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2.
Cancer Immunol Immunother ; 67(5): 805-814, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29484464

RESUMO

BACKGROUND: To characterize the expression of co-signaling molecules PD-L1, PD-1, and B7-H3 in cutaneous squamous cell carcinoma (cSCC) by immune status. METHODS: We retrospectively analyzed 66 cases of cSCC treated with surgical resection from 2012 to 2015. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (Tum-PD-L1%), B7-H3 (Tum-B7-H3%), density of peri and intratumoral CD8 T cells (CD8 density), proportion of CD8 T cells expressing PD-1 (CD8-PD-1%) and of tumor-infiltrating immune cells (TII) expressing PD-L1 (TII-PD-L1%). RESULTS: Of 66 cases, 42 were immunocompetent, 24 immunosuppressed (13 organ transplant, 8 HIV+, 3 other). Defining positive expression at > 5%, 26% of tumors were positive for PD-L1, 85% for B7-H3, 80% had CD8 T cells that expressed PD-1 and 55% had TII that expressed PD-L1. Tum-B7-H3% was significantly higher (median 60 vs. 28%, p = 0.025) in immunocompetent vs. immunosuppressed patients, including when factoring in cause of immunosuppression. No significant difference in Tum-PD-L1%, TII-PD-L1%, CD8 density, or CD8-PD-1% was observed. Tumors from HIV+ patients lacked PD-L1 expression, and had lower B7-H3% (median 2.5 vs. 60%, p = 0.007), and higher CD8 density (median 75% vs. 40%, p = 0.04) compared to immunocompetent patients. Higher tumor grade (Rs = 0.34, p = 0.006) and LVI (Rs = 0.61, p < 0.001) were both associated with higher Tum-PD-L1%. CONCLUSION: cSCC showed expression of PD-L1 on tumor in 26% of cases, and high tumor B7-H3 expression (85%) and PD-1 expression on CD8 TILs (80%). Tumor B7-H3 expression was significantly higher in immunocompetent vs. immunosuppressed patients, largely driven by very low expression in HIV+ patients.


Assuntos
Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Imunocompetência/imunologia , Hospedeiro Imunocomprometido/imunologia , Terapia de Imunossupressão , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
3.
Am J Obstet Gynecol ; 219(5): 459.e1-459.e11, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30096321

RESUMO

BACKGROUND: Black women with endometrial cancer are more likely to die of their disease compared with white women with endometrial cancer. These survival disparities persist even when disproportionately worse tumor characteristics among black women are accounted. Receipt of less complete adjuvant treatment among black patients with endometrial cancer could contribute to this disparity. OBJECTIVE: We assessed the hypothesis that black women with endometrial cancer are less likely than their white counterparts to receive adjuvant treatment within subgroups defined by tumor characteristics in the NRG Oncology/Gynecology Oncology Group 210 Study. STUDY DESIGN: Our analysis included 615 black and 4283 white women with endometrial cancer who underwent hysterectomy. Women completed a questionnaire that assessed race and endometrial cancer risk factors. Tumor characteristics were available from pathology reports and central review. We categorized women as low-, intermediate-, or high-risk based on the European Society for Medical Oncology definition. Adjuvant treatment was documented during postoperative visits and was categorized as no adjuvant treatment (54.3%), radiotherapy only (16.5%), chemotherapy only (15.2%), and radiotherapy plus chemotherapy (14.0%). We used polytomous logistic regression to estimate odds ratios and 95% confidence intervals for multivariable-adjusted associations between race and adjuvant treatment in the overall study population and stratified by tumor subtype, stage, or European Society for Medical Oncology risk category. RESULTS: Overall, black women were more likely to have received chemotherapy only (odds ratio, 1.40; 95% confidence interval, 1.04-1.86) or radiotherapy plus chemotherapy (odds ratio, 2.01; 95% confidence interval, 1.54-2.62) compared with white women in multivariable-adjusted models. No racial difference in the receipt of radiotherapy only was observed. In tumor subtype-stratified models, black women had higher odds of receiving radiotherapy plus chemotherapy than white women when diagnosed with low-grade endometrioid (odds ratio, 2.04; 95% confidence interval, 1.06-3.93) or serous tumors (odds ratio, 1.81; 95% confidence interval, 1.07-3.08). Race was not associated with adjuvant treatment among women who had been diagnosed with other tumor subtypes. In stage-stratified models, we observed no racial differences in the receipt of adjuvant treatment. In models that were stratified by European Society for Medical Oncology risk group, black women with high-risk cancer were more likely to receive radiotherapy plus chemotherapy compared with white women (odds ratio, 1.41; 95% confidence interval, 1.03-1.94). CONCLUSION: Contrary to our hypothesis, we observed higher odds of specific adjuvant treatment regimens among black women as compared with white women within specific subgroups of endometrial cancer characteristics.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Quimioterapia Adjuvante/estatística & dados numéricos , Neoplasias do Endométrio/terapia , Radioterapia Adjuvante/estatística & dados numéricos , População Branca/estatística & dados numéricos , Idoso , Terapia Combinada/estatística & dados numéricos , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Disparidades em Assistência à Saúde/etnologia , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances
4.
Gynecol Oncol ; 147(3): 648-653, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28969912

