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  • 1
    Language: English
    In: Leukemia, 2017-01, Vol.31 (1), p.18-25
    Description: Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR, 〈0.05). Forty-one percent of children with high levels of MRD after the 1st induction course, measured by a patient-specific real-time-PCR, had worse EFS (22.2 versus 59.4% in low-MRD patients, P〈0.05). Next, we correlated these parameters with gene expression, showing that patients with high ITD-AR or persistent MRD had characteristic expression profiles with deregulated genes involved in methylation and acetylation. Moreover, patients with high CyclinA1 expression presented an unfavorable EFS (20.3 versus 51.2% in low CyclinA1 group, P〈0.01). Our results suggest that ITD-AR levels and molecular MRD should be considered in planning clinical management of FLT3-ITD patients. Different transcriptional activation of epigenetic and oncogenic profiles may explain variability in outcome among these patients, for whom novel therapeutic approaches are desirable.
    Subject(s): fms-Like Tyrosine Kinase 3 - genetics ; Disease-Free Survival ; Leukemia, Myeloid, Acute - diagnosis ; Prognosis ; Epigenesis, Genetic - genetics ; Humans ; Child, Preschool ; Retrospective Studies ; Gene Expression Regulation, Leukemic ; Child ; Neoplasm, Residual - genetics ; Leukemia, Myeloid, Acute - genetics ; Molecular targeted therapy ; Gene mutations ; Gene expression ; Health aspects ; Innovations ; Index Medicus
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: Leukemia, 2017-04, Vol.31 (4), p.974-977
    Subject(s): Daunorubicin - therapeutic use ; Prognosis ; Cytarabine - therapeutic use ; Humans ; Up-Regulation - genetics ; Methotrexate - therapeutic use ; Mutation - genetics ; Cyclophosphamide - therapeutic use ; Down-Regulation - genetics ; Nuclear Pore Complex Proteins - genetics ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Mercaptopurine - therapeutic use ; Oncogene Proteins, Fusion - genetics ; Vincristine - therapeutic use ; Leukemia, Myeloid, Acute - drug therapy ; Biomarkers, Tumor - genetics ; Asparaginase - therapeutic use ; Prednisone - therapeutic use ; Leukemia, Myeloid, Acute - genetics ; Translocation, Genetic - genetics ; Index Medicus
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Leukemia, 2016-09-01, Vol.30 (9), p.1887
    Description: cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. We generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased CCAAT-enhancer-binding protein-[delta] (C/EBP[delta]) levels to cause myeloid differentiation arrest, and the silencing of CREB-C/EBP[delta] axis restored myeloid terminal differentiation. Then, C/EBP[delta] overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveils the aberrant activation of CREB-C/EBP[delta] axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement.
    Subject(s): Pediatrics ; Analysis ; Cyclic adenylic acid ; Genetic aspects ; Gene expression ; Cell differentiation ; Protein binding
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Human pathology, 2021-03, Vol.109, p.53-58
    Description: The spectrum of neuroendocrine (NE) tumors in the genitourinary tract ranges from the aggressive large and small cell carcinomas to the often benign paraganglioma and well-differentiated neuroendocrine tumor (WD-NET). At least 15 pure lower urinary tract (LUT) WD-NETs have been described. Owing to the rarity of WD-NET in the LUT and the limited number of reported cases, a better definition of their biologic long-term behavior is warranted. Herein, we aim to describe 10 new cases of WD-NET arising in the LUT and expand on follow-up findings. Ten consultation cases were identified and included 6 men and 4 women who ranged from 45 to 73 years of age. Seven cases arose in the bladder with one located in the bladder neck, 1 arose in the prostatic urethra, 1 arose in the female urethra, and 1 arose in the left ureteral orifice. All lesions were confined to the lamina propria, and tumor architecture was pseudoglandular in all cases. Associated cystitis cystica et glandularis was identified in 5 cases; urothelial papilloma and florid von Brunn's nests were found in 2 additional cases. Immunohistochemical staining for synaptophysin and chromogranin was diffusely positive in 9 cases and focal in 1 case, and the Ki-67 proliferation index was 5% or less in all tumors. Follow-up ranged from 37 to 137 months (mean = 82; median = 77), and there was no evidence of residual disease or recurrence in any of the 10 patients during the follow-up period. •Long follow-up of well-differentiated neuroendocrine tumor (WD-NET) of the lower urinary tract supports benign behavior.•We report the first case of WD-NET arising in a ureteral orifice.•We report the first case of WD-NET arising in a female urethra.•We report the third case of WD-NET arising in a prostatic urethra.
