Machine Learning-Directed Conversion of Glioblastoma Cells to Dendritic Cell-Like Antigen-Presenting Cells as Cancer Immunotherapy.

Immunotherapy has limited efficacy in glioblastoma (GBM) due to the blood-brain barrier and the immunosuppressed or "cold" tumor microenvironment (TME) of GBM, which is dominated by immune-inhibitory cells and depleted of CTL and dendritic cells (DC). Here, we report the development and application of a machine learning precision method to identify cell fate determinants (CFD) that specifically reprogram GBM cells into induced antigen-presenting cells with DC-like functions (iDC-APC). In murine GBM models, iDC-APCs acquired DC-like morphology, regulatory gene expression profile, and functions comparable to natural DCs. Among these acquired functions were phagocytosis, direct presentation of endogenous antigens, and cross-presentation of exogenous antigens. The latter endowed the iDC-APCs with the ability to prime naïve CD8+ CTLs, a hallmark DC function critical for antitumor immunity. Intratumor iDC-APCs reduced tumor growth and improved survival only in immunocompetent animals, which coincided with extensive infiltration of CD4+ T cells and activated CD8+ CTLs in the TME. The reactivated TME synergized with an intratumor soluble PD1 decoy immunotherapy and a DC-based GBM vaccine, resulting in robust killing of highly resistant GBM cells by tumor-specific CD8+ CTLs and significantly extended survival. Lastly, we defined a unique CFD combination specifically for the human GBM to iDC-APC conversion of both glioma stem-like cells and non-stem-like cell GBM cells, confirming the clinical utility of a computationally directed, tumor-specific conversion immunotherapy for GBM and potentially other solid tumors.

Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors - cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) - and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Dynamic and subtype-specific interactions between tumour burden and prognosis in breast cancer.

We investigated the relationship between the prognostic importance of anatomic tumour burden and subtypes of breast cancer using data from the Korean Breast Cancer Registry Database. In HR+/HER2+ and HR-/HER2-tumours, an increase in T stage profoundly increased the hazard of death, while the presence of lymph node metastasis was more important in HR+/HER2+ and HR-/HER2+ tumours among 131,178 patients with stage I-III breast cancer. The patterns of increasing mortality risk and tumour growth (per centimetre) and metastatic nodes (per node) were examined in 67,038 patients with a tumour diameter ≤ 7 cm and < 8 metastatic nodes. HR+/HER2- and HR-/HER2- tumours showed a persistent increase in mortality risk with an increase in tumour diameter, while the effect was modest in HER2+ tumours. Conversely, an increased number of metastatic nodes was accompanied by a persistently increased risk in HR-/HER2+ tumours, while the effect was minimal for HR-/HER2- tumours with > 3 or 4 nodes. The interactions between the prognostic significance of anatomic tumour burden and subtypes were significant. The prognostic relevance of the anatomic tumour burden was non-linear and highly dependent on the subtypes of breast cancer.

Long-term Survival Outcomes of Primary Breast Cancer in Women With or Without Preoperative Magnetic Resonance Imaging: A Matched Cohort Study.

AIMS: To investigate whether preoperative magnetic resonance imaging (MRI) in patients with primary breast cancer is predictive of disease-free (DFS) and overall survival and to determine the prognostic factors indicating survival. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. From 2009 to 2010, 828 women with primary breast cancer and preoperative MRI were matched with 1613 women without such imaging. Patients were matched with regards to 25 patient and tumour-related covariates. A Cox proportional hazards model was used to investigate the time to recurrence and to estimate the hazard ratio for preoperative MRI. Log-rank tests and Cox proportional hazards survival analysis were carried out on total recurrence DFS and overall survival in the unmatched datasets. RESULTS: In total, 799 matched pairs were available for survival analysis. The MRI group showed a tendency towards better survival outcome; however, there were no significant differences in DFS and overall survival. Age at diagnosis (DFS hazard ratio = 0.98; overall survival hazard ratio = 1.04), larger tumour size (DFS hazard ratio = 1.01; overall survival hazard ratio = 1.02), triple negative breast cancer (DFS hazard ratio = 2.64; overall survival hazard ratio = 3.44) and the presence of lymphovascular invasion (DFS hazard ratio = 2.12; overall survival hazard ratio = 2.70) were independent significant variables for worse DFS and overall survival. CONCLUSION: Preoperative MRI did not result in an improvement in a patient's outcome. Age at diagnosis, tumour size, molecular subtype and lymphovascular invasion were significant independent factors affecting both DFS and overall survival.

TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation.

Non-small cell lung cancer (NSCLC) remains one of the leading causes of death worldwide, and thus new molecular targets need to be identified to improve treatment efficacy. Although epidermal growth factor receptor (EGFR)/KRAS mutation-driven lung tumorigenesis is well understood, the mechanism of EGFR/KRAS-independent signal activation remains elusive. Enhanced TFAP2C (transcription factor activating enhancer-binding protein 2C) expression is associated with poor prognosis in some types of cancer patients, but little is known of its relation with the pathogenesis of lung cancer. In the present study, we found that TFAP2C overexpression was associated with cell cycle activation and NSCLC cell tumorigenesis. Interestingly, TFAP2C blocked AKAP12-mediated cyclin D1 inhibition by inducing the overexpression of oncogenic microRNA (miRNA)-183 and simultaneously activated cyclin-dependent kinase 6-mediated cell cycle progression by downregulating tumor-suppressive miRNA-33a. In a mouse xenograft model, TFAP2C promoted lung tumorigenesis and disease aggressiveness via the miR-183 and miR-33a pathways. The study provides a mechanism of mitogenic and oncogenic signaling via two functionally opposed miRNAs and suggests that TFAP2C-induced cell cycle hyperactivation contributes to lung tumorigenesis.

Comparison of mammography, sonography, MRI and clinical examination in patients with locally advanced or inflammatory breast cancer who underwent neoadjuvant chemotherapy.

OBJECTIVES: The purpose of this study was to determine the relative accuracies of mammography, sonography, MRI and clinical examination in predicting residual tumour size and pathological response after neoadjuvant chemotherapy for locally advanced or inflammatory breast cancer. Each prediction method was compared with the gold standard of surgical pathology. METHODS: 43 patients (age range, 25-62 years; mean age, 42.7 years) with locally advanced or inflammatory breast cancer who had been treated by neoadjuvant chemotherapy were enrolled prospectively. We compared the predicted residual tumour size and the predicted response on imaging and clinical examination with residual tumour size and response on pathology. Statistical analysis was performed using weighted kappa statistics and intraclass correlation coefficients (ICC). RESULTS: The ICC values between predicted tumour size and pathologically determined tumour size were 0.65 for clinical examination, 0.69 for mammography, 0.78 for sonography and 0.97 for MRI. Agreement between the response predictions at mid-treatment and the responses measured by pathology had kappa values of 0.28 for clinical examination, 0.32 for mammography, 0.46 for sonography and 0.68 for MRI. Agreement between the final response predictions and the responses measured by pathology had kappa values of 0.43 for clinical examination, 0.44 for mammography, 0.50 for sonography and 0.82 for MRI. CONCLUSION: Predictions of response and residual tumour size made on MRI were better correlated with the assessments of response and residual tumour size made upon pathology than were predictions made on the basis of clinical examination, mammography or sonography. Thus, the evaluation of predicted response using MRI could provide a relatively sensitive early assessment of chemotherapy efficacy.

Correlation between mammographic and sonographic findings and prognostic factors in patients with node-negative invasive breast cancer.

OBJECTIVES: The purpose of this study was to correlate sonographic and mammographic findings with prognostic factors in patients with node-negative invasive breast cancer. METHODS: Sonographic and mammographic findings in 710 consecutive patients (age range 21-81 years; mean age 49 years) with 715 node-negative invasive breast cancers were retrospectively evaluated. Pathology reports relating to tumour size, histological grade, lymphovascular invasion (LVI), extensive intraductal component (EIC), oestrogen receptor (ER) status and HER-2/neu status were reviewed and correlated with the imaging findings. Statistical analysis was performed using logistic regression analysis and intraclass correlation coefficient (ICC). RESULTS: On mammography, non-spiculated masses with calcifications were associated with all poor prognostic factors: high histological grade, positive LVI, EIC, HER-2/neu status and negative ER. Other lesions were associated with none of these poor prognostic factors. Hyperdense masses on mammography, the presence of mixed echogenicity, posterior enhancement, calcifications in-or-out of masses and diffusely increased vascularity on sonography were associated with high histological grade and negative ER. Associated calcifications on both mammograms and sonograms were correlated with EIC and HER-2/neu overexpression. The ICC value for the disease extent was 0.60 on mammography and 0.70 on sonography. CONCLUSION: Several sonographic and mammographic features can have a prognostic value in the subsequent treatment of patients with node-negative invasive breast cancer. Radiologists should pay more attention to masses that are associated with calcifications because on both mammography and sonography associated calcifications were predictors of positive EIC and HER-2/neu overexpression.

