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Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced RCC was investigated to identify putative actionable variants and signatures. In this prospective multicenter study (NCT01855477), whole-genome sequencing (WGS) data of locally advanced and metastatic tissue biopsies and matched whole-blood samples were collected from 91 patients with histopathologically confirmed RCC. WGS data were analyzed for small somatic variants, copy-number alterations and structural variants. For a subgroup of patients, RNA sequencing (RNA-Seq) data could be analyzed. RNA-Seq data were clustered on immunogenic and angiogenic gene expression patterns according to a previously developed angio-immunogenic gene signature. In all patients with papillary and clear cell RCC, putative actionable drug targets were detected by WGS, of which 94% were on-label available. RNA-Seq data of clear cell and papillary RCC were clustered using a previously developed angio-immunogenic gene signature. Analyses of driver mutations and RNA-Seq data revealed clear differences among different RCC subtypes, showing the added value of WGS and RNA-Seq over clinicopathological data. By improving both histological subtyping and the selection of treatment according to actionable targets and immune signatures, WGS and RNA-Seq may improve therapeutic decision making for most patients with advanced RCC, including patients with non-clear cell RCC for whom no standard treatment is available to data. Prospective clinical trials are needed to evaluate the impact of genomic and transcriptomic diagnostics on survival outcome for advanced RCC patients.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Transcriptoma , Estudios Prospectivos , GenómicaRESUMEN
BACKGROUND: Patients with locally advanced irresectable or clinically node positive urothelial cancer (UC) have a poor outcome. Currently, these patients can only be cured by receiving induction chemotherapy and, if an adequate radiological response is obtained, radical surgical resection. Long-term survival, however, strongly depends on the absence of residual tumor in the surgical resection specimen, i.e. a pathological complete response (pCR). The reported pCR rate following induction chemotherapy in locally advanced or clinically node-positive UC is 15%. The 5-year overall survival rate for patients achieving a pCR is 70-80% versus 20% for patients who have residual disease or nodal metastases. This clearly demonstrates the unmet need to improve clinical outcome of these patients. Recently, the JAVELIN Bladder 100 study demonstrated an overall survival benefit of sequential chemo-immunotherapy in patients with metastatic UC. The CHASIT study aims to translate these findings to the induction setting by assessing the efficacy and safety of sequential chemo-immunotherapy in patients with locally advanced or clinically node-positive UC. In addition, patient biomaterials are collected to investigate biological mechanisms of response and resistance to chemo-immunotherapy. METHODS: This multicenter, prospective phase II clinical trial includes patients with stage cT4NxM0 or cTxN1-N3M0 UC of the bladder, upper urinary tract or urethra. Patients who do not experience disease progression after 3 or 4 cycles of platinum-based chemotherapy are eligible for inclusion. Included patients receive 3 cycles of anti-PD-1 immunotherapy with avelumab followed by radical surgery. Primary endpoint is the pCR rate. It is hypothesized that sequential chemo-immunotherapy results in a pCR rate of ≥ 30%. To obtain a power of 80%, 64 patients are screened and 58 patients are included in the efficacy analysis. Secondary endpoints are toxicity, postoperative surgical complications, progression-free, cancer-specific and overall survival at 24 months. DISCUSSION: This is the first study to assess the potential benefit of sequential chemo-immunotherapy in patients with locally advanced or node positive UC. If the primary endpoint of the CHASIT study is met, i.e. a pCR rate of ≥ 30%, a randomized controlled trial is foreseen to compare this new treatment regimen to standard care. TRIAL REGISTRATION: NCT05600127 at Clinicaltrials gov, registered on 31/10/2022.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Inmunoterapia , Quimioterapia de Inducción , Neoplasia Residual , Complicaciones Posoperatorias , Estudios Prospectivos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping morphological features and an ETV6-NTRK3 fusion, suggesting a close relationship. An activating alteration of EGFR, based on an EGFR kinase domain duplication (KDD), occurs in a subset of CMNs lacking an NTRK3 rearrangement, especially in the classic and mixed type. So far no EGFR-KDDs have been detected in IFS. We describe four pediatric tumors at the extremities (leg, n = 2; foot and arm n = 1) with histological features of IFS/CMN. Two cases showed classic IFS morphology while two were similar to classic/mixed type CMN. In all cases, an EGFR-KDD was identified without detection of a fusion gene. There were no abnormalities of the kidneys in any of the patients. This is the first description of IFS with an EGFR-KDD as driver mutation, supporting that IFS and CMN are similar lesions with the same morphological and genetic spectrum. Pathologists should be aware of the more fibrous variant of IFS, similar to classic/mixed type CMN. Molecular analyses are crucial to treat these lesions adequately, especially with regard to the administration of tyrosine kinase inhibitors.
