The effect of aroma lymphatic tressage on taxane-induced lower-extremity edema in breast cancer patients.

BACKGROUND: Taxanes are effective chemotherapy drugs for breast cancer care, but adverse effects pose a significant challenge in cancer treatment. Taxane-induced fluid retention and lower-extremity edema are two of the important dose-limiting toxicity and result in decreased quality of life (QoL). However, there is no standard of care to alleviate the symptoms. We conducted a clinical study to assess the efficacy of short-term aroma lymphatic tressage therapy (ALTT) in reducing taxane-induced edema in breast cancer patients. METHODS: In this phase 2 clinical trial, patients with edema of CTCAE grade 2 or higher were enrolled and conducted 8 sessions of ALTT. The primary endpoint was to determine the proportion of patients with a reduction in lower extremity circumference of 3% or more before and 6 weeks after starting ALTT. The change in QoL was assessed as the secondary endpoint using QoL questionnaires. RESULTS: A total of 37 breast cancer patients completed the protocol and were analyzed. The median sum of the 3-point circumference (thigh, calf, and ankle) was 230.8 cm (IQR 218-243) in the baseline and 220.2 cm (IQR 212-236) at the end of the study. The average decrease of circumference was 3.8%. About, 23 patients (62%) experienced a circumference decrease of 3% or more. An improvement in every scale of FACT-TAXANE and EORTC-QLQ-C30 was observed when comparing questionnaire results before and at the end of the intervention (P < 0.0001). CONCLUSION: Eight sessions of ALTT over 4 weeks were effective in reducing lower-extremity edema and resulted in improvement of QoL in patients with breast cancer.

Carbohydrate Intake Levels and the Risk of Metabolic Syndrome in Korean Populations: A Prospective Study.

In Korea and other Asian countries, traditional high-carbohydrate diets are increasingly associated with metabolic syndrome (MetS) and its complications. As dietary patterns shift, there is a growing need to assess the effect of these changes on health outcomes related to MetS. This study aimed to investigate the prospective relationship between carbohydrate consumption and the risk of MetS and its components. We analyzed data from 7902 participants from the Korean Association Resource, part of the Korean Genome and Epidemiology Study Dietary intakes, including carbohydrates and fiber, were assessed using a validated semi-quantitative food frequency questionnaire, allowing for the calculation of the proportion of total energy from carbohydrates (P_CARB) and the carbohydrate-to-fiber ratio to assess carbohydrate quality. Blood samples were collected after at least eight hours of fasting for laboratory analysis. We employed Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals, focusing on the relationship between the P_CARB and the risk of developing MetS and its individual components, while adjusting for carbohydrate quality. In the fully adjusted model, which accounted for carbohydrate quality as a covariate, individuals in the highest percentile of the P_CARB showed a significantly increased risk of MetS, hypertriglyceridemia, hypo-high density lipoprotein cholesterolemia, dyslipidemia, and high blood pressure, compared to those in the lowest P_CARB group. Spline curve analyses indicated that the risks for MetS and its components consistently escalated with increasing P_CARB, with all p-values for nonlinearity exceeding 0.05. The findings suggest that higher levels of P_CARB are associated with an increased risk of MetS and related conditions, except for high fasting glucose. These results highlight the importance of dietary awareness and potential adjustments for populations consuming high-carbohydrate diets.

Phytochemical Index and the Risk of Gastritis/Gastric Ulcer among Korean Adults: A Prospective Cohort Study.

