Oral Manifestations: A Warning-Sign in Children with Hematological Disease Acute Lymphocytic Leukemia.

Acute lymphocytic leukemia (ALL) is the most frequent form of all childhood leukemias, mostly affecting children between 2 and 4 years old. Oral symptoms, such as mouth ulcers, mucositis, xerostomia, Herpes or Candidiasis, gingival enlargement and bleeding, petechiae, erythema, mucosal pallor and atrophic glossitis, are very common symptoms of ALL and can be early signs of the disease. Secondary and tertiary complications, a direct effect of chemo and radiotherapy, are associated with more severe bleeding, higher susceptibility to infections, ulcerations, inflammation of the mucous membranes, osteoradionecrosis, xerostomia, taste alterations, trismus, carious lesions and dental abnormalities. Immunotherapy, though less toxic, causes oral dysesthesia and pain. Overall, the effects in the oral cavity are transient but there are long-term consequences like caries, periodontal disease and tooth loss that impair endodontic and orthodontic treatments. Also, dental abnormalities resulting from disturbed odontogenesis are known to affect a child's quality of life. The medical dentist should identify these complications and perform appropriate oral care in tandem with other health professionals. Thus, poor oral hygiene can lead to systemic ALL complications. The aim of this review is to describe the oral complications in children with ALL who are undergoing chemo, radio or immunotherapy.

Oral Health Status and Multiple Sclerosis: Classic and Non-Classic Manifestations-Case Report.

BACKGROUND: Multiple sclerosis is an autoimmune disease of the central nervous system with neurological and motor symptoms that affect the orofacial region. The aim of this work is to present a patient that lacks the three classic orofacial manifestations but has other less common clinical alterations. CASE PRESENTATION: A 49-year-old female patient diagnosed with long-term relapsing-remitting multiple sclerosis visited the dentist complaining of mild but persistent orofacial pain including the temporomandibular joint and pain not specific to any tooth. She presented mucosal irritation, xerostomia, halitosis, and localized gingivitis. There was excessive wear of the upper and lower incisal edges and the occlusal faces of the upper canines and loss of six teeth due to caries. After a clinical oral examination, the diagnosis was temporomandibular joint disorder, gingivitis, dental hypersensitivity, bruxism, hyposalivation, xerostomia, and halitosis. CONCLUSIONS: Patients with multiple sclerosis present classic orofacial manifestations. Although these were not observed in this patient, she had others, such as gingivitis, tooth hypersensitivity, and bruxism. In addition, despite few studies associating a higher prevalence of caries with these patients, the number of carious and missing teeth in this patient highlight the evidence that multiple sclerosis has had a significant impact on the patient's dental status over the years.

Estrogen receptors in urogenital schistosomiasis and bladder cancer: Estrogen receptor alpha-mediated cell proliferation.

Estrogen-like metabolites have been identified in S. haematobium, the helminth parasite that causes urogenital schistosomiasis (UGS) and in patients´ blood and urine during UGS. Estrogen receptor (ER) activation is enriched in the luminal molecular subtype bladder cancer (BlaCa). To date, the significance of ER to these diseases remains elusive. We evaluated ERα and ERß expression in UGS-related BlaCa (n = 27), UGS-related non-malignant lesions (n = 35), and noninfected BlaCa (n = 80). We investigated the potential of ERα to recognize S. haematobium-derived metabolites by docking and molecular dynamics simulations and studied ERα modulation in vitro using 3 BlaCa cell lines, T24, 5637 and HT1376. ERα was expressed in tumor and stromal cells in approximately 20% noninfected cases and in 30% of UGS-related BlaCa, predominantly in the epithelial cells. Overall, ERα expression was associated with features of tumor aggressiveness such as high proliferation and p53 positive expression. ERα expression correlated with presence of schistosome eggs. ERß was widely expressed in both cohorts but weaker in UGS-related cases. molecular dynamics simulations of the 4 most abundant S. haematobium-derived metabolites revealed that smaller metabolites have comparable affinity for the ERα active state than 17ß-estradiol, while the larger metabolites present higher affinity. Our in vitro findings suggested that ERα activation promotes proliferation in ERα expressing BlaCa cells and that this can be reverted with anti-estrogenic therapy. In summary, we report differential ER expression between UGS-related BlaCa and noninfected BlaCa and provide evidence supporting a role of active ERα during UGS and UGS-induced carcinogenesis.

Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics.

Muscle invasive bladder cancer (MIBC, stage ≥T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer-associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non-muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin). This decreased the number of invasive lesions and, concomitantly, the expression of STn and also pS6, the downstream effector of the PI3K/Akt/mTOR pathway. In conclusion, STn was found to be marker of poor prognosis in bladder cancer and, in combination with PI3K/Akt/mTOR pathway evaluation, holds potential to improve the stratification of stage disease. Animal experiments suggest that mTOR pathway inhibition could be a potential therapeutic approach for this specific subtype of MIBC.