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Fibrosarcoma , Neoplasias Renales , Nefroma Mesoblástico , Niño , Receptores ErbB/genética , Fibrosarcoma/genética , Fibrosarcoma/patología , Humanos , Lactante , Neoplasias Renales/genética , Neoplasias Renales/patología , Nefroma Mesoblástico/congénito , Nefroma Mesoblástico/diagnóstico , Nefroma Mesoblástico/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genéticaRESUMEN
BACKGROUND: The recommended treatment for patients with non-metastatic muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Following NAC, 20-40% of patients experience a complete pathological response (pCR) in the RC specimen and these patients have excellent long-term overall survival. Subject to debate is, however, whether patients with a pCR to NAC benefit from RC, which is a major surgical procedure with substantial morbidity, and if these patients might be candidates for close surveillance instead. However, currently it is not possible to accurately identify patients with a pCR to NAC in whom RC might be withheld. The objective of this study is to assess whether pathological response in the RC specimen after NAC can be predicted based on clinical, radiological, and histological variables and on a wide set of molecular biomarkers assessed in tissue, blood and urine. METHODS: This is a multicentre, prospective cohort study, including patients with cT2a-T4a N0-N1 M0 urothelial cell MIBC who are scheduled to undergo cisplatin-based NAC followed by RC. Prior to start of therapy, a 2-Deoxy-2-[18F] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is performed. Response to NAC is evaluated by CT-scan. Blood and urine, including cytology, are prospectively collected for biomarker analyses before and after NAC. Immediately before RC, participants undergo cystoscopy with bimanual examination and a re-staging transurethral resection (TUR) of all visible cancerous lesions or with biopsies from scar tissue. Subsequently, RC is performed in all patients. Tissue from the diagnostic TUR, the re-staging TUR, and the RC specimen is examined for the presence of urothelial cancer carcinoma and DNA and RNA is isolated for molecular analysis. The primary endpoint is the pathological stage (ypTN) in the RC and ePLND specimen and its association with clinical response. DISCUSSION: If the PRE-PREVENCYS trial shows that the absence of residual disease after NAC in patients with MIBC is accurately predicted, a randomized controlled trial is scheduled comparing the overall survival of NAC plus RC versus NAC followed by close surveillance for patients with a clinically complete response (PREVENCYS trial). TRIAL REGISTRATION: Netherlands Trial Register: NL8678; Registered 20 May 2020 https://www.trialregister.nl/trial/8678.
