Jae Hwa Cho

Prognostic Impact of Minimal Pleural Effusion in Non–Small-Cell Lung Cancer

PURPOSE Minimal (< 10 mm thick) pleural effusion (PE) may represent an early phase of malignant PE, but its clinical relevance has rarely been studied. Therefore, we examined the proportion of minimal PE in patients with non-small-cell lung cancer (NSCLC) and its impact on survival. We also considered possible accumulation mechanisms in our data set. PATIENTS AND METHODS On the basis of PE status from chest computed tomography scans at diagnosis, 2,061 patients were classified into three groups: no PE, minimal PE, and malignant PE. Twenty-one variables associated with four factors-patient, stage migration, tumor, and treatment-were investigated for correlation with survival. RESULTS Minimal PE presented in 272 patients (13.2%). Of 2,061 patients, the proportion of each stage was the following: 5.2% stage I, 10.9% stage II, 13.2% stage IIIA, 23.8% stage IIIB, and 13.9% stage IV. Minimal PE correlated significantly with shorter survival time than did no PE (median survival time, 7.7 v 17.7 months; log-rank P < .001), even after full adjustment with all variables (adjusted hazard ratio, 1.40; 95% CI, 1.21 to 1.62). Prognostic impact of minimal PE was higher in early versus advanced stages (Pinteraction = .001). In 237 patients (87.8%) with minimal PE, pleural invasion or attachment as a direct mechanism was observed, and it was an independent factor predicting worse survival (P = .03). CONCLUSION Minimal PE is a commonly encountered clinical concern in staging NSCLCs. Its presence is an important prognostic factor of worse survival, especially in early-stage disease.

Long-term administration of acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid in obesity

Obesity is associated with an impairment of normal growth hormone (GH) secretion and blunted responses to all stimuli. A high plasma free fatty acid (FFA) level is frequently observed in obesity. FFA participates in the regulation of pituitary GH secretion. To determine whether the derangement of GH secretion in obesity is associated with high plasma FFA levels, tests with GH-releasing hormone (GHRH) and acipimox (ACX), an antilipolytic agent able to decrease FFA, were undertaken in six obese subjects and seven normal control subjects. In addition, the effect of prolonged suppression of FFA level on GH response to GHRH after administration of ACX for 1 month was also examined in each of the obese subjects. The GH response in obese subjects (median, 9.1 microg/L) to GHRH (1-29) (1 microg/kg intravenously [IV]) was significantly blunted as compared with normal control subjects (23.5 microg / L, P < .05). Basal FFA levels were higher in obese subjects (855.2 microEq / L than in normal control subjects (514.6 microEq / L, P < .05). One-dose ACX (500 mg) decreased FFA levels in both obese and normal subjects: the lowest FFA levels in obese subjects (158.3 microEq/L 2 to 2.5 hours after ACX were similar to those of normal control subjects (108.7 microEq/L). One-dose ACX potentiated GHRH-stimulated GH response in both obese and normal subjects. GH responses potentiated by ACX in obese subjects (27.1 microg/L) were similar to GH responses to GHRH in normal control subjects, but lower than in normal subjects treated with ACX plus GHRH (58.5 microg / L, P < .05). Thereafter, all of the obese subjects were treated with ACX for 1 month, after which the ACX plus GHRH tests were repeated. After 1 month of acipimox administration in the obese subjects, GH responses (38.8 microg/L) were significantly higher than those of obese subjects treated with GHRH and one-dose ACX plus GHRH (P < .05). They were similar to GH responses of normal control subjects receiving the one-dose ACX plus GHRH test. In conclusion, in obesity the prolonged suppression of FFA levels induced by long-term administration of ACX potentiated somatotrope responsiveness, likely acting at the pituitary level, suggesting that the duration of FFA suppression had an important relation to the magnitude of GH response.

