A Set of miRNAs, Their Gene and Protein Targets and Stromal Genes Distinguish Early from Late Onset ER Positive Breast Cancer.

UNLABELLED: Breast cancer (BC) in young adult patients (YA) has a more aggressive biological behavior and is associated with a worse prognosis than BC arising in middle aged patients (MA). We proposed that differentially expressed miRNAs could regulate genes and proteins underlying aggressive phenotypes of breast tumors in YA patients when compared to those arising in MA patients. OBJECTIVE: Using integrated expression analyses of miRs, their mRNA and protein targets and stromal gene expression, we aimed to identify differentially expressed profiles between tumors from YA-BC and MA-BC. METHODOLOGY AND RESULTS: Samples of ER+ invasive ductal breast carcinomas, divided into two groups: YA-BC (35 years or less) or MA-BC (50-65 years) were evaluated. Screening for BRCA1/2 status according to the BOADICEA program indicated low risk of patients being carriers of these mutations. Aggressive characteristics were more evident in YA-BC versus MA-BC. Performing qPCR, we identified eight miRs differentially expressed (miR-9, 18b, 33b, 106a, 106b, 210, 518a-3p and miR-372) between YA-BC and MA-BC tumors with high confidence statement, which were associated with aggressive clinicopathological characteristics. The expression profiles by microarray identified 602 predicted target genes associated to proliferation, cell cycle and development biological functions. Performing RPPA, 24 target proteins differed between both groups and 21 were interconnected within a network protein-protein interactions associated with proliferation, development and metabolism pathways over represented in YA-BC. Combination of eight mRNA targets or the combination of eight target proteins defined indicators able to classify individual samples into YA-BC or MA-BC groups. Fibroblast-enriched stroma expression profile analysis resulted in 308 stromal genes differentially expressed between YA-BC and MA-BC. CONCLUSION: We defined a set of differentially expressed miRNAs, their mRNAs and protein targets and stromal genes that distinguish early onset from late onset ER positive breast cancers which may be involved with tumor aggressiveness of YA-BC.

Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Background: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome. Objective: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed. Methods: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas. Results: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival. Conclusions: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.

Can FDG-PET/CT predict early response to neoadjuvant chemotherapy in breast cancer?

PURPOSE: Neoadjuvant chemotherapy (NAC) in breast cancer is currently used not only for locally advanced tumors, but also for large operable tumors when breast preservation is considered. It also provides the opportunity to evaluate chemotherapy tumor response. Our aim was to correlate the relative change in the standardized uptake value (SUV) of (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET/CT) with pathologic response after NAC. METHODS: We prospectively evaluated 40 patients with invasive ductal breast carcinomas from February 2010 to December 2011. FDG-PET/CT was performed at baseline and after the second cycle of NAC. All patients underwent surgery after NAC. Pathologic response was evaluated according to Residual Cancer Burden (RCB) index. RESULTS: The mean age was 41.9 years. Median primary tumor size was 6 cm. Pathologic complete response (pCR) was obtained in 12 (30%) patients. The tumor baseline mean maximum SUV (SUV(max)), and after second cycle were: 8.97 (sd.4.3) and 4.07 (sd.3.2), respectively. The relative change (ΔSUV) after the second course of NAC was significantly higher for patients with pCR (-81.58%) when compared to the non-pCR patients (-40.18%) (p = 0.001). The optimal ΔSUV threshold that discriminates between pCR and non-pCR was -71.8% (83.3% sensitivity; 78.5% specificity). Moreover, the optimal ΔSUV threshold to discriminate between NAC responders and non-responders was -59.1% (68% sensitivity; 75.0% specificity). CONCLUSIONS: Our data suggest that the FDG-PET/CT ΔSUV after the second course of NAC can predict pathological response in ductal breast carcinomas, and potentially identify a subgroup of non-responding patients for whom ineffective chemotherapy should be avoided. SYNOPSIS: Breast cancer is the most frequently diagnosed cancer in women. The indications for neoadjuvant chemotherapy are increasing. Early information on chemotherapy response is crucial and methods that predict the therapeutic effectiveness might avoid potentially ineffective chemotherapies in non-responding patients.