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Cistectomía , Terapia Neoadyuvante/métodos , Tratamientos Conservadores del Órgano , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugía , Algoritmos , Carcinoma de Células Transicionales/diagnóstico por imagen , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/cirugía , Quimioterapia Adyuvante/métodos , Cisplatino/administración & dosificación , Terapia Combinada , Fluorodesoxiglucosa F18 , Humanos , Invasividad Neoplásica , Neoplasia Residual , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Radiofármacos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Grading prostate biopsies has an important role in determining treatment strategy. Histopathological evaluations suffer from interobserver variability and therefore biopsies may be re-evaluated. OBJECTIVE: To provide insight into the extent of, characteristics associated with and clinical implications of prostate biopsy re-evaluations in daily clinical practice. METHODS: Patients diagnosed with prostate cancer (PCa) by biopsy between October 2015 and April 2016 identified through the Netherlands Cancer Registry were included. The proportion of re-evaluations was assessed and characteristics were compared between patients with and without biopsy re-evaluation. Interobserver concordance of ISUP grade and EAU prognostic risk classification was determined by calculating Cohen's kappa. RESULTS: Biopsy re-evaluation was performed in 172 (3.3%) of 5214 patients. Primary reason for re-evaluation in patients treated with curative intent was referral to another hospital. Most referred patients treated with curative intent (n = 1856) had no re-evaluation (93.0%, n = 1727). Patients with biopsy re-evaluation were younger and underwent more often prostatectomy compared to patients without re-evaluation. The disagreement rate for ISUP grade was 26.1% and interobserver concordance was substantial (κ-weighted = 0.74). Re-evaluation resulted in 21.1% (n = 14) of patients with localised PCa in a different prognostic risk group. More tumours were downgraded (57.1%) than upgraded (42.9%). Interobserver concordance was very good (κ weighted = 0.85). CONCLUSION: Pathology review of prostate biopsies is infrequently requested by clinicians in the Netherlands but in a non-negligible minority of patients with localised PCa the pathology review led to a change in prognostic risk group which might impact their treatment.
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Neoplasias de la Próstata/patología , Anciano , Biopsia , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , PronósticoRESUMEN
BACKGROUND: Although urinary adverse events after treatment of prostate cancer (CaP) are common, population-based studies on functional outcomes are scarce. The aim of this study is to evaluate the occurrence of urinary incontinence (UI) and erectile dysfunction (ED) in daily clinical practice using a nationwide Dutch cohort of patients with localized or locally advanced CaP. BASIC PROCEDURES: Patients were invited to complete the EPIC-26 questionnaire before treatment (baseline) and at 12 and 24 months after diagnosis. We calculated the mean EPIC-26 domain scores, stratified by treatment modality (i.e., radical prostatectomy, external radiotherapy, and no active treatment), and the proportions of patients with UI (defined as ≥ 2 pads per day) and ED (defined as erections not firm enough for sexual intercourse). Logistic regression modeling was used to explore the factors related to UI and ED after surgery. MAIN FINDINGS: In total 1,759 patients participated in this study. Patients undergoing radical prostatectomy experienced clinically relevant worsening in the urinary incontinence domain. After excluding patients who reported UI at baseline, 15% of patients with prostatectomy reported UI 24 months after diagnosis. Only comorbidity was associated with UI in surgically treated patients. Regardless of treatment, patients reported a clinically significant reduced sexual functioning over time. Before treatment, 54% of patients reported ED. Among the 46% remaining patients, 87% of patients treated with radical prostatectomy reported ED 24 months after diagnosis, 41% after radiotherapy, and 46% in patients without active treatment. Bilateral nerve-sparing surgery was the only factor associated with ED after 24 months. PRINCIPAL CONCLUSIONS: UI and ED frequently occur in patients with localized and locally advanced CaP, in particular after radical prostatectomy. The higher occurrence rate of UI and ED, compared with clinical trial participants, supports the importance of real-world data, which can be used for local treatment recommendations and patient information, but also to evaluate effects of future initiatives, such as treatment centralization and research aimed at improving functional outcomes.
