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1.
Cancer Res ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054768

RESUMO

Adipocytes are critical for ovarian cancer (OvCa) cells to home to the omentum, but the metabolic changes initiated by this interaction are unknown. To this end, we carried out unbiased mass spectrometry-based metabolomic and proteomic profiling of cancer cells co-cultured with primary human omental adipocytes. Cancer cells underwent significant proteo-metabolomic alteration(s), typified by changes in the lipidome with corresponding upregulation of lipid metabolism proteins. FABP4, a lipid chaperone protein, was identified as the critical regulator of lipid responses in OvCa cells co-cultured with adipocytes. Subsequently, knockdown of FABP4 resulted in increased 5-hydroxymethylcytosine levels in the DNA, downregulation of gene signatures associated with OvCa metastasis and reduced clonogenic cancer cell survival. In addition, CRISPR-mediated knockout of FABP4 in high-grade serous OvCa cells reduced metastatic tumor burden in mice. Consequently, a small molecule inhibitor of FABP4 (BMS309403) not only significantly reduced tumor burden in a syngeneic orthotopic mouse model but also increased the sensitivity of cancer cells towards carboplatin both in vitro and in vivo. Taken together, these results show that targeting FABP4 in OvCa cells can inhibit their ability to adapt and colonize lipid-rich tumor microenvironments, providing an opportunity for specific metabolic targeting of OvCa metastasis.

2.
Int J Gynecol Pathol ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31985579

RESUMO

Clear cell papillary cystadenoma of the epididymis is an uncommon benign neoplasm, usually seen in patients with von Hippel-Lindau disease. Morphologic and immunohistochemical examination aid in distinguishing clear cell papillary cystadenoma from malignant histologic mimics including low-grade mesothelial proliferations and metastatic clear cell renal cell carcinomas. Analogous lesions have been described in the female genital tract, often posing diagnostic challenges due to their low incidence. Here, we present the difficult diagnostic aspects of the first case of clear cell papillary cystadenoma involving the ovary, including the salient immunohistochemical, ultrastructural, and molecular characteristics.

3.
Acta Cytol ; 64(1-2): 63-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30889579

RESUMO

The association between high-risk genotypes of human papillomavirus (hr-HPV) and cervical cancer is well established. As hr-HPV testing is rapidly becoming a part of routine cervical cancer screening, either in conjunction with cytology or as primary testing, the management of hr-HPV-positive women has to be tailored in a way that increases the detection of cervical abnormalities while decreasing unnecessary colposcopic biopsies or other invasive procedures. In this review, we discuss the overall utility and strategies of hr-HPV testing, as well as the advantages and limitations of potential triage strategies for hr-HPV-positive women, including HPV genotyping, p16/Ki-67 dual staining, and methylation assays.


Assuntos
Citodiagnóstico/métodos , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Detecção Precoce de Câncer/métodos , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Papillomaviridae/fisiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Triagem , Neoplasias do Colo do Útero/complicações
4.
Pediatr Ann ; 48(12): e495-e500, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830290

RESUMO

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495-e500.].

5.
Mod Pathol ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591497

RESUMO

Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.

6.
Breast Cancer Res ; 21(1): 82, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340854

RESUMO

BACKGROUND: Non-ER nuclear receptor activity can alter estrogen receptor (ER) chromatin association and resultant ER-mediated transcription. Consistent with GR modulation of ER activity, high tumor glucocorticoid receptor (GR) expression correlates with improved relapse-free survival in ER+ breast cancer (BC) patients. METHODS: In vitro cell proliferation assays were used to assess ER-mediated BC cell proliferation following GR modulation. ER chromatin association following ER/GR co-liganding was measured using global ChIP sequencing and directed ChIP analysis of proliferative gene enhancers. RESULTS: We found that GR liganding with either a pure agonist or a selective GR modulator (SGRM) slowed estradiol (E2)-mediated proliferation in ER+ BC models. SGRMs that antagonized transcription of GR-unique genes both promoted GR chromatin association and inhibited ER chromatin localization at common DNA enhancer sites. Gene expression analysis revealed that ER and GR co-activation decreased proliferative gene activation (compared to ER activation alone), specifically reducing CCND1, CDK2, and CDK6 gene expression. We also found that ligand-dependent GR occupancy of common ER-bound enhancer regions suppressed both wild-type and mutant ER chromatin association and decreased corresponding gene expression. In vivo, treatment with structurally diverse SGRMs also reduced MCF-7 Y537S ER-expressing BC xenograft growth. CONCLUSION: These studies demonstrate that liganded GR can suppress ER chromatin occupancy at shared ER-regulated enhancers, including CCND1 (Cyclin D1), regardless of whether the ligand is a classic GR agonist or antagonist. Resulting GR-mediated suppression of ER+ BC proliferative gene expression and cell division suggests that SGRMs could decrease ER-driven gene expression.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Cromatina/metabolismo , Mutação , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Ligação Proteica , Transcrição Genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mod Pathol ; 32(10): 1508-1520, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31186530

