Precision Oncology Clinical Trials: A Systematic Review of Phase II Clinical Trials with Biomarker-Driven, Adaptive Design.

Purpose: Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. Materials and Methods: We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Results: Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration's marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Conclusion: Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs' efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.

Association of Metabolic Syndrome Components and Nutritional Status with Kidney Cancer in Young Adult Population: A Nationwide Population-Based Cohort Study in Korea.

The aim of this study was to determine the association of metabolic syndrome (MetS) with kidney cancer and the impact of age and gender on such an association. Using the Korean National Health Insurance Service database, 9,932,670 subjects who had check-ups in 2009 were followed up until the diagnosis of kidney cancer or death or until 2019. Kidney cancer was significantly associated with MetS (HR 1.56). This association was higher in the younger age group (HR: 1.82, 1.5, and 1.37 in 20-39 years, 40-64 years, and ≥65 years, respectively). In terms of the association of kidney cancer with obesity and central obesity, young-aged males showed higher HR for kidney cancer than old-aged ones (HR of obesity: 1.96, 1.52, and 1.25; HR of central obesity: 1.94, 1.53, and 1.3 in 20-39 years, 40-64 years, ≥65 years, respectively), while young-aged females showed lower HR. Kidney cancer was associated with obesity and MetS. The association was higher in younger populations than in older ones. Regarding gender, MetS, obesity, and central obesity showed higher associations with kidney cancer in younger aged male population, while there was no significant difference in such associations according to age in the female population.

The value measurement of emerging therapeutics in renal cell carcinoma: ASCO value framework and ESMO-MCBS.

PURPOSE: Rapid development of novel therapeutics in renal cell carcinoma (RCC) has led to financial burden for patients and society. Value including clinical benefit, toxicity affecting quality of life and cost-effectiveness are a concern, prompting the need for tools to facilitate value assessment of therapeutics. This study reviews the value assessment tools, and evaluates the value of emerging therapeutics in RCC. MATERIALS AND METHODS: Two medical oncologists used American Society of Clinical Oncology value framework (ASCO VF) v2.0 and European Society for Medical Oncology-magnitude of clinical benefit scale (ESMO-MCBS) v1.1 to phase 3 trials evaluating first-line therapy in patients with metastatic RCC. Follow-up (FU) reports and extended survival data were included. Equivocal aspects and limitations of the tools were discussed. RESULTS: Six trials (COMPARZ, CheckMate 214, JAVELIN renal 101, Keynote 426, CLEAR, and CheckMate 9ER) were assessed. The control arm was standard-of-care sunitinib in all trials. ASCO VF's net health benefit, calculated as clinical benefit, toxicity and other bonus point was 11 in pazopanib, 41.9 in nivolumab plus ipilimumab, 22.4 in axitinib plus avelumab, 48.7 in axitinib plus pembrolizumab, 35.2 in lenvatinib plus pembrolizumab, and 50.8 in cabozantinib plus nivolumab. A higher score means a greater treatment benefit. ESMO-MCBS gave grade 5 to nivolumab plus ipilimumab, 4 to pazopanib, lenvatinib plus pembrolizumab and cabozantinib plus nivolumab, 3 to axitinib plus avelumab or pembrolizumab. Both tools had unclear aspects to be applied to clinical practice, and should be more clearly defined, such as endpoint for determining survival benefits or how to standardize quality of life and toxicity. CONCLUSIONS: ASCO VF and ESMO-MCBS were applied to evaluate the newly emerging drugs in RCC and assessed their value. In-depth discussion by experts in various fields is required for appropriate clinical application in a real-world setting.

Perioperative Systemic Chemotherapy for Colorectal Liver Metastasis: Recent Updates.

