bluuebunny/crossref_metadata_2025 huggingface dataset:
In-depth analysis of responders in the phase 3 PhALLCON trial of ponatinib vs imatinib in newly diagnosed Ph+ ALL.
Authors: Jabbour Elias , Kantarjian Hagop M. , Aldoss Ibrahim , Montesinos Pau , Leonard Jessica Taft , Gomez-Almaguer David , Baer Maria R. , Gambacorti-Passerini Carlo , McCloskey James K. , Minami Yosuke , Papayannidis Cristina , Rousselot Philippe , Vachhani Pankit , Wang Eunice S. , Yang Lin , Hennessy Meliessa , Vorog Alexander , Patel Niti , Ribera-Santasusana Jose-Maria
Published: June 2024

6533

Background: Ponatinib, a third-generation BCR::ABL TKI, has potent activity against all clinically relevant BCR::ABL1 variants, including T315I. PhALLCON (NCT03589326), a phase 3 trial comparing frontline TKIs in adults with Ph+ ALL, met its primary endpoint with a higher rate of minimum residual disease–negative (MRD-neg) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4%/16.7%; P=0.002). Here, we report response rates of MRD-neg at any time and PFS by age and BCR::ABL1 variant subgroups. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg QD reduced to 15 mg QD upon MRD-neg CR at or after EOI) or imatinib (600 mg QD) plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles), followed by single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. Hematopoietic stem cell transplant (HSCT) was per investigator’s discretion. Post hoc analyses compared MRD-neg ( BCR:: ABL1IS ≤0.01%; MR4) at any time and PFS (any-cause death, failure to achieve CR by EOI, relapse from CR, or failure to achieve/loss of MRD-neg) by age (</≥65 y) and BCR:: ABL1 variant (p190/p210). Data cutoff: Aug 12, 2022. Results: In the population of randomized patients (pts) with p190/p210 confirmed by central lab (n=232; 154/78 ponatinib/imatinib; median follow-up 20.1 mo), 68% vs 50% in the ponatinib vs imatinib arms were MRD-neg at any time, with similar benefit of ponatinib across age and variant subgroups (Table). Median PFS was more than twice as long with ponatinib vs imatinib across subgroups (Table). Pts achieving MRD-neg at any time were less likely to have HSCT with ponatinib vs imatinib (32%/56%). Among 107/42 pts without HSCT, exposure was >2-fold longer in the ponatinib vs imatinib arms (median 12.8/5.1 mo) with comparable rates of arterial occlusive (3%/2%) and venous thromboembolic events (11%/12%), and discontinuations due to TEAEs (13%/14%). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy for frontline treatment of Ph+ ALL, with higher rates of MRD-neg at any time, substantially longer PFS across age and BCR::ABL1 variant subgroups, and a safety profile comparable to imatinib. Clinical trial information: NCT03589326 . [Table: see text]
Evaluation of treatment outcomes with CPX-351 in adults with AML: A meta-analysis.
Authors: Sandhu Michael , Ashok Kumar Prashanth , Shi Charles W , Sidhu Jasleen , Ombada Mulham , Parekh Deevyashali , Ghimire Krishna Bilas , Gentile Teresa
Published: June 2024

6540

Background: CPX-351 is a liposomal formulation of cytarabine and daunorubicin which has shown survival benefit when compared to 7+3 in older adults with myelodysplasia-related (AML-MRC) and therapy-related AML (t-AML). Aiming to investigate the clinical efficacy of CPX-351 against 7+3 in adults with AML, we performed a meta-analysis. Methods: A systematic search with controlled vocabulary encompassing AML, CPX-351 and 7+3 was conducted in PubMed, Embase, Scopus, and Cochrane on November 1, 2023 with no search restrictions. 3461 were found; 2581 were left after duplicates were removed using Mendeley 1.19.8. Remaining records were imported into Rayyan and independently screened by 2 reviewers. 8 studies were included in the analysis as they provided data for both CPX-351 and 7+3. 17 studies only including CPX-351 were identified. RevMan was used to analyze the Odds Ratio (OR) with 95% Confidence Interval (CI), derived from random effects (RE) model with Mantel-Haenszel (MH) method. Results: We identified 8 studies comparing CPX-351 to 7+3, encompassing a total of 1368 total patients: 44% (604/1368) received CPX-351, 56% (764/1368) received 7+3. Most patients had AML-MRC or t-AML. The median age in the CPX-351 group was 66 (range 58-67) and in the 7+3 group was 67 (range 58-67). The median overall survival grossly favored CPX-351 with 10.3 months (range 8.8-22 months) compared to 6.2 months (range 4.6-12 months) in 7+3. The OR of complete remission (CR) for CPX-351 versus 7+3 using the RE model was 1.66 (CI=1.15-2.39, p=0.006, I2=55%). Similarly, the OR of patients undergoing hematopoietic stem cell transplantation (HSCT) for CPX-351 versus 7+3 was 1.52 (CI=1.01-2.30, p=0.05, I2=47%). Including the additional 17 studies with CPX-351, the overall CR rate for all patients was 49%. Average 30-day mortality with CPX-351 was 4.9%. Conclusions: From our analysis, the OR of attaining CR and HSCT were shown to be significantly improved with CPX-351 when compared to conventional 7+3 chemotherapy in adult patients with AML. Both groups had similar median age, and patients in the CPX-351 arm had longer median overall survival. Our meta-analysis highlights that while CPX-351 achieves CR/HSCT at a higher rate than 7+3, data in younger populations (<60 years old) and patients with de novo AML are sparse. Heterogeneity between studies and lack of mutational analysis are limitations of our study. [Table: see text]
Treatment of acute myeloid leukemia with Orca-T.
Authors: Pantin Jeremy Mark , Patel Sagar S. , Faramand Rawan , Gandhi Arpita , Salhotra Amandeep , Oliai Caspian , Srour Samer Ali , Dholaria Bhagirathbhai R. , Pavlova Anna , McClellan J. Scott , Agodoa Irene , Li Ai , Fernhoff Nathaniel , Abedi Mehrdad , Meyer Everett
Published: June 2024

