Downregulation of collagen XI during late postnatal corneal development is followed by upregulation after injury.

Collagen XI plays a role in nucleating collagen fibrils and in controlling fibril diameter. The aim of this research was to elucidate the role that collagen XI plays in corneal fibrillogenesis during development and following injury. The temporal and spatial expression of collagen XI was evaluated in C57BL/6 wild-type mice. For wound-healing studies in adult mice, stromal injuries were created using techniques that avoid caustic chemicals. The temporal expression and spatial localization of collagen XI was studied following injury in a Col11a1 inducible knockout mouse model. We found that collagen XI expression occurs during early maturation and is upregulated after stromal injury in areas of regeneration and remodeling. Abnormal fibrillogenesis with new fibrils of heterogeneous size and shape occurs after injury in a decreased collagen XI matrix. In conclusion, collagen XI is expressed in the stroma during development and following injury in adults, and is a regulator of collagen fibrillogenesis in regenerating corneal tissue.

A systematic critical appraisal of clinical practice guidelines of antithrombotic agents in gastrointestinal endoscopy using the AGREE II tool.

BACKGROUND AND AIM: The quality of clinical practice guidelines (CPGs) for the management of antithrombotic agents in patients undergoing gastrointestinal (GI) endoscopy has not been systematically appraised. The goal of this study was to evaluate the methodological quality of CPGs for the management of antithrombotic agents in periendoscopic period published within last 6 years. METHODS: A systematic search of PubMed and Embase databases was performed to identify eligible CPGs published between January 1, 2016, and April 14, 2022, addressing the management of antithrombotic agents in the periendoscopic period. The quality of the CPG was independently assessed by six reviewers using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Domain scores were considered of sufficient quality when > 60% and of good quality when > 80%. RESULTS: The search yielded 343 citations, of which seven CPGs published by the gastroenterology associations in Asia (n = 3), Europe (n = 2), and North America (n = 2) were included for the critical appraisal. The overall median score for the AGREE II domains was 93% (interquartile range [IQR] 11%) for scope and purpose, 79% (IQR 61%) for stakeholder involvement, 79% (IQR 36%) for rigor of development, 100% (IQR 14%) for clarity of presentation, 32% (IQR 36%) for applicability, 93% (IQR 29%) for editorial independence, and 86% (IQR 29%) for overall assessment. CONCLUSIONS: The findings show that the overall methodological quality of the CPGs for the management of antithrombotic agents in the periendoscopic period varies across the domains. There is significant scope for improvement in the methodological rigor and applicability of CPGs.

Autologous hematopoietic cell transplantation versus whole-brain radiotherapy consolidation in primary central nervous system lymphoma: A systematic review and meta-analysis.

The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I2  = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I2  = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.

Quality of Pancreatic Cyst Clinical Practice Guidelines.

BACKGROUND: There are various published clinical practice guidelines (CPGs) for the management of pancreatic cystic lesions. However, the quality of these guidelines has not been systematically appraised. This study aimed to evaluate the quality of CPGs published in the last 5 years for the management of pancreatic cysts. METHODS: A systematic search of the PubMed database for eligible CPGs published between January 1, 2016 and November 17, 2021, using a sensitive filter. The quality of the CPGs was independently evaluated using the Appraisal of Guidelines for Research & Evaluation II instrument, with domain scores considered sufficient quality if >60% and good quality if >80%. RESULTS: The search yielded 4 eligible CPGs out of 426 citations. The scores varied for different domains for each CPG, with the overall median score being 79% for scope and purpose, 26% for stakeholder involvement, 51% for rigor of development, 69% for clarity of presentation, 14% for applicability, and 75% for editorial independence. CONCLUSIONS: The study revealed that the quality of the CPGs for pancreatic cyst management in adults remains moderate at best. Patient representatives were not involved in any of the CPG development process. There is a significant scope for improvement in methodological rigor and clarity of presentation.

Resident duty hours and resident and patient outcomes: Systematic review and meta-analysis.

