Sook Young Woo

Clinical Significance of the Differentiation Between Mycobacterium avium and Mycobacterium intracellulare in M avium Complex Lung Disease

BACKGROUND Mycobacterium avium and Mycobacterium intracellulare are grouped together as the M avium complex; however, little is known about the clinical impact of this species differentiation. This study compared the clinical features and prognoses of patients with M avium and M intracellulare lung disease. METHODS From 2000 to 2009, 590 patients were given a new diagnosis of M avium complex lung disease; 323 (55%) had M avium lung disease, and 267 (45%) had M intracellulare lung disease. RESULTS Compared with the patients with M avium lung disease, the patients with M intracellulare lung disease were more likely to have the following characteristics: older age (64 vs 59 years, P = .002), a lower BMI (19.5 kg/m² vs 20.6 kg/m², P < .001), respiratory symptoms such as cough (84% vs 74%, P = .005), a history of previous treatment for TB (51% vs 31%, P < .001), the fibrocavitary form of the disease (26% vs 13%, P < .001), smear-positive sputum (56% vs 38%, P < .001), antibiotic therapy during the 24 months of follow-up (58% vs 42%, P < .001), and an unfavorable microbiologic response after combination antibiotic treatment (56% vs 74%, P = .001). CONCLUSIONS Patients with M intracellulare lung disease exhibited a more severe presentation and had a worse prognosis than patients with M avium lung disease in terms of disease progression and treatment response. Therefore, species differentiation between M avium and M intracellulare may have prognostic and therapeutic implications.

Mycobacterial Genotypes Are Associated with Clinical Manifestation and Progression of Lung Disease caused by Mycobacterium abscessus and Mycobacterium massiliense

BACKGROUND Mycobacterium abscessus and Mycobacterium massiliense, which cause lung disease, are variable in their clinical manifestation and progression. We hypothesized that mycobacterial genotypes represent their pathogenic phenotypes, which would result in particular genotypes being associated with disease progression. METHODS Variable number tandem repeat (VNTR) loci were selected to establish a genotype assay that was capable of differentiating patients with heterogeneous prognoses in the development cohort (48 isolates). The analysis was reevaluated in the validation cohort (63 isolates). RESULTS A total of 53 M. abscessus and 58 M. massiliense isolates were assembled into 3 clusters based on their VNTR genotyping. The patients in cluster A were more likely to have stable disease of the nodular bronchiectatic form; 100% of M. abscessus patients and 96% of M. massiliense patients were followed without antibiotic treatment for >24 months after diagnosis. In contrast, the patients in cluster B were more likely to have progressive disease of the nodular bronchiectatic form; 96% of M. abscessus patients and 81% of M. massiliense patients started antibiotic treatment within 24 months after diagnosis. All patients in cluster C had fibrocavitary disease and started antibiotic treatment immediately after diagnosis. The genetic distance of each clinical isolate from the reference strain was associated with the highest likelihood of disease progression and a disease phenotype of the fibrocavitary form (P < .001). CONCLUSIONS Mycobacterial genotyping of M. abscessus and M. massiliense may provide valuable information for predicting disease phenotype and progression.

Statins and the risk of gastric cancer in diabetes patients

BackgroundSeveral studies have suggested a cancer risk reduction in statin users although the evidence remains weak for stomach cancer. The purpose of this study was to use an exact-matching case–control design to examine the risk of gastric cancer associated with the use of statins in a cohort of patients with diabetes.MethodsCases were defined as patients with incident gastric cancer identified by International Classification of Diseases 16.0 ~ 16.9 recorded at Samsung Medical Center database during the period of 1999 to 2008, at least 6 months after the entry date of diabetes code. Each gastric cancer case patient was matched with one control patient from the diabetes patient registry in a 1:1 fashion, blinded to patient outcomes.ResultsA total of 983 cases with gastric cancer and 983 controls without gastric cancer, matched by age and sex, were included in the analysis. The presence of prescription for any statin was inversely associated with gastric cancer risk in the unadjusted conditional logistic regression model (OR: 0.18; 95% CI: 0.14 – 0.24; P < .0001). Multivariate analysis using conditional logistic regression with Bonferroni’s correction against aspirin indicated a significant reduction in the risk of gastric cancer in diabetes patients with statin prescriptions (OR: 0.21; 95% CI: 0.16 – 0.28; P < .0001). After adjustment for aspirin use, a longer duration of statin use was associated with reduced risk of gastric cancer, with statistical significance (P<.0001).ConclusionsA strong inverse association was found between the risk of gastric adenocarcinoma and statin use in diabetic patients.

