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1.
Georgian Med News ; (290): 20-25, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31322508

RESUMO

Borderline ovarian tumors (BOTs) represent particular challenge for diagnosis and clinical management as they are characterized with the features of both benign cystadenomas and malignant carcinomas. The aim of our study was to investigate histomorphological and immunohistochemical characteristics of ovarian serous-papillary borderline tumors, compared to serous cystadenomas and low- and high-grade serous carcinomas. Altogether, 80 formalin fixed and paraffin embedded tissue specimens, distributed in four groups, including serous cystadenoma (group I), serous BOTs (group II), Low (group III) and high (group IV) grade serous carcinomas, were investigated by standard immunohistochemistry, using antibodies against CK7 CK20, WT1, Vimentin, CDX2, CEA, ER, cyclin D1, BCL2, E-cadherin, calretinin, СA125, Ki67, P53. Study results showed, that ovarian serous BOTs are characterized with slightly increase proliferative potential compared to benign cystadenomas, whilst apoptotic potential is retained with the difference from malignant serous carcinomas. p53 mutation is not present, as well as the expression of Vimentin. Overall, ovarian serous BOTs are characterized with highly variable immunohistochemical phenotype and the use of multiple immunohistochemical markers are recommended for the differential diagnosis from low grade serous carcinomas and benign cystadenomas.


Assuntos
Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/patologia , Cistadenoma Seroso/química , Cistadenoma Seroso/patologia , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Proteínas WT1/análise
3.
Gynecol Obstet Invest ; 84(3): 305-312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30423566

RESUMO

Ovarian endometriotic cysts have been identified as the possible origin of ovarian clear cell carcinoma (OCCC), so predicting or preventing future transformation is important. Early detection of clear cell carcinoma is important because it shows low sensitivity to chemotherapy and the prognosis is worse than for other histologic types. We recently treated 2 patients with OCCC. They were both young women with no family history of cancer who received long-term oral contraceptive therapy for endometriotic cysts, and the histologic diagnosis was typical clear cell carcinoma in both patients. However, in Case 1, the tumor was detected by periodic examination, tumor expression of WT1 was positive, and the stage was IA. On the other hand, Case 2 presented with fever of unknown origin, her tumor showed expression of p53, and the stage was IVB. Case 1 is alive with no evidence of disease at 38 months after surgery, while Case 2 died after 19 months despite intensive treatment. These contrasting cases suggest that we need to be aware of the risk of cancer in young women receiving long-term hormone therapy for endometriotic cysts and that OCCC may show greater heterogeneity than what has been reported previously.


Assuntos
Adenocarcinoma de Células Claras/patologia , Endometriose/patologia , Cistos Ovarianos/patologia , Neoplasias Ovarianas/patologia , Adulto , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/uso terapêutico , Endometriose/tratamento farmacológico , Feminino , Humanos , Estadiamento de Neoplasias , Cistos Ovarianos/tratamento farmacológico , Prognóstico , Proteína Supressora de Tumor p53/análise , Proteínas WT1/análise
4.
Br J Cancer ; 119(12): 1508-1517, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374123

RESUMO

BACKGROUND: The Wilms' tumour protein (WT1), which influences tumour development and angiogenesis, is a promising therapeutic target in breast cancer. We hypothesised that WT1 expression would vary in endothelial cells in distinct sub-classifications of breast cancer. METHODS: WT1 expression and vascular density were quantified by immunohistochemical analysis of human (n = 57) and murine breast cancers. Human tumours were sub-classified by histopathological grade, ER status and HER2 enrichment. RESULTS: WT1 was identified in endothelial (and epithelial and smooth muscle) cells in tumours and tumour-free tissues (controls) from patients and mice with breast cancer. WT1 expression was higher in tumours than in controls, but this was not due to increased endothelial WT1. Vascular WT1 in cancers decreased as histopathological grade increased. WT1 was higher in ER-positive versus ER-negative cancers. Strikingly, reduced WT1 expression in controls correlated with an increased Nottingham Prognostic Index score. CONCLUSIONS: Expression of WT1 is increased in breast cancers but this is not limited to the vascular compartment. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast.


