Importance Cytotoxic CD8+ T lymphocytes (TILs) participate in immune control of ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design Prospective survival cohort. Setting Multi-center observational. Participants Over 5,500 patients, including 3,196 high-grade serous ovarian carcinomas (HGSOCs), followed prospectively for over 24,650 person-years. Exposure(s) Following immunohistochemistry, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1–2), moderate (3–19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcome Measure(s) Overall survival time. Results Among the five major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (p-trend=4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors which drive infiltration will be key to unravelling outcome heterogeneity in this cancer.

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BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

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IntroduçãoFibrose cística (FC) é doença autossômica recessiva letal, a mais comum afeta populações caucasóides, cuja incidência varia de um para cada 2000 ou 3000 nascimentos em vários países: um indivíduo em cada 25 nestas populações é portador assintomático do gene. É menos freqüente em negros, um para 17.000, e rara em asiáticos, um para 90.000, na população americana 1,2 .Seu diagnóstico é sugerido pelas características clíni-cas de doença pulmonar obstrutiva crônica, colonização pulmonar persistente (particularmente com cepas mucói-des de Pseudomonas), íleo meconial, insuficiência pancreática com prejuízo do desenvolvimento ou história familiar da doença. Na presença dessas, o diagnóstico é confirmado por concentração de cloro no suor maior que 60 mEq/ L ou pela mutação FC patológica nos cromossomos. Marcos HistóricosDeve-se a Landsteiner a primeira descrição anátomo-patológica da FC em recém-nascido falecido no quinto dia de vida por Íleo Meconial, feita em 1905 3 .Em 1936, Fanconi descreveu o caso de criança portadora de síndrome celíaca com alterações pancreáticas que, em sua opinião, diferia da doença celíaca clássica, pois apresentava sintomas pulmonares e intestinais, em cuja necrópsia, encontraram-se bronquiectasias e fibrose císti-ca do pâncreas 4 . ResumoObjetivo: Devido aos grandes avanços recentes no tratamento da fibrose cística e à necessidade de maior conhecimento da doença pelos pediatras, os autores se propõem a fazer uma revisão extensa sobre o assunto.Material e Métodos: Foram selecionados os trabalhos científi-cos mais relevantes na literatura médica internacional em relação ao tema, no sentido de se obterem informações completas e atualizadas sobre o mesmo.Resultados: Foi elaborada uma revisão extensa sobre fibrose cística abordando os seguintes tópicos: introdução, marcos históri-cos, genética, fisiopatogenia, microbiologia das infecções pulmonares, manifestações clínicas, critérios clínicos e laboratoriais do diagnóstico, diagnóstico diferencial, tratamento e prognóstico. J. pediatr. (Rio J.). 1998; 74 (Supl.1): S76-S94:fibrose cística, mucoviscidose, diagnóstico, tratamento, prognóstico, fatores de risco. AbstractObjective: Due to the great advances recently achieved in the treatment of Cystic Fibrosis as well as to the fact that pediatricians need to have a better understanding of this disease, the authors propose an extensive review of the subject.Methods: We selected the most outstanding publications on Cystic Fibrosis in the international literature of the recent years, with the purpose of being up-to-date and at the same time offering a practical synthesis for the readers.Results: We elaborated an extensive review about Cystic Fibrosis covering the following topics: historical remarks, genetics, physiopathogenesis, microbiology of pulmonary infections, clinical manifestations, clinical and laboratorial criteria for diagnosis, differential diagnosis, treatment and prognosis.J. pediatr. (Rio J.). 1998; 74 (Supl.1): S76-S94: cystic fibrosis, mucoviscidosis, diagnosis, treatment, pro...