BRCA1 and BRCA2 mutation testing in Cyprus; a population based study.

This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.

Correlation of the derivative as a robust estimator of scatterer size in optical coherence tomography (OCT).

The size-dependent spectral variations, predicted by Mie theory, have already been considered as a contrast enhancement mechanism in optical coherence tomography. In this work, a new spectroscopic metric, the bandwidth of the correlation of the derivative, was developed for estimating scatterer size which is more robust and accurate compared to existing methods. Its feasibility was demonstrated using phantoms containing polystyrene microspheres as well as images of normal and cancerous human colon. The results are very promising, suggesting that the proposed metric could be utilized for measuring nuclear size distribution, a diagnostically valuable marker, in human tissues.

The MTHFR 677TT and 677CT/1298AC genotypes in Cypriot patients may be predisposing to hypertensive nephrosclerosis and chronic renal failure.

AIM: The homozygous 677TT mutation of the MTHFR gene has been linked to deep vein thrombosis and to arterial atherosclerotic events of the coronary, carotid and peripheral arteries. Its putative association with renal arteriosclerosis and chronic renal failure (CRF) in the presence of hypertensive nephrosclerosis is yet to be investigated. METHODS: Two hundred and twenty-one Greek-Cypriot patients with CRF from one single renal unit in Cyprus were divided into 6 diagnostic categories: 49 due to chronic glomerulonephritis (22.2%), 43 due to diabetes mellitus (19.4%), 26 due to autosomal dominant polycystic kidney disease (11.8%), 30 due to essential hypertension leading to nephrosclerosis (13.6%), including 4 patients with primary malignant hypertension, 32 with other rarer causes of CRF (14.5%) and 41 of uncertain etiology (18.5%). These 221 CRF patients had their MTHFR C677T and A1298C genotypes analyzed by the polymerase chain reaction and agarose gel electrophoresis after restriction enzyme digestion. The frequency of the homozygous states 677TT and 1298CC and the double heterozygous 677CT/1298AC were compared to those of 210 unrelated normal local controls. RESULTS: A statistically significant increase in the frequency of the 677TT genotype compared to controls was only found in the hypertensive nephrosclerosis CRF sub-group of patients. The prevalence rate of the 677TT genotype was 46.7% (controls 17.6%, P=0.0007). Combined together the homozygous 677TT and the double heterozygous 677CT/1298AC genotypes were found in 86.7% of the hypertensive nephrosclerotic CRF patients, compared to 46.6% in normal controls (P=0.0001). CONCLUSIONS: The findings support the hypothesis that Caucasian patients with essential hypertension, homozygous for 677TT or doubly heterozygous for 677CT/1298AC genotypes, are predisposed to develop hypertensive nephrosclerosis and CRF.

Medullary cystic kidney disease with hyperuricemia and gout in a large Cypriot family: no allelism with nephronophthisis type 1.

We describe a large Cypriot family with an interstitial type of nephropathy, inherited as an autosomal dominant trait that led to end stage renal failure between 51 to 78 years of age (mean 62.2 years). Twenty-three people are known to be affected, but several younger relatives with normal renal function may remain undiagnosed because of the absence of precise clinical and laboratory diagnostic criteria. This nephropathy is associated with medullary renal cysts, hypertension, hyperuricemia, and gout. Several relatives have typical medullary cystic disease (MCD), while in the others the findings are compatible with this diagnosis. Due to the similarity of clinical and pathologic findings, earlier reports had suggested that MCD may be allelic to autosomal recessive familial juvenile nephronophthisis, which was mapped recently to chromosome band 2q13. Linkage analysis of the present family with a closely linked marker excluded linkage to the above locus. Linkage was also excluded to the PKD1 locus of adult polycystic kidney disease type 1, and up to 5 cM on either side, on chromosome 16. We suggest that because of the element of hyperuricemia and gout found in this family, although with reduced penetrance, it may represent a variant of autosomal dominant MCD of the adult type. This variability may be the result of allelic or locus heterogeneity. Molecular genetic approaches including linkage analysis on appropriate families will certainly assist in classifying such related genetically heterogeneous disorders.

Extranodal follicular dendritic cell sarcoma of the gastrointestinal tract. Morphologic, immunohistochemical and ultrastructural analysis of two cases.

