Erosive Vulvar Lichen Planus and Risk of Vulvar Neoplasia.

OBJECTIVE: The aim of the study was to assess the risk of vulvar cancer and precursors in a cohort of women with vulvar lichen planus (LP) and the clinical and therapeutic features of these patients. MATERIALS AND METHODS: A retrospective cohort study, including all the women with the diagnosis of vulvar LP, followed in one institution during a period of 11 years, was performed. Demographic and clinical data, as well as treatment, follow-up, and histology results, were evaluated. RESULTS: A total of 127 women were diagnosed with vulvar LP. The mean follow-up time was 3.9 ± 0.5 years (range = 1-11 years). Ultrapotent topical corticosteroids were first-line treatment in 91.8% (n = 112), with 32 cases (25.2%) needing an alternative treatment. Overall, 30 biopsies were performed in 19 women (15%). Vulvar high-grade squamous intraepithelial lesion was diagnosed in 3 women (2.4%), 2 (1.6%) of whom were later diagnosed with vulvar squamous cell carcinoma. No cases of differentiated vulvar intraepithelial neoplasia were observed. CONCLUSIONS: Premalignant/malignant transformation in women with vulvar LP under surveillance and compliant with treatment is low. A close follow-up seems to be crucial to prevent future malignancy. Biopsies should be performed whenever a suspicious lesion seems during follow-up.

TERT Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients.

Telomerase reverse transcriptase gene promoter (TERTp) mutations are recognized as one of the most frequent genetic events in bladder cancer (BC). No studies have focused on the relevance of TERTp mutations in the specific group of tumors treated with Bacillus Calmette-Guérin (BCG) intravesical therapy. Methods - 125 non muscle invasive BC treated with BCG therapy (BCG-NMIBC) were screened for TERTp mutations, TERT rs2853669 single nucleotide polymorphism, and Fibroblast Growth Factor Receptor 3 (FGFR3) hotspot mutations. Results - TERTp mutations were found in 56.0% of BCG-NMIBC and were not associated with tumor stage or grade. FGFR3 mutations were found in 44.9% of the cases and were not associated with tumor stage or grade nor with TERTp mutations. The TERT rs2853669 single nucleotide polymorphism was associated with tumors of higher grade. The specific c.1-146G>A TERTp mutation was an independent predictor of nonrecurrence after BCG therapy (hazard ratio-0.382; 95% confidence interval-0.150-0.971, p = 0.048). Conclusions - TERTp mutations are frequent in BCG-NMIBC and -146G>A appears to be an independent predictive marker of response to BCG treatment with an impact in recurrence-free survival.

Medical Termination of Delayed Miscarriage: Four-Year Experience with an Outpatient Protocol / Terminação médica de gravidez inviável do 1° trimestre: quatro anos de experiência com um protocolo de tratamento em ambulatório

Abstract Purpose To evaluate the efficacy of an outpatient protocol with vaginal misoprostol to treat delayed miscarriage. Methods Retrospective analysis of prospectively collected data on women medically treated for missed abortion with an outpatient protocol. The inclusion criteria were: ultrasound-based diagnosis of missed abortion with less than 10 weeks; no heavy bleeding, infection, inflammatory bowel disease ormisoprostol allergy; nomore than 2 previous spontaneous abortions; the preference of the patient regarding the medical management. The protocol consisted of: 1) a single dose of 800 μg of misoprostol administered intravaginally at the emergency department, after which the patients were discharged home; 2) clinical and ultrasonographic evaluation 48 hours later - if the intrauterine gestational sac was still present, the application of 800 μg of vaginal misoprostol was repeated, and the patients were discharged home; 3) clinical and ultrasonography evaluation 7 days after the initiation of the protocol - if the intrauterine gestational sac was still present, surgical management was proposed. The protocol was introduced in January 2012. Every woman received oral analgesia and written general recommendations. We also gave them a paper form to be presented and filled out at each evaluation. Results Complete miscarriage with misoprostol occurred in 340 women (90.2%). Surgery was performed in 37 (9.8%) patients, representing the global failure rate of the protocol. Miscarriage was completed after the first misoprostol administration in 208 (55.2%) women, with a success rate after the second administration of 78.1% (132/169). The average age of the women with complete resolution using misoprostol was superior to the average age of those who required surgery (33.99 years versus 31.74 years; p = 0.031). Based on the ultrasonographic findings in the first evaluation, the women diagnosed with fetal loss achieved greater success rates compared with those diagnosed with empty sac (p = 0.049). Conclusions We conclude this is an effective and safe option in the majority of delayed miscarriage cases during the first trimester, reducing surgical procedures and their consequences.