OBJECTIVES: The policies regarding resident physician work hours are constantly being evaluated and changed. However, the results of randomised control trials (RCTs) are mixed. This systematic review of RCTs aims to synthesise the evidence associated with resident duty hour restrictions and its impact on resident- and patient-based outcomes. METHODS: A comprehensive search of the Cochrane Library, EMBASE and PubMed was conducted from inception until 31 July 2020. Any RCT evaluating the impact of longer resident physician work hours compared to shorter resident physician work hours on resident- and patient-based outcomes was eligible for inclusion. Two reviewers extracted data independently. The primary outcome was the impact of resident duty hour restrictions on emotional exhaustion, depersonalisation and personal accomplishment, as defined by the Maslach Burnout Inventory. The secondary patient-related outcomes were patient hospital length of stay, serious medical errors and preventable adverse events. Data were pooled using a random-effects model. RESULTS: Of the 873 references, nine RCTs met the inclusion criteria. A shorter shift length compared with longer shift length was associated with significantly less emotional exhaustion (standardised mean difference [SMD] = -0.11, 95% CI = -0.21, -0.00) and less dissatisfaction with overall well-being (OR = 0.61, 95% CI 0.38, 0.99) but not with hospital length of stay (SMD = -0.01, 95% CI = -0.05, 0.02, p = 0.45) and serious medical errors per 1000 patient hours (OR = 1.07, 95% CI = 0.52, 2.21; p = 0.86). CONCLUSIONS: Shorter resident duty hours is possibly associated with improvement in resident-based outcomes, specifically, emotional exhaustion, dissatisfaction with overall well-being, sleep duration and sleepiness. These findings may inform the policy change in support of reduced shift hours resulting in overall well-being for the residents with possible reduction in burnout without adverse impact on patient-based outcomes.

Evidence-based surgical guidelines for treating children with Wilms tumor in low-resource settings.

BACKGROUND: Survival of Wilms tumor (WT) is > 90% in high-resource settings but < 30% in low-resource settings. Adapting a standardized surgical approach to WT is challenging in low-resource settings, but a local control strategy is crucial to improving outcomes. OBJECTIVE: Provide resource-sensitive recommendations for the surgical management of WT. METHODS: We performed a systematic review of PubMed and EMBASE through July 7, 2020, and used the GRADE approach to assess evidence and recommendations. RECOMMENDATIONS: Initiation of treatment should be expedited, and surgery should be done in a high-volume setting. Cross-sectional imaging should be done to optimize preoperative planning. For patients with typical clinical features of WT, biopsy should not be done before chemotherapy, and neoadjuvant chemotherapy should precede surgical resection. Also, resection should include a large transperitoneal laparotomy, adequate lymph node sampling, and documentation of staging findings. For WT with tumor thrombus in the inferior vena cava, neoadjuvant chemotherapy should be given before en bloc resection of the tumor and thrombus and evaluation for viable tumor thrombus. For those with bilateral WT, neoadjuvant chemotherapy should be given for 6-12 weeks. Neither routine use of complex hilar control techniques during nephron-sparing surgery nor nephron-sparing resection for unilateral WT with a normal contralateral kidney is recommended. When indicated, postoperative radiotherapy should be administered within 14 days of surgery. Post-chemotherapy pulmonary oligometastasis should be resected when feasible, if local protocols allow omission of whole-lung irradiation in patients with nonanaplastic histology stage IV WT with pulmonary metastasis without evidence of extrapulmonary metastasis. CONCLUSION: We provide evidence-based recommendations for the surgical management of WT, considering the benefits/risks associated with limited-resource settings.

Is inguinal hernia associated with an increased risk of colon cancer? A systematic review and meta-analysis.

BACKGROUND: The presence of an inguinal hernia has been associated with an increased risk of identifying colon cancer, and therefore colonoscopy is recommended prior to inguinal hernia repair. However, the evidence on the association between the presence of an inguinal hernia and colon cancer is conflicting and uncertain. We performed a systematic review and meta-analysis to synthesize all available evidence on this topic. METHODS: A comprehensive search of PubMed and EMBASE was performed. Any comparative study (case-control or cohort study) comparing the rate of colon cancer detection in patients with and without inguinal hernias who underwent screening colonoscopy or flexible sigmoidoscopy was eligible for inclusion. Data were extracted and pooled under a random effects model. RESULTS: The initial search identified 692 references, of which 4 comparative studies (1462 patients) met the inclusion criteria. The overall risk of bias in the included studies was low. Pooled results showed a statistically non-significant difference in the incidence of detection of colon cancer, with patients with inguinal hernia having a 1.26 times increased likelihood of colon cancer diagnosis compared with patients without inguinal hernia (odds ratio (OR) 1.26; 95% confidence interval (CI) 0.63-2.51; P = 0.51). Although patients with inguinal hernia were also 1.23 times more likely to be diagnosed with colon polyps compared to patients without inguinal hernia, this difference was statistically non-significant (OR 1.23; 95% CI 0.94-1.60; P = 0.12). CONCLUSION: The findings from this first systematic review and meta-analysis show that there is no difference in the incidence of either colon cancer or colon polyps in patients presenting with inguinal hernias compared to those without. Nevertheless, larger prospective studies are needed to further investigate the relationship between the risk of colon cancer or polyps and the presence of inguinal hernia.

