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Interstitial fibrosis assessment by renal pathologists lacks good agreement, and we aimed to investigate its hidden properties and infer possible clinical impact. Fifty kidney biopsies were assessed by 9 renal pathologists and evaluated by intraclass correlation coefficients (ICCs) and kappa statistics. Probabilities of pathologists' assessments that would deviate far from true values were derived from quadratic regression and multilayer perceptron nonlinear regression. Likely causes of variation in interstitial fibrosis assessment were investigated. Possible misclassification rates were inferred on reported large cohorts. We found inter-rater reliabilities ranged from poor to good (ICCs 0.48 to 0.90), and pathologists' assessments had the worst agreements when the extent of interstitial fibrosis was moderate. 33.5% of pathologists' assessments were expected to deviate far from the true values. Variation in interstitial fibrosis assessment was found to be correlated with variation in interstitial inflammation assessment (r 2  = 32.1%). Taking IgA nephropathy as an example, the Oxford T scores for interstitial fibrosis were expected to be misclassified in 21.9% of patients. This study demonstrated the complexity of the inter-rater reliability of interstitial fibrosis assessment, and our proposed approaches discovered previously unknown properties in pathologists' practice and inferred a possible clinical impact on patients., (© 2023. Springer Nature Limited.)

Interstitial inflammation scoring is incorporated into the Banff Classification of Renal Allograft Pathology and is essential for the diagnosis of T-cell mediated rejection. However, its reproducibility, including inter-rater and intra-rater reliabilities, has not been carefully investigated. In this study, eight renal pathologists from different hospitals independently scored 45 kidney allograft biopsies with varying extents of interstitial inflammation. Inter-rater reliabilities and intra-rater reliabilities were investigated by kappa statistics and conditional agreement probabilities. Individual pathologists' scoring patterns were examined by chi-squared tests and proportions tests. The mean pairwise kappa values for inter-rater reliability were 0.27, 0.30, and 0.26 for the Banff i score, ti score, and i-IFTA, respectively. No rater pair performed consistently better or worse than others on all three scorings. After dichotomizing the scores into two groups (none/mild and moderate/severe inflammation), the averaged conditional agreements ranged from 47.1% to 50.0%. The distributions of the scores differed, but some pathologists persistently scored higher or lower than others. Given the important role of interstitial inflammation scoring in the diagnosis of T-cell mediated rejection, transplant practitioners should be aware of the possible clinical implications of the far-from-optimal reproducibility., (© 2023. The Author(s).)

Introduction: Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in AGT , REN , ACE , and AGTR is a very rare but fatal disorder with an unknown prevalence., Methods: We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined., Results: All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in AGT , which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous AGT mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. In silico modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels., Conclusion: This AGT mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Raising evidence suggested a prognostic utility of tubulointerstitial lesions in lupus nephritis (LN). The exact prevalence of tubulointerstitial abnormalities and its predictive value among pediatric onset systemic lupus erythematous (pSLE) cases, however, remained unknown., Methods: Sixty-seven pSLE subjects diagnosed with LN with initial renal samples available were enrolled and followed for an average of 6.49 ± 3.06 years. Renal histology was evaluated according to the International Society of Nephrology/Renal Pathology Society classification, National Institute of Health classification and tubulointerstitial activity index (TIAI)., Results: Tubulointerstitial injuries were observed in 38.81% of all LN cases, including 13.33% with non-proliferative lupus nephritis (nPLN) and 46.15% of with proliferative lupus nephritis (PLN). Tubulointerstitial injuries occurred solitarily in cases with nPLN(13.33%), but always associated glomerular changes and significantly impacted renal survival (p = 0.032) among those with PLN. TIAI associated glomerular abnormalities (p = 0.031) but did not correlate renal performance or subsequent outcome (p = 0.445). Among the chronicity index, it was the chronic tubulointerstitial lesions that provided prognostic information (p = 0.012). None of the individual tubulointerstitial factors, however, reached statistical significance in end-stage renal disease prediction. Finally, considering tubulointerstitial injuries in PLN further discriminated subsequent renal outcome (p = 0.006)., Conclusion: Tubulointerstitial abnormalities were found in nearly one-third of all pediatric LN cases. With its importance in early identifying those at risk of renal failure, histologic classification considering tubulointerstitial lesions may potentially assist outcome prediction., (Copyright © 2017. Published by Elsevier B.V.)

