Heterogeneous Results Research Articles

The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review

Abstract Background The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the “Core Outcome Measures in Effectiveness Trials” (COMET) initiative. Results Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.

Matrix metalloproteinase MMP-7 as a new prognostic biomarker for gastric cancer

BACKGROUND: According to statistics, gastric cancer is in a leading position among all gastrointestinal cancers. The most effective treatment for gastric cancer is surgery. There are now heterogeneous clinical outcomes for patients in the same stage of the disease. The main reason for this is the fact that differences in types of gastric cancer occur not only at the histological level, but also at the molecular level. Finding the universal biomarkers that can provide information about patient prognosis is a subject of interest to scientists around the world. MMP-7 is the smallest molecule in the family of matrix metalloproteinases that contributes significantly to oncogenesis by affecting apoptosis and degradation of the extracellular matrix. MMP-7 hyperexpression is associated with aggressive tumor phenotype and worsens prognosis in patients with gastric cancer. Therefore, MMP-7 can be a promising biomarker in the treatment of gastric cancer.
 AIM: To identify possible correlations between the expression of MMP-7 in patients with gastric cancer and their prognosis.
 MATERIALS AND METHODS: The study included samples of 80 patients diagnosed with diffuse gastric cancer, who were selected based on our inclusion and exclusion criteria. 30 sectional stomach samples were taken as a comparison group. Of the 80 patients included in the study, gastrectomy was performed in 55% cases (44 people) and gastric resection was performed in 45% cases (36 people).
 RESULTS: In our work, the expression level of MMP-7 0.8±0.07 was indicated as high, and the expression rate of 0.40±0.067 as low. During the study, we assessed the link between the level of MMP-7 expression and the clinical characteristics of the tumor. We evaluated the following indicators: the disease stage, the presence of lesions of lymph nodes, the size of the tumor. Patients with increased MMP-7 expression in tumor tissue have a better prognosis than patients with low MMP-7 expression.
 CONCLUSION: The results of our study showed high MMP-7 expression in tumor tissue, which allowed us to establish a correlation between MMP-7 expression and adverse clinical outcomes. The data obtained may indicate the possible use of MMP-7 as a biomarker for gastric cancer.

Does vitamin D deficiency affect functional outcomes in hip fracture patients? A meta-analysis of cohort studies.

Vitamin D deficiency is common in patients with hip fractures and may negatively affect functional recovery and quality of life (QOL). 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. 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. Seven studies with 1,972 patients were included. Vitamin D deficiency was defined as a 25(OH)D level < 20ng/mL. There were no significant differences in the ability to walk (OR 0.68, 95% CI 0.31-1.53, I2 = 69%) or length of hospital stay (MD 2.27days, 95% CI -2.47 to 7.01, I2 = 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, I2 = 96%). 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.

Trajectories of adaptive functioning from early childhood to adolescence in autism: Identifying turning points and key correlates of chronogeneity.

Previous research has demonstrated heterogeneous adaptive outcomes across the autism spectrum; however, the current literature remains limited in elucidating turning points and associated factors for longitudinal variability (chronogeneity). To address these empirical gaps, we aimed to provide a finer-grained characterization of trajectories of adaptive functioning from early childhood to adolescence in autism. Our sample (N=406) was drawn from an inception cohort of children diagnosed Autistic at ages 2-5. Adaptive functioning was assessed with Vineland Adaptive Behavior Scales (VABS, 2nd Edition) across 6 visits from the time of diagnosis by age 18. Parallel-process latent growth curve modeling were used to estimate domain-level VABS trajectories, followed by latent class growth analysis to identify trajectory subgroups. Child characteristics at diagnosis, family demographics, and participation outcomes at adolescence were compared across subgroups. Piecewise latent growth models best described VABS trajectories with two turning points identified at around ages 5-6 and 9-10, respectively reflecting transitions into school age and early adolescence. We parsed four VABS trajectory subgroups that vary by level of functioning and change rate for certain domains and periods. Around 16% of the sample exhibited overall adequate functioning (standard score >85) with notable early growth and social adaptation during adolescence. About 21% showed low adaptive functioning (standard score ≤70), with decreasing slopes by age 6 followed by improvements in communication and daily-living skills by age 10. The other two subgroups (63% in total) were characterized by adaptive functioning between low and adequate levels, with relatively stable trajectories entering school age. These subgroups differed most in their cognitive ability at diagnosis, household income, and social participation in adolescence. We identified key individual and family characteristics and time windows associated with distinct adaptive functioning trajectories, which have important implications for providing timely and tailored supports to Autistic people across developmental stages.

