Assessment Of Treatment Efficacy Research Articles

A machine learning radiomics based on enhanced computed tomography to predict neoadjuvant immunotherapy for resectable esophageal squamous cell carcinoma.

Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this study is to establish and validate a radiomics based on enhanced computed tomography (CT) and combined with clinical data to predict the major pathological response to NIT in ESCC patients. This retrospective study included 82 ESCC patients who were randomly divided into the training group (n = 57) and the validation group (n = 25). Radiomic features were derived from the tumor region in enhanced CT images obtained before treatment. After feature reduction and screening, radiomics was established. Logistic regression analysis was conducted to select clinical variables. The predictive model integrating radiomics and clinical data was constructed and presented as a nomogram. Area under curve (AUC) was applied to evaluate the predictive ability of the models, and decision curve analysis (DCA) and calibration curves were performed to test the application of the models. One clinical data (radiotherapy) and 10 radiomic features were identified and applied for the predictive model. The radiomics integrated with clinical data could achieve excellent predictive performance, with AUC values of 0.93 (95% CI 0.87-0.99) and 0.85 (95% CI 0.69-1.00) in the training group and the validation group, respectively. DCA and calibration curves demonstrated a good clinical feasibility and utility of this model. Enhanced CT image-based radiomics could predict the response of ESCC patients to NIT with high accuracy and robustness. The developed predictive model offers a valuable tool for assessing treatment efficacy prior to initiating therapy, thus providing individualized treatment regimens for patients.

DARC technology: Where do we stand?

The emergence of neuroprotection in glaucoma has emphasized the importance of new endpoints to assess disease and identify those at greatest risk of blindness. Several potential outcome measures have been advocated, including immunological, genetic, structural and functional biomarkers. The identification of in vivo apoptosis could serve as a potential biomarker of disease activity. The technology that has been developed to detect apoptosing retinal cells (DARC) is now being used to assess treatment efficacy in glaucoma, wet AMD, geographic atrophy and diabetic eye disease. It is currently used as an exploratory endpoint with future plans for its development as a clinically approved endpoint.

Value of CT-based radiomics in evaluating the response of bone metastases to systemic drug therapy in breast cancer patients.

This study aimed to investigate the value of nonenhanced computed tomography (CT)-based radiomics in determining disease progression in breast cancer patients with bone marrow metastases and to develop a model for assessing treatment efficacy. A total of 134 breast cancer patients with bone metastases were enrolled from three hospitals. Nonenhanced CT was performed after two cycles of drug treatment. The images were categorized into an invalid and a valid group according to disease progression status. The largest osteolytic lesions' maximum cross-sections in the CT images were selected as regions of interest (ROIs) for feature extraction. Variance threshold, SelectKBest, and least absolute shrinkage and selection operator (LASSO) were used to reduce feature dimensionality. K-nearest neighbor algorithm (KNN), support vector machine (SVM), extreme gradient boosting (XGBoost), random forest (RF), logistic regression (LR), and decision tree (DT) algorithms were trained to establish radiomics models. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of the models. The KNN classifier demonstrated the best performance compared to the random grouping method. In the validation group, the area under the ROC curve (AUC) was 0.810. In the cross-validation method, the RF classifier showed the best performance with an AUC of 0.84. Nonenhanced CT-based radiomics provides a promising method for evaluating the efficacy of systemic drug therapy in breast cancer patients with osteolytic bone metastases.

