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We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and ß-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9-98.5 %) for the nuclear model, 85.6 % (73.3-96.6 %) for the cytoplasmic model, and 78.4 % (75.5-84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.
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BACKGROUND: Current risk stratification tools for prostate cancer patients under active surveillance (AS) may inadequately identify those needing treatment. We investigated DNA ploidy and PTEN as potential biomarkers to predict aggressive disease in AS patients. METHODS: We assessed DNA ploidy by image cytometry and PTEN protein expression by immunohistochemistry in 3197 tumour-containing tissue blocks from 558 patients followed in AS at a Norwegian local hospital. The primary endpoint was treatment, with treatment failure (biochemical recurrence or initiation of salvage therapy) as the secondary endpoint. RESULTS: The combined DNA ploidy and PTEN (DPP) status at diagnosis was associated with treatment-free survival in univariable- and multivariable analysis, with a HR for DPP-aberrant vs. DPP-normal tumours of 2.12 (p < 0.0001) and 1.94 (p < 0.0001), respectively. Integration of DNA ploidy and PTEN status with the Cancer of the Prostate Risk Assessment (CAPRA) score improved risk stratification (c-index difference = 0.025; p = 0.0033). Among the treated patients, those with DPP-aberrant tumours exhibited a significantly higher likelihood of treatment failure (HR 2.01; p = 0.027). CONCLUSIONS: DNA ploidy and PTEN could serve as additional biomarkers to identify AS patients at increased risk of developing aggressive disease, enabling earlier intervention for nearly 50% of the patients that will eventually receive treatment with current protocol.
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INTRODUCTION: The role of molecular classification in patients with low/intermediate risk endometrial cancer (EC) is uncertain. Higher precision in diagnostics will inform the unsettled debate on optimal adjuvant treatment. We aimed to determine the association of molecular profiling with patterns of relapse and survival. MATERIAL AND METHODS: This retrospective cohort study included patients referred to The Norwegian Radium Hospital, Oslo University Hospital from 2006-2017. Patients with low/intermediate risk EC were molecularly classified as pathogenic polymerase epsilon (POLE)-mutated, mismatch repair deficient (MMRd), p53 abnormal, or no specific molecular profile (NSMP). The main outcomes were time to recurrence (TTR) and cancer-specific survival (CSS). RESULTS: Of 626 patients, 610 could be molecularly classified. Fifty-seven patients (9%) had POLE-mutated tumors, 202 (33%) had MMRd tumors, 34 (6%) had p53 abnormal tumors and 317 (52%) had NSMP tumors. After median follow-up time of 8.9 years, there was a statistically significant difference in TTR and CSS by molecular groups. Patients with p53 abnormal tumors had poor prognosis, with 10 of the 12 patients with relapse presenting with para-aortic/distant metastases. Patients with POLE mutations had excellent prognosis. In the NSMP group, L1CAM expression was associated with shorter CSS but not TTR. CONCLUSIONS: The differences in outcome by molecular groups are driven by differences in relapse frequency and -patterns and demand a higher precision in diagnostics, also in patients with low/intermediate risk EC. Tailored adjuvant treatment strategies need to consider systemic treatment for patients with p53 abnormal tumors and de-escalated treatment for patients with POLE mutated tumors.
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Neoplasias Endometriales , Proteína p53 Supresora de Tumor , Femenino , Humanos , Proteína p53 Supresora de Tumor/genética , Estudios Retrospectivos , Recurrencia Local de Neoplasia/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/terapia , Pronóstico , MutaciónRESUMEN
Introduction: Road traffic accidents are a public health problem and have emerged as the leading cause of mortality and morbidity. Head is the most commonly affected site of road traffic accidents. The aim of this study was to find out the prevalence of road traffic accidents among patients presenting to the emergency department of a tertiary care centre. Methods: A descriptive cross-sectional study was conducted at the Emergency Department from 12 January 2022 to 14 June 2022. Ethical approval was taken from the Institutional Review Committee (Reference number: COMSTH-IRC/2021-171). Data was collected using a self-structure questionnaire and from emergency tickets. A convenience sampling method was used. Point prevalence and 95% Confidence Interval were calculated. Results: Among 7654 patients, the prevalence of road traffic accidents was found to be 734 (9.58%) (8.49-10.66, 95% Confidence Interval). Most of the accidents took place on Friday 139 (18.94%). The majority of them were soft tissue injuries 279 (38.01%). Conclusions: The prevalence of road traffic accidents was found to be higher compared to similar studies done in similar settings. Accident preventive strategies should be focused on and implemented by all the stakeholders. Keywords: emergencies; mortality; soft tissue injury; traffic accidents.
