Youngil Koh

Therapeutic effects of BCG vaccination in adult asthmatic patients: a randomized, controlled trial

BACKGROUND Bacille Calmette-Guérin (BCG) vaccination in humans induces Th1 immune responses. Th1 and Th2 cells are reciprocally regulated. OBJECTIVE To examine whether BCG vaccination of adult patients with asthma, a Th2-associated allergic disease, is clinically effective. METHODS Forty-three moderate-to-severe asthma patients were randomly assigned into groups that received percutaneous injection of 58.2 x 10(7) CFUs BCG (n = 22) or placebo (n = 21) in a double-blinded fashion, on the first day of a 12-week treatment period. Medications were adjusted every 4 weeks to maintain optimal asthma control. Spirometric measurements were performed before treatment and at weeks 4, 8, and 12 after vaccination. The daily peak expiratory flow rate values, asthma symptoms, and medications were also recorded. Tuberculin skin tests, and sputum inflammatory cell and cytokine analyses were carried out before treatment and 12 weeks after vaccination. RESULTS BCG vaccination significantly increased forced expiratory volume in 1 second and forced expiratory flow rate 25% to 75% at weeks 4, 8, and 12. Morning peak expiratory flow rate was significantly increased only during the first 4 weeks. Although the asthma symptom scores were not significantly changed, the weekly medication scores were significantly decreased. Tuberculin skin reactivities were significantly increased without significant alterations in induced sputum profiles. In contrast, medication scores and sputum eosinophils were significantly increased, and the interferon-gamma:interleukin-4 ratio in sputum was significantly decreased in the placebo group. CONCLUSIONS BCG vaccination improved lung function and reduced medication use in adults with moderate-to-severe asthma. This amelioration was accompanied by a suppressed Th2-type immune response, suggesting that BCG vaccination might be an effective therapeutic modality against asthma.

Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study

BACKGROUND The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood. PATIENTS AND METHODS Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome. RESULTS The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs. CONCLUSIONS We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.

Clinicopathologic Characteristics and Outcomes of Patients with Anaplastic Lymphoma Kinase-Positive Advanced Pulmonary Adenocarcinoma Suggestion for an Effective Screening Strategy for These Tumors

Introduction:The purpose of this study was to analyze the clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase (ALK)-positive advanced pulmonary adenocarcinoma and to devise an effective screening strategy to identify such patients. Methods:We screened advanced pulmonary adenocarcinoma patients to identify ALK-positive cases. The presence of ALK rearrangements was confirmed by fluorescence in situ hybridization. Results:Of the 221 screened patients, 45 demonstrated ALK rearrangements, and these individuals were younger than the ALK-negative patients (p < 0.001). The proportion of never smokers and light smokers was found not to differ according to the ALK status (p = 0.537). Epidermal growth factor receptor (EGFR) mutations and ALK rearrangements were found to be mutually exclusive. Thyroid-transcription factor-1 (TTF-1) expression was observed in all ALK-positive tumors for which immunohistochemistry data were available. The objective response rate and progression-free survival to first-line platinum-based chemotherapy showed no significant differences between ALK-positive and ALK-negative patients. On the other hand, no patient with ALK-positive tumors achieved objective tumor responses to EGFR tyrosine kinase inhibitors (TKIs). ALK rearrangements were not found among individuals who had EGFR mutations, an objective response to a previous EGFR TKI treatment or TTF-1-negative tumors. Conclusion:The clinical outcomes of platinum-based chemotherapy were found not to differ according to the ALK status. Both smokers and never/light smokers should be candidates for ALK screening. We suggest that the exclusion of patients with activating EGFR mutations, an objective response to previous EGFR TKIs, or TTF-1-negative tumors from ALK screening could be an effective enrichment strategy for ALK-positive cases.

Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation.

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer (NSCLC) are mutually exclusive. However, several exceptional cases harboring both genetic alterations have been reported. In this study, a total of 444 patients with lung adenocarcinoma were examined for their EGFR and ALK status at Seoul National University Hospital between July 2008 and September 2011. EGFR mutations and ALK translocations were detected in 228 (51.4%) and 34 (7.7%) patients, respectively. Four patients (0.9%) had both genetic alterations and three underwent curative surgery. One patient who received both EGFR tyrosine kinase and ALK inhibitors, separately showed an objective response to the ALK inhibitor alone. Considering our and previous studies, patients harboring both EGFR mutation and ALK translocation showed differential sensitivities to both targeted therapies, suggesting a variable dependence on EGFR and ALK oncogenes.