Efficacy of proteasome inhibitor-based maintenance following autologous transplantation in multiple myeloma: A systematic review and meta-analysis.

INTRODUCTION: Lenalidomide maintenance, commonly prescribed in the postautologous transplantation (AHCT) setting for multiple myeloma (MM), is associated with development of secondary primary malignancies (SPM). Proteasome inhibitor maintenance (PIM) has also been evaluated in MM. We conduct a systematic review/meta-analysis to assess the efficacy of PIM in MM. METHODS: Performing a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019, we extracted data on clinical outcomes related to benefits (OS, PFS, and depth of hematologic response [DOHR]) and harms (SPM and adverse events). 2144 references were identified; three studies were eligible for inclusion. RESULTS: A total of 1760 patients were included in the analysis; 507 patients received bortezomib and 395 received ixazomib maintenance. Control arms were either placebo (n = 261) or thalidomide (n = 358). PIM did not improve OS (HR 0.88, 95% CI 0.73-1.05, P = .15) but improved PFS (HR 0.77, 95% CI 0.69-0.86, P ≤ .00001) and DOHR (HR 0.88, 95% CI 0.79-0.98, P = .02) compared with control. There were no significant differences between PIM and control regarding SPM (p = NS) and ≥grade 3 peripheral neuropathy (PN) (p = NS). CONCLUSIONS: PIM following AHCT in MM improves PFS and DOHR without an increase in development of SPM or severe PN compared with placebo/thalidomide.

Rehabilitation Needs at 5 Years Post-Traumatic Brain Injury: A VA TBI Model Systems Study.

OBJECTIVE: Describe rehabilitation needs and factors associated with unmet needs at 5 years post-traumatic brain injury (TBI). SETTING: Five Veterans Affairs (VA) polytrauma rehabilitation centers (PRCs). PARTICIPANTS: VA TBI Model Systems participants (N = 283; 96% male, 75%, 57% severe TBI). DESIGN: Prospective observational cohort. MAIN MEASURES: Rehabilitation Needs Survey (21-item survey that assesses cognitive, emotional, social, and functional needs); Craig Hospital Inventory of Environmental Factors (25-item survey of potential environmental barriers). RESULTS: Participants endorsed a mean of 8 (SD: 6.2) ongoing and 3 (SD: 4.7) unmet rehabilitation needs at 5 years post-TBI. Approximately 65% of participants reported at least 1 rehabilitation need that remained unmet. The number and nature of needs differed across TBI severity groups. In unadjusted and adjusted linear regression models, Black race and environmental barriers (Craig Hospital Inventory of Environmental Factors total score) were predictive of unmet needs (P < .001). Those with greater unmet needs reported the physical environment (54%-63%), informational sources (54%), social attitudes (55%), healthcare access (40%), public policy (32%-37%), transportation availability (33%), and in-home assistance (32%) as the most frequent environmental barriers at 5 years post-TBI. CONCLUSION: Veterans and Service Members continue to have rehabilitation needs at 5 years post-TBI. Veterans Affairs programs to address ongoing needs and policy to support them are needed.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Cutaneous T Cell Lymphoma: Results of a Systematic Review and Meta-Analysis.

Mycosis fungoides and Sézary syndrome are the most common types of primary cutaneous T cell lymphomas. The clinical presentation of mycosis fungoides is generally indolent, whereas Sézary syndrome represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early-stage disease, those who develop progressive disease or have an advanced stage represent a therapeutic challenge because of a lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. However, a lack of randomized controlled data remains, and the published literature is limited to mostly retrospective studies. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and nonrelapse mortality [NRM]) independently by 2 authors. Our search strategy identified 289 references. Five studies (266 patients) were included in this systematic review and meta-analysis. Reduced-intensity and nonmyeloablative regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95% confidence interval [CI], 50% to 69%) and 36% (95% CI, 27% to 45%), respectively. Pooled relapse rate was 47% (95% CI, 41% to 53%) and pooled NRM rate 19% (95% CI, 13% to 27%). Results of this systematic review and meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT before the development of resistant disease and reducing relapse by incorporating post-transplant maintenance therapies.

Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia.

