Is renal thrombotic angiopathy an emerging problem in the treatment of ovarian cancer recurrences?

BACKGROUND AND OBJECTIVE: Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions. PATIENTS AND METHODS: Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines. RESULTS: Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy. CONCLUSIONS: CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

Quantitative Analysis of Differential Expression of HOX Genes in Multiple Cancers.

Transcription factors encoded by Homeobox (HOX) genes play numerous key functions during early embryonic development and differentiation. Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers. Their expression levels in cancers tend to differ based on tissue and tumor type. Here, we performed a comprehensive analysis comparing HOX gene expression in different cancer types, obtained from The Cancer Genome Atlas (TCGA), with matched healthy tissues, obtained from Genotype-Tissue Expression (GTEx). We identified and quantified differential expression patterns that confirmed previously identified expression changes and highlighted new differential expression signatures. We discovered differential expression patterns that are in line with patient survival data. This comprehensive and quantitative analysis provides a global picture of HOX genes' differential expression patterns in different cancer types.

Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma.

The aim of this study was to analyze the expression and clinical role of DJ-1, a negative regulator of PTEN (phosphatase and tensin homolog deleted on chromosome 10), in ovarian carcinoma, and investigate the putative association between DJ-1 levels and expression of its transcriptional regulators specificity protein 1 (Sp1) and specificity protein 3 (Sp3). Effusions (n = 72) and solid tumors (n = 57, 42 primary and 15 metastases) were analyzed for DJ-1 messenger RNA (mRNA) expression using reverse transcriptase-polymerase chain reaction. Most specimens (48 effusions, 50 solid tumors) were additionally analyzed for Sp1 and Sp3 mRNA expression. PTEN protein expression was analyzed in 201 effusions and 92 solid tumors using immunohistochemistry. DJ-1 mRNA was expressed in more than 80% of specimens, with no preferential anatomical site. DJ-1 expression was positively associated with Sp1 expression in effusions (P = .03) and with Sp1 (P = .02) and Sp3 (P = .002) expression in solid tumors. In effusions, DJ-1 expression was higher in postchemotherapy compared with prechemotherapy specimens (P = .012). Higher DJ-1 levels (P = .027) and more advanced FIGO stage (IV versus III; P = .003) correlated with shorter progression-free survival in univariate analysis for patients with postchemotherapy effusions. PTEN expression was low in effusions and solid tumors (23% and 13%, respectively), and its expression showed no association with DJ-1 levels or survival. Our data show that DJ-1 is frequently expressed in advanced-stage ovarian carcinoma at all anatomical sites and is coexpressed with its transcriptional regulators Sp1 and Sp3. In contrast, PTEN expression is infrequent in this disease. These findings may provide one of the molecular mechanisms that mediate cancer cell survival and aggressiveness in this tumor.

Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.

The activated nerve growth factor receptor p-TrkA is selectively expressed in advanced-stage ovarian carcinoma.

The objective of this study was to compare the expression of the nerve growth factor (NGF) receptors TrkA and p75 in ovarian borderline tumors, International Federation of Gynecology and Obstetrics (FIGO) stage I carcinomas and advanced-stage (FIGO stage III-IV) carcinomas, and to assess a possible association between NGF receptor expression and mitogen-activated protein kinase (MAPK) activation in borderline tumors and FIGO stage I carcinomas. Sections from 119 borderline tumors, 57 FIGO stage I invasive ovarian carcinomas, and 56 advanced-stage carcinomas were evaluated for expression of activated phospho-TrkA (p-TrkA) and p75 using immunohistochemistry. MAPK activation was analyzed in stage I carcinomas and borderline tumors using phospho-specific antibodies against the extracellular-regulated kinase (p-ERK), the high osmolarity glycerol response kinase (p-p38), and the c-jun amino-terminal kinase (p-JNK). p-TrkA membrane expression was significantly more frequent in advanced-stage carcinomas compared with both borderline and stage I carcinomas (P < .001). p75 membrane expression was comparable in the 3 groups (P > .05). p-ERK and p-p38 expression was comparable in borderline and stage I carcinomas, whereas p-JNK was more frequently expressed in stage I ovarian carcinomas (P < .001). NGF receptor expression showed no association with MAPK activation in borderline and stage I carcinomas. In conclusion, expression of biologically active p-TrkA receptor at the cell membrane is up-regulated along tumor progression in ovarian carcinoma, whereas p75 expression remains unaltered. These data provide further evidence regarding the clinical role of p-TrkA in ovarian carcinoma. NGF receptors probably signal via MAPK-independent pathways in ovarian carcinoma.