In vivo visualization of tumor-associated macrophages re-education by photoacoustic/fluorescence dual-modal imaging with a metal-organic frames-based caspase-1 nanoreporter

Tumor-associated macrophages (TAMs) are vital in the tumor microenvironment, contributing to immunosuppression and therapy tolerance. Despite their importance, the precise re-education of TAMs in vivo continues to present a formidable challenge. Moreover, the lack of real-time and efficient methods to comprehend the spatiotemporal kinetics of TAMs repolarization remains a significant hurdle, severely hampering the accurate assessment of treatment efficacy and prognosis. Herein, we designed a metal–organic frameworks (MOFs) based Caspase-1 nanoreporter (MCNR) that can deliver a TLR7/8 agonist to the TAMs and track time-sensitive Caspase-1 activity as a direct method to monitor the initiation of immune reprogramming. This nanosystem exhibits excellent TAMs targeting ability, enhanced tumor accumulation, and stimuli-responsive behavior. By inducing the reprogramming of TAMs, they were able to enhance T-cell infiltration in tumor tissue, resulting in inhibited tumor growth and improved survival in mice model. Moreover, MCNR also serves as an activatable photoacoustic and fluorescent dual-mode imaging agent through Caspase-1-mediated specific enzyme digestion. This feature enables non-invasive and real-time antitumor immune activation monitoring. Overall, our findings indicate that MCNR has the potential to be a valuable tool for tumor immune microenvironment remodeling and noninvasive quantitative detection and real-time monitoring of TAMs repolarization to immunotherapy in the early stage.

A DIGITAL LIFE STORY BOOK ACTIVITY FOR OLDER ADULTS WITH MEMORY DIFFICULTIES: PROGRAM EVALUATION

Abstract Reminiscence activities are based on maintaining a core set of personal memories to aid self-continuity (Woods, 2012). Some interventions find limited effects (Charlesworth et al, 2016) but with participants reporting high satisfaction with the program. The aims of the current study were to: (i) demonstrate feasibility of intervention delivery to older individuals with memory difficulties, and (ii) provide analyses of program efficacy using a pre-posttest, control group design. Participants (N = 45; Mage = 76.12) were randomized to the Life Story Book intervention or Waitlist Control. A Life Story Book Interview was developed, using five evidence-based principles of autobiographical memory. Personalized multimedia books were created and reviewed by participants for fourteen days. To assess feasibility, participants in the intervention completed a memory quality questionnaire and feedback survey. Those who reviewed Life Story Books reported improved memory quality pre-post intervention, t(22) = -2.39, p = .026. Participants also positively rated their intervention experience at post-test, (M = 4.46/5). All participants completed self-related questionnaires (e.g., self-continuity, self-esteem) at pretest-posttest. No measure showed significant effects. Our results represent a conundrum for researchers. We provide evidence of feasibility of, and participant enthusiasm for, this reminiscence-based intervention. As seen in the literature, however, (Elfrink et al., 2021), sensitivity to detect pretest-postest change remains a challenge. The current study highlights participants positive reactions to reminiscence-based Life Story Books. Findings are discussed in terms of methods for assessing intervention efficacy in individuals with memory decline.

Pediatric long-term noninvasive respiratory support in children with central nervous system disorders.

The use of long-term noninvasive respiratory support is increasing in children along with an extension of indications, in particular in children with central nervous system (CNS) disorders. The aim of this study was to describe the characteristics of children with CNS disorders treated with long-term noninvasive respiratory support in France. Data were collected from 27 French pediatric university centers through an anonymous questionnaire filled for every child treated with noninvasive ventilatory support ≥3 months on 1st June 2019. The data of 182 patients (55% boys, median age: 10.2 [5.4;14.8] years old [range: 0.3-25]) were collected: 35 (19%) patients had nontumoral spinal cord injury, 22 (12%) CNS tumors, 63 (35%) multiple disabilities, 26 (14%) central alveolar hypoventilation and 36 (20%) other CNS disorders. Seventy five percent of the patients were treated with noninvasive ventilation (NIV) and 25% with continuous positive airway pressure (CPAP). The main investigations performed before CPAP/NIV initiation were nocturnal gas exchange recordings, alone or coupled with poly(somno)graphy (in 29% and 34% of the patients, respectively). CPAP/NIV was started in an acute setting in 10% of the patients. Median adherence was 8 [6;10] hours/night, with 12% of patients using treatment <4 h/day. Nasal mask was the most common interface (70%). Airway clearance techniques were used by 31% of patients. CPAP/NIV may be a therapeutic option in children with CNS disorders. Future studies should assess treatment efficacy and patient reported outcome measures.

