RESUMO
Percutaneous microwave ablation (MWA) is a promising technology for patients with breast cancer, as it may help treat individuals who have less aggressive cancers or do not respond to targeted therapies in the neoadjuvant or pre-surgical setting. In this study, we investigate changes to the microwave dielectric properties of breast tissue that are induced by MWA. While similar changes have been characterized for relatively homogeneous tissues, such as liver, those prior results are not directly translatable to breast tissue because of the extreme tissue heterogeneity present in the breast. This study was motivated, in part by the expectation that the changes in the dielectric properties of the microwave antenna's operation environment will be impacted by tissue composition of the ablation target, which includes not only the tumor, but also its margins. Accordingly, this target comprises a heterogeneous mix of malignant, healthy glandular, and adipose tissue. Therefore, knowledge of MWA impact on breast dielectric properties is essential for the successful development of MWA systems for breast cancer. We performed ablations in 14 human ex-vivo prophylactic mastectomy specimens from surgeries that were conducted at the UW Hospital and monitored the temperature in the vicinity of the MWA antenna during ablation. After ablation we measured the dielectric properties of the tissue and analyzed the tissue samples to determine both the tissue composition and the extent of damage due to the ablation. We observed that MWA induced cell damage across all tissue compositions, and found that the microwave frequency-dependent relative permittivity and conductivity of damaged tissue are lower than those of healthy tissue, especially for tissue with high fibroglandular content. The results provide information for future developments on breast MWA systems.
Assuntos
Técnicas de Ablação , Neoplasias da Mama/cirurgia , Micro-Ondas , Capacitância Elétrica , Condutividade Elétrica , Feminino , Humanos , Mastectomia , Projetos PilotoRESUMO
BACKGROUND: The purpose of this systematic review was to summarize previously published case reports of primary lung carcinoma metastasis to the breast to assess common clinical and pathologic features and management strategies. MATERIALS AND METHODS: Case reports describing breast metastasis of primary lung carcinoma were systematically evaluated in MEDLINE and EMBASE. RESULTS: Thirty-one reported cases of non-small-cell lung carcinoma (NSCLC) metastasized to the breast were identified, along with eight cases of small-cell lung carcinoma. Sixty-seven percent of reported NSCLC metastases to the breast were detected metachronously with the primary lung abnormality, whereas 80% of small-cell lung carcinoma breast metastases appeared synchronously. Thyroid transcription factor 1 was found to be expressed in 58% of total NSCLC breast metastases, including 83% of those of adenocarcinoma origin. Therapeutic strategies among NSCLC cases varied widely, and only 36% of NSCLC breast metastasis patients were administered chemotherapy. Additional sites of metastasis in these cases are summarized as well. CONCLUSIONS: It is recommended to include metastatic lung cancer in the differential diagnosis of patients presenting with a breast abnormality in the context of a suspected lung cancer. Thyroid transcription factor 1 expression should be examined in these cases. The metachronous versus synchronous nature of lung carcinoma metastasis to the breast has consequences for both detection of the primary and secondary lesions and patient outlook. Clinical correlation is vital to effective management of the care of patients harboring these atypical secondary lesions.
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Neoplasias da Mama/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares/patologia , Idoso , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/patologiaRESUMO
BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.
Assuntos
Antineoplásicos/administração & dosagem , Ciclofosfamida/administração & dosagem , Interleucina-2/análogos & derivados , Neoplasias/tratamento farmacológico , Idoso , Antígenos de Neoplasias , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Moléculas de Adesão Celular/metabolismo , Relação Dose-Resposta a Droga , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Interleucina-2/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/metabolismo , Análise de SobrevidaRESUMO
OBJECTIVE: During saline-infused sonohysterography (SIS), the distension fluid is typically discarded. If cytology analysis could identify those patients with endometrial cancer, many women would be spared from further procedures. METHODS: Thirty consecutive patients with clinical stage I or II endometrial adenocarcinoma were prospectively recruited preoperatively. Saline-infused sonohysterography was performed by instilling 5 mL of saline, withdrawing and sending for analysis. Saline was reinfused until complete SIS images were obtained and sent separately for cytology. RESULTS: Of the 30 women enrolled, SIS was technically successful in 29. Demographics included mean age (60.5 ± 6.99 years), body mass index (35.55 ± 8.18 kg/m), endometrioid histology (76%), and grade (grade 1, 67%). Prestudy diagnostic method included biopsy (70%), dilatation and curettage (17%), and hysteroscopy (10%). Adequate cytology specimens were obtained in 66% of the 5 mL flushes and 72% of the complete SIS collections. Of adequate specimens, the sensitivities to detect endometrial cancer for the 5-mL, complete, and combined fluid samples were 26% (95% confidence interval, 9%-51%), 36% (17%-59%), and 42% (22%-63%). Sensitivity based on the whole study sample (N = 30) was 33% (17%-53%). Statistical significance was not found in the association between a positive test and age, body mass index, grade, diagnostic method, or volume instilled or aspirated. CONCLUSIONS: Most patients with early endometrial cancer can undergo SIS procedures with adequate cytology specimens obtained from distention media. However, the sensitivity is low, and refinements are necessary before utilizing as a diagnostic test. In cases with positive results, the patient may be able to avoid other costly and painful procedures.
