RESUMO
Morphological features are critical in evaluation of renal tumors and directing molecular workup. The objective of this study was to review histomorphology of renal tumors with molecular alterations of known subtypes. Renal tumors in The Cancer Genome Atlas were reviewed to identify tumors with defining molecular alterations. Single representative digital slides and pathology reports were reviewed and morphologic features recorded. Sixty tumors were identified with molecular alterations in genes characteristic of defined renal cell carcinoma (RCC) subtypes. Findings included the presence of both low- and high-grade histology in TFE3 rearranged RCCs, TFEB amplified RCCs, succinate dehydrogenase (SDH) mutated RCCs and RCCs with mutations in mismatch repair genes. Three ELOC mutated RCCs were identified, one of which demonstrated infiltrative features. Pseudostratification of nuclei in fumarate hydratase mutated RCCs and nuclear grooves in SDH mutated RCCs were intriguing findings not previously reported. Mucinous features were noted in NF2, KRAS, and SDH mutated and ALK rearranged tumors. Significant morphologic overlap was noted across most categories with limited clues for subclassification. Whereas the number of diagnostic entities for kidney tumors continues to increase, many of these have overlapping features, highlighting the significant role molecular characterization currently plays and will continue to play in the future.
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Proliferação de Células , Senescência Celular , Inibidor de Quinase Dependente de Ciclina p27 , Neoplasia Prostática Intraepitelial , Neoplasias da Próstata , Humanos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Proliferação de Células/efeitos dos fármacos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Senescência Celular/efeitos dos fármacos , Neoplasia Prostática Intraepitelial/patologia , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasia Prostática Intraepitelial/genética , Animais , Progressão da Doença , Camundongos , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular/efeitos dos fármacosRESUMO
Somatic or germline homologous recombination repair (HRR) pathway gene mutations are commonly detected in prostate cancer, especially in advanced disease, and are associated with response to poly (ADP-ribose) polymerase (PARP) inhibitors. In this study, we evaluated whether histological patterns are predictive of HRR pathway gene mutations. The study population comprised 130 patients with advanced prostate carcinoma who underwent comprehensive genomic profiling (CGP) of tumor tissue at a CLIA-certified laboratory. HRR genes in the study included BRCA1, BRCA2, ATM, BARD1, BRIP, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D, EMSY, ATR, CHEK1, and FAM175A. Overall, 38 patients had mutations in BRCA1/2, 36 in other HRR genes, and 56 were negative for HRR mutations. All cases were re-reviewed and quantified by two genitourinary pathologists blinded to mutational status for the following histological patterns of prostate carcinoma: cribriform, ductal, intraductal carcinoma (IDC), small cell carcinoma, signet ring-like pattern, and lobular carcinoma-like pattern. Discordances were resolved by consensus review. Histologic patterns were analyzed for any correlation with mutations in HRR pathway genes (grouped as BRCA1/2 mutated or non-BRCA1/2 mutated) compared to tumors without mutations in HRR genes by Chi-square testing. Patterns with >20 % and >30 % of tumor volume were additionally evaluated for correlation with mutational status. We found no significant association between HRR pathway mutations and cribriform pattern, IDC, ductal carcinoma, small cell carcinoma, signet ring-like pattern, or lobular carcinoma-like patterns. Tumors with >20 % or >30 % histologic patterns by volume also demonstrated no significant association with mutational status. This study suggests that histopathologic examination alone is insufficient to distinguish prostate cancer with germline or somatic mutations in HRR pathway genes, highlighting the continuing importance of ancillary molecular diagnostics in guiding therapy selection for prostate cancer patients who may benefit from PARP inhibitors.
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Neoplasias da Mama , Carcinoma Lobular , Neoplasias da Próstata , Masculino , Humanos , Reparo de DNA por Recombinação , Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação , Neoplasias da Próstata/genéticaRESUMO
Aging markedly increases cancer risk, yet our mechanistic understanding of how aging influences cancer initiation is limited. Here we demonstrate that the loss of ZNRF3, an inhibitor of Wnt signaling that is frequently mutated in adrenocortical carcinoma, leads to the induction of cellular senescence that remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer in old animals. The effects are sexually dimorphic, with males exhibiting earlier senescence activation and a greater innate immune response, driven in part by androgens, resulting in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and increased susceptibility to metastatic cancer. Senescence-recruited myeloid cells become depleted as tumors progress, which is recapitulated in patients in whom a low myeloid signature is associated with worse outcomes. Our study uncovers a role for myeloid cells in restraining adrenal cancer with substantial prognostic value and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Masculino , Animais , Feminino , Carcinoma Adrenocortical/genética , Envelhecimento , Senescência Celular , Transdução de Sinais , Neoplasias do Córtex Suprarrenal/genética , Microambiente TumoralRESUMO
Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).