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Disfunción Eréctil/epidemiología , Complicaciones Posoperatorias/epidemiología , Prostatectomía , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Incontinencia Urinaria/epidemiología , Anciano , Estudios de Cohortes , Humanos , Masculino , Estadificación de Neoplasias , Países Bajos , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Well differentiated liposarcoma (WDLPS) can be difficult to distinguish from lipoma. Currently, this distinction is made by testing for MDM2 amplification, which requires a biopsy. The aim of this study was to develop a noninvasive method to predict MDM2 amplification status using radiomics features derived from MRI. METHODS: Patients with an MDM2-negative lipoma or MDM2-positive WDLPS and a pretreatment T1-weighted MRI scan who were referred to Erasmus MC between 2009 and 2018 were included. When available, other MRI sequences were included in the radiomics analysis. Features describing intensity, shape and texture were extracted from the tumour region. Classification was performed using various machine learning approaches. Evaluation was performed through a 100 times random-split cross-validation. The performance of the models was compared with the performance of three expert radiologists. RESULTS: The data set included 116 tumours (58 patients with lipoma, 58 with WDLPS) and originated from 41 different MRI scanners, resulting in wide heterogeneity in imaging hardware and acquisition protocols. The radiomics model based on T1 imaging features alone resulted in a mean area under the curve (AUC) of 0·83, sensitivity of 0·68 and specificity of 0·84. Adding the T2-weighted imaging features in an explorative analysis improved the model to a mean AUC of 0·89, sensitivity of 0·74 and specificity of 0·88. The three radiologists scored an AUC of 0·74 and 0·72 and 0·61 respectively; a sensitivity of 0·74, 0·91 and 0·64; and a specificity of 0·55, 0·36 and 0·59. CONCLUSION: Radiomics is a promising, non-invasive method for differentiating between WDLPS and lipoma, outperforming the scores of the radiologists. Further optimization and validation is needed before introduction into clinical practice.
ANTECEDENTES: Es difícil distinguir los liposarcomas bien diferenciados (well-differentiated liposarcomas, WDLPS) de los lipomas. En la actualidad, esta distinción se realiza mediante la prueba de amplificación del gen MDM2 por biopsia. El objetivo de este estudio fue predecir de forma no invasiva el estado de amplificación del gen MDM2 para diferenciar los lipomas de los WDLPS utilizando características radiómicas a partir de la resonancia magnética. MÉTODOS: Se incluyeron los pacientes remitidos al instituto Erasmus MC entre 2009-2018 por un lipoma MDM2 negativo o WDLPS MDM2 positivo y las resonancias magnéticas potenciadas en T1 correspondientes antes del tratamiento. Cuando estaban disponibles, se incluyeron otras secuencias de MRI en el análisis radiómico. Se describieron la intensidad, forma y textura de la región tumoral. Para la clasificación se utilizaron varios modelos de aprendizaje automático (machine learning). La evaluación se realizó mediante una validación cruzada aleatoria 100x. Se comparó el rendimiento de los modelos con la clasificación realizada por tres radiólogos expertos. RESULTADOS: Se incluyeron 116 pacientes (58 lipomas, 58 WDLPS) y 41 aparatos de MRI, con una gran heterogeneidad en las técnicas y protocolos para la adquisición de imágenes. El modelo radiómico basado únicamente en las características de las imagen en T1 dio como resultado una AUC media de 0,83, con una sensibilidad de 0,68 y una especificidad de 0,84. Un análisis adicional incorporando las imágenes ponderadas en T2 mejoró el modelo con una AUC media de 0,89, una sensibilidad de 0,74 y una especificidad de 0,88. Los tres radiólogos obtuvieron una AUC de 0,74/0,72/0,61, una sensibilidad de 0,74/0,91/0,64 y una especificidad de 0,55/0,36/0,59, respectivamente. CONCLUSIÓN: La radiómica es un método prometedor y no invasivo para diferenciar entre WDLPS y lipomas, superando la valoración de los radiólogos. Sin embargo, se necesita la optimización y validación de esta técnica antes de su introducción en la práctica clínica diaria.