Phytochemicals found in fruits, vegetables, and plant-based foods have potential protective effects against various diseases, including gastric disorders. This study aimed to analyze the longitudinal association between phytochemical intake and the risk of gastritis/gastric ulcer in Korean adults. This was a prospective cohort study, a community-based cohort conducted as part of the Korean Genome and Epidemiology Study, examining the association between phytochemical intake and the risk of gastritis/gastric ulcer in Korean adults. Dietary information was collected using a validated semi-quantitative food frequency questionnaire, and the phytochemical index (PI) was calculated. The study included 7377 Korean men and women aged 40-69 years without gastritis/gastric ulcer at baseline of the Korea Association Resource study in Korea. The incidence of gastritis/gastric ulcer was determined using a survey questionnaire administered by trained staff. Multivariate Cox proportional hazards regression was used to calculate the hazard ratio and 95% confidence interval to determine the association between PI and risk of gastritis/gastric ulcer. During the median follow-up period of 9.50 years, 729 cases were reported. The fully adjusted model showed a significantly lower risk of gastritis/gastric ulcer in the highest PI quartile compared to the lowest (hazard ratio: 0.78, 95% confidence interval: 0.61-0.98), and this association was linear (p for trend = 0.01). This research indicates that incorporating foods abundant in phytochemicals into one's diet could be associated with a reduced risk of developing gastritis/gastric ulcers. These findings underscore the importance of further investigating the role of phytochemical-rich diets in gastrointestinal health, as demonstrated in this study.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

Phase Ib and pharmacokinetics study of alpelisib, a PIK3CA inhibitor, and capecitabine in patients with advanced solid tumors.

Background: This phase Ib study was performed to determine the safety of combination capecitabine with alpleisib (phosphatidylinositol 3-kinase catalytic subunit p110α blockade) and determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination regimen in patients with advanced solid tumors refractory to standard therapy. The synergistic anti-tumor activity and pharmacokinetics (PK) were investigated. Methods: Dose escalation phases were conducted in patients with advanced solid cancers who were refractory to standard therapy regardless of PIK3CA mutation. Patients were administered orally once daily alpelisib (200mg and 300mg) and twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. The effect of alpelisib on the PK of capecitabine was assessed. Results: Patients with 6 colorectal cancer (three PIK3CA mutation) and 6 breast cancer (all PIK3CA mutation) were enrolled. The first three patients in dose level 0 (alpelisib 200mg daily, capecitabine 1,000 mg/m2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 1 (alpelisib increased to 300 mg daily, capecitabine 1,000mg twice daily), one of six patients had DLT (grade (Gr) 3 hyperglycemia). When dose level 2 (alpelisib 300mg daily, capecitabine 1,250 mg/m2 twice daily) was expanded to 3 patients, no patients had DLTs. The combination of alpelisib 300mg daily and capecitabine 1,250 mg/m2 twice daily was declared as the MTD/RP2D in patients with advanced solid tumors. The most common AEs were Gr 1-3 hyperglycemia (75.0%). Frequent all-grade, treatment-related AEs included Gr 2-3 nausea (75.0%), Gr 1-2 diarrhea (50.0%), Gr 1-2 hand-foot syndrome (41.7%), Gr 1-2 anorexia (41.7%), Gr 2 mucositis (33.3%). Antitumor activity was observed in patients with PIK3CA mutant breast cancer (3 partial response and 3 stable disease of total 6 patients). Alpelisib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine. Conclusions: The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.

Investigating miR-6880-5p in extracellular vesicle from plasma as a prognostic biomarker in endocrine therapy-treated castration-resistant prostate cancer.

BACKGROUND: Advancements in the diagnosis, treatment, and surveillance of castration-resistant prostate cancer (CRPC) have progressed considerably, but a new biomarker that combines existing clinical and pathological data could be useful for a more precise diagnosis and prognosis. Some investigations have found that extracellular vesicle (EV)-derived miRNAs play crucial roles in various types of malignant tumors. The objective of this study was to explore EV miRNA and identify its biologic function as a biomarker for the diagnosis and prognosis of CRPC. METHODS: Plasma samples were collected from five healthy donors (Control, CT) and 17 CRPC patients, categorizing into two groups based on their endocrine treatment response: partial response (PR; n = 10) and progressive disease (PD; n = 7). Candidate extracellular vesicle (EV) miRNAs were identified using miRNA microarray and RT-qPCR. The biological functions of the selected miRNAs were evaluated using the MTT assay, wound healing assay, trans-well assay, and RNA sequencing in CRPC cells after transient miRNA expression. RESULTS: Microarray analysis revealed a significant downregulation of EV-miR-6880-5p in the PD samples compared to both CT and PR samples (p < 0.01). The expression of EV-miR-6880-5p in CRPC patients was decreased compared with that CT group (p = 0.0336) using RT-qPCR. In the PR group, EV-miR-6880-5p was increased at follow-up compared with the baseline (p = 0.2803), while in the PD group, it decreased at follow-up compared with the baseline samples (p = 0.4356). Furthermore, overexpression of miR-6880-5p hampered cell proliferation, migration, and invasion, downregulated pathways associated with tumor progression, and simultaneously upregulated pathways associated with cell growth and apoptosis in CRPC cells. CONCLUSIONS: EV-miR-6880-5p shows promise as a prognostic biomarker in patients with CRPC. Further, prospective validations are necessary to evaluate the potential of these candidate miRNAs.

Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

AIMS: To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. RESULTS: A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. CONCLUSIONS: Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

Genome-Wide Polygenic Risk Score Predicts Incident Type 2 Diabetes in Women With History of Gestational Diabetes.

OBJECTIVE: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women. RESEARCH DESIGN AND METHODS: Using five independent cohorts representing four different ancestries (n = 1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility. RESULTS: Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (-0.08 vs. 0.31, P = 2.3 × 10-11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05-2.21, P = 0.03). In a model that includes age, family history of diabetes, systolic blood pressure, and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15-0.49, P = 3.0 × 10-4). Although there was variation, a similar trend was observed across study cohorts. CONCLUSIONS: In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D.

Higher Genetic Risk for Type 2 Diabetes Is Associated With a Faster Decline of ß-Cell Function in an East Asian Population.

OBJECTIVE: While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with ß-cell dysfunction cross sectionally, their association with the longitudinal change of ß-cell function remains largely unknown. RESEARCH DESIGN AND METHODS: We analyzed data from 6,311 participants without T2D at baseline (mean [SD] age 51.6 [8.7] years) from a community-based prospective cohort in Korea. Participants underwent biennial 2-h 75-g oral glucose tolerance tests (OGTTs) during 14 years of follow-up, and the OGTT-derived disposition index (DI) was used as a marker for ß-cell function. Genetic risk was quantified using the genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd-4th quintiles), and high (5th quintile) genetic risk. Lifestyle was assessed according to Life's Essential 8. RESULTS: During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%), and 188 (14.9%) participants developed T2D in the high, intermediate, and low genetic risk groups, respectively. Compared with the low genetic risk group, participants in the high genetic risk group had a 25% lower DI at baseline. Furthermore, in longitudinal analysis, we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs. -0.019, P = 2.1 × 10-3; per 1-SD increase in T2D PRS, P = 1.2 × 10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk groups. CONCLUSIONS: Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived ß-cell function at baseline but also a notably more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.

Molecular Classification of Breast Cancer Using Weakly Supervised Learning.

Purpose: The molecular classification of breast cancer is crucial for effective treatment. The emergence of digital pathology has ushered in a new era in which weakly supervised learning leveraging whole-slide images has gained prominence in developing deep learning models because this approach alleviates the need for extensive manual annotation. Weakly supervised learning was employed to classify the molecular subtypes of breast cancer. Methods: Our approach capitalizes on two whole-slide image datasets: one consisting of breast cancer cases from the Korea University Guro Hospital (KG) and the other originating from The Cancer Genomic Atlas dataset (TCGA). Furthermore, we visualized the inferred results using an attention-based heat map and reviewed the histomorphological features of the most attentive patches. Results: The KG+TCGA-trained model achieved an area under the receiver operating characteristics value of 0.749. An inherent challenge lies in the imbalance among subtypes. Additionally, discrepancies between the two datasets resulted in different molecular subtype proportions. To mitigate this imbalance, we merged the two datasets, and the resulting model exhibited improved performance. The attentive patches correlated well with widely recognized histomorphologic features. The triple-negative subtype has a high incidence of high-grade nuclei, tumor necrosis, and intratumoral tumor-infiltrating lymphocytes. The luminal A subtype showed a high incidence of collagen fibers. Conclusions: The artificial intelligence (AI) model based on weakly supervised learning showed promising performance. A review of the most attentive patches provided insights into the predictions of the AI model. AI models can become invaluable screening tools that reduce costs and workloads in practice.