6552

Background: Allogeneic hematopoietic stem cell transplants (alloHSCT) offer a potential curative treatment for many hematological cancers, however, traditional alloHSCT is associated with high mortality from complications including infection, graft versus host disease (GvHD) and relapse. Orca-T is an investigational allogeneic T-cell immunotherapy that includes stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. In this sub-group analysis, we evaluated the safety and efficacy of patients with acute myeloid leukemia who were treated with Orca-T. Methods: Data from 37 patients with the diagnosis of acute myeloid leukemia (AML) in CR/CRi who received myeloablative conditioning with busulfan, fludarabine, and thiotepa (BFT) followed by Orca-T by 6/30/22 as part of a multicenter phase 1b single-arm trial (NCT04013685) are reported here. Patients enrolled in the phase 1b trial who did not meet these criteria were not included in this analysis. Patients received BFT prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus, and had an 8/8 related or unrelated matched donor. Donors were matched via DNA-based high-resolution typing of HLA-A, -B, -C, and -DRB1. Results: Orca-T was successfully manufactured at a centralized GMP facility, distributed, and infused at study sites throughout the U.S. Vein-to-vein time (i.e. time between end of donor apheresis to start of recipient’s Orca-T infusion) was < 72 hours for all patients, with the majority < 60 hours. Median age was 51 years, 49% were female and 16% were of Hispanic or Latino ethnicity. Twenty-three (62%) had matched related donors and 14 (38%) had matched unrelated donors. Baseline HCT-CI score was 3 and 4 in 27% and 8% of the patients, respectively. The majority had intermediate DRI scores (89%) and 41% were MRD positive at baseline. The median duration of follow-up was 14 months. Relapse-free survival at 12 months was 81.4% (95% CI: 62.9, 91.2). Non-relapse mortality and overall survival were 0% and 100% at 12 months, respectively. Conclusions: These encouraging results suggest that investigational Orca-T could represent a reduced toxicity alternative to conventional alloHSCT. This combination of Orca-T with myeloablative BFT led to > 80% RFS without treatment related mortality, and 100% overall survival in this AML patient population. These outcomes were accomplished with consistent and reliable cell manufacturing and distribution of Orca-T at a national scale. A multi-center randomized controlled phase 3 trial comparing Orca-T to SOC, utilizing BFT or TBI-based conditioning, will complete enrollment during the first half of 2024. (NCT05316701). Clinical trial information: NCT04013685 .
Impact of pneumocystis pneumonia on clinical outcomes in patients with lung malignancy compared to other malignancies.
Authors: Olafimihan Ayobami Gbenga , Jackson Inimfon , Ozogbo Stanley , Olatunji Gbolahan , Kokori Emmanuel , Aderinto Nicholas , Fawehinmi Praise , Mullane Michael Russell , Sueldo Alexandra , Vallejo Alejandro
Published: June 2024

e20001

Background: Pneumocystis pneumonia (PCP) is an opportunistic infection that causes significant morbidity and mortality in cancer patients. Although infrequent in solid malignancies, limited studies suggest that PCP portends a worse outcome in patients with lung cancer. We examined hospitalization outcomes for PCP among patients with lung cancer relative to other malignancies. Methods: A retrospective cohort analysis using the Nationwide Inpatient Sample (NIS) database (2010-2019) was conducted. Using ICD-9 and ICD-10 codes, cancer patients admitted for PCP were identified and stratified based on their diagnosis of lung cancer versus other cancer types. Primary outcomes were inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included odds of mechanical ventilation, ICU care, bronchoscopy, and palliative care. Statistical analyses were performed using t-tests, univariate and multivariate logistic regression. Results: Among 5,408 hospitalizations for PCP in cancer patients, 10.6% had a diagnosis of lung cancer and 89.4% had other cancer types. Lung cancer patients were older (mean age: 66 vs 62 years; p = 0.001) and had a higher Charlson comorbidity burden (>2) compared to those with other cancers (69.8 vs 34.2%; p<0.001). 31% of lung cancer patients admitted for PCP died compared to 16% of patients with other cancer types ( p<0.001). Multivariate regression analysis showed that hospitalized PCP patients with lung cancer had two-fold higher odds of hospital-associated mortality relative to those with other cancer types (adjusted odds ratio (aOR): 2.2; 95% confidence interval (CI): 1.39-3.37; p = 0.001). Both cohorts had similar LOS (aOR: 0.86; P=0.61; 95% CI: 0.5-1.5) and THC (β -15,377; p=0.113; 95% CI= -34,407-3,653). Among secondary outcomes, lung cancer patients admitted for PCP had higher odds of mechanical ventilation (25.3 vs 17.7%; aOR: 1.61; p = 0.046) and palliative care utilization (24 vs 13%; p=0.002). Conclusions: Pneumocystis pneumonia is associated with significantly higher inpatient mortality among patients with lung cancer compared to other cancers. These patients also had higher rates of mechanical ventilation and palliative care utilization. Health care providers need to maintain a high index of suspicion to facilitate early diagnosis and intervention in order to mitigate adverse outcomes.[Table: see text]
Anticoagulation and lung cancer mortality: A National Inpatient Sample analysis 2020.
Authors: Kasire Sripada Preetham , Mylavarapu Maneeth , Neupane Karun
Published: June 2024

