiol, tetrahydrojasmonic acid, and growth factors received a recommendation grade of C. The remaining ingredients were assigned an inconclusive grade of recommendation due to lack of evidence. Cosmeceuticals included in the review had favorable safety profiles with few significant adverse events. The review analyzes numerous different ingredients to provide an evidence-based approach to decision-making for consumers and physicians on the use of cosmeceuticals for antiaging. Limitations to our review include a limited number of randomized controlled trials and a need for long-term data on each cosmeceutical's efficacy and safety. Future research is needed to establish the long-term effectiveness and safety of cosmeceuticals.

A Mediterranean diet improves glycation markers in healthy people and in those with chronic diseases: a systematic review of clinical trials.

Consumption of the Mediterranean diet (MedDiet) has beneficial effects on cardiometabolic health and aging. This systematic review aimed to critically investigate the effect of the MedDiet on glycation markers in healthy or overweight individuals with type 2 diabetes or cardiovascular disease. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched, using the terms "Mediterranean diet" AND "glycation end products, advanced". Three randomized and 3 nonrandomized clinical trials, containing data on 2935 adult and elderly individuals with normal weight or overweight, were included. All extracted data were compiled, compared, and critically analyzed. The authors of most of the studies demonstrated a reduction in serum concentrations of advanced glycation end products (AGEs), such as εN-carboxymethyllysine and methylglyoxal, and in skin autofluorescence levels after at least 4 weeks of adherence to the MedDiet. The MedDiet also led to positive effects on gene expression of receptors for AGEs, as RAGE and AGER1, and an enzyme involved in detoxification (glyoxalase I). There is no evidence that short-term adherence affects glycation markers. Glycation markers improved in response to the MedDiet. The possible mechanisms involved may be related to the low AGE and refined sugars content of the diet, as well as its high monounsaturated fatty acid, phenolic compound, and dietary fiber contents. PROSPERO registration no. CRD42021284006.

The Impact of Exercise on Interleukin-6 to Counteract Immunosenescence: Methodological Quality and Overview of Systematic Reviews.

This study evaluated the methodological quality of published systematic reviews on randomized and non-randomized clinical trials to synthesize evidence on the association between IL-6, immunosenescence, and aerobic and/or resistance exercise. The Preferred Reporting Items for Overviews of Systematic Reviews (PRIO-harms) guideline was used, with registration number CRD42022346142-PROSPERO. Relevant databases such as Cochrane Library, PubMed, Web of Science, Scopus, and Google Scholar were searched using English Medical Subject Headings terms. Inclusion criteria were systematic reviews analyzing aerobic exercise, resistance exercise, or a combination of both and assessing IL-6 as a biomarker of cellular immunosenescence in humans. The Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) was employed. Out of 742 identified articles, 18 were eligible, and 13 were selected for analysis. Sample sizes ranged from 249 to 1421 participants, mostly female, with ages ranging from 17 to 95 years. Aerobic exercise was the most studied type (46.15%), followed by combined exercise (38.46%) and resistance exercise (15.38%). Aerobic exercise showed a statistically significant reduction in IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) levels. Among the 13 reviews analyzed using AMSTAR-2, 8 were rated as critically low quality, and 5 were classified as low quality. Aerobic exercise has anti-inflammatory properties and the potential to modulate IL-6, CRP, and TNF-α levels in immunosenescence. However, the limited methodological quality of the analyzed systematic reviews highlights the urgent need for robust, high-quality studies to improve access to information and facilitate evidence-based decision-making in healthcare.

Abstract PO3-12-03: SAFETY AND TOLERABILITY OF SHOCKWAVE THERAPY FOR TREATMENT OF BREAST CANCER-RELATED LYMPHEDEMA: A SYSTEMATIC REVIEW