RESUMO

OBJECTIVE: Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , MicroRNAs/biossíntese , Recidiva Local de Neoplasia/genética , Receptor Notch2/biossíntese , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Recidiva Local de Neoplasia/metabolismo , Receptor Notch2/genética
5.
Gynecol Oncol ; 139(1): 70-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26341710

RESUMO

BACKGROUND: Few studies have analyzed relationships between risk factors for endometrial cancer, especially with regard to aggressive (non-endometrioid) histologic subtypes, and prognosis. We examined these relationships in the prospective NRG Oncology/Gynecologic Oncology Group 210 trial. METHODS: Prior to surgery, participants completed a questionnaire assessing risk factors for gynecologic cancers. Pathology data were derived from clinical reports and central review. We used the Fine and Gray subdistribution hazards model to estimate subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations between etiologic factors and cause-specific subhazards in the presence of competing risks. These models were stratified by tumor subtype and adjusted for stage and socioeconomic status indicators. RESULTS: Median follow-up was 60months after enrollment (range: 1day-118months). Among 4609 participants, a total of 854 deaths occurred, of which, 582 deaths were attributed to endometrial carcinoma. Among low-grade endometrioid cases, endometrial carcinoma-specific subhazards were significantly associated with age at diagnosis (HR=1.04, 95% CI=1.01-1.06 per year, P-trend) and BMI (class II obesity vs. normal BMI: HR=2.29, 95% CI=1.06-4.98, P-trend=0.01). Among high-grade endometrioid cases, endometrial carcinoma-specific subhazards were associated with age at diagnosis (HR=1.05, 95% CI=1.02-1.07 per year, P-trend<0.001). Among non-endometrioid cases, endometrial carcinoma-specific subhazards were associated with parity relative to nulliparity among serous (HR=0.55, 95% CI=0.36-0.82) and carcinosarcoma cases (HR=2.01, 95% CI=1.00-4.05). DISCUSSION: Several endometrial carcinoma risk factors are associated with prognosis, which occurs in a tumor-subtype specific context. If confirmed, these results would suggest that factors beyond histopathologic features and stage are related to prognosis. ClinicalTrials.gov Identifier: NCT00340808.


Assuntos
Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/mortalidade , Fatores Etários , Carcinoma Endometrioide/etiologia , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Obesidade/complicações , Obesidade/epidemiologia
6.
Int J Gynecol Pathol ; 34(4): 351-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25851710