Orbital marginal zone lymphomas: an immunohistochemical, polymerase chain reaction, and fluorescence in situ hybridization study.

Many studies have been performed on chromosomal aberrations of extranodal marginal zone lymphomas. However, only a few have been published so far on ocular adnexal marginal zone lymphomas. We studied 18 cases of orbital lymphoid cell infiltrates. Using fluorescence in situ hybridization (FISH), we studied some of the most common chromosomal aberrations found in extranodal marginal zone lymphomas as: trisomies 3, and rearrangements of the 18q21 MALTI gene to detect the translocations t(11;18)(q21;q21) and t(14;18)(q32;q21)MALT1. Our goals were as follows: (1) study those aberrations in our material and compare them with the literature, (2) check their prognostic significance, and (3) check whether studying those aberrations with FISH can be used as a diagnostic tool to differentiate reactive from neoplastic infiltrates, in addition to immunohistochemistry and polymerase chain reaction. We found a high frequency of trisomies 3 (68%) and 18 (56.6%), the highest published so far in orbital lymphomas. On the other hand, no rearrangement was seen in any of our cases. The histologic picture and the clinical course were the same when there was one or more aberrations. As for the diagnostic significance, the presence of a prior, concurrent, or subsequent lymphoma in almost all the positive for aberrations cases suggests that either the orbital infiltrates in these cases are lymphomas, or they have, at least, a malignant potential or a genetic instability. Therefore, the demonstration of these numerical aberrations by FISH may be an additional sensitive, reliable, and relatively simple tool to differentiate reactive from neoplastic orbital lymphoid cell infiltrates when the immunohistochemistry and polymerase chain reaction, performed in a busy and routine-based histopathology laboratory, are unsatisfactory.

PEA3 is the second Ets family transcription factor involved in tumor progression in ovarian carcinoma.

PURPOSE: The purpose of this study was to analyze the possible correlation between PEA3 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. EXPERIMENTAL DESIGN: Sections from 61 primary ovarian carcinomas and metastatic lesions from 36 patients diagnosed with advanced-stage ovarian carcinoma [International Federation of Gynecologists and Obstetricians (FIGO) stages III-IV] were evaluated for expression of PEA3 using mRNA in situ hybridization. Patients were divided into long-term (n = 16) and short-term (n = 20) survivors. RESULTS: The mean values for disease-free survival and overall survival were 119 and 137 months for long-term survivors, as compared with 4 and 22 months for short-term survivors, respectively. Expression of PEA3 mRNA was detected in carcinoma cells and stromal cells in 56 of 61 lesions (92%) and 54 of 61 lesions (89%), respectively. Intense stromal expression was detected only in the vicinity of grade 2-3 tumors (P = 0.04). PEA3 expression in stromal cells showed a significant association with matrix metalloproteinase 2 mRNA expression in carcinoma cells (P = 0.022). PEA3 expression in carcinoma cells showed an association with mRNA expression of the beta(1) integrin subunit in the same compartment (P = 0.039). It was also associated with mRNA expression of beta(1) integrin subunit (P = 0.012), basic fibroblast growth factor (P = 0.036), and the matrix metalloproteinase inducer EMMPRIN (P = 0.038) in stromal cells. PEA3 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P = 0.021 for stromal cells). In univariate survival analysis, PEA3 expression in stromal cells correlated with both shorter disease-free survival (P = 0.019) and overall survival (P = 0.029), whereas tumor cell expression predicted poor overall survival (P = 0.049). PEA3 mRNA expression in stromal cells emerged as an independent predictor of poor outcome in multivariate survival analysis, in which all molecules previously studied in this patient cohort were included (P = 0.015). CONCLUSIONS: To the best of our knowledge, this is the first evidence associating PEA3 mRNA expression and poor survival in human epithelial malignancy. PEA3 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between PEA3 mRNA expression and the expression of the beta(1) integrin subunit, basic fibroblast growth factor, and EMMPRIN, first documented in our patient cohort, points to the central role of this transcription factor in tumor progression in ovarian carcinoma.