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Accidentes de Tránsito , Traumatismos de los Tejidos Blandos , Humanos , Estudios Transversales , Centros de Atención Terciaria , Encuestas y Cuestionarios , Servicio de Urgencia en HospitalRESUMEN
BACKGROUND: Emergency medical care, including prehospital treatment, forms an important component of any healthcare system. Like most low-middle-income countries, Nepal has an emergency medical system that can be described as underdeveloped. Emergency physicians navigating this system may experience challenges or barriers in their treatment of patients. This study aimed to investigate physicians' perspectives on emergency and prehospital patient management in a low-income country, Nepal, and to understand the challenges and barriers they perceive in emergency treatment including both the prehospital treatment and the immediate in-hospital treatment at the emergency department. METHODS: Using a qualitative study, eight semi-structured interviews with physicians working in a Nepalese emergency department were performed. The interviews were conducted between September and November 2021 and were audio-recorded and transcribed verbatim. Data were subsequently analyzed using the systematic text condensation method. RESULTS: Four main themes and associated sub-themes were identified: (1) patients' sociocultural, educational, and financial factors (such as financial issues and financial inequality) and regional differences; (2) emergency department's organization and resources concerning human and material resources, protocols, and guidelines; (3) problems with the emergency department (ED) service's qualities and availability caused by an insufficient integration of the ED and the EMS, prehospital resources, and financial interests in the EMS; and (4) surrounding healthcare system's impact on the ED where, especially, the levels of organized primary care, governmental responsibilities, and healthcare structure were addressed. CONCLUSIONS: The physicians identified numerous regularly encountered challenges and barriers. These challenges stretched beyond the ED and into various aspects of society. The patients' financial problems were described as the greatest problem, restricting the treatment due to a given patient's inability or unwillingness to pay for the required procedures. The physicians were thus restricted in completing their duties to the desired levels. The low quality of prehospital care and a lack of education and awareness of common diseases and symptoms in a significant proportion of patients were identified by many participants as being significant issues. The aforementioned challenges or barriers directly resulted in patients arriving in critical conditions that could have been avoided if the disease were treated earlier.
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Machine learning (ML) is expected to improve biomarker assessment. Using convolution neural networks, we developed a fully-automated method for assessing PTEN protein status in immunohistochemically-stained slides using a radical prostatectomy (RP) cohort (n = 253). It was validated according to a predefined protocol in an independent RP cohort (n = 259), alone and by measuring its prognostic value in combination with DNA ploidy status determined by ML-based image cytometry. In the primary analysis, automatically assessed dichotomized PTEN status was associated with time to biochemical recurrence (TTBCR) (hazard ratio (HR) = 3.32, 95% CI 2.05 to 5.38). Patients with both non-diploid tumors and PTEN-low had an HR of 4.63 (95% CI 2.50 to 8.57), while patients with one of these characteristics had an HR of 1.94 (95% CI 1.15 to 3.30), compared to patients with diploid tumors and PTEN-high, in univariable analysis of TTBCR in the validation cohort. Automatic PTEN scoring was strongly predictive of the PTEN status assessed by human experts (area under the curve 0.987 (95% CI 0.968 to 0.994)). This suggests that PTEN status can be accurately assessed using ML, and that the combined marker of automatically assessed PTEN and DNA ploidy status may provide an objective supplement to the existing risk stratification factors in prostate cancer.
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BACKGROUND: Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. METHODS: More than 12â000â000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. FINDINGS: 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72-5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07-4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion. INTERPRETATION: A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes. FUNDING: The Research Council of Norway.
