Yu-Il Kim

Predictors of the Response to Gefitinib in Refractory Non–Small Cell Lung Cancer

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non–small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non–small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P < 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P < 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.

Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene

Purpose: High ribonucleotide reductase M1 (RRM1) expression in resected lung cancers has been associated with better clinical outcomes. However, gemcitabine-treated patients with high tumoral RRM1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy. This study was designed in accordance with the hypothesis that polymorphisms (−37 and −524) of the RRM1 promoter gene sequence, which regulate RRM1 expression, could influence the efficacy and prognosis of lung cancer patients treated with gemcitabine-based chemotherapy. Experimental Design: A retrospective dataset of 97 patients with advanced non–small cell lung cancer treated with gemcitabine regimens as a first-line treatment was studied in this work. The allelotyping of RRM1 promoter polymorphisms was conducted via real-time PCR using genomic DNA obtained from peripheral WBC. Results: The RRM1 promoter allelotype was RR37CC-R524TT in 58 patients, RR37AC-RR524CT in 29 patients, and other allelotypes in 10 patients. The response rate for gemcitabine-containing chemotherapy was 49.5%. The response rate was significantly higher in the RR37AC-RR524CT group (65.5%) compared with the group containing other allelotypes (42.6%; P = 0.039). Overall survival and progression-free survival did not differ significantly by allelotype. Conclusions: We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA. Further functional and clinical studies will be required before this can be used as a predictive marker.

Decrease in carotid intima media thickness after 1 year of cilostazol treatment in patients with type 2 diabetes mellitus

A multicenter exploratory study at three university hospitals was performed to evaluate the effect of oral cilostazol on intima media thickness (IMT) in diabetic patients. A total of 141 patients was recruited in this study and randomized into a cilostazol group and a placebo (control) group. One hundred and twenty patients completed the study (i.e. 60 on cilostazol and 60 on placebo). Biochemical profiles and the IMT of the common carotid artery (CCA) determined by high-resolution B-mode ultrasonography were measured at 0, 6, and 12 months after the oral administration of 100--200 mg of cilostazol or placebo (i.e. two or four times daily for 12 months). Clinical and biochemical characteristics, the treatment modality, and microvascular diabetic complications after randomization were not significantly different between the two groups after the study. In the cilostazol treatment group, left CCA average IMT significantly decreased from 0.94+/-0.03 to 0.91+/-0.02 mm at 6 months (P<0.05), and thereafter increased to 0.92+/-0.01 mm (P>0.05) at 12 months, whereas in the control group, it increased from 0.92+/-0.03 to 0.93+/-0.01 mm at 6 months (P>0.05), and to 0.94+/-0.01 mm at 12 months (P>0.05). As for the right CCA average IMT, it decreased from 0.83+/-0.03 to 0.82+/-0.01 mm at 6 months (P<0.05), and to 0.81+/-0.01 mm at 12 months (P<0.05) in the cilostazol group, whereas it increased from 0.87+/-0.03 to 0.89+/-0.01 mm at 6 months (P<0.05), and to 0.90+/-0.01 mm at 12 months (P<0.05) in the control group (P<0.05). After correction for risk factors such as blood pressure, smoking, and lipid profiles, there were significant changes in left and right CCA average IMT for both groups (P<0.05). Left and right CCA average IMT was significantly different between the two groups (P<0.05). After making statistical corrections for blood pressure, smoking, and lipid profiles, the differences between these two groups remained significant (P<0.05). Meanwhile, there were no differences between the groups in the change of risk factors such as BMI, blood pressure, blood sugar, HbA(1c), and lipid profiles. Generally, cilostazol was well tolerated and the most common side effect in the cilostazol group was headache (12/60), mostly early in the treatment regimen. The results suggest that oral cilostazol may be helpful in the treatment of atherosclerosis in type 2 diabetic patients, although conventional cardiovascular risk factors remained unmodified.

Differences in classification of COPD group using COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores: a cross-sectional analyses

BackgroundThe GOLD 2011 document proposed a new classification system for COPD combining symptom assessment by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores, and exacerbation risk. We postulated that classification of COPD would be different by the symptom scale; CAT vs mMRC.MethodsOutpatients with COPD were enrolled from January to June in 2012. The patients were categorized into A, B, C, and D according to the GOLD 2011; patients were categorized twice with mMRC and CAT score for symptom assessment, respectively. Additionally, correlations between mMRC scores and each item of CAT scores were analyzed.ResultsClassification of 257 patients using the CAT score vs mMRC scale was as follows. By using CAT score, 60 (23.3%) patients were assigned to group A, 55 (21.4%) to group B, 21 (8.2%) to group C, and 121 (47.1%) to group D. On the basis of the mMRC scale, 97 (37.7%) patients were assigned to group A, 18 (7.0%) to group B, 62 (24.1%) to group C, and 80 (31.1%) to group D. The kappa of agreement for the GOLD groups classified by CAT and mMRC was 0.510. The mMRC score displayed a wide range of correlation with each CAT item (r = 0.290 for sputum item to r = 0.731 for dyspnea item, p < 0.001).ConclusionsThe classification of COPD produced by the mMRC or CAT score was not identical. Care should be taken when stratifying COPD patients with one symptom scale versus another according to the GOLD 2011 document.