Patient-derived bladder cancer xenografts: a systematic review.

Patient-derived tumor xenografts (PDTXs) are said to accurately reflect the heterogeneity of human tumors. In the case of human bladder cancer, few studies are available featuring these models. The best methodology to develop and the real value of the model remain unclear. This systematic review aims to elucidate the best methodology to establish and use PDTXs to study the characteristics and behavior of human bladder tumors. The value and potential application of these models are also addressed. A comprehensive literature search was performed to identify published studies using xenograft models directly established from human bladder cancer samples into mice. A total of 12 studies were included in the final analysis. All studies differed in design; the reported take rate varied between 11% and 80%, with the implantation via dorsal incision and with matrigel obtaining the higher take rate. Advanced stage and high-grade tumors were associated with increased take rate. Xenografts preserved the original tumor identity in the establishment phase and after serial passages. Although some studies suggest a correlation between engraftment success and clinical prognosis, evidence about the association between the response of xenografts to treatment and the clinical response of the tumor of origin is still missing. All methodological approaches resulted in the establishment of tumor xenografts with preservation of the original tumor identity but variable take rate. The time needed to establish the model and propagate xenografts to a number suitable for drug testing is the main limitation of the model, along with the success rate and lack of consistency in the early passages. Comparison between tumor response in mice and clinical outcome remains to be assessed.

Patient-derived sialyl-Tn-positive invasive bladder cancer xenografts in nude mice: an exploratory model study.

BACKGROUND: More than 70% of muscle invasive bladder cancers (MIBC) express the cell-surface antigen sialyl-Tn (sTn) that promotes motility and invasive potential of tumor cells. Effective drug testing models to optimize therapy against these tumors are warranted. MATERIALS AND METHODS: Fragments of sTn-positive MIBC were subcutaneously engrafted into nude mice and expanded until the third passage. Histology and immunoexpression of tumor markers (p53, p63, Ki-67, CK20, sTn) were studied in order to evaluate tumor phenotype maintenance. RESULTS: Tumor take rate was low in the first passage (1/9) but increased and became consistent, therefore suitable for drug testing, in the third passage (13/13). Histology and immunoexpression patterns were similar between primary tumors and xenografts. However, p53 and ki-67 levels increased with passages suggesting a selection of more proliferative clones. STn expression, even though decreased, was preserved in xenografts. CONCLUSION: We describe the first patient-derived sTn-positive xenograft model to be used for drug testing and identification of prognostic biomarkers.

Bladder cancer-induced skeletal muscle wasting: disclosing the role of mitochondria plasticity.

Loss of skeletal muscle is a serious consequence of cancer as it leads to weakness and increased risk of death. To better understand the interplay between urothelial carcinoma and skeletal muscle wasting, cancer-induced catabolic profile and its relationship with muscle mitochondria dynamics were evaluated using a rat model of chemically induced urothelial carcinogenesis by the administration of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). The histologic signs of non-muscle-invasive bladder tumors observed in BBN animals were related to 17% loss of body weight and high serum levels of IL-1ß, TNF-α, TWEAK, C-reactive protein, myostatin and lactate and high urinary MMPs activities, suggesting a catabolic phenotype underlying urothelial carcinoma. The 12% loss of gastrocnemius mass was related to mitochondrial dysfunction, manifested by decreased activity of respiratory chain complexes due to, at least partially, the impairment of protein quality control (PQC) systems involving the mitochondrial proteases paraplegin and Lon. This was paralleled by the accumulation of oxidatively modified mitochondrial proteins. In overall, our data emphasize the relevance of studying the regulation of PQC systems in cancer cachexia aiming to identify therapeutic targets to counteract muscle wasting.

Overexpression of tumour-associated carbohydrate antigen sialyl-Tn in advanced bladder tumours.

Little is known on the expression of the tumour-associated carbohydrate antigen sialyl-Tn (STn), in bladder cancer. We report here that 75% of the high-grade bladder tumours, presenting elevated proliferation rates and high risk of recurrence/progression expressed STn. However, it was mainly found in non-proliferative areas of the tumour, namely in cells invading the basal and muscle layers. STn was also found in tumour-adjacent mucosa, which suggests its dependence on a field effect of the tumour. Furthermore, it was not expressed by the normal urothelium, demonstrating the cancer-specific nature of this antigen. STn expression correlated with that of sialyltransferase ST6GalNAc.I, its major biosynthetic enzyme. The stable expression of ST6GalNAc.I in the bladder cancer cell line MCR induced STn expression and a concomitant increase of cell motility and invasive capability. Altogether, these results indicate for the first time a link between STn expression and malignancy in bladder cancer. Hence, therapies targeting STn may constitute new treatment approaches for these tumours.