RESUMO

Low-grade appendiceal mucinous neoplasms (LAMNs) are commonly associated with deposition of mucin, with or without admixed low-grade epithelium, on peritoneal surfaces (pseudomyxoma peritonei). We describe a very rare presentation of LAMN as extensive mucin deposition in the endometrium of a 43-yr-old woman initially mistaken for a primary uterine myxoid neoplasm. The patient underwent endometrial curettage that demonstrated abundant myxoid/mucoid material interspersed with small vessels, bland eosinophilic spindled cells, scattered foci of typical endometrial stroma, and occasional endometrioid glands. The endometrial stroma was positive for CD10, and the eosinophilic spindled cells were positive for actin. The lesion was interpreted as "myxoid/mucinous neoplasm, most likely of smooth muscle/endometrial stromal origin." Subsequent laparotomy revealed peritoneal mucin in the anterior cul-de-sac and a dilated appendix. Pathologic review confirmed appendiceal LAMN and multifocal peritoneal mucinosis. The uterus contained scant residual mucoid material. On review of all pathologic material at our institution, the endometrial lesion was consistent with organizing mucin derived from the LAMN with entrapped benign endometrium. "Pseudomyxoma endometrii" is readily mistaken for a primary uterine myxoid neoplasm, particularly myxoid endometrial stromal tumor. A key to diagnosis is recognition that the material is mucin rather than myxoid stroma. This is evidenced by the absence of embedded stromal cells and presence of myofibroblastic, vascular, and macrophage infiltration associated with organization. Epithelium containing goblet cells is an important clue if present. The presence of rare endometrial glands within the endometrial stroma suggests that the latter is entrapped rather than neoplastic.


Assuntos
Neoplasias do Apêndice/patologia , Biomarcadores Tumorais/metabolismo , Tumores do Estroma Endometrial/patologia , Neoplasias Peritoneais/patologia , Pseudomixoma Peritoneal/patologia , Neoplasias Uterinas/patologia , Adenocarcinoma Mucinoso/patologia , Adulto , Neoplasias do Apêndice/metabolismo , Tumores do Estroma Endometrial/metabolismo , Feminino , Humanos , Mucinas/metabolismo , Neoplasias Peritoneais/metabolismo , Pseudomixoma Peritoneal/metabolismo , Neoplasias Uterinas/metabolismo , Útero/metabolismo , Útero/patologia
7.
Cancer Causes Control ; 24(4): 749-57, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23378140

RESUMO

BACKGROUND: Emerging data suggest that ovarian cancers differ by tumor grade. However, the reliability of microscopic grade from paraffin tissue in the general medical community and as reflected in population-based cancer registries is unknown. METHODS: We examined grade agreement between two gynecologic pathologists and the Surveillance Epidemiology and End Results Residual Tissue Repository (SEER). Grade agreement was assessed with percent observer agreement and kappa coefficients for 664 invasive ovarian carcinomas, using previously defined three-tier and two-tier grading systems. A random subset of ovarian carcinomas was selected to compare intra- and inter-pathologist agreement. RESULTS: Five hundred and eighty-six of SEER's 664 tumors were confirmed invasive. Percent agreement was 49 % with fair kappa coefficient = 0.25 (95 % CI: 0.20-0.30) for the 664 tumors. Agreement improved slightly when restricted to the 586 confirmed invasive cancers; it was better for high grade than low grade tumors, for two-tier than three-tier grading systems, and within (66 %) than between study pathologists (43 %). Grade was not a robust independent predictor of ovarian cancer-specific survival. CONCLUSIONS: Grade agreement was fair between SEER and study pathologists irrespective of grading system. Recorded grade in SEER should be used with caution and is probably not a reliable metric for ovarian cancer epidemiology.


Assuntos
Adenocarcinoma de Células Claras/etiologia , Adenocarcinoma Mucinoso/etiologia , Cistadenocarcinoma Seroso/etiologia , Neoplasias do Endométrio/etiologia , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/sangue , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma Mucinoso/sangue , Adenocarcinoma Mucinoso/diagnóstico , Adulto , Idoso , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/diagnóstico , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/diagnóstico , Feminino , Seguimentos , Formaldeído , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/mortalidade , Inclusão em Parafina , Vigilância da População , Prognóstico , Fatores de Risco , Programa de SEER , Taxa de Sobrevida , Estados Unidos/epidemiologia
8.
Semin Diagn Pathol ; 30(4): 321-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24342288