    Subject(s): Urinary bladder neoplasm ; Well-differentiated ; Lower urinary tract ; Carcinoid ; WD-NET ; Neuroendocrine ; Immunohistochemistry ; Tumors ; Cytokeratin ; Architecture ; Biopsy ; Cloning ; Bladder ; Urogenital system ; Prostate cancer ; Neuroendocrine tumors ; Index Medicus
    ISSN: 0046-8177
    E-ISSN: 1532-8392
    Source: ProQuest Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Language: English
    In: Cardiovascular and interventional radiology, 2018-07, Vol.41 (7), p.1089-1094
    Description: The objective was to determine the ablation size of a single 15-min freeze and compare it with the conventional 10-min freeze–8-min thaw–10-min freeze protocol. Secondary objectives were to determine the ablation margin and to ascertain whether islands of viable tissue remain within the ablation zone.Five adult swine under general anesthesia were used. After surgical abdominal exposure, two ablations were performed in liver and two in kidney. One ablation utilized the 15-min and the second the 10–8–10-min protocol. At maximum ice-ball, tissue ink was infused via an angiographic catheter in hepatic or renal artery to stain the non-frozen tissue. Animals were euthanized and organs examined macro- and microscopically.Three histological regions were observed: (A) a viable/stained region representing the tissue outside the ice-ball, (B) a central necrotic area representing the ablated region within the ice-ball and (C) an unstained but viable margin representing the non-lethal margin within ice-ball. Ablation size did not vary with protocol but did for tissue type. Renal ablation was approximately 5 × 4 cm with both protocols, whereas liver ablation was approximately 6.7 × 4.4 cm. Ablation margin was measured at 1 mm irrespective of ablation protocol or tissue. No islands of viable tissue were identified within the ablation zone.Fifteen-minute cryoablation yielded an ablation size and margin identical to that of the conventional 10–8–10-min protocol. Within the ablated region, cell death was uniform. The only difference was a larger cryoablation zone in hepatic tissue compared to renal tissue, likely attributable to differences in blood perfusion.
    Subject(s): Ablation size ; Medicine & Public Health ; Cryoablation ; Nuclear Medicine ; Imaging / Radiology ; Cardiology ; Ultrasound ; Margin ; Swine ; Ablation (Surgery) ; Liver ; Index Medicus
    ISSN: 0174-1551
    E-ISSN: 1432-086X
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Virchows Archiv : an international journal of pathology, 2019-09-01, Vol.475 (3), p.349-356
    Description: The Cancer Genome Atlas project introduced genomic taxonomy of basal and luminal molecular subtypes in muscle invasive bladder cancer. Fewer studies have addressed the molecular classification in non-muscle invasive bladder cancer (NMIBC). Our aim is to assess the applicability of the proposed phenotypic classification for NMIBC. Three TMAs were constructed from 193 TURBT specimens of 60 bladder cancer patients treated at one of the authors’ institutions (1998–2008). Follow-up data on recurrence, grade, or stage progression was obtained. Immunohistochemistry was performed using an automated Ventana System for markers indicative of luminal (GATA3, CK20, ER, Uroplakin II, and HER2/neu) and basal (CK5/6 and CD44) phenotype. Marker expression was evaluated by 3 urologic pathologists. Using unadjusted logistic regression, we found significant association between tumor recurrence at next biopsy and CD44 expression (OR = 2.51, P = 0.03), tumor recurrence at any subsequent biopsy and ER expression (OR = 0.24, P = 0.04), and tumor grade progression at any subsequent biopsy and HER2/neu expression (OR = 0.24, P = 0.04). After adjusting for pathologic stage, we found a significant association between CK5/6 expression and tumor stage progression at either next or any subsequent biopsy (OR = 0.94, P = 0.006; and OR = 0.97, P = 0.02, respectively). Our findings suggest that individual immunohistochemical markers may be of value as prognostic factors in NMIBC.
