Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

ABSTRACT Objective Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results We describe 4 families with PGL/PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

Circulating tumor cells as a new and additional approach to follow-up patients with serous low-grade ovarian adenocarcinoma: a case report and review of the literature

Background: Current methods for follow-up of Ovarian Cancer (OC) are widespread, especially with CA125, which, however, is not a perfect biomarker and thus further investigation for new methods of evaluation are warranted. The feasibility of Circulating Tumor Cells (CTCs) in advanced OC was investigated in this case report. Case presentation: A 19-year-old woman with advanced low-grade serous papillary adenocarcinoma and relapsed disease did not have a CA125 correspondent with disease relapse. CTCs were evaluated, compared with CA125 and with image exams. Relapses were not correspondent to elevations of CA125. CTCs demonstrated usefulness, being proportional to major disease relapse, especially in the peritoneum. CTCs may be used as a complementary diagnosis tool when marginal/small increases in CA-125 levels are observed. Conclusions: In OC, CTCs can be an important tool to predict recurrence, response to treatment and improve the quality of decision-making, in order to offer the best treatment to a determined group of patients (AU)

Alteração da via da recombinação homóloga de reparo de DNA no câncer epitelial de ovário / Homologous recombination deficiency in ovarian carcinoma

Justificativa:Os carcinomas de ovário apresentam deficiência da via da recombinação homóloga de reparo de DNA em aproximadamente 50% dos casos, em 15 a 20% dos casos atribuída a mutações germinativas em BRCA1 ou BRCA2. Tumores com mutações germinativas em BRCA1 ou BRCA2 são mais sensíveis aos tratamentos com inibidores de PARP e com esquemas quimioterápicos baseados em platina. O papel de outras alterações da via da recombinação homóloga na sensibilidade a essas modalidades de tratamento bem como a forma de identificar os tumores com deficiência dessa via ainda não estão definidos. Escores avaliando o perfil de alterações estruturais genômicas causadas especificamente por deficiência da via da recombinação homóloga têm sido estudados como potenciais marcadores da deficiência desta via. Nosso objetivo foi caracterizar uma coorte de pacientes com carcinoma de ovário quanto à deficiência da via da recombinação homóloga utilizando escores calculados a partir das alterações do número de cópias genômicas e de perdas de heterozigose e avaliar o papel destes escores na identificação de pacientes com sensibilidade prolongada à platina. Métodos: Selecionamos uma coorte de 31 pacientes com carcinoma de ovário com recidiva classificada clinicamente com platina resistente e que foram reexpostas ao tratamento com quimioterapia baseada em platina. Amostras de tumores armazenados em parafina de 14 pacientes foram submetidas ao ensaio ONCOSCAN para avaliação de alterações de números de cópias, perda de heterozigose e identificação de mutações específicas em 9 genes relacionados a neoplasias. A partir destes dados caracterizamos os escores de Telomeric Allelic Imbalance (TAI), escore de perda de heterozigose (cnLOH+L) escore de Large Scale Transition (LST) e escore de deficiência da recombinação homóloga (HRD) em cada tumor e avaliamos a sua associação com a taxa de resposta à quimioterapia, sobrevida global e fatores clínico patológicos. Resultados: Na coorte de 31 pacientes, DNA foi extraído de 28 amostras e 15 amostras de 14 pacientes foram analisadas de forma efetiva. Na maioria dos casos encontramos o padrão esperado de grande instabilidade genômica com diversas regiões de ganhos e perdas do genoma e regiões de perda de heterozigose. Todos os casos analisados mostraram cnLOH ou delLOH no cromossomo 17, 12 de 14 pacientes apresentaram cnLOH ou delLOH no braço longo do cromossomo 13 e o cromossomo 22 apresentou perdas ou ganhos na maioria dos casos. Mutação em TP53 foi encontrada em 2 casos, mutação em NRAS em 2 casos, e um caso com mutação em TP53apresentou mutação em PTEN associada a deleção da região do PTEN. A mediana dos escores foi de 19,5 para TAI, 12,5 para cnLOH+L, 26,0 para LST e 6,3 para HRD. Levando-se em conta os escores com pontos de corte previamente definidos na literatura encontramos 10 de 14 (escore cnLOH+L) e 9 de 14 (escore LST) pacientes com tumores com escores altos sugerindo deficiência da via da recombinação homóloga. Tanto a coorte como um todo quanto as 14 pacientes submetidas à análise molecular apresentaram taxa de resposta acima do esperado sendo 16 de 31 pacientes (51,6%) e 7 de 14 pacientes (50,0) respectivamente. Não houve diferença estatisticamente significativa entre as taxas de resposta das pacientes de com escores altos versus baixos, embora 6 de 10 pacientes com escore cnLOH+L elevado tenham apresentado resposta e 1 de 4 pacientes com escore cnLOH+L baixo tenham apresentado resposta e 6 de 9 pacientes com escore LST elevado tenham apresentado resposta e 1 de 5 pacientes com escore LST baixo tenham apresentado resposta. Numericamente os escores cnLOH+L, LST e HDR foram mais altos nas pacientes que responderam quando comparados com os escores das pacientes que não responderam, com medianas deTAI = 19,0 vs 24,0, TAIm = 16,0 vs 19,0, cnLOH+L 13 vs 12, LST = 28,0 vs 18,0, LSTm = -4,0 vs -20,0, HRD 8,7 vs 0,3 para respondedoras versus não respondedoras. Essa diferença não foi estatisticamente significativa. A sobrevida global mediana foi 13,4 meses desde o inicio do tratamento de reexposição à platina e não houve diferença de acordo com os valores dos escores. Dentre os fatores clinicopatológicos a presença de história familiar de câncer de mama ou ovário ou a história pessoal de câncer de mama foi o único fator associado a uma maior taxa de resposta. Os tumores primários apresentaram escore TAI mais elevado que os tumores coletados no momento da recidiva e comparando duas amostras de uma mesma paciente houve diferença na classificação da deficiência da via da recombinação homóloga de acordo com os escores cnLOH+L e LST. Conclusões: Os escores de deficiência da via da recombinação homóloga se mostraram potenciais marcadores de resposta à reexposição à platina no cenário de doença platina resistente, necessitando melhor definição dos pontos de corte e do impacto da heterogeneidade tumoral e da necessidade de avaliação do material coletado no momento da recidiva. História familiar positiva é um fator clínico capaz de identificar pacientes com mais chance de resposta á reexposição á platina. Nossos dados fortalecem a hipótese da contribuição de mutações em PTEN para o desenvolvimento de deficiência da via da recombinação homóloga e o papel das mutações de NRAS nos carcinomas serosos de ovário.