Assuntos
Neoplasias da Mama/patologia , Proteínas WT1/análise , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Camundongos , Gradação de Tumores , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Proteínas WT1/fisiologia
5.
Am J Surg Pathol ; 42(12): 1585-1595, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30285996

RESUMO

Renal mass lesions with a follicular architecture resembling atrophic kidney have been described, but their distinction from thyroid-like follicular carcinoma of the kidney remains controversial. We collected 8 cases of this purported "atrophic kidney"-like lesion to fully describe their clinical and histologic spectrum, their possible etiology, and to discuss their distinction from other renal neoplasms. Eight total cases were identified with patient ages ranging from 9 to 48 years (mean: 29 y; median: 28.5 y). Four patients were female and 4 were male. The tumors were unifocal and size ranged from 1.6 to 4.9 cm (mean: 3.4 cm; median: 3.4 cm). All 8 tumors had a remarkably similar histology. Each was enveloped by a smooth muscle rich capsule and had an overall low power "follicular" architecture. The luminal spaces of the "follicles" (or cysts) contained eosinophilic secretions and the lining epithelium was often flattened and atrophic, but some had more rounded cells with a distinctive hobnail arrangement. Many cysts contained discohesive round cells floating within the eosinophilic material, and some contained small intraluminal tufts with features of markedly atrophic glomeruli. Periodic acid-Schiff stains highlighted basement membrane material extending into these glomerular-like tufts, and some contained small distinct capillaries surrounded by endothelial cells, interspersed mesangial-like cells, and rare surrounding podocyte-like cells, providing additional evidence for glomerulocystic structures. Scattered calcifications were present within cysts (or within cyst walls) in varying numbers and were characterized by 2 types: psammoma body-like or more amorphous deposits. The tissue between cystic glomeruli contained predominantly small atrophic tubular structures, but collagenized stroma and smaller collapsed glomeruli were also present. The 2 tumors from the oldest 2 patients (48 and 39 y) had a more striking degree of stromal hyalinization. Immunohistochemically, the cyst lining cells had a predominant WT-positive/PAX-8 negative/CK7-negative phenotype, while tubules were typically WT-1 negative/PAX-8 positive/CK7-positive. Upon comparison to a control group of 10 kidneys containing incidental non-mass-forming glomerulocystic change, the morphologic features and immunophenotype were identical. To date, no patient has had any recurrence or aggressive clinical behavior based on follow status in 7 of 8 cases (follow-up range: 9 to 168 mo; median: 24 mo; mean: 40 mo). In summary, we describe the clinicopathologic features of 8 unique, benign "atrophic kidney"-like lesions that may simply represent a non-neoplastic form of organizing tubular atrophy and glomerulocystic change, and emphasize their distinction from thyroid-like follicular carcinoma of the kidney.


Assuntos
Adenocarcinoma Folicular/patologia , Neoplasias Renais/patologia , Adenocarcinoma Folicular/química , Adenocarcinoma Folicular/classificação , Adulto , Atrofia , Biomarcadores Tumorais/análise , Biópsia , Estudos de Casos e Controles , Criança , Diagnóstico Diferencial , Eosinófilos/patologia , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Queratina-7/análise , Neoplasias Renais/química , Neoplasias Renais/classificação , Masculino , Pessoa de Meia-Idade , Músculo Liso/patologia , Fator de Transcrição PAX8/análise , Valor Preditivo dos Testes , Estudos Prospectivos , Células Estromais/patologia , Carga Tumoral , Proteínas WT1/análise , Adulto Jovem
6.
J Chin Med Assoc ; 81(8): 691-698, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29748075