Short term results from GHRH analogue use in pre-menopausal breast cancer in Korea.

BACKGROUND: Hormone receptor-positive, pre-menopausal breast cancer patients can be treated by chemotherapy and/or ovarian suppression therapy. We reported our experience of gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa+T) or adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC-->T) in pre-menopausal women with hormone-response, node-negative breast cancer. METHODS: We retrospectively reviewed the records of 587 pre-menopausal women with hormone-responsive, node-negative breast cancer. Of these, 269 were treated with adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC-->T), and 318 were treated with gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa+T). Among them, 151 patients were treated by goserelin acetate 3.6 mg/kg and 125 patients were treated by leuprorelin acetate 3.75 mg/kg every 28 days subcutaneously. FINDINGS: At a median follow-up time of 30 months, eight patients had relapsed and three had died. DFS did not differ between the AC-->T and GnRHa+T groups. Of the three deaths, two were not related to breast cancer. The third patient, in the AC-->T group, died because of brain metastasis. GnRHa+T treatment had no effect on blood profile and did not cause the development of detrimental symptoms but decreased bone mineral density. The efficacy of leuprorelin was similar to that of goserelin. INTERPRETATION: GnRHa+T treatment can be an alternative treatment option in pre-menopausal women with endocrine-responsive, node-negative, breast cancer patients. The efficacy and tolerability of leuprorelin were similar to that of goserelin.

Tissue microarray-based study of patients with lymph node-negative breast cancer shows that HER2/neu overexpression is an important predictive marker of poor prognosis.

BACKGROUND: Despite good prognosis in most cases of lymph node (LN)-negative breast cancer, individual patients may have markedly different clinical outcomes. Here, we investigated the prognostic significance of HER2/neu overexpression in these tumors. MATERIALS AND METHODS: We employed a tissue microarray to examine HER2/neu overexpression by immunohistochemical staining in 359 consecutive patients diagnosed with LN-negative breast cancer, who underwent surgery from January 1993 to December 1998. RESULTS: HER2/neu overexpression was detected in 81 of 359 (23.1%) patients. The 10-year disease-free survival (DFS) values (81.2% versus 61.8%, P value 0.000) and overall survival (OS) rates (85.7% versus 63.9%, P value 0.000) were significantly different between cases with HER2/neu-negative or HER2/neu-positive tumors. After multivariate analysis, HER2/neu status and tumor size were identified as independent prognostic factors for 10-year OS. Moreover, HER2/neu overexpression was significantly associated with poorer clinical outcomes in an intermediate-risk group identified by the St Gallen classification (10-year DFS, 79.6% versus 61.8%, P value 0.000; 10-year OS, 84.7% versus 63.9%, P value 0.000). CONCLUSIONS: Our results show that HER2/neu overexpression is an important independent prognostic factor for LN-negative breast cancer cases and support the theory that more intensive adjuvant chemotherapy is required in the population with HER2/neu overexpression.

Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide.

The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

Variations of clonal marrow stem cell lines established from human bone marrow in surface epitopes, differentiation potential, gene expression, and cytokine secretion.