Background: Lupus nephritis (LN) is a major risk factor for systemic lupus erythematous (SLE)-related morbidity and mortality. With the aim of bypassing renal biopsy, we analyzed urinary biomarkers for their ability to predict renal histopathologic features and end-stage kidney disease (ESKD)., Methods: Urinary albumin, ß2-microglobulin (B2M), cystatin C, kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), clusterin, calbindin, interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), trefoil factor 3 (TFF3), osteopontin, and glutathione S-transferase π (GST-π) levels were measured at time of renal biopsy. Renal histopathologies were carefully reviewed., Results: Urine from 60 pediatric SLE cases with LN, 29 without and 22 healthy controls were collected. Median age at SLE diagnosis was 12.92 years (range = 4.27-17.30 years) and 10 cases progressed to ESKD during a period of 4.12 ± 2.17 years. Urinary albumin and clusterin were significantly elevated (p = 0.035 and 0.048, respectively) in patients with tubulointerstitial renal lesions. Urinary clusterin among all urinary markers, performed best at predicting ESKD with cutoff of 0.61 × 10 -4 (AUC = 0.804; p = 0.002). Interestingly, elevation of urinary clusterin likely resulted from local over-expression in tubulointerstitial tissue since the level of serum clusterin was not concomitantly higher (p = 0.424)., Conclusion: Urinary biomarkers are emerging as non-invasive indicators for lupus-related renal histopathology and renal outcome prediction in pediatric SLE patients. Urinary clusterin, a newly identified biomarker, is an indicator that shows an association with tubulointerstitial renal lesions and demonstrates the best ability to predict ESKD.

Background: Tbx5 deficiency in zebrafish causes several abnormal phenotypes of the heart and pectoral fins. It has been reported that exogenous human growth hormone can enhance expression of downstream mediators in the growth hormone and insulin-like growth factor I (IGF-I) pathway and partially restore dysmorphogenesis in tbx5 morphants. This study aimed to further evaluate the effects of IGF-I on cell apoptosis and dysmorphogenesis in zebrafish embryos deficient for tbx5., Results: Among the five studied groups of zebrafish embryos (wild-type embryos [WT], tbx5 morphants [MO], mismatched tbx5 morpholino-treated wild-type embryos [MIS], IGF-I-treated wild-type embryos [WTIGF1], and IGF-I-treated tbx5 morphants [MOIGF1]), the expression levels of the ifg1, igf1-ra, ifg-rb, erk1, and akt2 genes as well as the ERK and AKT proteins were significantly reduced in the MO group, but were partially restored in the MOIGF1 group. These expression levels remained normal in the WT, MIS, and WTIGF1 groups. Exogenous human IGF-I also reduced the incidence of phenotypic anomalies, decreased the expression levels of apoptotic genes and proteins, suppressed cell apoptosis, and improved survival of the MOIGF1 group., Conclusions: These results suggest that IGF-I has an anti-apoptotic protective effect in zebrafish embryos with tbx5 deficiency.