RESUMO

Atypical hyperplasia/endometrial intraepithelial neoplasia is an accepted precursor to endometrioid-type endometrial carcinoma. Mismatch repair-deficient endometrial carcinomas are also known to be a biologically and clinically distinct subset of tumors. However, the development of microsatellite instability in endometrial carcinogenesis has not yet been evaluated by novel next-generation sequencing-based methods. We examined 17 mismatch repair-deficient endometrioid endometrial carcinomas and their paired atypical hyperplasia/endometrial intraepithelial neoplasia precursors using a next-generation sequencing panel with quantitative microsatellite instability detection at 336 loci. Findings were compared to histological features, polymerase chain reaction-based microsatellite instability testing, immunohistochemical expression of mismatch repair proteins, and tumor mutational burden calculations. All 17 endometrial carcinomas and 8/17 atypical hyperplasia/endometrial intraepithelial neoplasia showed microsatellite instability by next-generation sequencing-based testing. Endometrial carcinoma specimens showed significantly more unstable microsatellite loci than paired atypical hyperplasia/endometrial intraepithelial neoplasia (mean: 40.0% vs 19.9 unstable loci, respectively). Out of nine microsatellite-stable atypical hyperplasia/endometrial intraepithelial neoplasia specimens, four showed mismatch repair loss by immunohistochemistry. All atypical hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens with microsatellite instability were also mismatch repair-deficient by immunohistochemistry. Tumor mutational burden was significantly greater in endometrial carcinoma than in paired atypical hyperplasia/endometrial intraepithelial neoplasia specimens, and tumor mutational burden was significantly correlated with percent unstable microsatellite loci. Paired atypical hyperplasia/endometrial intraepithelial neoplasia and endometrial carcinoma specimens show progressive accumulation of unstable microsatellite loci following loss of mismatch repair protein expression. Comprehensive next-generation sequencing-based testing of endometrial carcinomas offers new insights into endometrial carcinogenesis and opportunities for improved tumor surveillance, diagnosis, and management.

8.
Nature ; 569(7758): 723-728, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043742

RESUMO

High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Nicotinamida N-Metiltransferase/metabolismo , Proteômica , Fibroblastos Associados a Câncer/enzimologia , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA , Progressão da Doença , Feminino , Histonas/química , Histonas/metabolismo , Humanos , Metástase Neoplásica , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Prognóstico , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo
9.
CA Cancer J Clin ; 69(4): 258-279, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074865

RESUMO

Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite-instable, metastatic disease, anti- programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.

10.
Int J Gynecol Pathol ; 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30807370

RESUMO

We present an instructive case of FIGO grade 1 endometrioid endometrial carcinoma with a biphasic morphology, corresponding to subclonal loss of mismatch repair proteins (MMRP) MLH1 and PMS2 by immunohistochemistry and subclonal microsatellite instability. A pulmonary metastasis represented only the tumor component with retention of MMRPs. This case illustrates the need for pathologists to recognize and report heterogenous expression of MMRPs in endometrial carcinoma, to consider tumor heterogeneity when selecting foci for molecular studies, and to re-evaluate MMRP expression in tumor metastases, when clinically indicated. These considerations are particularly important as the relevance of MMRP expression in endometrial cancer expands beyond Lynch syndrome screening, into a new role as a predictive marker for immunotherapy.