Hoffa fractures are associated with concomitant soft tissue injures and a high postoperative complication rate

IntroductionHoffa fractures are a rare and often overlooked entity. The main goal of surgical treatment is to restore the articular surface and maintain knee function. However, current clinical data indicate heterogeneous outcomes. The aim of this multicenter study was to obtain a representative data set of patients with isolated Hoffa fractures with special emphasis on concomitant soft tissue injuries, diagnostic algorithms, treatment strategies and functional outcomes.Materials and methodsParticipating Level I trauma centres were asked to review their internal database for isolated Hoffa fractures treated surgically between 2010 and 2020. Demographics, mechanism of injury, diagnostic and therapeutic algorithm, Letenneur classification, concomitant soft tissue injuries, and postoperative knee function and complications were analysed.ResultsA total of 56 patients from six participating trauma centres were included. The median age at injury was 45 years (15–94) with a median follow-up of 19 months (2–108). The most common mechanism of injury was high-energy trauma, with unicondylar lateral Letenneur type I and II fractures being the most common. Surgical treatment was independent of the type of fracture and included isolated screw fixation, combined plate and screw fixation and isolated plate osteosynthesis. Isolated screw fixation resulted in significantly better range of motion (ROM) values (p = 0.032), but the highest number of postoperative complications (n = 14/20, n.s.) compared to the other fixation techniques. The highest number of fixation failures requiring revision was observed in the plate and screw fixation group (n = 3/8, p = 0.008). Osteochondral flake fractures (n = 12/43, 27%) and lateral meniscus injuries (n = 5/49, 10%) were commonly seen in Hoffa fractures.ConclusionsTreatment of Hoffa fractures with screw fixation resulted in significantly better functional outcomes, probably due to less comminuted fractures. Concomitant cartilage, meniscal and ligamentous injuries are common and warrant preoperative recognition and management.

Glioblastoma pseudoprogression and true progression reveal spatially variable transcriptional differences

Post-resection radiologic monitoring to identify areas of new or progressive enhancement concerning for cancer recurrence is critical during patients with glioblastoma follow-up. However, treatment-related pseudoprogression presents with similar imaging features but requires different clinical management. While pathologic diagnosis is the gold standard to differentiate true progression and pseudoprogression, the lack of objective clinical standards and admixed histologic presentation creates the needs to (1) validate the accuracy of current approaches and (2) characterize differences between these entities to objectively differentiate true disease. We demonstrated using an online RNAseq repository of recurrent glioblastoma samples that cancer-immune cell activity levels correlate with heterogenous clinical outcomes in patients. Furthermore, nCounter RNA expression analysis of 48 clinical samples taken from second neurosurgical resection supports that pseudoprogression gene expression pathways are dominated with immune activation, whereas progression is predominated with cell cycle activity. Automated image processing and spatial expression analysis however highlight a failure to apply these broad expressional differences in a subset of cases with clinically challenging admixed histology. Encouragingly, applying unsupervised clustering approaches over our segmented histologic images provides novel understanding of morphologically derived differences between progression and pseudoprogression. Spatially derived data further highlighted polarization of myeloid populations that may underscore the tumorgenicity of novel lesions. These findings not only help provide further clarity of potential targets for pathologists to better assist stratification of progression and pseudoprogression, but also highlight the evolution of tumor-immune microenvironment changes which promote tumor recurrence.

High-density transcranial direct current stimulation to improve upper limb motor function following stroke: study protocol for a double-blind randomized clinical trial targeting prefrontal and/or cerebellar cognitive contributions to voluntary motion

BackgroundFocal brain lesions following a stroke of the middle cerebral artery induce large-scale network disarray with a potential to impact multiple cognitive and behavioral domains. Over the last 20 years, non-invasive brain neuromodulation via electrical (tCS) stimulation has shown promise to modulate motor deficits and contribute to recovery. However, weak, inconsistent, or at times heterogeneous outcomes using these techniques have also highlighted the need for novel strategies and the assessment of their efficacy in ad hoc controlled clinical trials.MethodsWe here present a double-blind, sham-controlled, single-center, randomized pilot clinical trial involving participants having suffered a unilateral middle cerebral artery (MCA) stroke resulting in motor paralysis of the contralateral upper limb. Patients will undergo a 10-day regime (5 days a week for 2 consecutive weeks) of a newly designed high-definition transcranial direct current stimulation (HD-tDCS) protocol. Clinical evaluations (e.g., Fugl Meyer, NIHSS), computer-based cognitive assessments (visuo-motor adaptation and AX-CPT attention tasks), and electroencephalography (resting-state and task-evoked EEG) will be carried out at 3 time points: (I) Baseline, (II) Post-tDCS, and (III) Follow-up. The study consists of a four-arm trial comparing the impact on motor recovery of three active anodal tDCS conditions: ipsilesional DLPFC tDCS, contralesional cerebellar tDCS or combined DLPFC + contralesional cerebellar tDCS, and a sham tDCS intervention. The Fugl-Meyer Assessment for the upper extremity (FMA-UE) is selected as the primary outcome measure to quantify motor recovery. In every stimulation session, participants will receive 20 min of high-density tDCS stimulation (HD-tDCS) (up to 0.63 mA/cm2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mathrm{cm}}^{2}$$\\end{document}) with πcm2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mathrm{\\pi cm}}^{2}$$\\end{document} electrodes. Electrode scalp positioning relative to the cortical surface (anodes and cathodes) and intensities are based on a biophysical optimization model of current distribution ensuring a 0.25 V/m impact at each of the chosen targets.DiscussionOur trial will gauge the therapeutic potential of accumulative sessions of HD-tDCS to improve upper limb motor and cognitive dysfunctions presented by middle cerebral artery stroke patients. In parallel, we aim at characterizing changes in electroencephalographic (EEG) activity as biomarkers of clinical effects and at identifying potential interactions between tDCS impact and motor performance outcomes. Our work will enrich our mechanistic understanding on prefrontal and cerebellar contributions to motor function and its rehabilitation following brain damage.Trial registrationClinicalTrials.gov NCT05329818. April 15, 2022.

