Increased Apolipoprotein B/Apolipoprotein A-I Ratio Is Associated With Decline in Lung Function in Healthy Individuals: The Kangbuk Samsung Health Study.

BACKGROUND: Lung dysfunction and high apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio are both recognized risk factors for cardiovascular disease. However, few studies have examined the association between the apoB/ApoA-I ratio and lung function. Therefore, we investigated whether this ratio is associated with decreased lung function in a large healthy cohort. METHODS: We performed a cohort study on 68,418 healthy Koreans (34,797 males, mean age: 38.1 years) who underwent a health examination in 2019. ApoB/apoA-I ratio was categorized into quartiles. Spirometric values at the fifth percentile in our population were considered the lower limit of normal (LLN), which was used to define lung function impairment. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs), using the lowest quartile as the reference, were estimated to determine lung function impairment. RESULTS: Mean apoB/apoA-I ratio was 0.67 ± 0.21. Subjects with the highest quartile of this ratio had the lowest predicted forced expiratory volume in one second (FEV1%) and forced vital capacity (FVC%) after controlling for covariates (P < 0.001). However, FEV1/FVC ratio was not significantly different among the four quartiles (P = 0.059). Compared with the lowest quartile (Q1, reference), the aORs (95% CI) for FEV1% < LLN across increasing quartiles (from Q2 to Q4) were 1.216 (1.094-1.351), 1.293 (1.156-1.448), and 1.481 (1.311-1.672) (P for trend < 0.001), respectively. Similarly, the aORs for FVC% < LLN compared with the reference were 1.212 (1.090-1.348), 1.283 (1.147-1.436), and 1.502 (1.331-1.695) with increasing quartiles (P for trend < 0.001). However, the aORs for FEV1/FVC < LLN were not significantly different among groups (P for trend = 0.273). CONCLUSION: High apoB/apoA-I ratio was associated with decreased lung function. However, longitudinal follow-up studies are required to validate our findings.

Metabolically healthy and unhealthy obesity and the development of lung dysfunction.

We investigated the association of metabolically healthy (MH) and unhealthy (MU) obesity with incident lung dysfunction. This cohort study included 253,698 Korean lung disease-free adults (mean age, 37.4 years) at baseline. Spirometry-defined lung dysfunction was classified as a restrictive pattern (RP) or obstructive pattern (OP). We defined obesity as BMI ≥ 25 kg/m2 and MH as the absence of any metabolic syndrome components with a homeostasis model assessment of insulin resistance < 2.5: otherwise, participants were considered MU. During a median follow-up of 4.9 years, 10,775 RP cases and 7140 OP cases develped. Both MH and MU obesity showed a positive association with incident RP, with a stronger association in the MU than in the MH group (Pinteraction = 0.001). Multivariable-adjusted hazard ratios (95% CI) for incident RP comparing obesity to the normal-weight category was 1.15 (1.05-1.25) among the MH group and 1.38 (1.30-1.47) among MU group. Conversely, obesity was inversely associated with OP because of a greater decline in forced vital capacity than forced expiratory volume in 1 s. Both MH and MU obesity were positively associated with RP. However, the associations between obesity, metabolic health, and lung functions might vary depending on the type of lung disease.

The impact of insulin resistance on the association between metabolic syndrome and lung function: the Kangbuk Samsung Health Study.

BACKGROUND/OBJECTIVE: Metabolic syndrome (MS) is related to lung dysfunction. However, its impact according to insulin resistance (IR) remains unknown. Therefore, we evaluated whether the relation of MS with lung dysfunction differs by IR. SUBJECT/METHODS: This cross-sectional study included 114,143 Korean adults (mean age, 39.6 years) with health examinations who were divided into three groups: metabolically healthy (MH), MS without IR, and MS with IR. MS was defined as presence of any MS component, including IR estimated by HOMA-IR ≥ 2.5. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for lung dysfunction were obtained in MS, MS without IR, and MS with IR groups compared with the MH (reference) group. RESULTS: The prevalence of MS was 50.7%. The percent predicted forced expiratory volume in 1 s (FEV1%) and forced vital capacity (FVC%) showed statistically significant differences between MS with IR and MH and between MS with IR and MS without IR (all P < 0.001). However, those measures did not vary between MH and MS without IR (P = 1.000 and P = 0.711, respectively). Compared to MH, MS was not at risk for FEV1% < 80% (1.103 (0.993-1.224), P = 0.067) or FVC% < 80% (1.011 (0.901-1.136), P = 0.849). However, MS with IR was clearly associated with FEV1% < 80% (1.374 (1.205-1.566) and FVC% < 80% (1.428 (1.237-1.647) (all p < 0.001), though there was no evident association for MS without IR (FEV1%: 1.078 (0.975-1.192, P = 0.142) and FVC%: 1.000 (0.896-1.116, p = 0.998)). CONCLUSION: The association of MS with lung function can be affected by IR. However, longitudinal follow-up studies are required to validate our findings.

