Analysis Of Paired Samples Research Articles

Profound impact of ECOG performance status on clinical trial eligibility and access: Diverging effects by cancer type.

97 Background: The Eastern Cooperative Oncology Group (ECOG) performance status is a widely used measure of a patient's (pt) physical function and is often used as a criterion for clinical trial eligibility. Strict use of this criterion may exclude pts with comorbidities or poorer performance status, limiting the generalizability of trial results to the broader cancer pt population. This study aimed to evaluate the impact of ECOG performance status on eligibility for solid and non-solid cancer clinical trials (CTs) among pts using the Leal web-based platform. Methods: Leal (formerly, Trialjectory) is an AI-based platform that matches cancer pts to CTs based on a self-reported questionnaire that generates an individual clinical profile. The profile includes parameters essential for CT matching such as disease status, stage, biomarkers, treatment history, comorbidities and demographics. Data from pts with solid and non-solid cancers were analyzed. The number of matched trials per pt was determined based on the pt’s profile, location and travel preference. To assess the impact of ECOG score, the data set was edited to reflect a better performance status per pt. We used Yuen’s robust paired samples analysis to assess the association between improving the ECOG score and the number of matched CTs. Moreover, we have collected the cumulative ECOG distribution as an eligibility criteria in CTs in various cancer types. Results: In a data set of 5,018 cancer pts, high ECOG score (3 or 2) was significantly associated with fewer matched clinical trials per pt (p<0.001). This relationship was independent of ethnicity and gender. The relationship varied by cancer type, with a 3-fold greater effect size in solid tumors compared to non-solid tumors. When ECOG score per pt was edited from 3 to 2 or from 2 to 1, the number of matched CTs significantly increased by 246% and 189%, respectively, for all cancer types (p<0.001). Notably, the prevalence of CTs that allow worse ECOG scores (2 or higher) was significantly higher in non-solid CTs compared to solid tumors (p<0.001). Conclusions: Our results show that strict ECOG scores are significantly associated with fewer matched CTs per pt. This relationship varies by cancer type, with a greater impact on solid tumors. These findings suggest that cancer type may influence the relationship between ECOG scores and access to CTs. Pts with solid tumors may face more barriers to trial enrollment due to strict ECOG requirements. Our results highlight the need for a more nuanced approach to using ECOG performance status as an eligibility criterion in CTs, taking into account the specific cancer type and its associated physical demands. Further research is needed to fully understand the impact of ECOG performance status on trial enrollment and to determine the optimal balance between pt safety and representation in clinical research.

Lack of neutralizing antibodies against influenza A viruses in adults during the 2022/2023 winter season – a serological study using retrospective samples collected in Hong Kong

ObjectivesSince the onset of the COVID-19 pandemic in 2020, there has been a significant decline in seasonal influenza infection cases in Hong Kong. However, this decline has also resulted in reduced opportunities for the development of influenza-specific antibodies in the community. The levels of antibodies required for protection against recently circulating influenza A viruses in the post-COVID-19 era remain unclear. MethodsThis study involved the analysis of paired plasma samples collected from 479 healthy adults in Hong Kong in 2021 and 2022. The neutralizing titers of plasma against influenza A (H1N1) and (H3N2) viruses circulating before and after the COVID-19 outbreak were determined using a microneutralization assay. ResultsThe H1N1 and H3N2 vaccine strains selected for the 2022/23 season were found to be closely related to the recently circulating viruses. However, in the samples collected in 2022, only 14.61% and 0.42% showed a neutralization titer (MN50) ≥1:20 against H1N1 A/Wisconsin/588/2019 (H1/Wis19) and H3N2 A/Darwin/6/2021 (H3/Dar21), respectively. Notably, participants who reported receiving annual flu vaccinations exhibited a higher seropositive rate for H1/Wis19 compared to those who had never received the flu vaccine (28.06% vs. 5.30%). ConclusionOur results indicate that adults in Hong Kong generally lack neutralizing antibodies against circulating influenza A viruses, particularly H3N2. These findings underscore the importance of promoting flu vaccination in the post-COVID-19 era.

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.

Effects of Moringa oleifera leaves on the blood glucose, blood pressure, and lipid profile of type 2 diabetic subjects: A parallel group randomized clinical trial of efficacy.