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Neoplasias da Próstata , RNA Longo não Codificante , Humanos , Masculino , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/genética , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Estudos Retrospectivos , RNA Longo não Codificante/genéticaAssuntos
Neoplasias das Glândulas Suprarrenais , Ganglioneuroma , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Ganglioneuroma/genética , Mutação em Linhagem Germinativa , Humanos , Proteínas de Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genéticaRESUMO
BACKGROUND: Glomerular endotheliosis is the pathognomonic glomerular lesion in pre-eclampsia that has also been described in those taking tyrosine kinase inhibitors for cancer treatment. Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL). We report the first known case of glomerular endotheliosis on kidney biopsy in a patient on ibrutinib monotherapy. CASE PRESENTATION: The patient presented with acute on chronic kidney disease, proteinuria, low C3 and C4 and a high rheumatoid factor titer. A kidney biopsy was performed to confirm a preliminary diagnosis of membranoproliferative glomerulonephritis (MPGN), the most common glomerular disease in patients with CLL. Unexpectedly, the kidney biopsy showed pre-eclampsia-like lesions on light and electron microscopy: occlusion of glomerular peripheral capillary lumens by swollen reactive endothelial cells. Findings of glomerulonephritis were not seen, and there were no specific glomerular immune deposits by immunofluorescence or electron microscopy. CONCLUSIONS: CLL is known to cause glomerular lesions, mainly MPGN. There is increasing evidence that ibrutinib, a major treatment for CLL, can cause kidney disease, but the precise pathology is not characterized. We present a patient with CLL on ibrutinib with signs of glomerular endotheliosis. Based on the absence of CLL-induced kidney pathologies typically seen on the kidney biopsy and the non-selectivity of ibrutinib, we attributed the glomerular endotheliosis to ibrutinib. In pre-eclampsia, increased soluble fms-like tyrosine kinase 1 (sFlt1) levels induce endothelial dysfunction by decreasing vascular endothelial growth factor (VEGF). Ibrutinib has been demonstrated to have non-selective tyrosine kinase inhibition, including inhibition of VEGF receptor (VEGFR) and epidermal growth factor receptor (EGFR). VEGFR and EGFR inhibitors have recently been described in the literature to cause hypertension, proteinuria, and glomerular endotheliosis. Kidney biopsy should be performed in CLL patients on ibrutinib that present with acute kidney injury (AKI) or proteinuria to determine whether the clinical picture is attributable to the disease itself or a complication of the therapy.
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Adenina , Glomerulonefrite Membranoproliferativa , Nefropatias , Leucemia Linfocítica Crônica de Células B , Piperidinas , Adenina/efeitos adversos , Adenina/análogos & derivados , Idoso de 80 Anos ou mais , Células Endoteliais , Receptores ErbB , Glomerulonefrite Membranoproliferativa/induzido quimicamente , Glomerulonefrite Membranoproliferativa/diagnóstico , Humanos , Hipertensão , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/diagnóstico , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Piperidinas/efeitos adversos , Proteinúria/complicações , Fator A de Crescimento do Endotélio Vascular , Receptor 1 de Fatores de Crescimento do Endotélio VascularRESUMO
INTRODUCTION: Genomic and morphologic heterogeneity in clear cell renal cell carcinoma (ccRCC) presents a barrier to prognostication and treatment decisions. Data from pathology are used with clinical markers to predict disease progression after nephrectomy. However, determining the risk of cancer recurrence, and survival with metastatic cancer remains challenging. Recently, analysis of histologic growth patterns (HGP) in ccRCC revealed promising associations with survival outcomes. METHODS: To investigate whether HGPs can be used to predict overall survival (OS) after nephrectomy, we examined 24 HGPs in primary tumors of 147 patients that included 107 patients with metastatic disease. RESULTS: The median number of HGPs per case was 5 and was greater in metastatic and larger tumors. After adjustment for 6 pathologic and demographic variables, HGPs were significantly associated with OS post nephrectomy. Small nests, expansile nests and nests with high nuclear to cytoplasmic ratio were associated with favorable outcomes; while spindled low grade, fused nests/solid sheets, rhabdoid, and sarcomatoid patterns were associated