Tumors showing differentiation toward follicular dendritic cells are rare and usually occur in lymph nodes. Their occurrence at extranodal sites was recognized recently. This report documents two further extranodal cases, one arising in the small intestine of a 23-year-old woman and the second in periduodenal retroperitoneal soft tissue of a 63-year-old man. Both neoplasms displayed a typical biphasic morphologic pattern, composed of large cells with indistinct cytoplasmic borders creating a syncytial appearance, admixed with spindle cell areas resembling malignant fibrous histiocytoma, and infiltrated by numerous small T lymphocytes. Expression of CD21 and CD35, together with ultrastructural demonstration (in one case) of long cytoplasmic processes connected by desmosomes, confirmed follicular dendritic cell differentiation. One case also expressed HLA-DR, and both showed aberrant epithelial membrane antigen staining. Neither tumor showed CD45 expression. In both cases the tumors were treated by local excision. Case 1 has shown an unusually aggressive course with extensive intraperitoneal recurrence. The biphasic morphologic pattern and tumor immunophenotype are discussed in relation to increasing evidence of immunophenotypic and morphologic heterogeneity of normal follicular dendritic cells.

Prognostic variables in greek patients with stage II breast cancer: a Hellenic Cooperative Oncology Group study.

The independent effects of several patient, tumor and treatment-related prognostic factors on relapse-free survival (RFS) and overall survival (OS) were assessed by Cox multivariate regression analysis in 988 Greek patients with stage II breast cancer. At a median follow-up time of 83 (range 3.3-131+) months and after the evaluation of all patients together, the number of positive axillary nodes (p < 0.0001), tumor size (p = 0.0024) and tumor grade (p = 0.0008) were identified as significant prognostic factors for RFS. Also, the number of positive nodes (p < 0.0001), tumor size (p = 0.0002) and ER status (p = 0.0001) were found to be significant for OS. These short-term prognostic variables are similar to those reported for this group of patients in other European countries and in the USA.

A simplified method for measuring the thickness of glomerular basement membranes.

Measurement of the thickness of glomerular basement membranes is required for the diagnosis of thin membrane nephropathy. Over the years various morphometric methods have been used but some are laborious so there is a need for establishing a simplified method for measuring thickness. In the present study 20 renal biopsies were used to carry out a comparative morphometric analysis between 2 methods. The first method was based on measuring thickness at the maximum number of available points, whereas for the second method, thickness was measured at only 5 points per loop. Since both methods gave mean values that are not statistically different in each patient, the authors recommend that the simplified method be used routinely for diagnosis.

Correlation between morphology, immunohistochemistry and molecular pathology in hereditary and sporadic breast cancer cases.

Breast cancer still represents a serious health problem and is currently the most frequent malignancy in the female population in developed countries. In Cyprus, there are 300 new cases annually. In the present study, histology, electron microscopy, immunohistochemistry, and Western blot analysis were used to investigate 100 cases of invasive breast carcinoma. In addition, mutation analysis for the BRCA1 gene was carried out in patient DNA from 26 families with multiple cases of breast/ovarian cancers. Of note are the results of molecular biology which show that there are no germline truncating mutations in the BRCA1 gene in these 26 Cypriot breast cancer families. Furthermore, Western blot analysis revealed the presence of multiple BRCA1 bands in homogenates of tumor and normal tissues, and immunoelectron microscopy showed the presence of nuclear staining for BRCA1 antibodies.

Thin glomerular basement membranes in patients with hematuria and minimal change disease.

A detailed morphometric analysis of glomerular basement membrane (GBM) thickness was carried out on biopsies from 16 patients exhibiting normal histology and unremarkable immunofluorescence. Eleven of these patients presented with proteinuria, 8 in the nephrotic syndrome range, while 5 had hematuria as well. The remaining 5 patients presented with hematuria only. Eight patients had an initial diagnosis of minimal change disease, 4 were diagnosed as thin-membrane nephropathy, 2 had Alport syndrome, and the remaining 2 had hypertensive nephropathy. Quantitative morphometric analysis of GBM identified 3 subsets of patients. The first subset consisted of 6 patients: 5 adults, with an average GBM width of 361 +/- 34 nm, and 1 child. The second subset included 8 patients with thin GBMs and a mean thickness of 253 +/- 15 nm. The last subset comprised 2 patients with Alport syndrome showing marked variability in GBM thickness. This study has confirmed the presence of thin GBMs in hematurics, but has also revealed GBM thinning in 50% of patients with a diagnosis of minimal change disease.