In dogs with chronic enteropathy (idiopathic inflammatory bowel disease) is budesonide more effective than prednisolone or prednisone in resolving clinical signs?

PICO Question In dogs with chronic enteropathy (idiopathic inflammatory bowel disease) is budesonide more effective than prednisolone or prednisone in resolving clinical signs or improving the canine inflammatory bowel disease (IBD) activity index (CIBDAI) or the canine chronic enteropathy clinical activity index (CCECAI)? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed One double-blinded randomised control trial. Strength of evidence Moderate. Outcomes reported The outcome of this study identified that no significant differences in remission rates (&gt; 75% decrease in CIBDAI scores) were observed between the prednisone and budesonide groups. Frequency of adverse effects were also similar between the two groups. Conclusion A single study with moderate power of evidence alongside some significant limitations, particularly population size, cannot be used as the sole provider of an answer to the PICO question. As such, further studies with greater power would be required before a definitive assessment of comparative treatment efficacy can be made. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Treatment Effect Estimates From Pilot Trials Are Unreliable.

The CONSORT guideline defines a pilot trial as a small-scale version of a desired future efficacy trial that is intended to answer the key questions of whether and how a larger study should be done. For example, a pilot trial might evaluate different approaches to data collection or outcome measurement. However, pilot trials are unreliable for assessing treatment efficacy due to the statistical phenomenon called sampling variability. In this tutorial we use computer simulation to demonstrate the influence of sampling variability on efficacy estimates from pilot trials, illustrating why pilot trial designs should not be used to evaluate whether a treatment is promising or not. We simulate a 2-arm parallel group trial (N=20 per group) with a survival outcome as an example. Simulations are done under two scenarios: 1) the treatment is efficacious at the level of a hypothetical minimum clinically important difference (hazard ratio [HR] = 0.75); and 2) the treatment is not efficacious (HR=1). As expected, in both simulated scenarios the range of observed results is distributed around the true treatment effect, HR=0.75 or HR=1. Importantly, ∼20% of trials simulated under scenario 1 incorrectly suggest the treatment may be harmful (HR > 1). Under scenario 2, half of the simulated studies incorrectly suggest the treatment is beneficial. Treatment effect estimates from pilot trials should not be used to make future development decisions regarding a novel therapy because of the high risk of misleading conclusions.

Targeting toll-like receptor 4 (TLR4) and the NLRP3 inflammasome: Novel and emerging therapeutic targets for hyperuricaemia nephropathy.

The clinical manifestation of hyperuricaemia, known as hyperuricaemia nephropathy, is relatively common. Its pathophysiology is largely based on chronic inflammation in circulatory and renal tissues. Toll-like receptor 4 (TLR4), a subclass of innate immune receptors, detects both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), initiating inflammatory and immune responses that lead to the release of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). These cytokines are pivotal in renal inflammation, especially in conditions like hyperuricaemia, acute renal injury, ischemia-reperfusion injury, and acute renal failure. The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, an essential component of the innate immune signaling complex, plays a central role in inflammation. It finely regulates the activation of caspase-1 and the production and secretion of the pro-inflammatory cytokine IL-1β, mediating and amplifying the inflammatory cascade response. Activation of TLR4 indirectly promotes the assembly of the NLRP3 inflammasome by regulating the nuclear factor kappa B (NF-κB) signaling pathway, thereby amplifying the inflammatory process and playing a significant pro-inflammatory role in hyperuricaemia nephropathy. TLR4 and NLRP3 inflammasome are anticipated to be novel markers and therapeutic targets for assessing treatment efficacy and prognosis in hyperuricaemia nephropathy. This paper provides a comprehensive overview of the structural composition and biological functions of TLR4 and NLRP3 inflammasome and systematically reviews their relevance in the pathogenesis of hyperuricaemia nephropathy.

Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome

Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

The Association of Psychological Variants with Back Pain, Muscle Endurance, and Functional Limitations in an Individual with Chronic Back Pain.

Chronic low back pain (CLBP) substantially impacts quality of life through a multifarious interplay of physical and psychological elements. A comprehensive understanding of this relationship is imperative for developing effective treatment strategies. This study recruited 64 participants (35 males and 29 females) experiencing chronic low back pain to explore the associations between psychological factors, muscle endurance, and functional impairments. The study was conducted over six months in an outpatient department and a rehabilitation unit. The study utilized established outcome measures, such as the Biering-Sorensen Test and the Roland Morris Disability Questionnaire, and psychological variants as the core dependent variables, including the Beck Depression Inventory (BDI), STAI questionnaire, the FABQ-PA, and the Pain Catastrophizing Scale (PCS). The findings uncovered pronounced gender disparities, with females exhibiting elevated levels of depression (BDI: 27.68 ± 9.43, p < 0.001) and anxiety (STAI: 42.34 ± 8.94, p < 0.001) and diminished muscle endurance (130.47 ± 30.56 sec, p = 0.001). These revelations are congruent with the prevailing literature, emphasizing the need for gender-sensitive and personalized interventions. Bivariate correlations presented robust associations between psychological distress and decreased muscle endurance (r values ranging from -0.82 to -0.88, p < 0.001) alongside elevated functional impairments (r values from 0.89 to 0.94, p < 0.001) for both genders. Additionally, linear regression analyses illuminated the consequential impact of specific psychological variables such as the BDI, FABQ-PA, and PCS on muscle endurance and functional impairments (all p < 0.001). This study reveals gender-specific variations in chronic back pain, highlighting the influence of psychological factors on pain perception. It underscores the necessity for gender-sensitive treatment strategies. Future research is needed to explore these differences further and assess treatment efficacy to improve care and quality of life for chronic low back pain sufferers through personalized treatment plans.

Application and development of Deuterium Metabolic Imaging in tumor glucose metabolism: visualization of different metabolic pathways

Cancer metabolism has emerged as a pivotal area of research recently. The ability to visualize and comprehend the metabolic processes of cancer holds immense clinical value, particularly in the diagnosis of malignant tumors and the assessment of treatment responses. Deuterium Metabolic Imaging (DMI), as a robust, simple, and versatile MR spectroscopic imaging tool, demonstrates promise in tumor diagnosis and treatment efficacy assessment. This review explored the latest developments and applications of DMI in oncology across various tumor metabolic axes, with a specific emphasis on its potential for clinical translation. DMI offers invaluable insights into tumor biology, treatment responses, and prognostic outcomes. Notably, DMI can identify early responses to immunotherapy, a prominent area of current research interest. In conclusion, DMI harbors the potential to evolve into a convenient and efficient imaging technique in clinical practice, thereby advancing precision medicine and improving the diagnosis and evaluation of cancer treatments.