Everolimus combined with cisplatin has a potential role in treatment of urothelial bladder cancer.

Cisplatin (CDDP)-based chemotherapy is a commonly treatment for advanced urothelial carcinoma. However, episodes of cisplatin resistance have been referenced. Recently it has been reported that everolimus (RAD001) could have an important role to play in bladder-cancer treatment and that mTOR inhibitors may restore chemosensitivity in resistant tumours. The aim of this study was to assess RAD001 in vitro ability to enhance CDDP cytotoxicity in three human bladder-cancer cell lines. Over the course of 72h, the cells were exposed to different concentrations of CDDP and RAD001, isolated or combined. Treatment with CDDP statistically (P<0.05) decreased cell proliferation in cell lines in a dose-dependent manner. The anti-proliferative activity of CDDP used in combination with RAD001 was statistically significant (P<0.05) in the cell lines at all concentrations tested. RAD001 had a therapeutic effect when used in combination with CDDP and could therefore be a useful anti-cancer drug combination for patients with bladder cancer.

Tecnologias assistivas para pessoa idosa: revisão integrativa da literatura / Las tecnologia s de asistencia a los ancianos: revisión integradora de la literatura / Assistive technologies to elder: integrative literature review

Identificar a produção científica nas produções que abordam o assunto tecnologias assistivas direcionadas ao idoso. Método: realizou-se uma Revisão Integrativa da Literatura cujo universo do estudo foi constituído por publicações disseminadas nos bancos de dados, LILACS, MEDLINE e SCIELO, que contemplavam a temática. Como critérios de inclusão definiu-se artigos completos em português, com os descritores, Tecnologia Assistiva, tecnologia assistiva para idosos e assistência tecnológica para idosos, no período de 2005 a 2011. Resultados: foram encontrados 2 artigos completos, na LILACS que atendiam aos critérios de inclusão. Conclusão: a produção científica pertinente às tecnologias assistivas e idoso ainda é pouco expressiva na literatura nacional da área de Saúde. Devendo haver um enriquecimento do acervo bibliográfico dessa área de estudo resultando em disseminação do conhecimento acerca da aplicação de Tecnologia Assistivas como alternativa para o desempenho ativo desse crescente grupo populacional.

Identificar la producción científica en las produccionesque abordan el tema de las tecnologías de asistencia dirigidos alas personas mayores. Método: se realizó una revisión integradora de la literatura cuyo universo del estudio consistió enpublicaciones difundidas en bases de datos MEDLINE y LILACS, SciELO, que abordó la cuestión. Los criterios de inclusión se definieron los artículos completos en portugués, con sus descriptores, tecnología de asistencia, tecnología de asistenciapara la asistencia a los ancianos y tecnológica para las personas mayores, de 2005 a 2011. Resultados: 2 artículos completos fueron encontrados en LILACS, que cumplieron con los criterios de inclusión. Conclusión: La literatura científica relacionada con las tecnologías de asistencia y más aún no es significativo en el Área de Salud nacionales tendrían que ser un enriquecimiento de estaárea de estudio bibliográfico que resulta en la difusión de conocimientos sobre la aplicación de la tecnología de asistenciacomo una alternativa a los resultados activo a este grupo depoblación en crecimiento.

Objective: To identify the scientific production in the productions that address the subject of assistive technologies targeted to the elderly. Method: it was an Integrative Review of Literature whose universe of the study consisted of publications disseminated in data bases, LILACS, MEDLINE and SciELO, which addressed theissue. Inclusion criteria were defined complete articles in Portuguese, with descriptors, assistive technology, assistive technology for elderly and technological assistance for the elderly,from 2005 to 2011. Results: 2 full articles were found in LILACS that met the inclusion criteria. Conclusion: The scientific literaturerelevant to assistive technologies and older is still not significant in the national Area Health Having to be an enrichment of thisbibliographic study area resulting in dissemination of knowledgeabout the application of Assistive Technology as an alternative toperformance asset to this growing population group.

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification.

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki-67 immunoexpression in low-grade (GI-II) USPC in order to predict the potential outcome of these tumors. P53 and Ki-67 immunoexpression were studied in function of recurrence-free and progression-free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki-67 index (>/=18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression-free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki-67 index into the risk model, single pTa/T1-GI Ki-67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1-G1 with a high risk of recurrence and progression. Ki-67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low-grade USPC, the accuracy of the prognostic discrimination is enhanced.