Abstract Introduction: Breast cancer is currently the most common malignancy among women, after non-melanoma skin cancer. Upper limb lymphedema is the most feared complication of breast cancer treatment. Currently, the approach described in the literature as the most effective for the treatment of lymphedema is Complex Physical Therapy. In the search for more efficient therapeutic actions, Shockwave Therapy emerges as an alternative in the treatment of upper limb lymphedema secondary to breast cancer. Objective: to systematically review the available literature and verify the safety, tolerance and efficacy of using Shockwave Therapy (ESWT) in the treatment of upper limb lymphedema secondary to breast cancer. Methods: The following databases were used: PubMed; PEDro, The Cochrane Library, EMBASE, Web of science and Scopus and through manual search of articles. The PICO research method was adopted, and the descriptors adjusted according to the respective database. This study was registered in PROSPERO: CRD42020209588. Results: Combined searches, including reference lists, manual searches, and database searches, yielded 64 articles, of which 35 articles were duplicates, 23 studies were excluded by title, abstract, or full reading. Six full-text articles were selected. Of these, only 3 randomized clinical trials and 3 non-randomized clinical trials met all established inclusion criteria and were analyzed in this systematic review. Two more RCTs were added by manual search of references from other articles. None of the studies found had safety and tolerability as their primary objective, and one reported transient redness with the use of the device. Shockwave Therapy, combined with other resources, can significantly improve lymphedema volume and shoulder range of motion, but there is not enough evidence to support the use of ESWT as a substitute for complex physical therapy (CPT). Final considerations: There is evidence that it can improve ROM and upper limb volume when used in association with CPT, which is the gold standard for the treatment of lymphedema. Keywords: Lymphedema, Breast Cancer, Extracorporeal Shockwave Therapy. Citation Format: Patricia Lima Ventura, Cinira Haddad, Afonso Nazário, Gil Facina, Vanessa Sanvido, Amanda Estevao, Samantha Lopes de Almeida Rizzi. SAFETY AND TOLERABILITY OF SHOCKWAVE THERAPY FOR TREATMENT OF BREAST CANCER-RELATED LYMPHEDEMA: A SYSTEMATIC REVIEW [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-03.

Primary Tumor Resection Before Systemic Therapy in Patients With Colon Cancer and Unresectable Metastases: Combined Results of the SYNCHRONOUS and CCRe-IV Trials.

Chemotherapy is established as primary treatment in patients with stage IV colorectal cancer and unresectable metastases. Data from nonrandomized clinical trials have fueled persistent uncertainty if primary tumor resection (PTR) before chemotherapy prolongs survival. We investigated the prognostic value of PTR in patients with newly diagnosed stage IV colon cancer who were not amenable to curative treatment. Patients enrolled in the multicenter, randomized SYNCHRONOUS and CCRe-IV trials were included in the analysis. Patients with colon cancer with synchronous unresectable metastases were randomly assigned at 100 sites in Austria, Germany, and Spain to undergo PTR or up-front chemotherapy (No PTR group). The chemotherapy regimen was left at discretion of the local team. Patients with tumor-related symptoms, inability to tolerate surgery and/or systemic chemotherapy, and history of another cancer were excluded. The primary end point was overall survival (OS), and the analyses were performed with intention-to-treat. A total of 393 patients were randomly assigned to undergo PTR (n = 187) or no PTR (n = 206) between November 2011 and March 2017. Chemotherapy was not administered to 6.4% in the No PTR group and 24.1% in the PTR group. The median follow-up time was 36.7 months (95% CI, 36.6 to 37.3). The median OS was 16.7 months (95% CI, 13.2 to 19.2) in the PTR group and 18.6 months (95% CI, 16.2 to 22.3) in the No PTR group (P = .191). Comparable OS between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944 [95% CI, 0.738 to 1.209], P = .65) and across all subgroups. Patients with serious adverse events were more common in the No PTR group (10.2% v 18.0%; P = .027). Among patients with colon cancer and synchronous unresectable metastases, PTR before systemic chemotherapy was not associated with prolonged OS.

Systematic review of continuous positive airway pressure for the treatment of obstructive sleep apnea in patients with Down syndrome