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Neoplasias Colorrectales/diagnóstico , Aprendizaje Profundo , Anciano , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Detección Precoz del Cáncer/métodos , Eosina Amarillenta-(YS)/metabolismo , Femenino , Hematoxilina/metabolismo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Estudios ProspectivosRESUMEN
The mitotic checkpoint protein BUB3, cyclin B1 (CCNB1) and pituitary tumor-transforming 1 (PTTG1) regulates cell division, and are sparsely studied in prostate cancer. Deregulation of these genes can lead to genomic instability, a characteristic of more aggressive tumors. We aimed to determine the expression levels of BUB3, CCNB1, and PTTG1 as potential prognostic markers of recurrence after radical prostatectomy. Protein levels were determined by immunohistochemistry on three formalin-fixed paraffin-embedded tissue sections from each of the 253 patients treated with radical prostatectomy. Immunohistochemistry scores were obtained by automated image analysis for CCNB1 and PTTG1. Recurrence, defined as locoregional recurrence, distant metastasis or death from prostate cancer, was used as endpoint for survival analysis. Tumors having both positive and negative tumor areas for cytoplasmic BUB3 (30%), CCNB1 (28%), or PTTG1 (35%) were considered heterogeneous. Patients with ≥1 positive tumor area had significantly increased risk of disease recurrence in univariable analysis compared with patients where all tumor areas were negative for cytoplasmic BUB3 (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.41-3.36), CCNB1 (HR = 2.98, 95% CI 1.93-4.61) and PTTG1 (HR = 1.91, 95% CI 1.23-2.97). Combining the scores of cytoplasmic BUB3 and CCNB1 improved risk stratification when integrated with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score (difference in concordance index = 0.024, 95% CI 0.001-0.05). In analysis of multiple tumor areas, prognostic value was observed for cytoplasmic BUB3, CCNB1, and PTTG1.
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Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/biosíntesis , Ciclina B1/biosíntesis , Proteínas de Unión a Poli-ADP-Ribosa/biosíntesis , Neoplasias de la Próstata/patología , Securina/biosíntesis , Anciano , Biomarcadores de Tumor/análisis , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The combination of DNA ploidy and automatically estimated stroma fraction has been shown to correlate with recurrence and cancer death in colorectal cancer. We aimed to extend this observation and evaluate the prognostic importance of this combined marker in prostate cancer. DNA ploidy status was determined by image cytometry and the stroma fraction was estimated automatically on hematoxylin and eosin stained sections in three tumor samples from each patient to account for tumor heterogeneity. The optimal threshold for low (≤56%) and high (>56%) stroma fraction was identified in a discovery cohort (n = 253). The combined marker was validated in an independent patient cohort (n = 259) with biochemical recurrence as endpoint. The combined marker predicted biochemical recurrence independently in the validation cohort. Multivariable analysis showed that the highest risk of recurrence was observed for patients with samples that had both non-diploid ploidy status and a high stroma fraction (hazard ratio: 2.51, 95% confidence interval: 1.18-5.34). In conclusion, we suggest the combination of DNA ploidy and automatically estimated stroma fraction as a prognostic marker for the risk stratification of prostate cancer patients. It may also be a potential generic marker as concurrent results have been described in colorectal cancer.
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Automatización de Laboratorios/métodos , Biomarcadores de Tumor/genética , ADN de Neoplasias/genética , Ploidias , Neoplasias de la Próstata/diagnóstico , Coloración y Etiquetado/métodos , Anciano , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Citometría de Flujo/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Pronóstico , Prostatectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Factores de RiesgoRESUMEN
Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.