e20003

Background: Cancer can induce a hypercoagulable state, which can lead to clinically apparent venous thromboembolism. Studies have established a relationship between hypercoagulable state and lung cancer. However, the prognosis of lung cancer patients on anticoagulation is not well studied. Furthermore, the effect of anticoagulation has remained ambiguous due to the risk of bleeding, and the decision is made clinically. In this study, we aim to determine the impact of long-term anticoagulation on mortality in patients with lung cancer hospitalizations. Methods: This is a retrospective analysis with data extracted from National Inpatient Sample (NIS) data from 2020. All the hospitalizations with lung cancer using the ICD 10 (International Classification of Diseases tenth revision) codes were included. The study cohort was grouped into those who were on long-term anticoagulants and those who were not. Demographics (age, race, sex, region, and hospital size), co-morbidities, and hospitalization costs were compared between the two groups of patients. As the primary outcome, the odds of mortality were analyzed. A p < 0.05 was considered statistically significant. Results: Out of 378470 patients who were hospitalized with lung cancer in 2020, 51,100 (13.5%) were on long-term anticoagulation therapy. The anticoagulation group was relatively older (median age, 71.64 years vs. 69.15 years), male predominant (54.69% vs 50.69%), and predominantly white (81.39% vs 76.49%). The anticoagulant group had a higher prevalence of prior history of DVT/PE (31.78% vs. 4.31%) and a higher Charleston co-morbidity index score (6.08 vs 5.85). The adjusted odds ratio of mortality in the anticoagulation group was 0.77, 95% CI (0.71-0.84, p < 0.0001). Furthermore, the average length of stay was approximately half a day shorter, and the total cost of hospitalization was $12,539 less in the anticoagulation group. Conclusions: This NIS study showed statistically significant findings, indicating that lung cancer patients who are on anticoagulation experienced lower odds of mortality, shorter length of stay, and lesser costs of hospitalization. However, the anticoagulation group was found to have a higher prevalence of co-morbidities and a higher co-morbidity index. Hence, further research with prospective studies needs to be done to understand the reasons behind these associations.
Reducing the risk of grade 3 or greater radiation pneumonitis after radical radiotherapy to the lung.
Authors: Yan Yujie , Kang Jingjing , Yang Shuangyan , Qian Cheng , Zhang Ying , Yuan Xiaoshuai , Hu Min , Zhu Yaoyao , Jiang Chenxue , Hu Minren , Zhao Ruifeng , Zhao Lan , Yaping Xu
Published: June 2024

e20008

Background: Radiation pneumonitis (RP) is the most common adverse response in patients with lung cancer receiving thoracic radiotherapy. Higher grade RP is more likely to lead to mortality and poor quality of life, which could be abated by rigorous treatment standards formulated with individualized clinical characteristics. In this study, we aimed to identify the best clinical prognostic model for evaluating patients with lung cancer after radical radiotherapy. Methods: We collected information of RP patients in recent years and established the new consensus on the diagnosis and treatment of radiation-related pneumonitis. In a nutshell, clinical data of patients treated with radical radiotherapy were collected from August 2020 to August 2022, and part of patients from August 2021 to August 2022 was been intervented by treatment methods. The interventions included limited irradiation of the planning target volume (PTV), individualized lung dose limitation, and standardized steroid therapy. Clinical characteristics including baseline and treatment data were obtained from 693 patients, including 623 patients in the training cohort and 70 patients in the test cohort. Three models were built using different screening methods, including multivariate logistics regression (MLR), backward stepwise regression (BSR), and random forest regression (RFR), to evaluate their prognostic power. Overoptimism in the training cohorts was evaluated by four validation methods including hold-out, 10-fold, leave-one-out, and bootstrap methods, and extra data were used to evaluate the predictive performance of the model. Model calibration, Decision curve analysis (DCA), and evaluation of the nomograms for the three models were completed. Results: The incidence of RP was significantly decreased after the interventions compared to before (68.80% vs. 59.56%, P < 0.05), and the probability of grade 3 or higher RP also decreased from 11.97% to 6.67% (P < 0.05). A model of intervention, interstitial lung disease (ILD), concurrent chemoradiotherapy, standardized steroids, carbon monoxide diffusing capacity (DLCO) > 86.9%, and total lung volume exceeding 5 Gy (V5) > 35.2% for the radiological parameter had the best discriminative ability with an area under the curve of 0.963 (95% CI: 0.938–0.989) in the training chort . The calibration curve showed good agreement between the predicted and actual values, and the DCA showed a positive net benefit for the final model based on the nomogram. Conclusions: The implementation of standardized interventions for the prevention and treatment of RP accompanied with standardized use of steroids resulted in a significant decrease in the incidence of grade 3 or higher RP. Early intervention and methods for reducing the complications of high-dose steroids will be explored in future work.
Constructing a machine learning-based non-invasive liquid biopsy model for lung cancer detection via miRNA sequencing.
Authors: Hsieh Jason Chia-Hsun , Hsieh Tsung-Ting , Lee Ko-Han , Tu Yu-Hsuen , Chang Po-Ya , Wu Eva Yi-Hsuan , Chang Yu-Chuan , Lu Yen-Jung
Published: June 2024