What should be measured and reported in clinical trials for the treatment of patients with acute pancreatitis? A study protocol for establishing a core outcome set

IntroductionAcute pancreatitis (AP) is characterised by inflammation of the exocrine pancreas, which potentially leads to local complications and organ failure resulting in significant morbidity and mortality. A long-term follow-up by...

Ramsay Hunt Syndrome in Asymptomatic COVID-19 Infection: A Case Report and a Literature Review

(1) Background: COVID-19 infection has affected almost 6 million people worldwide. Geniculate Ganglion Zoster resulting in Ramsay Hunt Syndrome (RHS) has been rarely described in this context. (2) Methods: Here, a case of RHS in the context of asymptomatic COVID-19 infection is reported followed by a literature review of the previously published cases (PubMed research combining “COVID-19” and “Ramsay Hunt Syndrome” or their abbreviations/synonyms, searching for data published at any time till October 2023). (3) Results: Five cases have been previously published (age range: 25–67 years; n = 3 males). Three patients were known to be immunocompetent prior to infection, one was receiving corticotherapy for lung disease, and one had an unspecified immune status. RHS predominantly involved both facial and vestibulocochlear nerves, with one case exclusively involving the facial nerve as the presented case. Regarding facial nerve palsy, three were right-sided (like the current report) and two were left-sided. Two cases were asymptomatic to COVID-19 (like the present patient), one had mild fatigue, and two had classical COVID-19 symptoms preceding RHS symptoms. Workup included serological testing against Varicella Zoster Virus and PCR assays that can detect the viral DNA in saliva, blood, tears, exudates, and cerebrospinal fluid. The treatment combined antiviral and corticosteroid therapies which yielded heterogeneous outcomes that might be related to some demographic and clinical data. (4) Conclusions: RHS rarely occurs in the context of COVID-19. Early recognition is important. Management seems to be similar to the classical condition. Some data may help predict facial nerve recovery.

Data-driven grading of acute graft-versus-host disease

Despite advances in allogeneic hematopoietic cell transplantation, acute graft-versus-host disease (aGVHD) remains its leading complication, yet with heterogeneous outcomes. Here, we analyzed aGVHD phenotypes and clinical classifications in depth in large, multicenter cohorts involving 3019 patients and addressed prevailing gaps by developing data-driven models. We compared, tested and verified these along with all conventional classifications in independent cohorts and found that data-driven grading outperformed conventional grading in Akaike information criterion and concordance index metrics. Data-driven classifications refined aGVHD assessment with up to 12 severity grades, which were associated with distinct nonrelapse mortality (NRM) and confirmed the key role of intestinal aGVHD. We developed an online calculator for physicians to implement principal component-derived grading (PC1). These results provide substantial insight into the evaluation of aGVHD phenotypes and multiorgan involvement, which relegates the exclusive reporting of overall aGVHD severity grades in transplant registries and clinical trials. Data-driven aGVHD grading provides an expandable platform to refine classification and transplant risk assessment.

Outcomes, Prognostic Factors, Predictors for Transformation to High-Grade B-Cell Lymphoma, and Therapeutic Management in Follicular Lymphoma: Real-World Evidence from a Large and Long-Term Latin-American Cohort