Background: Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies., Methods: We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria., Results: IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis., Conclusions: The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Thyroid ultrasound and ultrasound-guided fine-needle aspiration (USG/FNA) biopsy are currently used for diagnosing papillary thyroid carcinoma (PTC), but their detection limit could be improved by combining other biomarkers. To discover novel PTC biomarkers, we herein applied a GeLC-MS/MS strategy to analyze the proteome profiles of serum-abundant-protein-depleted FNA cystic fluid from benign and PTC patients, as well as two PTC cell line secretomes. From them, we identified 346, 488, and 2105 proteins, respectively. Comparative analysis revealed that 191 proteins were detected in the PTC but not the benign cystic fluid samples, and thus may represent potential PTC biomarkers. Among these proteins, 101 were detected in the PTC cell line secretomes, and seven of them (NPC2, CTSC, AGRN, GPNMB, DPP4, ERAP2, and SH3BGRL3) were reported in public PTC transcriptome datasets as having 4681 elevated mRNA expression in PTC. Immunoblot analysis confirmed the elevated expression levels of five proteins (NPC2, CTSC, GPNMB, DPP4, and ERAP2) in PTC versus benign cystic fluids. Immunohistochemical studies from near 100 pairs of PTC tissue and their adjacent non-tumor counterparts further showed that AGRN ( n = 98), CTSC ( n = 99), ERAP2 ( n = 98) and GPNMB ( n = 100) were significantly ( p < 0.05) overexpressed in PTC and higher expression levels of AGRN and CTSC were also significantly associated with metastasis and poor prognosis of PTC patients. Collectively, our results indicate that an integrated analysis of FNA cystic fluid proteome, cancer cell secretome and tissue transcriptome datasets represents a useful strategy for efficiently discovering novel PTC biomarker candidates., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Although aberrant complement activation is involved in the pathogenesis of systemic lupus erythematosus (SLE), the role of complement regulatory proteins in disease activity of SLE remains limited. We enrolled the pediatric-onset SLE patients from our cohort study over 10 years. The clinical and laboratory data including SLEDAI disease activity score, and serum complement factor H (CFH), CFI, CD46, C5a, and C5b-9 in the active and remission phases were determined. Glomerular C5b-9 deposition as a complement activity marker was also examined. Forty patients (35 female and 5 male, aged 13.9 ± 3.8 years) met the criteria of investigation were assessed. Fever and kidney were the most common symptom and organ involved, respectively. Mean SLEDAI in the active and remission phases were 12.6 vs 1.7, respectively. All patients exhibited lower serum C3, C4, CFH and CFI and higher serum anti-dsDNA and CD46 in the active pahse. There was a significant difference in serum CFH, CFI and CD46 between active and remissive phases. Serum CFI but not CFH and CD46 level was negatively correlated with SLEDAI score in active phase. Compared to classical activity markers, serum CFI was superior to C4 and anti-dsDNA in reflecting disease activity and also significantly correlated with white blood count and hemoglobin. Glomerular C5b-9 depositions were detected in patients with nephritis during active phase but not in disease controls. Serum CFI level may not only be a promising biomarker for disease activity of SLE, but also reflects the hematological features of SLE., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interest.

Aims: To characterize the clinicopathological and genetic features of pleomorphic mantle cell lymphoma (PMCL), which morphologically mimics diffuse large B cell lymphoma (DLBCL)., Methods and Results: We screened systematically 500 B cell lymphomas morphologically compatible with DLBCL using an immunohistochemical algorithm of three markers (CD5, cyclin D1 and SOX11). Ten cases of PMCL were identified for further study and, surprisingly, four (40%) of them were cyclin D1-negative. These 10 patients were mainly elderly males with advanced disease, and their median survival was only 11 months. All cyclin D1-positive PMCLs tested showed an IGH-CCND1 translocation, whereas one of the four cyclin D1-negative PMCLs had a translocation involving CCND2 and a high CCND2 mRNA level (P < 0.000001). The genomewide copy number profiles of both cyclin D1-positive and cyclin D1-negative PMCLs were similar to those of classical mantle cell lymphoma (MCL) reported previously, confirming the diagnosis. Secondary genetic alterations involved in oncogenic pathways of MCL were observed more frequently in these PMCLs, possibly decreasing the dependence on the driving CCND1 translocation and accounting for the common cyclin D1 negativity. Copy number gains of PIK3CA and CCDC50 were detected in all cyclin D1-negative PMCLs but in only 40% of the cyclin D1-positive PMCLs. These additional oncogenic signals may compensate for the common absence of CCND2 translocation in cyclin D1-negative PMCL., Conclusion: We demonstrate for the first time that cyclin D1 negativity is surprisingly common in PMCL morphologically mimicking DLBCL, and the use of a simple immunohistochemical algorithm can prevent misclassification and inappropriate treatment., (© 2016 John Wiley & Sons Ltd.)

