Serial T1 mapping of right ventricle in pulmonary hypertension: comparison with histology in an animal study.

BACKGROUND: Right ventricular (RV) free wall fibrosis is an important component of adverse remodeling with RV dysfunction in pulmonary hypertension (PH). However, no previous reports have compared cardiovascular magnetic resonance (CMR) findings and histological analysis for RV free wall fibrosis in PH. We aimed to assess the feasibility of CMR T1 mapping with extracellular volume fraction (ECV) for evaluating the progression of RV free wall fibrosis in PH, and compared imaging findings to histological collagen density through an animal study. METHODS: Among 42 6-week-old Wistar male rats, 30 were classified according to disease duration (baseline before monocrotaline injection, and 2, 4, 6 and 8 weeks after injection) and 12 were used to control for aging (4 and 8 weeks after the baseline). We obtained pre and post-contrast T1 maps for native T1 and ECV of RV and left ventricular (LV) free wall for six animals in each disease-duration group. Collagen density of RV free wall was calculated with Masson's trichrome staining. The Kruskall-Wallis test was performed to compare the groups. Native T1 and ECV to collagen density were analyzed with Spearman's correlation. RESULTS: The mean values of native T1, ECV and collagen density of the RV free wall at baseline were 1541 ± 33 ms, 17.2 ± 1.3%, and 4.7 ± 0.5%, respectively. The values of RV free wall did not differ according to aging (P = 0.244, 0.504 and 0.331, respectively). However, the values significantly increased according to disease duration (P < 0.001 for all). Significant correlations were observed between native T1 and collagen density (r = 0.770, P < 0.001), and between ECV and collagen density for the RV free wall (r = 0.815, P < 0.001) in PH. However, there was no significant difference in native T1 and ECV values for the LV free wall according to the disease duration from the baseline (P = 0.349 and 0.240, respectively). CONCLUSIONS: We observed significantly increased values for native T1 and ECV of the RV free wall without significant increase of the LV free wall according to the disease duration of PH, and findings were well correlated with histological collagen density.

Tumor perfusion-related parameter of diffusion-weighted magnetic resonance imaging: correlation with histological microvessel density.

PURPOSE: We obtained intravoxel incoherent motion (IVIM) parameters through biexponential analysis on diffusion-weighted MR imaging (DWI) using multiple b values. Correlation was evaluated between these parameters and histological microvessel density (MVD) for the possibility of noninvasive evaluation of MVD with DWI. METHODS: Twenty-five nude mice with the HT29 colorectal cancer cells implanted were analyzed after undergoing DWI with multiple b values (0, 50, 100, 300, 500, 700, and 1000 s/mm(2)). Tissue diffusivity (D(t)), pseudo-diffusion coefficient (D(p)), and perfusion fraction (f(p)) were calculated using a biexponential analysis, and these parameters were correlated with MVD. The MVD was determined with the CD31 stain. For statistical analysis, Spearman's rank correlation was applied. RESULTS: The mean value and correlation coefficient with MVD for each IVIM parameter were as follows: D(t) = 0.98 ± 0.06 × 10(-3) mm(2)/s with r = 0.139 (P = 0.508); D(p) = 23.70 ± 7.94 × 10(-3) mm(2)/s with r = 0.782 (P < 0.001); and f(p) = 15.58 ± 5.7% with r = 0.749 (P < 0.001). D(p) and f(p) showed significant correlation with MVD, but D(t) did not. CONCLUSION: The IVIM parameters, D(p) and f(p), on DWI might be used in the noninvasive evaluation of MVD.

TGF-ß1 T869C polymorphism may affect susceptibility to idiopathic pulmonary fibrosis and disease severity.

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (IPF). The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease. METHODS: We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 (T â†’ C) of the TGF-ß1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. RESULTS: The IPF patients consisted of 55 men and 30 women. The mean age was 61 ± 8 years. Fifty-one (60 %) of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different (IPF: TT 43.5 % and TC or CC 56.5 %; controls: TT 27.1 % and TC or CC 72.9 %, p = 0.037). TT genotype was significantly associated with decreased PaO2 and increased D(A-a)O2 upon initial diagnosis (p = 0.006 and 0.009, respectively). There was a positive association between TT genotype and IPF development (odds ratio [OR] = 2.1, 95 % confidence interval [CI] = 1.1-4.0, p = 0.028). CONCLUSIONS: This study suggests that the TGF-ß1 gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-ß1 gene polymorphism and IPF.

Detection of sexually transmitted infection and human papillomavirus in negative cytology by multiplex-PCR.