RATIONALE Down syndrome (DS) is a congenital condition highly associated with obstructive sleep apnea (OSA), a complex disorder with significant clinical consequences. Treatment options for OSA encompass drugs, intraoral devices, surgery, and continuous positive airway pressure (CPAP) Therapy. OBJECTIVES This systematic review aims to evaluate the impact of CPAP to treat OSA in individuals with DS, generating valuable insights on how to manage the condition in this population, preventing complications, and improving quality of life. METHODS A literature search was conducted using the MEDLINE (PubMed), EMBASE, Cochrane Library and LILACS databases. The search strategy combined individuals with DS and intervention with CPAP. MEASUREMENTS Observational studies, randomized and non-randomized clinical trials that reported outcomes such as AHI, mean oxygen saturation, EQ-5D, OSA-18, adherence, tolerance, ESS or ESS-CHAD were included. The methodological quality and risk of bias of the included studies were evaluated using ROB 2.0, ROBINS-I, and a questionnaire for non-comparative studies. The certainty of evidence was rated according to GRADE. MAIN RESULTS Eight studies were included, most favored CPAP in DS patients. Overall, CPAP reduced obstructive events during sleep, and patients showed good adherence and tolerance. Individuals also experienced improvements in daytime sleepiness; however, the intervention did not alter the patients’ quality of life. All outcomes were assessed with low or very low certainty of evidence. CONCLUSION The evidence found should be cautiously evaluated for extrapolation to clinical practice, due to methodological limitations and low-certainty outcomes.

Effects of Electronic Nicotine Delivery Systems Substitution on Body Weight Status: Protocol for a Systematic Review and Meta-Analysis.

Weight gain following smoking cessation is a well-documented concern, often attributed to the absence of nicotine's metabolic influence. The adoption of Electronic Nicotine Delivery Systems (ENDS) has been used to achieve smoking cessation, with claims of aiding weight control. However, existing reviews present conflicting conclusions on ENDS' impact on weight status, necessitating a rigorous evaluation. We aim to conduct a systematic review with meta-analysis to assess the actual impact of ENDS on weight status in individuals who have ceased or reduced conventional smoking. The primary goal is to provide clinicians with evidence-based insights into the potential effects of ENDS use as a smoking substitute on weight control. Adhering to PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines, our systematic review will analyze randomized and nonrandomized controlled trials, clinical trials (quasi-experimental), and prospective or retrospective cohort studies on the weight status effects of ENDS among individuals who have either quit or reduced smoking. Searches will include PubMed, Scopus, and Cochrane Library, covering the period from 2010 to January 2024. A gray literature search and supplementary searches will be performed. Data will be extracted independently by 2 reviewers and quality assessments will be conducted concurrently. Quality assessments will use Joanna Briggs Institute tools, 2020 version, along with bias assessments for internal validity and reporting bias based on the Catalogue of Bias. The included studies will be examined for any internal data reporting discrepancies by using Puljak's checklist. Meta-analysis and subgroup analyses (ie, general ENDS usage, ENDS use coupled with a reduction in smoking exceeding 50%, and exclusive ENDS use for achieving smoking cessation) are planned. Certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The protocol has been registered in PROSPERO (CRD42023494974) and the entire systematic review is expected to be completed by April 2024. The main goal of this review is to retrieve all current human research studies investigating the influence of ENDS on weight management among individuals who have quit or reduced smoking. Furthermore, the review will assess the quality of these studies and examine potential biases to identify the most dependable evidence available. Dissemination strategies will include traditional journal publications, social media announcements, and a white paper. The latter, available for download and distributed at conferences, aims to reach a broad audience, including clinicians and ENDS users. The review will address the importance of informing health care professionals and patients about the current and robust evidence regarding the effects of transitioning to ENDS for smoking cessation on weight status. PROSPERO CRD42023494974; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=494974. PRR1-10.2196/56324.

Conscious prone positioning in nonintubated COVID-19 patients with acute respiratory distress syndrome: systematic review and meta-analysis.

To systematically review the effect of the prone position on endotracheal intubation and mortality in nonintubated COVID-19 patients with acute respiratory distress syndrome. We registered the protocol (CRD42021286711) and searched for four databases and gray literature from inception to December 31, 2022. We included observational studies and clinical trials. There was no limit by date or the language of publication. We excluded case reports, case series, studies not available in full text, and those studies that included children < 18-years-old. We included ten observational studies, eight clinical trials, 3,969 patients, 1,120 endotracheal intubation events, and 843 deaths. All of the studies had a low risk of bias (Newcastle-Ottawa Scale and Risk of Bias 2 tools). We found that the conscious prone position decreased the odds of endotracheal intubation by 44% (OR 0.56; 95%CI 0.40 - 0.78) and mortality by 43% (OR 0.57; 95%CI 0.39 - 0.84) in nonintubated COVID-19 patients with acute respiratory distress syndrome. This protective effect on endotracheal intubation and mortality was more robust in those who spent > 8 hours/day in the conscious prone position (OR 0.43; 95%CI 0.26 - 0.72 and OR 0.38; 95%CI 0.24 - 0.60, respectively). The certainty of the evidence according to the GRADE criteria was moderate. The conscious prone position decreased the odds of endotracheal intubation and mortality, especially when patients spent over 8 hours/day in the conscious prone position and treatment in the intensive care unit. However, our results should be cautiously interpreted due to limitations in evaluating randomized clinical trials, nonrandomized clinical trials and observational studies. However, despite systematic reviews with meta-analyses of randomized clinical trials, we must keep in mind that these studies remain heterogeneous from a clinical and methodological point of view.