Multiplexed Gene Expression and Fusion Transcript Analysis to Detect ALK Fusions in Lung Cancer

Anaplastic lymphoma kinase gene (ALK) fusions have been identified in approximately 5% of non-small-cell lung carcinomas (NSCLCs) and define a distinct subpopulation of patients with lung cancer who are highly responsive to ALK kinase inhibitors, such as crizotinib. Because of this profound therapeutic implication, the latest National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology recommend upfront ALK screening for all patients with NSCLC. The Food and Drug Administration-approved companion diagnostic test (ie, fluorescence in situ hybridization) for identification of ALK-positive patients, however, is complex and has considerable limitations in terms of cost and throughput, making it difficult to screen many patients. To explore alternative screening modalities for detecting ALK fusions, we designed a combination of two transcript-based assays to detect for presence or absence of ALK fusions using NanoStrings nCounter technology. By using this combined gene expression and ALK fusion detection strategy, we developed a multiplexed assay with a quantitative scoring modality that is highly sensitive, reproducible, and capable of detecting low-abundant ALK fusion transcripts, even in samples with a low tumor cell content. In 66 archival NSCLC samples, our results were highly concordant to prior results obtained by fluorescence in situ hybridization and IHC. Our assay offers a cost-effective, easy-to-perform, high-throughput, and FFPE-compatible screening alternative for detection of ALK fusions.

Early metabolic response using FDG PET/CT and molecular phenotypes of breast cancer treated with neoadjuvant chemotherapy

BackgroundThis study was aimed 1) to investigate the predictive value of FDG PET/CT (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography) for histopathologic response and 2) to explore the results of FDG PET/CT by molecular phenotypes of breast cancer patients who received neoadjuvant chemotherapy.MethodsSeventy-eight stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. FDG PET/CTs were acquired before chemotherapy and after the first cycle of chemotherapy for evaluating early metabolic response.ResultsThe mean pre- and post-chemotherapy standard uptake value (SUV) were 7.5 and 3.9, respectively. The early metabolic response provided by FDG PET/CT after one cycle of neoadjuvant chemotherapy was correlated with the histopathologic response after completion of neoadjuvant chemotherapy (P = 0.002). Sensitivity and negative predictive value were 85.7% and 95.1%, respectively. The estrogen receptor negative phenotype had a higher pre-chemotherapy SUV (8.6 vs. 6.4, P = 0.047) and percent change in SUV (48% vs. 30%, P = 0.038). In triple negative breast cancer (TNBC), the pre-chemotherapy SUV was higher than in non-TNBC (9.8 vs. 6.4, P = 0.008).ConclusionsThe early metabolic response using FDG PET/CT could have a predictive value for the assessment of histopathologic non-response of stage II/III breast cancer treated with neoadjuvant chemotherapy. Our findings suggest that the initial SUV and the decline in SUV differed based on the molecular phenotype.Trial RegistrationClinicalTrials.gov: NCT01396655

Class III β-tubulin, but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma

BACKGROUND Recent researches revealed that class III beta-tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in head and neck squamous cell carcinoma (HNSCC) is not defined yet. We analyzed the significance of TUBB3 expression along with p53 and ERCC1 in locally advanced HNSCC patients receiving cisplatin-based induction chemotherapy. MATERIALS AND METHODS Retrospective review of medical records at Seoul National University Hospital between 1998 and 2007 was carried out. Immunohistochemical stain of TUBB3, p53, and ERCC1 was done in paraffin-embedded tumor tissue. We assessed response to treatment, progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). RESULTS Eighty-five patients with oropharyngeal, hypopharyngeal, and laryngeal cancers received induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (n = 55), or 5-FU, cisplatin, and docetaxel (Taxotere) (n = 30). Eighty-three received definitive treatment after induction chemotherapy, where 62 received radiotherapy and 21 received surgery. TUBB3-positive patients showed lower response rate than TUBB3-negative patients (69% versus 88%, P = 0.039). Shorter median PFS was observed in TUBB3-positive group (12 versus 47 months, P = 0.001). Shorter median OS was observed in TUBB-positive group not reaching statistical significance (30 versus 59 months, P = 0.072). TUBB3 status significantly influenced CSS (35 months versus not reached, P = 0.017). Positive p53 status was related to poorer OS and CSS. ERCC1 showed no influence on chemotherapy response, PFS, OS, and CSS. CONCLUSION TUBB3 is a predictive and prognostic marker along with well-known p53 in HNSCC patients receiving cisplatin-based induction chemotherapy. Clinical impact of ERCC1 is not evident in this setting.