The liver is the most common site of metastases for colorectal cancer. Complete resection in some patients with resectable liver metastases (LM) can lead to long-term survival and cure. Adjuvant systemic chemotherapy after complete resection of LM improves recurrence-free survival; however, the overall survival benefit is not clear. In selected patients, preoperative systemic treatment for metastatic colorectal cancer can convert unresectable to resectable cancer. This review will focus on patient selection, and integration of perioperative and postoperative systemic treatment to surgery in resectable and initially unresectable LM. Additionally, new drugs and biomarkers will be discussed.

Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells.

BACKGROUND: The mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells. METHODS: The ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry. RESULTS: TamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells. CONCLUSIONS: The EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.

Value Frameworks: Adaptation of Korean Versions of Value Frameworks for Oncology.

This study sought to adapt the existing value framework (VF) to produce a reliable and valid Korean oncology VF. Two VFs developed by The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) were selected for examination in the present study. Forward and backward translations were conducted for six high-priced drugs indicated for non-small-cell lung cancer and multiple myeloma. Inter-rater reliability was measured based on the intraclass correlation coefficient (ICC) and variation was described using the coefficient of variation. The relative weights of factors critically considered by Korean oncologists were derived following the analytic hierarchy process (AHP), and focus group interviews (FGIs) were used to obtain qualitative data regarding the applications of these two VFs in the Korean setting. The ICCs of the Korean VFs were 0.895 (0.654-0.983) for ASCO and 0.726 (0-0.982) for ESMO translations, suggesting excellent reliability for ASCO and good reliability for ESMO. AHP demonstrated that clinical benefit has the highest priority, which is consistent with the ASCO VF. The FGIs suggested that the result for AHP is acceptable and that both ESMO and ASCO VFs should be used complementarily. Although further evaluation with a larger sample size is needed, the Korean versions of ESMO/ASCO VFs are valid and reliable tools and are acceptable to Korean stakeholders, yet they should be applied with caution.

Real-World Clinical Data of Palbociclib in Asian Metastatic Breast Cancer Patients: Experiences from Eight Institutions.

PURPOSE: Use of cyclin-dependent kinase 4/6 inhibitors improved survival outcome of hormone receptor (HR) positive metastatic breast cancer (MBC) patients, including Asian population. However, Asian real-world data of palbociclib is limited. We analyzed the real-world clinical practice patterns and outcome in HR-positive, MBC Asian patients treated with palbociclib. MATERIALS AND METHODS: Between April 2017 to November 2019, 169 HR-positive, human epidermal growth factor-2-negative MBC patients treated with letrozole or fulvestrant plus palbocilib were enrolled from eight institutions. Survival outcome (progression-free survival [PFS]), treatment response and toxicity profiles were analyzed. RESULTS: Median age of letrozole plus palbociclib (145 patients, 85.8%) and fulvestrant plus palbociclib (24 patients, 14.2%) was 58 and 53.5 years, with median follow-up duration of 14.63 months (range 0.2 to 33.9 months). Median PFS (mPFS) of letrozole plus palbociclib and fulvestrant plus palbociclib was 25.6 (95% confidence interval [CI], 19.1 to not reached) and 6.37 months (95% CI, 5.33 to not reached), comparable to previous phase 3 trials. In letrozole plus palbociclib arm, luminal A (hazard ratio, 2.86; 95% CI, 1.20 to 6.80; p=0.017) and patients with good performance (Eastern Cooperative Oncology Group 0-1 [hazard ratio, 3.68; 95% CI, 1.70 to 7.96]) showed better mPFS. In fulvestrant plus palbociclib group, chemotherapy naïve patients showed better mPFS (hazard ratio, 12.51, 95% CI, 1.59 to 99.17; p=0.017). The most common grade 3 or 4 adverse event was neutropenia (letrozole 86.3%, fulvestrant 88.3%). CONCLUSION: To our knowledge, this is the first real-world data of palbociclib reported in Asia. Palbociclib showed comparable benefit to previous phase 3 trials in Asian patients during daily clinical practice.

Clinical Characteristics of Clear Cell Ovarian Cancer: A Retrospective Multicenter Experience of 308 Patients in South Korea.