The Association of Adiponectin with Computed Tomography Phenotypes in Chronic Obstructive Pulmonary Disease

RATIONALE Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder associated with systemic manifestations that contribute to its morbidity and mortality. Recent work suggests that biomarker signatures in the blood may be useful in evaluating COPD phenotypes and may provide insight into the pathophysiology of systemic manifestations. Adiponectin, primarily produced by fat cells, has been implicated in the pathophysiology of emphysema. OBJECTIVES To investigate the association of adiponectin with clinical and radiologic COPD phenotypes. METHODS Adiponectin levels were determined in 633 individuals, including 432 individuals with COPD from a cohort of former or current smokers enrolled in the COPDGene study. Univariate and multiple regression analysis were used to examine the association of adiponectin with clinical and physiologic data together with quantitative high-resolution computed tomography parameters. MEASUREMENTS AND MAIN RESULTS Multiple regression analysis confirmed that higher plasma adiponectin levels were independently associated with emphysema, decreasing body mass index, female sex, older age, and lower percentage change in prebronchodilator/post-bronchodilator FEV1. CONCLUSIONS The association between plasma adiponectin and computed tomography-assessed emphysema suggests a contribution of adiponectin to the development of emphysema and highlights a role for metabolic derangements in the pathophysiology of emphysema.

Endovascular Stenting as a First Choice for the Palliation of Superior Vena Cava Syndrome

To assess the effectiveness of endovascular stenting for the palliation of superior vena cava (SVC) syndrome, endovascular stent insertion was attempted in 10 patients with symptomatic occlusion of the SVC. All the patients had known malignant disease of the thorax. Eight patients had been treated previously with chemotherapy and radiotherapy (n=5), chemotherapy alone (n=2), or pneumonectomy and radiotherapy (n=1). After developing SVC syndrome, all the patients were stented before receiving any other treatment. After single or multiple endovascular stents were inserted, five of eight patients were treated with chemotherapy and radiotherapy (n=2) or chemotherapy alone (n=3). Resolution of symptoms was achieved in nine patients within 72 hr (90%). In one patient, the symptoms did not disappear until a second intervention. At follow up, symptoms had recurred in two of ten patients (20%) after intervals of 15 and 60 days. Five patients have died from their cancers, although they remained free of symptoms of SVC occlusion until death. In conclusion, endovascular stent insertion is an effective treatment for palliation of SVC syndrome. Endovascular stent insertion can be considered the first choice of treatment, due to the immediate relief of symptoms and excellent sustained symptomatic relief.

Characteristics and management of ruptured distal middle cerebral artery aneurysms

SummaryObjective. Distal middle cerebral artery (dMCA) aneurysms are very rare with a reported frequency of 2–6%. Typically, patients with ruptured distal MCA aneurysms have poor clinical outcomes because often there is both a subarachnoid haemorrhage (SAH) and an intracerebral haematoma (ICH). The goals of this study were to identify the characteristics of the distal MCA aneurysms and evaluate the optimal treatment for a good outcome. Methods. The clinical, neuroradiological and operative records of 8 patients with a ruptured distal MCA aneurysm who underwent surgical management were reviewed retrospectively. The outcomes were presented according to the Glasgow Outcome Scale (GOS). Results. The clinical characteristics of the patients with ruptured dMCA aneurysms included the following: (1) a fusiform appearance in five out of eight (63%) patients. (2) Mean aneurysm size of 9.4 mm (range 2–35 mm). (3) The location being M2 (insular segment) in three, M2-3 junction in three, and M3 (opercular segment) in two patients. (4) Brain CT images revealed both SAH and an ICH in six of eight (75%) patients with the mean size of the ICH being 10 cc (range 5–25 cc). (5) Re-bleeding occurred in four out of eight (50%) of patients. All patients underwent early surgical treatment and the procedures used for surgical repair were, clipping in five patients, trapping in two, and trapping with end-to-end bypass surgery in one patient. Clinical outcomes were poor in two patients (death) due to severe brain swelling. Conclusions. In this study, dMCA aneurysms had a fusiform shape and a high re-bleeding rate; if ruptured, there was generally ICH and SAH. A good clinical outcome was associated with adequate control of brain swelling and early surgery to prevent re-bleeding.