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Factor de Transcripción Activador 4/fisiología , Biomarcadores de Tumor/fisiología , Proteínas de Neoplasias/fisiología , Neoplasias de la Próstata/metabolismo , Respuesta de Proteína Desplegada/genética , Animales , Proliferación Celular/genética , Estrés del Retículo Endoplásmico/genética , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/genética , Células Tumorales CultivadasRESUMEN
PURPOSE: To our knowledge, we conducted the first prospective oncologic clinical trial in Nepal aimed at providing state-of-the-art chemotherapy to patients with Ewing sarcoma. The efficacy of external-beam radiotherapy (RT) as the sole local treatment modality was explored and deemed justified as a result of the lack of available advanced tumor-orthopedic services in Nepal. PATIENTS AND METHODS: Twenty patients, 11 female and 9 male patients between the ages of 6 and 37 years, with newly diagnosed Ewing sarcoma were enrolled. Neoadjuvant combination chemotherapy, comprising well-established drug combinations, was administered in five courses before external-beam RT, during which one course of etoposide and ifosfamide was given. After RT, six additional chemotherapy courses were scheduled. RESULTS: RT was tolerated well, providing rapid symptom relief and local tumor control, with no pathologic fractures observed among the 15 patients who received such treatment. Eleven patients completed the entire treatment protocol; seven patients were under continued follow-up, with no evidence of disease in six patients at a median follow-up time of 2.3 years (range, 1.3 to 3.1 years) and one patient alive but with a regional recurrence. Four patients experienced metastatic relapse and died as a result of their disease. Three treatment-related deaths linked to toxicity from chemotherapy occurred. Four of the six patients who refused to complete the treatment protocol and were lost to follow-up experienced progressive disease and were assumed dead. CONCLUSION: This study was feasible with RT as the sole local treatment modality in combination with chemotherapy. As a result of the high number of patients lost to follow-up, no firm conclusions can be drawn, but the majority of the patients who completed treatment obtained durable long-term remissions.
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Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/radioterapia , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Nepal , Estudios Prospectivos , Adulto JovenRESUMEN
Background: Nuclear texture analysis measuring differences in chromatin structure has provided prognostic biomarkers in several cancers. There is a need for improved cell-by-cell chromatin analysis to detect nuclei with highly disorganized chromatin. The purpose of this study was to develop a method for detecting nuclei with high chromatin entropy and to evaluate the association between the presence of such deviating nuclei and prognosis. Methods: A new texture-based biomarker that characterizes each cancer based on the proportion of high-chromatin entropy nuclei (<25% vs ≥25%) was developed on a discovery set of 175 uterine sarcomas. The prognostic impact of this biomarker was evaluated on a validation set of 179 uterine sarcomas, as well as on independent validation sets of 246 early-stage ovarian carcinomas and 791 endometrial carcinomas. More than 1 million images of nuclei stained for DNA were included in the study. All statistical tests were two-sided. Results: An increased proportion of high-chromatin entropy nuclei was associated with poor clinical outcome. The biomarker predicted five-year overall survival for uterine sarcoma patients with a hazard ratio (HR) of 2.02 (95% confidence interval [CI] = 1.43 to 2.84), time to recurrence for ovarian cancer patients (HR = 2.91, 95% CI = 1.74 to 4.88), and cancer-specific survival for endometrial cancer patients (HR = 3.74, 95% CI = 2.24 to 6.24). Chromatin entropy was an independent prognostic marker in multivariable analyses with clinicopathological parameters (HR = 1.81, 95% CI = 1.21 to 2.70, for sarcoma; HR = 1.71, 95% CI = 1.01 to 2.90, for ovarian cancer; and HR = 2.03, 95% CI = 1.19 to 3.45, for endometrial cancer). Conclusions: A novel method detected high-chromatin entropy nuclei, and an increased proportion of such nuclei was associated with poor prognosis. Chromatin entropy supplemented existing prognostic markers in multivariable analyses of three gynecological cancer cohorts.
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Biomarcadores de Tumor , Núcleo Celular/patología , Neoplasias de los Genitales Femeninos/mortalidad , Neoplasias de los Genitales Femeninos/patología , Anciano , Anciano de 80 o más Años , Cromatina , Estudios de Cohortes , Entropía , Femenino , Neoplasias de los Genitales Femeninos/epidemiología , Neoplasias de los Genitales Femeninos/etiología , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Noruega/epidemiología , Pronóstico , Sistema de RegistrosRESUMEN
BACKGROUND: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation. METHODS: Machine learning algorithms analysed the chromatin organisation in 461â000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival. FINDINGS: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer. INTERPRETATION: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings. FUNDING: The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust.