RESUMO

BACKGROUND: Hypertension is a major global public health issue. Uncontrolled hypertension leads to organ damage, especially renal damage. Calcitriol is used to treat osteoporosis, promote bone formation, and increase bone mass. Previous studies have demonstrated that 1,25(OH)2D3, in addition to its classic role, also has multiple immune regulation and renoprotective functions and inhibits the activity of the renin-angiotensin-aldosterone system (RASS). The aim of the current study was to investigate the renoprotective effects of calcitriol in a spontaneously hypertensive rat (SHR) model. METHODS: A total of 18 SHRs and 8 age-matched normal Wistar rats were enrolled. SHRs were randomly divided into a hypertensive nephropathy group (H), a hypertensive nephropathy treated with calcitriol group (D) and a control group (NS). The rats were sacrificed after 16 weeks of treatment. The blood pressure (BP) of rats were measured one time every 4 weeks. The levels of serum albumin, serum creatinine, blood calcium, serum Vitamin D and 24-h urinary protein were measured after 16 weeks treatment. The protein level of WT1, nephrin and vitamin D receptor (VDR) was examined by Western blotting and immunohistochemical staining. RESULTS: There were no notable changes in blood pressure or serum creatinine in group H and D compared with group NS. The albumin, calcium and vitamin D serum levels in group H were significantly decreased compared with group NS and significantly increased in group D compared with group H. The level of 24-h urine protein significantly increased in group H compared with group NS and significantly decreased in group D compared with group H. The expression of VDR, WT1 and nephrin in the kidney were all significantly decreased in group H compared with group NS and significantly increased in group D compared with group H. CONCLUSION: The present results indicated that there was injury of podocytes in hypertensive nephropathy, which can be ameliorated by calcitriol in SHR, but there was no significant anti-hypertensive effect. Vitamin D/VDR decreased proteinuria perhaps by increasing expression of nephrin and WT1 protein in podocyte of SHRs.


Assuntos
Calcitriol/farmacologia , Hipertensão/complicações , Nefropatias/prevenção & controle , Podócitos/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Masculino , Proteínas de Membrana/análise , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Receptores de Calcitriol/análise , Sistema Renina-Angiotensina/efeitos dos fármacos , Proteínas WT1/análise
7.
Zhonghua Bing Li Xue Za Zhi ; 47(3): 180-185, 2018 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-29534357

RESUMO

Objective: To investigate the diagnostic value of some antibodies in peritoneal fluid of patients with gastric cancer and malignant epithelioid mesothelioma in serous effusion. Methods: One hundred and eighty-two cases of serous effusion were collected at Jilin Cancer Hospital, from July 2012 to July 2016. The expression of GLUT1, CDX2, Villin, calretinin and WT1 was evaluated using SP immunocytochemical technique in peritoneal fluid samples collected from 98 patients with gastric cancer and 74 patients with reactive mesothelial cells. The expression of GLUT1, calretinin and WT1 was also evaluated in serous effusion from 10 patients with mesothelioma. Results: The sensitivity of GLUT1, CDX2 and Villin in adenocarcinoma cells was 91.8%(90/98), 68.4% (67/98) and 88.8%(87/98), respectively. The specificity was 95.9% (71/74), 100.0%(74/74) and 100.0% (74/74), respectively. The sensitivity of calretinin and WT1 for reactive mesothelium was 93.2% (69/74) and 79.7% (59/74), respectively. The specificity was 96.9% (95/98) and 100.0% (98/98), respectively. The sensitivity of GLUT1, calretinin and WT1 for mesothelioma was 9/10, 9/10 and 7/10. The reactivity of GLUT1, CDX2, Villin, calretinin and WT1 showed a significant difference (P<0.01) between adenocarcinoma cells and reactive mesothelium. The reactivity of GLUT1 showed a significant difference (P<0.01) between mesothelioma and reactive mesothelium. Conclusions: The optimal combination is a panel of GLUT1, CDX2, Villin, calretinin and WT1 for differential diagnosis between adenocarcinoma cells and reactive mesothelium in peritoneal fluid of patients with gastric cancer. Whereas GLUT1, calretinin and WT1 is the best for differential diagnosis between reactive mesothelium and mesothelioma in serous effusions.


Assuntos
Adenocarcinoma/química , Líquido Ascítico/química , Neoplasias Pulmonares/química , Mesotelioma/química , Proteínas de Neoplasias/análise , Neoplasias Gástricas/química , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/análise , Calbindina 2/análise , Diagnóstico Diferencial , Epitélio/química , Transportador de Glucose Tipo 1/análise , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Proteínas dos Microfilamentos/análise , Sensibilidade e Especificidade , Neoplasias Gástricas/diagnóstico , Proteínas WT1/análise
8.
Elife ; 72018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29405914

RESUMO

Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that wt1b+cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. Wt1b+sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, wt1b+and entpd5+ cells constitute separate, tightly-associated subpopulations. Surprisingly, wt1b expression at the site of injury is maintained even into adult stages in developing vertebrae, which form in an untypical manner via a cartilage intermediate. Given that notochord cells are retained in adult intervertebral discs, the identification of novel subpopulations may have important implications for regenerative spine disorder treatments.