Background: The prognostic relevance of topoisomerase II alpha (TOP2A) copy number change remains not well established. This study is aimed to investigate the frequency and pattern of TOP2A aberrations; to correlate TOP2A alterations with human epidermal growth factor receptor 2 (HER2) status and clinicopathological parameters, and further to explore prognostic value of TOP2A and HER2 status in breast cancer in Taiwan., Methods: We analyzed tissue samples from 311 invasive carcinomas in tissue microarrays for TOP2A and HER2 status by fluorescent in situ hybridization., Results: TOP2A copy number change is an infrequent genetic event (9.8% amplification and 2.7% deletion) and is present in both HER2-amplified and nonamplified tumors. TOP2A amplification is statistically associated with age >50 at diagnosis (P = 0.016) and HER2 amplification (P < 0.001). HER2 amplification, but not TOP2A amplification, is a predictor of unfavorable prognosis (P = 0.002). Univariate and multivariate analysis showed that higher histologic grading, positive nodal involvement, and HER2 positivity were associated with poorer overall survival. Cytogenetically, double minutes-type amplification is the predominant pattern for both genes (HER2: 64% and TOP2A: 93.1%). Homogeneous staining region-type signals of both genes are resistant to RNase digestion, supporting that these were not nuclear accumulation of mRNA transcripts., Conclusion: Our results demonstrate the prognostic value of tumor grading, nodal involvement, and HER2 status in Taiwanese breast cancer. TOP2A aberrations are an infrequent event independent of HER2 status, and TOP2A amplification carries no prognostic value. The predictive value of TOP2A aberrations in patients of breast cancer taking athracycline-containing treatment in Taiwan remains to be determined in prospectively well-designed clinical trials., Competing Interests: The authors have declared that no conflicting interests exist.

The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen's kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40

Overexpression of receptor tyrosine kinase-like orphan receptor (ROR1) in a variety of human malignancies is associated with aggressive behaviour. Therapeutic agents targeting ROR1 have shown promising results in vivo and in vitro studies. In breast cancer, high-level expression of ROR1 mRNA is associated with high-grade tumours and metastasis. We investigated the prevalence and prognostic significance of ROR1 expression in triple negative breast cancer (TNBC). ROR1 was immunohistochemically stained on full-face sections of 210 TNBC patient samples. Forty-seven TNBC cases (22.4 %) showed strong ROR1 expression, which was associated with shorter disease-free survival (DFS; P = 0.00015), distant metastasis-free survival (DMFS; P = 0.00013) and overall survival (OS; P = 0.026) in univariate analyses. Results were confirmed by multivariate analysis. Seventy TNBC cases (33.3 %) with medullary features showed longer OS (P = 0.00013). We divided the whole series into two subgroups based on the presence or absence of medullary features. Strong ROR1 expression retained a predictive value of shorter DFS and DMFS in both subgroups. Our study suggests that strong ROR1 expression might be an independent adverse prognostic factor in TNBC patients and may serve as a potential marker for patient selection in ROR1-targeted therapy. More large-scale studies are needed to clarify its potential usefulness.

Stem cell markers are upregulated in various cancers and have potential as prognostic indicators. The objective of this study was to determine the expression of three stem cell markers, aldehyde dehydrogenase 1 (ALDH-1), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), and Nanog, in esophageal squamous cell carcinoma (ESCC) tissues. Immunohistochemistry was used to measure the expression of ALDH-1, Bmi-1, and Nanog in ESCC tissues from 41 patients who received pre-operative chemoradiation. We evaluated the relationship between expression of these markers, and clinicopathological features, tumor regression grade (TRG), and 5-year overall survival (OS). There were no significant associations of ALDH-1 or Bmi-1 expression with age, gender, clinical stage, and treatments (p>0.05). However, patients with Nanog-positive tumors were significantly older than those whose tumors were Nanog-negative (p = 0.033). TRG after treatment was significantly associated with expression of ALDH-1 (p = 0.001), Bmi-1 (p = 0.004), and Nanog (p<0.001). Although OS was significantly better in patients with low TRGs (p = 0.001), there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS. Expression of ALDH-1, Bmi-1, and Nanog correlated with TRG, but not OS. Further large studies are necessary to fully elucidate the prognostic value of these stem cell markers for ESCC patients.