Bone marrow has been considered to contain many different types of progenitor or stem cells. This study aims to establish a new strategy that provides for the rapid establishment of human clonal marrow stem cell (hcMSC) lines with a relatively small amount of bone marrow aspirate and to characterize newly generated hcMSC lines for their cell phenotype, differentiation potential, lineage-specific gene expression, and cytokine secretion. Human cMSC lines were generated with human bone marrow aspirates using a new protocol, called the subfractionation culturing method. The newly established hcMSC lines were analyzed for their cell surface epitopes by fluorescence-activated cell sorting (FACS), differentiation potential by in vitro differentiation assays, lineage-specific gene expression by RT-PCR, and cytokine secretion by enzyme-linked immunoassay (ELISA). The overall profile of the cell-surface epitopes of the newly established hcMSC lines was similar to those of the known MSCs. These hcMSC lines were capable of differentiating into multilineages with some differences in differentiation capability. In addition, these hcMSC lines secrete high levels of transforming growth factor-beta1 (TGF-beta1), leukemia inhibitory factor (LIF), TGF-alpha, and interleukein-10 (IL-10), again with some variation in each cell line. The newly designed protocol may be an efficient method to establish hcMSC lines rapidly with a relatively small amount of bone marrow sample, and these newly established hcMSC lines possess stem cell characteristics and exhibit some differences in cell-surface epitopes, differentiation potential, lineage-specific gene expression, and cytokine secretion.

Comparison of frame-based and frameless stereotactic hematoma puncture and subsequent fibrinolytic therapy for the treatment of supratentorial deep seated spontaneous intracerebral hemorrhage.

OBJECTIVE: This study compared the technical implications and clinical outcome of patients treated for an intracerebral hemorrhage using two minimally invasive procedures: frame-based stereotactic hematoma aspiration and frameless navigation-guided hematoma aspiration followed by fibrinolysis. METHODS: Thirty patients with a spontaneous supratentorial intracerebral hemorrhage, which was treated by a frame-based (n=15) and frameless (n=15) hematoma aspiration followed by subsequent fibrinolysis with urokinase, were retrospectively reviewed. The data for the two subsets of patients were analyzed with regard to hematoma reduction, Glasgow Coma Scale (GCS), and degree of weakness. RESULTS: In the frame-based stereotactic hematoma aspiration group, the volume of the hematoma was 15.4-100.0 mL (mean: 40.7+/-24.4), the GCS upon admission was 4-15 (mean: 10.1+/-3.0), and the grade of weakness upon admission was 1-5 (mean: 2.1+/-0.9). On the other hand, in the frameless navigation-guided hematoma aspiration group, the hematoma volume was 15.2-62.0 mL (mean: 30.0+/-15.2), the GCS upon admission was 7-15 (mean: 13.0+/-2.4), and the grade of weakness upon admission was 1-4 (mean: 2.3+/-1.2). The drainage catheter was in place for a mean duration of 5.1+/-2.4 days (range: 1-12 days). In the frame-based group, the initial hematoma was reduced by -115-88.5% (mean: 52+/-31.5) immediately after surgery, and 90.5% (41-100%) of the initial volume 14 days after surgery. In the frameless group, the initial hematoma was reduced by 11.7-90.8% (mean 57.3+/-25.1) immediately after surgery and 95.8% (87.7-100%) 14 days after surgery. The GCS score and the degree of weakness were evaluated 14 days after surgery, and the Glasgow outcome scale (GOS) score was evaluated at discharge. There were no statistically significant differences between the two groups. CONCLUSION: The frame-based group and the frameless group followed by fibrinolysis had similar outcomes, and both procedures effectively reduced the intracerebral hemorrhage volume within a short period of time. In addition, these procedures are simple, precise, safe, and brief with a very low rebleeding rate and mortality.

Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity.

Adaphostin is a dihydroquinone derivative that is undergoing extensive preclinical testing as a potential anticancer drug. Previous studies have suggested that the generation of reactive oxygen species (ROS) plays a critical role in the cytotoxicity of this agent. In this study, we investigated the source of these ROS. Consistent with the known chemical properties of dihydroquinones, adaphostin simultaneously underwent oxidation to the corresponding quinone and generated ROS under aqueous conditions. Interestingly, however, this quinone was not detected in intact cells. Instead, high performance liquid chromatography demonstrated that adaphostin was concentrated by up to 300-fold in cells relative to the extracellular medium and that the highest concentration of adaphostin (3000-fold over extracellular concentrations) was detected in mitochondria. Consistent with a mitochondrial site for adaphostin action, adaphostin-induced ROS production was diminished by >75% in MOLT-4 rho(0) cells, which lack mitochondrial electron transport, relative to parental MOLT-4 cells. In addition, inhibition of oxygen consumption was observed when intact cells were treated with adaphostin. Loading of isolated mitochondria to equivalent adaphostin concentrations caused inhibition of uncoupled oxygen consumption in mitochondria incubated with the complex I substrates pyruvate and malate or the complex II substrate succinate. Further analysis demonstrated that adaphostin had no effect on pyruvate or succinate dehydrogenase activity. Instead, adaphostin inhibited reduced decylubiquinone-induced cytochrome c reduction, identifying complex III as the site of inhibition by this agent. Moreover, adaphostin enhanced the production of ROS by succinate-charged mitochondria. Collectively, these observations demonstrate that mitochondrial respiration rather than direct redox cycling of the hydroquinone moiety is a source of adaphostin-induced ROS and identify complex III as a potential target for antineoplastic agents.