Assuntos
Regeneração Nervosa , Neuroglia/química , Neuroglia/fisiologia , Notocorda/lesões , Proteínas WT1/análise , Cicatrização , Animais , Movimento Celular , Peixe-Zebra
9.
Am J Surg Pathol ; 42(4): 534-544, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29309296

RESUMO

Although infrequently encountered, the diagnosis of ovarian high-grade endometrioid carcinoma remains a diagnostic challenge with potential consequences for targeted therapies and genetic counselling. We studied the clinical, morphologic, and immunohistochemical features of ovarian high-grade endometrioid carcinomas and their diagnostic reproducibility compared with tuboovarian high-grade serous carcinomas. Thirty cases confirmed as International Federation of Gynecology and Obstetrics grade 3 endometrioid carcinomas were identified from 182 ovarian endometrioid carcinomas diagnosed in Alberta, Canada, between 1978 and 2010, from the population-based Alberta Ovarian Tumor Types cohort. Cases of lower grade endometrioid and high-grade serous carcinoma served for comparison. Ten immunohistochemical markers were assessed on tissue microarrays. Clinical data were abstracted and survival analyses performed using Cox regression. Interobserver reproducibility for histologic type was assessed using 1 representative hematoxylin and eosin-stained slide from 25 randomly selected grade 3 endometrioid carcinomas and 25 high-grade serous carcinomas. Histotype was independently assigned by 5 pathologists initially blinded to immunohistochemical WT1/p53 status, with subsequent reassessment unblinded to WT1/p53 status. Patients diagnosed with grade 3 endometrioid carcinoma had a significantly longer survival compared with high-grade serous carcinoma in univariate analysis (hazard ratio [HR]=0.34, 95% confidence interval [CI]=0.16-0.67, P=0.0012) but not after adjusting for age, stage, treatment center, and residual tumor (HR=1.01, 95% CI=0.43-2.16, P=0.98). Grade 3 endometrioid carcinoma cases (N=30) were identical to grade 2 endometrioid carcinoma cases (N=23) with respect to survival in univariate analysis (HR=1.07, 95% CI=0.39-3.21, P=0.89) and immunohistochemical profile. Using histomorphology alone, interobserver agreement for the diagnosis of grade 3 endometrioid or high-grade serous carcinoma was 69%, which significantly increased (P<0.0001) to 96% agreement with the knowledge of WT1/p53 status. Our data support the diagnostic value of WT1/p53 status in differentiating between grade 3 endometrioid carcinoma and high-grade serous carcinoma. However, grade 3 and grade 2 endometrioid carcinomas showed no differences in immunophenotype or clinical parameters, suggesting that they could be combined into a single group.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alberta/epidemiologia , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Feminino , Humanos , Imuno-Histoquímica , Incidência , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/química , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo , Análise Serial de Tecidos , Resultado do Tratamento , Proteína Supressora de Tumor p53/análise , Proteínas WT1/análise
10.
Biol Blood Marrow Transplant ; 24(1): 55-63, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28939453

