Essentials
An international collaboration provides a consensus for clinical definitions.
This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP).
The consensus ...defines diagnosis, disease monitoring and response to treatment.
Requirements for ADAMTS‐13 are given.
Summary
Background
Thrombotic thrombocytopenic purpura (TTP) and hemolytic–uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small‐vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre‐eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways.
Objectives
To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs).
Methods
The International Working Group has proposed definitions and terminology based on published information and consensus‐based recommendations.
Conclusion
The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune‐mediated TTP.
Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed ...multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T
). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T
was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T
was 3.1 years. The median number of lines of therapy before T
was 4 (range 3-13). The median overall survival (OS) from T
for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T
in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T
of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.
Objectives
The objective of this meta-analysis was to investigate the association between hypoalbuminemia and postoperative complications in patients undergoing shoulder arthroplasty.
Methods
This ...meta-analysis study was registered in PROSPERO (CRD42023442466) and adhered to the PRISMA guidelines. Studies focused on shoulder arthroplasty that compared hypoalbuminemia and normal albumin levels were included. A systematic literature search was conducted in PubMed, EMBASE, Scopus, and the Cochrane Collaboration database. Seven comparative studies were included, and odds ratios with a 95% confidence interval were calculated for the dichotomous variables. A fixed-effect model was used when there was no statistical evidence of heterogeneity, and a random-effect model was used when significant heterogeneity was observed. Review Manager 5.4 software was used for data analysis.
Results
The meta-analysis included a total of 20,290 patients from seven studies. Hypoalbuminemia was significantly associated with a higher risk of readmissions (OR 2.92, 95%CI 1.74 to 4.91), reoperations (OR 3.23, 95%CI 1.98 to 5.27), an increase in hospital stay duration (MD 1.59, 95%CI 0.86 to 2.32), and complications such as death (OR 5.75, 95% CI 2.98 to 11.08; studies = 4), thromboembolic events (OR 2.43, 95% CI 1.46 to 4.06; studies = 4), cardiac events (OR 2.78, 95% CI 1.07 to 7.24; studies = 3), pulmonary infections (OR 3.09, 95% CI 1.54 to 6.20; studies = 3), systemic infections (OR 2.19, 95% CI 1.51 to 3.16; studies = 3), and transfusions (OR 3.16, 95% CI 2.23 to 4.48; studies = 2). However, there was no significant association between hypoalbuminemia and renal complications, surgical site infections, urinary tract infections, wound problems, or cardiovascular events.
Conclusion
This meta-analysis provides strong evidence that hypoalbuminemia is associated with a higher risk of postoperative complications in patients undergoing shoulder arthroplasty.
The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, ...bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m
on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P=0.03). Overall survival was not significantly different among the three arms. Grade 2-3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).
We have analyzed the applicability, sensitivity and prognostic value of allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) as a method for minimal residual disease (MRD) ...assessment in patients with multiple myeloma (MM), comparing the results with those of multiparameter flow cytometry (MFC). A total of 170 patients enrolled in three consecutive Spanish trials achieving at least partial response after treatment were included. Lack of clonality detection (n=31), unsuccessful sequencing (n=17) and suboptimal ASO performance (n=51) limited the applicability of PCR to 42% of cases. MRD was finally investigated in 103 patients (including 32 previously studied) with persistent disease identified by PCR and MFC in 54% and 46% of cases, respectively. A significant correlation in MRD quantitation by both the techniques was noted (r=0.881, P<0.001), being reflective of treatment intensity. Patients with <10(-4) residual tumor cells showed longer progression-free survival (PFS) compared with the rest (not reached (NR) vs 31 months, P=0.002), with similar results observed with MFC. Among complete responders (n=62), PCR discriminated two risk groups with different PFS (49 vs 26 months, P=0.001) and overall survival (NR vs 60 months, P=0.008). Thus, although less applicable than MFC, ASO RQ-PCR is a powerful technique to assess treatment efficacy and risk stratification in MM.
Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do ...not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.
Drug use among adolescents is a serious problem in our society, as some individuals develop dependence and addiction. MDMA/Esctasy is one of the most typically used substances by this age group. It ...is well known that environmental factors can alter the rewarding properties of drugs and the propensity to drug-related disorders. In this sense, exposure to social stress induces long-term effects in mice, enhancing the rewarding effects of MDMA in the conditioned place preference (CPP) paradigm. On the other hand, previous research has not provided conclusive results regarding the short-term effects of social defeat on MDMA reward in adolescent animals, probably due to the use of very low or very high doses. Thus, in the present study, we set out to evaluate whether exposure to social defeat immediately before each conditioning session with an intermediate dose of MDMA (2.25 mg/kg) modulates the rewarding effect of this drug in adolescent animals. Our results indicate that both control and socially defeated mice acquired CPP, but only stressed mice showed reinstatement. These findings indicate that social defeat induces an increase in the rewarding effect of MDMA, suggesting that this type of stress is a potential factor in the development of MDMA addiction.
This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma ...(RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m
on days 1 and 2 of cycle 1; 27 mg/m
thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.
Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late ...relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19
, CD27
, CD38
, CD45
, CD81
, CD117
and CD138
expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38
CD81
CD117
expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients.
Background
Vitamin D deficiency is common in patients with hip fractures and may negatively affect functional recovery and quality of life (QOL).
Objective
This study aimed to conduct a meta-analysis ...to quantify the effects of vitamin D deficiency on physical function and quality of life after hip fractures.
Methods
The PubMed, EMBASE, Scopus, and Cochrane Library databases were searched for relevant studies. The inclusion criteria were hip fracture, comparison between vitamin D deficiency and normal vitamin D levels in patients with hip fracture, and functional outcome as the primary outcome. The exclusion criteria were case reports, reviews, duplicates, studies with a high risk of bias, and non-comparable or missing data. Two independent reviewers selected studies, extracted data, assessed bias, and performed meta-analyses using the Review Manager. Heterogeneity and publication bias were also assessed. Two independent reviewers selected the studies, extracted data, and assessed the risk of bias. We performed a meta-analysis using Review Manager and assessed heterogeneity and publication bias.
Results
Seven studies with 1,972 patients were included. Vitamin D deficiency was defined as a 25(OH)D level < 20 ng/mL. There were no significant differences in the ability to walk (OR 0.68, 95% CI 0.31–1.53, I
2
= 69%) or length of hospital stay (MD 2.27 days, 95% CI − 2.47 to 7.01, I
2
= 93%) between patients with and without vitamin D deficiency. However, patients with vitamin D deficiency had significantly worse functional ability and quality of life (SMD − 1.50, 95% CI − 2.88 to − 0.12, I
2
= 96%).
Conclusions
Despite the limitations of this study, such as small sample size, heterogeneous outcome assessments, and variable vitamin D measurement techniques, the results demonstrated that screening for vitamin D status and optimizing levels through supplementation could facilitate rehabilitation, promote lifestyle changes, aid in the recovery of independence, and help reduce long-term burdens.
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