RESUMO

Breast cancer is the most common women cancer and is the second leading cause of cancer-related mortality in women. While the last two decades revolutionized breast cancer treatment with the development and use of therapies targeting steroid receptors and HER2/neu, there are limits to the risk estimation provided by traditional clinicopathologic parameters and IHC. Therefore, there is continued potential for inaccurate risk stratification of breast cancer patients which may lead to over- or under-treatment. In this review, we discuss the latest developments in the area of breast cancer research which have lead to better understanding of the breast cancer mechanisms, provided more accurate risk stratification, and identified potential new treatment targets. Specifically, we review the new dualistic model of breast carcinogenesis, which can inform pathologic diagnosis and tumor grading; we also discuss the intrinsic molecular classification of breast cancer and its impact on diagnosis and treatment; lastly, we compare the most common commercial molecular prognostic and predictive assays, with their respective strengths and weaknesses, and their clinical utility.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transcriptoma/genética , Biomarcadores Tumorais/análise , Feminino , Perfilação da Expressão Gênica , Humanos
9.
Int J Cancer ; 131(8): 1921-9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22290745

RESUMO

Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.


Assuntos
Hiperplasia Endometrial/epidemiologia , Neoplasias do Endométrio/epidemiologia , Histerectomia , Planos de Pré-Pagamento em Saúde , Adulto , Hiperplasia Endometrial/cirurgia , Neoplasias do Endométrio/cirurgia , Feminino , Seguimentos , Humanos , Incidência , Prognóstico , Fatores de Tempo
10.
Breast Cancer Res Treat ; 131(1): 287-94, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21870130

RESUMO

Elevated levels of circulating estrogens and androgens are linked to higher breast cancer risk among postmenopausal women; however, little is known about hormone levels within the breast. Hormone concentrations within the breast may not be reflected in the blood and are likely important contributors to breast carcinogenesis. We used a previously validated method to measure levels of estrone, estradiol, androstenedione, and testosterone in adipose tissue removed as part of breast excisions performed for cancer in 100 postmenopausal women (69 ER/PR +/+ and 31 ER/PR -/-) participating in a breast cancer case-control study. We also measured the same steroid hormones, as well as estrone sulfate, and sex hormone-binding globulin (SHBG) in serum from these patients and 100 controls matched on ages at blood collection and on menopause. Overall, concentrations of serum hormones did not vary significantly between controls and cases. However, women with ER-/PR- breast cancers had lower circulating levels of all measured sex steroid hormones and higher SHBG levels than women with ER+/PR+ breast cancers and controls. Similarly, hormone concentrations in breast adipose tissue were higher among women with ER+/PR+ compared to ER-/PR- breast cancer, although differences were only significant for testosterone. These data demonstrate that high sex steroid concentrations in both serum and adipose tissues are more strongly related to ER+/PR+ than ER-/PR- breast cancers. Measurement of sex hormones in serum and in the microenvironment may help in understanding the hormonal etiology of breast cancer, suggest methods for prevention, and have value in gauging treatment response and prognosis.


Assuntos
Tecido Adiposo/fisiologia , Neoplasias da Mama/sangue , Hormônios Esteroides Gonadais/sangue , Adulto , Idoso , Androstenodiona/sangue , Índice de Massa Corporal , Estradiol/sangue , Estrona/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue
11.
J Clin Oncol ; 40(9): 968-977, 2022 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-35007153

RESUMO

PURPOSE: This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS). PATIENTS AND METHODS: Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test. RESULTS: The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant. CONCLUSION: PC was not inferior to the active regimen PI and should be standard treatment for UCS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinossarcoma , Neoplasias Ovarianas , Neoplasias Uterinas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Ifosfamida/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico
12.
Aging Cell ; 20(7): e13411, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34089289

RESUMO

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.


Assuntos
Envelhecimento/fisiologia , Células Satélites de Músculo Esquelético/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
JNCI Cancer Spectr ; 4(1): pkz075, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32337492