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes

Background: Frequent episodes of vaso-occlusion are the hallmark of sickle cell disease (SCD), but the definition of what constitutes a vaso-occlusive episode is not consistently applied across clinical trials, creating challenges in evaluating and comparing efficacy results among different therapies. Here, we compare vaso-occlusion endpoint definitions from clinical trials for various therapies, including genetic therapies, and use clinical trial data to demonstrate the potential for outcomes differences based on differing definitions of vaso-occlusive episodes. Methods: We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Outcomes related to vaso-occlusion were compared across variables including care setting, care duration, treatments, and complications. Data from the CLIMB SCD-121 trial of exa-cel in patients aged 12 to 35 years with severe SCD (data cut as of 10 Feb 2023) were evaluated using different published definitions of vaso-occlusion. Results: The most substantial differences in vaso-occlusion endpoint definitions were associated with frequency and duration of visits to medical facilities for acute pain and inclusion of specific SCD specific complications. Definitions of vaso-occlusions for acute pain related events differed across studies. The definitions of severe vaso-occlusive crises for exa-cel (severe VOC; exa-cel), sickle cell pain-related crises (SCPC; crizanlizumab and L-glutamine), and VOC (VOC; voxelotor) include events with medical facility visits of any duration (severe VOC and SCPC) or medical records of a patient being seen or contacting a physician within 1 business day of an event (VOC), whereas the definition of severe vaso-occlusive events (severe VOE; lovo-cel) requires a ≥ 24-hour hospital or emergency room (ER) observation unit visit or ≥2 visits to a day unit or ER over 72 hours. Vaso-occlusion definition for HU (painful crisis) required a facility visit of ≥4 hours duration. All endpoints include acute chest syndrome and priapism; however, the definition of severe VOE requires ≥4 visits to a medical facility for priapism to meet criterion, while others require only a single visit. The exa-cel phase 3 trial in SCD employs a broad and inclusive definition for severe VOC which counts each individual medical facility visit, regardless of frequency or duration of hospitalization. Based on this, 19 out of 20 patients (95%) met the primary endpoint of freedom from severe VOCs for at least 12 consecutive months (95% CI, 75.1%, 99.9%; P&amp;lt;0.0001). However, when the primary endpoint was analyzed using the severe VOE definition, all patients (20/20; 100.0%) were free from severe VOEs for at least 12 consecutive months (95% CI: 83.2%, 100.0%; P&amp;lt;0.0001). Conclusions: Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion definitions have the potential to impact assessments of treatment efficacy across different SCD therapies.

Efficacy and Safety of CD19-Specific CAR-T Cell Therapy Following Immunochemotherapy in Newly Diagnosed B-Cell Lymphoma Associated Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) represents a grave and potentially fatal systemic inflammatory condition. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS), as a common type in secondary HLH, suffers the worst outcome among sHLH. B cell Lymphoma associated hemophagocytic lymphohistiocytosis (B-LAHS) typically presents as high-risk lymphoma and is associated with a poorer prognosis compared to B cell lymphoma without HLH with standard first-line chemoimmunotherapy. As a result, there is an urgent need for more effective therapeutic strategies. Recent advancements in chimeric antigen receptor (CAR) T-cell therapy have demonstrated remarkable responses in relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL), as well as in some high-risk newly diagnosed B-cell lymphoma. However, There have been no clinical reports regarding the application of CAR-T cell treatment as part of first-line therapy in B-LAHS. We assessed the effectiveness and safety of autologous anti-CD19 CAR-T cell therapy following an immunochemotherapeutic regimen based on R-DEP (Rituximab-doxorubicin-etoposide-methylprednisolone) as a first-line treatment option for patients with B-LAHS. As of 1 July 2023, a cohort of 13 patients diagnosed with B-LAHS（with 3 cases enrolled before registration for clinical trials）was recruited for evaluation and met the criteria for assessing treatment efficacy at our institution. The overall response rate (ORR) for HLH was 100% (with 7 cases achieving complete response and 6 cases achieving partial response) prior to infuse CAR-T cells and the ORR for lymphoma also was 100% (with 10 cases achieving complete response and 3 cases achieving partial response) on the time of a month after CAR-T cell infusion. As of the follow-up date on 1 July 2023 (with a median follow-up time of 14 months), all 13 patients were still alive, 12 cases maintained sustained remission, while 1 case experienced relapse at 16 months after CAR-T cell infusion. The median overall survival (OS) has not been reached, and the median progression-free survival (PFS) was 31.5 months. To provide comparison, we included a group of 26 patients diagnosed with B-LAHS who did not receive CAR-T cell therapy during the same period. The non-CAR-T group demonstrated a significantly lower median OS of 5.93 months and a median PFS of 4.43 months, highlighting the superior prognosis of the CAR-T group (p &amp;lt; 0.001). Regarding adverse events, the CAR-T group exhibited a cytokine release syndrome (CRS) incidence of 53.8% (7/13) and an immune effector cell-associated neurotoxicity syndrome (ICANS) incidence of 30.7% (4 /13), all of which were classified as grade 1. None of the patients experienced non-hematologic toxicity of grade ≥3. While all 13 patients developed cytopenias, hematologic toxicity reactions ≥ grade 3 were observed in 76.9% (10 /13) of patients, but blood cell counts recovered within 3 weeks. Robust expansion of CAR T-cells occurred in all patients, with a median time to peak expansion of 8 days. Importantly, no exacerbation of hemophagocytic syndrome occurred following CAR-T cell infusion, and no patients succumbed to adverse events. In conclusion, our findings suggest that CD19 CAR-T cell treatment exhibits high efficacy as part of first-line therapy for B-LAHS, with a manageable safety profile.