Background: Homologous recombination deficiency s presente in up to 50% of ovarian carcinomas, in 15 to 20% due to germline BRCA1 or BRCA2 mutations. BRCA mutated tumors are more sensitive to PARP inhibitors and platinum based chemotherapy. The role of other homologous recombination mechanisms on PARP inhibitors and platinum sensitivity as well as the methods to identify homologous recombination deficiency is not clear yet. Scores evaluating structural genomic abnormalities caused specifically by homologous recombination deficiency have been studied as markers of deficiency of this DNA repair pathway. The main objective of the present study was to characterize a cohort of ovarian cancer patients regarding homologous recombination deficiency using scores based on copy number alterations and loss of heterozygosity and to evaluate the impact of these scores in prolonged platinum sensitivity. Methods: We selected a cohort of 31 ovarian cancer patients with platinum resistant recurrence reexposed to platinum based chemotherapy. Paraffin embedded tumor samples from 14 patients were analyzed through ONCOSCAN assay for copy number alterations, loss of heterozygosity and specific point mutations in 9 cancer related genes. Based on these alterations we calculated the scores Telomeric Allelic Imbalance (TAI), loss of heterozygosity score (cnLOH+L) Large Scale Transition score (LST) and homologous recombination deficiency score (HRD) for each tumor sample and tested their association to response rate to platinum rechallenge, overall survival and to the clinical pathologic factors. Results: From the cohort of 31 patients, DNA was extracted from 28 samples and 15 samples from 14 patients were effectively analyzed. Most cases presented the expected high genomic instability pattern with lots of genomic losses, genomic gains and loss of heterozygosity segments. All cases showed cnLOH or delLOH in chromosome 17, 12 of 14 patients showed cnLOH or delLOH in the long arm of chromosome 13, and chromosome 22 presented losses or gains in most of cases.TP53 mutations were present in 2 cases, NRAS mutations in 2 cases, and one patient with TP53 mutation showed also a PTEN mutation together with a genomic loss in PTEN region. Median scores were 19,5 for TAI, 12,5 for cnLOH+L, 26,0 for LST and 6,3 for HRD. Considering previously literature defined cutoffs we found 10 out of 14 (for cnLOH+L score) and 9 out of 14 (for LST score) patients with tumors with high scores suggesting homologous recombination deficiency. In the cohort of 31 patients 16 had response to platinum reexposition and in the cohort of 14 patients analyzed by ONCOSCAN assay 7 patients had response. There was no statistically significant difference between response rates for high versus low scores, even though 6 out of 10 patient with high cnLOH+L score while 1 out of 4 patients with low cnLOH+L score had response and 6 out of 9 patient with high cnLOH+L score while 1 out of 5 patients with low cnLOH+L score had response. Numerically, the scores cnLOH+L, LST and HDR were higher in patients with response to treatment compared to those without a response, with medians of TAI = 19,0 vs 24,0, TAIm = 16,0 vs 19,0, cnLOH+L 13 vs 12, LST = 28,0 vs 18,0, LSTm = -4,0 vs -20,0, HRD 8,7 vs 0,3 for responders versus non responders respectively. These differences were not statistically significant. Median overall survival was 13,4 months from the beginning of platinum rechallenge and there was no difference in survival according to scores. Among clinical pathologic factors, family history of breast or ovarian cancer or personal history of breast cancer was associated to a higher response rate to platinum rechallenge. Primary tumors had a higher TAI score compared to recurrent tumors and comparing two different samples from the same patient there was divergence on the homologous recombination deficiency classification according to cnLOH+L and LST scores. Conclusions: Homologous recombination deficiency scores showed to be potential markers of response to platinum rechallenge in the platinum resistant setting. It is still necessary to clarify the best cutoffs for each score, the impact of tumor heterogeneity and the need of tumor samples to be collected in the moment of treatment. Positive family history is a clinical factor predictvie of platinum rechallenge response. Our data support the hypothesis of a role for PTEN in homologous recombination deficiency as well as a role of NRAS mutations in ovarian serous carcinomas.