Relationship Between Azathioprine Dosage, 6-Thioguanine Nucleotide Levels, and Therapeutic Response in Pediatric Patients with IBD Treated with Azathioprine

Background:Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine. Methods:We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis. Additional factors affecting metabolite levels and therapeutic response were also analyzed. Results:A positive correlation was observed between AZA dosage and 6-thioguanine nucleotide (6-TGN) level (P < 0.0001). Variant TPMT genotype (P < 0.001) and concomitant use of mesalazine (P < 0.001) were predictors of higher 6-TGN levels. Leukopenia (P = 0.025) and lymphopenia (P = 0.045) were associated with higher levels of 6-TGN. Poor AZA compliance affected median 6-TGN levels (P < 0.001). The frequency of patients with median 6-TGN levels >235 pmol per 8 × 108 red blood cells was the highest in the sustained therapeutic response group (P = 0.015). Age, sex, IBD type, and duration of AZA therapy did not influence 6-TGN levels or therapeutic effect. Conclusions:AZA dosage is positively correlated with 6-TGN level. Higher 6-TGN levels are related to leukopenia, lymphopenia, and concurrent use of mesalazine. These results provide the rationale for monitoring metabolites to optimize drug dosing and minimize drug-related toxicity. In addition, maintenance of 6-TGN levels within a beneficial therapeutic range by direct monitoring should be helpful in attaining therapeutic efficacy, although this possibility should be verified in prospective studies.

Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine.

Background:Thiopurine-related toxicity results in discontinuation of therapy in up to 30% of patients with inflammatory bowel disease. Although thiopurine S-methyltransferase (TPMT) is implicated in toxicity, not all toxicity can be attributed to TPMT polymorphisms. We investigated the effects of polymorphisms of genes involved in thiopurine and folate metabolism pathways on 6-thioguanine nucleotide levels and toxicity. Methods:Retrospective clinical data and blood samples were collected from 132 pediatric patients with inflammatory bowel disease treated with azathioprine. Eighty-seven genetic polymorphisms of 30 genes were screened using the MassARRAY system, and 70 polymorphisms of 28 genes were selected for further analysis. Results:TPMT genotype (P < 0.001), concurrent use of mesalazine (P = 0.006), ABCC5 (rs2293001) (P < 0.001), ITPA (rs2236206 and rs8362) (P = 0.010 and P = 0.003), and ABCB1 (rs2032582) (P = 0.028) were all associated with the ratio of 6-thioguanine nucleotides to azathioprine dose. ADK (rs10824095) (P = 0.004, odds ratio [OR] = 6.220), SLC29A1 (rs747199) (P = 0.016, OR = 5.681), and TYMS (rs34743033) (P = 0.045, OR = 3.846) were associated with neutropenia. ABCC1 (rs2074087) (P = 0.022, OR = 3.406), IMPDH1 (rs2278294) (P = 0.027, OR = 0.276), and IMPDH2 (rs11706052) (P = 0.034, OR = 3.639) had a significant impact on lymphopenia. Conclusions:This study describes genetic polymorphisms in genes whose products may affect pharmacokinetics and which may predict the relative likelihood of benefit or risk from thiopurine treatment. These findings may serve as a basis for personalized thiopurine therapy in pediatric patients with inflammatory bowel disease, although our data need to be validated in further studies.

Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

BACKGROUND Paclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy. METHODS A total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed. RESULTS The median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5-9.6 months) and 26.9 months (95% CI: 23.6-30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1-6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13-10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity. CONCLUSION Genetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted.

Diagnostic criterion to distinguish between incomplete and complete discoid lateral meniscus on MRI.

To determine a new cutoff value that can further distinguish between the incomplete and complete discoid lateral meniscus (DLM).