The effect of metabolic health and obesity on lung function: A cross sectional study of 114,143 participants from Kangbuk Samsung Health Study.

OBJECTIVE: Although the role of obesity-induced metabolic abnormalities in impaired lung function is well-established, the risk of impaired lung function among obese individuals without metabolic abnormalities, referred to metabolically-healthy obesity (MHO), is largely unexplored. Therefore, we evaluated the impact of MHO on lung function in a large health-screening cohort. METHODS: 114,143 subjects (65,342 men, mean age and BMI: 39.6 years and 23.6) with health examinations in 2019 were divided into four groups as follows: metabolically healthy non-obese (MHNO), MHO, metabolically unhealthy non-obese (MUHNO), and metabolically unhealthy obese (MUHO). Metabolic health was defined as fewer than two metabolic syndrome components. Obesity was defined as BMI ≥25 kg/m2. Adjusted odds ratios (aORs), using MHNO as a reference, were calculated to determine lung function impairment. RESULTS: Approximately one-third (30.6%) of the study subjects were obese. The prevalence of MHO was 15.1%. Subjects with MHO had the highest FEV1% and FVC% values but the lowest FEV1/FVC ratio (p<0.001). These results persisted after controlling for covariates. Compared with MHNO, the aORs (95% confidence interval) for FEV1% < 80% in MHO, MUHNO and MUHO were 0.871 (0.775-0.978), 1.274 (1.114-1.456), and 1.176 (1.102-1.366), respectively (P for trend = 0.014). Similarly, the aORs in MHO, MUHNO, and MUHO were 0.704 (0.615-0.805), 1.241 (1.075-1.432), and 1.226 (1.043-1.441), respectively, for FVC% < 80% (p for trend = 0.013). However, the aORs for FEV1/FVC<0.7 were not significantly different between groups (p for trend = 0.173). CONCLUSIONS: The MHO group had better lung function than other groups. However, longitudinal follow-up studies are required to validate our findings.

Decreased lung function is associated with vitamin D deficiency in apparently health, middle aged Koreans: the Kangbuk Samsung Health Study.

BACKGROUND/OBJECTIVES: There has been inconsistent relationships between serum vitamin D levels and lung function in previous studies. However, previous studies included patients with medical diseases, affecting both vitamin D levels and lung function. Considering this view of potential confounders, we investigated if vitamin D deficiency (VDD) is linked to lung function in health screening examinee without overt medical conditions. SUBJECTS/METHODS: We conducted a cohort study on 68,457 healthy Koreans (36,759 males, mean age: 37.7 years) with a health examination in 2015. Measured forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were categorized in quartiles. To examine the relationships between VDD and lung function, adjusted odds ratios (aORs) for VDD were estimated by logistic regression. RESULTS: Median vitamin D level was 14.9 ng/mL. The prevalence of VDD (defined as <20 ng/ml) was 74.5%. Compared with the highest quartile (Q4, reference), the aORs for VDD across decreasing quartiles (from Q3 to Q1) were 1.05, 1.06, 1.10 for FVC, and 1.07, 1.10, 1.10 for FEV1 (P for trend < 0.01 for both), in all subjects. Similarly, the aOR of having VDD for men also increased with decreasing quartiles of FVC and FEV1 in a dose-response manner (p for trend < 0.01 for both). However, neither FVC nor FEV1 was associated with VDD in women. CONCLUSIONS: VDD was associated with decreased lung function in middle aged Korean men without overt medical conditions. VDD could be a modifiable risk factor for impaired lung function, in men but not in women.

Decreased lung function is associated with elevated ferritin but not iron or transferrin saturation in 42,927 healthy Korean men: A cross-sectional study.