Syringomatous adenoma of the nipple: a case report.

We present a case of a 33-year-old woman who underwent excisional breast biopsy due to a left nipple mass. Histological examination revealed the morphologic and immunohistochemical pattern of syringomatous adenoma of the nipple. This is a rare lesion of the breast that can clinically mimic breast carcinoma, but harbors a benign and only locally aggressive course. Awareness of both the clinician and the pathologist for the possibility of diagnosing this tumor in the nipple region is mandatory to avoid mastectomy and lymph node dissection.

The clinical role of the PEA3 transcription factor in ovarian and breast carcinoma in effusions.

Ets transcription factors play a central role in invasion and metastasis through regulation of synthesis of proteolytic enzymes and angiogenic molecules. The objective of this study was to investigate the role of PEA3 in tumor progression of ovarian and breast carcinoma metastatic to effusions, and to evaluate the expression of Ets-2 and Erg in ovarian carcinoma. Ovarian (83 malignant effusions, 102 corresponding solid lesions) and breast (33 malignant effusions, 40 corresponding solid lesions) carcinomas were evaluated for expression of PEA3 using mRNA in situ Hybridization (ISH). Expression of Ets-2 and Erg mRNA was analyzed in 50 ovarian carcinoma effusions using the same method. PEA3 mRNA expression was comparable at all sites in ovarian carcinoma (44 out of 83; 53% of effusions, 48 out of 102; 47% of solid tumors). PEA3 mRNA expression in effusions correlated with mRNA expression of the previously studied alphav (P = 0.022), alpha6 (P < 0.001) and beta1 (P < 0.001) integrin subunits, the matrix metalloproteinase (MMP) inducer EMMPRIN (P = 0.015) and interleukin-8 (IL-8) (P = 0.033). Erg and Ets-2 mRNA was expressed in 15 out of 50 (30%) and 18 out of 50 (36%) effusions, respectively, and co-localized with PEA3 (P = 0.017 for Erg, P = 0.004 for Ets-2). In breast carcinoma, PEA3 expression was seen in 19/40 (48%) of solid lesions, with a significant upregulation in corresponding effusions compared to primary tumors (24 out of 33; 73%, P = 0.038). PEA3 mRNA expression in effusions obtained prior to the institution of chemotherapy predicted significantly shorter overall survival in univariate analysis (24 vs 37 months, P = 0.03), with a similar trend for Erg (13 vs 30 months, P = 0.1). In conclusion, PEA3 is expressed at all anatomic sites in serous ovarian cancer and co-localizes with Erg, Ets-2 and several metastasis-associated molecules. PEA3 mRNA expression is a novel marker for tumor progression to malignant effusion in breast carcinoma, and predicts poor outcome in effusions sampled prior to therapeutic intervention in ovarian carcinoma. These findings support a biological role for Ets transcription factors in these malignancies and suggests that they may be targets for therapeutic intervention.

Interleukin-8 and vascular endothelial growth factor mRNA and protein levels are down-regulated in ovarian carcinoma cells in serous effusions.