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Núcleo Celular/genética , Ensamble y Desensamble de Cromatina , Cromatina/genética , Neoplasias Colorrectales/genética , Interpretación de Imagen Asistida por Computador/métodos , Microscopía/métodos , Coloración y Etiquetado/métodos , Anciano , Núcleo Celular/patología , Toma de Decisiones Clínicas , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Epigénesis Genética , Europa (Continente) , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Aprendizaje Automático , Masculino , Inestabilidad de Microsatélites , Estadificación de Neoplasias , Reconocimiento de Normas Patrones Automatizadas , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: When diagnosing cancer, it is often difficult to predict the further growth and spread of the tumour. One of the features of cancer is an abnormality in the amount of DNA in cancer cell nuclei, so-called DNA aneuploidy. Extensive abnormalities are often due to an unstable genome, which leads to an accumulation of mutations, dysregulation of genes and loss of cell cycle control. This article aims to provide an overview of the prognostic value of DNA ploidy analyses in ovarian, endometrial, prostate and colorectal carcinoma. MATERIAL AND METHOD: This review article is based on literature searches in PubMed for the period 20002016. RESULTS: The search resulted in 308 articles. Thirty-three of these, representing an analysis of more than 18 000 tumours, fulfilled the inclusion criteria. In 30 of the 33 articles, a significant correlation was found between DNA ploidy and disease outcome for patients with ovarian, endometrial, prostate and colorectal carcinoma. Patients with aneuploid tumours had a poorer prognosis than those with diploid tumours. INTERPRETATION: DNA ploidy analysis is a prognostic method for patients with ovarian and endometrial carcinoma, and is used as a guide to options for supplemental treatment and fertility-sparing surgery. A review of publications in recent years of DNA ploidy analyses for prostate and colorectal carcinoma reveals that these patient groups may also benefit from these measurements. In general terms, DNA ploidy analyses may help to increase knowledge of who needs supplemental treatment and who does not which may be advantageous in avoiding overtreatment.
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Carcinoma/genética , ADN de Neoplasias/genética , Neoplasias/genética , Ploidias , Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Femenino , Inestabilidad Genómica , Humanos , Masculino , Neoplasias Ováricas/genética , Pronóstico , Neoplasias de la Próstata/genéticaRESUMEN
BACKGROUND: The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model. METHODS: We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6-12). GS was assessed for every tumour-containing block and DNA ploidy for a median of four samples for each RP. In a subgroup of 40 patients we assessed DNA ploidy and PTEN status in every tumour-containing block. In 102 patients assigned to active surveillance (AS), GS and DNA ploidy were studied in needle biopsies. RESULTS: Extensive heterogeneity was observed for GS (89% of the patients) and DNA ploidy (40% of the patients) in the cohort, and DNA ploidy (60% of the patients) and PTEN expression (75% of the patients) in the subgroup. DNA ploidy was a significant prognostic marker when heterogeneity was taken into consideration. In the AS cohort we found heterogeneity in GS (24%) and in DNA ploidy (25%) specimens. CONCLUSIONS: Multi-sample analysis should be performed to support clinical treatment decisions.