Response and Safety of Selinexor with VRD Regimen in Newly Diagnosed Multiple Myeloma (NDMM) with Extramedullary Disease (EMD): A Prospective, Open-Label, Multicenter, Phase 2 Study

INTRODUCTION: Extramedullary disease (EMD) is a rare but increasingly recognized complication in newly diagnosed multiple myeloma (NDMM) patients, associated with a poorer prognosis and drug resistance. However, data on treatment outcomes for EMD are primarily based on retrospective studies, necessitating prospective studies with well-defined EMD to assess treatment efficacy and safety accurately. In this context, we present the preliminary findings from a prospective phase 2 study evaluating the safety and efficacy of selinexor in combination with VRd as a first-line treatment for NDMM patients with EMD(NCT05900882). METHODS: The study enrolled NDMM patients under the age of 75 who had measurable extramedullary disease (defined as paraosseous or extramedullary plasmacytoma ≥2cm. Patients received selinexor (60 mg QW) in combination with VRd (SVRD) regimen as induction therapy for 4 cycles (28 days of each cycle). Following the induction phase, patients underwent two cycles of VRd consolidation therapy after autologous stem cell transplantation (ASCT), while those who did not undergo ASCT received another 4 cycles of SVRD consolidation therapy. All pts received bortezomib plus lenalidomide for maintenance for at least 24 months. The primary endpoint of the study was the best response rate during induction therapy, and secondary endpoints included complete response (CR) rate, duration of response (DOR), safety, and survival outcomes. RESULTS: Between Oct 17, 2022 and May 12, 2023, a total of 10 NDMM pts with EMD were enrolled and received treatment at The First Affiliated Hospital of Nanjing Medical University. The median age was 62 years (range 48-70). Among them, 7 patients (70%) had RISS stage II/III disease, 7 patients (70%) were classified as high risk based on the mSMART stratification, and 3 patients (30%) had extra-osseous extramedullary plasmacytomas (EMP) as per Table 1. By the data cut-off date of July 15, 2023, at a median follow-up of 5.5 months (range 2.2-9.3 months), 5 pts completed 4 cycles of SVRd inductive treatment, 2 pts underwent ASCT, 1 pts discontinued the clinical trial due to progressive disease, and 3 pts were now receiving consolidation therapy ( Figure 1). Among the 10 evaluable pts for best serological response, 4 pts (40%) achieved serological CR/sCR, and 6 pts (60%) achieved VGPR. The depth of remission improved with the continuous treatment. Extramedullary disease evaluation in 9 patients showed complete disappearance of extramedullary lesions in 3 patients (30%), partial response in 5 patients (50%), and stable disease in 1 patient (10%). 8 (80%) pts experienced any grade AE. Grade 3 or 4 AEs were reported in 2 pts (9 events in total), with the most common being leukopenia (3), neutropenia (3) and thrombocytopenia (3). Non-hematological AEs were mainly grade 1-2, except for 1 pt with grade 3 anorexia. No pts required dose reductions or discontinuations due to AEs. CONCLUSIONS: The combination of selinexor with VRd regimen demonstrated early, deep, and durable responses in NDMM patients with extramedullary disease, both in serological and extramedullary responses, with a manageable safety profile. These results suggest that this therapeutic intervention holds promise as an effective and well-tolerated treatment option for multiple myeloma patients with EMD. Further studies are warranted to validate these findings and establish the long-term benefits of this combination therapy.