Comparison of Low-Dose Interleukin 2 Therapy in Conjunction With Standard Therapy in Patients With Systemic Lupus Erythematosus vs Rheumatoid Arthritis: A Systematic Review.

This systematic review aims to compare the efficacy and safety of a novel immunotherapy with low-dose interleukin 2 (IL2) across two of the most prevalent autoimmune diseases i.e. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Contemporary therapeutic practices have not been able to achieve complete remission from these autoimmune disorders. In contrast, low-dose IL2has shown promise in achieving this therapeutic goal via inducing self-tolerance in patients with autoimmune diseases; however, due to variable irregularities among autoimmune processes of variable diseases, the benefit of low-dose IL2 could not be determined among different autoimmune diseases. Therefore, we conducted a study to compare low-dose IL2 therapy effects on SLE and RA. We systematically screened four databases: PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed Central (PMC), and Google Scholar. Inclusion and exclusion criteria were implemented. Quality appraisal of studies chosen for the review was done using the Cochrane Risk-of-Bias (RoB) assessment tool for randomized controlled trials, and the Newcastle-Ottawa Scale (NOS) and JBI critical appraisal tool for non-randomized clinical trials. Information was gathered from seven articles: three randomized controlled trials and four non-randomized clinical trials. Our review concluded that low-dose IL2 therapy in conjunction with respective standard therapies for SLE and RA has a higher efficacy and safety profile as compared to standard therapy alone and the therapeutic effects were comparable in both SLE and RA patients treated with low-dose IL2; however, this novel intervention does not seem to have a significant corrective effect on the biomarkers of RA as it does for SLE biomarkers.

Complications and Patient-Centered Outcomes of an Implant- Supported Single Crown after Immediate and Delayed Loading: A Systematic Review and Meta-analysis.

Single implants are a predictable treatment, and immediate loading can be an option with acceptable survival rates. Clinical and patient-centered outcomes comparing immediate and delayed protocol of single implants are unclear. The purpose of this study was to assess complications, satisfaction, and quality of life of patients rehabilitated with delayed and immediate loading single crowns. An electronic search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, and Embase databases up to February 2023. Only prospective studies, randomized and non-randomized clinical trials comparing immediate and delayed loading were included. For the quantitative analysis, dichotomous and continuous variables were evaluated with a 95% confidence interval. A total of 20 studies were evaluated. No statistically significant difference between protocols was observed: satisfaction (I2: 0%; P = 0.42), quality of life (I2: 0 %; P = 0.05), biological complications (I2: 9%; P = 0.17) mechanical complications (I2: 58%; P = 0.84), and survival rate (I2: 0%; P = 0.38). Subgroup analysis showed significant differences only for marginal bone loss when immediate implants were placed in the mandible (IÇ: 15%; P = 0.01) and posterior zone (I2: 0%; P = 0.001). Complications and patient-centered outcomes for immediate single-implant crowns were comparable to delayed loading. Scientific evidence showed no significant difference between loading protocols for survival rates. Although several factors could interfere with the complication events, implant failures, and marginal bone loss, the subgroup analysis evidenced that only immediate implants placed in the posterior mandible zone had higher statistically significant mean marginal bone loss.

Safety outcomes of low versus high dose imatinib mesylate in patients with advanced, metastatic, or nonresectable gastrointestinal stromal tumors: A systematic review.

