The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis

The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis.BackgroundDuring glomerulogenesis, visceral glomerular epithelial cells (VECs) exit the cell cycle and become terminally differentiated and quiescent. In contrast to other resident glomerular cells, VECs undergo little if any proliferation in response to injury. However, the mechanisms for this remain unclear. Cell proliferation is controlled by cell-cycle regulatory proteins where the cyclin-dependent kinase inhibitor p21Cip1,WAF1 (p21) inhibits cell proliferation and is required for differentiation of many nonrenal cell types.MethodsTo test the hypothesis that p21 is required to maintain a differentiated and quiescent VEC phenotype, experimental glomerulonephritis was induced in p21 knockout (-/-) and p21 wild-type (+/+) mice with antiglomerular antibody. DNA synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC proliferation (multilayers of cells in Bowman's space), matrix accumulation (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point). VECs were identified by location, morphology, ezrin staining, and electron microscopy. VEC differentiation was measured by staining for Wilms’ tumor-1 gene.ResultsKidneys from unmanipulated p21-/- mice were histologically normal and did not have increased DNA synthesis, suggesting that p21 was not required for the induction of VEC terminal differentiation. Proliferating cell nuclear antigen and bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21-/- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice). At each time point, VEC proliferation was also increased in nephritic p21-/- mice (P < 0.0001 vs. p21+/+ mice). VEC re-entry into the cell cycle was associated with the loss of Wilms’ tumor-1 gene staining. Nephritic p21-/- mice had increased extracellular matrix protein accumulation and apoptosis and decreased renal function (serum urea nitrogen) compared with p21+/+ mice (P < 0.001).ConclusionThese results show that the cyclin kinase inhibitor p21 is not required by VECs to attain a terminally differentiated VEC phenotype. However, the loss of p21, in disease states, is associated with VEC re-entry into the cell cycle and the development of a dedifferentiated proliferative phenotype

Cáncer de próstata localizado de alto riesgo tratado mediante prostatectomía radical. Pronóstico y estudio de variables influyentes

Fundamento. Estudiar la supervivencia libre de progresión bioquímica (SLPB) que ha obtenido un grupo de pacientes de alto riesgo de acuerdo con la clasificación de D’Amico mediante prostatectomía radical. Identificar las variables clínico-patológicas influyentes en la supervivencia libre de progresión bioquímica y diseñar con ellas, si es posible, un modelo pronóstico. Material y métodos. Se estudian 232 pacientes, de una serie de 1.054, diagnosticados de cáncer de próstata clínicamente localizado y calificados de alto riesgo en la clasificación de D’Amico (PSA >20 ng/ml ó Gleason 8-10 ó T3) tratados mediante prostatectomía radical. Se estudia la SLPB y se analizan las variables clínico-patológicas recogidas (PSA, Gleason de la biopsia y de la pieza, estadio clínico y patológico, afectación unilateral o bilateral, márgenes de la pieza de prostatectomía, expresión de Ki-67) para identificar si influyen en la SLPB. Se ha utilizado para el estudio estadístico: tablas de contingencia y para el análisis de la supervivencia: Kaplan-Meyer, Log-rank y modelos de Cox. Resultados. Estudio descriptivo: PSA: 23,3 ng/ml (mediana); cGleason 2-6: 33%; 7: 13%; 8-10: 54%; T2: 58%; Afectación bilateral en la biopsia diagnóstica: 59%; RNM T2: 60%; RNM T3: 40%. pGleason 2-6: 24%; 7: 28%; 8-10: 48%; pT2: 43%; pT3a: 30%; pT3b: 27%; Margen afectado: 51%; N1:13%. Supervivencia libre de progresión: con una media y mediana de seguimiento de 64 meses; el 53% evidencia progresión bioquímica. La mediana hasta progresión: 42 meses. La supervivencia libre de progresión a 5 y 10 años es 43±3% y 26±7%. El estudio multivariado (modelos de Cox) evidencia que las variables influyentes de forma independiente en la SLPB son la afectación de márgenes (HR: 3,5; 95% IC.1,9-6,7; p<0001); y Ki67 >10% (HR: 2,3; 95% IC: 1,2-4,3; P: 0,009). Grupos de riesgo: utilizando las dos variables influyentes y utilizando modelos de Cox se diseñan tres grupos de riesgo como mejor modelo: Grupo 1 (0 variables presentes); Grupo 2 (1 variable); Grupo 3 (2 variables). La supervivencia libre de progresión es de 69±8%; 27±6% y 18±11% a los 5 años. Las diferencias son significativas entre los tres grupos. Conclusión. El grupo de alto riesgo de la clasificación de D’Amico es heterogéneo en relación con la progresión bioquímica y puede ser desglosado en tres grupos de riesgo utilizando las dos variables de influencia independiente (márgenes afectados y porcentaje de Ki67)

A Proinflammatory Cytokine Inhibits P53 Tumor Suppressor Activity

p53 has a key role in the negative regulation of cell proliferation, in the maintenance of genomic stability, and in the suppression of transformation and tumorigenesis. To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosis. In both screens, we isolated cDNAs encoding macrophage migration inhibitory factor (MIF), a cytokine that was shown previously to exert both local and systemic proinflammatory activities. Treatment with MIF overcame p53 activity in three different biological assays, and suppressed its activity as a transcriptional activator. The observation that a proinflammatory cytokine, MIF, is capable of functionally inactivating a tumor suppressor, p53, may provide a link between inflammation and tumorigenesis

