Lai Fa Sheu

Experimental Focal Segmental Glomerulosclerosis in Mice

Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.

The clinicopathological analysis of 303 cases with malignant lymphoma classified according to the World Health Organization classification system in a single institute of Taiwan

Several reports have shown a different distribution of malignant lymphoma (ML) in Asian and Western populations. The purpose of our survey was to elucidate whether there are substantial differences in the frequencies of subtypes of ML between different geographical areas. All entities diagnosed as ML between June 1995 and December 2007 were selected according to the 2008 World Health Organization (WHO) classification and searched for clinical outcomes. The cases were retrieved and reviewed by a panel of clinical haematologists and haematopathologists. A total of 303 patients with ML were identified for retrospective analysis. Of the 303 patients with ML, 278 patients (91.7%) had non-Hodgkin’s lymphoma (NHL), and 25 (9.2%) had Hodgkin’s lymphoma. Of the 278 patients with NHL, 223 (73.6%) had lymphoma of B-cell lineage, and 55 (18.1%) had lymphoma of T-cell lineage. One hundred and thirty-seven patients were diagnosed with diffuse large B-cell lymphoma, which was the most common B-cell lineage subtype and accounted for 45.2% of patients with NHL. Peripheral T-cell lymphomas were the most frequent subset of the T-cell neoplasms, comprising 10.6% of ML. Extranodal involvement was found in 125 (44.9%) of the 278 patients with NHL, and the lymph node was the site of primary involvement in 153 patients (55.1%). Fifty-nine (47.2%) of the 125 patients with extranodal presentation had gastrointestinal tract involvement. Outcome was worse in patients with extranodal NHL than in those with nodal NHL through the entire follow-up period; the difference in survival rates was significant. Our findings clarify the applicability and prognostic relevance of the WHO classification system and provide further information about the incidence of various lymphoma subtypes in Taiwan. Primary extranodal NHL was associated with a worse prognosis and distinct characteristics compared with nodal NHL. The outcome of different types of extranodal NHL should be investigated further.

Prediction of Metastasis to Non-sentinel Nodes by Sentinel Node Status and Primary Tumor Characteristics in Primary Breast Cancer in Taiwan

We aimed to determine how to approach the axilla after finding a positive sentinel node (SN) for a woman with breast cancer in Taiwan. We used blue dye staining to identify the SN in 824 procedures on 811 patients with breast cancer small than 3 cm by a single surgeon. All patients underwent SN biopsy, followed by at least level II axillary dissection. All SNs were evaluated histologically and immunohistochemically with anti-cytokeratin antibodies. Non-SNs were examined by routine histology. SNs were identified in 814/824 procedures (98.8%). SN metastases were found in 286/814 (35.1%). Subsequent axillary dissections revealed tumors in non-SNs in 188 (65.7%) of these patients. There was a relatively high incidence of non-SN metastases in our population. Tumor exhibiting high nuclear grading, ER-, PR-, Erb-2/neu overexpression, lymphovascular invasion, increasing tumor size, multiple positive SNs, and macrometastatic size in SNs (> 2 mm) were all significantly correlated with non-SN metastases. Multivariate analysis showed that tumor size, the number of positive SNs, and the metastatic size in SNs were independent factors predicting the presence of positive non-SNs. Small (< 2 cm) cancers, having only micrometastatic foci in the SN and having only one SN involved are closely correlated with the tumor-free non-SNs. Our data will assist such patients regarding the need for axillary dissection after finding a positive SN.

Increasing expression of extracellular matrix metalloprotease inducer in renal cell carcinoma: tissue microarray analysis of immunostaining score with clinicopathological parameters.

Aim:  Renal tumor cell invasion is responsible for both local tissue destruction and distant metastasis. Invasion is largely mediated by matrix metalloproteases that are thought to be induced by tumor cell‐derived extracellular matrix metalloprotease inducer (EMMPRIN) in surrounding fibroblasts. We hypothesized that EMMPRIN and matrix metalloproteinase‐9 (MMP‐9) are over‐expressed in renal cell carcinoma.