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62; P<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61; P<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Human T Cell Lymphotropic Virus Type 1-Associated Adult T Cell Leukemia/Lymphoma: Results of a Systematic Review/Meta-Analysis.

Human T cell lymphotropic virus type 1 (HTLV1)-associated adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disorder. Intensive conventional chemotherapy regimens and autologous hematopoietic cell transplantation (HCT) have failed to improve outcomes in ATLL. Allogeneic HCT (allo-HCT) is commonly offered as front-line consolidation despite lack of randomized controlled trials. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 10, 2018. We extracted data on clinical outcomes related to benefits (complete response [CR], overall survival [OS], and progression-free survival [PFS]) and harms (relapse and nonrelapse mortality [NRM]), independently by 2 authors. Our search strategy identified a total of 801 references. Nineteen studies (n = 2446 patients) were included in the systematic review; however, only 18 studies (n = 1767 patients) were included in the meta-analysis. Reduced intensity conditioning regimens were more commonly prescribed (52%). Bone marrow (50%) and peripheral blood (40%) were more frequently used as stem cell source. The pooled post-allografting CR, OS, and PFS rates were 73% (95% confidence interval [CI], 57% to 87%), 40% (95% CI, 33% to 46%), and 37% (95% CI, 27% to 48%), respectively. Pooled relapse and NRM rates were 36% (95% CI, 28% to 43%) and 29% (95% CI, 21% to 37%), respectively. The heterogeneity among the included studies was generally high. These results support the use of allo-HCT as an effective treatment for patients with ATLL, yielding pooled OS rates of 40%, but relapse still occurs in over one-third of cases. Future studies should evaluate strategies to help reduce relapse in patients with ATLL undergoing allo-HCT.

Upfront autologous hematopoietic stem cell transplantation consolidation for patients with aggressive B-cell lymphomas in first remission in the rituximab era: A systematic review and meta-analysis.

BACKGROUND: The outcomes for patients with diffuse large B-cell lymphoma (DLBCL) with adverse clinical prognostic factors such as a high age-adjusted International Prognostic Index (aaIPI) are not optimal. In the current study, the authors performed a systematic review and meta-analysis to assess the totality of evidence pertaining to the efficacy of autologous hematopoietic stem cell transplantation (auto-HCT) consolidation for patients with DLBCL in first remission. METHODS: The authors searched the Cochrane and MEDLINE/PubMed databases through December 1, 2018, for studies comparing conventional chemotherapy with rituximab (R-chemo) versus R-chemo and auto-HCT. Two authors independently reviewed all references for study inclusion and extracted data related to benefits (overall survival, progression-free survival, and response rates) and harms (treatment-related mortality and adverse events). RESULTS: Four studies (1173 patients) met the inclusion criteria and were included in the current analysis. The median duration of follow-up ranged from 42 to 76 months. There was no difference noted with regard to the overall survival (hazard ratio, 1.01; 95% CI, 0.74-1.37), progression-free survival (hazard ratio, 0.77; 95% CI, 0.58-1.04), or response rates (risk ratio, 0.98; 95% CI, 0.92-1.04) between patients who received R-chemo and auto-HCT and those who received R-chemo alone. The risk of mortality and therapy failure was not found to be different when the analysis was limited to high aaIPI between the 2 groups. Although there was no difference noted with regard to the risk of treatment-related mortality, there was a significantly higher incidence of CTCAE grade 3 or 4 adverse events in patients who received R-chemo and auto-HCT compared with patients treated with R-chemo alone. CONCLUSIONS: The findings from what to the authors' knowledge is the first meta-analysis performed in the rituximab era demonstrated no beneficial effect of upfront auto-HCT consolidation in patients with aggressive B-cell non-Hodgkin lymphoma, including high-risk clinical groups (high aaIPI).

Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in Peripheral T Cell Lymphomas as Front-Line Consolidation or in the Relapsed/Refractory Setting: A Systematic Review/Meta-Analysis.

