Interpregnancy Interval and Birth Outcomes: A Propensity Matching Study in the California Population

Maternal and Child Health Journal - Previous studies that used traditional multivariable and sibling matched analyses to investigate interpregnancy interval (IPI) and birth outcomes have reached...     

Identification of a Major Epitope Recognized by PLA2R Autoantibodies in Primary Membranous Nephropathy

Phospholipase A₂ receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD). However, in nondenaturing conditions the epitope was protected against reduction in larger fragments, including the full-length extracellular region of PLA2R. To determine the composition of the epitope, we isolated immunoreactive tryptic fragments by Western blotting and analyzed them by mass spectrometry. The identified peptides were tested as inhibitors of autoantibody binding to PLA2R by surface plasmon resonance. Two peptides from the ricin domain showed strong inhibition, with a longer sequence covering both peptides (31-mer) producing 85% inhibition of autoantibody binding to PLA2R. Anti-PLA2R antibody directly bound this 31-mer peptide under nondenaturing conditions and binding was sensitive to reduction. Analysis of PLA2R and the PLA2R-anti-PLA2R complex using electron microscopy and homology-based representations allowed us to generate a structural model of this major epitope and its antibody binding site, which is independent of pH-induced conformational change in PLA2R. Identification of this major PLA2R epitope will enable further therapeutic advances for patients with idiopathic membranous nephropathy, including antibody inhibition therapy and immunoadsorption of circulating autoantibodies.     

A comparison of immunohistochemical staining for oestrogen receptor, progesterone receptor and HER-2 in breast core biopsies and subsequent excisions

AIMS: To compare immunohistochemical staining for oestrogen receptor, progesterone receptor and HER-2 between core biopsy and matched subsequent excisional specimens. METHODS: One hundred consecutive core biopsy cases and subsequent excisional specimens were retrieved and immunohistochemical staining performed. Proportion and intensity of staining for hormone receptors and HercepTest score were recorded for each case in a blinded fashion by the authors. RESULTS: Overall hormone receptor status was concordant between cores and excisions in 96.9% of cases. ER status was concordant between the core and excision in 95.8% of cases. The intensity of staining for ER was similar in both core and excision specimens. PR status was concordant in cores and excisions in 90.3% of cases. There was weaker PR staining in the excisional specimens when compared with the cores. HER-2 status was concordant in cores and excisions in 86.6% of cases. CONCLUSIONS: Hormone receptor staining produced similar results on core and excisional specimens, although a small number of additional hormone receptor positive cases could be detected by performing staining on a previously received core in the case of a negative result on the excisional specimen. HER-2 staining is less reproducible between cores and excisions, but the clinical significance of this observation remains to be tested.     

High density of small vessels expressing the tyrosine kinase receptor KDRin primary invasive breast carcinoma correlates with axillary lymph node metastases

Although it is generally accepted that tumour growth is angiogenesis dependent, little is known about the role of angiogenesis in the metastatic process. Recent evidence suggests that the angiogenic tyrosine kinase receptor KDR is pivotal in new vessel formation. To investigate, therefore, the association between new vessel formation in primary breast carcinoma and axillary lymph node metastasis we have used computer assisted video analysis to assess the vascular distribution as well as the level of expression of KDR in individual vessels in sections of invasive breast carcinomas, some of which had metastasized to the axillary lymph nodes and some that had not. We specifically assessed the frequency distribution, perimeter, area, and density of KDR positive vessels in the same sections of tumours. Our results show that in invasive mammary carcinoma KDR is expressed exclusively on the surface and cytoplasm of endothelial cells of approximately 71% of vessels, but the level of expression in individual vessels does not correlate with the presence of axillary lymph node metastases (P > 0.10). However, we found that small vessels express higher levels of KDR (P < 0.02) than larger vessels and that there is a significantly higher frequency of relatively small (< 90 μm in perimeter) KDR positive vessels in breast tumours that had metastasized to the axillary lymph nodes than those that had not (P < 0.001). In conclusion, increased density and frequency of KDR positive small vessels in primary invasive breast carcinoma correlates with axillary lymph node metastases. This revised version was published online in June 2006 with corrections to the Cover Date.     

Predicting axillary lymph node metastases in breast carcinoma patients

Routine axillary dissection is primarily used as a means of assessing prognosis to establish appropriate treatment plans for patients with primary breast carcinoma. However, axillary dissection offers no therapeutic benefit to node negative patients and patients may incur unnecessary morbidity, including mild to severe impairment of arm motion and lymphedema, as a result. This paper outlines a method of evaluating the probability of harbouring lymph node metastases at the time of initial surgery by assessment of tumour based parameters, in order to provide an objective basis for further selection of patients for treatment or investigation. The novel aspect of this study is the use of Maximum Entropy Estimation (MEE) to construct probabilistic models of the relationship between the risk factors and the outcome. Two hundred and seventeen patients with invasive breast carcinoma were studied. Surgical treatment included axillary clearance in all cases, so that the pathologic status of the nodes was known. Tumour size was found to be significantly correlated (P < 0.001) to the axillary lymph node status in the multivariate analysis with age (P = 0.089) and vascular invasion (P = 0.08) marginally correlated. Using the multivariate model constructed, 38 patients were predicted to have risk of nodal metastases lower than 20%, of these only 4 (10%) patients had lymph node metastases. A comparison with the Multivariate Logistic Regression (MLR) was carried out. It was found that the predictive quality of the MEE model was better than that of the MLR model. In view of the small sample size, further verification of this model is required in assessing its practical application to a larger population.     

Bullous pemphigoid in children. Report of three cases

Bullous pemphigo?d (BP) is an acquired immunobullous disease that usually affects adults and rarely children. About 60 cases of infant PB have been reported. Diagnosis is based on immunofluorescence investigations. Clinical, histological and immunopathological findings in childhood PB appear to be not different from the adult. Nevertheless, oral mucosal and palm and sole lesions seem to occur more frequently. We report 3 cases of children BP in one girl and 2 boys, aged respectively of 7.2 and 3 years. Palm and sole were affected in 1 case, and no oral mucosal lesion was noted. Recovery was reached in all cases under dapsone. Characteristics of BP in children are discussed with comparison to literature data.     

Detection of estradiol-induced messenger RNA (pS2) in uninvolved breast tissue from mastectomies for breast cancer

Summary pS2 mRNA was estimated in uninvolved breast tissue and breast carcinoma from the same patients. pS2 mRNA was clearly detected in 14 of 59 uninvolved breast tissues and in 30 of 58 breast carcinomas. pS2 mRNA was found more frequently in uninvolved breast tissue of premenopausal women than in that of post-menopausal women.     

Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.