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Lipoma/diagnóstico por imagen , Liposarcoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The microRNA-371a-3p (miR-371a-3p) has been reported to be an informative liquid biopsy (serum and plasma) molecular biomarker for both diagnosis and follow-up of patients with a malignant (testicular) germ cell tumor ((T)GCT). It is expressed in all histological cancer elements, with the exception of mature teratoma. However, normal testis, semen, and serum of males with a disrupted testicular integrity without a TGCT may contain miR-371a-3p levels above threshold, of which the cellular origin is unknown. OBJECTIVES: Therefore, a series of relevant tissues (frozen and formalin-fixed paraffin-embedded (FFPE), when available) from the complete male urogenital tract (i.e., kidney to urethra and testis to urethra) and semen was investigated for miR-371a-3p levels using targeted quantitative RT-PCR (qRT-PCR). MATERIALS AND METHODS: In total, semen of males with normospermia (n = 11) and oligospermia (n = 3) was investigated, as well as 88 samples derived from 32 different patients. The samples represented one set of tissues related to the entire male urogenital tract (11 anatomical locations), three sets for 10 locations, and four sets for six locations. RESULTS: All testis parenchyma (n = 17) cases showed low miR-371a-3p levels. Eight out of 14 (57%) semen samples showed detectable miR-371a-3p levels, irrespective of the amount of motile spermatozoa, but related to sperm concentration and matched Johnsen score (Spearman's rho correlation coefficient 0.849 and 0.871, p = 0.000, respectively). In all other tissues investigated, miR-371a-3p could not be detected. DISCUSSION: This study demonstrates that the miR-371a-3p in healthy adult males is solely derived from the germ cell compartment. CONCLUSIONS: The observation is important in the context of applying miR-371a-3p as molecular liquid biopsy biomarker for diagnosis and follow-up of patients with malignant (T)GCT. Moreover, miR-371a-3p might be an informative seminal biomarker for testicular germ cell composition.
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Genitales Masculinos/metabolismo , MicroARNs/metabolismo , Semen/metabolismo , Sistema Urinario/metabolismo , Humanos , Masculino , Oligospermia/metabolismo , Valores de ReferenciaRESUMEN
BACKGROUND: Liposarcomas can be divided into four subtypes and are most frequently located in the extremities. There are currently no studies comparing the clinical outcomes, such as local recurrence and distant metastasis, between the distinct subtypes of primary LPS of the extremity specifically. METHODS: Retrospective databases of two expertise centres (Rotterdam-R, Warsaw-W) of patients with liposarcoma located in the extremities from 1985 to 2015 were used to analyse 5-year local recurrence-free survival (5y-LRFS), 5-year distant metastasis-free survival (5y-DMFS) and 5-year overall survival (5y-OS). RESULTS: We identified 456 patients: 192 well-differentiated liposarcomas (WDLPS), 172 myxoid liposarcomas (MLPS), 54 pleomorphic liposarcomas (PLPS), 23 dedifferentiated liposarcomas (DDLPS) and 15 other subtypes. The frequency of (neo)adjuvant radiotherapy (R: 34.5% vs. W: 78.4%) and R0-resections (R: 41.0% vs. W: 84.1%) differed between the datasets. Local recurrences (LR) were observed most frequently in DDLPS (5y-LRFS 62.4%), followed by PLPS (71.4%), WDLPS (77.0%) and MLPS (84.5%, p = 0.054). Distant metastases (DM) were most commonly observed in PLPS (5y-DMFS 46.9%), followed by MLPS (74.0%), DDLPS (86.3%) and WDLPS (97.3%). 5y-OS was poorest in patients with PLPS (47.6%) and DDLPS (54.4%), followed by MLPS (79.7%) and WDLPS (92.4%, p < 0.001). Male gender significantly increased the risk of LR and DM. The subtypes MLPS and PLPS were significant prognostic factors for DM and OS. Additionally, DDLPS and age had significant impact on OS. CONCLUSION: In the largest cohort of extremity LPS patients reported to date, LPS subtypes show distinct patterns of LR, DM and OS, stressing that 'extremity LPS' is not a single entity.