Evaluating the effect of a mobile-based symptom monitoring system for improving physical function in patients with cancer during chemotherapy: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Symptoms due to chemotherapy are common in patients with cancer. Cancer-related symptoms are closely associated with the deterioration of physical function which can be associated with decreased quality of life and increased mortality. Thus, timely symptom identification is critical for improving cancer prognosis and survival. Recently, remote symptom monitoring system using digital technology has demonstrated its effects on symptom control or survival. However, few studies examined whether remote monitoring would contribute to retaining physical function among patients with cancer. Therefore, this study aimed to evaluate the effectiveness of mobile-based symptom monitoring in improving physical function among patients with cancer under chemotherapy. METHODS AND ANALYSIS: This study is a multicentre, open-label, parallel-group, randomised controlled trial. We will recruit 372 patients at three tertiary hospitals located in Seoul, South Korea. Study participants will be randomly assigned to either an intervention group receiving the ePRO-CTCAE app and a control group receiving routine clinical practice only. The primary outcome is changes in physical function from commencement to completion of planned chemotherapy. A linear mixed model will be performed under the intention-to-treat principle. The secondary outcomes include physical activity level; changes in pain interference; changes in depressive symptom; unplanned clinical visits; additional medical expenditure for symptom management; completion rate of planned chemotherapy; changes in symptom burden and health-related quality of life; and 1-year overall mortality. ETHICS AND DISSEMINATION: The study has been approved by the institutional review board and ethics committee at the three university hospitals involved in this trial. Written informed consent will be obtained from all the participants. The results of the trial will be submitted for publication in peer-reviewed academic journals and disseminated through relevant literatures. TRIAL REGISTRATION NUMBER: KCT0007220.

A 10-Gene Signature to Predict the Prognosis of Early-Stage Triple-Negative Breast Cancer.

Purpose: Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies. Materials and Methods: In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing. Results: By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor ß diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores. Conclusion: Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.

Integrated clinical and genomic models using machine-learning methods to predict the efficacy of paclitaxel-based chemotherapy in patients with advanced gastric cancer.

BACKGROUND: Paclitaxel is commonly used as a second-line therapy for advanced gastric cancer (AGC). The decision to proceed with second-line chemotherapy and select an appropriate regimen is critical for vulnerable patients with AGC progressing after first-line chemotherapy. However, no predictive biomarkers exist to identify patients with AGC who would benefit from paclitaxel-based chemotherapy. METHODS: This study included 288 patients with AGC receiving second-line paclitaxel-based chemotherapy between 2017 and 2022 as part of the K-MASTER project, a nationwide government-funded precision medicine initiative. The data included clinical (age [young-onset vs. others], sex, histology [intestinal vs. diffuse type], prior trastuzumab use, duration of first-line chemotherapy), and genomic factors (pathogenic or likely pathogenic variants). Data were randomly divided into training and validation sets (0.8:0.2). Four machine learning (ML) methods, namely random forest (RF), logistic regression (LR), artificial neural network (ANN), and ANN with genetic embedding (ANN with GE), were used to develop the prediction model and validated in the validation sets. RESULTS: The median patient age was 64 years (range 25-91), and 65.6% of those were male. A total of 288 patients were divided into the training (n = 230) and validation (n = 58) sets. No significant differences existed in baseline characteristics between the training and validation sets. In the training set, the areas under the ROC curves (AUROC) for predicting better progression-free survival (PFS) with paclitaxel-based chemotherapy were 0.499, 0.679, 0.618, and 0.732 in the RF, LR, ANN, and ANN with GE models, respectively. The ANN with the GE model that achieved the highest AUROC recorded accuracy, sensitivity, specificity, and F1-score performance of 0.458, 0.912, 0.724, and 0.579, respectively. In the validation set, the ANN with GE model predicted that paclitaxel-sensitive patients had significantly longer PFS (median PFS 7.59 vs. 2.07 months, P = 0.020) and overall survival (OS) (median OS 14.70 vs. 7.50 months, P = 0.008). The LR model predicted that paclitaxel-sensitive patients showed a trend for longer PFS (median PFS 6.48 vs. 2.33 months, P = 0.078) and OS (median OS 12.20 vs. 8.61 months, P = 0.099). CONCLUSIONS: These ML models, integrated with clinical and genomic factors, offer the possibility to help identify patients with AGC who may benefit from paclitaxel chemotherapy.