Gastrointestinal stromal tumors (GIST) are a rare cancer where tumors grow along the gastrointestinal tract. While treatment options aim towards surgical resection, some patients present with advanced metastatic and/or nonresectable diseases. The tyrosine kinase inhibitor imatinib mesylate is approved for this indication. However, dose escalation from 400 to 600 mg/d or 800 mg/d is allowed. The present study systematically evaluates the safety outcomes, particularly the incidence of grade ⩾ 3 adverse events (AEs) with low dose compared with high dose imatinib in these patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines were utilized to identify relevant studies through the PubMed, Cochrane Library, and Ovid databases and included randomized and non-randomized clinical trials comparing a low dose intervention of imatinib 400 mg/d with a high dose comparator of 600 or 800 mg/d in patients with histologically confirmed advanced metastatic and/or nonresectable GIST. Four studies were reviewed regarding study summaries and patient characteristics, patient demographics, and risk of bias, with a main emphasis on the evaluation of both efficacy outcomes and safety outcomes. Three of the four studies did not provide significant differences in response outcomes; however, all four studies reported a higher incidence of grade ⩾ 3 AEs in the high dose imatinib groups. Individual study reports of more high dose patients experiencing a grade ⩾ 3 event ranged from 0.6% to 19.8%, while combined low and high dose patient arms revealed a 17.1% difference favoring a high dose patient event. A sub-analysis of the three most frequently occurring categories, blood and lymphatic system disorders, gastrointestinal disorders, and general disorders and administration site conditions each revealed more high dose patients experiencing said category events compared to those low dose counterparts. Low dose imatinib provides clinically meaningful response and demonstrated better tolerability with less frequently reported reactions. This evidence supports further research into the maintenance of 400 mg/d for this patient population compared to a dose escalation.

Effect of low-intensity laser therapy on levels of biomarkers during orthodontic tooth movement – A systematic review

This systematic review aimed to explore the association between low-intensity laser therapy (LILT) and various biomarkers, elucidating the potential of this therapeutic modality to expedite orthodontic tooth movement (OTM). A systematic literature search was conducted using electronic databases including PubMed, Central of the Cochrane Library, and Google Scholar databases. Randomized controlled trials (RCTs) and non-randomized controlled clinical trials (nRCTs) using LILT as an adjunct to the standard orthodontic procedures in human and animal subjects as participants were included in the study. The quality of the human and animal studies was assessed using the Revised Cochrane risk of bias tool and Systematic Review Centre for Laboratory Animal Experimentation’s (SYRCLE’s) risk of bias tool respectively. Animal studies revealed increased receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL), matrix metalloproteinase-9 (MMP-9), and collagen type I expression. Human studies showed elevated interleukin-1-beta (IL-1β), interleukin-16 (IL-16) and RANKL levels, suggesting LILT influences biomarkers associated with bone resorption and connective tissue rearrangement. A high risk of bias was observed in all animal studies and 5 out of 6 human studies. The systematic review concluded that LILT emerges as a promising technique for enhancing orthodontic tooth movement, influencing key biomarkers linked to osteoclastic activity and collagen synthesis. However, the high risk of bias in animal and human studies emphasizes the need for further research to validate findings and optimize laser parameters for clinical benefits.

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial. To evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs. PubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023. Two authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1-positive and -negative tumors. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies. Primary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1-positive tumors and patients with PD-L1-negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1-positive and -negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials. A total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1-positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1-positive tumors and 5.1% to 63.2% in patients with PD-L1-negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1-positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P < .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1-positive tumors and from 6.0 to 19.1 months in patients with PD-L1-negative tumors. The pooled HR showed a significant reduction for patients with PD-L1-positive tumors compared with those with PD-L1-negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P < .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response. This systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

Severity of Complications after Locking Plate Osteosynthesis in Distal Femur Fractures.