PURPOSE: The purpose of this study was to evaluate clinical characteristics and treatment pattern of ovarian clear cell carcinoma (OCCC) in Korea and the role of adjuvant chemotherapy in early stage. MATERIALS AND METHODS: Medical records of 308 cases of from 21 institutions were reviewed and data including age, performance status, endometriosis, thromboembolism, stage, cancer antigen 125, treatment, recurrence, and death were collected. RESULTS: Regarding stage of OCCC, it was stage I in 194 (63.6%), stage II in 34 (11.1%), stage III in 66 (21.6%), and stage IV in 11 (3.6%) patients. All patients underwent surgery. Optimal surgery (residual disease ≤ 1 cm) was achieved in 89.3%. Majority of patients (80.5%) received postoperative chemotherapy. The most common regimen was taxane-platinum combination (96%). Median relapse-free survival (RFS) was 138.5 months for stage I, 33.4 for stage II, 19.3 for stage III, and 9.7 for stage IV. Median overall survival (OS) were not reached, 112.4, 48.7, and 18.3 months for stage I, II, III, and IV, respectively. Early-stage (stage I), endometriosis, and optimal debulking were identified as favorable prognostic factors for RFS. Early-stage and optimal debulking were also favorable prognostic factors for OS. Majority of patients with early-stage received adjuvant chemotherapy. However, additional survival benefit was not found in terms of recurrence. CONCLUSION: Majority of patients had early-stage and received postoperative chemotherapy regardless of stage. Early-stage and optimal debulking were identified as favorable prognostic factors. In stage IA or IB, adding adjuvant chemotherapy did not show difference in survival. Further study focusing on OCCC is required.

Prognostic value of 18F-FDG PET parameters in patients with locally advanced non-small cell lung cancer treated with induction chemotherapy.

AIM: To investigate predictive and prognostic role of metabolic parameters using [18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with docetaxel-platinum induction chemotherapy (IC). METHODS: Medical records of 31 patients with pre- and post-IC 18 F-FDG PET were reviewed. Using 18 F-FDG PET, metabolic parameters, including metabolic tumor response, adjusted peak standardized uptake values using lean body mass at baseline (pre-SULpeak ) and after IC (post-SULpeak ), and percentage change of pre- and post-SULpeak (ΔSULpeak ), were assessed. RESULTS: Response rate (RR) was 71%, with a metabolic RR of 83.9%. Nineteen (61.3%) patients underwent surgery, R0 resection was achieved for 17 (89.5%) patients. Median relapse-free survival (RFS) and overall survival (OS) were 8.9 months (95% CI: 4.5-12.1) and 24.1 months (95% CI: 17.1-34.1), respectively. Post-SULpeak  < 2 was identified as a favorable prognostic factor for RFS (hazard ratio [HR]: 0.12; P = .004), while ΔSULpeak ≥60% and R0 resection were found as positive prognostic factors for OS (HR: 0.09 and 0.13; P = .011 and P = .042, respectively). Using a receiver operating characteristics curve, post-SULpeak  > 1.4 could predict recurrence with a sensitivity of 84% and a specificity of 100%. CONCLUSION: In patients with locally advanced NSCLC receiving IC, post-SULpeak and ΔSULpeak showed clinical significance for survival outcome.

Prognostic role of beclin-1 in locally advanced non-small cell lung cancer in patients receiving docetaxel-platinum induction chemotherapy.