Assuntos
Adenocarcinoma Papilar/patologia , Carcinoma Adenoescamoso/patologia , Cistadenocarcinoma Seroso/patologia , Citodiagnóstico , Neoplasias do Endométrio/patologia , Endossonografia , Histeroscopia , Adenocarcinoma Papilar/diagnóstico por imagem , Carcinoma Adenoescamoso/diagnóstico por imagem , Cistadenocarcinoma Seroso/diagnóstico por imagem , Neoplasias do Endométrio/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos ProspectivosRESUMO
Uterine leiomyosarcoma comprises <1 % of uterine malignancies and is known for its clinically aggressive course. Extrapelvic recurrences are common and often lethal. No adjuvant therapies have been shown to significantly improve overall survival, highlighting the need for new and novel therapies. Our objective was to determine whether GD2-specific immunocytokine therapy may be explored for the treatment for uterine leiomyosarcoma. To do so, frozen tissue sections were obtained from the Gynecologic Oncology Group tumor bank and evaluated by immunohistochemistry (IHC) for GD2 expression using both the parent mouse monoclonal antibody 14G2A and immunocytokine 14.18-IL2 generated from the 14G2A sequence. Immunoreactivity was detected by avidin-biotin complex with DAB substrate. Specimens were reviewed by a pathologist with light microscopy and classified as negative, 1+, 2+ or 3+, compared to human melanoma cells as positive control and tissue incubated in the absence of primary antibody as negative control. GD2 was diffusely present in all evaluable samples. 10 tumors (67 %) demonstrated 3+ IHC intensity for GD2, two tumors (13 %) demonstrated 2+ intensity, and 3 (20 %) tumors demonstrated 1+ intensity. Eleven cases had sufficient tissue to assess 14.18-IL2 binding. All 11 cases bound 14.18-IL2 in a pattern identical to the parent antibody. Uterine leiomyosarcoma diffusely express GD2 and bind the therapeutic immunocytokine 14.18-IL2. This warrants further exploration to determine whether immunocytokine therapy may have a clinical role in the management of these aggressive tumors.
Assuntos
Anticorpos Monoclonais/imunologia , Gangliosídeos/biossíntese , Interleucina-2/metabolismo , Leiomiossarcoma/imunologia , Leiomiossarcoma/terapia , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/terapia , Animais , Anticorpos Monoclonais/metabolismo , Feminino , Gangliosídeos/imunologia , Humanos , Imuno-Histoquímica , Imunoterapia , Interleucina-2/imunologia , Leiomiossarcoma/metabolismo , Leiomiossarcoma/patologia , Camundongos , Estadiamento de Neoplasias , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologiaRESUMO
BACKGROUND: Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) is often used to assist in the evaluation of pancreatic lesions and may help to diagnose benign versus malignant neoplasms. However, there is a paucity of literature regarding comparative EUS characteristics of various malignant pancreatic neoplasms (primary and metastatic). OBJECTIVE: To compare and characterize primary pancreatic adenocarcinoma versus other malignant neoplasms, hereafter referred to as nonprimary pancreatic adenocarcinoma (NPPA), diagnosed by EUS-guided FNA. METHODS: The present study was a retrospective analysis of a prospectively maintained database. The setting was a tertiary care, academic medical centre. Patients referred for suspected pancreatic neoplasms were evaluated. Based on EUS-FNA characteristics, primary pancreatic adenocarcinoma was differentiated from other malignant neoplasms. The subset of other neoplasms was defined as malignant lesions that were 'NPPAs' (ie, predominantly solid or solid/cystic based on EUS appearance and primary malignant lesions or metastatic lesions to the pancreas). Pancreatic masses that were benign cystic lesions (pseudocyst, simple cyst, serous cystadenoma) and