There is a paucity of information on the antidiabetic potential of graded amounts of Moringa leaves on diabetes human subjects. To ascertain the effeccts of Moringa leaves on type 2 diabetic subjects' blood glucose, blood pressure, and lipid profile levels in a rural Nigerian community. This study adopted a parallel group randomized control design. Participants included 40 adult male and female diabetic subjects who met the inclusion criteria and consented to participate in the study. The participants were randomly assigned to four groups. The control group was fed diets without Moringa oleifera leaves while the experimental groups received 20, 40, and 60 g of Moringa leaves respectively daily for 14 days in addition to the diets. The subjects' baseline data and post-intervention data were collected before and after the intervention, respectively. Data were analyzed using paired-sample t-test and analysis of covariance. Significance was accepted at p < 0.05. The mean fasting blood glucose levels in all the groups did not differ significantly from one another. Group 3 had significantly (p = 0.01) lower mean systolic pressure (from 136.40 ± 7.66 to 123.90 ± 13.82) after the intervention. Group 3 subjects had a significant (p = 0.04) increase in their triglyceride values (from 123.80 ± 53.69 before intervention to 151.20 ± 41.47) after intervention. After adjusting for the pre-intervention values, there was no significant (p > 0.05) difference in all the parameters at the end of the intervention. There were marginal improvements in the parameters assessed which were not dose-dependent.

Refined expression quantitative trait locus analysis on adenocarcinoma at the gastroesophageal junction reveals susceptibility and prognostic markers.

Objectives: This study aimed to explore cell type level expression quantitative trait loci (eQTL) in adenocarcinoma at the gastroesophageal junction (ACGEJ) and identify susceptibility and prognosis markers. Methods: Whole-genome sequencing (WGS) was performed on 120 paired samples from Chinese ACGEJ patients. Germline mutations were detected by GATK tools. RNA sequencing (RNA-seq) data on ACGEJ samples were taken from our previous studies. Public single-cell RNA sequencing (scRNA-seq) data were used to produce the proportion of epithelial cells. Matrix eQTL and a linear mixed model were used to identify condition-specific cis-eQTLs. The R package coloc was used to perform co-localization analysis with the public data of genome-wide association studies (GWASs). Log-rank and Cox regression tests were used to identify survival-associated eQTL and genes. Functions of candidate risk loci were explored by experimental validation. Results: Refined eQTL analyses of paired ACGEJ samples were performed and 2,036 potential ACGEJ-specific eQTLs with East Asian specificity were identified in total. ACGEJ-gain eQTLs were enriched at promoter regions more than ACGEJ-loss eQTLs. rs658524 was identified as the top eQTL close to the transcription start site of its paired gene (CTSW). rs2240191-RASAL1, rs4236599-FOXP2, rs4947311-PSORS1C1, rs13134812-LOC391674, and rs17508585-CDK13-DT were identified as ACGEJ-specific susceptibility eQTLs. rs309483-LINC01355 was associated with the overall survival of ACGEJ patients. We explored functions of candidate eQTLs such as rs658524, rs309483, rs2240191, and rs4947311 by experimental validation. Conclusion: This study provides new risk loci for ACGEJ susceptibility and effective disease prognosis biomarkers.

Enhanced recovery protocol after cesarean delivery: impact on opioid use and pain perception