e20014

Background: Lung cancer is a prevalent and fatal disease, ranking second among common cancers globally. Early detection and prompt treatment significantly improve survival rates for most cancers, including lung cancer. Presently, low-dose computed tomography (LDCT) is a widely accepted tool for early lung cancer screening. However, it exhibits a high false-positive rate of up to 95%, resulting in overdiagnosis and causing anxiety among patients awaiting diagnosis results. Therefore, investigating alternative effective interventions would provide physicians with additional tools for evaluating lung cancer and making informed decisions. This study employs the concept of liquid biopsy, utilizing next-generation sequencing (NGS) to gather miRNA profiles, aiming to construct a machine learning-driven model for the detection of lung cancer. Methods: We assembled case-control cohorts, comprising 74 lung cancer cases (stage 0-II: 66; III-IV: 8) and 74 age- and gender-matched healthy control subjects, recruited from Chang Gung Memorial Hospital in Linkuo, Taiwan. Plasma derived from whole blood was collected from each subject before any cancer surgery or treatment. Subsequently, we extracted miRNA from the plasma and constructed libraries using the QIAseq miRNA Library kit for miRNA sequencing conducted on the Illumina NextSeq550 platform. RNA-seq data analysis was performed on miRNA sequencing data using the QIAGEN RNA-seq Analysis Portal 5.0. The count per million base (CPM) derived from the quantification results was utilized for differential analysis and constructing the machine learning model. To assess the model's performance, we reserved 10% of the subjects for isolated testing, while the remaining 90% underwent 10-fold cross-validation (CV). Results: The final model, built using logistic regression with six significant differentially expressed miRNAs (fold change > = 2 and P-value < = 0.01), achieved optimal performance. The 10-fold CV demonstrated accuracy: 97.73%; sensitivity: 98.48%; specificity: 96.97%; positive predictive value: 97.01%; negative predictive value: 98.46%. In isolated testing, all 16 subjects, including 8 cases and 8 controls, were correctly identified. Conclusions: This study with 148 subjects showcases the potential of NGS and machine learning for early-stage lung cancer detection via liquid biopsy. However, the sample size is relatively small, lacking cross-site subjects. Therefore, an additional multi-center clinical trial is underway to gather more subjects, aiming for a deeper investigation and more concrete conclusions in the near future.
Comparative genomic landscape of patients with lung cancer with high-load versus low-load Epstein-Barr virus infection.
Authors: Liu Ming , Li Yingxiang , Chen Shifu , Mu Tianhao
Published: June 2024

e20017

Background: As the first known oncogenic virus, Epstein–Barr virus (EBV) has been proven to be associated with nasopharyngeal carcinoma, gastric cancer, and lymphomas. Its relationship with lung cancer, however, remains ambiguous. Given that over 90% of adults globally harbor EBV infections and that EBV can be detected in the tumor cells of lung cancer patients, we hypothesize that lung cancer may be associated with high-load EBV infection, whereas low-load infection is less likely. Here, we compared the genomic landscapes of lung cancer patients with high-load and low-load EBV infections. Methods: We conducted a study on 2,268 Chinese lung cancer patients, collecting tumor tissue samples for analysis. Targeted sequencing of 680 cancer-related genes and EBV genome was performed using the HapOnco StarPanel NGS Assay (HaploX Biotechnology, Shenzhen). The EBV infection load was evaluated based on the proportion of reads aligned to the EBV reference genome in the total sequenced reads for each patient. 99% of these samples could be detected with at least two EBV reads. From them, we selected a total of 32 high-load EBV cases (2.1% - 64.3%) and 35 low-load EBV cases (0.1% - 1.7%). Their genomic profiles and altered signaling pathways were subsequently analyzed. Results: In the high-load EBV group, we identified 122 somatic mutations with no recurrent mutations between cases. As for genes, the most frequently mutated were TP53 (25.0%), LRP1B (15.6%), NFKBIA (12.5%), ERBB4 (9.4%), and CNTNAP5 (9.4%), with these mutations being notably enriched in EBV infection pathways according to KEGG, and IL−7 Signal Transduction pathways as per BioCarta. The most common copy number variation events were FGFR3 (12.5%), CDKN2A (12.5%) and FOXP1 (12.5%) gene deletions. In contrast, the low-load EBV group presented with 316 somatic mutations, with the most recurrent mutations being EGFR L858R (17.1%) and E746_A750del (17.1%). The top frequently mutated genes were TP53 (55.3%), EGFR (44.7%), ARID1A (10.5%) and KRAS (10.5%). Conclusions: The genomic profiles of lung cancer patients with high-load EBV infection differ significantly from those with low-load infection. Notably, the genomic mutations in the high-load EBV group are closely associated with EBV infection, suggesting that high-load EBV infection may be linked to lung cancer, unlike low-load infection.
Application of ctDNA sequencing in patients with metastasized lung cancer.
Authors: Zheng Zhi , Wen Jiale , Chen Yaru , Guo Wei , Zhou Yanqing
Published: June 2024