focal inflammatory lesions (acute, chronic and autoimmune pancreatitis) were excluded. RESULTS: A total of 230 patients were evaluated using EUS-FNA for suspected pancreatic mass lesions. Thirty-eight patients were excluded because they were diagnosed with inflammatory lesions or had purely benign cysts. One hundred ninety-two patients had confirmed malignant pancreatic neoplasms (ie, pancreatic adenocarcinoma [n=144], NPPA [n=48]). When comparing adenocarcinoma with NPPA lesions, there was no significant difference in mean age (P=0.0675), sex (P=0.3595) or average lesion size (P=0.3801). On average, four FNA passes were necessary to establish a cytological diagnosis in both lesion subtypes (P=0.396). Adenocarcinomas were more likely to be located in the pancreatic head (P=0.0198), whereas masses in the tail were more likely to be NPPAs (P=0.0006). Adenocarcinomas were also more likely to exhibit vascular invasion (OR 4.37; P=0.0011), malignant lymphadenopathy (P=0.0006), pancreatic duct dilation (OR 2.4; P=0.022) and common bile duct dilation (OR 2.87; P=0.039). CONCLUSIONS: Adenocarcinoma was more likely to be present in the head of the pancreas, have lymph node and vascular involvement, as well as evidence of pancreatic duct and common bile duct obstruction. Of all malignant pancreatic lesions analyzed by EUS-FNA, 25% were NPPA, suggesting that FNA is crucial in establishing a diagnosis and may be helpful in preoperative planning.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Idoso , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Use of genomic assays to determine distant recurrence risk in patients with early stage breast cancer has expanded and is now included in the American Joint Committee on Cancer staging manual. Algorithmic alternatives using standard clinical and pathology information may provide equivalent benefit in settings where genomic tests, such as OncotypeDx, are unavailable. We developed an artificial neural network (ANN) model to nonlinearly estimate risk of distant cancer recurrence. In addition to clinical and pathological variables, we enhanced our model using intraoperatively determined global mammographic breast density (MBD) and local breast density (LBD). LBD was measured with optical spectral imaging capable of sensing regional concentrations of tissue constituents. A cohort of 56 ER+ patients with an OncotypeDx score was evaluated. We demonstrated that combining MBD/LBD measurements with clinical and pathological variables improves distant recurrence risk prediction accuracy, with high correlation (r = 0.98) to the OncotypeDx recurrence score.
Assuntos
Neoplasias da Mama , Recidiva Local de Neoplasia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Humanos , Recidiva Local de Neoplasia/diagnóstico por imagem , Estadiamento de Neoplasias , Medição de RiscoRESUMO
We explored the use of both empirical (Partial Least Squares, PLS) and Monte Carlo model based approaches for the analysis of fluorescence and diffuse reflectance spectra measured ex vivo from freshly excised breast tissues and for the diagnosis of breast cancer. Features extracted using both approaches, i.e. principal components (PCs) obtained from empirical analysis or tissue properties obtained from model based analysis, displayed statistically significant difference between malignant and non-malignant tissues, and can be used to discriminate breast malignancy with comparable sensitivity and specificity of up to 90%. The PC scores of a subset of PCs also displayed significant correlation with the tissue properties extracted from the model based analysis, suggesting both approaches likely probe the same sources of contrast in the tissue spectra that discriminate between malignant and non-malignant breast tissues but in different ways.