Opioids are routinely prescribed to patients postoperatively after cesarean delivery. With rates of cesarean deliveries increasing globally and the opioid epidemic continuing to have deleterious effects, finding methods to achieve effective pain control without opioids is of increasing importance. The ERAS (Enhanced Recovery After Surgery) protocol applied following cesarean delivery engages multimodal perioperative management techniques to encourage early recovery. In the obstetrical surgery setting, these interventions include increasing scheduled nonsteroidal anti-inflammatory drug administration and laxative use to improve postoperative gastrointestinal motility and pain scores. Postcesarean patients are also encouraged to use abdominal binders, incentive spirometry, and early movement as pain modulators. This quality improvement study aimed to measure whether the introduction of an ERAS protocol following cesarean delivery at a United States-based health network would improve outcomes such as the use of opioid medications for pain and pain control. This single-center retrospective cohort study compared patients who gave birth via cesarean delivery before (n=1425) and after (n=3478) the implementation of the postsurgical recovery protocol. Outcomes of interest included total postoperative opioid medications used, discharge opioid prescription, average pain score, pain scores by postoperative day, and highest pain score. Patients with a history of opioid use disorder, those who underwent a cesarean hysterectomy, and those who experienced a major surgical complication at delivery were excluded. Data were collected from the electronic medical record. Patients in the postimplementation period used significantly fewer opioid medications than those who gave birth before the protocol was introduced at the institution. The total median opioid use before implementation was 75 morphine milligram equivalents (interquartile range, 45-112.5) vs 30 (interquartile range, 15-52.5) after implementation (P<.001). The median discharge prescription was 225 (interquartile range, 150-225) before implementation vs 112.5 (interquartile range, 75-150) after implementation (P<.001). Pain scores were also significantly lower after implementation. The median highest pain score was 8 (interquartile range, 6-8) on a 10-point pain scale before implementation vs 7 (interquartile range, 6-8) after implementation (P<.001). The average pain score before implementation was 3.4 (interquartile range, 2.4-4.5) vs 2.9 (interquartile range, 1.9-3.9) after implementation (P<.001). Results of paired-sample analyses of 177 patients who gave birth by cesarean delivery in both time periods showed statistically significant outcomes similar to those of the larger cohort groups. Implementation of multimodal pain regimens following cesarean delivery, such as the ERAS protocol, which incorporate both pharmacologic (nonsteroidal anti-inflammatory drugs, laxatives) and nonpharmacologic methods (abdominal binders, deep breathing, movement) can be effective for pain control and may decrease postoperative opioid prescribing needs, thus mitigating the potential for opioid misuse and dependence.

Quantitative analysis of remineralization of artificial carious lesions with commercially available toothpastes using EDAX: An in vitro study

Introduction: Noninvasive approach for treating demineralized teeth is gaining importance in preventive dentistry. Various fluoridated and nonfluoridated remineralizing agents are utilized for treating early enamel carious lesions. Aim: To quantitatively assess the remineralizing potential of various dentifrices quantitatively from the array of products available in the market. Materials and Methods: Enamel blocks were prepared from seventy sound permanent teeth. The baseline amount of calcium, phosphorous, and fluoride was evaluated. After those samples were transferred in Modified TenCate’s solution for demineralization for 96 h, the amount of demineralization carried out to detect change in mineral content. Following this, samples were randomly grouped into five – Group 1: Fluoridated sensitive toothpaste, Group 2: Fluoridated toothpaste with Anticay Technology, Group 3: Nonfluoridated natural extracts toothpaste, Group 4: Nonfluoridated ayurvedic toothpaste, and Group 5: De-ionized water. Remineralizing agents applied twice daily for 28 days. The final mineral content of remineralized enamel was evaluated. Intra-group and inter-group comparisons were statistically analyzed using independent and paired sample t-test and analysis of variance. Results and Discussion: The mean calcium, phosphorous, fluoride, and Ca/P ratio of fluoridated and nonfluoridated toothpastes showed statistically significant difference (significant at P &lt; 0.05). Intergroup comparison shows fluoridated toothpaste showing greater potential for remineralization (significant at P &lt; 0.05). Conclusion: Fluoridated toothpaste with anticay technology showed better remineralizing capacity followed by sensitive and nonfluoridated natural toothpaste. Nonfluoridated ayurvedic toothpaste showed the least remineralizing potential.

Exploration of the immunogenetic landscape of hyperprogressive disease after combined immunotherapy in cancer patients

The immune-genetic changes that occur in cancer patients experiencing hyperprogressive disease (HPD) during combined immunotherapy are unclear. In thisstudy, HPD patients with pre- and post-HPD samples and non-HPD patients with solid tumors were molecularly characterized by genetic and tumor immune microenvironment (TiME) analyses of paired samples by whole-exome sequencing, RNA sequencing, and multiplex immunofluorescence. The genetic analysis of paired samples showed that almost all the tumor driver gene mutations were preserved between pre- and post-HPD tumors. HPD patients had higher frequencies of mutations in TP53 and CNN2, and a significantly higher mutant-allele tumor heterogeneity than non-HPD patients. Tumor IL-6 mRNA was upregulated in post-HPD samples vs. pre-HPD, accompanied by a potential immune suppressive TiME with an elevated M2/M1 ratio. Salvage treatment with irinotecan plus bevacizumab was effective in one HPD patient, who experienced prolonged survival. These genetic features and TiME characteristics might help identify the features of HPD after immunotherapy.

Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group.

Background: Next generation sequencing (NGS) has become indispensable for diagnosis, risk stratification, prognostication, and monitoring of response in patients with myeloid neoplasias. Guidelines require bone marrow evaluations for the above, which are often not performed outside of clinical trials, indicating a need for surrogate samples. Methods: Myeloid NGS analyses (40 genes and 29 fusion drivers) of 240 consecutive, non-selected, prospectively collected, paired bone marrow/peripheral blood samples were compared. Findings: Very strong correlation (r = 0.91, p < 0.0001), high concordance (99.6%), sensitivity (98.8%), specificity (99.9%), positive predictive value (99.8%), and negative predictive value (99.6%) between NGS analyses of paired samples was observed. A total of 9/1321 (0.68%) detected mutations were discordant, 8 of which had a variant allele frequency (VAF) ≤ 3.7%. VAFs between peripheral blood and bone marrow samples were very strongly correlated in the total cohort (r = 0.93, p = 0.0001) and in subgroups without circulating blasts (r = 0.92, p < 0.0001) or with neutropenia (r = 0.88, p < 0.0001). There was a weak correlation between the VAF of a detected mutation and the blast count in either the peripheral blood (r = 0.19) or the bone marrow (r = 0.11). Interpretation: Peripheral blood samples can be used to molecularly classify and monitor myeloid neoplasms via NGS without loss of sensitivity/specificity, even in the absence of circulating blasts or in neutropenic patients.

Analysis of time for diagnosis of nontuberculous mycobacterial lung disease and its associated factors in a tuberculosis-designated hospital in Shanghai

Objective: To investigate the pathogenic characteristics, bacteriological diagnosis time and its associated factors among patients with nontuberculous mycobacterial (NTM) lung disease in a large tuberculosis-designated hospital in Shanghai from 2020 to 2021, in order to improve diagnosis efficiency and formulate precision treatment. Methods: On the basis of the Tuberculosis Database in Shanghai Pulmonary Hospital, NTM patients diagnosed by the Department of Tuberculosis between January 2020 and December 2021 were screened. Demographic, clinical and bacterial information were retrospectively collected. Chi-square test, paired-sample nonparametric test and logistic regression model were used to analyze the factors associated with the diagnosis time of NTM lung disease. Results: A total of 294 patients with bacteriologically confirmed NTM lung disease were included in this study, 147 males and 147 females with a median age of 61(46, 69) years. Of them, 227 (77.2%) patients had comorbidity of bronchiectasis. Species identification results showed that Mycobacterium Avium-Intracellulare Complex was the main pathogen of NTM lung disease (56.1%), followed by Mycobacterium kansasii (19.0%) and Mycobacterium abscessus (15.3%). Species such as Mycobacterium xenopi and Mycobacterium malmoense were rarely identified, accounting for a total proportion of only 3.1%. Positive culture rates for sputum, bronchoalveolar lavage fluid and puncture fluid were 87.4%, 80.3% and 61.5%, respectively. Paired-sample analysis showed that the positive rate of sputum culture was significantly higher than that of smear microscopy (87.1% vs. 48.4%, P<0.01), while no statistical difference was observed between sputum and bronchoalveolar lavage fluid on positive culture rate (78.7% vs. 77.3%, P>0.05). Patients with cough or expectoration were observed with 4.04-fold (95%CI 1.80-9.05) or 2.95-fold (95%CI 1.34-6.52) higher probability of positive sputum culture, compared to those without. Regarding bronchoalveolar lavage fluid, female or patients with bronchiectasis had a 2.82-fold (95%CI 1.16-6.88) or 2.38-fold (95%CI 1.01-5.63) higher probability to achieve a positive culture. The median time to diagnosis of NTM lung disease was 32 (interquartile range: 26-42) days. The results of multivariable analysis showed that patients with symptom of expectoration (aOR=0.48, 95%CI 0.29-0.80) needed a shorter diagnosis time in comparison with patients without expectoration. With Mycobacterium Avium-Intracellulare Complex as a reference, lung disease caused by Mycobacterium abscessus needed shorter diagnosis time (aOR=0.43, 95%CI 0.21-0.88), whereas those caused by rare NTM species were observed to require a longer diagnosis time (aOR=8.31, 95%CI 1.01-68.6). Conclusion: The main pathogen causing NTM lung disease in Shanghai was Mycobacterium Avium-Intracellulare Complex. Sex, clinical symptoms and bronchiectasis had an impact on the positive rate of mycobacterial culture. The majority of patients in study hospital were timely diagnosed. Clinical symptoms and NTM species were associated with the bacteriological diagnosis time of NTM lung disease.

