Almader-Douglas, Diana

ImportanceMeasurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.ObjectiveTo assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment.Data SourcesClinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023.Study SelectionProspective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded.Data Extraction and SynthesisStudy sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted.Main Outcomes and MeasuresAnalyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model.ResultsA total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).Conclusions and RelevanceThe findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.

Purpose: The purpose of this article was to appraise the various methods of reconstruction for meningomyelocele (MMC) defects. Methods: A systematic review of the literature was performed to evaluate all reconstructions for MMC. The method of reconstruction was categorized by: primary closure with and without fascial flaps, random pattern flaps, VY advancement flaps (VY), perforator flaps, and myocutaneous flaps. Perforator flaps were subsequently subcategorized based on the type of flap. Results: Upon systematic review, 567 articles were screened with 104 articles assessed for eligibility. Twenty-nine articles were further reviewed and included for qualitative synthesis. Two hundred seventy patients underwent MMC repair. The lowest rates of major wound complications (MWC) were associated with myocutaneous and random pattern flaps. A majority of MWC was in the lumbrosacral/sacral region (87.5% of MWC). In this region, random patterns and perforator flaps demonstrated the lowest rate of MWC (4.5, 8.1%). Conclusions: Plastic surgery consultation should be strongly considered for MMC with defects in the lumbosacral/sacral region. Perforator flaps are excellent options for the reconstruction of these defects.

PURPOSE We conducted a systematic review to evaluate the outcome of patients with early-stage (stages I-III) mismatch repair deficient (dMMR) colorectal cancer (CRC) receiving neoadjuvant immunotherapy (NIT) with immune checkpoint inhibitor (ICI)–based regimens. METHODS MEDLINE, Scopus, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched for publications reporting the outcome of patients with early-stage dMMR CRC receiving NIT. The primary outcome measures were the complete response (CR) rate (clinical CR [cCR] or pathologic CR [pCR]) and the incidence of grade 3 or higher toxicities. RESULTS The search identified 37 publications that included 423 patients with colon (n = 326, 77%) and rectal (n = 97,23%) cancers aged 19-82 years; most patients had stage III CRC (88%). Approximately 67% of patients received monotherapy with anti–PD-1 agents; the rest received dual ICIs (ipilimumab plus nivolumab). The CR rate (pCR + cCR) in the overall population was 72% (305 of 423). The R0 resection and pCR rates were 99.3% and 70% among the patients undergoing surgery, respectively. Only four (0.9%) patients had primary resistance to NIT. After median follow-up periods ranging from 4 to 27 months, 3 (0.7%) patients progressed after an initial response. Grade 3 or higher toxicities were uncommon (6.3%), rarely delaying planned surgery. CONCLUSION NIT in patients with early-stage dMMR CRC is associated with a high response rate, low primary resistance to immunotherapy and cancer recurrence rate, and an excellent safety profile. The findings of the present systematic review support further investigation of NIT in patients with early-stage dMMR CRC, with a particular emphasis on the organ-preserving potential of this strategy.

Abstract Background Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. Methods We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). Results Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. Conclusions This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

AbstractBackgroundAtrial fibrillation (AF) and coronary artery disease (CAD) are commonly associated. Cotreatment with multiple antithrombotic agents can increase the risk of bleeding. We sought to evaluate patient‐centered outcomes in patients with AF on double therapy with direct oral anticoagulants (DOACs) compared to patients with standard triple therapy, [a vitamin K antagonist (VKA) plus dual antiplatelet therapy].MethodsWe performed a literature search of randomized controlled trials (RCTs) reporting outcomes of patients receiving double therapy with DOACs compared to triple therapy with VKAs in patients with AF undergoing percutaneous coronary intervention (PCI). Patient‐centered outcomes were the International Society of Thrombosis and Hemostasis (ISTH) major or clinically relevant nonmajor bleeding (CRNB), all‐cause mortality, major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction, and stroke.ResultsFour RCTs (9602 patients) met our inclusion criteria. Compared to VKAs, DOACs were associated with significantly lower ISTH major bleeding/ CRNB (RR: 0.75, 95% CI: 0.67‐0.82, P < .00001, I2 = 11%). There were no statistically significant differences in the efficacy outcomes, including myocardial infarction (RR: 0.99, 95% CI :0.79‐1.25, P = .96), stent thrombosis (RR: 0.97, 95% CI: 0.6‐1.55, P = .89), ischemic stroke (RR: 0.76, 95% CI: 0.5‐1.15, P = .19), all‐cause mortality (RR: 1.06, 95% CI: 0.85‐1.31, P = .61), and MACE (RR: 1.06, 95% CI: 0.91‐1.22, P = .97).ConclusionCompared with triple therapy with VKAS, double therapy with DOACs is associated with a reduced risk of bleeding and is as effective in patients with AF undergoing PCI.