RESUMO

The outcome of allogeneic hematopoietic stem cell transplantation (HCT) in patients with myeloid malignancies is better in those without minimal residual disease (MRD) than in those with MRD+, as assessed by multiparametric flow cytometry (MPFC). WT1 quantitation also has been used to assess the probability of relapse in acute myelogenous leukemia (AML) treated with chemotherapy. We analyzed the clinical value of normalized bone marrow WT1 levels as a measure of the expanded myeloid progenitor compartment in a consecutive series of 193 adult patients with myeloid malignancies who underwent HCT. Bone marrow WT1 levels before the HCT, at the first bone marrow aspirate after infusion, and in the follow-up samples after HCT were determined by means of real-time PCR using the European LeukemiaNet normalized method. We sought to clarify the prognostic relevance in terms of overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse (CIR). Based on earlier experience in AML, we selected a threshold of 100 copies, defining 2 groups: patients with <100 WT1 copies and those with ≥100 copies. Patients with <100 WT1 copies before HCT (median time, 36 days; range, 4 to 268 days) had a better OS, PFS, and CIR than those with ≥100 copies (40 ± 1 versus 29 ± 6 days, P = .004; 35 ± 9 versus 26 ± 6 days, P = .002; and 29 ± 7 versus 37 ± 6 days, P = .051). In the first bone marrow study after the HCT (median time, 42 days; range 14 to 157 days, respectively), patients with <100 WT1 copies also had better outcomes in terms of OS, PFS, and CIR (40 ± 7 versus 31 ± 9 days, P = .025; 36 ± 7 versus 30 ± 8 days, P = .004; and 29 ± 6 days versus 54 ± 9, P < .001, respectively). At this time point, bone marrrow samples with >100 copies also included patients who were negative for MRD as assessed by MPFC (19 of 32). During the HCT follow-up, patients with sustained WT1 levels <100 copies showed a marked benefit in terms of OS, PFS, and CIR even compared with those with only a single measurement >100 copies (mean, 68 ± 11 versus 26 ± 7 days, P < .001; 63 ± 11 versus 20 ± 8 days, P < .001; and 20 ± 8 vs. 71 ± 8 days, P < .001, respectively). Standardized bone marrow WT1 levels using a 100-copy threshold in samples obtained before HCT, at leukocyte recovery, and during follow-up provided relevant prognostic information in patients with myeloid malignacies submitted to HCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , Proteínas WT1/análise , Adolescente , Adulto , Medula Óssea/química , Feminino , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Neoplasia Residual/diagnóstico , Prognóstico , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Adulto Jovem
11.
APMIS ; 126(1): 45-55, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29266433

RESUMO

Clear cell carcinoma (CCC) of the ovary is an uncommon, but an aggressive epithelial ovarian cancer (EOC), which has overlapping histopathologic features with other ovarian tumours. Lately, Napsin A has been identified as its useful diagnostic immunohistochemical (IHC) marker. Fifty-eight prospectively diagnosed ovarian CCCs, 53 high-grade serous carcinomas (HGSCs), 16 endometrioid adenocarcinomas (EMACs), six mixed carcinomas, containing components of CCC and EMAC, seven metastatic mucinous adenocarcinomas and six ovarian yolk sac tumours (YSTs) were tested for Napsin A immunostaining. Fifty ovarian CCCs, 50 HGSCs, seven ovarian EMACs and five mixed carcinomas were tested for WT1 immunostaining. Napsin A was positively expressed in all 58 (100%) CCCs; was focally positive in 1 of 6 YSTs; in 1/16 EMACs and in six cases of mixed carcinomas, while it was negative in all 53 HGSCs and in seven metastatic mucinous adenocarcinomas. Other IHC markers expressed in cases of CCC ovary were CK7 (31/31) (100%), WT1 (0/50), p53 (20/26, 'wild type'), ER (4/31, focal) (12.9%), PAX8 (14/14) (100%), glypican-3 (4/10, focal) (44.4%), p16INK4 (5/5, focal) and CK20 (0/5). Various IHC markers expressed in HGSCs were WT1 (48/50) (96%), p53 (31/31, mostly 'mutation type'), CK7 (9/9) (100%) ER (13/16, variable) (81.2%) and PAX8 (14/14) (100%). IHC markers expressed in EMACs were ER (15/16) (93.7%), CK7 (2/2) (100%) and WT1 (0/7). IHC markers expressed in mixed carcinomas were CK7 (2/2) (100%), WT1 (0/2), focal Napsin A (6/6) and focal ER (5/6). The sensitivity and specificity of Napsin A for the diagnosis of CCC ovary was 100% and 90.9%, respectively. The sensitivity and specificity of WT1 for diagnosis of HGSC ovary was found to be 96% and 100%, respectively. Napsin A and WT1 are highly sensitive and specific IHC markers for diagnosing ovarian CCCs and HGSCs, respectively, and in differentiating these tumours from their mimics. Napsin A is useful in identification of component of CCC in certain EMACs.


Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Ácido Aspártico Endopeptidases/análise , Cistadenocarcinoma Seroso/diagnóstico , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Ovarianas/diagnóstico , Proteínas WT1/análise , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/patologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Estudos Prospectivos
12.
Leuk Res ; 61: 10-17, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28846953

RESUMO

In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) is still under investigation. The aim of the present retrospective study was to assess the role of Wilms tumor gene 1 (WT1) overexpression in a large monocentric cohort of AML patients. Among 255 enrolled patients, MRD was investigated in those in complete remission (CR) with an available WT1 at baseline (>250 copies) and at two further time-points: after induction (n=117) and prior allogeneic hematopoietic cell transplantation (allo-HCT), n=65. Baseline BM WT1 overexpression was not associated with response to induction (p=0.244). Median overall survival (OS) and disease-free survival (DFS) were significantly shorter in patients with >350 WT1 copies after induction compared to those with ≤350 (HR for mortality 2.13; 95% CI 1.14-3.97, p=0.018 and HR for relapse 2.81; 95% CI 1.14-6.93, p=0.025). Patients with WT1>150 copies pre allo-HCT had a significantly higher 2-year cumulative incidence of relapse (CIR) compared to those with WT1≤150 (HR 4.61; 95% CI 1.72-12.31, p=0.002). The prognostic role of WT1 overexpression resulted independent from other well-established risk factors. According to these results, WT1 overexpression might represent an additional MRD tool for risk stratification in patients classified nowadays in CR.


Assuntos
Biomarcadores Tumorais/análise , Leucemia Mieloide Aguda/patologia , Neoplasia Residual/patologia , Proteínas WT1/biossíntese , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/mortalidade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Proteínas WT1/análise , Adulto Jovem
13.
Histopathology ; 71(5): 736-742, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28570008

RESUMO

AIMS: The treatment of patients with tubo-ovarian high-grade serous carcinoma (HGSC) is increasingly based on diagnosis on small biopsy samples, and the first surgical sample is often taken post-chemotherapy. p53 and WT1 are important diagnostic markers for HGSC. The effect of neoadjuvant chemotherapy on p53 and WT1 expression has not been widely studied. We aimed to compare p53 and WT1 expression in paired pre-chemotherapy and post-chemotherapy samples of HGSC. METHODS AND RESULTS: Immunohistochemistry (IHC) was carried out for p53 and WT1 on paired omental HGSC samples pre-chemotherapy and post-chemotherapy. p53 IHC was recorded as normal (wild-type) or abnormal (mutation-type), and was further classified as overexpression, complete absence, or cytoplasmic. WT1 IHC was classified as positive or negative. A subset of cases were further assessed for the extent of nuclear immunoreactivity of WT1 by use of the H-score. Fifty-seven paired samples were stained with p53. Fifty-six of 57 (98%) cases showed mutation-type p53 staining. Pre-chemotherapy and post-chemotherapy IHC results were concordant in 55 of 57 (96%) cases. For WT1, pre-chemotherapy and post-chemotherapy IHC results were concordant in 56 of 58 (97%) cases. In 23 paired WT1 cases, the mean post-treatment H-score decreased from 227 [range 20-298, standard deviation (SD) 64] to 151 (range 0-288, SD 78) (P = 0.0008). CONCLUSIONS: Immunohistochemical expression of p53 (abnormal/mutation-type pattern) and WT1 in HGSC is almost universal and is largely concordant before and after chemotherapy. This finding underscores the reliability of these diagnostic markers in small samples and in surgical samples following neoadjuvant chemotherapy, with very few exceptions. A novel finding was the significant diminution in intensity of WT1 staining following chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteínas WT1/efeitos dos fármacos , Quimioterapia Adjuvante , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/biossíntese , Proteínas WT1/análise , Proteínas WT1/biossíntese
15.
J Hematol Oncol ; 10(1): 30, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28114959

RESUMO

Wilms' tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/104 ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0002079.