Effect of BRCA1 Haplotype on Survival of Non–Small-Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy

PURPOSE To determine whether germ-line variations in BRCA1 affect outcome in non-small-cell lung cancer (NSCLC) patients treated with platinum combination chemotherapy. PATIENTS AND METHODS We evaluated the associations of four tagging BRCA1 polymorphisms and their haplotypes with treatment outcome in 300 NSCLC patients at stages IIIA (16%), IIIB (31%), and IV (53%). RESULTS The median age was 63 years (range, 28 to 89 years). Histologically, 139 (46.3%) of the patients had squamous cell carcinomas and 137 (45.7%) had adenocarcinomas. Patient median survival time (MST) was 13.0 months. We observed no significant association between any of the tagging polymorphisms [S1613G, IVS13-1893 (A>C), IVS12-1207 (C>T), and IVS12+112 (C>A)] and overall survival. Of the five haplotypes evaluated (AACC, AACA, GCTC, GATC, and AATC), the survival of patients with two copies of the AACC (wild-type) haplotype was significantly shorter than that of patients with zero to one copies (MST, 8.47 v 14.57 months; log-rank P = .0066), even after adjustment for body weight loss, performance status, stage, second-line treatment, and radiation therapy (hazard ratio = 2.097; 95% CI, 1.339 to 3.284). The survival of patients with squamous cell carcinoma and two copies was significantly shorter than that of other patients with squamous cell carcinoma (MST, 6.8 v 15.3 months; log-rank P = 3.6 x 10(-5)), whereas differences in survival between the two adenocarcinoma groups was not significant (log-rank P = .677). CONCLUSION These findings suggest that the AACC haplotype of the BRCA1 gene is an important prognostic marker in NSCLC patients treated with platinum combination chemotherapy.

Differential Effect of Polymorphisms of CMPK1 and RRM1 on Survival in Advanced Non-small Cell Lung Cancer Patients Treated with Gemcitabine or Taxane/Cisplatinum

Introduction: To determine whether genetic variations in CMPK1 or RRM1, which impact the pharmacodynamics of gemcitabine, differentially affect the outcomes of non-small cell lung cancer (NSCLC) patients treated with gemcitabine or taxane/cisplatinum. Methods: We conducted retrospective study evaluating the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane (159)/cisplatinum and 14 tagging single-nucleotide polymorphisms (tSNPs): 4 in CMPK1 and 10 in RRM1. Results: The wild-type genotypes of CMPK1 IVS1+1057 and IVS1−928 were associated with shorter overall survival in patients treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 1.97 and 1.89; Cox pBonferroni = 0.008 and 0.020), whereas this effect was not observed in patients treated with taxane/cisplatinum. No associations were observed for the other 2 CMPK1 or 10 RRM1 tSNPs. Analysis of the interaction between the CMPK1 and RRM1 genes showed that the survival of patients with CMPK1 IVS1+1057 CC and RRM1 IVS1−2374 TT, IVS7+25 AA, IVS7−425 AA, or IVS8+287 TT was significantly shorter when they were treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 3.00, 2.89, 3.14, and 3.00; Cox pBonferroni = 0.007, 0.012, 0.006, and 0.007). However, these effects were not observed in patients treated with taxane/cisplatinum. Conclusions: These findings suggest that polymorphisms of CMPK1 and their combination with those of RRM1 are helpful in identifying patients who will benefit less from a gemcitabine/cisplatinum as the first-line regimen.

The implication of elevated carcinoembryonic antigen level in pleural fluid of patients with non‐malignant pleural effusion

Objective:  The aim of this study was to evaluate the false positive rate for pleural fluid carcinoembryonic antigen (CEA) level in non‐malignant pleural effusions and to determine whether the falsely elevated CEA level has any relation to other biochemical parameters of pleural effusions.