Association of obesity, serum glucose and lipids with the risk of advanced colorectal adenoma and cancer: a case-control study in Korea.

BACKGROUND: Previous studies on colorectal cancer risk suggest that obesity, serum lipids and glucose might be related to colorectal carcinogenesis. This case-control study was conducted to investigate the association between obesity, serum lipids and glucose, and the risk of advanced colorectal adenoma and cancer. METHODS: Patients with histologically confirmed colorectal cancers (n=105), same number of patients with advanced colorectal adenomas matched by age and sex, and the same number of controls matched by age and sex were selected in Hanyang University Guri Hospital between January 2002 and June 2004. RESULTS: Adenoma and cancer group showed significantly higher levels of mean body mass index and serum glucose. Cancer group also showed significantly lower mean serum lipids levels than controls. We used an unordered polytomous logistic model to calculate multivariate odds ratios for advanced adenoma and cancer relative to controls. Higher serum glucose level was more strongly associated with increased risk of cancer relative to controls (odds ratio, 3.0; 95% confidence interval, 0.9-9.8) than with increased risk of advanced adenoma (odds ratio, 2.1; 95% confidence interval, 0.9-5.4). Higher body mass index was strongly associated with increased risk of advanced adenoma (odds ratio, 10.8; 95% confidence interval, 4.6-25.3), but associated with attenuated risk of cancer (odds ratio, 2.3; 95% confidence interval, 0.9-5.8). Serum triglycerides and cholesterol levels were strongly associated with reduced risk of cancer (odds ratio, 0.3; 95% confidence interval, 0.1-0.8 and odds ratio, 0.2; 95% confidence interval, 0.1-0.6, respectively). CONCLUSIONS: Obesity and hyperglycaemia are positively related to advanced colorectal adenoma formation. Furthermore, hyperglycaemia plays an important role in progression to cancer. Findings on an inverse relationship between serum triglyceride and cholesterol levels and the risk of colorectal cancer may be the secondary results from metabolic or nutritional changes in advanced colorectal cancer patients and should be clarified in further studies.

Prognostic values of KAI1 and survivin expression in an infiltrating ductal carcinoma of the breast.

AIMS: To investigate KAI1 and survivin expression in infiltrating ductal carcinomas, and to evaluate the relationship between clinicopathological factors and KAI1 and survivin expression levels in breast cancers. METHODS AND RESULTS: KAI and survivin expression levels were measured in 62 patients, using immunohistochemical staining. Western blot analysis was performed on eight frozen cases. DNA ploidy was determined by flow cytometry. The results of the KAI1 expression analyses were as follows: in 14 cases (22.6%) levels were preserved (++), in 30 cases (48.4%) levels were reduced (+), in 18 cases (29.0%) no KAI1 expression was detected, so these were designated 'lost' (-). Results of assessments of survivin expression were as follows: six cases (9.7%) were strong positive (++), 28 cases (45.15%) were positive (+), and 28 cases (45.15%) were negative. Survivin (p=0.0009) and KAI1 (p=0.0091) expression levels were directly correlated with survival rate. However, no significant difference was determined to exist between survivin and KAI1 expression levels and the clinicopathological factors. DNA ploidy did not correlate with survivin and KAI1 expression levels and survival rate. Four different groups, according to their survivin and KAI1 expression levels, correlated with the clinical stage and survival rate. CONCLUSION: KAI1 and survivin expression levels might be prognostic factors in breast cancers.

Delayed occurrence of intracranial supratentorial chondroma following compound depressed skull fracture.

We describe an exceptional case of a frontal convexity chondroma arising at the site of a compound depressed skull fracture operated on 12 years earlier. We conclude that intracranial chondroma should be included in the differential diagnosis of a calcified mass for the patients who had had a compound, depressed skull fracture along the suture line, especially in cases of dural laceration by the fragmented bone.