RESUMO

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) has been associated with approximately 50% breast cancer risk reduction among women with a pathogenic variant in BRCA1 or BRCA2 (BRCA1/2), a finding that has recently been questioned. METHODS: We estimated incidence rates of breast cancer and all cancers combined during 5 years of follow-up among participants selecting RRSO or ovarian cancer screening (OCS) among women with a BRCA1/2 pathogenic variant or strong breast and/or ovarian cancer family history. Ovarian or fallopian tube or peritoneal cancer incidence rates were estimated for the OCS group. Breast cancer hazard ratios (HRs) for time-dependent RRSO were estimated using Cox regression with age time-scale (4943 and 4990 women-years in RRSO and OCS cohorts, respectively). All statistical tests were two-sided. RESULTS: The RRSO cohort included 925 participants, and 1453 participants were in the OCS cohort (381 underwent RRSO during follow-up), with 88 incident breast cancers diagnosed. Among BRCA1/2 pathogenic variant carriers, a non-statistically significant lower breast cancer incidence was observed in the RRSO compared with the OCS cohort (HR = 0.86, 95% confidence interval = 0.45 to 1.67; P = .67). No difference was observed in the overall population or among subgroups stratified by prior breast cancer history or menopausal status. Seven fallopian tube and four ovarian cancers were prospectively diagnosed in the OCS cohort, and one primary peritoneal carcinoma occurred in the RRSO cohort. CONCLUSIONS: These data suggest that RRSO might be associated with reduced breast cancer incidence among women with a BRCA1/2 pathogenic variant, although the effect, if present, is small. This evolving evidence warrants a thorough discussion regarding the impact of RRSO on breast cancer risk with women considering this intervention.

14.
Mod Pathol ; 22(3): 450-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19136935

RESUMO

Selective progesterone receptor modulators are a class of drugs with progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating sex hormones, is likely to be perturbed by progesterone receptor modulators through their progesterone antagonist properties. We examined endometrial histology in 58 premenopausal women treated with the progesterone receptor modulator CDB-4124 (also known as Proellex) for endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after 3 or 6 months with doses of 12.5, 25, or 50 mg daily oral CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174 biopsies) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124-treated patients was generally inactive or atrophic, and less frequently, proliferative or secretory, superimposed upon which were novel changes including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124-treated subjects correlated with increased endometrial thickness by ultrasound. None of the CDB-4124-treated patients developed endometrial carcinoma or hyperplasia while on therapy. CDB-4124 therapy for 3-6 months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, particularly as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other progesterone receptor modulators, including cystic architecture and mixed non-physiologic epithelial changes will prevent misdiagnosis.


Assuntos
Endometriose/tratamento farmacológico , Endométrio/efeitos dos fármacos , Endométrio/patologia , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Endometriose/patologia , Feminino , Humanos , Leiomioma/patologia , Pré-Menopausa , Receptores de Progesterona/efeitos dos fármacos , Neoplasias Uterinas/patologia
15.
Int J Gynecol Pathol ; 28(3): 234-8, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19620941

RESUMO

Clear cell sarcoma of soft tissue (CCSST) is a rare soft tissue neoplasm with marked variable tumor progression and prognosis. Although morphologically similar to malignant melanoma, CCSST can be distinguished by the presence of a t(12; 22)(q13; q12) and/or associated EWSR1-ATF1 chimeric gene. CCSST has an affinity for the extremities and is capable of metastasizing to a wide variety of sites including bone, lung, and lymph nodes and rarely to skin, liver, heart, muscle, and brain. Metastases have been known to occur as late as 29 years after initial presentation. We report a case of a 33-year-old woman who presented with bilateral ovarian cystic tumors, ascites, and pulmonary nodules. Her past medical history was significant for clear cell sarcoma of the left foot 2 years earlier. Bilateral salpingo-oophorectomy was performed and the light microscopic and immunohistochemical findings coupled with the detection of an EWSR1 rearrangement by fluorescence in situ hybridization were compatible with a diagnosis of CCSST metastases to the ovaries. To the best of our knowledge, this is the first reported case of CCSST metastatic to the ovaries.


Assuntos
Neoplasias Ovarianas/secundário , Sarcoma de Células Claras/secundário , Neoplasias de Tecidos Moles/patologia , Adulto , Proteínas de Ligação a Calmodulina/genética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Ovariectomia , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/cirurgia , Neoplasias de Tecidos Moles/genética
16.
Cancer Epidemiol Biomarkers Prev ; 17(8): 1891-5, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18708377