[Ecologic study in Mexico (2003-2009) on cleft lip and/or palate and associated sociodemographic, socioeconomic and pollution factors]. / Estudio ecológico en México (2003-2009) sobre labio y/o paladar hendido y factores sociodemográficos, socioeconómicos y de contaminación asociados.

OBJECTIVE: To analyze the rates of cleft lip and/or cleft palate (CLP) in Mexico between 2003 and 2009 and assess their association with variables at ecological level, sociodemographic, socioeconomic, and pollution. MATERIAL AND METHODS: An ecological study was conducted with data from the 32 states of Mexico for incidence of CLP, obtained from the Ministry of Health. We included sociodemographic, socioeconomic, and pollution information, obtained from governmental agencies. CLP incidence rates were used as dependent variable; independent variables were socioeconomic, demographic and pollution indicators. Statistical analysis was performed using Spearman correlation and chi(2) tests. RESULTS: During the study period 10573 new cases presented (mean 1510.43 per year). The States with the highest rate (per 1000 births) were: in 2003 the Federal District (Mexico City) (1.76), in 2004 Jalisco (2.62), in 2005 Oaxaca (1.66), in 2006 the State of Mexico (1.29), in 2007, 2008 and 2009 Jalisco (2.17, 2.92, and 1.99). For all the years men were more likely affected than women (P<.05). Variables found positively correlated to LPH rates were total population, solid waste, life expectancy, urban solid waste. The variables negatively correlated were population percentages of high alcohol users, and of alcohol abuse or addiction. CONCLUSIONS: The State of Jalisco was one of the most affected locations over the years. Ecologic positive correlations existed between cleft lip and/or palate and sociodemographic, socioeconomic, and pollution factors. Incidence rate was negatively correlated with alcohol use and abuse. More detailed epidemiological studies are needed to fully characterize risk factors in Mexican populations.

Sentinel node biopsy in breast cancer: results in a large series.

Sentinel lymph node biopsy (SLNB) is an appropriate method for the evaluation of axillary status in cases of early breast cancer. We report our experience in treating cases evaluated using SLNB. We analyzed a total of 1192 cases assessed by means of SLNB from July 1999 to December 2007. SLNB processing was successfully completed in 1154 cases with the use of blue dye or radiolabeled 99mTc-Dextran-500, or both. Of these 1154 patients, 857 were N0(i-) (no regional lymph node metastasis, negative immunohistochemistry, IHC), 96 were N0(i+) (no regional lymph node metastasis histologically, positive IHC, no IHC cluster greater than 0.2 mm) and 201 were N1mi (greater than 0.2 mm, none greater than 2.0 mm). Most of the tumors (70%) were invasive ductal carcinomas and tumors were staged as T1 in 770 patients (65%). A total of 274 patients underwent SLNB and axillary dissections up to April 2003. The inclusion criteria were tumor size equal to or less than 3 cm in diameter, no clinically palpable axillary lymph nodes, no neoadjuvant therapy. In 19 cases, the SLN could not be identified intraoperatively. A false-negative rate of 11% and a negative predictive value of 88.2% were obtained for the 255 assessable patients. The overall concordance between SLNB and axillary lymph node status was 92%. SLNB sensitivity for nodes was 81% and specificity was 100%. The higher sensitivity, specificity, accuracy, and lower false-negative rates of SLNB suggest that this method may be an appropriate alternative to total axillary dissection in early breast cancer patients.