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Biomarcadores de Tumor , ADN de Neoplasias/análisis , Recurrencia Local de Neoplasia/genética , Fosfohidrolasa PTEN/análisis , Ploidias , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Anciano , Biopsia con Aguja , Heterogeneidad Genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Próstata/patología , Prostatectomía , Neoplasias de la Próstata/química , Neoplasias de la Próstata/terapia , Carga Tumoral , Espera VigilanteRESUMEN
BACKGROUND: Most endometrial carcinoma patients are diagnosed at an early stage with a good prognosis. However, a relatively low fraction with lethal disease constitutes a substantial number of patients due to the high incidence rate. Preoperative identification of patients with high risk and low risk for poor outcome is necessary to tailor treatment. Nucleotyping refers to characterization of cell nuclei by image cytometry, including the assessment of chromatin structure by nuclear texture analysis. This method is a strong prognostic marker in many cancers but has not been evaluated in preoperative curettage specimens from endometrial carcinoma. METHODS: The prognostic impact of changes in chromatin structure quantified with Nucleotyping was evaluated in preoperative curettage specimens from 791 endometrial carcinoma patients prospectively included in the MoMaTEC multicenter trial. RESULTS: Nucleotyping was an independent prognostic marker of disease-specific survival in preoperative curettage specimens among patients with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I-II disease (HR=2.9; 95% CI, 1.2-6.5; P = 0.013) and significantly associated with age, FIGO stage, histologic type, histologic grade, myometrial infiltration, lymph node status, curettage histology type, and DNA ploidy. CONCLUSIONS: Nucleotyping in preoperative curettage specimens is an independent prognostic marker for disease-specific survival, with potential to supplement existing parameters for risk stratification to tailor treatment. IMPACT: This is the first study to evaluate the prognostic impact of Nucleotyping in curettage specimens from endometrial carcinoma and shows that this may be a clinically useful prognostic marker in endometrial cancer. External validation is warranted. Cancer Epidemiol Biomarkers Prev; 26(1); 61-67. ©2016 AACR.
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Biomarcadores de Tumor/análisis , Cromatina/genética , ADN/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/mortalidad , Adulto , Anciano , Análisis de Varianza , Bases de Datos Factuales , Dilatación y Legrado Uterino/métodos , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Noruega , Ploidias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Manejo de Especímenes , Tasa de SupervivenciaRESUMEN
Overtreatment is a major concern in men diagnosed with prostate cancer. The aim of this study was to evaluate the combined prognostic role of three frequent molecular alterations in prostate cancer, namely relative 8q gain, ERG overexpression, and loss of PTEN expression, in a series of 136 patients with prostate cancer treated with prostatectomy and with a long follow-up. Fluorescent in situ hybridization was used to detect the relative copy number of 8q and immunohistochemistry was used for quantitative assessment of ERG and PTEN expression. During a median follow-up period of 117.8 months, 66 (49%) patients had disease recurrence. Relative 8q gain, ERG overexpression, and loss of PTEN expression were observed in 18%, 56%, and 33% of the cases, respectively. No association with patient recurrence-free survival was found for relative 8q gain or ERG overexpression on their own, whereas loss of PTEN expression was associated with worse recurrence-free survival (P=.006). Interestingly, in the subgroup of patients with normal PTEN expression, we found that the combined relative 8q gain/ERG overexpression is associated with high risk of recurrence (P=.008), suggesting that alternative mechanisms exist for progression into clinically aggressive disease. Additionally, in intermediate-risk patients with normal PTEN expression in their tumors, the combination of 8q gain/ERG overexpression was associated with a poor recurrence-free survival (P<.001), thus indicating independent prognostic value. This study shows that the combined analysis of 8q, ERG and PTEN contributes to an improved clinical outcome stratification of prostate cancer patients treated with radical prostatectomy.
RESUMEN
BACKGROUND: Pathological evaluations give the best prognostic markers for prostate cancer patients after radical prostatectomy, but the observer variance is substantial. These risk assessments should be supported and supplemented by objective methods for identifying patients at increased risk of recurrence. Markers of epigenetic aberrations have shown promising results in several cancer types and can be assessed by automatic analysis of chromatin organisation in tumour cell nuclei. METHODS: A consecutive series of 317 prostate cancer patients treated with radical prostatectomy at a national hospital between 1987 and 2005 were followed for a median of 10 years (interquartile range, 7-14). On average three tumour block samples from each patient were included to account for tumour heterogeneity. We developed a novel marker, termed Nucleotyping, based on automatic assessment of disordered chromatin organisation, and validated its ability to predict recurrence after radical prostatectomy. RESULTS: Nucleotyping predicted recurrence with a hazard ratio (HR) of 3.3 (95% confidence interval (CI), 2.1-5.1). With adjustment for clinical and pathological characteristics, the HR was 2.5 (95% CI, 1.5-4.1). An updated stratification into three risk groups significantly improved the concordance with patient outcome compared with a state-of-the-art risk-stratification tool (P<0.001). The prognostic impact was most evident for the patients who were high-risk by clinical and pathological characteristics and for patients with Gleason score 7. CONCLUSION: A novel assessment of epigenetic aberrations was capable of improving risk stratification after radical prostatectomy.