Angiogenic factors are involved in tumor growth and spread. The aim of this study was to evaluate the expression of angiogenesis-related genes in malignant serous effusions of patients with advanced-stage (FIGO stage III and IV) ovarian carcinoma. In addition, to compare the results for carcinoma cells in effusions with corresponding primary tumors and metastatic lesions, and analyze their prognostic role. Sections from 66 effusions and 90 primary and metastatic lesions from 62 ovarian and primary peritoneal carcinoma patients, were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA in situ hybridization (ISH). Protein expression was evaluated in a subset of specimens using immunohistochemistry (IHC). ISH results were correlated with clinical parameters. In both effusions and solid tumors, bFGF mRNA was the most commonly expressed factor (93% of effusions and 95% of solid tumors) followed by IL-8, while VEGF was expressed in a minority of the specimens (P < 0.001 for bFGF vs. IL-8 and VEGF). In solid tumors, angiogenic mRNA expression was seen in both tumor and stromal cells in the majority of positive cases. ISH results did not differ in primary and metastatic tumors. However, carcinoma cells in effusions showed down-regulated expression of VEGF, when compared with both primary tumors (P = 0.029) and metastases (P = 0.015). IL-8 showed a similar down-regulation in effusions, when compared with metastases (P = 0.005). IHC showed excellent agreement with mRNA findings on protein level. In the study of clinico-pathologic parameters, IL-8 mRNA expression in effusions was associated with higher tumor grade (P = 0.044). Angiogenic gene expression in effusions showed no correlation with patient age, previous treatment, residual tumor size, FIGO stage or disease outcome in survival analysis (P > 0.05). Peritoneal and pleural effusions showed similar expression patterns. In conclusion, bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. It is highly expressed in both solid tumors and serous effusions, while IL-8 and VEGF are down regulated in carcinoma cells in effusions, possibly due to the lack of interaction with stromal cells. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma. Carcinoma cells in pleural and peritoneal effusions show a similar metastatic expression profile, in agreement with our previous findings, supporting the true metastatic nature of ovarian carcinoma cells in ascites.

The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma.

The objective of this study was to analyze the correlation between matrix metalloproteinases (MMPs) and angiogenic genes and survival in advanced-stage ovarian carcinomas. Primary and metastatic ovarian carcinomas from patients diagnosed with FIGO stage III-IV disease and followed up to 20 years were studied using mRNA in situ hybridization (ISH). Expression of MMP-2, MMP-9, membrane-type 1-MMP (MT1-MMP), the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF) was studied. MMP-2, MMP-9 and TIMP-2 mRNA was detected in both tumor and stromal cells, while MT1-MMP was largely confined to tumor cells. In univariate analysis of primary tumors, TIMP-2 and MMP-9 mRNA expression correlated with poor outcome. In metastatic lesions, mRNA expression of TIMP-2, MMP-2, and MT1-MMP correlated with poor survival. In a multivariate analysis of primary tumors, TIMP-2 expression in stromal cells (P=0.006) and MMP-9 expression in tumor cells (P=0.011) retained their predictive value. Intense expression of bFGF mRNA and weak expression of IL-8 mRNA was detected in both stromal and tumor cells in most cases, while VEGF mRNA expression was limited to a few cases. Angiogenic mRNA expression showed no correlation with disease outcome in survival analysis (P>0.05). We conclude that bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.

Lentigo maligna and superficial spreading melanoma are different in their in situ phase: an immunohistochemical study.

Clinical and pathologic observations have prompted the categorization of malignant melanoma into 4 subtypes. Although some authorities challenge the value of this classification, nevertheless it is generally accepted that lentigo maligna (LM), or melanoma on sun-damaged skin, has a different biological behavior than so-called superficial spreading melanoma (SSM), at least in the early stage of its evolution. To characterize some aspects of this different behavior, the in situ phase of SSM and LM was studied using immunohistochemical methods. Seventeen cases of SSM in situ and 13 cases of LM were chosen for the study. All cases qualified with strict histologic criteria. Sections from these lesions were stained with antibodies against HMB-45 antigen, basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), and factor VIII. Semiquantitative analysis was performed. Cases classified as either LM or SSM corresponded well to the epidemiologic and clinical characteristics as described in the literature; that is, LM appeared in older patients and occurred mostly on the face, whereas SSM occurred mostly on the trunk and lower limbs. Although no difference in HMB-45 stain was observed, melanoctyes of SSM showed greater proliferative activity, as reflected by PCNA stain (P < 0.02) and higher levels of bFGF (P < 0.001), than melanocytes of LM. More blood vessels were counted under SSM than under LM (P < 0.05). These results are in accordance with the biological behavior of SSM and LM, that is, the longer in situ phase of the latter. bFGF is both a growth factor for melanocytes and an angiogentic factor. The differences in PCNA, a proliferation marker, and blood vessel count may be related to the bFGF effect. Thus this study reveals some of the biological differences between LM and SSM. Location and sun exposure habits may contribute to these differences, which already exist in the in situ phase.