Sentinel node biopsy in breast cancer: results in a large series

Sentinel lymph node biopsy (SLNB) is an appropriate method for the evaluation of axillary status in cases of early breast cancer. We report our experience in treating cases evaluated using SLNB. We analyzed a total of 1192 cases assessed by means of SLNB from July 1999 to December 2007. SLNB processing was successfully completed in 1154 cases with the use of blue dye or radiolabeled 99mTc-Dextran-500, or both. Of these 1154 patients, 857 were N0(i-) (no regional lymph node metastasis, negative immunohistochemistry, IHC), 96 were N0(i+) (no regional lymph node metastasis histologically, positive IHC, no IHC cluster greater than 0.2 mm) and 201 were N1mi (greater than 0.2 mm, none greater than 2.0 mm). Most of the tumors (70 percent) were invasive ductal carcinomas and tumors were staged as T1 in 770 patients (65 percent). A total of 274 patients underwent SLNB and axillary dissections up to April 2003. The inclusion criteria were tumor size equal to or less than 3 cm in diameter, no clinically palpable axillary lymph nodes, no neoadjuvant therapy. In 19 cases, the SLN could not be identified intraoperatively. A false-negative rate of 11 percent and a negative predictive value of 88.2 percent were obtained for the 255 assessable patients. The overall concordance between SLNB and axillary lymph node status was 92 percent. SLNB sensitivity for nodes was 81 percent and specificity was 100 percent. The higher sensitivity, specificity, accuracy, and lower false-negative rates of SLNB suggest that this method may be an appropriate alternative to total axillary dissection in early breast cancer patients.

Expression of E-cadherin, Snail and Hakai in epithelial cells isolated from the primary tumor and from peritumoral tissue of invasive ductal breast carcinomas

Epithelial intercellular cohesion, mainly mediated by E-cadherin (CDH1) expression and function, may be deregulated during cancer cell invasion of adjacent tissues and lymphatic and vascular channels. CDH1 expression is down-modulated in invasive lobular breast carcinomas but its regulation in invasive ductal carcinomas (IDC) is less clear. CDH1 expression is repressed by transcription factors such as Snail (SNAI1) and its product is degraded after Hakai ubiquitination. We compared CDH1, SNAI1 and HAKAI mRNA expression in IDC and paired adjacent normal breast tissue and evaluated its relation with node metastasis and circulating tumor cells. Matched tumor/peritumoral and blood samples were collected from 30 patients with early IDC. Epithelial cells from each compartment (tumor/peritumoral) were recovered by an immunomagnetic method and gene expression was determined by real time RT-PCR. There were no differences in CDH1, SNAI1 and HAKAI mRNA expression between tumor and corresponding peritumoral samples and no differential tumoral gene expression according to nodal involvement. Another 30 patients with a long-term follow-up (at least 5 years) and a differential prognosis (good or poor, as defined by breast cancer death) had E-cadherin and Snail protein detected by immunohistochemistry in tumor samples. In this group, E-cadherin-positive expression, but not Snail, may be associated with a better prognosis. This is the first report simultaneously analyzing CDH1, SNAI1 and HAKAI mRNA expression in matched tumor and peritumoral samples from patients with IDC. However, no clear pattern of their expression could distinguish the invasive tumor compartment from its adjacent normal tissue.

Expression of E-cadherin, Snail and Hakai in epithelial cells isolated from the primary tumor and from peritumoral tissue of invasive ductal breast carcinomas.

Epithelial intercellular cohesion, mainly mediated by E-cadherin (CDH1) expression and function, may be deregulated during cancer cell invasion of adjacent tissues and lymphatic and vascular channels. CDH1 expression is down-modulated in invasive lobular breast carcinomas but its regulation in invasive ductal carcinomas (IDC) is less clear. CDH1 expression is repressed by transcription factors such as Snail (SNAI1) and its product is degraded after Hakai ubiquitination. We compared CDH1, SNAI1 and HAKAI mRNA expression in IDC and paired adjacent normal breast tissue and evaluated its relation with node metastasis and circulating tumor cells. Matched tumor/peritumoral and blood samples were collected from 30 patients with early IDC. Epithelial cells from each compartment (tumor/peritumoral) were recovered by an immunomagnetic method and gene expression was determined by real time RT-PCR. There were no differences in CDH1, SNAI1 and HAKAI mRNA expression between tumor and corresponding peritumoral samples and no differential tumoral gene expression according to nodal involvement. Another 30 patients with a long-term follow-up (at least 5 years) and a differential prognosis (good or poor, as defined by breast cancer death) had E-cadherin and Snail protein detected by immunohistochemistry in tumor samples. In this group, E-cadherin-positive expression, but not Snail, may be associated with a better prognosis. This is the first report simultaneously analyzing CDH1, SNAI1 and HAKAI mRNA expression in matched tumor and peritumoral samples from patients with IDC. However, no clear pattern of their expression could distinguish the invasive tumor compartment from its adjacent normal tissue.