Resumo Objetivo Avaliar a eficácia de um protocolo de tratamento médico da gravidez inviável do primeiro trimestre (GI1°T) com misoprostol vaginal em regime de ambulatório. Métodos Análise retrospectiva de dados colhidos prospectivamente de grávidas tratadas com misoprostol vaginal em ambulatório. Os critérios de inclusão foram: diagnóstico de GI1°T com < 10 semanas de gestação; ausência de hemorragia abundante, infeção, doença inflamatória intestinal ou alergia ao misoprostol; 2 abortamentos anteriores; e preferência da paciente por tratamento médico. O protocolo consiste em: dia 0-aplicação demisoprostol intravaginal (800μg) no Serviço de Urgência e alta para o domicílio; dia 2-se persistência de saco gestacional intrauterino, aplicação de segunda dose de misoprostol (800μg) e alta; Dia 7-se persistência de saco gestacional intrauterino, proposto esvaziamento uterino instrumentado. O protocolo foi implementado em janeiro de 2012. Todas as grávidas receberam analgesia oral e informação por escrito com recomendações gerais. Receberam ainda um formulário a ser preenchido em cada vinda à urgência. Resultados Das 377 mulheres incluídas, observou-se abortamento completo em 340 (90,2%). As restantes 37 (9,8%) necessitaram de tratamento cirúrgico - taxa de falência global do protocolo. Em 208 (55,2%), o sucesso foi observado ao fim da 1ª dose, com uma taxa de eficácia da 2ª dose de 78,1% (132/169). A idade média das mulheres com sucesso do tratamento médico foi superior à das mulheres sem sucesso do mesmo (33,99 versus 31,74 anos; p = 0,031). O sucesso do tratamento foi maior quando o diagnóstico ecográfico inicial era de um embrião sem vitalidade comparado com os casos de ovo anembrionado (p = 0.049). Conclusões Conclui-se que esta é uma opção de tratamento eficaz e segura na maioria das situações de GI1°T, evitando a necessidade de internamento e de intervenção cirúrgica.

Medical Termination of Delayed Miscarriage: Four-Year Experience with an Outpatient Protocol.

Purpose To evaluate the efficacy of an outpatient protocol with vaginal misoprostol to treat delayed miscarriage. Methods Retrospective analysis of prospectively collected data on women medically treated for missed abortion with an outpatient protocol. The inclusion criteria were: ultrasound-based diagnosis of missed abortion with less than 10 weeks; no heavy bleeding, infection, inflammatory bowel disease or misoprostol allergy; no more than 2 previous spontaneous abortions; the preference of the patient regarding the medical management. The protocol consisted of: 1) a single dose of 800 µg of misoprostol administered intravaginally at the emergency department, after which the patients were discharged home; 2) clinical and ultrasonographic evaluation 48 hours later - if the intrauterine gestational sac was still present, the application of 800 µg of vaginal misoprostol was repeated, and the patients were discharged home; 3) clinical and ultrasonography evaluation 7 days after the initiation of the protocol - if the intrauterine gestational sac was still present, surgical management was proposed. The protocol was introduced in January 2012. Every woman received oral analgesia and written general recommendations. We also gave them a paper form to be presented and filled out at each evaluation. Results Complete miscarriage with misoprostol occurred in 340 women (90.2%). Surgery was performed in 37 (9.8%) patients, representing the global failure rate of the protocol. Miscarriage was completed after the first misoprostol administration in 208 (55.2%) women, with a success rate after the second administration of 78.1% (132/169). The average age of the women with complete resolution using misoprostol was superior to the average age of those who required surgery (33.99 years versus 31.74 years; p = 0.031). Based on the ultrasonographic findings in the first evaluation, the women diagnosed with fetal loss achieved greater success rates compared with those diagnosed with empty sac (p = 0.049). Conclusions We conclude this is an effective and safe option in the majority of delayed miscarriage cases during the first trimester, reducing surgical procedures and their consequences.