Immunohistochemical expression of ERα, encoded by the ESR1 (estrogen receptor 1) gene located at 6q25.1, is the most important determinant of responsiveness to endocrine therapy in breast cancer. The prevalence and significance of ESR1 amplification in breast cancer remain controversial. We set out to assess ESR1 status and its relevance in breast cancer in Taiwan. We tested tissue samples from 311 invasive carcinomas in a tissue microarray for ESR1 status by fluorescent in situ hybridization (FISH) and chromogenic in situ hybridization (CISH). In order to examine its association with ERα and ESR1 status, HER2 status was determined by FISH. Of the carcinomas, 58.8 % (183/311) was ERα positive. None of the carcinomas showed amplification of ESR1 by either method, whereas 24.1 % (75/311) of the carcinomas harbored HER2 amplification. Of the carcinomas, 9.6 % (26/301) showed ESR1 gain (1.3 ≤ ratio ESR1/chromosome 6 < 2) by FISH and 10 % (24/299) by CISH. FISH and CISH results showed a good correlation (κ-coefficient = 0.786). ESR1 gain by FISH and CISH was significantly associated with high-grade (P = 0.0294 and 0.0417, respectively) but not with ERα expression, HER2 status, or overall survival. ERα positivity was significantly associated with better overall survival (P = 0.039). HER2 amplification was significantly related with poor overall survival (P = 0.002). Our data confirm that in breast cancer, HER2 amplification is a frequent genetic aberration and a negative prognostic factor, and show that ESR1 amplification is not a key genetic abnormality in the tumorigenesis of breast cancer in Taiwan.

The residues of four insecticides belonging to different families were studied on head lettuce (Lactuca sativa L. var. capitata L.), cabbage (Brassica oleracea Linn. var. capitata DC.), Chinese cabbage (Brassica pekinensis Skeels), and broccoli (Brassica oleracea var. italica) after pesticide application. To reduce application variability, a tank mix of acetamiprid 20% SP, chlorpyrifos 22.5% EC, deltamethrin 2.4% SC, and methomyl 40% SP was applied at recommended and double doses. Initial deposits of all pesticides on head lettuce were higher than those of the other three crops. The residues of chlorpyrifos and deltamethrin were higher than the maximum residue limits (MRLs) at recommended preharvest intervals (PHIs) on head lettuce and Chinese broccoli treated with higher doses. The residues of methomyl on head lettuce also showed the same phenomenon.

This study aimed to investigate the clinical efficacy of using broadband white light (BWL) to observe morphologic appearance, narrow-band imaging (NBI) to observe intraepithelial microvasculature, and both BWL and NBI for the detection of high-grade dysplasia and carcinoma in oral leukoplakia. Among 317 patients (274 males and 43 females; aged 52.4±10.7 years), the odds ratio (95% confidence interval) for detecting high-grade dysplasia and carcinomatous lesions based on morphologic appearances of BWL, and microvasculature patterns of NBI, were 39.12 (9.33-64.10), and 97.16 (38.19-247.21), respectively, which were significantly better than BWL (p<1×10(-15)). The sensitivity, specificity, positive and negative predictive values, and accuracy of use of traditional BWL classification, NBI classification, and combined BWL and NBI classification for detecting high-grade dysplasia and carcinomatous lesions were 96.30, 60.08, 33.12, 98.75, 66.25, 39.92, and 3.70%; 87.04, 93.54, 73.44, 97.23, and 92.43%; and 100.00, 60.08, 33.96, 100.00, and 66.88%, respectively. In conclusion, the diagnostic accuracy by NBI classification of oral leukoplakia based on the intraepithelial microvasculature patterns is significantly better than BWL indicating that NBI is a promising non-invasive tool in detecting high-grade dysplasia and carcinomatous lesions in oral leukoplakia., (Copyright © 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Lung cancer is one of the leading causes of cancer-related mortality worldwide. Gastrointestinal metastasis from primary lung cancer is rare. Only a few reports have been published and the majority of described metastatic sites involved the small intestine. In the present study, we report the first case of primary lung adenocarcinoma with both gastric and colonic metastases. We also review the published literature of primary lung cancer with gastrointestinal metastasis.