Abstract 1036: Detection of circulating tumor DNA by whole genome sequencing enables prediction of recurrence in stage III colorectal cancer patients with great inter-lab reproducibility

Abstract Background: Detection of circulating tumor DNA (ctDNA) in plasma indicates the presence of cancer. In patients with very few copies of tumor DNA circulating in the blood, the blood sampling process becomes a potentially limiting factor. For ctDNA methods based on a single or a few genomic targets, it becomes stochastic whether the collected sample contains any tumor DNA fragments from targeted regions. To overcome this sampling limitation, we developed C2inform; a whole genome sequencing (WGS) approach, which detects ctDNA using a cumulative patient-specific signal from thousands of mutations throughout the entire genome. Aim: Here, we aim to I) evaluate the performance of C2inform in patients with UICC stage III colorectal cancer (CRC) using samples collected after the end of curatively intended treatment and serially during surveillance, II) assess the inter-lab reproducibility of C2inform and, III) investigate the potential for using the serial WGS data to track tumor genomic evolution in recurrence patients. Methods: From a cohort of 146 stage III CRC patients, including 37 patients with recurrence, 2 mL plasma samples were collected serially for up to three years (n = 1309, median 10 samples per patient). By WGS of tumor and blood-derived normal DNA, a mutational signature was established for each patient. Enhanced by an AI-based error suppression model, this signature was used to screen 20x WGS plasma cfDNA profiles for the presence of ctDNA. To evaluate the reproducibility, paired samples (n = 2 x 187 samples) were processed and sequenced at two independent laboratories while the bioinformatics processing of samples was identical. Using coverage, split-read, and discordant read-pair information, genomic structural alterations were identified in serial plasma samples from 19 recurrence patients and compared to tissue WGS from subsequent recurrence metastasis. Results: Preliminary results showed that detection of ctDNA after the end of treatment was associated with poor prognosis (HR = 7.1, 95% CI: 3.2-15.9). The presence of ctDNA during surveillance was a predictor of recurrence (HR = 9.5, 95% CI: 3.6-25.5) and enabled the detection of recurrence up to 21 months (median: 9.5 months) before detection by radiological imaging. We found indication of tumor evolution by searching serially collected plasma samples for novel genomic changes, which were confirmed by WGS of the metastatic tissue. Analysis of paired samples showed great reproducibility of C2inform with a high agreement between both ctDNA detection (Cohens Kappa = 0.9) and the estimated ctDNA level (r² = 0.99). Conclusion: C2inform showed great inter-lab reproducibility and enabled prediction of recurrence after treatment and during surveillance. Thus, C2inform has the potential to guide clinical decision-making during the postoperative management of CRC patients. Citation Format: Amanda Frydendahl, Jesper Nors, Mads Heilskov, Ester Ellegaard Sørensen, Thomas Reinert, Jesper Bramsen, Danielle Afterman, Tomer Lauterman, Maja Kuzman, Santiago Gonzalez, Dunja Glavas, James Samdbeck, Dillon Maloney, Jurica Levatic, Sunil Deochand, Michael Yahalom, Ryan Ptashkin, Iman Tavassoly, Zohar Donenhirsh, Eric White, Ravi Kandasamy, Ury Alon, Paz Polak, Anders Husted Madsen, Uffe Schou Løve, Per Vadgaard Andersen, Ole Thorlacius-Ussing, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, Boris Oklander, Asaf Zviran, Claus Lindbjerg Andersen. Detection of circulating tumor DNA by whole genome sequencing enables prediction of recurrence in stage III colorectal cancer patients with great inter-lab reproducibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1036.