OBJECTIVES: Though elevated ferritin level and decreased lung function both predispose people to cardio-metabolic disease, few reports have investigated the association between them. Furthermore, it remains unclear whether the association reflects a change in iron stores or an epiphenomenon reflecting metabolic stress. Therefore, we looked for possible associations between ferritin, iron, and transferrin saturation (TSAT) and lung function to clarify the role of iron-related parameters in healthy men. METHODS: We conducted a cohort study of 42,927 healthy Korean men (mean age: 38.6 years). Percent predicted forced expiratory volume in one second (FEV1%) and forced vital capacity (FVC%) were categorized into quartiles. Adjusted odds ratios (aORs) and 95% confidence intervals (using the highest quartile as reference) were calculated for hyperferritinemia, high iron, and high TSAT after controlling for potential confounders. RESULTS: The median ferritin level was 199.8 (141.5-275.6) ng/mL. The prevalence of hyperferritinemia (defined as >300 ng/mL) was 19.3%. Subjects with hyperferritinemia had lower FEV1% and FVC% than those with normal ferritin level with a slight difference, but those were statistically significant (99.22% vs.99.61% for FEV1%, p = 0.015 and 98.43% vs. 98.87% for FVC, p = 0.001). However, FEV1/FVC ratio was not significantly different between groups (P = 0.797). Compared with the highest quartile, the aORs for hyperferritinemia across decreasing quartiles were 1.081 (1.005-1.163), 1.100 (1.007-1.200), and 1.140 (1.053-1.233) for FEV1% (p for trend = 0.007) and 1.094 (1.018-1.176), 1.101 (1.021-1.188), and 1.150 (1.056-1.252) for FVC% (p for trend = 0.001). However, neither FEV1% nor FVC% was associated with iron or TSAT. CONCLUSIONS: Hyperferritinemia was associated with decreased lung function in healthy Korean men, but iron and TSAT were not. Longitudinal follow-up studies are required to validate our findings.

Decreased lung function is associated with risk of developing non-alcoholic fatty liver disease: A longitudinal cohort study.

BACKGROUND: Decreased lung function is associated with non-alcoholic fatty liver disease (NAFLD), based on linking mechanisms such as insulin resistance and systemic inflammation However, its association with the risk of developing NAFLD is unclear. Our aim was to investigate whether baseline lung function is associated with incident NAFLD in middle-aged healthy Koreans. METHODS: A cohort study of 96,104 subjects (mean age: 35.7 years) without NAFLD were followed up from 2002 to 2015. NAFLD was diagnosed by ultrasound after the exclusion of other possible causes of liver diseases. Baseline percent predicted forced expiratory volume in one second (FEV1%) and forced vital capacity (FVC%) were categorized in quartiles. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) (using the highest quartile as reference) were calculated for incident NAFLD at follow-up, controlling for covariates and potential confounders. RESULTS: During 579,714.5 person-years of follow-up, 24,450 participants developed NAFLD (incidence rate, 42.2 per 1,000 person-years). The mean follow-up period was 5.9±3.4 years. Regardless of smoking history, the risk for incident NAFLD increased with decreasing quartiles of FEV1 (%) and FVC (%) in a dose-response manner (p for trend<0.001). In never smokers, the aHRs (95% CIs) for incident NAFLD were 1.15 (1.08-1.21), 1.11 (1.05-1.18), and 1.08 (1.02-1.14) in quartiles 1-3 for FEV1 (%) and 1.12 (1.06-1.18), 1.11 (1.05-1.18), and 1.09 (1.03-1.15) in quartiles 1-3 for FVC (%), compared with the highest quartile reference. Similar inverse association was present in smoke-exposed subjects (aHR for incident NAFLD were 1.14, 1.21, 1.13 and 1.17, 1.11, 1.09 across FEV1(%) and FVC(%) quartile in increasing order, respectively). CONCLUSIONS: Reduced lung function was a risk factor for incident NAFLD in a large middle-aged Korean cohort with over half a million person-years of follow-up.

Treatment of isoniazid-resistant pulmonary tuberculosis.