Introduction: Follicular lymphoma (FL) is the most common low-grade B-cell NHL, encompassing 20-25% of all NHLs. Although classically indolent, it has heterogeneous biological behavior and variable clinical outcomes. Histologic transformation (HT) to high-grade B-cell NHL compose its natural history, being associated with dismal survival. The therapeutic management of FL and its prognosis are highly dependent on its staging and tumor burden. Based on this premise, the present study aims to describe clinical-laboratory characteristics, assess outcomes, determine predictors of survival and HT, and compare responses between different therapeutic strategies applied in a large cohort of FL patients. Methods: This retrospective and single-center study involved 223 patients with FL grades 1-3A, diagnosed at the University of São Paulo, Brazil, from 2006 to 2022. FL patients were categorized into early-stage disease (I/II) (ES), advanced-stage (AS) (III/IV) with low tumor burden (LTV), and AS with high tumor burden (HTV) according to the GELF criteria. Endpoints included OS, PFS, early-relapse (&amp;lt; 24 months from diagnosis) and HT rates. Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in HR and 95% CI, and a p-value ≤ 0.05 was considered statistically significant. Results: The median age at diagnosis was 60 years (30-98) and 54.8% (121/223) were female. Approximately 15% of cases (33/223) had ES, 18.4% (41/224) had AS-LTV, and 66.8% (149/223) had AS-HTV. BM involvement, leukemic presentation, splenomegaly, and serous effusions occurred in 48.9% (109/223), 11.7% (26/223), 12.6% (28/223), and 21.1% (47/223), respectively. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and involvement of ≥ 4 nodal areas were observed in 44.4% (99/223), 51.6% (115/223), 15.2% (34/223), and 56% (125/223), respectively - Table 1. Forty-nine percent of patients (110/223) were categorized as high-risk according to the FLIPI score. Table 2 summarizes the main outcomes and up-front therapeutic modalities applied in the whole cohort. With a median follow-up of 79.5 months (95% CI: 67.0-92.0) the OS medians were 18 years (95% CI: 14.9-21.1), 11 years (95% CI: 9.2-12.9), and 10.5 years (95% CI: 9.3-11.8) for ES, AS-LTV, and AS-HTV, respectively, p=0.138 Figure 1A. Similarly, the PFS medians were 6.7 years (95% CI: 3.6-9.8), 8.4 years (95% CI: 2.0-14.8), and 3.5 years (95 CI: 1.8-5.3) for ES, AS-LTV, and AS-HTV, respectively, p=0.171 Figure 1B. Early-relapses occurred in 36.3% (81/223) of cases, being 18.2% (6/33), 31.7% (13/41), and 41.0% (62/149) for ES, AS-LTV, and AS-HTV, respectively, p=0.032 Table 2. The overall mortality rate was 29.1% (65/223) for the whole cohort. HT was documented in 16.7% (37/223) of cases, being 3.0% (1/33), 14.6% (6/41) and 20.1% (30/149) for ES, AS-LTV, and AS-HTV, respectively, p=0.053 Table 2. Among patients with AS-HTV, the R-CHOP regimen did not promote increased OS compared to the R-CVP regimen (p=0.415), however it was associated with a substantial increase in PFS (p=0.005) Figure 2. Age ≥ 60 years (HR: 1.06, p&amp;lt;0.001), ≥ 2 comorbidities (HR: 3.85, p=0.014), B-symptoms (HR: 2.35, p=0.015), HT (HR: 2.77, p=0.002) and thrombocytopenia (HR: 2.96, p=0.028) were predictors of poor OS. Similarly, age ≥ 60 years (HR&amp;gt; 1.08, p&amp;lt;0.001), involvelment of ≥ 4 nodal areas (HR: 1.27, p&amp;lt;0.001), and high LDH levels (HR: 1.65, p=0.002) predicted decreased PFS. Additionally, serous effusions (HR: 2.09, p=0.05), albumin &amp;lt; 3.5 g/dL (HR: 2.82, p=0.05), B-symptoms (HR: 2.00, p=0.006), involvement of ≥ 4 nodal areas (HR: 1.21, p=0.014), and BM infiltration (HR: 2.11, p=0 .05) were the main predictors for HT. Conclusion: Although it is characteristically an indolent disease, our study demonstrated that a significant portion of FL patients have shortened survival. Here, we confirmed this prognostic heterogeneity, particularly considering the clinical staging and tumor burden. Therefore, FL patients with AS-HTV had higher HT rates and early-relapses, both classic adverse prognostic markers, as well as a tendency to higher mortality. We also identified clinical and laboratory predictors for HT, which may in a near future direct adapted-risk therapeutic strategies.

Comprehensive Geriatric Assessment and Geriatric Intervention in Older Patients with Newly Diagnosed Lymphoma: A Prospective Study

Introduction: Aggressive and indolent non-Hodgkin lymphomas have a median age at diagnosis of 70 years. Above this age, this population is very heterogeneous and clinical outcomes may be worsened due to patient's frailty phenotype. Very few studies of comprehensive geriatric assessment (CGA) guided approach to care have been published. Methods: A prospective follow-up with baseline CGA were performed in a cohort of consecutive patients older than 70 years with newly diagnosed Hodgkin and non-Hodgkin lymphoma as standard of care. CGA tools are described in Table 1. Clinical outcome has been analyzed in patients diagnosed between May 2016 and March 2021. Results: Ninety-three consecutive patients (55.9% of them were women) were included in this analysis, with a median age of 81.1 years (+/- 5.7). 23 patients (24.7%) were classified as robust (type I), 30 patients (32.3%) as pre-frail (type II) with potentially reversable impairments, 38 patients (40.9%) as frail (type III), and only 2 patients (2.2%) as unfit (type IV). Patients' characteristics are shown in Table 1. All patients received antineoplastic therapy. Treatment modifications were carried out in 64.5% of patients based on CGA results. In the follow-up, with a median follow-up 27.3 months (range 18-74 months), the relapse rate was of 25.8%, with no differences between groups. Overall survival was around 2-fold higher among the fit patients (type I) (42.5 ±19.6 months) than in the disabled patient's group (types III-IV) (23.7 ±20.5 months) (p 0.002) Statistically significant differences in overall survival (p 0.002), response to treatment (p&amp;lt;0.001) and likelihood of increased frailty at the end of treatment (p 0.024) were observed among groups, with type III-IV patients showing worse overall survival (Figure 1), lower response rates, and higher incidence of frailty. Conclusion: Systematic CGA allows physicians to address the functional reserve or resilience in older patients with lymphoma in the need of antineoplastic treatment. A frailty-guide approach to care may allow to improve clinical outcomes in this group of high-risk patients.