Metabolic syndrome as a risk factor for the development of kidney dysfunction: a meta-analysis of observational cohort studies.

Chronic kidney disease (CKD) is a major global health concern with increasing prevalence and associated complications. Metabolic syndrome (MetS) has been linked to CKD, but the evidence remains inconsistent. We conducted a systematic review and meta-analysis to investigate the association between MetS and kidney dysfunction. We conducted a comprehensive search of databases until December 2022 for cohort studies assessing the association between MetS and incident kidney dysfunction. Meta-analysis was performed using fixed and random effects models. Subgroup analyses were conducted to explore heterogeneity. Publication bias was assessed using Egger's and Begg's tests. A total of 24 eligible studies, involving 6,573,911 participants, were included in this meta-analysis. MetS was significantly associated with an increased risk of developing CKD (OR, 1.42; 95% CI, 1.28, 1.57), albuminuria or proteinuria (OR, 1.43; 95% CI, 1.10, 1.86), and rapid decline in kidney function (OR, 1.25; 95% CI, 1.07, 1.47). Subgroup analyses showed a stronger association as the number of MetS components increased. However, gender-specific subgroups demonstrated varying associations. Metabolic syndrome is a significant risk factor for kidney dysfunction, requiring close renal monitoring. Lifestyle changes and targeted interventions may help reduce CKD burden. Further research is needed to understand the connection fully and assess intervention efficacy. The online version contains supplementary material available at 10.1007/s40200-023-01348-5.

Motor Rehabilitation Provides Modest Functional Benefits After Intracerebral Hemorrhage: a Systematic Review and Meta-Analysis of Translational Rehabilitation Studies.

Few certainties exist regarding the optimal type, timing, or dosage of rehabilitation after stroke. Despite differing injury mechanisms and recovery patterns following ischemic and hemorrhagic stroke, most translational stroke research is conducted after ischemia. As we enter the era of personalized medicine, exploring subtype-specific treatment efficacy is essential to optimizing recovery. Our objective was to characterize common rehabilitation interventions used after in vivo preclinical intracerebral hemorrhage (ICH) and assess the impact of post-ICH rehabilitation (vs. no-rehabilitation) on recovery of motor function. Following PRISMA guidelines, a systematic review (Academic Search Complete, CINAHL, EMBASE, Medline, PubMed Central) identified eligible articles published up to December 2022. Risk of bias (SYRCLE) and study quality (CAMARADES) were evaluated, and random-effects meta-analysis was used to assess treatment efficacy in recovery of forelimb and locomotor functions. Thirty articles met inclusion criteria, and 48 rehabilitation intervention groups were identified. Most used collagenase to model striatal ICH in young, male rodents. Aerobic exercise, enriched rehabilitation, and constraint-induced movement therapy represented ~ 70% of interventions. Study quality was low (median 4/10, range 2-8), and risk of bias was unclear. Rehabilitation provided modest benefits in skilled reaching, spontaneous impaired forelimb use, and locomotor function; however, effects varied substantially by endpoint, treatment type, and study quality. Rehabilitation statistically improves motor function after preclinical ICH, but whether these effects are functionally meaningful is unclear. Incomplete reporting and variable research quality hinder our capacity to analyze and interpret how treatment factors influence rehabilitation efficacy and recovery after ICH.