Purpose: To evaluate the clinical usefulness of endoscopy with a narrow-band imaging (NBI) system for the evaluation and management of homogeneous oral leukoplakia., Methods: The chart records, morphology of vascular architecture of NBI, and histopathology of patients with homogeneous leukoplakia were retrospectively reviewed and analyzed., Results: A total of 160 patients, with an average age of 50.96 ± 10.25 years, were enrolled. In 35 cases of thin leukoplakia, only intraepithelium papillary capillary loop (IPCL) type I was shown by NBI, and only squamous hyperplasia was revealed pathologically. In 125 cases of thick leukoplakia, IPCL type I was found in 94, IPCL type II in 29, and IPCL type III in 2. The Kendall rank correlation between pathology and NBI images was significant (p < 0.0001)., Conclusions: The dichotomous classification of homogeneous leukoplakia by NBI is meaningful, and endoscopy with the NBI system is a promising tool for the evaluation and management of homogeneous oral leukoplakia., (Copyright © 2012 S. Karger AG, Basel.)

The mammalian target of rapamycin (mTOR) plays an important role in cell growth, proliferation, and metabolism. Some studies have associated phosphorylated mTOR (p-mTOR) expression with worse outcome in breast cancers. However, the significance of p-mTOR expression specifically in triple negative breast carcinoma (TNBC) is unknown. In this study, p-mTOR expression was evaluated by immunohistochemistry in 172 TNBCs and the result was correlated with clinicopathologic variables and disease outcome. The majority of tumors (72.1%) were p-mTOR positive; p-mTOR expression did not correlate with age, tumor size, grade, lymph node status, or tumor stage. In patients at stage 1 and 2 disease, those with p-mTOR expression had significantly worse overall as well as recurrence-free survival compared to those without p-mTOR expression. p-mTOR expression appears to be an adverse prognostic indicator in early-stage TNBCs. The assessment of p-mTOR expression in these tumors may also help to stratify patients for future target therapy studies.

Adrenal cystic lesions are uncommon and we analyzed clinical and pathologic features of 25 such cases from a single institute over 23 years. There were 16 pseudocysts, eight endothelial cysts, and one epithelial cyst. Seven of eight endothelial cysts were confirmed to be lymphangiomatous by D2-40 immunostaining. We suggest that pseudocysts and endothelial cysts may have different histogenesis. The proposed mesothelial origin of adrenal epithelial cyst cannot be confirmed in our example. Seven adrenal pseudocysts were associated with tumor, including two pheochromocytomas, one neuroblastoma, one adrenal cortical carcinoma, one adrenal cortical adenoma, one myelolipoma, and one schwannoma. The distinction of true cystic lesion from cystic neoplasm is important and requires thorough sampling of the specimens.