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Extremidades , Liposarcoma/mortalidad , Estadificación de Neoplasias , Adulto , Anciano , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Liposarcoma/diagnóstico , Liposarcoma/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Países Bajos/epidemiología , Polonia/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de TiempoRESUMEN
CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.
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Neoplasias Óseas/secundario , Proteínas Ligadas a GPI/metabolismo , Proteínas de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/patología , Animales , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Chaperón BiP del Retículo Endoplásmico , Proteínas Ligadas a GPI/genética , Técnicas de Silenciamiento del Gen , Proteínas de Choque Térmico/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Neoplasias de la Próstata/genéticaRESUMEN
BACKGROUND: To assess the clinical value of peritoneal washing cytology (PWC) in women with BRCA1 or BRCA2 mutations and women from a family with hereditary breast and/or ovarian cancer (HBOC) undergoing risk-reducing salpingo-oophorectomy (RRSO) in detecting primary peritoneal cancer (PPC) or occult ovarian/fallopian tube cancer. METHODS: A retrospective study of patients with known BRCA1 or BRCA2 mutation or HBOC who underwent RRSO at the Erasmus Medical Centre, Rotterdam, The Netherlands between January 2000-2014. Patients with an elevated risk of malignancy prior to the procedure were excluded from primary analysis (elevated CA-125, an ovarian mass, abdominal pain or another gynecological malignancy). A review of the literature was conducted. RESULTS: Of the 471 patients who underwent RRSO, a total of 267 cytology samples were available for analysis. Four samples showed malignant cells, all four patients were diagnosed with ovarian and/or fallopian tube cancer at histologic examination. A fifth patient, of whom no cytology sample was obtained during RRSO, developed primary peritoneal cancer 80 months post RRSO. CONCLUSIONS: This study failed to show that cytology is of value during RRSO in detecting primary peritoneal cancer, however 36% of patients with concomitant ovarian or fallopian tube cancer had positive cytology. Therefore, the routine sampling of peritoneal washings during RRSO is not found to be useful to detect subsequent PPC.
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Citodiagnóstico/métodos , Neoplasias de las Trompas Uterinas/genética , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de las Trompas Uterinas/patología , Neoplasias de las Trompas Uterinas/cirugía , Femenino , Humanos , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Ovariectomía , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/cirugía , Peritoneo/patología , Valor Predictivo de las Pruebas , Medición de Riesgo , SalpingectomíaRESUMEN
BACKGROUND: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. METHODS: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold>3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. RESULTS: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). CONCLUSIONS: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/cirugía , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Análisis de Secuencia de ARNRESUMEN
Objective. We evaluated histological outcome of intraoperative biopsies at laparoscopic renal mass cryoablation (LCA), prevalence of peritumoral fat tissue invasion, and risk of tract seeding. Methods. Patients were biopsied 3-5 times (16-gauge). Histology was analyzed by general pathologists and reviewed. Peritumoral fat was histologically examined. The trocar used for biopsy-guidance was examined by cytology. Records were studied for reporting tract metastasis. Results. 77 biopsied renal masses with mean ± SD diameter 30 ± 7.4 mm were histologically classified by primary and review pathology revealing 64 and 62 malignancies, 13 and 15 benign lesions, respectively. In 30/34, the fat covered a carcinoma but revealed no malignancy. Cytology showed no malignant cells but was inconclusive in 1 case. No tract metastasis occurred. Conclusions. The use of an intraoperative biopsy protocol provides histological diagnosis of all renal masses. No existence of peritumoral fat tissue invasion or tract seeding was found.