Fourth-Line Therapy in Metastatic Renal Cell Carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC)

Background: Fourth-line therapy (4LT) in the treatment of metastatic renal cell carcinoma (mRCC) varies significantly due to the lack of data and recommendations to guide treatment decisions. Objective: To evaluate the use and efficacy of 4LT in mRCC patients. Methods: The International mRCC Database Consortium (IMDC) dataset was used to identify patients with mRCC treated with 4LT. This is a multicenter, retrospective cohort study. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier curves. Patients were evaluated for overall response. The six prognostic variables included in the IMDC prognostic model were used to stratify patients into favorable-, intermediate- and poor-risk groups. Exploratory analyses were performed examining the elderly (>70 years old) and non-clear cell RCC subgroups. Proportional hazards regression modelling was performed adjusting these covariates by IMDC criteria measured at initiation of 4th line therapy. Results: 7498 patients were treated with first line targeted therapy and out of these 594 (7.9%) received 4LT. Everolimus was the most frequently used 4LT (16.8%). Sorafenib, axitinib, pazopanib, sunitinib and clinical trial drugs were also used in >10% of patients. The OS of patients on any 4LT was 12.8 months, with a PFS of 4.4 months. The overall response rate (ORR) was 13.7%. Favorable-risk patients using IMDC criteria (5%) displayed an OS of 23.1 months, intermediate-risk patients (66%) had an OS of 13.8 months and poor-risk patients (29%) had an OS of 7.8 (p 70 years and non-clear cell histology did not impact OS. Our study is limited by its retrospective design. Conclusions: 4LT use appears to have activity in mRCC patients. The IMDC continues to be of prognostic value in the fourth-line setting for OS. This study helps to set a benchmark for response rate and survival for which clinical trials can plan sample size calculations and aim to improve upon

Perspectives in immunotherapy: meeting report from the Immunotherapy Bridge (29-30 November, 2017, Naples, Italy)

Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these different immunotherapeutic options in various combinations with one another and with other treatment modalities is an area of particular promise. The third Immunotherapy Bridge meeting (29-30 November, 2017, Naples, Italy) focused on recent advances in immunotherapy across various cancer types and is summarised in this report

Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer

Among more than 200 -mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, has emerged as a key regulator of gene-environment interaction.

Cáncer de próstata localizado de alto riesgo tratado mediante prostatectomía radical. Pronóstico y estudio de variables influyentes

Fundamento. Estudiar la supervivencia libre de progresión bioquímica (SLPB) que ha obtenido un grupo de pacientes de alto riesgo de acuerdo con la clasificación de D’Amico mediante prostatectomía radical. Identificar las variables clínico-patológicas influyentes en la supervivencia libre de progresión bioquímica y diseñar con ellas, si es posible, un modelo pronóstico. Material y métodos. Se estudian 232 pacientes, de una serie de 1.054, diagnosticados de cáncer de próstata clínicamente localizado y calificados de alto riesgo en la clasificación de D’Amico (PSA >20 ng/ml ó Gleason 8-10 ó T3) tratados mediante prostatectomía radical. Se estudia la SLPB y se analizan las variables clínico-patológicas recogidas (PSA, Gleason de la biopsia y de la pieza, estadio clínico y patológico, afectación unilateral o bilateral, márgenes de la pieza de prostatectomía, expresión de Ki-67) para identificar si influyen en la SLPB. Se ha utilizado para el estudio estadístico: tablas de contingencia y para el análisis de la supervivencia: Kaplan-Meyer, Log-rank y modelos de Cox. Resultados. Estudio descriptivo: PSA: 23,3 ng/ml (mediana); cGleason 2-6: 33%; 7: 13%; 8-10: 54%; T2: 58%; Afectación bilateral en la biopsia diagnóstica: 59%; RNM T2: 60%; RNM T3: 40%. pGleason 2-6: 24%; 7: 28%; 8-10: 48%; pT2: 43%; pT3a: 30%; pT3b: 27%; Margen afectado: 51%; N1:13%. Supervivencia libre de progresión: con una media y mediana de seguimiento de 64 meses; el 53% evidencia progresión bioquímica. La mediana hasta progresión: 42 meses. La supervivencia libre de progresión a 5 y 10 años es 43±3% y 26±7%. El estudio multivariado (modelos de Cox) evidencia que las variables influyentes de forma independiente en la SLPB son la afectación de márgenes (HR: 3,5; 95% IC.1,9-6,7; p<0001); y Ki67 >10% (HR: 2,3; 95% IC: 1,2-4,3; P: 0,009). Grupos de riesgo: utilizando las dos variables influyentes y utilizando modelos de Cox se diseñan tres grupos de riesgo como mejor modelo: Grupo 1 (0 variables presentes); Grupo 2 (1 variable); Grupo 3 (2 variables). La supervivencia libre de progresión es de 69±8%; 27±6% y 18±11% a los 5 años. Las diferencias son significativas entre los tres grupos. Conclusión. El grupo de alto riesgo de la clasificación de D’Amico es heterogéneo en relación con la progresión bioquímica y puede ser desglosado en tres grupos de riesgo utilizando las dos variables de influencia independiente (márgenes afectados y porcentaje de Ki67)

Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights.

CONTEXT: Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years. OBJECTIVE: To review and summarise the recent preclinical and clinical literature in hereditary renal cancer. EVIDENCE ACQUISITION: A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management. EVIDENCE SYNTHESIS: Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy. CONCLUSIONS: There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection. PATIENT SUMMARY: This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes