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2.
Brachytherapy ; 19(1): 51-59, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31690516

RESUMO

PURPOSE: We hypothesized that radiation doses delivered with high-dose-rate (HDR) and pulsed-dose-rate (PDR) brachytherapy in patients with cervical cancer could trigger immune stimulation by modulating immune cells in the tumor microenvironment. The objective was to determine CD68, CD163, and PD-L1 expression in biopsies from patients with cervical cancer and to compare the effects of HDR vs. PDR brachytherapy on the expression of these proteins. METHODS AND MATERIALS: Nineteen consecutive women (mean age, 55.9 years) with histologically proven cervical cancer scheduled for brachytherapy after standard external beam irradiation therapy combined with platinum-based chemotherapy were included in a prospective study. Core tissue biopsies were obtained before radiochemotherapy (biopsy #1), after completion of radiochemotherapy and before brachytherapy (biopsy #2), and 2 weeks after completion of brachytherapy (biopsy #3). HDR or PDR brachytherapy was delivered according to availability of equipment. CD68, CD163, and PD-L1 immunohistochemical expression was estimated using a quantitative method. Conditional logistic regression models were used to assess the relationship between gene expression and time of biopsy for each brachytherapy technique. RESULTS: In relation to CD68 and CD163, statistically significant relationships between gene expression and biopsy tissue samples were not found in any of the brachytherapy techniques, although there was trend toward downexpression of CD68 and CD163 in biopsies #2 and #3 in the HDR brachytherapy cohort only. There was a significant increase in PD-L1 expression in biopsy #3 also in the HDR cohort as compared with the PDR cohort. CONCLUSIONS: Decreased CD68 and CD163 expression did not reach statistical significance, but this trend may have clinical translational potential. Overexpression of PD-L1 in tissue biopsies taken at 14 days in the HDR brachytherapy cohort may tentatively suggest that this time period would be an adequate interval for blockade of the PD-1/PD-L1 axis.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-H1/metabolismo , Braquiterapia/métodos , Receptores de Superfície Celular/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Quimiorradioterapia , Feminino , Humanos , Sistema Imunitário/efeitos da radiação , Pessoa de Meia-Idade , Estudos Prospectivos , Dosagem Radioterapêutica , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Neoplasias do Colo do Útero/tratamento farmacológico
3.
Onco Targets Ther ; 12: 9265-9275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807008

RESUMO

BACKGROUND: Primary cardiac tumors are extremely rare; most are myxomas with a benign prognosis. However, primary sarcomas are highly aggressive and treatment options are limited. Radical surgery is often not feasible and conventional therapies provide only modest results. Due to the rare nature of primary cardiac tumors, there are no proper randomized studies to guide treatment. Their complexity requires alternative approaches in order to improve treatment efficacy. METHODS: We isolated DNA from 5 primary cardiac sarcomas; the quality of DNA from 3 of them was sufficient to perform high-resolution single nucleotide polymorphism (SNP) array analysis. RESULTS: In the present study, molecular karyotyping revealed numerous segmental chromosomal alterations and amplifications affecting actionable genes that may be involved in disease initiation and/or progression. These include chromosomal break flanking AKT2 in undifferentiated pleomorphic rhabdomyosarcoma, chromosomal break in promoter of TERT, and gain of CDK4 and amplification of MDM2 in inflammatory myofibroblastic tumor. We detected segmental break flanking MOS in high-grade myxofibrosarcoma. In addition, the high number of chromosomal aberrations in high-grade myxofibrosarcoma may cause multiple tumor-specific epitopes, supporting the study of immunotherapy treatment in this type of aggressive tumor. CONCLUSION: Our results provide a genetic rationale that supports an alternative, personalized therapeutic management of primary cardiac sarcomas.

4.
Ann Diagn Pathol ; 39: 63-68, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30785029

RESUMO

Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma (HLRCC)/fumarate hydratase deficient renal cell carcinoma (FHRCC) is defined by molecular genetic changes (mutation/LOH in fumarate hydratase (FH) gene). We investigated chromosomal numerical aberration pattern (CNV) in FHRCC/HLRCC using array comparative genomic hybridization analysis and low pass whole genome sequencing. Genetic analysis was successfully completed in 12 tumors. Most common chromosomal aberrations detected were a complete or partial loss of chromosome 4 (5/12 cases), chromosome 15 (4/12 cases), and chromosomes 9, 13, and 14 (each in 3/12 cases), as well as a complete or partial gain of chromosome 17 (in 4/12 cases). No chromosomal losses or gains were detected in 4 cases. Copy number variation pattern in FHRCC/HLRCC appears to be highly variable and does not provide a useful diagnostic tool in identifying these cases. Immunohistochemical staining and especially molecular genetic evaluation of FH gene mutations/LOH remain the gold standard in identifying FHRCC/HLRCC.