Objetivo Avaliar a eficácia de um protocolo de tratamento médico da gravidez inviável do primeiro trimestre (GI1°T) com misoprostol vaginal em regime de ambulatório. Métodos Análise retrospectiva de dados colhidos prospectivamente de grávidas tratadas com misoprostol vaginal em ambulatório. Os critérios de inclusão foram: diagnóstico de GI1°T com < 10 semanas de gestação; ausência de hemorragia abundante, infeção, doença inflamatória intestinal ou alergia ao misoprostol; ≤ 2 abortamentos anteriores; e preferência da paciente por tratamento médico. O protocolo consiste em: dia 0­aplicação de misoprostol intravaginal (800µg) no Serviço de Urgência e alta para o domicílio; dia 2­se persistência de saco gestacional intrauterino, aplicação de segunda dose de misoprostol (800µg) e alta; Dia 7­se persistência de saco gestacional intrauterino, proposto esvaziamento uterino instrumentado. O protocolo foi implementado em janeiro de 2012. Todas as grávidas receberam analgesia oral e informação por escrito com recomendações gerais. Receberam ainda um formulário a ser preenchido em cada vinda à urgência. Resultados Das 377 mulheres incluídas, observou-se abortamento completo em 340 (90,2%). As restantes 37 (9,8%) necessitaram de tratamento cirúrgico ­ taxa de falência global do protocolo. Em 208 (55,2%), o sucesso foi observado ao fim da 1ª dose, com uma taxa de eficácia da 2ª dose de 78,1% (132/169). A idade média das mulheres com sucesso do tratamento médico foi superior à das mulheres sem sucesso do mesmo (33,99 versus 31,74 anos; p = 0,031). O sucesso do tratamento foi maior quando o diagnóstico ecográfico inicial era de um embrião sem vitalidade comparado com os casos de ovo anembrionado (p = 0.049). Conclusões Conclui-se que esta é uma opção de tratamento eficaz e segura na maioria das situações de GI1°T, evitando a necessidade de internamento e de intervenção cirúrgica.

TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes.

One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.

Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma.

BACKGROUND: Osteopontin (OPN) or secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and has been shown to be involved in tumourigenesis and metastasis in many malignancies, including follicular cell-derived thyroid carcinomas. Its role in C-cell-derived thyroid lesions and tumours remains to be established. OBJECTIVE: The objective of this study is to clarify the role of OPN expression in the development of medullary thyroid carcinoma (MTC). METHODS: OPN expression was analysed in a series of 116 MTCs by immunohistochemistry and by qPCR mRNA quantification of the 3 OPN isoforms (OPNa, OPNb and OPNc) in six cases from which fresh frozen tissue was available. Statistical tests were used to evaluate the relationship of OPN expression and the clinicopathological and molecular characteristics of patients and tumours. RESULTS: OPN expression was detected in 91 of 116 (78.4%) of the MTC. We also observed high OPN expression in C-cell hyperplasia as well as in C-cells scattered in the thyroid parenchyma adjacent to the tumours. OPN expression was significantly associated with smaller tumour size, PTEN nuclear expression and RAS status, and suggestively associated with non-invasive tumours. OPNa isoform was expressed significantly at higher levels in tumours than in non-tumour samples. OPNb and OPNc presented similar levels of expression in all samples. Furthermore, OPNa isoform overexpression was significantly associated with reduced growth and viability in the MTC-derived cell line (TT). CONCLUSION: The expression of OPN in normal C-cells and C-cell hyperplasia suggests that OPN is a differentiation marker of C-cells, rather than a marker of biological aggressiveness in this setting. At variance with other cancers, OPN expression is associated with good prognostic features in MTC.

mTOR activation in medullary thyroid carcinoma with RAS mutation.

OBJECTIVE: Rearranged during transfection (RET) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma (FMTC). The presence of RAS mutations in sporadic cases, challenging the RET paradigm in these tumors, has been recently reported. We intend to evaluate mTOR pathway activation in RET- and RAS-mutated MTC. MATERIALS AND METHODS: In this study, we analysed the presence of RET, H-RAS, and K-RAS mutations in a series of 87 MTCs (82 apparently sporadic and five FMTCs; five apparently sporadic MTCs were eventually found to be familial). We also evaluated mTOR activation--using the expression of its downstream effector phospho-S6 ribosomal protein (p-S6) and the expression of the mTOR inhibitor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN)--by immunohistochemistry. RESULTS: Our results revealed that RET mutations were present in 52.9% of the cases (46/87) and RAS mutations in 12.6% (11/87) of the whole series of MTCs and 14.3% of the 77 sporadic MTCs. The presence of RET and RAS mutations was mutually exclusive. RAS mutations were significantly associated with higher intensity of p-S6 expression (P=0.007), suggesting that the mTOR pathway is activated in such MTCs. We observed also an increased expression of p-S6 in invasive tumors (P=0.042) and in MTCs with lymph node metastases (P=0.046). Cytoplasmic PTEN expression was detected in 58.8% of the cases; cases WT for RAS showed a significantly lower expression of PTEN (P=0.045). CONCLUSIONS: We confirmed the presence of RAS mutation in 14.3% of sporadic MTCs and report, for the first time, an association between such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an indicator of invasive MTC.

Frequency of TERT promoter mutations in human cancers.

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.