with unfavorable outcomes. A 3-tiered and a 2-tiered risk model were developed based on combinations of HGPs. The models performed equally well as WHO/ISUP nucleolar plus necrosis grade (necrosis grade), and better than WHO/ISUP nucleolar grade alone in predicting OS at the median OS of 6 years. Pairwise correlations between HGPs revealed 2 tumor evolutionary branches that differed in risk of metastatic disease: one with mesenchymal differentiation, and other with epithelial tubulopapillary differentiation. While 44 of 107 (41%) patients with metastatic ccRCC displayed evidence of mesenchymal differentiation, mesenchymal features were only observed in 1 of 40 (3%) patients without evidence of metastatic disease. CONCLUSION: These findings suggest that HGPs may provide a novel path to refine the estimation of OS after nephrectomy and to determine the molecular basis of tumor evolution.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Necrose , Recidiva Local de Neoplasia , Nefrectomia , PrognósticoRESUMO
Radiation therapy (RT) is a cornerstone of treatment in the management of head and neck squamous cell carcinomas (HNSCC), yet treatment failure and disease recurrence are common. The p38/MK2 pathway is activated in response to cellular stressors, including radiation, and promotes tumor inflammation in a variety of cancers. We investigated MK2 pathway activation in HNSCC and the interaction of MK2 and RT in vitro and in vivo. We used a combination of an oropharyngeal SCC tissue microarray, HNSCC cell lines, and patient-derived xenograft (PDX) tumor models to study the effect of RT on MK2 pathway activation and to determine how inhibition of MK2 by pharmacologic (PF-3644022) and genetic (siRNA) methods impacts tumor growth. We show that high phosphorylated MK2 (p-MK2) levels are associated with worsened disease-specific survival in p16-negative HNSCC patients. RT increased p-MK2 in both p16-positive, HPV-positive and p16-negative, HPV-negative HNSCC cell lines. Pharmacologic inhibition or gene silencing of MK2 in vitro abrogated RT-induced increases in p-MK2; inflammatory cytokine expression and expression of the downstream MK2 target, heat shock protein 27 (HSP27); and markers of epithelial-to-mesenchymal transition. Mouse PDX models treated with a combination of RT and MK2 inhibitor experienced decreased tumor growth and increased survival. Our results suggest that MK2 is a potential prognostic biomarker for head and neck cancer and that MK2 pathway activation can mediate radiation resistance in HNSCC.
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Citocinas/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Infecções por Papillomavirus/complicações , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Radioterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/virologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Nus , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Fosforilação , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Recent cancer survival trends among American Indian and Alaska Native (AN) people are not well understood; survival has not been reported among AN people since 2001. METHODS: This study examined cause-specific survival among AN cancer patients for lung, colorectal, female breast, prostate, and kidney cancers. It evaluated whether survival differed between cancers diagnosed in 1992-2002 (the earlier period) and cancers diagnosed in 2003-2013 (the later period) and by the age at diagnosis (<65 vs ≥65 years), stage at diagnosis (local or regional/distant/unknown), and sex. Kaplan-Meier and Cox proportional hazards models were used to estimate univariate and multivariate-adjusted cause-specific survival for each cancer. RESULTS: An improvement was observed in 5-year survival over time from lung cancer (hazard ratio [HR] for the later period vs the earlier period, 0.83; 95% confidence interval [CI], 0.72-0.97), and a marginally nonsignificant improvement was observed for colorectal cancer (HR, 0.81; 95% CI, 0.66-1.01). Site-specific differences in survival were observed by age and stage at diagnosis. CONCLUSIONS: This study presents the first data on cancer survival among AN people in almost 2 decades. During this time, AN people have experienced improvements in survival from lung and colorectal cancers. The reasons for these improvements may include increased access to care (including screening) as well as improvements in treatment. Improving cancer survival should be a priority for reducing the burden of cancer among AN people and eliminating cancer disparities. Cancer 2018;124:2570-7. © 2018 American Cancer Society.
