Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS: 18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

Avaliação da onda V da audiometria de tronco cerebral de crianças reprovadas na triagem auditiva neonatal / Evaluation of the five wave from auditory brain response of children who not passed in neonatal screening

Já está bem estabelecido a importância do diagnóstico precoce das disacusias em neonatos. Muito se tem falado da triagem auditiva neonatal (TAN), mas pouco se comenta do encaminhamento e seguimento das crianças com emissão otoacústica (EOA) alterada. A audiometria de tronco cerebral (ABR) é a próxima etapa para o diagnóstico de disacusia nesta faixa etária. OBJETIVOS: Os objetivos deste trabalho são avaliar a adesão ao programa de TAN e avaliar as ABRs das crianças reprovadas na TAN, concentrando a análise nos limiares obtidos e na latência da onda V. TIPO DE ESTUDO: Clínico prospectivo. MATERIAL E MÉTODO: Análise de 75 ABRs de crianças atendidas no serviço de EOA da Maternidade de Campinas. RESULTADOS: A maioria das crianças apresentou ABR com limiares e latências dentro dos valores normais. A alteração mais encontrada foi o aumento da latência da onda V, que pode ser decorrente da incompleta mielinização do sistema nervoso central, da presença de secreção em ouvido médio e de alterações retrococleares. CONCLUSÃO: Concluímos que o aumento da latência da onda V é a alteração mais freqüente nas ABRs; que muitos pacientes se perdem durante a execução do protocolo de triagem auditiva, retardando ou impossibilitando o diagnóstico correto e precoce e que a maior parte das crianças reprovadas nas otoemissões acústicas têm limiar eletrofisiológico auditivo normal.

Comparação das respostas em neonatos normais para emissões otoacústicas evocadas nos equipamentos: ILO 292 e ILO Ecocheck / Comparison of otoacustic evoked responses in normal neonates for ILO 292 and ILO Ecocheck

O equipamento portátil (ILO ECOCHECK, AUDX, entre outros) é uma outra alternativa, além dos aparelhos tradicionais (ILO 292, Byologic, Celesta, etc.) para a triagem auditiva em neonatos. OBJETIVO: Realizamos Emissöes Otoacústicas Evocadas Transitórias com os dois equipamentos, em 88 recém-nascidos normais sem risco auditivo para observar as respostas obtidas, procurando determinar, assim, a concordância entre os dois equipamentos. FORMA DE ESTUDO: Clínico prospectivo. RESULTADO: Observamos que os neonatos que falharam no ILO 292 também falharam no ILO ECOCHECK, no entanto, nem todos que falharam no ILO ECOCHECK falharam no ILO 292. Também notamos que os que falharam no ILO ECOCHECK apresentaram ausência de resposta na primeira banda de freqüência analisável do ILO 292. CONCLUSÄO: Concluímos que o equipamento portátil mostrou-se mais rigoroso na caracterizaçäo do exame normal do que o critério de normalidade utilizado na avaliaçäo do exame convencional