Assuntos
Carcinoma de Células Renais/genética , Aberrações Cromossômicas , Fumarato Hidratase/deficiência , Neoplasias Renais/genética , Adulto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Sequenciamento Completo do Genoma
5.
Ann Diagn Pathol ; 29: 17-22, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28807336

RESUMO

Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR. By IHC, PD-1 was negative in tumor cells in all 13 cases. PD-L1 was positive in tumor cells in 2/13 cases, weak positive in 7/13, and negative in 4/13 cases, respectively. In TILs, PD-1 was positive in 1/13, weak positive in 3/13, and negative in 9/13 cases. In TILs, PD-L1 was weak positive by IHC in 5/13, and negative in 8/13 cases, respectively. qPCR confirmed the result for 2 of 3 IHC weak positive PD-1 samples. Of 7 IHC weak positive samples (in tumor cells), PD-L1 mRNA was detected in all 7 tumors. The majority of FH-RCCs did not express PD-1/PD-L1 by IHC, which was confirmed by molecular analysis. PD-1/PD-L1 expression in FH-RCC is restricted to a proportion of cases which may benefit from targeted therapies.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Carcinoma de Células Renais/patologia , Intervalo Livre de Doença , Feminino , Fumarato Hidratase/deficiência , Fumarato Hidratase/metabolismo , Humanos , Imuno-Histoquímica/métodos , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade
6.
Am J Surg Pathol ; 40(5): 664-75, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26999503

RESUMO

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.


Assuntos
Carcinoma de Células Renais/secundário , Neoplasias Renais/patologia , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Carcinoma de Células Renais/química , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/cirurgia , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Emperipolese , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Renais/química , Neoplasias Renais/classificação , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Valor Preditivo dos Testes , Terminologia como Assunto , Fatores de Tempo , Carga Tumoral
7.
Histopathology ; 67(6): 918-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25953530

RESUMO

AIMS: Here we report two cases of follicular lymphoma that transformed to CD30 positive diffuse large B cell lymphoma and review the literature on this topic. RESULTS: The first case represents an example of early transformation of conventional low-grade follicular lymphoma to CD30-positive large B cell lymphoma. Immunoglobulin (Ig)H and cytogenetic identity was demonstrated between both components. High-dose and auto-stem cell transplant (SCT) was applied and complete response was achieved. The second case represents an example of d'emblee transformation of intrafollicular neoplasia to CD30-positive large B cell lymphoma. Immunoglobulin K deleting element (IgKde) and cytogenetic identity between both phases was demonstrated. The patient was in partial response after four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). CONCLUSIONS: CD30 expression was found to be associated in these cases to the transformation event and could be considered a therapeutic target to add to conventional immunochemotherapeutic regimens, even in combination with auto-SCT. We suggest looking for CD30 expression in transformed follicular lymphoma cases.


Assuntos
Transformação Celular Neoplásica/patologia , Antígeno Ki-1/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Idoso , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/metabolismo , Ciclofosfamida/uso terapêutico , Progressão da Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Rituximab , Resultado do Tratamento , Vincristina/uso terapêutico
8.
Virchows Arch ; 466(2): 229-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25433814

RESUMO

Bruton's tyrosine kinase (Btk) is a member of the Tec family of protein tyrosine kinases involved in B cell development and proliferation in neoplastic human lymphoid tissues. We used immunohistochemistry to evaluate a polyclonal anti-Btk antibody on formalin-fixed paraffin-embedded tissue blocks. The tested samples included normal lymphoid tissues, tissue samples of 395 different lymphomas and 14 malignant lymphoid cell lines. Btk was expressed more often in B cell lymphomas than in T cell lymphomas. This correlated well with the results obtained on B cell lymphoma cell lines, which strongly expressed Btk, in contrast to T cell lymphoma cell lines. More than 60% of myelomas expressed Btk. Among Hodgkin lymphomas, the nodular lymphocyte predominant variant was more often positive (14/16) than the classical variant (6/27). Only one out of three Hodgkin lymphoma-derived cell lines showed a few atypical large cells expressing Btk. Btk represents a useful marker to identify B cell non-Hodgkin lymphomas. Furthermore, Btk might help to distinguish the nodular lymphocyte predominant variant of Hodgkin lymphomas from the classical form. Finally, in view of the recently discovered therapeutic potential of Btk inhibitors in lymphoma, we report the pattern of expression of Btk in a large collection of different types of lymphoma.


Assuntos
Biomarcadores Tumorais/análise , Doença de Hodgkin/enzimologia , Linfoma não Hodgkin/enzimologia , Proteínas Tirosina Quinases/biossíntese , Tirosina Quinase da Agamaglobulinemia , Humanos , Imuno-Histoquímica , Proteínas Tirosina Quinases/análise , Análise Serial de Tecidos
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