Tai Sun Park

Sunitinib, a Novel Therapy for Anthracycline- and Cisplatin-refractory Malignant Pheochromocytoma

We report a case of malignant pheochromocytoma recurred after debulking surgery. A 17-year-old male patient visited our hospital for right flank pain. He had not experienced palpitations, headache, sweating or weight loss. Level of urinary catecholamine and its metabolite increased above normal values and abdominal computed tomography showed a huge right adrenal mass. One month after debulking surgery, anterior mediastinal and multiple liver metastases were found. These tumors had no response to two conventional regimens of combination chemotherapy (cyclophosphamide, vincristine, dacarbazine and anthracycline; and etoposide and cisplatin). We treated the patient with sunitinib, a multiple tyrosine kinase inhibitor. The tumor showed very good metabolic response to the therapy. In patient with malignant pheochromocytoma, sunitinib might be one therapeutic strategy for malignant pheochromocytomas.

Survival Benefit of Pemetrexed in Lung Adenocarcinoma Patients With Anaplastic Lymphoma Kinase Gene Rearrangements

BACKGROUND There have been conflicting findings regarding the efficacy of pemetrexed for lung cancer with anaplastic lymphoma kinase (ALK) rearrangement. This study was conducted to explore the benefits of pemetrexed in this patient group. PATIENTS AND METHODS Among patients who had received pemetrexed therapy between January 2010 and March 2014 for advanced stage lung adenocarcinoma, cases were selected with a confirmed ALK rearrangement, epidermal growth factor receptor (EGFR) mutation, or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. Clinical outcomes resulting from the pemetrexed-based regimen were analyzed according to the genetic alteration. RESULTS A total of 442 patients were enrolled, including 52 with ALK translocation, 188 with EGFR mutation, 34 with KRAS mutation, and 168 wild type patients. The mean age was 57 ± 11 years and women were predominant in the ALK-positive and EGFR mutant groups. Pemetrexed-platinum combination therapy was usually performed as first-line therapy, whereas pemetrexed monotherapy was usually used as second-line therapy and beyond. The response rate (RR) was greater in the ALK-positive group than in the other groups (26.9% vs. 12.8%, 8.8%, and 18.5%; P = .046). The median progression-free survival (PFS) of ALK-positive patients was longer than that of the others (7.8 months vs. 2.5, 2.3, and 2.9 months; P < .001). This benefit on survival was more evident when pemetrexed was used as a single agent (P < .001). CONCLUSION ALK-positive patients showed a greater RR and longer PFS with pemetrexed-based therapy than patients without ALK rearrangements, suggesting that pemetrexed should be preferentially considered for the treatment of ALK-positive lung adenocarcinoma when use of crizotinib is not feasible.

Study Design and Outcomes of Korean Obstructive Lung Disease (KOLD) Cohort Study

Background The Korean Obstructive Lung Disease (KOLD) Cohort Study is a prospective longitudinal study of patients with chronic obstructive pulmonary disease (COPD), asthma, or other unclassified obstructive lung diseases. It was designed to develop new classification models and biomarkers that predict clinically relevant outcomes for patients with obstructive lung diseases. Methods Patients over 18 years old who have chronic respiratory symptoms and airflow limitations or bronchial hyper-responsiveness were enrolled at 17 centers in South Korea. After a baseline visit, the subjects were followed up every 3 months for various assessments. Results From June 2005 to October 2013, a total of 477 subjects (433 [91%] males; 381 [80%] diagnosed with COPD) were enrolled. Analyses of the KOLD Cohort Study identified distinct phenotypes in patients with COPD, and predictors of therapeutic responses and exacerbations as well as the factors related to pulmonary hypertension in COPD. In addition, several genotypes were associated with radiological phenotypes and therapeutic responses among Korean COPD patients. Conclusion The KOLD Cohort Study is one of the leading long-term prospective longitudinal studies investigating heterogeneity of the COPD and is expected to provide new insights for pathogenesis and the long-term progression of COPD.