Genetic and Cytometric Characteristics of Pediatric B-Other Acute Lymphoblastic Leukemia Cohort

Background: According to WHO-HAEM5, the majority of precursor B-cell acute lymphoblastic leukemia (B-ALL) cases are classified based on cytogenetic testing according to ploidy changes or well-known chromosomal rearrangements. Approximately 30% of patients with B-ALL, however, display none of the major chromosomal abnormalities. This population is classified together as B-other-ALL, a highly diverse subgroup with heterogenous genetic profiles, clinical characteristics, and outcomes. Recent advances in gene expression profiling and sequencing allowed to identify multiple genetic drivers that confer distinct clinical and prognostic features in B-other ALL resulting in better understanding of this subgroup. Among them, B-ALL with specific gene expression signatures (i.e. BCR-ABL1-like and ETV6-RUNX1-like) have been described and included in the classification. However, due to the complex mechanisms underlying the phenotype, standard molecular and cytogenetic workup is not sufficient to make a diagnosis and there is still no universally accepted definition or diagnostic algorithm. Therefore, there is a need to improve our understanding of genetic aberrations driving B-other ALL, screen for unknown lesions, and associate these findings with clinical picture. Aims: Genetic and cytometric characteristics of pediatric B-other ALL cohort treated in a single center in Poland to evaluate population frequencies of known ALL subtypes, genetic aberrations, immunophenotypes, and evaluate their associations with outcome and clinical and demographic parameters. Methods The study included 54 consecutive children (aged 1-18 years) diagnosed in 2014-2022 with B-other ALL, i.e. excluding hyperdiploidy, hypodiploidy, ETV6-RUNX1, BCR-ABL1, TCF3-PBX1, and KMT2A-fusions. In all samples, targeted RNA sequencing using FusionPlex Acute Lymphoblastic Leukemia library preparation kit (ArcherDx) and digital MLPA using SALSA digital MLPA assay were performed. The samples were sequenced on Illumina MiSeq platform. RNAseq data were analyzed using Archer Analysis software v7.0 and aimed to identify fusions, point mutations and expression levels in 81 genes, including fusion transcripts with unknown partners. MLPA data were analyzed using Coffalyser digitalMLPA software. All novel in-frame fusion transcripts were confirmed with Sanger sequencing. Cytometric evaluation included both standard and extended panel of immunophenotypic markers, i.e. CD45, CD3, CD19, CD34, HLA-DR, phospho-TYR, phospho-STAT3, phospho-STAT5, phospho-CRKL, CRLF2 CD127, CD115, CD25, SOCS1, BLNK, CD97, CD99, CD140A, CD140B, and viability stains (FVS780 and/or 7AAD). Clinical data was obtained retrospectively from medical records. Results: The cohort included 35% of BCR-ABL1-like cases, 2% ETV6-RUNX-like, and 5,5% PAX5 rearranged (1 fusion, 2 mutations). Mutations activating RAS/RAF-MAPK signaling were observed in 64% of cases and spread across all subtypes. JAK-STAT class aberrations were observed in 37% cases whereas ABL-class aberrations - in 7,2%. Three novel in-frame fusion transcripts were detected, including two lesions affecting cytokine/kinase signaling related to BCR-ABL1-like phenotype (TCOF3/PDGFRB and CD74/PDGFRB) and one affecting DNA repair mechanisms (SSBP2/CHD1). Novel aberrations were associated with poor prognosis. In addition, HOOK3/FGFR1 fusion transcript previously described for other hematological malignancies, but not in ALL, was detected in a single subject. Except for CRLF2, none of the single markers alone allowed to distinguish new subtypes of ALL. However, multiparameter statistical analysis of the data allowed to build a Ph-like ALL predictor for the identification of Ph-like ALL cases Conclusion: Our study shows population-based frequencies of novel ALL subtypes, including both recurrent and novel genetic aberrations. This data widens our knowledge on the interplay between molecular aberrations and clinical course of the disease and provides clues for diagnostics optimization.