Implantes cocleares: aspectos tecnológicos e papel socioeconômico / Cochlear implants: technological aspects and socioeconomic role

INTRODUÇÃO: O grande número de deficientes auditivos faz da perda auditiva um sério problema social, econômico e de saúde pública. Próteses auditivas e implantes cocleares representam os principais dispositivos utilizados como paliativos por pessoas com deficiência auditiva, sendo que os implantes cocleares são muitas vezes a única opção nos casos de deficiência auditiva severa e profunda. Nesse artigo discute-se de maneira geral os diferentes aspectos envolvendo implantes cocleares, tanto de âmbito tecnológico como seu papel socioeconômico. MÉTODOS: Baseado em dados do SUS, IBGE e outras fontes, um levantamento qualitativo e quantitativo é feito pela primeira vez especificamente para a população brasileira. O artigo discute ainda o estado da arte das tecnologias envolvidas no implante coclear, com base em literatura científica e informações de fabricantes, bem como as perspectivas para as próximas gerações de implantes cocleares. CONCLUSÃO: Há potencial e demanda para evoluções nos implantes atuais. A implantação precoce é benéfica para pacientes e sociedade, compensando os custos econômica e socialmente. No entanto, as políticas públicas de reabilitação necessitam se adequar para atender com eficácia à crescente população afetada pela deficiência auditiva.

INTRODUCTION: Due to the great number of affected people, hearing loss is considered a serious social, economic and public health problem. Hearing aids and cochlear implants are the primary devices used as palliatives for people with hearing loss, and cochlear implants are often the only option in cases of severe to profound hearing impairment. This paper covers both technological and socio-economic aspects of cochlear implant, which is considered as one of most recommended treatments to alleviate severe to profound hearing loss. METHODS: Brazilian unified health system data is used to display qualitative and quantitative analysis impact on Brazilian population and government. A state-of-art review based on scientific literature and manufacturer data is provided, as well as perspectives for the next cochlear implant generation. CONCLUSION: There is potential and demand for evolutions in current implants. Early implantation is beneficial for patients and society, compensating the costs economic and socially. However, public programs need to adapt in order to efficiently attend the increasing affected population.