The Impact of the 2007 ATS/IDSA Diagnostic Criteria for Nontuberculous Mycobacterial Disease on the Diagnosis of Nontuberculous Mycobacterial Lung Disease

Background: In 2007, the American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) published new diagnostic guidelines for nontuberculous mycobacterial (NTM) disease. Bacteriological criteria have become simpler compared to the 1997 ATS diagnostic criteria. Objective: For assessing the impact of the 2007 ATS/IDSA diagnostic criteria, we compared the diagnosis rate and time to diagnosis of NTM lung disease using the 1997 and 2007 ATS guidelines. Methods: Sixty-four patients who had excreted Mycobacterium intracellulare, M. avium, M. abscessus or M. kansasii at least one time in their respiratory specimens at Chonnam National University Hospital were reviewed. The 1997 ATS and 2007 ATS/IDSA guidelines were applied to these patients. Results: Thirty-seven of 64 patients (57.8%) were diagnosed with NTM lung disease by the 1997 ATS criteria. When the 2007 ATS/IDSA criteria were applied, 6 patients were newly diagnosed with NTM lung disease. The diagnosis rate significantly increased from 57.8 to 67.2% (p < 0.001). The time to diagnosis in the 1997 ATS and 2007 ATS/IDSA guidelines was 46.4 ± 53.0 and 36.2 ± 38.5 days, respectively (p = 0.002). Conclusion: These data suggest that we can shorten the time to diagnose NTM lung disease and diagnose more simply by using the 2007 ATS/IDSA guidelines. Further study will be needed to assess that these changes affect the management of NTM disease.

Gender Differences of Airway Dimensions in Anatomically Matched Sites on CT in Smokers

Rationale and Objectives: There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. Multi-detector CT (MDCT) images were analyzed to examine whether gender could explain differences in airway dimensions of anatomically matched airways in smokers. Materials and Methods: We used VIDA imaging software to analyze MDCT scans from 2047 smokers (M:F, 1021:1026) from the COPDGene® cohort. The airway dimensions were analyzed from segmental to subsubsegmental bronchi. We compared the differences of luminal area, inner diameter, wall thickness, wall area percentage (WA%) for each airway between men and women, and multiple linear regression including covariates (age, gender, body sizes, and other relevant confounding factors) was used to determine the predictors of each airway dimensions. Results: Lumen area, internal diameter and wall thickness were smaller for women than men in all measured airway (18.4 vs 22.5 mm2 for segmental bronchial lumen area, 10.4 vs 12.5 mm2 for subsegmental bronchi, 6.5 vs 7.7 mm2 for subsubsegmental bronchi, respectively p < 0.001). However, women had greater WA% in subsegmental and subsubsegmental bronchi. In multivariate regression, gender remained one of the most significant predictors of WA%, lumen area, inner diameter and wall thickness. Conclusion: Women smokers have higher WA%, but lower luminal area, internal diameter and airway thickness in anatomically matched airways as measured by CT scan than do male smokers. This difference may explain, in part, gender differences in the prevalence of COPD and airflow limitation.

Quantitative computed tomography measurements to evaluate airway disease in chronic obstructive pulmonary disease: Relationship to physiological measurements, clinical index and visual assessment of airway disease

PURPOSE To correlate currently available quantitative CT measurements for airway disease with physiological indices and the body-mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS This study was approved by our institutional review board (IRB number 2778). Written informed consent was obtained from all subjects. The subjects included 188 current and former cigarette smokers from the COPDGene cohort who underwent inspiratory and expiratory CT and also had physiological measurements for the evaluation of airflow limitation, including FEF25-75%, airway resistance (Raw), and specific airway conductance (sGaw). The BODE index was used as the index of clinical symptoms. Quantitative CT measures included % low attenuation areas [% voxels≤950 Hounsfield unit (HU) on inspiratory CT, %LAA-950ins], percent gas trapping (% voxels≤-856HU on expiratory CT, %LAA -856exp), relative inspiratory to expiratory volume change of voxels with attenuation values from -856 to -950HU [Relative Volume Change (RVC)-856 to -950], expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD), Pi10, and airway wall thickness (WT), luminal diameter (LD) and airway wall area percent (WA%) in the segmental, subsegmental and subsubsegmental bronchi on inspiratory CT. Correlation coefficients were calculated between the QCT measurements and physiological measurements in all subjects and in the subjects with mild emphysema (%LAA-950ins <10%). Univariate and multiple variable analysis for the BODE index were also performed. Adjustments were made for age, gender, smoking pack years, FEF25-75%, Raw, and sGaw. RESULTS Quantitative CT measurements had significant correlations with physiological indices. Among them, E/I-ratio MLD had the strongest correlations with FEF25-75% (r=-0.648, <0.001) and sGaw (r=-0.624, <0.001) while in the subjects with mild emphysema subsegmental WA% and segmental WA% had the strongest correlation with FEF25-75% (r=-0.669, <0.001) and sGaw (r=-0.638, <0.001), respectively. The multiple variable analyses showed that RVC-856 to -950 was an independent predictor of the BODE index showing the highest R2 (0.468) as an independent variable among the QCT measurements. CONCLUSION Quantitative CT measurements of gas trapping such as E/I-ratio MLD, correlate better with physiological indices for airway disease than those of airway such as WA% or LD. In mild emphysema, however, quantitative CT measurements of airway correlate better with the physiological indices. RVC-856 to -950 is a predictor of the BODE index.