Risk Stratification of Patients with RUNX1-mutated Acute Myeloid Leukemia

Mutations in RUNX1 ( RUNX1mut) occur in ~15% of intensively treated AML cases. RUNX1mut have no specific hotspot and various types of alteration are observed. The European LeukemiaNet (ELN) risk stratification assigns adverse prognosis to RUNX1mut if they do not co-occur with favorable-risk genotypes. Considering the biological complexity of RUNX1 it seems implausible that all alterations have similar consequences. Using clinical and genetic variables, we developed a prognostic risk stratification model for ELN adverse-risk RUNX1mut AML patients. We combined data from five groups, totaling 609 patients with intensively treated RUNX1mut AML, to develop the model. Our training set included 448 patients treated on trials of the AML Cooperative Group (AMLCG; Herold et al, Leukemia, 2020; (n=178)), AML Study Group (Gerstung et al, NEJM, 2016; (n=116)) and Study Alliance Leukemia (n=154). Patients from the Munich Leukemia Laboratory (MLL; (n=107)) and of the Alliance group (trials NCT00048958, NCT00899223, NCT00900224; Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; (n=54)) served as independent validation cohorts. Additionally, 955 patients without RUNX1mut treated on AMLCG trials served as controls. Patients with t(15;17), prior treatment, or RUNX1mut with co-occurring favorable-risk genotypes according to ELN 2017 were excluded. Differences between RUNX1mut patients and controls were investigated using univariate logistic regression. Testing was performed using likelihood ratio tests and adjusted for study group. Univariate analyses were adjusted for multiple testing using the Benjamini-Hochberg procedure. We obtained risk prediction models using multivariate Cox regression. Missing values were imputed using the missForest approach. Model selection was performed using forward selection based on the Bayesian information criterion. Cut-offs were based on the 25 th- 50 th- and 75 th-percentile score values obtained in the training data. Performance was evaluated using Kaplan-Meier curves. For internal validation Harrell's C index was estimated using cross-study validation. For external validation, the final risk prediction models were separately applied to the external datasets. RUNX1mut were more common in older, male patients and sAML (table). White blood cells, lactate dehydrogenase and bone marrow blasts were lower in RUNX1mut patients. Mutations in several myelodysplasia-related genes were enriched in RUNX1mut patients ( ASXL1, BCOR, BCORL1, EZH2, KMT2A, PHF6, and STAG2, SF3B1, SRSF2, and U2AF1), whereas DNMT3A, NPM1 and FLT3 were more frequently altered in controls. A strong association with mutations of the splicing factor complex was identified (49% vs. 13%, p&amp;lt;0.0001). Contradicting previous reports, we found no association with IDH mutations. The risk prediction score we obtained for OS is as follows: 0.03054 x age (y) + 0.74996 x adverse MRC + 0.43779 x FLT3-ITD + 0.00317 x WBC count (10^9/L) - 0.00158 x platelet count (10^9/L) + 0.37401 x NRAS-mutation, where the obtained cut-off values are: &amp;lt;1.592 (low risk); 1.592 to 2.303 (moderate risk) &amp;gt;2.303 (high risk). Binary variables are coded as 0 or 1. Harrell's C index estimated using internal validation was 0.6. Kaplan-Meier curves estimated using the training set suggest strong differences in survival between the risk categories. Median overall survival (OS) was 2.5, 1.0 and 0.6 years for low-, intermediate-, and high-risk. External validation using the Alliance cohort shows similar results (Figure). Results obtained for the MLL cohort show smaller differences. However, we still observe clear separation of risk groups with a significant difference between low- and high-risk groups (adjusted p-value: 0.0266). Scores for relapse-free survival (RFS) as well as for OS and RFS censored for allogeneic transplant show similar results. We analyzed a large collection of intensively treated RUNX1mut AML patients and observed heterogenous outcomes that could be predicted by applying few variables (age, MRC-score, FLT3/NRAS mutation-status, and WBC/platelet count). The OS of RUNX1mut high-risk patients is discouraging, highlighting the unmet need of these patients. In addition, our work demonstrates that ELN risk groups can be further stratified and that integrated approaches using routinely available variables can further advance risk prediction.

Patterns of Care and Prognostic Modeling Following Follicular Lymphoma Transformation to Aggressive B-Cell Lymphoma: An Analysis from the LEO Consortium