Sentinel Node Biopsy in Early Breast Cancer in Taiwan

The purpose of this study is to report the results of sentinel node (SN) biopsy for assessment of early breast cancer in Taiwan and to compare our results with those in other Asian countries and worldwide. We used methylene blue dye to identify SN in patients with clinically non-palpable breast mass and palpable breast mass smaller than 3 cm. We also explored the role of imprint cytology and immunochemical studies to identify metastatic cancer cells in the lymph nodes. A total of 221 procedures on 218 patients were performed by a single surgeon. The SN was identified in 85.5% of the cases. The overall accuracy of identifying tumors in SN was 97.4%, with a sensitivity of 90.9%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 96.4%. The use of immunochemical techniques helped to identify micrometasta-sis in SN or non-SN. Our results on SN biopsy with the dye method were similar to those reported from Japan and elsewhere. We concluded that sentinel node biopsy, together with the use of immunochemical techniques to identify micrometastatic foci, has allowed surgeons to decide at the time of surgery whether to perform axillary node dissection.RésuméAfin de rapporter les résultats des biopsies du ganglion sentinelle (GS) pour évaluer le cancer précoce du sein à Taiwan et de comparer nos résultats avec ceux d’autres pays asiatiques et du monde. Nous avons utilisé du bleu de méthylène pour identifier le GS chez les patientes porteuses de tumeur du sein cliniquement non-palpable ou plus petite que 3 cm. Nous avons exploré le rôle de la cytologie et des études immunochimiques pour identifier les cellules cancéreuses métastatiques dans les ganglions lymphatiques. Au total, 221 procédés chez 218 patients ont été réalisés par un seul chirurgien. On a identifié le GS dans 85.5% des cas. La précision globale pour identifier les tumeurs par la biopsie du GS a été de 97.4%, avec une sensibilité de 90.9%, une spécificité de 100%, une valeur prédictive positive de 100%, et une valeur prédictive négative de 96.4%. L’utilisation de techniques immunochimiques a permis d’identifier des micrométastases chez les patients ayant eu ou non une biopsie du GS. Nos résultats de biopsie par la méthode de coloration étaient similaires à ceux rapportés au Japon et ailleurs. Nous concluons que la biopsie du GS combinée aux techniques immunochimiques pour identifier les foyers micrométastatiques ont permis aux chirurgiens de décider s’il fallait practiquer ou pas, au moment de la chirurgie, une lymphadénectomie.ResumenEl trabajo presenta los resultados sobre el valor de las biopsias del ganglio centinela (SN), en pacientes con cáncer de mama en Taiwan, comparándolos con los obtenidos en otros paÍses de Asia y del Mundo. En pacientes con una tumoración de mama, no palpable o de un tamaño<3 cm, utilizamos para identificar el SN el azul de metileno. Se efectúan estudios citológicos e inmunoquÍmicos, para identificar las células metastásicas en los ganglios linfáticos. Un solo cirujano realizó 221 biopsias en 218 pacientes. El SN se identificó en el 85.5% de los casos. La exactitud global para la identificación de metástasis en el SN fue del 97.4%, con una sensibilidad del 90.0% y especificidad del 100%, valor predictivo del 100% y negativo del 96.4%. El empleo de técnicas inmunoquÍmicas ayuda a la detección, en los SN, de micrometástasis. Nuestros resultados en la identificación del SN mediante contraste con azul de metileno son similares a los obtenidos en Japón y en otros lugares. En conclusión, la biopsia del ganglio centinela junto con el empleo de técnicas inmunoquÍmicas para la detección de los focos micrometastásicos, permiten al cirujano decidir, durante el acto quirúrgico, si el vaciamiento axilar es o no necesario.

Higher expression of epidermal growth factor receptor is associated with extracellular matrix metalloprotease inducer in colorectal adenocarcinoma: Tissue microarray analysis of immunostaining score with clinicopathological parameters

Aim: Extracellular matrix metalloprotease inducer (EMMPRIN) expression was demonstrated in several cancers, but its expression profile in colorectal cancers remains unclear. Epidermal growth factor receptor (EGFR) was reported to regulate EMMPRIN expression in human epithelial cancers. Our purpose was to determine EMMPRIN expression and its relationship with EGFR in colorectal cancers. Methods: Immunohistochemical analysis of EMMPRIN and EGFR was performed in tissue microarray slides of 90 surgical specimens including 32 well differentiated, 35 moderately differentiated, and 23 poorly differentiated colorectal adenocarcinomas. Results: All colorectal adenocarcinomas showed significant immunohistochemical expression of EMMPRIN. The EMMPRIN scores in poorly differentiated (303 ± 21) and moderately differentiated (326 ± 17) colorectal adenocarcinoma were significantly higher than in well differentiated (166 ± 20) colorectal adenocarcinoma. EGFR expression was mainly on the cell surface of tumor cells and the immunostaining scores of EGFR were significantly associated with the advanced clinical T and N stages. A significantly positive relationship between EMMPRIN and EGFR immunostaining scores was also noted. Conclusions: Increased expression of EMMPRIN and EGFR in colorectal adenocarcinomas is associated with clinicopathological parameters of advanced colorectal adenocarcinoma stages. In addition, the data from this study support the notion that EGFR expression may up-regulate EMMPRIN expression.

Diabetes insipidus revealing an isolated pituitary stalk metastasis of breast cancer

Diabetes insipidus (DI) resulting from isolated metastasis of the posterior pituitary-hypothalamic axis is a rare presentation of advanced malignancy. We report a 37-year-old woman with advanced breast cancer who suffered from polyuria and polydipsia for 2 weeks. Low urine osmolality and remarkably increased urine osmolality following 1-desamino-8D-arginine vasopressin (DDAVP) administration established the diagnosis of central DI. Endocrinological studies also demonstrated panhypopituitarism. Magnetic resonance imaging of the sella turcica displayed a thickened and enlarged pituitary stalk. A biopsy of the enlarged pituitary stalk exhibited a metastatic breast cancer. Supplements of DDAVP, levothyroxine, and cortisone combined with local radiotherapy completely resolved the clinical symptoms of DI and panhypopituitarism. Pituitary stalk metastasis should be considered in advanced breast cancer patients presenting with DI. A surgical approach to obtain histological diagnosis is recommended in such patients.

Involvement of Immunopathogenic Mechanisms in a Spontaneously Occurring Glomerulopathy in Mice

Mice have been found to be susceptible to spontaneous renal localization of immune deposits. However, the significance of these immune deposits is still debated. We investigated the immunopathogenesis of a naturally occurring glomerulopathy associated with progressive proteinuria and glomerulosclerosis in 75 BALB/c mice. The mice were divided into five groups of 15 and killed at the age of 1, 3, 6, 12, or 18 months for laboratory and renal pathologic studies. These mice showed persistently increasing serum levels of immune complexes, a marked increase of glomerular immune deposits which were capable of fixing C3, and interstitial infiltration of lymphocytes and plasma cells, followed by the occurrence of proteinuria, mesangiopathy, and glomerulosclerosis. Our findings suggest that an immune system mediated process occurred in the kidneys of the mice tested.