Evolving Early Lung Cancers Detected During Follow-Up of Idiopathic Interstitial Pneumonia: Serial CT Features

OBJECTIVE The purpose of this study was to evaluate the CT characteristics of newly developed lung cancer on CT studies obtained during follow-up of idiopathic interstitial pneumonia (IIP) before the appearance of identifiable tumors to the time of detectable lung cancer and thereafter. MATERIALS AND METHODS The study sample included 66 cancers diagnosed in 63 patients with IIP and lung cancer (59 men, four women; median age, 64 years; range, 40-85 years) between October 1998 and July 2012. Two radiologists independently reviewed 193 CT scans, determined the earliest presence of cancer and IIP, and evaluated tumor size, lobar and axial location, shape, and tumor density. Delay in clinical diagnosis and doubling time were measured with first and second follow-up CT examinations. RESULTS Interobserver agreement was good (κ > 0.77). The median tumor size was 17 mm (range, 5-30 mm) for the 46 T1a and 20 T1b cancers. Most of the tumors (42 [63.6%]) were located in the lower lobes. Thirty-five tumors (53.0%) were at the interface between fibrotic cyst and normal lung, and 21 (31.8%) were in the midst of fibrotic lung cysts. Most of the tumors had a round or oval shape (52 [78.8%]) and were solid (62 [93.9%]). The median delay in diagnosis was 46 days (range, 8-760 days). The first median doubling time was 77 days (range, 15-525 days), and the second was 53 days (27-248). CONCLUSION New lung cancers during CT follow-up of IIP usually appear as small solid nodules with a round or oval shape. Most cancers are located at the interface between fibrotic cyst and normal lung or in the midst of fibrotic cysts of the lower lobes of subpleural lung.

A combination of early warning score and lactate to predict intensive care unit transfer of inpatients with severe sepsis/septic shock

Background/Aims The modified early warning score (MEWS) is used to predict patient intensive care unit (ICU) admission and mortality. Lactate (LA) in the blood lactate (BLA) is measured to evaluate disease severity and treatment efficacy in patients with severe sepsis/septic shock. The usefulness of a combination of MEWS and BLA to predict ICU transfer in severe sepsis/septic shock patients is unclear. We evaluated whether use of a combination of MEWS and BLA enhances prediction of ICU transfer and mortality in hospitalized patients with severe sepsis/septic shock. Methods Patients with severe sepsis/septic shock who were screened or contacted by a medical emergency team between January 2012 and August 2012 were enrolled at a university-affiliated hospital with ~2,700 beds, including 28 medical ICU beds. Results One hundred patients were enrolled and the rate of ICU admittance was 38%. MEWS (7.37 vs. 4.85) and BLA concentration (5 mmol/L vs. 2.19 mmol/L) were significantly higher in patients transferred to ICU than those in patients treated in general wards. The combination of MEWS and BLA was more accurate than MEWS alone in terms of ICU transfer (C-statistics: 0.898 vs. 0.816, p = 0.019). The 28-day mortality rate was 19%. MEWS was the only factor significantly associated with 28-day mortality rate (odds ratio, 1.462; 95% confidence interval, 1.122 to 1.905; p = 0.005). Conclusions The combination of MEWS and BLA may enhance prediction of ICU transfer in patients with severe sepsis/septic shock.

Bronchoscopic lung volume reduction by endobronchial valve in advanced emphysema: the first Asian report

Purpose Endobronchial valve (EBV) therapy is increasingly being seen as a therapeutic option for advanced emphysema, but its clinical utility in Asian populations, who may have different phenotypes to other ethnic populations, has not been assessed. Patients and methods This prospective open-label single-arm clinical trial examined the clinical efficacy and the safety of EBV in 43 consecutive patients (mean age 68.4±7.5, forced expiratory volume in 1 second [FEV1] 24.5%±10.7% predicted, residual volume 208.7%±47.9% predicted) with severe emphysema with complete fissure and no collateral ventilation in a tertiary referral hospital in Korea. Results Compared to baseline, the patients exhibited significant improvements 6 months after EBV therapy in terms of FEV1 (from 0.68±0.26 L to 0.92±0.40 L; P<0.001), 6-minute walk distance (from 233.5±114.8 m to 299.6±87.5 m; P=0.012), modified Medical Research Council dyspnea scale (from 3.7±0.6 to 2.4±1.2; P<0.001), and St George’s Respiratory Questionnaire (from 65.59±13.07 to 53.76±11.40; P=0.028). Nine patients (20.9%) had a tuberculosis scar, but these scars did not affect target lobe volume reduction or pneumothorax frequency. Thirteen patients had adverse events, ten (23.3%) developed pneumothorax, which included one death due to tension pneumothorax. Conclusion EBV therapy was as effective and safe in Korean patients as it has been shown to be in Western countries. (Trial registration: ClinicalTrials.gov: NCT01869205).