    Subject(s): Molecular classification ; Basal ; Immunohistochemistry ; Non-muscle invasive bladder cancer ; Pathology ; Medicine & Public Health ; Luminal ; Urothelial carcinoma ; Medical colleges ; Carcinoma ; Oncology, Experimental ; Analysis ; Medical societies ; Genomics ; Development and progression ; Research ; Cancer ; Index Medicus
    ISSN: 0945-6317
    E-ISSN: 1432-2307
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 7
    Language: English
    In: Histopathology, 2017-02, Vol.70 (3), p.435-441
    Description: Aims GATA3 has been reported as a specific urothelial marker among organs in the pelvic region, and has been classified as highly sensitive and specific for urothelial and breast carcinomas. Our aim was to verify GATA3 expression in extramammary Paget disease, and to determine whether it can be use to differentiate primary vulvar Paget disease from pagetoid urothelial intraepithelial neoplasia (PUIN). We also analysed HER2 protein expression and HER2 gene amplification and their roles as prognostic factors in extramammary Paget disease. Methods and results We analysed GATA3 and HER2 expression in 11 primary vulvar Paget disease cases and two PUIN cases. All cases showed nuclear expression of GATA3. Of 13 cases, five were equivocal for HER2 expression (score 2+) and one was positive (3+). Fluorescence in‐situ hybridization results showed amplification in two of these six cases. Both HER2‐amplified cases were invasive. Conclusion GATA3 was positive in all extramammary Paget disease cases tested (13 cases), and it has no value for differentiating between primary and secondary vulvar Paget disease from the urological tract. HER2 amplification might confer an aggressive and invasive pattern in primary vulvar Paget disease, as both amplified cases showed an invasive pattern.
    Subject(s): vulvar Paget disease ; GATA3 ; pagetoid urothelial intraepithelial neoplasia ; extramammary Paget disease ; Immunohistochemistry ; Urologic Neoplasms - diagnosis ; Humans ; Middle Aged ; GATA3 Transcription Factor - biosynthesis ; Paget Disease, Extramammary - metabolism ; Urologic Neoplasms - pathology ; Vulvar Neoplasms - pathology ; Diagnostic Errors ; Vulvar Neoplasms - metabolism ; Aged, 80 and over ; Adult ; Female ; Vulvar Neoplasms - diagnosis ; GATA3 Transcription Factor - analysis ; Urologic Neoplasms - metabolism ; Biomarkers, Tumor - analysis ; Carcinoma in Situ - pathology ; In Situ Hybridization, Fluorescence ; Paget Disease, Extramammary - pathology ; Paget Disease, Extramammary - diagnosis ; Aged ; Carcinoma in Situ - diagnosis ; Receptor, ErbB-2 - analysis ; Carcinoma in Situ - metabolism ; Epidemiology ; Index Medicus
    ISSN: 0309-0167
    E-ISSN: 1365-2559
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 8
    Language: English
    In: Virchows Archiv : an international journal of pathology, 2019-01-18, Vol.474 (1), p.21-27
    Description: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor that plays a crucial role in cell proliferation, growth, differentiation, and apoptosis. IGF1R overexpression has been observed in several cancers, including invasive bladder carcinomas, as a potential prognostic factor. Given known biologic differences between upper and lower urinary tract urothelial carcinoma, we assessed the expression status and prognostic significance of IGF1R in upper tract urothelial carcinoma (UTUC). Two tissue microarrays (TMAs) were built from 99 Japanese patients with non-metastatic UTUC submitted to radical nephroureterectomy between 1997 and 2011. TMAs were constructed with triplicate tumor and paired benign urothelium. Membranous IGF1R staining was evaluated using immunohistochemistry. Two scoring methods were applied (Her2-score and H-score). The highest score was assigned to each tumor. IGF1R positivity was defined as Her2-score ≥ 1+. Association with clinicopathologic parameters and outcome was assessed using hazard ratios (HR) with 95% confidence intervals (CI) and adjusted P values. We found positive IGF1R expression in 70% of UTUC. Outcomes were as follows: tumor recurrence, 33%; tumor progression, 59%; overall mortality, 33%; and cancer-specific mortality, 30%. IGF1R was not associated with any clinicopathologic features. In addition, IGF1R expression was not associated with tumor recurrence (HR = 0.54, CI = 0.25–1.1, P = 0.11), tumor progression (HR = 1.6, CI = 0.8–3.1, P = 0.19), overall mortality (HR = 1.5, CI = 0.68–3.4, P = 0.31), or cancer-specific mortality (HR = 1.6, CI = 0.68–3.8, P = 0.27). Positive IGF1R expression was found in more than two thirds of UTUC. This finding provides a rationale to investigate IGF1R as a potential therapeutic target in UTUC. In contrast to bladder cancer, IGF1R expression in UTUC did not correlate with outcome, further pointing to biologic differences between UTUC and bladder cancer.