BACKGROUND/AIMS: The outcome of local treatment for advanced non-small cell lung cancer (NSCLC) remains poor, with therapies such as induction chemotherapy (IC) yielding conflicting results. This study aimed to assess the clinicopathologic and prognostic significance of the excision repair cross-complementation group 1 (ERCC1), beclin-1, and glucose-regulated protein of molecular mass 78 (GRP78) in patients with locally advanced NSCLC receiving docetaxel-platinum IC, along with efficacy and safety. METHODS: This is a retrospective observational cohort study. We reviewed medical records of 31 NSCLC patients receiving docetaxel-platinum IC, and conducted immunohistochemical staining of ERCC1, beclin-1, and GRP78. RESULTS: Response rate was 67.8% with 10.7 months of median relapse-free survival (RFS) and 23.1 months of median overall survival (OS), and no treatment-related death was reported. High expression of ERCC1, beclin-1, and GRP78 was identified in 67.7%, 87.1%, and 67.7%, respectively. Expression of ERCC1 and GRP78 did not reveal statistical significance in survival, whereas high beclin-1 expression revealed longer OS (7.6 months vs. 23.2 months; log-rank p = 0.024). In multivariate analysis, histologic differentiation (hazard ratio [HR], 3.48; p < 0.001), stage (HR, 8.5; p = 0.024), and adjuvant treatment (HR, 16.1; p = 0.001) were related to RFS, and in OS, stage (HR, 5.4; p = 0.037), adjuvant treatment (HR, 8.6; p = 0.004), and beclin-1 expression (HR, 8.2; p = 0.011) were identified as significant prognostic factors. CONCLUSION: Our findings suggest that high beclin-1 expression predicts longer survival in locally advanced NSCLC and docetaxel-platinum IC is a treatment option that deserves consideration.

GRP78 Protein Expression as Prognostic Values in Neoadjuvant Chemoradiotherapy and Laparoscopic Surgery for Locally Advanced Rectal Cancer.

PURPOSE: We investigated the relationships between biomarkers related to endoplasmic reticulum stress proteins (glucose-regulated protein of molecular mass 78 [GRP78] and Cripto-1 [teratocarcinoma-derived growth factor 1 protein]), pathologic response, and prognosis in locally advanced rectal cancer. MATERIALS AND METHODS: All clinical stage II and III rectal cancer patients received 50.4 Gy over 5.5 weeks, plus 5-fluorouracil (400 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GRP78 and Cripto-1 proteins was determined by immunohistochemistry and was assessed in 101 patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). RESULTS: High expression of GRP78 and Cripto-1 proteins was observed in 86 patients (85.1%) and 49 patients (48.5%), respectively. Low expression of GRP78 protein was associated with a significantly high rate of down staging (80.0% vs. 52.3%, respectively; p=0.046) and a significantly low rate of recurrence (0% vs. 33.7%, respectively; p=0.008) compared with high expression of GRP78 protein. Mean recurrence-free survival according to GRP78 expression could not be estimated because the low expression group did not develop recurrence events but showed a significant correlation with time to recurrence, based on the log rank method (p=0.007). GRP78 also showed correlation with overall survival, based on the log rank method (p=0.045). CONCLUSION: GRP78 expression is a predictive and prognostic factor for down staging, recurrence, and survival in rectal cancer patients treated with 5-fluorouracil and leucovorin neoadjuvant CRT.

A Randomized Double-Blind, Double-Dummy, Multicenter Trial of Azasetron versus Ondansetron to Evaluate Efficacy and Safety in the Prevention of Delayed Nausea and Vomiting Induced by Chemotherapy.

PURPOSE: This study was conducted to evaluate the efficacy and safety of azasetron compared to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting. MATERIALS AND METHODS: This study was a multi-center, prospective, randomized, double-dummy, double-blind and parallel-group trial involving 12 institutions in Korea between May 2005 and December 2005. A total of 265 patients with moderately and highly emetogenic chemotherapy were included and randomly assigned to either the azasetron or ondansetron group. All patients received azasetron (10 mg intravenously) and dexamethasone (20 mg intravenously) on day 1 and dexamethasone (4 mg orally every 12 hours) on days 2-4. The azasetron group received azasetron (10 mg orally) with placebo of ondansetron (orally every 12 hours), and the ondansetron group received ondansetron (8 mg orally every 12 hours) with placebo of azasetron (orally) on days 2-6. RESULTS: Over days 2-6, the effective ratio of complete response in the azasetron and ondansetron groups was 45% and 54.5%, respectively (95% confidence interval, -21.4 to 2.5%). Thus, the non-inferiority of azasetron compared with ondansetron in delayed chemotherapy-induced nausea and vomiting was not proven in the present study. All treatments were well tolerated and no unexpected drug-related adverse events were reported. The most common adverse events related to the treatment were constipation and hiccups, and there were no differences in the overall incidence of adverse events. CONCLUSION: In the present study, azasetron showed inferiority in the control of delayed chemotherapy-induced nausea and vomiting compared with ondansetron whereas safety profiles were similar between the two groups.