RESUMEN
Prostate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in Western countries. Current clinical and pathological methods are limited in the prediction of postoperative outcome. It is becoming increasingly evident that small non-coding RNA (ncRNA) species are associated with the development and progression of this malignancy. To assess the diversity and abundance of small ncRNAs in PCa, we analyzed the composition of the entire small transcriptome by Illumina/Solexa deep sequencing. We further analyzed the microRNA (miRNA) expression signatures of 102 fresh-frozen patient samples during PCa progression by miRNA microarrays. Both platforms were cross-validated by quantitative reverse transcriptase-PCR. Besides the altered expression of several miRNAs, our deep sequencing analyses revealed strong differential expression of small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs). From microarray analysis, we derived a miRNA diagnostic classifier that accurately distinguishes normal from cancer samples. Furthermore, we were able to construct a PCa prognostic predictor that independently forecasts postoperative outcome. Importantly, the majority of miRNAs included in the predictor also exhibit high sequence counts and concordant differential expression in Illumina PCa samples, supported by quantitative reverse transcriptase-PCR. Our findings provide miRNA expression signatures that may serve as an accurate tool for the diagnosis and prognosis of PCa.
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Biomarcadores de Tumor/metabolismo , MicroARNs/metabolismo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Expresión Génica , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , MicroARNs/genética , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Cultivo Primario de Células , Pronóstico , Próstata/metabolismo , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Curva ROC , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: OCT3/4 (POU5F1) is an established diagnostic immunohistochemical marker for specific histological variants of human malignant germ cell tumours (GCTs), including the seminomatous types and the stem cell component of non-seminomas, known as embryonal carcinoma. OCT3/4 is crucial for the regulation of pluripotency and the self-renewal of normal embryonic stem- and germ cells. Detection of expression of this transcription factor is complicated by the existence of multiple pseudogenes and isoforms. Various claims have been made about OCT3/4 expression in non-GCTs, possibly related to using nonspecific detection methods. False-positive findings undermine the applicability of OCT3/4 as a specific diagnostic tool in a clinical setting. In addition, false-positive findings could result in misinterpretation of pluripotency regulation in solid somatic cancers and their stem cells. Of the three identified isoforms--OCT4A, OCT4B and OCT4B1--only OCT4A proved to regulate pluripotency. Up until now, no convincing nuclear OCT4A protein expression has been shown in somatic cancers or tissues. METHODS: This study investigates expression of the various OCT3/4 isoforms in GCTs (both differentiated and undifferentiated) and somatic (non-germ cell) cancers, including representative cell lines and xenografts. RESULTS: Using specific methods, OCT4A and OCT4B1 are shown to be preferentially expressed in undifferentiated GCTs. The OCT4B variant shows no difference in expression between GCTs (either differentiated or undifferentiated) and somatic cancers. In spite of the presence of OCT4A mRNA in somatic cancer-derived cell lines, no OCT3/4 protein is detected. Significant positive correlations between all isoforms of OCT3/4 were identified in both tumours with and without a known stem cell component, possibly indicating synergistic roles of these isoforms. CONCLUSION: This study confirms that OCT4A protein only appears in seminomatous GCTs, embryonal carcinoma and representative cell lines. Furthermore, it emphasises that in order to correctly assess the presence of functional OCT3/4, both isoform specific mRNA and protein detection are required.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Carcinoma Embrionario/metabolismo , Línea Celular Tumoral , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias , Factor 3 de Transcripción de Unión a Octámeros/genética , Isoformas de Proteínas/metabolismo , Seudogenes , ARN Mensajero/metabolismo , Seminoma/metabolismo , Sensibilidad y EspecificidadRESUMEN
This study was performed to characterize coronary plaque types by optical coherence tomography (OCT) and intravascular ultrasound (IVUS) radiofrequency (RF) data analysis, and to investigate the possibility of error reduction by combining these techniques. Intracoronary imaging methods have greatly enhanced the diagnostic capabilities for the detection of high-risk atherosclerotic plaques. IVUS RF data analysis and OCT are two techniques focusing on plaque morphology and composition. Regions of interest were selected and imaged with OCT and IVUS in 50 sections, from 14 human coronary arteries, sectioned post-mortem from 14 hearts of patients dying of non-cardiovascular causes. Plaques were classified based on IVUS RF data analysis (VH-IVUS(TM)), OCT and the combination of those. Histology was the benchmark. Imaging with both modalities and coregistered histology was successful in 36 sections. OCT correctly classified 24; VH-IVUS 25, and VH-IVUS/OCT combined, 27 out of 36 cross-sections. Systematic misclassifications in OCT were intimal thickening classified as fibroatheroma in 8 cross-sections. Misclassifications in VH-IVUS were mainly fibroatheroma as intimal thickening in 5 cross-sections. Typical image artifacts were found to affect the interpretation of OCT data, misclassifying intimal thickening as fibroatheroma or thin-cap fibroatheroma. Adding VH-IVUS to OCT reduced the error rate in this study.