11.
Diagn Cytopathol ; 47(6): 579-583, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30794347

RESUMO

BACKGROUND: Fine-needle aspiration (FNA) is frequently utilized in the diagnostic workup of lymphadenopathy. We evaluated the correlation of cytopathology with flow cytometry and tissue biopsy results and assessed the prevalence of specific malignancies in young adults presenting with cervical lymphadenopathy. METHODS: Database was searched for cervical lymph node FNA performed by a cytopathologist in patients aged 18-30 years from 2005 to 2017. RESULTS: Cervical lymph node FNA was performed on 48 patients without prior history of malignancy. Nineteen patients had cytology results only, of which all were interpreted as benign reactive lymph node. None developed subsequent malignancies. The remaining 29 patients had cytology with flow cytometry and/or tissue biopsy results. A benign reactive cytology diagnosis was rendered in 18 (62%) cases, of which 11 had concordant diagnosis on flow cytometry, 2 had tissue biopsy, and 3 had both. Eleven (38%) patients had cytology results concerning for a hematologic malignancy, of which 7 were confirmed by flow cytometry and 3 by both flow cytometry and tissue biopsy. Cervical lymph node FNA has 94.1% sensitivity, 83.3% specificity, 88.9% positive predictive value, and 90.9% negative predictive value. The most common hematologic malignancy in our young adult population presenting with cervical lymphadenopathy was Hodgkin lymphoma. CONCLUSION: FNA is a useful first-line diagnostic procedure for assessing cervical lymphadenopathy in young adults to allow for better triage of specimens for flow cytometry and/or tissue biopsy concerning for a hematologic malignancy and potentially avoid invasive excisional biopsy in a proportion of cases.


Assuntos
Vértebras Cervicais/patologia , Citometria de Fluxo , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/diagnóstico , Linfadenopatia/complicações , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
12.
Int J Gynecol Pathol ; 38(4): 346-352, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29620587

RESUMO

Mucolipidosis type II, also known as I-cell disease, is an autosomal recessive inborn error of metabolism, resulting from loss-of-function mutations in GNPTAB. Affected infants exhibit multiple physical anomalies and developmental delay, and death from disease follows in early childhood. Here we present an instructive case of mucolipidosis type II affecting 1 fetus and placental disk in a dichorionic-diamnionic twin pregnancy delivered at 36-wk gestation. The second twin and placental disk showed no abnormality. On microscopic examination, the affected placenta displayed marked vacuolization of the syncytiotrophoblast and Hofbauer cells, which was confirmed on ultrastructural examination. To our knowledge, this is the first description of placental findings in a twin pregnancy, wherein only 1 twin is affected by an inborn error of metabolism. This provides an opportunity to highlight the placental abnormalities seen in this group of diseases, and to emphasize the role of pathologic examination in early detection of otherwise unsuspected inborn errors of metabolism.


Assuntos
Mucolipidoses/diagnóstico por imagem , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Adulto , Feminino , Feto , Humanos , Recém-Nascido , Masculino , Mucolipidoses/genética , Mucolipidoses/patologia , Placenta/anormalidades , Placenta/diagnóstico por imagem , Placenta/patologia , Gravidez , Gravidez de Gêmeos , Gêmeos
13.
Am J Clin Pathol ; 151(1): 86-94, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30212867

RESUMO

Objectives: Bethesda category III (atypia of undetermined significance/follicular lesion of undetermined significance) includes sparsely cellular specimens with nuclear atypia (3N) and/or architectural atypia (3A). This study investigates whether the two types of atypia have different rates of malignancy (ROMs). Methods: Cytologic and histologic diagnoses of resected thyroid nodules were recorded. ROM was calculated for all Bethesda categories and for 3N and 3A subcategories. Possible noninvasive follicular thyroid neoplasms with papillary-like nuclear features were reviewed and removed from malignancies, and ROM was recalculated. Results: A total of 1,396 nodules were included. ROM of 3N (33.3%-26.0%) was higher than 3A (7.7%-5.0%) (P < .0001) and was similar to suspicious for follicular neoplasm (25.0%-20.3%) (P = .3). ROM of 3A approached benign (2.4%-1.5%) (P = .02). Conclusions: Strong consideration should be given to separating 3N (nuclear atypia with higher risk for papillary thyroid carcinoma) from 3A (architectural atypia with higher chance of being benign) to convey different ROMs.