Age specificity in general and rehabilitation medical services in children with cerebral palsy.

OBJECTIVE: To review the medical utilization in children with cerebral palsy according to age and discern particularities. METHODS: From January 2007 to December 2007, 10,659 children and adolescents between 1 and 18 years of age who had filed national insurance claims for a diagnosis of cerebral palsy were selected. Age was chosen as an independent variable, and the population was categorized into specific age groups to verify any differences in medical service utilization. Admission duration to rehabilitation, number of visits to rehabilitation outpatient clinics, numbers of admission dates and outpatient clinic visits for general medical services, number of rehabilitation utilizations, and type of rehabilitations treatment were selected as dependent variables. One-way ANOVA was used for statistical evaluation, and analysis was done with SAS software. RESULTS: In general medical use, adolescences diagnosed with cerebral palsy had the highest mean admission duration (p<0.001). The mean visit day to outpatient clinics for general medical services was highest for infants (p<0.001). In rehabilitation treatment, infants diagnosed with cerebral palsy had the highest mean admission duration (p<0.001). The mean visit day to outpatient clinics for rehabilitation treatment was highest for infants (p<0.001). CONCLUSION: Significant differences in use of general and rehabilitation medical services among pediatric age groups with cerebral palsy were evident. This implies that particular attention is necessary when setting up a national medical care policy for patient with cerebral palsy.

Secondary prophylaxis of docetaxel induced diarrhea with loperamide: case report.

Diarrhea is a common adverse event of docetaxel with 20%-40% of incidence and severe diarrhea occurs in 5%-6%. Several treatment guidelines for chemotherapy induced diarrhea (CID) exist, however the prophylaxis for that is not well known. We describe a new prophylactic approach for the CID with loperamide. A 72-yr-old male patient with stage IV non-small-cell lung cancer developed diarrhea repeatedly after docetaxel-cisplatin chemotherapy. His diarrhea persisted despite treatment including loperamide and fasting. However, the diarrhea was successfully prevented when loperamide was given before and after the chemotherapy. To our knowledge, this is the first report of prophylactic approach for the CID with loperamide.

Serum adiponectin as a useful marker for metabolic syndrome in type 2 diabetic patients.

BACKGROUND: Although adiponectin is generally known as a predictor of metabolic syndrome, potential of adiponectin as a predictor for metabolic syndrome in type 2 diabetes is debated. The purpose of this study is to determine the association between adiponectin and metabolic syndrome in patients with type 2 diabetes. METHODS: Adiponectin and the risk of metabolic syndrome were examined among 1013 type 2 diabetes patients who visited Huh's Diabetes Center from January 2003 to June 2006. Adiponectin levels were classified into quartile groups, and metabolic syndrome was defined according to the standard of National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III. Insulin sensitivity was directly assessed using the short insulin tolerance test (SITT) (Kitt: %/ min). RESULTS: Adiponectin was significantly correlated with metabolic syndrome components. The age-adjusted correlations between adiponectin and clinical parameters including metabolic components were significant; adiponectin was negatively correlated with waist circumference, diastolic blood pressure and triglyceride, and positively correlated with high-density lipoprotein (HDL) cholesterol. Subjects with metabolic syndrome showed lower adiponectin levels than those without metabolic syndrome. After multivariate adjustment, participants with lower adiponectin levels also had a higher risk for metabolic syndrome (OR for lowest quartiles 2.21; 95% CI, 1.51-3.24). Metabolic syndrome risk was stronger among those with low adiponectin and severe insulin resistance simultaneously. This study has shown additive effects of adiponectin and insulin resistance on metabolic syndrome. CONCLUSIONS: In type 2 diabetic patients, the adiponectin was a useful predictor of metabolic syndrome independent of potential confounding variables.