The clinical effect of an electric massage chair on chemotherapy-induced nausea and vomiting in cancer patients: randomized phase II cross-over trial.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse events in cancer patients and can negatively affect their quality of life (QoL). This study aimed to evaluate the clinical efficacy of an electric massage chair (EMC) for the treatment of CINV. METHODS: A randomized phase II cross-over trial was conducted on solid cancer patients who received moderate (MEC) to high emetogenic chemotherapy (HEC). The participants were randomly assigned to receive their first chemotherapy either on a standard bed (Group A) or in an EMC (Group B) during the infusion. The patients were then crossed over to the next cycle. CINV and QoL questionnaires were collected from the participants. RESULTS: A total of 59 patients completed the trial protocol and were included in the analysis, with 29 and 30 patients in Groups A and B, respectively. The mean INVR (Index of Nausea, Vomiting, and Retching) score in the 2nd day of the first cycle was higher in Group B (3.63 ± 5.35) than Group A (2.76 ± 4.78), but the difference was not statistically significant (p = 0.5367). The complete response rate showed little difference between the groups. Among the high-emetic risk subgroups, patients who received HEC (p = 0.04595), younger patients (p = 0.0108), and non-colorectal cancer patients (p = 0.0495) presented significantly lower CINV scores when EMC was applied. CONCLUSION: Overall, there was no significant difference in INVR scores between standard care and EMC. Applying EMC at the first chemotherapy infusion may help preserve QoL and reduce CINV in high-risk patients. TRIAL REGISTRATION: KCT0008200, 17/02/2023, Retrospectively registered.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06).

BACKGROUND: Immune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage response and repair (DDR) genes can lead to genetic instability, often accompanied by a high tumor mutation burden (TMB). However, few studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies. METHODS: The KM-06 open-label, multicenter, single-arm, phase II trial evaluated the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations assessed by clinically targeted sequencing. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or for 24 months. The primary endpoint was the objective response rate (ORR) as per RECIST V.1.1 criteria. RESULTS: A total of 48 patients were enrolled in the study (median age 61, 58.3% male). The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3% each). Eight patients achieved a partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate was 60.0%. The median progression-free survival was 2.9 months. Treatment-related adverse events of any grade and grade ≥3 occurred in 44 (91.7%) and 4 (8.3%) patients, respectively. Clinically targeted sequencing data inferred both TMB and microsatellite instability (MSI). Using a TMB cut-off of 12 mut/Mb, there were significant differences in overall survival (p=0.00035), progression-free survival (p=0.0061), and the best overall response (p=0.05). In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high epithelial-mesenchymal transition signaling pathway activation. The responders exhibited a marked increase in PD-1-/Ki67+CD8 T cells at the early stage of treatment (C3D1) compared with non-responders (p=0.03). CONCLUSIONS: In this phase II trial, nivolumab demonstrated moderate efficacy and manageable toxicity in patients with solid cancer harboring DDR gene mutations. A high TMB (>12 mut/Mb) and MSI score (>2.5) determined through clinically target sequencing presented significant discriminatory power for the nivolumab response. TRIAL REGISTRATION NUMBER: NCT04761744.

Effectiveness of lumbar motion style acupuncture treatment on inpatients with acute low back pain: A pragmatic, randomized controlled trial.