To date, no prospective randomized trials exist comparing high-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (auto-HCT) against conventional therapy for management of peripheral T cell lymphomas either as upfront consolidation or in the relapsed/refractory setting. Available data supporting this approach are limited to single-arm prospective or retrospective studies only. Accordingly, we performed a systematic review/meta-analysis of the published literature. Our search identified 1586 publications, but only 27 (n = 1368) met our inclusion criteria. In the front-line setting, pooled analysis of only prospective studies showed rates of progression-free survival (PFS) of 33% (95% confidence interval [CI], 14% to 56%), overall survival (OS) of 54% (95% CI, 32% to 75%), relapse/progression of 26% (95% CI, 20% to 33%), and transplantation-related mortality (TRM) of 2% (95% CI, 0% to 5%); for retrospective studies, rates of PFS, OS, relapse/progression, TRM, and secondary malignancies were 55% (95% CI, 40% to 69%), 68% (95% CI, 56% to 78%), 36% (95% CI, 24% to 48%), 6% (95% CI, 2% to 11%), and 7% (95% CI, 2% to 14%), respectively. On the other hand, pooled analysis of retrospective studies evaluating HDT/auto-HCT in the relapsed/refractory setting showed pooled rates of PFS, OS, relapse/progression, and TRM of 36% (95% CI, 32% to 40%), 47% (95% CI, 43% to 51%), 51% (95% CI, 39% to 62%), and 10% (95% CI, 5% to 17%), respectively. Among the various histologic subtypes, PFS and OS rates appear to be higher in anaplastic large cell lymphoma, regardless of disease stage. In the absence of a multicenter, randomized controlled trial comparing HDT/auto-HCT to a nontransplantation strategy, the findings of this systematic review/meta-analysis may represent the best evidence supporting the role of HDT/auto-HCT for treatment of peripheral T cell lymphomas as front-line consolidation or in the relapsed/refractory setting.

Reduced-intensity or myeloablative allogeneic hematopoietic cell transplantation for mantle cell lymphoma: a systematic review.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only known treatment that can offer a cure in mantle cell lymphoma, but it is unclear if regimen dose-intensity offers any advantage. We performed a systematic review/meta-analysis to assess efficacy of allo-HCT using myeloablative or reduced-intensity conditioning. We report results according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. On the basis of a relatively lower nonrelapse mortality and a slightly better progression-free survival/event-free survival and overall survival rates, reduced-intensity allo-HCT regimens appear to be the preferred choice when an allo-HCT is being considered for mantle cell lymphoma. The higher rate of relapse when offering reduced-intensity regimens cannot be ignored but certainly highlights opportunities to incorporate post-transplant strategies to mitigate this risk. A prospective comparative study is ultimately needed to generate more conclusive evidence.

Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies.

Acute and chronic graft-versus-host disease (GVHD) remain major obstacles for successful allogeneic hematopoietic cell transplantation. Extracorporeal photopheresis (ECP) modulates immune cells, such as alloreactive T cells and dendritic cells, and improves GVHD target organ function(s) in steroid-refractory GVHD patients. We performed a systematic review to evaluate the totality of evidence regarding the efficacy of ECP for treatment of acute and chronic steroid-refractory or steroid-dependent GVHD. Nine studies, including 1 randomized controlled trial, met inclusion criteria, with a total of 323 subjects. In pooled analyses, overall response rates (ORR) were .69 (95% confidence interval [CI], .34 to .95) and .64 (95% CI, .47 to .79) for acute and chronic GVHD, respectively. In acute GVHD organ-specific responses, ECP resulted in the highest ORR for cutaneous, with .84 (95% CI, .75 to .92), followed by gastrointestinal with .65 (95% CI, .52 to .78). Similar response rates were seen in chronic GVHD involving the skin and gastrointestinal tract. Conversely, ORR for chronic GVHD involving the lungs was only .15 (95% CI, 0 to .5). In chronic GVHD, grades 3 to 4 adverse events were reported at .38 (95% CI, .06 to .78). ECP-related mortality rates were extremely low. Rates of immunosuppression discontinuation were .55 (95% CI, .40 to .70) and .23 (95% CI, .07 to .44) for acute and chronic GVHD, respectively. In summary, albeit limited by numbers of available studies, pooled analyses of prospective studies demonstrate encouraging responses after ECP treatment in acute and chronic GVHD after failing corticosteroids. Further research efforts are needed to improve organ-specific responses.

Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allo-HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo-HCT. Conflicting results regarding various clinical outcomes following allo-HCT have been observed when comparing mycophenolate mofetil-based regimens against methotrexate-based regimens for acute GVHD prophylaxis. PRIMARY OBJECTIVE: to assess the effect of mycophenolate mofetil versus methotrexate for prevention of acute GVHD in people undergoing allo-HCT. SECONDARY OBJECTIVES: to evaluate the effect of mycophenolate mofetil versus methotrexate for overall survival, prevention of chronic GVHD, incidence of relapse, treatment-related harms, nonrelapse mortality, and quality of life. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to March 2014. We handsearched conference abstracts from the last two meetings (2011 and 2012) of relevant societies in the field. We searched ClinicalTrials.gov, Novartis clinical trials database (www.novctrd.com), Roche clinical trial protocol registry (www.roche-trials.com), Australian New Zealand Clinical Trials Registry (ANZCTR), and the metaRegister of Controlled Trials for ongoing trials. SELECTION CRITERIA: Two review authors independently reviewed all titles/abstracts and selected full-text articles for inclusion. We included all references that reported results of randomized controlled trials (RCTs) of mycophenolate mofetil versus methotrexate for the prophylaxis of GVHD among people undergoing allo-HCT in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on outcomes from all studies and compared prior to data entry and analysis. We expressed results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and hazard ratios (HR) and 95% CIs for time-to-event outcomes. We pooled the individual study effects using the random-effects model. Estimates lower than one indicate that mycophenolate mofetil was favored over methotrexate. MAIN RESULTS: We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low-quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low-quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low-quality evidence), non-relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low-quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low-quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low-quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low-quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low. AUTHORS' CONCLUSIONS: The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant-associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high-quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions.

How do physicians decide to treat: an empirical evaluation of the threshold model.

BACKGROUND: According to the threshold model, when faced with a decision under diagnostic uncertainty, physicians should administer treatment if the probability of disease is above a specified threshold and withhold treatment otherwise. The objectives of the present study are to a) evaluate if physicians act according to a threshold model, b) examine which of the existing threshold models [expected utility theory model (EUT), regret-based threshold model, or dual-processing theory] explains the physicians' decision-making best. METHODS: A survey employing realistic clinical treatment vignettes for patients with pulmonary embolism and acute myeloid leukemia was administered to forty-one practicing physicians across different medical specialties. Participants were randomly assigned to the order of presentation of the case vignettes and re-randomized to the order of "high" versus "low" threshold case. The main outcome measure was the proportion of physicians who would or would not prescribe treatment in relation to perceived changes in threshold probability. RESULTS: Fewer physicians choose to treat as the benefit/harms ratio decreased (i.e. the threshold increased) and more physicians administered treatment as the benefit/harms ratio increased (and the threshold decreased). When compared to the actual treatment recommendations, we found that the regret model was marginally superior to the EUT model [Odds ratio (OR) = 1.49; 95% confidence interval (CI) 1.00 to 2.23; p = 0.056]. The dual-processing model was statistically significantly superior to both EUT model [OR = 1.75, 95% CI 1.67 to 4.08; p < 0.001] and regret model [OR = 2.61, 95% CI 1.11 to 2.77; p = 0.018]. CONCLUSIONS: We provide the first empirical evidence that physicians' decision-making can be explained by the threshold model. Of the threshold models tested, the dual-processing theory of decision-making provides the best explanation for the observed empirical results.

Efficacy of Decision Aids in The Use of Left Ventricular Assist Device in Patients With Advanced Heart Failure: A Systematic Review and Meta-Analysis of Randomized Control Trials.

Although left ventricular assist device (LVAD) implantation can improve survival in patients with end-stage heart failure, it is not without risk. Numerous complications are possible, and durable support requires substantial lifestyle changes. The use of various knowledge-assessment tools may allow for more informed patient decisions. To synthesize the totality of the evidence, we conducted a systematic review and meta-analysis to summarize the efficacy of decision aid (DA) use in patients with advanced heart failure who are eligible for LVAD. Any randomized controlled trial (RCT) evaluating the efficacy of DAs in patients considering LVAD was eligible for inclusion. A complete search of EMBASE and PubMed was conducted from the start until June 8, 2023. The primary outcome was patients' LVAD knowledge. Data extraction was performed independently by 2 reviewers. Data were pooled using a random-effects model. Of the 575 references, 2 RCTs randomizing 490 patients were included in this study. DAs were associated with no significant change in LVAD knowledge (standardized mean difference 0.07, 95% confidence interval -0.24 to 0.39, p = 0.64) or decisional conflict (mean difference -1.48, 95% confidence interval -5.28 to 2.32, p = 0.45). The certainty of the evidence ranged from moderate to very low. The use of DAs in LVAD-eligible patients with advanced heart failure resulted in no difference in patients' knowledge of LVAD after LVAD education. The findings from this study will aid in the power analysis of a well-designed RCT to evaluate and encourage further investigation into the efficacy and relevance of DAs in preparing patients for a life with LVAD.