Tumores de células germinativas intracranianos na infância: avaliação de 14 casos / Primary intracranial germ cell tumors in children: evaluation of fourteen cases

This study evaluates the diagnosis, therapy and survival of 14 patients with primary intracranial germ cell tumors during the period from 1991 to 2001. There were 11 males and 3 females. Mean age was 12.2 years old (20 days-18 years). On admission, the most common symptoms were headache (10/14), vomiting (6/14) and visual (6/14). The tumor was in pineal and hypothalamic region in 10 cases, suprasellar in 3 cases, and in the cerebral parenchyma in 1 case. Histologically there were 1 embryonal carcinoma, 5 germinomas, 2 mature teratomas, 1 immature teratoma and 5 mixed germ cell tumors. Treatment differed among the patients according to the type of tumor. Three patients died after tumor progression or relapse and one patient died from another condition. The remaining patients are alive and without disease.

Este estudo avalia o diagnóstico, a terapia e a sobrevida de 14 pacientes com tumor de células germinativas intracraniano durante o período entre 1991 e 2001. Onze pacientes eram do sexo masculino e três do feminino. A média de idade do grupo foi 12,5 anos (20 dias-18 anos). Na admissão, os mais comuns sintomas foram cefaléia (10/14), vômitos (6/14) e visuais (6/14). Os tumores estavam localizados em região hipotalâmica/hipofisária em 10 casos, suprasselar em 3 casos e intraparenquimatosa em 1 caso. Histologicamente, havia 1 caso de carcinoma embrionário, 5 de germinomas, 2 de teratoma maduro, 1 de teratoma imaturo e 5 de tumores mistos. O tratamento foi variável, dependendo da histologia da lesão. Três pacientes morreram após a progressão tumoral ou recidiva e um paciente morreu devido causa não relacionada ao tumor. Os demais estão vivos e sem doença.

Relationship between angiogenesis and grade of histologic differentiation in endometrial adenocarcinoma.

The objective of the study was to quantify vessels and to relate them to the degree of histologic differentiation in endometrial adenocarcinoma. We studied 35 cases of which ten were G1, 13 G2 and 12 G3 adenocarcinomas. The control group consisted of 11 atrophic and 10 proliferative endometria. From each case two histologic sections were obtained: one for hematoxylin-eosin staining and the other for immunohistochemical study with anti-CD34. Vessel count was performed by morphometric study. Mean vessel count was 15.3 for G1; 19 for G2 and 22.7 for G3 adenocarcinomas; in the control group it was 11.6 for atrophic and 13.2 for proliferative endometria. Slightly differentiated adenocarcinoma presented greater angiogenesis than normal and well-differentiated carcinoma. In contrast, moderately differentiated carcinoma showed greater angiogenicity as related to normal endometrium, but did not differ from other tumoral endometria.

The use of 99mTc-phytate for sentinel node mapping in melanoma, breast cancer and vulvar cancer: a study of 100 cases.

Sentinel node mapping reduces surgical morbidity and allows the use of more accurate tumour staging techniques. Radionuclide studies are preferentially performed using small colloids, which have limited availability in our country. The possibility of using phytate for sentinel node mapping was raised because of the similarity between its biodistribution and that of nanocolloids in the reticulo-endothelial system. In this paper we evaluated the use of 99mTc-phytate for sentinel node mapping, correlating the histopathological results with the status of the rest of the lymph node chain in different malignant tumours. A total of 100 patients were studied. group 1 consisted of 62 patients with breast cancer, group 2 of 20 patients with melanoma and group 3 of 18 patients with vulvar carcinoma. Lymph node scintigraphy was carried out after injecting 99mTc-phytate subdermally, and the sentinel node projection was marked on the skin. After 18-24 h, intraoperative sentinel node localisation was performed using a gamma probe (combined with visual localisation using patent blue dye) in 75 patients, and lymph node dissection was then carried out. Radionuclide scintigraphy identified the sentinel node in 98% of all studies. Intraoperative detection using the gamma probe was equally efficient: group 1=93% (38/41), group 2=95% (18/19) and group 3=100% (15/15). The sentinel node was involved in 41%, 31% and 20% of cases in groups 1, 2 and 3, respectively. Among the patients with positive nodes, the sentinel node was the only one affected in 53% of group 1, 50% of group 2 and 67% of group 3 cases. The method's negative predictive value was 91% in group 1 and 100% in the other groups. One false-negative study occurred in a patient who had a multifocal tumour and an intraparenchymatous lymph node; another occurred in a patient with a macroscopically affected node found during surgery. There were no side-effects related to the 99mTc-phytate. It is concluded that scintigraphic and intraoperative sentinel node identification was satisfactorily performed using 99mTc-phytate. The results were comparable to those previously described in the literature using other radiopharmaceuticals. Easy availability and low cost justify the use of phytate in our practice.