Resolvin D1 prevents smoking-induced emphysema and promotes lung tissue regeneration

Purpose Emphysema is an irreversible disease that is characterized by destruction of lung tissue as a result of inflammation caused by smoking. Resolvin D1 (RvD1), derived from docosahexaenoic acid, is a novel lipid that resolves inflammation. The present study tested whether RvD1 prevents smoking-induced emphysema and promotes lung tissue regeneration. Materials and methods C57BL/6 mice, 8 weeks of age, were randomly divided into four groups: control, RvD1 only, smoking only, and smoking with RvD1 administration. Four different protocols were used to induce emphysema and administer RvD1: mice were exposed to smoking for 4 weeks with poly(I:C) or to smoking only for 24 weeks, and RvD1 was injected within the smoking exposure period to prevent regeneration or after completion of smoking exposure to assess regeneration. The mean linear intercept and inflammation scores were measured in the lung tissue, and inflammatory cells and cytokines were measured in the bronchoalveolar lavage fluid. Results Measurements of mean linear intercept showed that RvD1 significantly attenuated smoking-induced lung destruction in all emphysema models. RvD1 also reduced smoking-induced inflammatory cell infiltration, which causes the structural derangements observed in emphysema. In the 4-week prevention model, RvD1 reduced the smoking-induced increase in eosinophils and interleukin-6 in the bronchoalveolar lavage fluid. In the 24-week prevention model, RvD1 also reduced the increased neutrophils and total cell counts induced by smoking. Conclusion RvD1 attenuated smoking-induced emphysema in vivo by reducing inflammation and promoting tissue regeneration. This result suggests that RvD1 may be useful in the prevention and treatment of emphysema.

Heat shock protein 70 as a predictive marker for platinum-based adjuvant chemotherapy in patients with resected non-small cell lung cancer

OBJECTIVES Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We evaluated whether the expression of heat shock protein 70 (Hsp70) is associated with clinical outcomes in patients with completely resected NSCLC who were treated with or without adjuvant platinum-based chemotherapy. PATIENTS AND METHODS Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA were included. Immunohistochemical staining for Hsp70 was performed on surgical specimens and survival rates were compared by Hsp70 expression and adjuvant platinum-based chemotherapy. RESULTS Of 327 enrolled patients, Hsp70 expression was positive in 220 (67.3%). For patients who did not receive adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for patients who received adjuvant chemotherapy, those with Hsp70-positive tumors had a longer disease-free survival outcome than cases with Hsp70-negative tumors (not reached vs. 27.3 months; P=0.002), although there was no significant difference in overall survival (97.0 vs. 58.9 months, P=0.080). In the adjuvant chemotherapy group, multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death after adjusting for age, sex, performance status, pathologic stage, and histological type (disease-free survival: adjusted hazard ratio, 0.537; 95% CI, 0.362-0.796; P=0.002; overall survival: adjusted hazard ratio, 0.663; 95% CI, 0.419-1.051; P=0.080). CONCLUSION Hsp70 is a positive predictive factor in completely resected NSCLC with received platinum-based adjuvant chemotherapy.

Efficacy of Bronchoscopic Lung Volume Reduction by Endobronchial Valves in Patients with Heterogeneous Emphysema: Report on the First Asian Cases

Although many patients with severe emphysema have benefited from bronchoscopic lung volume reduction (BLVR) worldwide, experience of BLVR in Asian emphysema patients is scarce. Between July 2012 and March 2013, seven patients with advanced heterogeneous emphysema underwent BLVR in the Asan Medical Center. They had severe dyspnea and poor lung function (Modified Medical Research Council dyspnea scale 3-4; median forced expiratory volume in 1 sec [FEV1], 0.59 L [19.0 % predicted]; median 6-min walk distance [6MWD], 195 m). Endobronchial valves were inserted into the target lobe which was most hyperinflated and least perfused, and had no collateral ventilation with other lobes. Six patients showed clinical improvement after 1 month. Of them, 2 patients improved to dyspnea scale 1 and 4 patients did to scale 2 (P = 0.026). The median FEV1 increased from 0.59 to 0.89 L (51%; P = 0.028) and the median 6MWD increased from 195 to 252 m (29.2%; P = 0.028). Two patients developed a pneumothorax (one requiring drainage) and one patient experienced slight hemoptysis; however, there were no other serious adverse events. BLVR is effective in Asian advanced emphysema patients, with noted clinical improvements in lung function and exercise capacity. Graphical Abstract

Three-month Treatment Response and Exacerbation in Chronic Obstructive Pulmonary Disease

The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients. Graphical Abstract