BACKGROUND: Although resistance to isoniazid (INH) is the most common form of drug resistance seen among Mycobacterium tuberculosis isolates, there have been few studies on the efficacy and optimal duration of treatment for patients with INH-resistant tuberculosis (TB). METHODS: We evaluated retrospectively the treatment outcomes of 39 patients who were treated for INH-resistant pulmonary TB. The treatment regimens consisted of a 12-month regimen of rifampin (RIF) and ethambutol (EMB), with pyrazinamide (PZA) given during the first 2 months (2HREZ/10RE) (n = 21), a 9-month regimen of RIF and EMB with PZA during the first 2 months (2HREZ/7RE) (n = 5), and a 6-month regimen of RIF, EMB, and PZA (2HREZ/4REZ) (n = 13). After drug susceptibility testing confirmed the INH-resistance of the isolated M. tuberculosis strains, INH was discontinued for all the patients. RESULTS: Among the 39 patients, treatment was successfully completed by 36 patients (92%). However, treatment failure occurred, and acquired resistance to other first-line drugs, such as RIF, developed in three patients (8%). Cavitary and bilateral extensive lesions were commonly found in the chest radiographs of the patients who exhibited treatment failure. CONCLUSION: These findings underline the seriousness of concerns regarding treatment failure and the development of multidrug-resistant TB in patients with INH-resistant TB following treatment with recommended regimens.

The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test.

BACKGROUND & AIMS: Systemic chemotherapy may damage gastrointestinal epithelium. Mucositis is associated with increased intestinal permeability (IP). It is known that IP test with chromium 51-ethylene diaminetetra-acetate (51Cr-EDTA) is a useful tool to assess the mucositis. Oral glutamine supplements (OGS) may have a role in the prevention of chemotherapy-induced mucositis/stomatitis. The aim of this study was to characterize the relationship between the urinary excretion of 51Cr-EDTA and the severity of mucositis, and the effect of OGS on 5-fluorouracil/leucovorin (FU/LV)-induced mucositis/stomatitis. METHODS: Fifty-one patients with advanced or metastatic cancer received FU/LV chemotherapy. The control group included 18 healthy volunteers. IP was assessed via the measurement of 51Cr-EDTA urinary excretion after oral challenge, on days 7 after the discontinuation of chemotherapy. Of the 51 patients, 22 patients received OGS (30 g/day) and 29 received only best supportive care (BSC). Glutamine supplementation continued for 15 days. It was initiated at least 3 days before the beginning of chemotherapy. Mucositis/stomatitis was graded according to version 3.0 of the Common Terminology Criteria for Adverse Events. RESULTS: In the chemotherapy group, the median (25 percentile, 75 percentile) IP test score was significantly higher than those of the control group [6.78% (4.63, 10.66) vs. 2.17% (1.38, 2.40), P<0.001]. The severity of stomatitis was significantly correlated with IP test scores (r=0.898, P<0.001). In the OGS group, the median IP test score was significantly lower than that of the BSC group [4.69% (3.10, 6.48) vs. 8.54% (6.48, 15.31), P<0.001]. A mucositis/stomatitis of grade 2-4 was observed in two patients of the OGS group (9%), and in 11 patients (38%) in the BSC group (P<0.001). CONCLUSIONS: The IP test may be a useful tool in the evaluation of mucositis/stomatitis. OGS may exert a protective effect on FU/LV-induced mucositis/stomatitis. Further studies, however, will be necessary to define the role of glutamine supplementation in FU/LV-induced mucositis/stomatitis.

Usefulness of open lung biopsy in mechanically ventilated patients with undiagnosed diffuse pulmonary infiltrates: influence of comorbidities and organ dysfunction.

BACKGROUND: The purpose of this study was to evaluate the clinical usefulness of open lung biopsy (OLB) in patients undergoing mechanical ventilation for diffuse pulmonary infiltrates of unknown etiology. METHODS: This was a 10-year retrospective study in a 10-bed medical intensive care unit. The medical records of 36 ventilator-dependent patients who underwent OLB for the diagnosis of unknown pulmonary infiltrates from 1994 to 2004 were reviewed retrospectively. Data analyzed included demographic data, Charlson age-comorbidity score, number of organ dysfunctions, Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, ventilation variables, and radiological patterns. Diagnostic yield, effect on subsequent treatment changes, and complications of OLB were also assessed. RESULTS: A specific clinico-pathologic diagnosis was obtained for 31 patients (86%). The most common diagnoses were interstitial pneumonia (n = 17, including 8 acute interstitial pneumonia) and viral pneumonia (n = 4). Therapeutic modifications were made in 64% of patients. Patients who received OLB less than 1 week after initiation of mechanical ventilation were more likely to survive (63% versus 11%; P = 0.018). There were no major complications associated with the procedure. Factors independently associated with survival were the Charlson age-comorbidity score, number of organ dysfunction and the PaO2/FiO2 ratio on the day of the OLB. CONCLUSION: OLB can provide a specific diagnosis in many ventilator-dependent patients with undiagnosed pulmonary infiltrate. Early OLB seems to be useful in critically ill patients with isolated respiratory failure.