e20033

Background: Circulating tumor DNA (ctDNA) is a form of cell-free DNA (cfDNA) found in blood that originates from tumor cells, which has emerged as a promising non-invasive biomarker in monitoring cancer prognosis and precision medicine with the advancement of deep sequencing. Here we compared the mutational landscape between solid tumor and cfDNA in metastasis-free and metastasized lung cancer patients using targeted NGS to investigate the feasibility of ctDNA sequencing in monitoring cancer prognosis. Methods: Blood-derived cfDNA samples and formalin-fixed paraffin embedded tissue were collected from 217 Chinese patients with metastatic lung cancer (n = 39) or metastasis-free lung cancer (n = 178). Blood samples were collected after surgery. Panel sequencing targeting 680 cancer-related genes was performed on both samples. Somatic single nucleotide variations and indels were analyzed. Results: Among the 178 metastasis-free patients, 89.3% of the patients have at least one mutation both detected in tumor and blood samples. On average, 50.4% of tumor mutations were detected in blood for each patients. EGFR, TP53, CSMD3, LRP1B and SYNE1 were the top five most frequently mutated genes, with the proportion of tumor mutation found in blood of 89.1%, 80.2%, 70.0%, 61.3% and 64.3% respectively. In the metastasized cohort, all 39 individuals have at least one tumor mutations found in blood, achieving a concordance of 100%. On average, 59.9% of tumor mutations were detected in blood for each patients. Notably, the proportion of tumor mutations detected in blood for each patients is significantly higher than the metastasis-free cohort (unpaired T-test, p = 0.0167). EGFR, TP53, RBM10, PIK3CA and CSMD3 were the top five most frequently mutated genes, with the proportion of tumor mutation found in blood of 93.5%, 80.8%, 57.1%, 83.3% and 42.9% respectively. Moreover, the proportion of patients having EGFR p.L858R mutation in metastasized cohort was higher than the metastasis-free cohort (54.3% vs 32.8%). While within the metastasized cohort, blood samples detected a higher proportion of EGFR p.T790M (12.9% vs 7.69%) but a lower proportion of EGFR exon19 deletion (p.E746_A750del, 19.4% vs 27.7%) comparing to tumor sample, which can indicate drug resistance. Conclusions: We demonstrated a high mutation detection concordance between tumor and blood using targeted NGS, with an exceptional performance especially in driver oncogenes like EGFR and TP53. Our findings showed that metastasized lung cancer patients exhibit a higher positive concordance rate compared to metastasis-free cohort using ctDNA. We also showed a varied mutational landscape between ctDNA and tumor sequencing in metastasized lung cancer patients. Overall, this study not only reaffirms the viability of using blood as an alternative of tissue biopsy, but also provides new insights on application of ctDNA monitoring lung cancer metastasis and its clinically targetable mutations.
Exploring the role of UMP as a molecular marker in the tumor microenvironment of lung adenocarcinoma.
Authors: Meng Yiran , Liu Yang , Zheng Liuqing , Wang Li
Published: June 2024

e20064

Background: Currently, there is a relatively extensive research emphasis on tumor microenvironment based on single-cell transcriptomics. However, the investigation of the metabolic aspects of tumor microenvironment is relatively rare due to technological limitations. To address this gap, our study employes scFEA and MEBOCOST, which are metabolic level prediction tools based on single-cell transcriptomics, to explore the metabolic landscape of tumor microenvironment in lung adenocarcinoma(LUAD). Methods: This study utilized four single-cell sequencing (scRNA-seq) datasets, two targeted metabolomics datasets, and the TCGA-LUAD RNA sequencing dataset obtained from the Cancer Genomics Data Portal. To perform dimensionality reduction, the Seurat package was employed. Cell annotation was carried out using scType, followed by manual correction using the FindAllMarkers function. Tumor cell clusters were identified by utilizing tumor marker genes and the R package inferCNV. Single-cell metabolic levels were inferred using scFEA. The TCGA-LUAD datasets underwent analysis to estimate and analyze immune levels using estimate and cibersort algorithms. Additionally, scFEA was used for metabolic level analysis, and survival analysis was conducted. UMP differential expression analysis was performed on the targeted metabolomics datasets. Results: Across all four single-cell sequence datasets, metabolites such as (GlcNAc)4 (Man)3 (Asn)1[G00015], B-Alanine[C00099], and UMP[C00105] exhibited significantly higher levels in immune cells compared to tumor cells (P < 0.05). These findings were further validated using the TCGA-LUAD datasets. Cox regression analysis was performed using immune scores and tumor purity scores and based on the median value of risk scores, high and low-risk groups were distinguished. it was observed that UMP levels were higher in the low-risk group. Moreover, higher UMP levels were associated with elevated immune levels and decreased tumor purity. Analysis of targeted metabolomics datasets from various pan-cancer cell lines revealed that UMP expression level in tumor cells was lower than that in B and T cells. Furthermore, in different subtypes of LUAD, including AAH, AIS, MIA, and IAC, UMP expression in tissues gradually decreased as the severity of the subtype increased (P < 0.05). Conclusions: The study revealed that UMP metabolites are expressed at higher levels in immune cells compared to tumor cells within LUAD. Moreover, UMP expression levels showed significant variations among different disease severities of LUAD. These findings indicate that UMP has the potential to serve as a molecular marker for distinguishing between different disease severities. Further research is needed to investigate the underlying mechanisms and validate the diagnostic usefulness of UMP in LUAD.
Trends in malignant pleural mesothelioma prevalence in the United States from 2000 to 2020.
Authors: Ganesh Bharath , Micaily Ida
Published: June 2024

e20094

Background: Malignant pleural mesothelioma (MPM) is a rare cancer that is closely associated with prolonged asbestos exposure. Its incidence has steadily declined over time with decreasing prevalence of asbestos-related lung disease. Our study aims to provide an update on recent MPM trends in the United States from 2000 to 2020. Methods: This is a retrospective cohort study design. The primary endpoints of this study are age-adjusted MPM rates and annual percentage change (APC) in rates from 2000-2020. We queried the Surveillance, Epidemiology, and End Results (SEER) 17 database for information about demographics, cause of death, and survival time for patients diagnosed with MPM from 2000-2020. For rate analysis, we used the SEER 22 database which covers 22 national cancer registries and approximately 41.9% of the US population. Age-adjusted rate analysis was performed using the National Cancer Institute (NCI) joinpoint regression program. Results: We identified 13,018 patients diagnosed with MPM from 2000-2020 who were eligible for analysis in the SEER 17 database. Individuals with MPM were primarily male (78.2%) and belonged to Non-Hispanic White (80.7%) ancestry. The mean age at diagnosis overall was 72.4 (SD +/- 10.6) years. The overall age-adjusted rate of MPM for all groups decreased from 0.97 (cases per 100,000 population) in 2000 to 0.55 in 2020. When stratified by sex, the MPM rate in males decreased from 1.91 to 0.93. The rate decrease in females over the same period was more modest, from 0.33 to 0.27. Overall APC for all groups from 2000-2013 was -1.45 (95% CI -2.01 to -0.40, p<.05), and from 2013-2020 it was -5.22 (95% CI -8.92 to -3.76, p<.05). The APC for males from 2000-2013 was -1.88 (95% CI -2.62 to -0.62, p<.05) and -6.46 (95% CI -10.49 to -4.57, p<.05) from 2013-2020. The rate decrease for females demonstrated a consistent APC of -0.87 (95% CI -1.54 to -0.26, p<.05) from 2000-2020. Conclusions: MPM is a disease that is best managed at large academic cancer centers due to its rarity. Our study demonstrates an accelerated decline in overall MPM rates since 2013, mainly driven by a similar fall in rates in males over the same period. MPM rates are lower in females and continue to decline, albeit slowly. The continued and reassuring decrease in rates of MPM likely reflects the effectiveness of regulations targeting widespread industrial and residential asbestos use that have been in place since the 1990s. [Table: see text]
Potentielle therapie neurodegenerativer retinopathien über die aktivierung des BDNF-TrkB-signalweges mittels modifizierten aptamers
Authors: Λίλου Ευαγγελία
Published: June 2024