Background: Locked plating for distal femur fractures is widely recommended and used. We systematically reviewed clinical studies assessing the benefits and harms of fracture fixation with locked plates in AO/OTA Type 32 and 33 femur fractures. Methods: A comprehensive literature search of PubMed, Embase, Cinahl, Web of Science, and the Cochrane Database was performed. The studies included randomized and non-randomized clinical trials, observational studies, and case series involving patients with distal femur fractures. Studies of other fracture patterns, studies conducted on children, pathological fractures, cadaveric studies, animal models, and those with non-clinical study designs were excluded. Results: 53 studies with 1788 patients were found to satisfy the inclusion and exclusion criteria. The most common harms were nonunion (14.8%), malunion (13%), fixation failure (5.3%), infection (3.7%), and symptomatic implant (3.1%). Time to full weight-bearing ranged from 5 to 24 weeks, averaging 12.3 weeks. The average duration of follow-up was 18.18 months, ranging from 0.5 to 108 months. Surgical time ranged between 40 and 540 min, with an average of 141 min. The length of stay in days was 12.7, ranging from 1 to 61. The average plate length was ten holes, ranging from 5 to 20 holes. Conclusion: This review aimed to systematically synthesize the available evidence on the risk associated with locked plating osteosynthesis in distal femur fractures. Nonunion is the most common harm and is the primary cause of reoperation. The overall combined risk of a major and critical complication (i.e., requiring reoperation) is approximately 20%.

Effectiveness of reframing as behaviour management technique in paediatric dentistry: A scoping review

Background: For children with fear and anxiety, dental appointments are considered as stressful situations. The dental literature has mentioned various behaviour management techniques used to reduce the dental fear and anxiety. Reframing is one such technique which is used for behaviour management with wide applications in health sciences. Hence, exploring this technique in the dental literature is of prime importance.Objectives: This scoping review aims to identify the evidence on the effectiveness of reframing as behaviour management technique in children undergoing dental treatment in the available literature.Method: The Joanna Briggs Institute methodology for scoping reviews is followed in this study and relevant published data from case reports, randomized and nonrandomized controlled clinical trials and literature reviews published without restricting time line till August 2023 from online databases of PubMed, Scopus, ProQuest were assessed by two reviewers for their suitability with our aim of study. The data were synthesized using content analysis.Results: Through literature search, 108 articles were found based on search strategy. After screening the titles, keywords and abstract and removing the duplicates only 10 articles were included for full text review. In the end only 5 articles were included for scoping review for their content analysis.Conclusions: The searched literature has revealed that reframing had changed the behaviour of the child towards dental outcomes but the literature is sparse regarding behaviour management technique for children to alleviate fear and anxiety. Also, there were no clinical trials done to know the efficacy of this technique and means to measure the outcome.

Assessing Patient Risk, Benefit, and Outcomes in Drug Development: A Decade of Lenvatinib Clinical Trials: A Systematic Review.

Chemotherapy agents are typically initially tested in their most promising indications; however, following initial US FDA approval, new clinical trials are often initiated in less promising indications where patients experience a worse burden-benefit ratio. The current literature on the burden-benefit profile of lenvatinib in non-FDA-approved indications is lacking. This study aimed to evaluate published clinical trials of lenvatinib in order to determine the burden-benefit profile for patients over time. On 25 May 2023, we searched the Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov databases for clinical trials of lenvatinib used to treat solid cancers. Eligible articles were clinical trials, containing adult participants, published in English, and involving solid tumors. Screening and data collection took place in a masked, duplicate fashion. For each eligible study, we collected adverse event data, trial characteristics, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Trials were classified as positive when meeting their primary endpoint and safety, negative (not meeting either criteria), or indeterminate (lacking prespecified primary endpoint). Expansion of clinical trial testing beyond lenvatinib's initial FDA indication demonstrated a consistent rise in cumulative adverse events, along with a decline in drug efficacy. Lenvatinib was tested in 16 cancer indications, receiving FDA approval in 4. A total of 5390 Grade 3-5 adverse events were experienced across 6225 clinical trial participants. Expanded indication testing further demonstrated widely variable ORR (11-69%), OS (6.2-32 months), and PFS (3.6-15.7 months) across all indications. After initial FDA approval, clinical trial results in expanded indications were less likely to meet their primary endpoints, particularly among non-randomized clinical trials. Our paper evaluated the effectiveness of lenvatinib for its FDA-approved indications; however, expansion of clinical trials into novel indications was characterized by diminished efficacy, while patients experienced a high burden of adverse events consistent with lenvatinib's established safety profile. Furthermore, clinical trials testing in novel indications was marked by repeated phase I and II clinical trials along with a failure to progress to phase III clinical trials. Future clinical trials using lenvatinib as an intervention should carefully evaluate the potential benefits and burden patients may experience.

Influence of occlusal appliances on the masticatory muscle function in individuals with sleep bruxism: A systematic review and meta-analysis.