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/estatística & dados numéricos , Causas de Morte/tendências , Efeitos Psicossociais da Doença , Neoplasias/mortalidade , Sistema de Registros/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Alaska/epidemiologia , Detecção Precoce de Câncer/estatística & dados numéricos , Detecção Precoce de Câncer/tendências , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Programas de Rastreamento/estatística & dados numéricos , Programas de Rastreamento/tendências , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/etnologia , Neoplasias/patologia , Modelos de Riscos Proporcionais , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Taxa de Sobrevida/tendênciasRESUMO
PURPOSE: The role of appropriate therapy in breast cancer survival and survival disparities by race/ethnicity has not been fully elucidated. We investigated whether lack of guideline-recommended therapy contributed to survival differences overall and among Hispanics relative to non-Hispanic white (NHW) women in a case-cohort study. METHODS: The study included a 15% random sample of female invasive breast cancer patients diagnosed from 1997 to 2009 in 6 New Mexico counties and all deaths due to breast cancer-related causes. Information was obtained from comprehensive medical chart reviews. National Comprehensive Cancer Network (NCCN®) guideline-recommended treatment was assessed among white women aged < 70 who were free of contraindications for recommended therapy, had stage I-III tumors, and survived ≥ 12 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer death were estimated using Cox proportional hazards models. RESULTS: Included women represented 4635 patients and 449 breast cancer deaths. Women who did not receive radiotherapy (HR 2.3; 95% CI 1.2-4.4) or endocrine therapy (HR 2.0; 95% CI 1.0-4.0) as recommended by guidelines had an increased risk of breast cancer death, relative to those treated appropriately. Receipt of guideline-recommended therapy did not differ between Hispanic and NHW women for chemotherapy (84.2% vs. 81.3%, respectively), radiotherapy (89.2% vs. 91.1%), or endocrine therapy (89.2% vs. 85.8%), thus did not influence Hispanic survival disparities. CONCLUSIONS: Lack of guideline-recommended radiotherapy or endocrine therapy contributed to survival as strongly as other established prognostic indicators. Hispanic survival disparities in this population do not appear to be attributable to treatment differences.
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Neoplasias da Mama/mortalidade , Disparidades em Assistência à Saúde , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Fidelidade a Diretrizes , Hispânico ou Latino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vigilância da População , Guias de Prática Clínica como Assunto , Prognóstico , Programa de SEER , Análise de SobrevidaRESUMO
PURPOSE: While the estrogen receptor (ER) is the single most widely used biomarker to evaluate breast cancer outcomes, aspects of ER marker biology remain poorly understood. We sought to determine whether quantitative measures of ER, such as protein expression and intensity, were associated with survival, or with survival disparities experienced by Hispanic women. METHODS: A case-cohort study included a 15% random sample of invasive breast cancer cases diagnosed from 1997 to 2009 in six New Mexico counties and all deaths due to breast cancer-related causes. Pathology reports and tissue microarrays served as sources of ER information. Analyses were restricted to women with ≥1% ER immunohistochemical staining. Hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer death were estimated using Cox proportional hazards models. RESULTS: Included women represented 4336 ER+ breast cancer cases and 448 deaths. Median follow-up was 93 months. ER percent expression was not associated with breast cancer survival after adjustment for standard prognostic factors (p trend = 0.76). ER intensity remained a strong and independent risk factor for breast cancer survival in multivariate analyses: Women whose tumors expressed ER at intensity = 2 (HR 0.6; 95% CI 0.4-1.0) or 3 (HR 0.5; 95% CI 0.2-0.9) had a reduced risk of breast cancer mortality, compared to ER intensity = 1 (p trend = 0.02). Neither ER protein expression nor intensity influenced Hispanic survival disparities. CONCLUSIONS: Estrogen receptor percent positive staining is not independently related to breast cancer survival after adjustment for other survival-related factors. ER intensity, in contrast, demonstrates promise for prognostic utility.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Prognóstico , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/patologia , Feminino , Hispânico ou Latino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Receptor ErbB-2/genética , Fatores de RiscoAssuntos
Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Vírus Oncogênicos/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/virologia , RNA Longo não Codificante/genética , Animais , Sequência de Bases , Simulação por Computador , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Infecções Tumorais por Vírus/genéticaRESUMO
Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.