RESUMO

BACKGROUND: The lack of validated methods for measuring sex steroid hormones in breast tissue has limited our knowledge of their role in the development of breast cancer. We explored the feasibility of measuring hormones in breast adipocytes for epidemiologic and clinical studies by refining an existing assay procedure and assessing the reliability of hormone measurements using the modified assay. This report presents the reproducibility of measurements of androstenedione (A), testosterone (T), estrone (E(1)), and estradiol (E(2)), using breast adipose tissue samples obtained from women undergoing surgical resection for a variety of pathologic conditions. METHODS: Breast adipose tissues were obtained from 20 women. Measurements of the steroid hormones were carried out by harvesting oil from adipocytes following enzymatic digestion of the adipose tissue, extracting and chromatographing the steroids, and quantifying them by RIA. The study was conducted in three phases: first, samples from five women were used to assess the assay procedure; following this, tissues from an additional five women were assayed repeatedly to determine reproducibility of the hormone measurements. Finally, using samples from 10 women undergoing surgical resection of a breast tumor, we evaluated hormone concentrations in samples distal and proximal to the tumor. The assay coefficient of variation and intraclass correlation coefficient were used to assess hormone reproducibility. RESULTS: The within-batch coefficients of variation ranged from 5% to 17%, and between-batch estimates were between 2% and 10%, suggesting that E(1), E(2), A, and T can be reliably measured in breast adipocytes. Among samples obtained from women undergoing surgical resection of a breast tumor, hormone levels did not differ between adipose tissue fragments that were distal or proximal to the tumor, with the possible exception of E(1) in which levels were 10% higher in distal fragments. CONCLUSION: These data support the feasibility of measuring steroid hormone concentrations in breast adipocytes in epidemiologic studies. Future investigations that include the measurement of hormones in the breast microenvironment may have value in understanding breast carcinogenesis, developing prevention strategies, and assessing hormonal treatments.


Assuntos
Adipócitos/metabolismo , Neoplasias da Mama/metabolismo , Mama/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Mama/citologia , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Radioimunoensaio , Reprodutibilidade dos Testes
17.
Int J Gynecol Pathol ; 27(3): 318-25, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18580308

RESUMO

BACKGROUND: Identifying which categories in the World Health Organization classification of endometrial hyperplasia contribute to suboptimal reproducibility is clinically important. METHODS: A 2-member panel reviewed 209 endometrial biopsy/curettage specimens originally diagnosed as incident endometrial hyperplasia as part of a progression study. Original diagnoses included the following: disordered proliferative endometrium, simple hyperplasia, complex hyperplasia, and atypical hyperplasia; panel diagnoses also included negative and carcinoma. We assessed percentage agreement and kappa statistics+/-standard errors (K+/-SE). RESULTS: Original and panel diagnoses (combining negative with disordered proliferative endometrium; atypical hyperplasia with carcinoma) agreed for 34.9% of biopsies (K-unweighted+/-SE=0.18+/-0.03; K-weighted+/-SE=0.27+/-0.04). Panelists' diagnoses agreed (using 6 categories) for 51.7% of biopsies, corresponding to K-unweighted+/-SE=0.37+/-0.03, improving with weighting to K-weighted+/-SE=0.63+/-0.05. Reproducibility based on a 2-tier classification ([negative, disordered proliferative endometrium, simple hyperplasia, or complex hyperplasia] versus [atypical hyperplasia or carcinoma]) increased agreement between original and panel diagnoses to 82.8%, K-unweighted+/-SE=0.37+/-0.06, and between panelists to 87.0%, K-unweighted+/-SE=0.63+/-0.07. Agreement between panelists at a cutpoint of complex hyperplasia and more severe versus simple hyperplasia or less severe was 88.0%, K-unweighted+/-SE=0.72+/-0.07. CONCLUSIONS: Developing and prospectively testing a binary system of classifying endometrial hyperplasia on endometrial biopsy may aid efforts to improve interobserver reproducibility.