Caveolin-1 expression in ovarian carcinoma is MDR1 independent.

We studied the role of caveolin-1 in tumor progression and prognosis in serous ovarian carcinoma and the association between caveolin-1 and MDR1 expression. The study involved immunohistochemical analysis for caveolin-1 and P-glycoprotein (P-gp) expression in 75 effusions and 90 solid lesions from ovarian and primary peritoneal carcinoma; in situ hybridization for MDR1 messenger RNA (mRNA) expression in 62 effusions and all 90 tumors; and reverse transcription-polymerase chain reaction (RT-PCR) for caveolin-1 mRNA expression in 23 effusions. Immunohistochemical analysis localized caveolin-1 to the cell membrane in 43 effusions and 24 tumors. P-gp membrane expression was detected in 14 effusions and 11 tumors; MDR1 mRNA, in 20 effusions and 30 tumors. Caveolin-1 mRNA was expressed in 19 effusions. Caveolin-1 protein expression showed no association with that of P-gp protein or MDR1 mRNA. The expression of all markers was similar in carcinoma cells in pleural and peritoneal effusions. Caveolin-1 is a novel diagnostic marker for effusions; expression is moderately elevated in tumor cells in effusions, possibly owing to altered signal transduction and metabolism in cancer cells at this site. Expression seems MDR1 independent.

Chronic cholecystitis with bone metaplasia. A case report.

Bone metaplasia is a rare phenomenon in the gastrointestinal tract. We present a case of a 58-year-old man who underwent laparoscopic cholecystectomy for symptoms of chronic cholecystitis. Histologic examination of the removed gallbladder revealed intramural bone metaplasia in association with chronic cholecystitis. To the best of our knowledge, such a case has not yet been reported. The clinical significance of this finding remains to be elucidated.

Different beta-catenin immunoexpression in carcinoid tumors of the appendix in comparison to other gastrointestinal carcinoid tumors.

Carcinoid tumor of the appendix is an endocrine tumor that is histologically similar to, but biologically less aggressive than carcinoids arising from other parts of the gastrointestinal tract. In this study, we examined E-cadherin, beta-catenin, DCC, p53 and Ki67 immunoexpression in cases of carcinoid of the appendix and made a comparison with non-appendiceal carcinoid tumors. Nine cases of appendiceal carcinoid and 11 biopsies of carcinoid of other parts of the gastrointestinal tract, five cases of the small intestine and six of the stomach were immunohistochemically evaluated for Ki67, p53, DCC, E-cadherin and beta-catenin. Two main patterns of beta-catenin staining were observed. The first pattern was characterized as membranous and cytoplasmic, and was seen mainly in the peripheral cells of the nests. The second pattern was diffuse, predominantly membranous. Most (five of seven) appendiceal carcinoids and only three of 11 non-appendiceal cases showed the first staining pattern (p < 0.05). Immunoexpression of E-cadherin and DCC was similar in both groups. p53 and Ki-67 immunostaining revealed stronger nuclear positivity in the non-appendiceal carcinoid tumors (statistically not significant). We found a pattern of beta-catenin immunostaining in typical carcinoid tumors of the appendix that was different from the pattern seen in non-appendiceal carcinoid tumors. This alteration suggests that carcinoid of the appendix may represent a different subtype of carcinoid tumors with different immunohistochemical and biological behavior.

[Tissue microarray technology--a new and powerful tool for the molecular profiling of tumors].

Tissue Microarrays (TMA) are the products of a new technology that offers rapid and simultaneous analysis of up to 1000 different archival samples. Sections from TMA blocks can be used for all different types of in situ tissue analysis including immunohistochemistry and in situ hybridization. The technology helps to implement the vast knowledge that was discovered by the human genome project and facilitates the molecular understanding of various benign and malignant processes. In this article we describe the process of TMA construction and review the main studies that applied the technology to characterizing tumors and precancerous lesions.