BACKGROUND AND PURPOSE: This parallel, single-center, pragmatic, randomized controlled study aimed to investigate the effectiveness and safety of motion style acupuncture treatment (MSAT; a combination of acupuncture and Doin therapy) to reduce pain and improve the functional disability of patients with acute low back pain (aLBP) due to road traffic accidents. MATERIALS AND METHODS: Ninety-six patients with aLBP admitted to the Haeundae Jaseng Hospital of Korean Medicine in South Korea due to traffic accidents were treated with integrative Korean medicine (IKM) with additional 3-day MSAT sessions during hospitalization (MSAT group, 48 patients) or without (control group, 48 patients), and followed up for 90 days. RESULTS: The mean numeric rating scale (NRS) scores of low back pain (LBP) of the MSAT and control groups were both 6.7 (95% confidence interval [CI]: 6.3, 7.1) at baseline. After completing the third round of all applicable treatment sessions (the primary endpoint in this study), the mean NRS scores of the MSAT and control groups were 3.76 (95% CI: 3.54, 3.99) and 5.32 (95% CI: 5.09, 5.55), respectively. The difference in the mean NRS score between the two groups was 1.56 (95% CI: 1.25, 1.87). CONCLUSION: IKM treatment combined with MSAT can reduce pain and improve the range of motion of patients with aLBP. TRIAL REGISTRATION: This trial is registered at ClinicalTrial.gov (NCT04956458).

Large-Scale Cancer Genomic Analysis Reveals Significant Disparities between Microsatellite Instability and Tumor Mutational Burden.

BACKGROUND: Microsatellite instability (MSI) and tumor mutational burden (TMB) are predictive biomarkers for pan-cancer immunotherapy. The interrelationship between MSI-high (MSI-H) and TMB-high (TMB-H) in human cancers and their predictive value for immunotherapy in lung cancer remain unclear. METHODS: We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (n = 46,320) to determine the relationship between MSI-H and TMB-H in human cancers using adjusted multivariate regression models. Patient survival was examined using the Cox proportional hazards model. The association between MSI and genetic mutations was assessed. RESULTS: Patients (31-89%) with MSI-H had TMB-low phenotypes across 22 cancer types. Colorectal and stomach cancers showed the strongest association between TMB and MSI. TMB-H patients with lung cancer who received immunotherapy exhibited significantly higher overall survival [HR, 0.61; 95% confidence interval (CI), 0.44-0.86] and progression-free survival (HR, 0.65; 95% CI, 0.47-0.91) compared to the TMB-low group; no significant benefit was observed in the MSI-H group. Patients with TMB and MSI phenotypes showed further improvement in overall survival and PFS. We identified several mutated genes associated with MSI-H phenotypes, including known mismatch repair genes and novel mutated genes, such as ARID1A and ARID1B. CONCLUSIONS: Our results demonstrate that TMB-H and/or a combination of MSI-H can serve as biomarkers for immunotherapies in lung cancer. IMPACT: These findings suggest that distinct or combined biomarkers should be considered for immunotherapy in human cancers because notable discrepancies exist between MSI-H and TMB-H across different cancer types.

Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea.

Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Effects of a Remote Physical Activity Improvement Program on Male Office Workers with Metabolic Syndrome in Their 30s and 40s with Sedentary Behavior: A Randomized Controlled Trial.

PURPOSE: Sedentary office workers lack physical activity and have a high prevalence of metabolic syndrome (MetS). This study attempted to develop a remote physical activity improvement program for sedentary office workers and verify its effectiveness by applying it to male workers in their 30s and 40s with MetS. METHODS: This study used a randomized control group pretest-posttest design, and the study sample was 75 male workers recruited from an information and technology company. They were randomly assigned to either the intervention (n = 38) or control (n = 37) group. The remote physical activity improvement program was constructed based on the self-regulation theory emphasizing autonomy, and was conducted through non-face-to-face Zoom once a week for a total of 12 weeks. Health education, exercise training, small group meetings, and individual counseling were provided, and tailored text messages were sent to participants every day to encourage them to reflect on their lifestyle and practice exercise. RESULTS: The remote physical activity program significantly increased basic psychological needs (Z = -7.55, p < .001), intrinsic motivation (Z = -6.94, p < .001), health promotion behavior, (Z = -6.63, p < .001), and physical and physiological indicators (p < .05) in the intervention group compared to those in the control group. CONCLUSIONS: In managing MetS among office workers, it was found that remote education using the Zoom platform was effective, even during the coronavirus pandemic. As a strategy for health education in the workplace, remote education content needs to be developed and applied. TRIAL REGISTRATION: Clinical Research Information Service, KCT0009322.