Efficacy and safety of ifosfamide in combination with carboplatin and etoposide in small cell lung cancer.

PURPOSE: Ifosfamide, a potent alkylating agent, is rarely incorporated into small cell lung cancer (SCLC) treatment. The aim of this study was to assess the efficacy and safety of ifosfamide in combination with carboplatin and etoposide (ICE) in previously untreated patients with SCLC. METHODS: From January 2002 to January 2014, we consecutively enrolled 69 patients with SCLC who were treated with ICE as initial chemotherapy at Kangbuk Samsung Hospital. The modified ICE regimen consists of ifosfamide 1200 mg/m(2)/day on days 1, 2, and 3 with mesna, etoposide 80 mg/m(2)/day on days 1, 2, and 3, and carboplatin AUC 6 on day 1. Treatment was repeated every 3 weeks and continued for up to nine cycles. Response assessments were performed every three cycles with computed tomography. RESULTS: Among 69 patients with SCLC, the median age was 69 years (range 51-88 years). Sixteen (23 %) patients had limited disease (LD), and 53 (77 %) had extensive disease (ED). The overall response rate was 73 %. Stable disease rate was 20 %. The median overall survival was 11.3 months [95 % confidence interval (CI) 8.9-14.1] in the overall population, 20.6 months (95 % CI 14.2-21.2) for LD and 9.1 months (95 % CI 7.8-11.6) for ED. The median number of administered cycles was 6 (range 1-9). Grade ≥3 hematological toxicities included neutropenia (34 %), anemia (59 %), and thrombocytopenia (31 %). Grade ≥3 non-hematological toxicities included peripheral neuropathy in 2 %. CONCLUSION: In chemonaïve patients with SCLC, modified ICE is well tolerated and shows favorable efficacy.

Differential effects of Fas cross-linking on phospholipase D activation and related lipid metabolism in Fas-resistant A20 cells.

A20 murine lymphoma cells undergoing Fas-mediated apoptosis showed increase in the activity of phospholipase D (PLD), which is involved in proliferative or mitogenic cellular responses. Using A20 cell lines that were resistant to Fas-induced apoptosis, we investigated the differential effects of Fas cross-linking on PLD activity and sphingolipid metabolism. The basal PLD activities in all of the selected three Fas-resistant clones (#5, #8, and #11) were about 2~4 folds higher than that of wild type A20 cells. Among the PLD isoforms, PLD2 expression was increased in all of the selected Fas-resistant clones. The Fas downstream signaling events triggered by Fas cross-linking, including the activations of PLD, phosphatidylcholine-specific phospholipase C (PC-PLC), sphingomyelinase (SMase), the increase in diacylglycerol (DAG) and protein phosphorylation levels, and the translocation of protein kinase C to membrane were not changed in both of Fas-resistant clone #5 and #8. In contrast, Fas cross-linking stimulated the activity of PLD, PC-PLC, and SMase, translocation of PKC, and protein phosphorylation in Fas-resistant clone #11, similar to that of wild type cells. We also found that clone #11 had a different Fas sequence encoding Fas B which has been known to inhibit Fas-induced apoptosis. These findings suggest that increased PLD2 expression resulting in increased basal PLD activity and the blockade of Fas downstream signaling cascades may be involved to limit apoptosis induced by Fas cross-linking.

A case of metachronous metastasis to the breast from non-small cell lung carcinoma.

Breast metastases from an extramammary primary tumor are very rare and the prognosis for such patients is generally poor. We report here on a case of a 42-year-old female with metastasis of non-small cell lung cancer to the breast, and she is now being followed up on an outpatient basis. In 2004, she presented with a solitary pulmonary nodule in the left lung, and this lesion had been noted to have gradually increased in size over time. The final pathological diagnosis was adenocarcinoma, and the diagnosis was made by performing percutaneous needle aspiration and lobectomy of the left upper lobe. Adjuvant chemotherapy and radiotherapy were given. Unfortunately, a nodule in the left breast was noted three years later, and metastatic non-small-cell lung cancer to the breast was diagnosed by excisional biopsy. Making the correct diagnosis to distinguish a primary breast carcinoma from a metastatic one is important, because the therapeutic plan and outcome for these two types of cancer are quite different.