Assuntos
Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Biópsia por Agulha Fina , Citodiagnóstico , Humanos , Neoplasias , Câncer Papilífero da Tireoide/diagnóstico , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/patologia
14.
Int J Gynecol Pathol ; 38(1): 97-102, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29257039

RESUMO

Urothelial carcinoma (UC) invasive into the muscularis propria or tumors unresponsive to treatment are indications for cystectomy. In females, with the goal of achieving complete cancer eradication and for concerns of UC extension into the adjacent pelvic organs, this may also warrant resection of the gynecologic organs. This study is aimed to assess the prevalence of unanticipated gynecologic neoplasms in anterior pelvic exenteration specimens. A retrospective review of pathology reports to identify women undergoing anterior pelvic exenteration for UC was performed (N=221), and incidentally discovered gynecologic tract neoplasms were recorded. Concomitant malignant or premalignant lesions of the gynecologic tract were identified in 8 patients (3.6%). These included endometrial adenocarcinoma [endometrioid type, International Federation of Gynecology and Obstetrics grade 1 (n=2, 0.9%)], cervical high-grade squamous intraepithelial lesion (n=2, 0.9%), Sertoli-Leydig cell tumor of intermediate differentiation (n=1, 0.5%), endometrioid adenocarcinoma of the ovary (n=1, 0.5%), and high-grade serous carcinoma of the ovary (n=1, 0.5%) and fallopian tube (n=1, 0.5%). Benign uterine neoplasms included leiomyomas (n=81, 37%), adenomyoma (n=3, 1.4%), and adenomatoid tumors (n=2, 0.9%). Benign ovarian neoplasms included serous cystadenoma (n=7, 3%), serous cystadenofibroma (n=4, 2%), benign Brenner tumor (n=5, 2.3%), mature teratoma (n=4, 2%), stromal luteoma (n=2, 0.9%), mucinous cystadenoma (n=1, 0.5%), thecoma (n=1, 0.5%), and endometrioid cystadenoma (n=1, 0.5%). Involvement of the gynecologic tract by UC was identified in 11 patients (5%). Spread of UC to the reproductive organs is rare in anterior pelvic exenteration specimens. Coexisting neoplasms of the gynecologic tract are occasionally identified, therefore careful evaluation of these organs is necessary.


Assuntos
Carcinoma de Células de Transição/patologia , Neoplasias dos Genitais Femininos/patologia , Neoplasias Urológicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/cirurgia , Cistectomia , Feminino , Humanos , Pessoa de Meia-Idade , Exenteração Pélvica , Estudos Retrospectivos , Neoplasias Urológicas/cirurgia
15.
Autops. Case Rep ; 8(4): e2018049, Oct.-Dec. 2018. ilus, graf
Artigo em Inglês | LILACS | ID: biblio-986574

RESUMO

5-Fluorouracil (5-FU), in combination with other cytotoxic drugs, is commonly used to treat a variety of cancers. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite. Approximately 0.3% of the population demonstrate complete DPD deficiency, translating to extreme toxicity of 5-FU. Here we present a case of a patient who had a fatal outcome after treatment with 5-FU who was found to have an unknown DPD deficiency discovered at autopsy.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Deficiência da Di-Hidropirimidina Desidrogenase/patologia , Fluoruracila/toxicidade , Neoplasias de Cabeça e Pescoço , Autopsia , Evolução Fatal , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Fluoruracila/uso terapêutico , Linfonodos
16.
Gynecol Oncol Rep ; 25: 94-97, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30014022

RESUMO

•Embryonal rhabdomyosarcoma of the uterine cervix and ovarian Sertoli-Leydig cell tumors are associated with DICER1 mutation•DICER1-associated tumors should prompt genetic counseling and testing•Somatic and germline genetic mutation profiles can be used to differentiate second primary from recurrent tumors.

17.
J Mammary Gland Biol Neoplasia ; 23(1-2): 59-73, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29687293

RESUMO

Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown. Here, in the first comprehensive longitudinal study of MG development in nulliparous female rats (from puberty through young adulthood; 8-25 wks of age), we quantify the spatial gradient of differentiation within the MG of socially stressed (isolated) and control (grouped) rats. We then demonstrate that social isolation increased stress reactivity to everyday stressors, resulting in downregulation of glucocorticoid receptor (GR) expression in the MG epithelium. Surprisingly, given that chemical carcinogens increase MG cancer risk by preventing normal terminal end bud (TEB) differentiation, chronic isolation stress did not alter TEBs. Instead, isolation blunted MG growth and alveolobular differentiation and reduced epithelial cell proliferation in these structures. Social isolation also enhanced corpora luteal progesterone at all ages but reduced estrogenization only in early adulthood, a pattern that precludes modulated ovarian function as a sufficient mechanism for the effects of isolation on MG development. This longitudinal study of natural variation provides an integrated view of MG development and the importance of increased GR activation in nulliparous ductal growth and alveolobular differentiation. Thus, social isolation and its physiological sequelae disrupt MG growth and differentiation and suggest a contribution of stress exposure during puberty and young adulthood to the previously observed increase in invasive MG cancer observed in chronically socially-isolated adult Sprague-Dawley rats.