Asunto(s)
Enfermedad de la Arteria Coronaria/diagnóstico , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Tomografía de Coherencia Óptica , Ultrasonografía Intervencional , Artefactos , Autopsia , Enfermedad de la Arteria Coronaria/clasificación , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Países Bajos , Valor Predictivo de las Pruebas , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The phosphatidylinositol 3-kinase (PI3K)-AKT pathway is activated in many cancers. Mutational hotspots in AKT1 and in the regulatory and catalytic subunits of PI3K have been detected in multiple tumour types. In AKT1, the E17K substitution leads to a PI3K-independent activation of AKT1. METHODS: A mutational profiling of AKT1 and of the mutational hotspots in PIK3CA and PIK3R1 was carried out in samples from primary and recurrent prostate tumours. RESULTS: We show that, in prostate cancer, AKT1(E17K) had a prevalence of 1.4%. The mutation seemed to be associated with a favourable clinical course but it was not associated with a specific tumour growth pattern. Activating mutations in PIK3CA or PIK3R1 were not found in prostate cancer. CONCLUSION: The E17K substitution in AKT1 is rare in prostate cancer. It seems associated with a favourable clinical outcome but not with a specific histology of the tumour.
Asunto(s)
Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-akt/genética , Anciano , Análisis Mutacional de ADN , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
Ectopic adrenocorticotropin (ACTH) secretion accounts for less than 10% of all causes of endogenous Cushing's syndrome (CS) and is usually associated with neuroendocrine tumors and small cell carcinoma of the lung. We report the case of a 62-year-old man with CS due to ectopic ACTH production by small cell carcinoma of the prostate. He presented with severe hypercortisolism and associated symptoms. Plasma neuron specific enolase (NSE) was grossly elevated. Despite performing a laparoscopic bilateral adrenalectomy, the patient died as a result of sepsis with multi-organ failure. Post-mortem immunohistochemical staining of prostate tumor tissue showed ACTH expression. ACTH staining was also performed in four additional patients with small cell carcinoma of the urinary tract without CS. None of these additional cases showed a positive staining for ACTH. Although a rare cause of ectopic ACTH production, neuroendocrine prostate carcinoma should be considered in male patients with Cushing's syndrome, in particular in those with an occult source of ACTH overproduction.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Síndrome de Cushing/etiología , Síndrome de Cushing/metabolismo , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/metabolismo , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Síndrome de Cushing/patología , Resultado Fatal , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The possibility and possible aetiology of local prostate cancer (PC) recurrence despite undetectable prostate-specific antigen (PSA) levels are highlighted. A case of a local recurrence 8.5 years after radical prostatectomy for Gleason 3+4 PC is presented. It demonstrates that PC can recur, even after a prolonged period of time (8.5 years), despite undetectable levels (i.e. <0.02 ng/ml) of PSA. In conclusion, the decision to omit digital rectal examination from the follow-up regimens of men with undetectable PSA levels could be justified. In such exceptional cases, however, PC recurrence would be either missed or would only be diagnosed after a considerable delay.