BACKGROUND: The aim of this study was to determine the prevalence of human papillomavirus (HPV) and 15 species that cause sexually transmitted infections (STIs) in negative cytology. In addition, we compared the diagnostic performance of multiplex polymerase chain reaction (PCR) with widely available techniques used to detect HPV. METHODS: We recruited 235 women of reproductive age who had negative cytology findings in a liquid-based cervical smear. STIs were identified by multiplex PCR, and HPV genotypes by multiplex PCR, hybrid capture 2, and DNA microaray; discordant results were analyzed by direct sequencing. RESULTS: Approximately 96.6% of patients with negative cytology results were positive for pathogens that cause STIs. The pathogens most frequently detected were Gardnerella vaginalis, Ureaplasma urealyticum. The incidence of HPV in negative cytology was 23.3%. Low-risk HPV infection was significantly correlated with Chalmaydia trachomatis, and high-risk HPV infection was significantly correlated with Group ß streptococcus. The analytical sensitivities of the multiplex PCR and DNA microarray were higher than 80%, and the analytical specificity was nearly 100% for all tests. CONCLUSIONS: Multiplex PCR yielded results that most of patients with negative cytology were positive for pathogens that cause STIs, and were more similar to that of DNA microarray, than that of hybrid capture 2 in terms of analytical sensitivity and prediction value of HPV infection.

Expression of androgen receptors and inhibin/activin alpha and betaA subunits in breast apocrine lesions.

The importance of androgens and their receptors inhibin and activin remains unknown for mammary epithelial cells. We investigated the role of these hormones in breast apocrine lesions (BAL) using immunohistochemistry to study androgen receptors (AR) and the inhibin/activin alpha and betaA subunits. Forty-two cases of BAL were evaluated, including 22 cases of fibrocystic disease (FCD) showing prominent apocrine changes, 10 intraductal papillomas with extensive apocrine metaplasia, 5 cases of apocrine carcinoma in situ (CIS), and 5 cases of apocrine carcinoma. Fifty non-apocrine lesions were included as controls: 20 cases of FCD, 5 cases of DCIS, and 25 cases of invasive ductal carcinoma. AR was more frequently expressed in BAL than in non-apocrine lesions (p=0.001). AR expression was not related to tumor progression. AR showed a significant positive correlation with betaA subunits (r=0.832, p<0.001), and an inverse correlation with alpha subunits (r=-0.233). The alpha and betaA subunits demonstrated a significant inverse correlation with each other (r=-0.271, p=0.0048). As the expression of the alpha and betaA subunits reflects inhibin and activin A, respectively, AR and activin A may be implicated in apocrine morphogenesis, but not in tumor progression.

Diffuse interstitial infiltrative lung metastasis of malignant melanoma: a case report.

A diffuse interstitial infiltrative pattern of lung metastasis in a patient with malignant melanoma is rare and can be confused with benign conditions such as pulmonary edema or drug-induced pneumonitis. We experienced a case of diffuse interstitial infiltrative lung metastasis in malignant melanoma in a 37-year-old man. This case was confirmed by a transbronchial lung biopsy. We herein describe the findings on CT and positron emission tomography scan.

A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results.

PURPOSE: This study was undertaken to determine safety and tolerability of nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, in combination with radiotherapy in stages IIB-IV non-small cell lung cancer (NSCLC) patients who are unsuitable for radical therapy or chemotherapy. METHODS: Nimotuzumab (100mg, 200mg and 400mg) was administered weekly from week 1 to week 8 with palliative radiotherapy (30-36 Gy, 3 Gy/day). If tumor control was achieved, nimotuzumab was continued every 2 weeks until unacceptable toxicity or disease progression. Serial skin biopsies were collected for pharmacodynamic assessment. RESULTS: Fifteen patients were enrolled in the study, with cohorts of five patients assigned in each dose level of nimotuzumab. Patients and disease characteristics included median age 73 years; Eastern Cooperative Oncology Group performance status (PS) 0-1/2 (n=3/12); female sex (n=2); adenocarcinoma (n=5); never-smoker status (n=2); and stages IIB/IIIB/IV (n=1/8/6). All patients were unable to tolerate radical therapy because of old age or multiple comorbidities. The most commonly reported adverse events were lymphopenia and asthenia (grades 1-2 in most patients). No skin rash or allergic toxicities appeared. Dose-limiting toxicity occurred with pneumonia with grade 4 neutropenia at the 200mg dose of nimotuzumab. Objective response rate and disease control rate inside the radiation field were 46.7% and 100.0%, respectively. CONCLUSIONS: Nimotuzumab in combination with radiotherapy is well-tolerated and feasible. Further clinical investigation of nimotuzumab in NSCLC patients is warranted.

Dose effect of cigarette smoking on frequency and spectrum of epidermal growth factor receptor gene mutations in Korean patients with non-small cell lung cancer.