Asunto(s)
Adenocarcinoma/ultraestructura , Cromatina/ultraestructura , Recurrencia Local de Neoplasia/epidemiología , Prostatectomía , Neoplasias de la Próstata/ultraestructura , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Anciano , Aneuploidia , Núcleo Celular/ultraestructura , Epigénesis Genética , Estudios de Seguimiento , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Pronóstico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Medición de Riesgo , Índice de Severidad de la Enfermedad , Insuficiencia del TratamientoRESUMEN
Chromosome instability (CIN) is gaining increasing interest as a central process in cancer. CIN, either past or present, is indicated whenever tumour cells harbour an abnormal quantity of DNA, termed 'aneuploidy'. At present, the most widely used approach to detecting aneuploidy is DNA cytometry - a well-known research assay that involves staining of DNA in the nuclei of cells from a tissue sample, followed by analysis using quantitative flow cytometry or microscopic imaging. Aneuploidy in cancer tissue has been implicated as a predictor of a poor prognosis. In this Review, we have explored this hypothesis by surveying the current landscape of peer-reviewed research in which DNA cytometry has been applied in studies with disease-appropriate clinical follow up. This area of research is broad, however, and we restricted our survey to results published since 2000 relating to seven common epithelial cancers (those of the breast; endometrium, ovary, and uterine cervix; oesophagus; colon and rectum; lung; prostate; and bladder). We placed particular emphasis on results from multivariate analyses to pinpoint situations in which the prognostic value of aneuploidy as a biomarker is strong compared with that of existing indicators, such as clinical stage, histological grade, and specific molecular markers. We summarize the implications of our findings for the prognostic use of ploidy analysis in the clinic and for the theoretical understanding of the role of CIN in carcinogenesis.
Asunto(s)
Aneuploidia , Inestabilidad Cromosómica , ADN de Neoplasias/genética , Neoplasias/genética , Biomarcadores de Tumor/genética , Citometría de Flujo/métodos , Humanos , Neoplasias/diagnóstico , Pronóstico , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
In patients with serous adenocarcinoma (SAC) of the endometrium, we evaluated the prognostic importance of clinicopathological parameters, DNA ploidy, and immunoexpression of p53, estrogen receptor (ER), progesterone receptor (PR), and Ki-67. In a series of 73 stage I and II SAC, DNA ploidy analysis was performed on hysterectomy specimens using DNA image cytometry. Immunohistochemical analysis of p53, ER, PR, and Ki-67 expression was additionally performed. In the review of the histological slides by three gynecologic pathologists, the presence of a serous component was not agreed upon in 17 (23 %) cases. The remaining 56 cases, consisting of pure SAC or SAC mixed with endometrioid adenocarcinoma, were further analyzed. Tumor recurrence was observed in 14 patients, and 28 patients died during the follow-up period. Patients with diploid (n = 19), aneuploid (n = 29), and tetraploid (n = 8) tumor had 5-year recurrence rates of 10, 38, and 53 %, respectively (p = 0.09). A DNA ploidy parameter, 5c exceeding rate, was found to be a prognostic marker for recurrence (p = 0.03), progression-free survival (p < 0.01), and overall survival (p = 0.02). Immunoexpression of p53, ER, PR, and Ki-67 did not have prognostic value, and the same was true for FIGO stage, lymphovascular invasion, the extent of myometrial invasion, and lymphadenectomy. The histological diagnosis of SAC may be difficult in some cases. Established clinicopathological parameters do not seem to be strong prognosticators in stage I and II disease. A DNA ploidy parameter, 5c exceeding rate, may be a prognostic marker in this patient group and should be further validated in larger series.