Thymic Epithelial Tumors: Prognostic Determinants Among Clinical, Histopathologic, and Computed Tomography Findings

BACKGROUND The Masaoka-Koga staging system has been known as the strongest prognostic factor for both survival and recurrence of thymic epithelial tumor (TET). The purpose of our study was to find prognostic determinants among computed tomography (CT), histopathologic, and clinical features of TET. METHODS Two radiologists reviewed retrospectively CT findings of 437 patients (male 242, female 195; mean age, 51 years) with TET. With medical record review, surgico-histopathologic results were subcategorized into Masaoka-Koga stages I through IV and World Health Organization histopathologic classifications A-B1, B2-B3, and carcinoma. Overall survival and progression-free survival were analyzed. Clinical, histopathologic, and CT features were correlated from each other. RESULTS In all, 437 tumors were in Masaoka-Koga stage I (n = 147, 33.6%), stage II (n = 121, 27.7%), stage III (n = 76, 17.4%), or stage IV (n = 93, 21.3%); A and B1 (n = 114, 26.1%) and B2 and B3 TET (n = 223, 51.0%); and thymic carcinoma (n = 100, 22.9%). In multivariable analyses, age, Masaoka-Koga stage IV, thymic carcinoma, and CT stages III and IV were significantly correlated with overall survival (p < 0.05), whereas adjuvant treatment, Masaoka-Koga stages III and IV, World Health Organization B2 and B3, thymic carcinoma, R2 resection, CT size, and CT stage IV were significantly associated with progression-free survival (p < 0.05). Computed tomography stages showed moderate association with Masaoka-Koga stages (K = 0.621). CONCLUSIONS For TET, CT staging is effective in distinguishing both overall survival and progression-free survival, and patients with Masaoka-Koga stage IV or thymic carcinoma or CT stage IV have the worst prognosis.

The effect of body mass index and fasting glucose on the relationship between blood pressure and incident diabetes mellitus: a 5-year follow-up study

There is no consensus on the relationship between high blood pressure (BP) and incident diabetes mellitus (DM). Therefore, the aim of the current study was to investigate the independent association between BP and incident DM and identify the metabolic components that influence incident DM in Korean subjects. The current study included 14 054 non-diabetic subjects (mean age of 41 years) at the start of the study who were followed for an average of 5 years. We measured the risk for incident DM according to the subjects’ baseline BP. Subjects were separated into three groups as follows: normotensive (<120/80 mm Hg), pre-hypertensive (120/80 mm Hg ⩽BP <140/90 mm Hg) and hypertensive (⩾140/90 mm Hg). The overall incidence of DM was 1.8% (246 subjects), comprising 0.9% of the normotensive group, 1.9% of the pre-hypertensive group and 4.0% of the hypertensive group (P<0.01). Within the hypertensive group, subjects with high body mass index (BMI) and high fasting-glucose levels were 40 times more likely to develop DM compared with those with low BMI and low glucose levels (0.3 vs. 13.2%, P=0.001). The risk for incident DM was significantly higher in the hypertensive group compared with that in the normotensive group (OR 3.41 vs. 1.00, P<0.0001). However, the significance disappeared after making adjustments for the baseline BMI and fasting glucose levels (OR 1.18 vs. 1.00, P=0.83). We found that the significance of high BP in predicting incident DM was influenced by the baseline BMI and fasting glucose levels of the subjects.

Validation and Comparison of CS-IHC4 Scores with a Nomogram to Predict Recurrence in Hormone Receptor-Positive Breast Cancers

The aim of this study was to both develop and validate a nomogram based on the Ki-67 index to predict recurrence. We constructed a nomogram using the Cox proportional hazards model with 953 N0 and N1 postoperative hormone receptor (HR)-positive breast cancer patients and validated it in an external cohort of 895 patients. A prognostic model that used classical variables, Adjuvant! Online, St. Gallen risk stratification, and the four immunohistochemistry (IHC) markers (IHC4 score) was created and assessed by the likelihood ratio χ2 (LR-χ2) test using the bootstrapping method. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.75 (95% CI 0.72-0.77) in the training set. The validation set showed good discrimination with an AUC of 0.63 (95% CI 0.60-0.66). In the LR-χ2 test, the nomogram score was found to be more informative than the IHC4 with clinical score (CS) [LR-χ2 13.365 (1 d.f.); 95% CI 2.50-24.23 for CS-IHC4 + nomogram score vs. CS-IHC4] on distant recurrence-free survival. This study implies that the amount of prognostic information contained in the nomogram is superior to that in the CS-IHC4 score in HR-positive N0 and N1 breast cancer patients (NCT1273415).