Proteins involved in DNA damage response pathways and survival of stage I non-small-cell lung cancer patients

BACKGROUND Biological complexity leads to significant variation in the survival of patients with stage I non-small-cell lung cancer (NSCLC). DNA damage response (DDR) pathways play a critical role in maintaining genomic stability and in the progression of NSCLC. Therefore, the development of a prognostic biomarker focusing on DDR pathways is an intriguing issue. PATIENTS AND METHODS Expression of several proteins (ATM, ATMpS1981, γH2AX, 53BP1, 53BP1pS25, Chk2, Chk2pT68, MDC1, MDC1pS964, BRCA1pS1423, and ERCC1) and overall survival were investigated in 889 pathological stage I NSCLC patients. RESULTS Low expression of BRCA1pS1423 or ERCC1 was significantly associated with worse survival in the whole cohort of patients. Analysis performed based on histology revealed that low expression of γH2AX, Chk2pT68, or ERCC1 was a poor prognostic factor in squamous cell carcinoma patients [adjusted hazard ratio (aHR), Cox P: 1.544, 0.012 for γH2AX; 1.624, 0.010 for Chk2pT68; 1.569, 0.011 for ERCC1]. The analysis of the interaction between two proteins showed that this effect was more pronounced in squamous cell carcinoma patients. However, these effects were not detected in adenocarcinoma patients. CONCLUSIONS The proteins involved in DDR pathways exhibited differential expression between squamous cell carcinoma and adenocarcinoma and were important determinants of survival in stage I squamous cell carcinoma patients.BACKGROUND Biological complexity leads to significant variation in the survival of patients with stage I non-small-cell lung cancer (NSCLC). DNA damage response (DDR) pathways play a critical role in maintaining genomic stability and in the progression of NSCLC. Therefore, the development of a prognostic biomarker focusing on DDR pathways is an intriguing issue. PATIENTS AND METHODS Expression of several proteins (ATM, ATMpS1981, γH2AX, 53BP1, 53BP1pS25, Chk2, Chk2pT68, MDC1, MDC1pS964, BRCA1pS1423, and ERCC1) and overall survival were investigated in 889 pathological stage I NSCLC patients. RESULTS Low expression of BRCA1pS1423 or ERCC1 was significantly associated with worse survival in the whole cohort of patients. Analysis performed based on histology revealed that low expression of γH2AX, Chk2pT68, or ERCC1 was a poor prognostic factor in squamous cell carcinoma patients [adjusted hazard ratio (aHR), Cox P: 1.544, 0.012 for γH2AX; 1.624, 0.010 for Chk2pT68; 1.569, 0.011 for ERCC1]. The analysis of the interaction between two proteins showed that this effect was more pronounced in squamous cell carcinoma patients. However, these effects were not detected in adenocarcinoma patients. CONCLUSIONS The proteins involved in DDR pathways exhibited differential expression between squamous cell carcinoma and adenocarcinoma and were important determinants of survival in stage I squamous cell carcinoma patients.

Acute kidney injury in critically ill patients with pandemic influenza A pneumonia 2009 in Korea: a multicenter study.

OBJECTIVES We assessed the incidence and clinical characteristics of acute kidney injury (AKI) in critically ill patients infected with pandemic influenza A (H1N1) and its effect on clinical outcomes. METHODS We conducted a multicenter, retrospective, observational study of patients with pandemic H1N1-related critical illness admitted to intensive care units (ICUs) of 28 tertiary or referral hospitals in South Korea between September 1, 2009, and February 28, 2010. Outcomes were AKI within 72 hours after ICU admission and 30-day mortality. Acute kidney injury was defined according to the Risk, Injury, Failure, Loss, and End-stage renal failure criteria. RESULTS Of the 221 patients, 50 (22.6%) developed AKI within 72 hours after ICU admission. Independent risk factors for AKI were age (odds ratio [OR], 1.05; P = .003), chronic kidney disease (OR, 14.82; P = .004), and Sequential Organ Failure Assessment score (OR, 1.45; P < .001). Age (OR, 1.04; P = .003), Sequential Organ Failure Assessment score (OR, 1.28; P = .012), state of immune suppression (OR, 4.09; P = .01), mechanical ventilation (OR, 18.24; P = .001), corticosteroid use (OR, 3.09; P = .007), and AKI (OR, 2.86; P = .035) were significantly associated with 30-day mortality. CONCLUSIONS A significant number of patients with H1N1-related critical illness developed AKI within 72 hours of ICU admission, and this early development of AKI was associated with 30-day mortality.