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Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.
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Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research.
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BACKGROUND: The advent of PSA testing in the late 1980s substantially increased prostate cancer incidence rates. Concerns about overscreening and overdiagnosis subsequently led professional guidelines (circa 2000 and later) to recommend against routine PSA testing. We evaluated trends in prostate cancer incidence, including late-stage diagnoses, from 1995 through 2012. METHODS: We used joinpoint regression analyses to evaluate all-, localized/regional-, and distant-stage prostate cancer incidence trends based on Surveillance, Epidemiology, and End Results (SEER) data. We stratified analyses by age (50-69, 70+). We reported incidence trends as annual percent change (APC). RESULTS: Overall age-adjusted incidence rates for localized/regional stage prostate cancer have been declining since 2001, sharply from 2010 to 2012 [APC, -13.1; 95% confidence intervals (CI), -23.5 to -1.3]. Distant-stage incidence rates have declined since 1995, with greater declines from 1995 to 1997 (APC, -8.4; 95% CI, -2.3 to -14.1) than from 2003 to 2012 (APC, -1.0; 95% CI, -1.7 to -0.4). Distant-stage incidence rates declined for men ages 70+ from 1995 to 2012, but increased in men ages 50 to 69 years from 2004 to 2012 (APC, 1.7; 95% CI, 0.2 to 3.2). CONCLUSIONS: Guidelines discouraging routine prostate cancer screening were temporally associated with declining localized/regional prostate cancer incidence rates; however, incidence rates of distant-stage disease are now increasing in younger men. IMPACT: This trend may adversely affect prostate cancer mortality rates.
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Neoplasias da Próstata/epidemiologia , Fatores Etários , Idoso , Detecção Precoce de Câncer , História do Século XX , História do Século XXI , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Programa de SEER , Estados UnidosRESUMO
Hyperoxaluria can cause not only nephrolithiasis and nephrocalcinosis, but also renal parenchymal disease histologically characterized by deposition of calcium oxalate crystals throughout the renal parenchyma, profound tubular damage and interstitial inflammation and fibrosis. Hyperoxaluric nephropathy presents clinically as acute or chronic renal failure that may progress to end-stage renal disease (ESRD). This sequence of events, well recognized in the past in primary and enteric hyperoxalurias, has also been documented in a few cases of dietary hyperoxaluria. Estimates of oxalate intake in patients with chronic dietary hyperoxaluria who developed chronic kidney disease or ESRD were comparable to the reported average oxalate content of the diets of certain populations worldwide, thus raising the question whether dietary hyperoxaluria is a primary cause of ESRD in these regions. Studies addressing this question have the potential of improving population health and should be undertaken, alongside ongoing studies which are yielding fresh insights into the mechanisms of intestinal absorption and renal excretion of oxalate, and into the mechanisms of development of oxalate-induced renal parenchymal disease. Novel preventive and therapeutic strategies for treating all types of hyperoxaluria are expected to develop from these studies.
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Amyloidosis derived from leukocyte chemotactic factor 2 (ALECT2) is a recently described disease. Here, we report the characteristics and outcome of 72 patients with renal ALECT2, which included 19 who had another kidney disease on biopsy. Ninety-two percent of patients were Hispanics and over half were elderly. Three had other organ, but not cardiac, amyloidosis involvement. All patients without concurrent disease, except three, presented with chronic renal insufficiency. Proteinuria was variable and absent in a third, whereas nephrotic syndrome and hematuria were rare. After a median follow-up of 26 months, one-third developed end-stage renal disease (ESRD). The median renal survival was 62 months. Independent predictors of renal survival were serum creatinine at diagnosis, with a value of 2.0 mg/dl being the best cutoff for predicting ESRD, percentage global glomerulosclerosis, and presence of diabetes. Only four patients died and four had received chemotherapy for an erroneous diagnosis of immunoglobulin light chain-derived amyloidosis. Five patients underwent kidney transplantation; none had graft loss but one had disease recurrence. Patient survival is superior to renal immunoglobulin light chain-derived amyloidosis and reactive amyloidosis largely due to the absence of cardiac involvement. Thus, renal ALECT2 mainly affects elderly Hispanics who typically present with chronic renal insufficiency and bland urine sediment, with or without proteinuria.