Εκφυλιστικές οφθαλμικές παθήσεις όπως η διαβητική αμφιβληστροειδοπάθεια, το γλαύκωμα ή η μελαγχρωστική αμφιβληστροειδίτιδα αποτελούν αντικείμενο έρευνας τα τελευταία χρόνια, έτσι ώστε να διατίθενται όλο και περισσότερες μελέτες για πιθανές θεραπείες. Ο νευροτροφικός παράγοντας BDNF είναι ένας πολλά υποσχόμενος αυξητικός παράγοντας, ο οποίος ξεδιπλώνει τα αποτελέσματά του μέσω του μεμβρανικού υποδοχέα τυροκινάσων Β (TrkB) και ο οποίος εκπληρώνει πολλές κρίσιμες λειτουργίες στο κεντρικό νευρικό σύστημα (ΚΝΣ). Η παρούσα εργασία σκοπεύει αφενός να μιμηθεί τη νευροπροστατευτική δράση του BDNF χρησιμοποιώντας ένα ήδη δημοσιευμένο απταμερές και αφετέρου να αποφύγει τις ανεπιθύμητες παρενέργειες. Πρώτα απ 'όλα, το απταμερές δεν έδειξε βλάβη στα κύτταρα του αμφιβληστροειδούς και στα εκφυτεύματα του αμφιβληστροειδούς. Σε ένα περαιτέρω βήμα, επιβεβαιώθηκαν τόσο ο χρόνος κατακράτησης όσο και η αποτελεσματικότητα δέσμευσης του απταμερούς TrkB σε κύτταρα αμφιβληστροειδούς και σε εκφυτεύματα αμφιβληστροειδούς. Αποδείχθηκε επίσης όχι μόνο ότι το απταμερές TrkB ενεργοποιεί το μονοπάτι σηματοδότησης BDNF, αλλά και ότι δεσμεύεται ειδικά. Αφού επιβεβαιώθηκε η ειδικότητα του απταμερούς TrkB, πραγματοποιήθηκε μακροχρόνια επώαση για αρκετές ημέρες. Ως αποτέλεσμα, η μακροχρόνια καλλιέργεια με το απταμερές TrkB είχε νευροπροστατευτική δράση. Στη συνέχεια, η νευροπροστατευτική δράση του απταμερούς TrkB επιβεβαιώθηκε σε ένα ήδη καθιερωμένο μοντέλο βλάβης χλωριούχου κοβαλτίου αμφιβληστροειδούς (CoCl2). Με την απόκτηση των νέων ερευνητικών αποτελεσμάτων, ελπίζεται ότι θα συμβάλουν σημαντικά στην ανάπτυξη νέων θεραπευτικών επιλογών για τις εκφυλιστικές παθήσεις του αμφιβληστροειδούς.
Effect of Maraviroc and/or Favipiravir plus systemic steroids versus systemic steroids only on the viral load of adults with severe COVID-19: clinical trial
Authors: Medina Elba , Sanchez-Sandoval Ana Laura , Barrón-Palma Eira Valeria , Espinosa-García Ana María , Villalobos-Osnaya Alma Maria de la Luz , León-Hernández Mireya , Hernández-Medel María Luisa , Hernández-Ruiz Joselin , Medeiros Mara , Cedro-Tanda Alberto , Pérez-García Adolfo , Pérez-Navarro Lucía Monserrat
Published: June 2024

Background Coronavirus disease 2019 (COVID-19) has created the need to evaluate drugs such as favipiravir (FPV), an antiviral inhibitor of RNA-dependent RNA-polymerase (RdRp), and Maraviroc (MVC), an antiretroviral that antagonizes the chemokine receptor CCR5, which could affect the modulation of inflammation and viral replication in the treatment of COVID-19. We sought to evaluate the effect of MVC and/or FPV plus systemic steroid (SS) vs. SS alone on the viral load and progression to critical disease. Methods Sixteen patients with severe COVID-19 were evaluated in three treatment arms: 1) SS only (n=6), 2) SS plus one test drug MVC or FPV (n=5), and 3) SS plus both test drugs (MVC and FPV, n=5). The viral load was determined for N, E, and RdRp viral genes. Results A significant decrease in viral load was observed in the three treatment groups, with a larger effect size in the group that combined SS with both test drugs. The E, N, and RdRp genes with Cohen’s d were 120%, 123%, and 50%, respectively. Conclusions The largest effect on viral load reduction, as measured by effect size, was observed in the combination treatment group; however, no statistical significance was found, and it did not prevent progression to critical illness.
An Evaluation of Sagittal Balance and the Influence of Spinopelvic Components on Sagittal Balance through the Correction and Stabilization Using the Pedicle Screw Rod System on Patients with Adolescent Idiopathic Scoliosis
Authors: Mahmud Ayiq , Asmiragani Saifullah , Gatam Luthfi
Published: June 2024