Background and Purpose: The association of chronic hepatitis B virus (HBV) infection and decreased levels of high-density lipoprotein cholesterol (HDL-C) has been well documented. However, the relationship between dyslipidemia and asymptomatic chronic HBV infection is still unclear., Methods: In 1997, 1330 medical center employees (405 men and 925 women) were recruited to evaluate the effects of chronic HBV infection on serum lipid profile, including total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol, and triglycerides (TG). Among these patients, 195 were found to have chronic HBV infection and 35 (17.9%) of them were found to have elevated alanine aminotransferase (ALT). Multiple linear regression analyses were used to evaluate the effects of chronic HBV infection on serum lipids., Results: The most significant finding was that levels of TC and HDL-C were decreased by 5.8 and 2.7 mg/dL respectively, among patients with asymptomatic chronic HBV infection (serum ALT < 40 U/L). After controlling for other determinants, male gender, old age, higher body mass index (BMI) and waist-to-hip ratio, current smoking, and hepatitis B surface antigen-negative status with ALT > or = 40 U/L were associated with lower serum HDL-C and higher TG levels. However, moderate to heavy alcohol drinking, physically active lifestyle, and lower BMI were associated with higher levels of HDL-C., Conclusions: Asymptomatic chronic HBV infection was associated with lower serum levels of TC and HDL-C. Elevation of ALT was also an indicator of lower levels of HDL-C in patients with chronic hepatitis B and lower serum HDL-C and higher TG levels in patients without HBV infection. These findings also indicated the need to monitor the risk of atherosclerotic diseases in patients with asymptomatic chronic HBV infection, especially those with lower HDL-C levels.

The purpose of this study was to determine whether the levels of heterozygosity and microdeletion of specific loci within the DiGeorge critical region (del22q11) are associated with different phenotypes of tetralogy of Fallot (TF). Examinations were conducted on 84 sporadic TF patients and their unaffected parents for del22q11, using the following 9 simple tandem repeat polymorphic microsatellite markers: D22S420, D22S427, D22S941, D22S944, D22S264, D22S311, D22S425, D22S303, D22S257. The microdeletions were confirmed using quantitative PCR with markers TUPLE1, exon 2 of the UFD1L gene, and D22S264; the boundaries of these microdeletions were estimated using genotypic analyses of the unaffected family members. The del22q11 was identified in 14 patients (16.6%). The boundary of the shortest region of deletion overlap (SRO) in these 14 TF patients was identified, proximally using D22S427 and distally using the TUPLE 1 gene. The deletion of exon 2 of the UFD1L gene and TUPLE1 gene was identified in 13 patients (13/14 cases; 93%). The SRO in TF patients with del22q11 was at or close to the ADU breakpoint and centromeric to the UFD1L gene. The level of heterozygosity for the marker D22S944 in TF patients without del22q11 (n = 70) was found to be significantly lower than expected. Overall, this study demonstrated the significantly low level of heterozygosity within DiGeorge critical region in TF patients with or without del22q11. Our results suggest that the genetic factors leading to DiGeorge/velocardiofacial syndrome might also be partly responsible for TF phenotypes.

Using genotype analysis and multiplex quantitative polymerase chain reaction (PCR), chromosome 22q11 deletions were examined in 252 patients with syndromic or isolated conotruncal heart defect. Of these patients, 19 (7.5%) were found to be hemizygous for chromosome 22q11. Parental origin of the deleted chromosome was determined in 16 cases: one patient (6.3%) inherited a deleted chromosome 22 from his mother; all the others (93.7%) consisted of de novo mutations. One-third (5/15) of the de novo 22q11 deletions were of paternal origin and the remainder derived maternally. These results lend further support to our current knowledge of chromosome 22q11 microdeletion syndromes and their implications for the genetic counseling of individuals diagnosed with conotruncal heart defects. Possible mechanisms for gender-biased parental origin are discussed.

Monozygotic twins with chromosome 22q11 microdeletions offer an ideal situation to observe the association of microdeletion and disrupted cardiovascular patterning. We report monozygotic twins concordant for 22q11.2 microdeletion but discordant for cardiovascular patterning. Both twins showed identical intracardiac defects including tetralogy of Fallot with pulmonary atresia. Nevertheless, their great vessel patternings were variable. These twins show that the mispatterning of the great vessels may not correlate with intracardiac morphogenesis. The discordant development of the great vessels, especially in the pulmonary vascular system, has clinical significance for prognosis. The phenotypic variability of cardiovascular anomalies seen in 22q11 microdeletion cannot be explained on the basis of genotypic difference.