Seasonal Difference in the Occurrence of Exercise-Induced Bronchospasm in Asthmatics: Dependence on Humidity

Background: Most studies on the effects of temperature and humidity on exercise-induced bronchospasm (EIB) in asthmatics have been carried out under indoor conditions. However, any asthmatic patient is exposed to varying climatic conditions. Objective: To investigate whether temperature or relative humidity plays a more important role in determining the degree of EIB in asthmatics under naturally exposed climate conditions. Methods: To exclude the effects of pollen on EIB, we enrolled 69 subjects with perennial asthma (mean ± SD: 20.1 ± 1.5 years). The subjects performed outdoor free running tests. They were divided into winter (n = 25), spring/autumn (n = 22), and summer (n = 22) groups according to the season when they performed the tests. Initial spirometry and skin prick tests were performed. Methacholine bronchial challenge testing and, one day later, the free running tests were done. Results: There were significant differences in temperature and relative humidity among the three groups: However, the relative humidity in winter did not differ from that in spring/autumn. There were no differences in pulmonary functions, airway responsiveness, and atopy score among the three groups. The percentage of cases of positive EIB – fall in forced expiratory volume in 1s FEV1 of >15% from baseline – in winter (84%, p < 0.05) or spring/autumn (86.4%, p < 0.05) was higher than that in summer (50%). However, the percentage of subjects with a positive EIB in winter did not differ from that in spring/autumn. The maximal percent fall in FEV1 after exercise in winter did not differ from that in spring/autumn. Conclusions: The occurrence of EIB is associated with environmental temperature and humidity. Under such climatic conditions as in Korea, relative humidity may be a more important factor than temperature in contributing to EIB in patients with perennial asthma.

Effects of BCG revaccination on asthma

In a study conducted 1 year ago, we found that Th1 immune enhancement following Bacille Calmette–Guérin (BCG) vaccination effectively suppressed human asthma. To investigate whether revaccination would further improve lung function, BCG vaccine was given again. Current lung function tended to improve in the Repeated BCG group (n = 9), but not in the Single BCG group (previously the placebo group) (n = 11), compared with that 1 year ago. The BCG vaccination improved lung function in both groups, and the Repeated BCG group showed a significant increase in the peripheral blood interferon γ/interleukin 4 ratio. These findings suggest that repeated BCG vaccinations might be effective in asthma therapy.

BCG Infection in Allergen-Presensitized Rats Suppresses Th2 Immune Response and Prevents the Development of Allergic Asthmatic Reaction

Recent investigations demonstrate that bacille Calmette–Gu´erin (BCG), a potent inducer of Th1 response, infection prior to allergen sensitization inhibits Th2 immune responses to the allergen. However, it is not clear whether BCG infection in allergen-presensitized rats switches off Th2 response and prevents allergic asthmatic reaction to the subsequent allergen exposure. In this study we investigate whether BCG infection in ovalbumin (OVA)-presensitized Sprague-Dawley rats suppresses airway hyperresponsiveness and eosinophilic inflammation induced by OVA and Th2 cytokine production. BCG infection in OVA-presensitized rats significantly inhibited not only the sensitivity of airway smooth muscle to electrical field stimulation and acetylcholine but also absolute eosinophil counts in bronchoalveolar lavage fluid. As a correlate, interleukin-4 (IL-4) production significantly decreased and interferon-γ (IFN-γ) slightly increased, resulting in a markedly decreased ratio of IL-4–IFN-γ in OVA-presensitized rats with BCG infection. These results indicate that BCG infection in pre-sensitized rats suppresses allergic asthmatic reaction and Th2 immune response. It is possible from these findings that BCG vaccine may be used as an immunomodulating agent for the sensitized host with preestablished Th2 memory.