Background: The treatment of heart failure with reduced ejection fraction has been the subject of numerous randomized controlled trials involving medications and cardiac implantable electronic device therapies. As newer effective pharmacological therapies suggest significant reductions in all-cause mortality, the role of additional device therapy in heart failure with reduced ejection fraction deserves further scrutiny. Methods: A systematic review and network meta-analysis on the effect of medication and device therapies in heart failure with reduced ejection fraction on all-cause mortality was performed. Randomized controlled trials published between January 1980 and July 2017 were identified using Medline, EMBASE, and Cochrane Controlled Register of Trials databases. Pcnetmeta package in R was used to calculate treatment arm–based estimated rates, rate ratios, and probability ranks with 95% credible intervals. Results: Combination therapy of ACE (angiotensin-converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) with β-blockers (BBs) alone or in addition to implantable cardiac defibrillators or cardiac resynchronization therapy with defibrillators demonstrated a significant reduction of all-cause mortality when compared with placebo. By probability rank, implantable cardiac defibrillator+ACE inhibitor or ARB+BB+mineralocorticoid receptor antagonist, implantable cardiac defibrillator+ACE inhibitor or ARB+BB, and angiotensin receptor-neprilysin inhibitor+BB+mineralocorticoid receptor antagonist combination therapies have the highest probability of being ranked the best treatment. There was no significant difference in the rate of mortality when comparing angiotensin receptor-neprilysin inhibitor+BB+mineralocorticoid receptor antagonist to implantable cardiac defibrillator+optimal pharmacological combination therapy. Conclusions: BB and renin-angiotensin system blockers alone or in combination with defibrillator device therapy have robust evidence for a reduction in mortality compared with placebo. The comparative efficacy of pharmacological therapy with angiotensin receptor-neprilysin inhibitors and device therapy deserves further investigation.

AbstractBackgroundAtrial fibrillation (AF) among patients with heart failure with reduced ejection fraction (HFrEF) is associated with adverse clinical outcomes. Our primary aim was to evaluate patient‐centered outcomes and surrogate outcomes following catheter ablation (CA) of AF among patients with HFrEF compared to standard medical therapy with or without device therapy (atrioventricular node ablation and cardiac resynchronization therapy).MethodsA systematic literature review was performed limiting our searches to randomized control trials reporting outcomes of CA compared to standard medical therapy with or without device therapy were included. Patient‐centered outcomes were relative reduction in all‐cause mortality, heart failure readmissions, and recurrence of AF. Surrogate outcomes of interest were change in ejection fraction, change in peak oxygen consumption, reduction in brain natriuretic peptide levels, change in 6‐minute walk distance, and change in Minnesota living with heart failure score.ResultsSeven randomized control trials (Patient n = 721) met our inclusion criteria. All trials used radiofrequency energy for CA of AF. CA for AF was associated with significantly lower all‐cause mortality (Risk ratio [RR] = 0.52, 95% confidence interval [CI] = 0.35‐0.76, P = 0.001, I2 = 0%), lower rate of heart failure readmission (RR = 0.58, 95% CI = 0.46‐0.74, P < 0.001, I2 = 0%) and lower rate of AF recurrence (RR = 0.33, 95% CI = 0.22‐0.50, P < 0.001, I2 = 68%) as compared to standard medical therapy. Surrogate outcomes showed a similar benefit favoring CA.Conclusion and RelevanceCatheter ablation for AF in HFrEF is associated with improvement in patient‐centered outcomes and surrogate outcomes when compared to standard medical therapy with or without device therapy.

Background: The risk of developing intracerebral hemorrhage (ICH) after the administration of intravenous tissue plasminogen activator for acute ischemic stroke is well established in the general population. However, the risk associated with stroke thrombolysis in patients with a history of cerebral microbleeds (CMBs) is undetermined. Objective: The main objective of this study was to critically assess current evidence with regard to the risk of development of ICH after the administration of intravenous tissue plasminogen activator for acute ischemic stroke in patients with CMBs. Methods: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular and hospital neurology. Results: A recent individual patient data meta-analysis was selected for critical appraisal. Cohorts were analyzed with pretreatment magnetic resonance imaging to determine CMB burden and were followed-up to assess subsequent symptomatic ICH, hemorrhagic transformation, parenchymal hemorrhage (PH), and remote PH (PHr) following intravenous thrombolysis. Risk of symptomatic ICH, PH, and PHr was increased in the presence of CMBs, with PHr having the strongest association with increasing CMB burden. Only patients with >10 CMBs were found to have associations with poor outcome at 3 to 6 months, whereas there was no association with 3 to 6 months’ mortality. Conclusions: CMBs are associated with an increased risk of postthrombolysis ICH; however, the clinical implications have yet to be determined.