[Advances in pathogenesis and molecular biology of endometrial carcinoma].

Cancer research has evolved at a phenomenal pace over the past two decades. Advances in genetics and molecular biology expand the knowledge gathered in the subject. Endometrial carcinoma is a common invasive malignancy in the female genital tract and presents an important diagnostic and treatment challenge. The research aims to develop new molecular tools for early diagnosis and optimal treatment of the disease and its precursors. An updated review of the molecular and genetic research is presented with correlation to the pathological and clinical characteristics of the tumor.

Familial Mediterranean fever (FMF) with proteinuria: clinical features, histology, predictors, and prognosis in a cohort of 25 patients.

OBJECTIVE: Reactive (AA) amyloidosis may complicate familial Mediterranean fever (FMF), the prototype of autoinflammatory diseases. Thus, proteinuria in FMF is commonly viewed as resulting from amyloidosis, and kidney biopsy is deemed superfluous. However, nephropathy other than amyloidosis has been described in FMF, but its rate and distinctive characteristics are unknown. Our aim was to determine the rate and underlying pathology of FMF-related nonamyloidotic proteinuria and compare its clinical course, demographic, and genetic features to those of FMF-amyloid nephropathy. METHODS: This study is a retrospective analysis of data from patients with FMF undergoing kidney biopsy for proteinuria above 0.5 g/24 h, over 10 years (2001-2011). Clinical, laboratory, genetic, and pathology data were abstracted from patient files. Biopsies were viewed by an experienced pathologist, as necessary. RESULTS: Of the 25 patients referred for kidney biopsy, only 15 (60%) were diagnosed with amyloid kidney disease (AKD), and 10 were diagnosed with another nephropathy. The AKD and nonamyloid kidney disease (NAKD) groups were comparable on most variables, but showed distinct characteristics with regard to the degree of proteinuria (6.45 ± 4.3 g vs 2.14 ± 1.6 g, p = 0.006), rate of severe FMF (14 vs 5 patients, p = 0.022), and rate of development of end stage renal disease (73.3% vs 20%, p = 0.015), respectively. CONCLUSION: NAKD is common in FMF and, compared to amyloidosis, it is featured with milder course and better prognosis. Contrary to common practice, it is highly recommended to obtain a kidney biopsy from patients with FMF and proteinuria more than 0.5 g/24 h.

Analysis of the prognostic impact of nestin expression in non-small cell lung cancer.

BACKGROUND: Nestin is an intermediary filament protein, expressed in progenitor cells of neural and muscle origin and in activated endothelium. The expression of this protein in tumours can be associated with degree of differentiation, biological potential and/or neoangiogenesis. AIMS: The aim of this study was to examine the immunohistochemical expression of nestin in primary non-small cell lung carcinomas (NSCLC) and to determine its prognostic significance. METHODS: Immunohistochemical detection of nestin was carried out on tissue microarrays constructed from 114 formalin-fixed and paraffin-embedded NSCLC samples. These included 78 squamous cell carcinomas and 37 adenocarcinomas. Expression of nestin was also analysed in 35 primary tumour independent NSCLC brain metastasis. The H-score and degree of nestin positive microvascularisation were determined. Both parameters correlated with the clinicopathological characteristics including disease-free and overall survival. Results. We demonstrated that expression of nestin is not significantly higher in tumour cells of adenocarcinomas than in sqamous cell carcinomas despite the fact that adenocarcinomas were more frequently positive (P≤0.30). On the other hand, nestin positivity and nestin positive neovascularisation were significantly more often found in stage IIIa tumours than tumours in stages I and II (P≤0.04, P≤0.02). Nestin expression was also significantly higher in brain metastases of squamous cell carcinomas than brain metastases of adenocarcinomas (P≤0.003). The expression of nestin, in general, did not significantly correspond to disease-free or overall survival. CONCLUSION: Nestin expression in NSCLCs is associated with poorer prognosis and with greater nestin-positive microvessel density.