Introduction: Histologic transformation (HT) from follicular lymphoma (FL) to an aggressive lymphoma is infrequent but has unfavorable outcomes. Sarkozy et al. (J Clin Oncol, 2019) reported that approximately half of FL-related deaths within the first decade of diagnosis occurred following HT. Our recent analysis showed heterogeneous outcomes with median overall survival (OS) of 61 months (Day et al., ASH, 2022). Prognostic tools post HT would be clinically useful but development has been limited by small cohort sizes. Factors previously associated with outcomes following HT have included age, time to progression, prior therapy, anthracycline exposure, and early HT. Utilizing the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real World Evidence (CReWE), we describe patterns of care and evaluate other prognostic factors following HT. Methods: This multicenter observational cohort consists of prospectively enrolled patients in the LEO Cohort, and patients with HT retrospectively identified at LEO centers. Patients diagnosed with biopsy proven grade 1-3A FL at diagnosis, and a subsequent biopsy showing HT to an aggressive lymphoma (FL grade 3B, diffuse large B cell lymphoma [DLBCL], or high-grade B cell lymphoma [HGBCL]) between 2002-2022, were eligible for the study. Patients with a component of FL grade 3B, DLBCL, or HGBCL at diagnosis were excluded. HGBCL was defined as double or triple hit or another aggressive subtype. OS was defined as the time from HT until death from any cause and calculated via Kaplan-Meier. Associations between clinical factors at time of HT and/or diagnosis and OS were evaluated using Cox models. Cause of death was evaluated using a competing risk approach. Results: Overall, 328 patients were confirmed with HT during the study period, 41% were female, and the median age at HT was 63 years (interquartile range [IQR] 56-70). The median time from diagnosis to transformation (TDT) was 35 months (IQR 12-66). At HT, 88% had advanced stage disease (III-IV) and LDH was elevated in 49%, while few patients exhibited B symptoms (5%) and ECOG performance status was &amp;gt;2 in 9%. 23% did not receive systemic therapy prior to HT. For those with prior therapy, the median time from prior therapy to HT was 15 months (IQR 7-39). The most frequent treatment regimens following HT were CD20-CHOP (42%), followed by platinum-based salvage therapy (20%), R-EPOCH (10%), CD20-Benda (8%), R-Mono (4%), and R-Gem-Ox (3%). 50 (15%) patients underwent consolidation with autologous stem cell transplant, 3 underwent allogeneic transplant (30 platinum-based, 15 CD20-CHOP, 5 R-EPOCH, 3 Other), and 2 received CAR T-cell therapy (Figure 1). After median follow-up of 85 months from HT, 170 patients had died; 5-year OS was 52% and median OS was 65 months (95% CI: 55-107). Among 160 patient deaths, cause was most often lymphoma-related (progression, n=107 [63%]; therapy-related, n=14 [7%]) compared to non-lymphoma (n=20, 13%) or missing/unknown causes (n=29, 17%). Clinical factors at the time of HT that were associated with worse OS include: ECOG PS &amp;gt;2, age ≥70, IPI 3-5, and shorter TDT (&amp;lt;24 months), hemoglobin &amp;lt;10 g/dl and elevated LDH. A transformation to HGBCL was also associated with inferior OS (Table 1). OS did not significantly differ by gender, BMI, stage, presence of B-symptoms, absolute lymphocyte count, number of extranodal groups, presence of bulky disease at HT, or response to prior FL treatment. Factors at the time of FL diagnosis that were associated with decreased OS after HT included FLIPI score 3-5 (high risk), FLIPI 2 (moderate risk), and FL grade 3A at diagnosis. Exposure to any systemic therapy for FL prior to HT was associated with shorter OS, with the worst outcomes in patients receiving an anthracycline prior to HT. POD24 to frontline immunochemotherapy was associated with inferior OS after HT (Table 1). Conclusions: Patterns of care in Transformed FL are heterogeneous and vary greatly in intensity. These data confirm previous reports that age, early HT, and any systemic therapies prior to HT are negative prognostic indicators for OS. At HT elevated LDH, low hemoglobin, POD24 status, poor performance status, and HT to HGBCL were associated with poor outcomes following HT. These data provide a basis for future prognostic indices to identify patients with highest risk of lymphoma related mortality for whom study of novel treatments is greatly needed.

Update of a Phase II Trial of Guadecitabine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Under the International Working Group 2023 Criteria

Introduction: Guadecitabine is a dinucleotide of decitabine which has shown high response rates in higher-risk myelodysplastic syndrome. In this update we seek to evaluate the performance of the International Working Group (IWG) 2023 criteria in a prospective, systematically annotated clinical trial. Methods: Patients older than 18 years old with higher-risk MDS/CMML as defined by the International Prognostic Scoring System - Revised (IPSS-R), or those with more than 10% bone marrow blasts were eligible. Guadecitabine was administered at a dose of 60 mg/m2 subcutaneously daily for 5 days every 28 days. We re-classified patients by World Health Organization 2022, calculated IPSS-Molecular (IPSS-M) scores and clinical responses were reassessed under the IWG-2023 criteria and compared to IWG-2006. Results: From 2014 to 2018, 82 patients with MDS and 18 patients with CMML were enrolled and treated. Median age was 69 (IQR 62.5 - 75), 62% were male, 38.4% had complex karyotype, 86.6% were categorized as IPSS-M high or very-high risk. Additionally, 33.7% were TP53 mut, 21.4% were TP53 multi-hit. Forty percent of patients were classified as MDS-IB-2, 21.4% as MDS-biTP53, and 17.1% as MDS-IB1. Common mutations were TP53 (38.5%), ASXL1 (22%), DNMT3A (18%) in MDS. ASXL1 (61%), TET2 (61%), NRAS (28%), and SRSF2 (22 %) for CMML patients. Most common treatment-emergent adverse events were fatigue (79% G1-2, 6% G3), nausea (37% G1), injection site reaction (29% G1), and constipation (23% G1). Grade 3 events were febrile neutropenia (32%), infection (25%), and thrombocytopenia (16%). Eight-week mortality was 4%. Ninety-six patients were evaluable for response. The median number of cycles was 5 (IQR:3-8) number of cycles to best response was 3 (IQR:2-5). Median overall survival (mOS) was 16.8 months. Survival was response-dependent with mOS in months being 32, 23.3, 15.5 and 8 for complete remission (CR), mCR (marrow complete remission), HI (hematologic improvement) and NR (no response) by IWG 2006 criteria (Figure 1). By IWG-2023 overall response rate (ORR) was 52%, with a complete remission (CR) of 29%, 3% with complete remission with bilineage limited hematologic recovery (CRLbi), 11% with CRL with unilineage recovery (CRLuni), 5% complete remission with incomplete hematologic recovery (CRh), and 4% had hematologic improvement (HI). Patients classified as mCR by 2006 criteria (n=30) were reclassified as CR (6.6%), CRLbi (6.6%), CRLuni (33.3%), CRh (16.6%), HI (6.6%), NR (26.6%),and PR (3.3%). Patients in mCR who underwent allogeneic-stem cell transplant (allo-SCT) (n=9) had a mOS of 46 months, compared to 14.4 months to those who did not (log-rank, p &amp;lt; 0.005). Median OS in months was 32.8, 28.6, 17.5, 7.8, 16.8, and 9.2 for CR, CRLbi, CRLuni, CRh, HI, and NR, respectively (log-rank &amp;lt; 0.005). In a multivariate analysis TP53 multi-hitwas the only factor significant in prognosticating response (p = 0.023) and overall survival (p =0.03). Discussion: In this report we examine the performance of the IWG 2023 criteria in a prospective clinical trial. Patients classified as mCR had significantly heterogenous outcomes which were more precise when re-classified by IWG-2023. Patients in mCR may still benefit from allo-SCT. These criteria also demonstrate response-dependent overall survival outcomes. TP53 multi-hitwas predictive of response and overall survival. This analysis shows the improved accuracy of the IWG 2023 model in stratifying clinical responses and survival. These may serve as future benchmarks for drug development and trial design. Figure 1. Overall survival by A) IWG 2006 criteria and B) IWG 2023 criteria.