Assuntos
Hiperplasia Endometrial/classificação , Hiperplasia Endometrial/patologia , Biópsia , Feminino , Humanos , Reprodutibilidade dos Testes
18.
Int J Surg Pathol ; 26(4): 356-359, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29169272

RESUMO

Phyllodes tumor is a relatively uncommon fibroepithelial neoplasm of the breast characterized by proliferation of both stromal and epithelial elements. Benign phyllodes tumors are distinguished from fibroadenomas by their prominent leaf-like architecture and exaggerated intracanalicular stromal growth pattern. Typically, these lesions affect older natal females; however, we present what we believe is the first reported case of benign phyllodes tumor in a hormonally treated transgender woman.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Estrogênios/efeitos adversos , Tumor Filoide/induzido quimicamente , Pessoas Transgênero , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Tumor Filoide/patologia
19.
Lung Cancer ; 123: 87-90, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089601

RESUMO

OBJECTIVE: Co-signaling molecules PD-L1, B7-H3, and PD-1 play a key role in cancer immunology. There are limited but emerging data on expression of these molecules in HIV-infected lung cancer patients. MATERIALS AND METHODS: We reviewed archived lung cancer tissue samples from HIV-infected cases (n = 13) and HIV-uninfected controls (n = 13) from 2001-2015. Cases and controls were matched by histology and stage. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 and B7-H3, and percent of tumor infiltrating immune cells (TII) expressing PD-1 and PD-L1. Positive expression was defined as >5%. Statistical analysis was performed using the non-parametric Mann-Whitney test and the chi-square test. RESULTS: PD-L1 expression on tumor cells was positive in 23% of cases and 46% of controls. B7-H3 expression on tumor cells was positive in 92% of cases and 69% of controls. PD-1 expression on TII was positive in 69% of cases and 54% of controls. PD-L1 expression on TII was positive in 31% of cases and 69% of controls. B7-H3 percent expression on tumor cells was significantly higher in cases vs. controls (median 90% vs 20%, p = 0.005), but there were no significant differences in percent expression of PD-L1 on tumor cells, PD-1 on TII or PD-L1 on TII. CONCLUSION: HIV-infected lung cancer patients had significantly higher B7-H3 tumor expression compared to HIV-uninfected controls, with similar rates of tumor PD-L1 expression, as well as PD-1 and PD-L1 expression on TII. These results support inclusion of HIV-infected lung cancer patients in future immunotherapy trials.


Assuntos
Antígenos B7/genética , Antígeno B7-H1/genética , Infecções por HIV/complicações , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/genética , Adulto , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Feminino , Expressão Gênica , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/virologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos
20.
Gynecol Oncol ; 107(2): 177-85, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17822748

RESUMO

PURPOSE: After initial surgery, there has been no established consensus regarding adjunctive therapy for patients with uterine carcinosarcoma (CS). This study was designed to compare patient outcome following treatment with adjuvant whole abdominal irradiation (WAI) versus (vs.) chemotherapy for patients with this rare group of female pelvic malignancies. PATIENTS AND METHODS: Eligible, consenting women with stage I-IV uterine CS, no more than 1 cm postsurgical residuum and/or no extra-abdominal spread had their treatments randomly assigned as either WAI or three cycles of cisplatin (C), ifosfamide (I), and mesna (M). RESULTS: 232 patients were enrolled, of whom 206 (WAI=105; CIM=101) were deemed eligible. Patient demographics and characteristics were similar between arms. FIGO stage (both arms) was: I=64 (31%); II=26 (13%); III=92 (45%); IV=24 (12%). The estimated crude probability of recurring within 5 years was 58% (WAI) and 52% (CIM). Adjusting for stage and age, the recurrence rate was 21% lower for CIM patients than for WAI patients (relative hazard [RH]=0.789, 95% confidence interval [CI]: (0.530-1.176), p=0.245, 2-tail test). The estimated death rate was 29% lower among the CIM group (RH=0.712, 95% CI: 0.484-1.048, p=0.085, two-tail test). CONCLUSION: We did not find a statistically significant advantage in recurrence rate or survival for adjuvant CIM over WAI in patients with uterine CS. However, the observed differences favor the use of combination chemotherapy in future trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/radioterapia , Histerectomia , Mesna/uso terapêutico , Substâncias Protetoras/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/radioterapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinossarcoma/patologia , Carcinossarcoma/cirurgia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Esquema de Medicação , Feminino , Humanos , Ifosfamida/administração & dosagem , Incidência , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Radioterapia Adjuvante , Fatores de Risco , Análise de Sobrevida , Falha de Tratamento , Resultado do Tratamento , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
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