Abstract 5597: Enhanced detection and classification of cell-free DNA alterations through matched normal analyses with PGDx elioTM plasma complete

Abstract Liquid biopsies represent a transformation in the management of cancer as they have the potential to detect, characterize, and monitor cancers earlier than can be achieved with conventional diagnostic modalities. However, cell-free DNA (cfDNA)-based alterations can be derived from the tumor, germline, or may be associated with clonal hematopoiesis (CH), which can confound non-invasive tumor profiling, molecular response assessment, and clonal evolution analyses through inaccurate variant classification. To facilitate global access to a decentralized liquid biopsy solution to address this, we developed and validated the 521 gene PGDx elio plasma complete test for paired analysis of cfDNA and matched leukocyte DNA. PGDx elio plasma complete enables detection of single nucleotide variants, insertions and deletions, copy number amplifications, translocations, microsatellite instability, blood tumor mutation burden, and loss of heterozygosity. We first optimized the assay workflow to incorporate genomic DNA derived from leukocytes to facilitate direct detection and characterization of germline alterations as well as those that may be associated with CH, resulting in de-duplicated, error-corrected sequencing coverage of approximately 1,750-fold. A fully automated bioinformatics algorithm was then developed and validated to perform integrated analyses of cfDNA-derived alterations to assign the appropriate biological source of these variants. To assess the impact of these paired sample analyses, we analyzed the blood samples obtained from 24 patients representing seven different solid tumor types (breast, colorectal, gastric, gastro-esophageal junction, lung, and melanoma). Across this cohort, of the alterations detected in cfDNA (n=322), 87.3% were correctly classified as somatic, germline or CH without the patient-matched normal blood sample. Specifically, of the variants that were determined to be associated with CH (n=26), only 35% were appropriately assigned without the paired comparison. Additional sources of discordance for somatic and germline alterations were primarily attributed to patients with high levels of ctDNA where differentiation of these variant sources can be challenging through solely computational-based techniques. Taken together, these data demonstrate that through the integrated analysis of cell-free DNA and matched leukocyte DNA, classification of the source of cfDNA-derived alterations can be achieved, which may improve the accuracy of non-invasive tumor profiling, molecular response assessment, and clonal evolution analyses. Citation Format: Tonya N. Watkins, Paul McGregor, David Riley, Tolga Ayazseven, Kristy Waskiewicz, Kelly M. Gerding, Ellen L. Verner, Amy Greer, Aanavi Karandikar, Rami Zahr, Kenneth C. Valkenburg, Jamie Platt, Samuel V. Angiuoli, Mark Sausen. Enhanced detection and classification of cell-free DNA alterations through matched normal analyses with PGDx elioTM plasma complete. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5597.

Opposing effects of KDM6A and JDP2 on glucocorticoid sensitivity in T-ALL.

Glucocorticoids (GCs) are the cornerstone of acute lymphoblastic leukemia (ALL) therapy. Although mutations in NR3C1, which encodes the GC receptor (GR), and other genes involved in GC signaling occur at relapse, additional mechanisms of adaptive GC resistance are uncertain. We transplanted and treated 10 primary mouse T-lineage acute lymphoblastic leukemias (T-ALLs) initiated by retroviral insertional mutagenesis with GC dexamethasone (DEX). Multiple distinct relapsed clones from 1 such leukemia (T-ALL 8633) exhibited discrete retroviral integrations that upregulated Jdp2 expression. This leukemia harbored a Kdm6a mutation. In the human T-ALL cell line CCRF-CEM, enforced JDP2 overexpression conferred GC resistance, whereas KDM6A inactivation unexpectedly enhanced GC sensitivity. In the context of KDM6A knockout, JDP2 overexpression induced profound GC resistance, counteracting the sensitization conferred by KDM6A loss. These resistant "double mutant" cells with combined KDM6A loss and JDP2 overexpression exhibited decreased NR3C1 mRNA and GR protein upregulation upon DEX exposure. Analysis of paired samples from 2 patients with KDM6A-mutant T-ALL in a relapsed pediatric ALL cohort revealed a somatic NR3C1 mutation at relapse in 1 patient and a markedly elevated JDP2 expression in the other. Together, these data implicate JDP2 overexpression as a mechanism of adaptive GC resistance in T-ALL, which functionally interacts with KDM6A inactivation.