A Case of Pulmonary Cryptococcosis with Non-Small Cell Lung Cancer in Idiopathic CD4+ T-Lymphocytopenia

Cryptococcus neoformans commonly causes opportunistic infections in immunocompromised patients, especially in patients with AIDS. CD4+ T-lymphocytopenia in AIDS indicates an increased risk of opportunistic infection and a decline in immunological function. Idiopathic CD4 T-lymphocytopenia (ICL) is characterized by depletions in the CD4+ T-cell subsets, without evidence of HIV infection. Immunodeficiency can exist in the absence of laboratory evidence of HIV infection, and T-cell subsets should be evaluated in patients who present with unusual opportunistic infections. We report a case of pulmonary cryptococcosis and lung cancer in a patient with persistently low CD4+ cell counts, without evidence of HIV infection.

Acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid levels in hyperthyroidism.

Hyperthyroidism is associated with an impairment of growth hormone (GH) responses to secretagogues. The aim of this study was to evaluate the effect of acipimox, an antilipolytic agent able to decrease free fatty acids (FFA), on GH response to GH-releasing hormone (GHRH) in hyperthyroid and normal control subjects. We studied six men with hyperthyroidism; seven normal men served as control subjects. Each subject underwent treatment with (1) 2 tablets of placebo orally or (2) 500 mg acipimox orally, 120 minutes before intravenous (IV) injection of 1 microgram/kg GHRH-(1-29)NH2. GH response to GHRH in hyperthyroid patients was markedly reduced; the mean peak GH response (9.6 +/- 1.0 microgram/L) and the area under the GH response curve (12.9 +/- 1.3 micrograms/L x 2 h) were lower than those of control subjects (25.7 +/- 1.8 micrograms/L, P < .05; 28.7 +/- 2.1 micrograms/L x 2 h, P < .05). Hyperthyroid patients had higher baseline levels of plasma FFA than control subjects (998.0 +/- 38.9 v 498.0 +/- 36.0 muEq/L, P < .01). Acipimox decreased FFA levels in both hyperthyroid and control subjects; the lowest FFA levels of hyperthyroid subjects induced by acipimox were similar to those of control subjects. After acipimox pretreatment, GH responses to GHRH increased significantly (P < .05); the mean peak plasma GH level (25.9 +/- 4.6 micrograms/L) was similar to the peak GH levels of control subjects during the GHRH test, and the area under the GH response curve (41.1 +/- 6.7 micrograms/L x 2 h) was even higher than that of control subjects with the GHRH test.(ABSTRACT TRUNCATED AT 250 WORDS)

Gender Differences in Susceptibility to Smoking among Patients with Lung Cancer

Background/Aims To determine whether female smokers are more or less susceptible to the detrimental pulmonary-function effects of smoking when compared to male smokers among patients with lung cancer. Methods Pack-years and pulmonary function indices were compared between 1,594 men and women with lung cancer ifferences in individual susceptibility to smoking were estimated using a susceptibility index formula. Results Of the patients, 959 (92.8%) men and 74 (7.2%) women were current smokers. Common histological types of lung cancer were squamous cell carcinoma, adenocarcinoma, and small cell carcinoma, among others. Women had a lower number of pack-years, forced expiratory volume in 1 second (FEV1, liters), forced vital capacity (FVC, liters), and total lung capacity (TLC, liters) compared to those of men (25.0 ± 19.2 vs. 42.9 ± 21.7 for pack-years; 1.4 ± 0.5 vs. 2.0 ± 0.6 for FEV1; 3.0 ± 0.7 vs. 2.0 ± 0.6 for FVC; 4.5 ± 0.8 vs. 5.7 ± 1.0 for TLC; all p < 0.001). The susceptibility index for women was significantly higher compared to that of men (1.1 ± 4.1 vs. 0.7 ± 1.1; p = 0.001). A significant inverse association was shown between the susceptibility index and TLC and FVC (r = -0.200 for TLC, -0.273 for FVC; all p < 0.001). Conclusions The results suggest that the detrimental effects of smoking on pulmonary function are greater in women, as compared to those in men, among patients with lung cancer.