The use of (99m)Tc-phytate for sentinel node mapping in melanoma, breast cancer and vulvar cancer: a study of 100 cases.

Sentinel node mapping reduces surgical morbidity and allows the use of more accurate tumour staging techniques. Radionuclide studies are preferentially performed using small colloids, which have limited availability in our country. The possibility of using phytate for sentinel node mapping was raised because of the similarity between its biodistribution and that of nanocolloids in the reticulo-endothelial system. In this paper we evaluated the use of (99m)Tc-phytate for sentinel node mapping, correlating the histopathological results with the status of the rest of the lymph node chain in different malignant tumours. A total of 100 patients were studied. group 1 consisted of 62 patients with breast cancer, group 2 of 20 patients with melanoma and group 3 of 18 patients with vulvar carcinoma. Lymph node scintigraphy was carried out after injecting (99m)Tc-phytate subdermally, and the sentinel node projection was marked on the skin. After 18-24 h, intraoperative sentinel node localisation was performed using a gamma probe (combined with visual localisation using patent blue dye) in 75 patients, and lymph node dissection was then carried out. Radionuclide scintigraphy identified the sentinel node in 98% of all studies. Intraoperative detection using the gamma probe was equally efficient: group 1=93% (38/41), group 2=95% (18/19) and group 3=100% (15/15). The sentinel node was involved in 41%, 31% and 20% of cases in groups 1, 2 and 3, respectively. Among the patients with positive nodes, the sentinel node was the only one affected in 53% of group 1, 50% of group 2 and 67% of group 3 cases. The method's negative predictive value was 91% in group 1 and 100% in the other groups. One false-negative study occurred in a patient who had a multifocal tumour and an intraparenchymatous lymph node; another occurred in a patient with a macroscopically affected node found during surgery. There were no side-effects related to the (99m)Tc-phytate. It is concluded that scintigraphic and intraoperative sentinel node identification was satisfactorily performed using (99m)Tc-phytate. The results were comparable to those previously described in the literature using other radiopharmaceuticals. Easy availability and low cost justify the use of phytate in our practice.

Pediatric multiple sclerosis report of 14 cases.

We present clinical data from 14 multiple sclerosis (MS) patients who have been admitted to our hospital between January 1980 and May 1992, whose age of onset ranged from 2-15 years. Our patients could be classified as having a clinically definite form of the disease. Initial symptoms varied from minor, such as motor or sensory impairment, bladder dysfunction, to the worst clinical presentation, suggesting diffuse encephalopathy. All the patients had a relapsing-remitting course. We report the paraclinical and laboratory examinations that were done in these patients. Over the period 1980 to 1992 these patients had 39 attacks. CSF analysis was performed in the phase of activity of the disease on 23 occasions and was normal in 12. At least one brain CT scan was performed in 9 patients and showed white matter abnormalities in 6. Cranial magnetic resonance imaging was done in 6 patients and were abnormal in 5. Visual evoked potential (EP) was abnormal in 7 of 8 patients; brainstem acoustic EP was abnormal in 4 of 8 patients and somatosensory EP in 4 of 8. MS is not so rare in childhood and although its diagnosis is essentially a clinical one, paraclinical investigations are of great value in the identification of demyelinating disorders in childhood.