Heterogeneity of tumor immune microenvironment of EGFR/ALK-positive tumors versus EGFR/ALK-negative tumors in resected brain metastases from lung adenocarcinoma

BackgroundPrevious studies found that lung adenocarcinomas (LUAD) with EGFR-positive and ALK-positive were less responsive to immunotherapy, which may be associated with a suppressive tumor immune microenvironment (TIME). Given the discordance...

Increased CD4/CD8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer: A prospective pilot study.

Despite optimal neoadjuvant chemotherapy only 40% of gastric cancer tumours achieve complete or partial treatment response. In the absence of treatment response, neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone. Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Predictive biomarkers detected using immunohistochemistry (IHC) methods may provide useful data regarding treatment response. To investigate the utility of CD4, CD8, Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma. Forty-three adult patients with gastric adenocarcinoma, of which 18 underwent neoadjuvant chemotherapy, were included in a prospective clinical cohort. Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa. Differences in expression of Galectin-3, E-cadherin, CD4+ and CD8+ molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC. Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria. Treatment response was defined as complete or near complete tumour response, whereas partial or poor/no response was defined as incomplete. Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1. Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test. Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy. We performed a preliminary multivariate analysis and power analysis to guide future study. Statistical analyses were completed using R 4.1.2. The ratio between CD4+ and CD8+ lymphocytes was significantly greater in treatment responsive tumours (Wilcoxon, P = 0.03). In univariate models, CD4+/CD8+ ratio was the only biomarker that significantly predicted favourable treatment response (Accuracy 86%, P < 0.001). Using a glmnet multivariate model, high CD4+/CD8+ ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response. Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4+ and CD8+ tumour infiltrating lymphocytes (Paired Wilcoxon, P = 0.002 and P = 0.008, respectively). Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules, whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers. We demonstrate that an elevated CD4+/CD8+ Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer.

The effects of medium cut-off and high-flux membranes on activated clotting time of patients on hemodialysis.

The interaction between blood and dialysis membrane increases the risk of clot formation. Membrane properties can interfere with coagulation activation during dialysis. Heparin is usually used to ensure anticoagulation, which can be monitored by the Activated Clotting Time (ACT) test. The purpose of this study was to compare the ACT of patients with chronic kidney disease (CKD) undergoing hemodialysis with high-flux (HF) and medium cut-off (MCO) membranes. This is a prospective, randomized, crossover study in which 32 CKD patients were dialyzed for 12 weeks with each membrane. Blood clotting measured by ACT was evaluated at the beginning, 2nd, and 4th hour of the dialysis session. Throughout the study, there were no changes in the dose or administration method of heparin. Patients mainly were middle-aged, non-black males on hemodialysis for eight years. Before randomization, ACT values were 132 ± 56, 195 ± 60, and 128 ± 32 seconds at pre-heparinization, 2nd and 4th hour, respectively. After 12 weeks, ACT values in HF and MCO groups were 129 ± 17, 205 ± 65 and 139 ± 38 seconds, and 143 ± 54, 219 ± 68 and 142 ± 45 seconds, respectively. An ANOVA model adjusted and unadjusted for repeated measures showed a significant time but no treatment or interaction effects. In an additional paired-sample analysis, no difference between ACT values of HF and MCO Groups was observed. There was no difference regarding the ACT test during dialysis therapy using HF or MCO membranes. This data suggests that no adjustment in the dose or administration method of heparin is necessary with the use of MCO dialysis membranes.