Assuntos
Glândulas Mamárias Animais/patologia , Estresse Psicológico/patologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Epiteliais/patologia , Feminino , Estudos Longitudinais , Neoplasias Mamárias Animais/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
18.
Gynecol Oncol ; 149(3): 570-574, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29656794

RESUMO

OBJECTIVE: Universal screening of endometrial cancer (EC) for Lynch syndrome (LS) has been increasingly implemented in the past five to ten years. Most pathologists initiate screening with immunohistochemistry (IHC) for mismatch repair proteins (MMRPs), using either pre-surgical samplings (endometrial biopsy or curettage, EMB/C) or hysterectomy specimens. We report a systematic assessment of the equivalence of IHC for LS screening on EMB/C versus hysterectomy specimens. METHODS: We identified 99 patients diagnosed with endometrioid EC and performed IHC for MMRPs MLH1, MSH2, MSH6, and PMS2 on their diagnostic EMB/C and paired hysterectomy specimen. Each specimen was scored as MMRP-retained or MMRP-deficient. RESULTS: Ninety-one EMB/Cs had carcinoma, while 8 EMB/Cs showed only complex atypical hyperplasia (CAH). Carcinoma was identified in all 99 hysterectomy specimens. Considering all 99 patients tested, concordance of MMRP expression pattern between EMB/C and paired hysterectomy specimen was 100%. Sixty-nine cases retained all four MMRPs, while 30 were MMRP deficient (26 MLH1- and PMS2-deficient, 3 MSH2- and MSH6-deficient, 1 PMS2-deficient). CONCLUSIONS: In screening for LS in EC, IHC for MMRPs can be performed with identical accuracy on either EMB/C or hysterectomy specimens. Routine testing of diagnostic EMB/Cs may lead to earlier detection of MMRP deficiency, with improved patient uptake of genetic counseling and potential for earlier identification of immunotherapy candidates. Furthermore, reliable IHC-based LS screening performed on EMB/C can guide patient management and genetic counseling in patients unable to undergo hysterectomy.


Assuntos
Carcinoma Endometrioide/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Curetagem , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Imuno-Histoquímica , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Adulto Jovem
19.
Clin Cancer Res ; 24(14): 3433-3446, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29636357

RESUMO

Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone.Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig).Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012).Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. Clin Cancer Res; 24(14); 3433-46. ©2018 AACR.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Transcriptoma , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Prognóstico , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , Receptores Estrogênicos/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Neuroradiol J ; 31(4): 415-419, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29513076

RESUMO

N-methyl-D-aspartate receptor encephalitis (NMDARe) is one of 13 autoimmune-mediated encephalitides that have been discovered over the last decade. This case report describes the course of a 26-year-old female who presented with new-onset seizures and insomnia, complicated by encephalitis. The initial workup ruled out common causes of encephalitis, while a transvaginal ultrasound (TVUS), and computed tomography (CT) scans of the chest, abdomen, and pelvis did not identify a mass. Based on the suspicion that she may have autoimmune encephalitis, the patient was treated with intravenous immunoglobulins and plasma exchange, but continued to deteriorate. Whole-body positron emission tomography (PET) scan identified a small hypermetabolic pelvic mass. Shortly thereafter serum and cerebral spinal fluid NMDAR antibody titers were reported as positive, prompting repetition of the TVUS, which confirmed the presence of an ovarian teratoma. The patient had a laparoscopic oophorectomy with subsequent resolution of her symptoms, further confirming the diagnosis. Despite the sensitivities of TVUS and CT of up to 94% and 98%, respectively, the teratoma was unusually small, necessitating the addition of a PET scan to identify the lesion. These neoplasms are thought to have low uptake on PET; however, it is possible that focal inflammation may have enhanced the detection. It is unlikely that the teratoma grew during hospitalization as the average growth rate is 1.8 mm per year. Regardless, the lesson that can be learned is that imaging modalities beyond CT and TVUS, such as PET, can be helpful, as identification of a resectable tumor may alter management and ultimately improve outcomes.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encéfalo/diagnóstico por imagem , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico , Ovário/diagnóstico por imagem , Teratoma/complicações , Teratoma/diagnóstico , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/terapia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/terapia , Convulsões/diagnóstico , Convulsões/etiologia , Convulsões/terapia , Teratoma/patologia , Teratoma/terapia
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