This systematic review answers the question: "Does occlusal appliance use influence masticatory muscle function of dentate individuals with sleep bruxism?". The literature search included six databases, grey literature, and manual search for articles. Randomized and non-randomized clinical trials were included comparing muscle function of sleep bruxers before and after receiving occlusal appliances. Risk of bias was assessed with risk of bias assessment for randomized and non-randomized clinical trials tool. Twelve studies, three represent randomized clinical trials, were included. Risk of bias was considered low, moderate, or serious. Meta-analyses indicated that soft and hard appliances did not influence muscle activity and bite force of bruxers. Qualitative analysis showed that occlusal appliance use did not influence masticatory performance and muscle volume. However, it was effective in reducing tongue force. Certainty of evidence was considered very low for muscle activity when evaluated with hard appliances, and for bite force evaluated with both appliance materials. Low certainty of evidence was observed for muscle activity with soft appliances. Based on the findings of this meta-analysis, occlusal appliances do not affect masticatory muscle function of sleep bruxers. Regardless of appliance material, the activity of masseter and temporal, and bite force of sleep bruxers was not influenced.

Cyanoacrylate tissue adhesive versus silk sutures for mandibular third molar surgery: a systematic review and meta-analysis.

Cyanoacrylate tissue adhesive has been presented as an alternative to sutures and several studies have compared them. The objective of this meta-analysis was to evaluate the effect of cyanoacrylate tissue adhesive on postoperative pain and swelling, following mandibular third molar surgery. Database search was conducted in MEDLINE/PubMed and Scopus, along with extensive search in the grey literature, including randomized and non-randomized clinical trials that applied cyanoacrylate adhesive for closing mandibular third molar surgical sites and compared it with silk sutures, assessing postoperative pain and swelling. The search ended on September 22, 2023. Of 886 identified articles, six were included and meta-analyzed. Applying cyanoacrylate demonstrated a reduction in the overall postoperative pain (SMD = -0.57, 95% CI -1.00 to -0.15, p = 0.009). A similar outcome was noted when pain was evaluated on the first and last postoperative days, based on controlled clinical trials (SMD = -0.47, 95% CI -0.92 to -0.03, p = 0.04), and randomized trials (SMD = -0.97, 95% CI -1.31 to -0.62, p < 0.00001). Patients/sides received cyanoacrylate showed a decrease in postoperative swelling (SMD = -0.26, 95% CI -0.51 to -0.01, p = 0.04). Following the GRADE rating system, the quality of evidence on pain and swelling was judged as moderate and low, respectively. The use of cyanoacrylate adhesive may offer benefit in reducing postoperative pain and swelling following mandibular third molar surgery. Nevertheless, this should be further investigated, considering the low number of included reports. The current results could help clinicians who perform this procedure to manage postoperative pain and swelling more effectively.

Outcomes of endoscopic management of benign maxillary sinus lesions 5-year experience, non-randomized clinical trials

BackgroundWhen medical therapy fails to control maxillary sinus (MS) disease, surgery is required. There are many advanced MS endoscopic approaches, each one with its anatomical limitations and possible complications. This study aimed to review the outcomes of three endoscopic approaches to the MS (middle meatal antrostomy approach (MMAA), prelacrimal recess approach (PLRA), and canine fossa approach (CFA)) to manage benign MS lesions.MethodsSixty-three patients with diseased MS require surgery. Endoscopic MS approaches used include MMAA, PLRA, and CFA. Each approach was used in 21 patients. The outcome of each approach was measured regarding lesion accessibility and clearance, complications (intraoperative or postoperative), and recurrence.ResultsThe maxillary sinus posterior wall was accessible in all approaches. Other walls and different recesses were also accessible in the case of PLRA and CFA with statistically significant difference between the three approaches. There was no significant difference between patients operated by PLRA and CFA regarding accessibility to different walls and recesses of the MS. Endoscopic and radiological recurrence were found in three (15%) patients who were operated by MMAA. There was no evidence of recurrence in patients operated by the other approaches. Complications like crustations, fascial pain, fascial welling, and fascial hypoesthesia occurred in a few patients.ConclusionBy using a suitable endoscopic approach, the different walls and recesses of the MS were completely accessible, so benign MS lesions that required open surgical approaches can be managed endoscopically while preserving the sinus structure and function.