    Subject(s): Pathology ; Upper tract urothelial carcinoma ; Insulin-like growth factor-1 receptor ; Medicine & Public Health ; Urothelial carcinoma ; IGF1R ; Immunohistochemistry ; Receptors, Somatomedin - analysis ; Tissue Array Analysis ; Humans ; Middle Aged ; Ureteral Neoplasms - pathology ; Male ; Kidney Neoplasms - chemistry ; Urothelium - pathology ; Carcinoma - chemistry ; Kidney Neoplasms - surgery ; Aged, 80 and over ; Female ; Retrospective Studies ; Carcinoma - pathology ; Biomarkers, Tumor - analysis ; Ureteral Neoplasms - chemistry ; Japan ; Neoplasm Recurrence, Local ; Treatment Outcome ; Kidney Neoplasms - mortality ; Disease Progression ; Urothelium - chemistry ; Kidney Neoplasms - pathology ; Aged ; Ureteral Neoplasms - mortality ; Ureteral Neoplasms - surgery ; Index Medicus
    ISSN: 0945-6317
    E-ISSN: 1432-2307
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 9
    Language: English
    In: Virchows Archiv : an international journal of pathology, 2017-12, Vol.471 (6), p.761-767
    Description: Our group and others have previously demonstrated the presence of TERT promoter mutations (TERT-mut) in 60–80% of urothelial carcinomas and some of their histologic variants. Five other genes have been frequently implicated in bladder cancer: FGRF3, TP53, PIK3CA, HRAS, and CDKN2A. In the current study, we sought to determine the prevalence of mutations in TERT and these five other genes in de novo papillary urothelial neoplasms of low malignant potential (PUNLMP) of the urinary bladder. A retrospective search of our archives for PUNLMP was performed and 30 de novo cases were identified and included in the study. We found mutations in TERT (TERT-mut) and FGFR3 (FGFR3-mut) to be the most common alterations in the cohort (63 and 60%, respectively). The majority of the TERT-mut-positive tumors (84%) had a g.1295228C 〉 T alteration with the remaining tumors demonstrating g.1295250C 〉 T. Approximately one fourth of tumors had TP53 mutations. These findings support the potential utility of a uniform genetic mutation panel to detect bladder cancers of various subtypes.
    Subject(s): PUNLMP ; Pathology ; Bladder neoplasm ; Medicine & Public Health ; TERT ; PIK3CA ; FGRF3 ; TP53 ; Early detection ; Genetic research ; Genetic aspects ; Diagnosis ; Gene mutations ; Tumor proteins ; Cancer ; Index Medicus
    ISSN: 0945-6317
    E-ISSN: 1432-2307
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 10
    Language: English
    In: Modern pathology, 2019-10, Vol.32 (10), p.1544-1550
    Description: Noninvasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine- based molecular assay for the detection and surveillance of bladder neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that include most common genetic alterations in bladder cancer. In this study, we analyzed 527 cases, including 373 noninvasive and 154 invasive urothelial carcinomas of bladder from transurethral resections or cystectomies performed at four institutions (1991-2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 (FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL) genes (UroSeqS). Overall, 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade noninvasive papillary carcinomas, with a relatively lower incidence of 65% in high-grade noninvasive papillary carcinomas and carcinomas in situ; p = 0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C〉T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade noninvasive papillary carcinomas compared with high-grade noninvasive papillary carcinomas and carcinomas in situ (p 〈 0.0001), while the opposite was true for TP53 (p 〈 0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates (p = 0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared with those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes, confirming the comprehensive coverage of the panel and supporting its potential utility as a noninvasive urine-based assay.
    Subject(s): Index Medicus
    ISSN: 0893-3952
    E-ISSN: 1530-0285
    Source: Nature Open Access
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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