Assuntos
Antraciclinas/uso terapêutico , Leucemia Promielocítica Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Proteínas WT1/genética , Anticorpos/uso terapêutico , Estudos de Coortes , Intervalo Livre de Doença , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Proteínas de Fusão Oncogênica/análise , Recidiva , Indução de Remissão , Estudos Retrospectivos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Tretinoína/uso terapêutico , Proteínas WT1/análise
16.
Bone Marrow Transplant ; 52(4): 539-543, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28067876

RESUMO

The monitoring of the minimal residual disease by Wilms' tumor 1 expression (MRDWT1) is a standardized test, which can be used in over 80% of patients with AML. To investigate the prognostic value of MRDWT1 in patients undergoing allogeneic stem cell transplantation (allo-SCT) for AML, MRDWT1 was monitored 3 months after transplantation in 139 patients. MRDWT1 positivity did not lead to any therapeutic intervention. Median follow-up was 39.3 (6.4-99.8) months. Patients with positive MRDWT1 at 3 months experienced more often post-transplant relapse (27/30, 90%) than those with negative MRDWT1 (16/109, 14.7%) (P<0.0001). Similarly, a shorter 3-year event-free survival (EFS) was observed in MRDWT1-positive patients (10% vs 72.3% in MRDWT1-negative patients, P<0.0001). The correlation between relapse and MRDWT1 was stronger in blood than in bone marrow samples. Multivariate analysis confirmed the detrimental role of 3-month positive MRDWT1 for relapse (hazard ratio (HR): 15.42; 95% confidence interval (CI): 7.53-31.59; P<0.0001) and EFS (HR: 10.71; 95% CI: 5.41-21.21; P<0.0001). Interestingly, 3-month chimerism was less predictive of relapse than positive MRDWT1. In conclusion, our results demonstrate the usefulness of peripheral blood MRDWT1 monitoring in identifying very high-risk patients, who could benefit from an early preemptive treatment, and those who do not need such an intervention.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Proteínas WT1/análise , Medula Óssea/química , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Recidiva , Transplante Homólogo , Resultado do Tratamento , Proteínas WT1/sangue , Tumor de Wilms/química
17.
J Cutan Med Surg ; 21(2): 164-166, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27708135

RESUMO

Hobnail hemangioma, also known as targetoid hemosiderotic hemangioma, is an uncommon vascular proliferation that clinically presents as a small solitary red to purple papule or macule, located on the limbs or trunk. Multiple lesions and atypical locations have been described. Histopathologically, it exhibits a biphasic pattern, with dilated vessels in the superficial dermis and angulated vessels in the deeper dermis, with endothelial cells that show a hobnail appearance. There is controversy about the histogenetic origin of hobnail hemangioma, although recent studies support that it is a lymphatic malformation. The investigators report the case of a 41-year-old man with an irregular lesion, red to purple in color, with a maximum diameter of 4 cm, on the scalp. The location and in particular the clinical appearance are uncommon. Immunohistochemical analysis showed negativity for WT1 and focal positivity for D2-40. Clinical-pathologic correlation acquires particular importance in the case of lesions with atypical clinical presentation.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Hemangioma/patologia , Couro Cabeludo , Neoplasias Cutâneas/patologia , Adulto , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/diagnóstico , Hemangioma/química , Hemangioma/diagnóstico , Humanos , Masculino , Glicoproteínas de Membrana/análise , Neoplasias Cutâneas/química , Neoplasias Cutâneas/diagnóstico , Proteínas WT1/análise
18.
Leukemia ; 31(8): 1788-1797, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27924074

RESUMO

CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This in vivo functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.


Assuntos
Leucemia/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas WT1/imunologia , Animais , Linhagem Celular , Feminino , Antígenos HLA-A/análise , Humanos , Imunoterapia , Interleucina-12/biossíntese , Camundongos , Neoplasias Ovarianas/terapia , Proteínas Recombinantes de Fusão/imunologia , Retroviridae/genética , Transcriptoma , Proteínas WT1/análise
19.
Curr Res Transl Med ; 64(3): 161-163, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27765277