Background The pedicle screw rod system is believed to correction of 3-dimensional deformity and maintain the results of the correction, so the better sagittal balance correction can be expected. Methods We conducted a retrospective cohort study on 43 adolescent idiopathic scoliosis (AIS) patients who performed correction, stabilization and posterior fusion to determine the effect of spinal and spinopelvic components on sagittal balance correction. X-ray data were measured for thoracic kyphosis and lumbar lordosis as the spinal components and pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) as the spinopelvic components. Further evaluations include sagittal spinal balance (C7PL), global sagittal balance, and sacrofemoral distance pre- and post-surgery. Statistical evaluation is performed to determine the correlation between the spinal and the spinopelvic components and the achievement of sagittal balance correction. Results TK/Sagittal Modifier obtained a significant correction with an average is 18.69° (±9.57), while LL (lumbar lordosis) has 44.58 ° (±11.94). Average of C7PL correction is 0.68 cm (±3.13), Global Sagittal Balance is -2.04 cm (±3.24), and SCFD is 2.69 cm (±2.48). The TK/LL degree doesn’t significantly influence on Global Sagittal Balance and C7PL. The TK degree significantly affects SCFD, whereas LL doesn’t significantly affect SCFD. Changes in each spinopelvic component are not significant in affecting Global Sagittal Balance. Conclusions Correction and stabilization of AIS’s patients using the pedicle screw rod system resulted in significant Spinal Component TK/Sagittal Modifier and LL correction. Meanwhile, Spinopelvic Components didn’t achieve significant correction. Mean correction of C7PL is -2.66 (±4.4) and Global Sagittal is -3.11 cm (±4.94), SCFD only managed to correct 37.3%. Global Sagittal Balance is not significantly affected by all components of Spinopelvic components, while the C7PL is only affected by PT. Only PT and SS that significantly affected SCFD.
Case Report: A Case Report on an 18-Year-Old Female with Cerebral Vasculitis in Systemic Lupus Erythematosus (SLE).
Authors: Dudhe Sakshi , Mishra Gaurav V , Parihar Pratap Singh , Nimodia Devyansh , Shinde Dhananjay , Kumari Anjali
Published: June 2024

Cerebral vasculitis is a rare but severe complication of Systemic Lupus Erythematosus (SLE), presenting significant challenges in management due to its potential for devastating neurological consequences and poor prognosis. We present a case of an 18-year-old female with known SLE who presented with seizures, declining cognitive function, and unresponsiveness. Neurological examination, laboratory investigations, and radiological imaging supported the diagnosis of cerebral vasculitis secondary to SLE. Despite aggressive immunosuppressive therapy, the patient’s neurological status continued to deteriorate, leading to respiratory failure and multiorgan dysfunction. Ultimately, the patient succumbed to multiorgan failure attributed to severe CNS vasculitis and its complications. This case underscores the importance of early recognition and aggressive management of cerebral vasculitis in SLE while highlighting the need for further research into more effective therapeutic strategies to improve patient outcomes.
Prácticas sociales de mipymes ubicadas en la región metropolitana Bogotá-Cundinamarca (Colombia) y su relación con los criterios de mercadeo social
Authors: Urrea Urrea Freddy , Rodríguez Hernández Reina Helena
Published: June 2024

En el contexto global, las grandes empresas suelen realizar prácticas de mercadeo social a partir de criterios o puntos de referencia preestablecidos que permiten su buena imagen. Las exigencias de ese mismo contexto plantean retos para las mipymes, que deben incorporarlas y visibilizarlas en aras de lograr competitividad. Objetivo: identificar las prácticas de carácter social en seis mipymes con y sin ánimo de lucro para determinar si estas se enmarcan en los criterios o puntos de referencia del mercadeo social. Metodología: se situó en el paradigma sociocrítico con enfoque cualitativo, soportada en estudio de casos, documentados mediante revisión bibliográfica, grupo focal y entrevistas semiestructuradas. Resultados principales: se mostraron prácticas orientadas al desarrollo social, el cuidado del medio ambiente y el consumo responsable que se pueden situar dentro de las categorías preestablecidas. Se observó que las prácticas se llevan a cabo de manera intuitiva, que serían más aprovechables si las mipymes tuvieran un bagaje del mercadeo social y su valor para el fortalecimiento de la imagen empresarial y la obtención de beneficios dentro del mercado. Conclusiones: relevante visibilizar las prácticas sociales y cualificar a las mipymes en temas relacionados con mercadeo social para la instrumentalización de sus programas desde la planeación empresarial.
Reflexiones sobre la justicia transicional en el Sistema Interamericano de Derechos Humanos
Authors: Patiño Palacios Luz Ángela
Published: June 2024

Por tal razón, el presente capítulo tiene como objetivo generar algunas reflexiones sobre el abordaje de la justicia transicional en el Sistema Interamericano, dado que cada tema se podría explorar de forma independiente. La metodología que se usará será esencialmente cualitativa, a través de jurisprudencia y referencias académicas.
Derecho de acceso a la información: desclasificación de archivos de graves violaciones de derechos humanos en el Sistema Interamericano de Derechos Humanos
Authors: Fierro Barreto Paula Viviana
Published: June 2024

El presente documento muestra el alcance e importancia del derecho de acceso a la información pública en los casos de graves violaciones de derechos humanos, y cómo la desclasificación y apertura de información resulta ser una herramienta para la satisfacción de dicho derecho en el SIDH.
La justicia transicional: mecanismo polifacético de armonización entre la paz y la justicia
Authors: Restrepo Medina Manuel Alberto
Published: June 2024