Income inequality and export‐oriented commercialization in colonial Africa: Evidence from six countries

AbstractLimited knowledge of African historical inequality trajectories hampers our understanding of inequality outcomes today and leads to a major omission in debates about global inequality. Economies in colonial Africa were characterized by a process of export‐oriented commercialization. We hypothesize that this process itself, the capital intensity of the commodities produced, and the relative importance of European and Asian expatriates and settlers in the economy shaped heterogeneous inequality outcomes. We evaluate these hypotheses using 33 social tables from six predominately agricultural countries between 1914 and 1969. Social tables capture income across the full distribution, aggregated in classes. We assess and improve the commensurability of the different social tables. We then apply different inequality metrics, and find that Gini and Theil coefficients and Inequality Extraction Ratios rose over time. Gini coefficients moved in conjunction with the real value of commodity exports per capita. Using Theil decompositions, we observe a trade‐off between inequality among African classes on the one hand, and among non‐Africans and between races on the other. Whenever present, non‐Africans captured a large share of the export profits. Inequality patterns towards the end of the period suggest that capital‐intensive commodities were associated with higher levels of inequality in the agricultural sector.

High Levels of NfL, GFAP, TAU, and UCH-L1 as Potential Predictor Biomarkers of Severity and Lethality in Acute COVID-19.

Few studies showed that neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tubulin-associated unit (TAU), and ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) may be related to neurological manifestations and severity during and after SARS-CoV-2 infection. The objective of this work was to investigate the relationship among nervous system biomarkers (NfL, TAU, GFAP, and UCH-L1), biochemical parameters, and viral loads with heterogeneous outcomes in a cohort of severe COVID-19 patients admitted in Intensive Care Unit (ICU) of a university hospital. For that, 108 subjects were recruited within the first 5days at ICU. In parallel, 16 mild COVID-19 patients were enrolled. Severe COVID-19 group was divided between "deceased" and "survivor." All subjects were positive for SARS-CoV-2 detection. NfL, total TAU, GFAP, and UCH-L1 quantification in plasma was performed using SIMOA SR-X platform. Of 108 severe patients, 36 (33.33%) presented neurological manifestation and 41 (37.96%) died. All four biomarkers - GFAP, NfL, TAU, and UCH-L1 - were significantly higher among deceased patients in comparison to survivors (p < 0.05). Analyzing biochemical biomarkers, higher Peak Serum Ferritin, D-Dimer Peak, Gamma-glutamyltransferase, and C-Reactive Protein levels were related to death (p < 0.0001). In multivariate analysis, GFAP, NfL, TAU, UCH-L1, and Peak Serum Ferritin levels were correlated to death. Regarding SARS-CoV-2 viral load, no statistical difference was observed for any group. Thus, Ferritin, NFL, GFAP, TAU, and UCH-L1 are early biomarkers of severity and lethality of SARS-COV-2 infection and may be important tools for therapeutic decision-making in the acute phase of disease.

Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Cardiac Laterality: Surgical Results of Right Atrial Isomerism.

Right atrial isomerism (RAI) is a complex entity with varying diagnostic and treatment outcomes due to its rarity. Treatment options range from palliative to corrective surgeries, resulting in heterogeneous outcomes. The aim of this study was to analyze the results obtained after cardiac surgery in patients with RAI. A retrospective study was conducted, including patients diagnosed with RAI who underwent cardiac surgery. Their follow-up was from 1 January 2010 to 31 March 2020. Demographic characteristics and perioperative conditions were described. Thirty-eight patients were included, the median age was 4 years (IQR 2-9.2) and 57.9% were men. The main diagnoses were atrioventricular canal (63.2%) and pulmonary stenosis (55.3%). The most common surgical procedures were modified Blalock-Taussig shunt (65.8%) and total cavopulmonary connection with an extracardiac conduit fenestrated without cardiopulmonary bypass (15.9%). We did not find any factors associated with negative outcomes in these patients. The overall survival was 86.8%, with a better outcome in those who did not require reintubation (log rank, p < 0.01). The survival of RAI was similar to other centers. Individuals with RAI should be evaluated rigorously to determine an adequate repair strategy, considering high morbidity and mortality.