Serum adiponectin is associated with family history of diabetes independently of obesity and insulin resistance in healthy Korean men and women.

BACKGROUND: Adiponectin has been reported as a new risk factor for the development of diabetes. However, it is not clear whether adiponectin levels are associated with family history of diabetes (FHD). OBJECTIVE: The objective of this study was to measure the independent association of serum adiponectin with FHD in relation to insulin resistance and obesity. METHODS: In 2006, a cross-sectional study was conducted in which waist circumference (WC), body mass index (BMI), and serum adiponectin were measured in 5919 healthy Korean men and women. Multiple linear regression models were used to assess the association of serum adiponectin levels with FHD. The population was classified into two groups according to median values for each of the following variables: WC, BMI, and homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: The positive FHD group had higher HOMA-IR and lower adiponectin levels in both men and women than those without FHD. Adiponectin levels were significantly associated with FHD in men and women respectively, after adjusting for age, BMI, and alcohol consumption (P=0.0123 and 0.0004). The relationship between adiponectin and FHD was similar between the high and low insulin resistance, BMI, and WC groups in male non-smokers and in all Korean women. CONCLUSION: These results confirm that adiponectin levels are associated with FHD. These data also suggest that the association of serum adiponectin with FHD may be independent of obesity and insulin resistance.

The association between adiponectin and diabetes in the Korean population.

As indicators of obesity, waist circumference (WC), body mass index (BMI), and adiponectin are well-known risk factors for diabetes mellitus. The objectives of this study were to measure the independent association between these obesity indicators and diabetes and to examine the combined effect of these indicators on diabetes in a Korean population. The WC, BMI, and serum adiponectin were measured in 4459 healthy Koreans and were classified into tertile groups for men and women. The independent and combined associations of the obesity indicators with diabetes were measured using logistic regression analyses. Diabetes was defined as fasting serum glucose greater than 126 mg/dL or taking medication. Levels of adiponectin were inversely associated with BMI and WC and directly associated with age and high-density lipoprotein (HDL) cholesterol (P < .001). After adjusting for age, BMI, WC, and other lifestyle factors, low levels of adiponectin were associated with an increased prevalence of diabetes. Further adjustment for HDL cholesterol and triglyceride attenuated this association in women but not men. The combined effects of WC and adiponectin on diabetes progressively increased; however, the interaction of these 2 variables was not statistically significant. The combined effect of BMI and adiponectin on diabetes showed similar results. These results suggest that adiponectin was associated with diabetes. The association was independent of BMI and WC and was partly modified by HDL and triglyceride. There were no effect modifications of adiponectin with WC and BMI on diabetes.

Cytotoxicity and apoptosis induction of sodium fluoride in human promyelocytic leukemia (HL-60) cells.

The role of sodium fluoride (NaF) in cytotoxicity and induction of apoptosis was investigated by treating human promyelocytic leukemia (HL-60) cells with varying concentrations of NaF, from 0 to 250 ppm for different periods (0-72 h). At lower concentrations (0-50 ppm), no significant cytotoxicity was observed in response to NaF treatment. However, at higher concentrations (100-250 ppm), NaF reduced cell viability, and decreased DNA and protein biosynthesis capability in cultured HL-60 cells. The growth inhibitory and antiproliferative effects of NaF appear to be attributable to its induction of apoptotic cell death, as NaF induced morphological changes, internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells. NaF treatment also gradually decreased the expression of the anti-apoptotic protein Bcl-2, and increased activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase. These results provides important information towards understanding the mechanism by which NaF mediates cytotoxicity and apoptosis.