Background: In a period of 18 months, we have encountered 4 cases of right middle lobe atelectasis associated with endobronchial silicotic lesions of right middle lobe bronchi. All patients had occupational exposure to mineral dusts (3 coal miners and 1 sand blaster) for months to decades., Methods: The nature of the endobronchial silicotic lesions that caused the bronchial obstruction has been confirmed by endobronchial biopsies and energy-dispersive spectrometry of the lesions. Extrinsic compression has been excluded by careful radiographic and computed tomographic image analysis., Results: The endobronchial silicosis does not appear to correlate with the degree of pneumoconiosis of the lung parenchyma. The endobronchial silicosis may cause bronchial obstruction in the absence of radiographic evidence of pulmonary silicosis., Conclusion: The endobronchial silicosis and consequent lung atelectasis may be associated with silica exposure.

Setting: Taiwan Provincial Chronic Disease Control Bureau., Objective: To evaluate the rate of recovery and the mean time to detection (TTD) of mycobacteria in clinical specimens with two culture systems, the BACTEC MGIT 960 and Löwenstein-Jensen (LJ) medium., Design: We studied 365 specimens, collected from 166 patients. Specimens were processed with standard N-acetyl-L-cysteine (NALC)-NaOH method, then inoculated onto BACTEC MGIT 960 and onto LJ slants., Results: A total of 124 mycobacterial isolates (114 Mycobacterium tuberculosis and 10 non-tuberculous mycobacteria) were detected. The recovery rates were 94% (117/124) with BACTEC MGIT 960 and 75.8% (94/124) with LJ. The rates of contamination for each of the systems were 5.5% with BACTEC MGIT 960 and 4.1% with LJ. The TTDs for mycobacteria were 10.7 days with BACTEC MGIT 960 and 30.6 days with LJ. Excluding the non-tuberculous mycobacteria, the TTDs for M. tuberculosis were 11.1 days with BACTEC MGIT 960 and 30.7 days with LJ. The difference in TTD between smear-positive and smear-negative specimens for either mycobacteria (10.0 vs 12.6 days; P = 0.06) or M. tuberculosis (10.1 vs 12.7 days; P = 0.06) with BACTEC MGIT 960 was not statistically significant., Conclusion: The BACTEC MGIT 960 system can expedite the recovery of mycobacteria in culture. Combined with conventional solid medium, it also increases the overall recovery of mycobacteria in culture.

Background and Purpose: To determine the in vitro activity of rifabutin against Mycobacterium tuberculosis (MTB) and the cross-resistance rate between rifampin and rifabutin., Methods: A total of 56 clinical isolates of MTB, including 23 multidrug-resistant (MDR) isolates and 33 susceptible isolates, were tested for susceptibility to rifampin and rifabutin using the absolute concentration method. The concentrations of drugs tested were 2.5 and 5 mg/mL for rifampin and 0.1, 0.5, 1, 2.5, 5, and 10 mg/mL for rifabutin., Results: All 33 MTB isolates that were susceptible to rifampin were also susceptible to rifabutin. None of the 23 MDR-MTB isolates were inhibited by rifabutin at a concentration of 0.1 mg/mL. Among these 23 MDR isolates, three were susceptible to rifabutin at concentrations > or = 0.5 mg/mL, six were susceptible to rifabutin at concentrations > or = 5 mg/mL, 18 were susceptible to rifabutin at concentrations > or = 10 mg/mL and five were not inhibited at any of the concentrations tested. The cross-resistance rate between rifampin and rifabutin was 87%., Conclusions: Our results indicate that the in vitro activity of rifabutin against drug-susceptible MTB isolates is greater than that of rifampin. For MDR-MTB isolates, the cross-resistance is high between rifampin and rifabutin.

A 55-year-old man presented with the suspicion of pulmonary tuberculosis. He was treated with isoniazid, ethambutol, rifampicin and pyrazinamide. However, he developed high fever, skin rash and pulmonary infiltrates following 10 days of treatment. The above-mentioned conditions subsided promptly after stopping ethambutol therapy and reappeared after rechallenge, marking ethambutol as the offender. To present knowledge, this is the second case of an ethambutol-induced hypersensitivity lung reaction reported in English literature.