Self-reported prevalence and risk factors of asthma among Korean adolescents: 5-year follow-up study, 1995-2000.

OBJECTIVES: The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires have shown that the prevalence of childhood asthma is increasing worldwide. Although Asian countries used to have lower prevalence rates of allergic disease than Western countries, this prevalence is increasing in several Asian countries. To determine whether the prevalence of childhood asthma is changing in Korean adolescents, we compared findings from nationwide cross-sectional surveys in 1995 and 2000 on populations of middle-school children using the Korean version of the ISAAC questionnaire. METHODS: We developed Korean versions of the ISAAC written (WQ) and video (AVQ) questionnaires for allergic diseases. In 1995, the enrolled population consisted of 15,481 children, ages 12-15, and encompassing all three grades in middle school, selected from 34 schools across the nation; the response rate was 97.3%. In 2000, 15,894 children were selected from 31 of the same schools, and the response rate was 96.4%. The SAS system version 8.0 was utilized for all statistical analyses. RESULTS: The WQ showed that the lifetime and 12-month prevalence of wheeze did not change from 1995 to 2000. While the 12-month prevalence rates of sleep disturbed by wheezing and night cough increased, the rates of severe attack of wheezing and exercise-induced wheeze did not change, over this period of time. The lifetime prevalence of asthma diagnosis, however, increased significantly, from 2.7% in 1995 to 5.3% in 2000, as did the 12-month prevalence of asthma treatment, from 1.0% in 1995 to 1.9% in 2000. The AVQ also showed increases in the lifetime and 12-month prevalence rates of wheeze at rest, exercise-induced wheeze, nocturnal wheeze, nocturnal cough, and severe wheeze over this period of time. These were especially because of significant increases in the Provincial cities of Korea. Interestingly, the 12-month prevalence of wheeze was consistently high in Cheju with low air pollution indices, whereas this rate was low in Ulsan and Ansan with very high air pollution indices. Risk factor analysis showed that body mass index (BMI), passive smoking, and living with a dog or cat, but not air pollution, were associated with higher risk of wheeze. CONCLUSIONS: In the 5-year period from 1995 to 2000, the prevalence of asthma symptoms has increased in Korean adolescents, much of it because of increases in Provincial Centers. BMI, passive smoking, and living with a dog or cat are important risk factors. Environmental factors other than air pollution may be associated with increases in asthma, especially in Provincial Centers.

Multimodal spinal anesthesia.

BACKGROUND AND OBJECTIVES: Cystoscopy and extracorporeal shock wave lithotripsy (ESWL) are common urologic procedures in the treatment of ureteral calculi. Spinal anesthesia with local anesthetics is the anesthetic technique of choice for these procedures. Sufentanil and/or clonidine have been combined with local anesthetics to provide effective and safe neuroaxial anesthesia. Our objectives were to review the efficacy and safety of combining both sufentanil and clonidine with reduced doses of intrathecal lidocaine in patients undergoing cystoscopy and ESWL. METHODS: We reviewed the medical records of 12 patients who underwent such urologic procedures using an intrathecal mixture consisting of 20 mg of lidocaine, 10 micrograms of sufentanil, and 50 micrograms clonidine from May 1st, 1998 to December 31st, 1998. Patients' demographics, intraoperative analgesia and adverse side effects as well as recovery times were reviewed. RESULTS: All 12 patients tolerated their urologic treatments using this combination of drugs without requiring conversion to another anesthetic technique or significant supplementation with intravenous analgesics. Motor power returned to normal by the end of the procedure. The systolic blood pressure dropped 26 +/- 8% intra-operatively and 25 +/- 9% postoperatively. The incidences of other adverse side effects were low. Time spent in recovery area was short, 45 +/- 15 minutes (mean +/- standard deviation). CONCLUSIONS: Intrathecal admixtures of sufentanil 10 micrograms, clonidine 50 micrograms, and lidocaine 20 mg can provided effective and prolonged analgesia in patients undergoing cystoscopy and ESWL. Patients had recovery of their motor power in their lower extremities by the end of the procedure. No urinary retention was noted. Mild hypotension was the most common adverse side effect and was the main confounding factor for the prolongation of the discharge time.