Immunophenotypic markers for the evaluation of minimal/measurable residual disease in acute megakaryoblastic leukemia

Acute megakaryoblastic leukemia is characterized by heterogeneous biology and clinical behavior. Immunophenotypic characteristics include the expression of megakaryocytic differentiation markers (e.g. CD41, CD42a, CD42b, CD61) associated with immaturity markers (CD34, CD117, HLA-DR) and myeloid markers (e.g. CD13, CD33) and even with lymphoid cross-lineage markers (e.g. CD7, CD56). Although the diagnostic immunophenotype has already been well described, given the rarity of the disease, its immunophenotypic heterogeneity and post-therapeutic instability, there is no consensus on the combination of monoclonal markers to detect minimal/measurable residual disease (MRD).Currently, MRD is an important tool for assessing treatment efficacy and prognostic risk. In this study, we evaluated the immunophenotypic profile of MRD in a retrospective cohort of patients diagnosed with acute megakaryoblastic leukemia, to identify which markers, positive or negative, were more stable after treatment and which could be useful for MRD evaluation. The expression profile of each marker was evaluated in sequential MRD samples. In conclusion, the markers evaluated in this study can be combined in an MRD immunophenotypic panel to investigate for megakaryoblastic leukemia. Although this study is retrospective and some data are missing, the information obtained may contribute to prospective studies to validate more specific strategies in the detection of MRD in acute megakaryoblastic leukemia.

A Systematic Review of Potential Biomarkers for Bacterial Burden and Treatment Efficacy Assessment in Tuberculosis Platform-Based Clinical Trials.

Adaptive platform trials can be more efficient than classic trials for developing new treatments. Moving from culture-based to simpler- or faster-to-measure biomarkers as efficacy surrogates may enhance this advantage. We performed a systematic review of treatment efficacy biomarkers in adults with tuberculosis. Platform trials can span different development phases. We grouped biomarkers as: α, bacterial load estimates used in phase 2a trials; β, early and end-of treatment end points, phase 2b-c trials; γ, posttreatment or trial-level estimates, phase 2c-3 trials. We considered as analysis unit (biomarker entry) each combination of biomarker, predicted outcome, and their respective measurement times or intervals. Performance metrics included: sensitivity, specificity, area under the receiver-operator curve (AUC), and correlation measures, and classified as poor, promising, or good. Eighty-six studies included 22 864 participants. From 1356 biomarker entries, 318 were reported with the performance metrics of interest, with 103 promising and 41 good predictors. Group results were: α, mycobacterial RNA and lipoarabinomannan (LAM) in sputum, and host metabolites in urine; β, mycobacterial RNA and host transcriptomic or cytokine signatures for early treatment response; and γ, host transcriptomics for recurrence. A combination of biomarkers from different categories could help in designing more efficient platform trials. Efforts to develop efficacy surrogates should be better coordinated.

Fluid-Based Protein Biomarkers in Traumatic Brain Injury: The View from the Bedside.

There has been an explosion of research into biofluid (blood, cerebrospinal fluid, CSF)-based protein biomarkers in traumatic brain injury (TBI) over the past decade. The availability of very large datasets, such as CENTRE-TBI and TRACK-TBI, allows for correlation of blood- and CSF-based molecular (protein), radiological (structural) and clinical (physiological) marker data to adverse clinical outcomes. The quality of a given biomarker has often been framed in relation to the predictive power on the outcome quantified from the area under the Receiver Operating Characteristic (ROC) curve. However, this does not in itself provide clinical utility but reflects a statistical association in any given population between one or more variables and clinical outcome. It is not currently established how to incorporate and integrate biofluid-based biomarker data into patient management because there is no standardized role for such data in clinical decision making. We review the current status of biomarker research and discuss how we can integrate existing markers into current clinical practice and what additional biomarkers do we need to improve diagnoses and to guide therapy and to assess treatment efficacy. Furthermore, we argue for employing machine learning (ML) capabilities to integrate the protein biomarker data with other established, routinely used clinical diagnostic tools, to provide the clinician with actionable information to guide medical intervention.