El objeto de este capítulo es mostrar la evolución de los mecanismos que se han empleado en aquellas sociedades nacionales que han padecido violaciones sistemáticas de los derechos humanos para superar su pasado y transitar hacia un estadio de respeto de estos que permita la reconstrucción social y la construcción de la paz.
Constitucionalismo transicional colombiano. Aproximación a los enfoques diferenciales en escenarios de construcción de paz
Authors: Forero Salcedo José Rory
Published: June 2024

En consecuencia, se realiza un estudio ordenado conforme a los temas generales señalados en el sumario, a fin de que el capítulo guarde coherencia, acompañado en lo pertinente el desarrollo normativo, jurisprudencial y doctrinal de las categorías dogmáticas analizadas, procurando hacer el análisis valorativo, crítico y reflexivo que el asunto demanda y amerita. En aras de una mayor ilustración, la relación de textos y autores se detallará de manera general al finalizar el capítulo.
Licenciamiento ambiental luego de la expedición del Decreto Único Reglamentario del Sector Ambiente y Desarrollo Sostenible
Authors: Salas-Pérez Yuliana , Rojas Mejía Lilian Bibiana
Published: June 2024

El presente capítulo tiene por objetivo exponer algunas problemáticas relacionadas con la aplicación del marco normativo del licenciamiento ambiental en el periodo 2015-2018.
Riesgos en el lavado de activos y la financiación del terrorismo: el caso de la comercialización del oro
Authors: Cante Carlos , Güiza-Suárez Leonardo , Salas-Pérez Yuliana
Published: June 2024

En razón a lo anterior, el presente capítulo tiene por objetivo realizar una revisión descriptiva de la problemática relacionada con la comercialización del oro en Colombia, a partir de la caracterización de los contextos: social, institucional y organizacional, y a partir de esto, identificar los riesgos de lavado de activos y financiación del terrorismo a través de su cadena de suministro.
Herramientas tecnológicas en la lucha contra la deforestación en el país
Authors: Salas-Pérez Yuliana
Published: June 2024

Frente a las necesidades y a las propuestas expuestas desde la política pública y desde la ejecución de la misma, se identifica la necesidad de implementar sistemas de monitoreo y aumentar el control del seguimiento a las actividades desarrolladas en las distintas regiones del país. El presente documento tiene por objetivo identificar las principales herramientas tecnológicas para aumentar la eficiencia de las estrategias de prevención, seguimiento y control a la deforestación en Colombia.
Cutaneous Pneumocystis jirovecii infection in an allogeneic stem cell transplant recipient
Authors: Sood Nikhil , Vadnerkar Aniket , Kodali Murali , Hamacher Lyn K.
Published: June 2024

Pneumocystis jirovecii is an opportunistic fungus that infects the lungs but can involve other organs, including the skin and lymph nodes. Risk factors include human immunodeficiency virus (HIV), solid organ/haematological malignancies and a CD4 cell count of fewer than 200 cells/µl. Pneumocystis jirovecii pneumonia (PJP) infection is reported less frequently these days with the advent of prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX). We report a case of extrapulmonary PJP infection in a patient while receiving pentamidine prophylaxis in a T-cell prolymphocytic leukaemia, who underwent an allogeneic stem cell transplant. There are plenty of reported cases of PJP on pentamidine prophylaxis; however, none had cutaneous PJP infection. Cutaneous P. jirovecii infection (CPJ) is an extrapulmonary infection that is rarely reported. Our patient’s skin biopsy was inconclusive, but the skin nodules improved once he was initiated on TMP-SMX. Many transplant patients cannot tolerate TMP-SMX for various reasons and are placed on second-line prophylaxis for PJP, which does not prevent extrapulmonary PJP infections. Our case highlights the challenges of diagnosing such a rare infection in immunocompromised patients. Extrapulmonary PJP should be suspected in patients with a history of pulmonary PJP and persistent elevated Fungitell® levels in low CD4 counts.
A rare case of membranous nephropathy complicated by chylothorax
Authors: Farouji Abdelhadi , Kloub Mohammad N. , Haddad Ahmad W. , Ahmad Amaar S. , Chow Priscilla , Miller Richard
Published: June 2024

Background: Chylothorax can be classified into traumatic and nontraumatic based on the etiology. Nephrotic syndrome is a very rare cause of nontraumatic chylothorax in adults. Case presentation: A 66-year-old woman with membranous nephropathy who was non-compliant with her management, presented with dyspnea, and was found to have a large right sided chylothorax. Her chylothorax was secondary to membranous nephropathy after excluding other causes, which has been rarely reported in literature. Conclusion: This case highlights the possibility of nephrotic syndrome causing chylothorax, especially in patients with undiagnosed nephrotic syndrome or patients non-compliant with their management. When evaluating a patient with chylothorax, providers should consider nephrotic syndrome in the differential diagnosis.
Tafamidis use in amyloid cardiomyopathy
Authors: Robertson Deborah
Published: June 2024

Deborah Robertson provides an overview of recently published articles that may be of interest to non-medical prescribers. Should you wish to look at any of the papers in more detail, a full reference is provided
When the Five Senses Are Not Enough: An Interview with Fausta Orecchio
Authors: Malpezzi Chiara
Published: June 2024

Abstract: Orecchio Acerbo is a publishing house that stands out for its high-quality picture-books. Its significant role within contemporary Italian children’s literature was also recognized in 2017, when it won the Bologna BOP Best Children’s Publishers of the Year Prize–Europe. The editor, Fausta Orecchio, unveils the inception of the publisher’s pioneering picturebooks, the books’ design as artistic objects, and the pedagogical stance toward their young readers.