PURPOSE: This study aimed to determine the dose effect of smoking on the mutational frequency and spectrum of epidermal growth factor receptor (EGFR) gene in Korean non-small cell lung cancer (NSCLC). METHODS: Detailed smoking histories were obtained from 324 consecutively enrolled Korean NSCLC patients. Mutational status of EGFR (exon 18-21) was determined using nested polymerase chain reaction amplification. RESULTS: A total of 108 EGFR mutations (33.3%) were identified in 107 patients. Decreased EGFR mutation rate with increased smoking dose was observed, with 48.0% (82 of 171) in never smokers, 23.1% (15 of 65) in former smokers, and 11.4% (10 of 88) in current smokers. The incidence of EGFR mutation was significantly lower in patients who smoked for more than 25 pack-years (P < 0.0001) or who stopped smoking cigarettes less than 10 years ago (P < 0.0001). Mutations in exon 19 or 21 were associated with fewer total smoke years (5.0 vs. 25.0 years in exon 20, P = 0.024), fewer total pack-years (6.3 vs. 38.9 pack-years in exon 20, P = 0.079), and more smoke-free years (11.1 vs. 3.6 years in exon 20, P = 0.027), compared with those in exon 20. Mutations in exon 19 or 21 were associated with female (P < 0.0001), never smoker (P < 0.0001), and adenocarcinoma (P < 0.0001), whereas those in exon 20 were not. CONCLUSIONS: Smoking dosage affects the incidence of EGFR mutations. EGFR mutations in exon 19 or 21 are associated with low exposure to cigarette smoke, whereas EGFR mutation in exon 20 is more common in smokers.

Malignant glomus tumor of the urinary bladder.

We present a case of a malignant glomus tumor arising in the urinary bladder of a 57-year-old woman with metastatic pulmonary nodules who died 2 months later. Pathologically and clinically confirmed malignant glomus tumors are exceedingly rare, especially those that arise in the visceral organs. The present case retained its architectural similarity to a benign glomus tumor and consisted of sheets of highly malignant round cells showing cytoplasmic positivity for smooth muscle actin. On reticulin histochemical staining, we found that reticulum fibrils surrounded individual tumor cells, suggesting cellular investment by basement membrane. We discuss the concept of malignant glomus tumors and emphasize the criteria that distinguish them from other malignant tumors.

Estrogen receptor is significantly associated with the epithelioid variants of renal angiomyolipoma: a clinicopathological and immunohistochemical study of 67 cases.

Perivascular epithelioid cells (PEC) in angiomyolipoma (AML) were recently proposed to be its most common progenitor cells. Histologically, triphasic components were present in various proportions, but were overwhelmingly myogenic in epithelioid variants of AML. Despite histological discrimination, the immunophenotypic profiles between triphasic and epithelioid AML have never been compared. The aim of the present study was to clarify the identity of PEC by using immunoreactivity to estrogen receptor (ER), progesterone receptor (PR), bcl-2 and placenta alkaline phosphatase (PLAP), and to use this information to compare triphasic and epithelioid AML. A total of 33 out of 67 cases of renal angiomyolipoma that underwent surgery were reviewed over the period 1998-2003. Two cases were associated with tuberous sclerosis. Ten patients had other malignant tumors, and three patients had a nodal extension. Immunohistochemistry showed that bcl-2 (59.4%), PLAP (46.9%), HMB-45 (100%) was predominantly localized around vessels. The stem cell markers were absolutely negative in all AML types. The estrogen receptors were positive in 14 cases (42.4%) and the progesterone receptors were positive in five cases. Bcl-2 and both female sex hormone receptors were significantly more frequent in the epithelioid variant of AML than in the triphasic type. Perivascular epithelioid cells express bcl-2, ER, PR and PLAP, and ER could be partly associated with myogenic proliferation.

Increased expression of matrix metalloproteinase 9 correlates with poor prognostic variables in renal cell carcinoma.

BACKGROUND: MMP2 and MMP9 are two gelatinolytic enzymes, which are key regulators of tumor invasion and metastasis. This study aimed to clarify the prognostic significance of MMP2 and MMP9 with particular regard to their transcript levels, enzymatic activities in renal cell carcinomas (RCCs). MATERIALS AND METHODS: Through cDNA array, the differential expression of the MMP superfamily was evaluated in RCC. Various properties of MMP2 and MMP9 were quantified, in 178 patients with RCC, based on the Heidelberg classification. Of these, 145 cases including 16 fresh-frozen cases were available for MMP2 and MMP9 transcript level evaluation. In addition, gelatinolytic activity was assessed by zymography in 16 other fresh-frozen samples from new RCC cases. RESULTS: MMP2, 9, 11, 14, and 16 were upregulated in the conventional RCC in comparison with the chromophobe RCC, whereas MMP1, 11 and 16 were pronounced in papillary RCC. MMP9 transcript levels were strongly associated with the MMP9 enzymatic activity (p=0.001), and therefore, with disease-free survival (p=0.001) and metastasis (p=0.011). Gelatinolytic activity of MMP9 by zymography was strongly associated with MMP9 mRNA expression, which was more intense in 'conventional' RCC than in 'chromophobe' RCC (p=0.001), irrespective of tumor grade or stage. MMP9 was proven to be a significant prognostic predictor by multi-variate survival analysis (p=0.0054). MMP2 enzymatic activity disappeared in spite of its constant transcript expression in RCC. CONCLUSIONS: MMP9 appears to be regulated at the transcript level, whereas MMP2 is regulated at the posttranscriptional level. Poor survival with a high frequency of metastases in 'conventional' RCC is associated with MMP9, which exhibits a high transcriptional level, and a high gelatinolytic activity. As a result, MMP9 may be a candidate of predictors of disease-free survival in RCC.