The Effect of Warm Ginger Water Foot Bath on Blood Pressure Reduction in Hypertensive Elderly at Sialang Baru

Hypertension is a degenerative disease, a disease that occurs due to aging, and lower’s the body’s organs productivity. The aim of this research is to know the effect of warm ginger water foot bath on blood pressure reduction in hypertensive elderly at Sialang Baru. The research design used is pre-experimental with pre and post-test designs. The technique of sampling purposive was performed on 20 respondents. The instrument was in observation form. The research results were obtained from the respondent’s average blood pressure before and after giving ginger warm water foot bath (systolic blood pressure 165.50 mmhg becomes 158,55 mmHg and diastolic 98.05 mmHg becomes 90,15 mmHg). The results of the study paired sample analysis showed p=value &lt;0,005, which means a warm ginger water foot bath is effective for lowering blood pressure hypertension in the elderly at Sialang Baru. It is recommended that the puskesmas can provide counseling and information to patients suffering from hypertension to do warm ginger water foot bath as herbal medicine for hypertension.&#x0D; Keywords: foot bath, hypertension, red ginger, warm water

Effect of mHealth Training on Treatment Adherence in Hemodialysis Patients

Background: Technological advancements and ease of communicating with and educating patients with kidney failure using various technologies have facilitated the achievement of treatment goals. Objectives: The present study aimed to examine the effect of mHealth training on treatment adherence in hemodialysis patients in Zahedan. Methods: This quasi-experimental study was conducted on 80 hemodialysis patients admitted to teaching hospitals in Zahedan in 2022. The participants were selected using convenience sampling and were divided into two intervention and control groups by allocation with permutation blocks. In addition to routine training, the participants in the intervention group received mHealth training in five areas of treatment adherence using a smartphone application (My Dialysis) developed by the researcher. The participants in the control group received only routine training. The data were collected by a demographic information form, the Media Literacy Questionnaire, and the End-Stage Renal Disease Adherence Questionnaire (ESRD-AQ) in both groups before and three months after the intervention. The collected data were analyzed with SPSS (version 26) using the paired and independent samples t-test, chi-square test, and analysis of covariance (ANCOVA) at the significance level of less than 0.05 (P &lt; 0.05). Results: The mean treatment adherence score for the patients in the control group increased from 1011.87 ± 150.96 before the intervention to 1110.62 ± 86.95 after the intervention, showing a significant increase (P &lt; 0.001). Besides, the mean treatment adherence score for the patients in the intervention group increased significantly from 1067.50 ± 122.24 before the intervention to 1161.25 ± 49.98 after the intervention (P &gt; 0.001). The results of ANCOVA to control for the significant effect of the pretest scores and the disease duration showed that the patients' mean treatment adherence scores in the two groups significantly differed after the intervention (P &lt; 0.05). Conclusions: This study confirmed the significant positive effects of mHealth training on the treatment adherence of dialysis patients. Thus, considering the effectiveness of routine training, mHealth training can be used with routine training in treatment programs for hemodialysis patients to improve their treatment adherence.

Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses

BackgroundAlterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM).ResultsWe identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract.ConclusionsAlterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of “mouth-to-gut” transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant “mouth-to-gut” transfer in a disease context.-ty1jDZXmZLP8xpyFozf8UVideo

Investigation of Cerebrospinal Fluid Electrolytes and Acid-Base Expressions in Asian Adults.

In previous literature, reference values for cerebrospinal fluid (CSF) may be based on patients who were not truly healthy, other species, or outdated information. In the present study, we performed a lumbar puncture in patients requiring spinal anesthesia by a reasonable indication to evaluate CSF parameters in healthy adults. All patients between the ages of 20 and 70 years scheduled for elective orthopedic or urologic surgery requiring spinal anesthesia were enrolled in this study. We measured electrolytes and gas tension analysis in CSF and whole blood samples in adult humans. A total of 28 patients were included with an average age of 44.2 years. The concentration of Na^+ in blood was slightly lower when compared with that in CSF. There were significantly higher levels of K^+ and Ca^(2+) in the blood when we compared with CSF. Significantly lower levels of Cl^- and Mg^(2+) in the blood were observed when compared with CSF. The glucose level of CSF was about half of that in blood. We provided updated reference values for various solutes in blood and CSF in adults. Analysis of CSF parameters and relevant paired blood samples is highly informative, helping clinicians diagnose a variety of central nervous system diseases.