RESUMO

AIM: Ovarian cancer is a common cause of death in women worldwide. The purpose of this article was to report a case series and draw physicians' attention to the benefits of histpathologic techniques in determining uncommon metastatic diseases. METHODS: In this study, we report a case series of axillary involvement of ovarian cancer in 6 patients. The data were collected between 2006 and 2015 by analyzing patient's characteristics, and biochemical and immunohistochemical features. No pathologic lesions were detected in breasts. Specific immunohistochemical methods such as GCDFP-15, CA12-5, WT-1, and PAX-8 supported evidence of metastasis from ovarian cancer to axillary lymph nodes. RESULTS: Biochemical tests showed increased levels of CA12-5 in all patients. In 5 patients, GCDFP-15 was negative and WT-1 was positive with specific immunohistochemical staining. PAX-8 was positive in 3 of 5 patients. CONCLUSIONS: Physicians need to be aware that histopathologic and immunohistochemical results can make a significant contribution in determining the true primary tissue of metastatic adenocarcinoma, even in the absence of typical clinical findings.


Assuntos
Axila , Carcinoma/secundário , Metástase Linfática/diagnóstico , Neoplasias Ovarianas/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Antígeno Ca-125/análise , Carcinoma/química , Carcinoma/diagnóstico , Proteínas de Transporte/análise , Diagnóstico Diferencial , Feminino , Glicoproteínas/análise , Humanos , Proteínas de Membrana Transportadoras , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/patologia , Fator de Transcrição PAX8/análise , Proteínas WT1/análise
20.
Mod Pathol ; 29(11): 1324-1334, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27443513

RESUMO

A distinct subset of round cell sarcomas harbors capicua transcriptional repressor (CIC) rearrangement. Diagnosing these sarcomas can be difficult owing to their resemblance to Ewing sarcoma and other 'small round blue cell tumors'; molecular techniques are generally required. Recent gene expression studies of CIC-rearranged sarcomas identified the upregulation of ETV4. We assessed the sensitivity and specificity of ETV4 and WT1 immunohistochemistry for CIC-rearranged sarcoma. We evaluated whole-tissue sections from 40 CIC-rearranged sarcomas, 40 Ewing sarcomas, 4 BCOR-CCNB3 sarcomas, 6 unclassified round cell sarcomas, and 150 histologic mimics. Moderate-to-strong nuclear immunoreactivity for ETV4 in at least 50% of cells was observed in 36 (90%) CIC-rearranged sarcomas and 10 (5%) other tumors, including 5 unclassified round cell sarcomas, 2 Wilms tumors, and 1 each desmoplastic small round cell tumor, melanoma, and small cell carcinoma. Thirty-eight (95%) CIC-rearranged sarcomas showed nuclear staining for WT1, and 34 (85%) were positive for both ETV4 and WT1. Of 182 other tumors evaluated, 34 (19%) showed nuclear WT1 positivity, including all Wilms tumors and desmoplastic small round cell tumors, 5 unclassified round cell sarcomas, and a subset of lymphoblastic lymphomas, rhabdomyosarcomas, mesenchymal chondrosarcomas, carcinomas, and melanomas. In summary, diffuse moderate-to-strong ETV4 expression is present in most CIC-rearranged sarcomas and unclassified round cell sarcomas. More limited expression is seen in small subsets of various other round cell neoplasms. Nuclear WT1 expression is also present in most CIC-rearranged sarcomas and unclassified round cell sarcomas, along with Wilms tumors and desmoplastic small round cell tumors, and subsets of various histologic mimics. The sensitivity and specificity of diffuse ETV4 expression for CIC-rearranged sarcomas are 90% and 95%, respectively, whereas the sensitivity and specificity of WT1 are 95% and 81%, respectively. Diffuse ETV4 along with at least focal WT1 expression is helpful to distinguish CIC-rearranged sarcoma from Ewing sarcoma and other histologic mimics.


Assuntos
Proteínas E1A de Adenovirus/biossíntese , Biomarcadores Tumorais/análise , Proteínas Proto-Oncogênicas/biossíntese , Sarcoma de Ewing/diagnóstico , Sarcoma de Células Pequenas/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Proteínas WT1/biossíntese , Proteínas E1A de Adenovirus/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/análise , Proteínas Repressoras/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Células Pequenas/genética , Sarcoma de Células Pequenas/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Proteínas WT1/análise , Adulto Jovem
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