Assuntos
Algoritmos , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Diagnóstico por Computador/métodos , Modelos Biológicos , Espectrometria de Fluorescência/métodos , Simulação por Computador , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: The purpose of this study was to evaluate sonohysterography in patients with endometrial cancer and to determine whether (1) transtubal fluid spill occurs during routine sonohysterography, (2) a critical infusion volume for spill exists, or (3) disseminated cancer cells demonstrate viability. STUDY DESIGN: At laparotomy, sonohysterography was performed on 16 patients with endometrial adenocarcinoma. Volumes at which tubal spill occurred were recorded. Collected specimens were processed and incubated. After evaluation for viable cells, cytologic analysis was undertaken. RESULTS: The median volume that was required for adequate sonohysterography was 8.5 mL. Five patients (31%) had transtubal spill. With an additional saline solution flush, the median total volume for a spill was 20.5 mL. Two patients (12.5%) had viable benign cells that were cultured after routine sonohysterography. One patient (6%) had nonviable carcinoma cells that were identified. CONCLUSION: Transtubal spill occurs during sonohysterography. No critical spill volume was identified. A highly diagnostic tool when abnormal bleeding is evaluated, sonohysterography has a low probability of cancer cell dissemination.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/patologia , Histerossalpingografia/efeitos adversos , Histerossalpingografia/métodos , Inoculação de Neoplasia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sobrevivência Celular , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Manejo de Espécimes , Ultrassonografia , Vagina/diagnóstico por imagemRESUMO
We explore the use of Monte-Carlo-model-based approaches for the analysis of fluorescence and diffuse reflectance spectra measured ex vivo from breast tissues. These models are used to extract the absorption, scattering, and fluorescence properties of malignant and nonmalignant tissues and to diagnose breast cancer based on these intrinsic tissue properties. Absorption and scattering properties, including beta-carotene concentration, total hemoglobin concentration, hemoglobin saturation, and the mean reduced scattering coefficient are derived from diffuse reflectance spectra using a previously developed Monte Carlo model of diffuse reflectance. A Monte Carlo model of fluorescence described in an earlier manuscript was employed to retrieve the intrinsic fluorescence spectra. The intrinsic fluorescence spectra were decomposed into several contributing components, which we attribute to endogenous fluorophores that may present in breast tissues including collagen, NADH, and retinol/vitamin A. The model-based approaches removes any dependency on the instrument and probe geometry. The relative fluorescence contributions of individual fluorescing components, as well as beta-carotene concentration, hemoglobin saturation, and the mean reduced scattering coefficient display statistically significant differences between malignant and adipose breast tissues. The hemoglobin saturation and the reduced scattering coefficient display statistically significant differences between malignant and fibrous/benign breast tissues. A linear support vector machine classification using (1) fluorescence properties alone, (2) absorption and scattering properties alone, and (3) the combination of all tissue properties achieves comparable classification accuracies of 81 to 84% in sensitivity and 75 to 89% in specificity for discriminating malignant from nonmalignant breast tissues, suggesting each set of tissue properties are diagnostically useful for the discrimination of breast malignancy.
Assuntos
Neoplasias da Mama/diagnóstico , Diagnóstico por Computador/métodos , Modelos Biológicos , Fotometria/métodos , Espectrometria de Fluorescência/métodos , Simulação por Computador , Feminino , Humanos , Modelos Estatísticos , Método de Monte Carlo , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Clostridium perfringens is an anaerobic gram positive rod that is found in normal vaginal and cervical flora in 1-10% of healthy women. Uterine infection with Clostridium perfringens is seen rarely but is often related to underlying uterine pathology and can progress quickly to sepsis. Early recognition of sepsis, prompt treatment with antibiotics, and source control with surgical management allow for optimal chance of recovery. We present a case of a postmenopausal woman who presented with sepsis, vaginal bleeding, and back pain who was found to have Clostridium perfringens infection in the setting of undifferentiated uterine sarcoma.
RESUMO
We describe a side-firing fiber optic sensor based on near-infrared spectroscopy for guiding core needle biopsy diagnosis of breast cancer. The sensor is composed of three side firing optical fibers (two source fibers and one detection fiber), providing two source-detector separations. The entire assembly is inserted into a core biopsy needle, allowing for sampling to occur at the biopsy site. A multi-wavelength frequency-domain near-infrared instrument is used to collect diffuse reflectance in the breast tissue through an aperture on the biopsy needle before the tissue is removed for histology. Preliminary in vivo measurements performed on 10 normal or benign breast tissues from 5 women undergoing stereo- or ultrasound-guided core needle biopsy show the ability of the system to determine tissue optical properties and constituent concentrations, which are correlated with breast tissue composition derived from histopathology.
RESUMO
The efficacy of emerging microwave breast cancer detection and treatment techniques will depend, in part, on the dielectric properties of normal breast tissue. However, knowledge of these properties at microwave frequencies has been limited due to gaps and discrepancies in previously reported small-scale studies. To address these issues, we experimentally characterized the wideband microwave-frequency dielectric properties of a large number of normal breast tissue samples obtained from breast reduction surgeries at the University of Wisconsin and University of Calgary hospitals. The dielectric spectroscopy measurements were conducted from 0.5 to 20 GHz using a precision open-ended coaxial probe. The tissue composition within the probe's sensing region was quantified in terms of percentages of adipose, fibroconnective and glandular tissues. We fit a one-pole Cole-Cole model to the complex permittivity data set obtained for each sample and determined median Cole-Cole parameters for three groups of normal breast tissues, categorized by adipose tissue content (0-30%, 31-84% and 85-100%). Our analysis of the dielectric properties data for 354 tissue samples reveals that there is a large variation in the dielectric properties of normal breast tissue due to substantial tissue heterogeneity. We observed no statistically significant difference between the within-patient and between-patient variability in the dielectric properties.
Assuntos
Mama/fisiologia , Capacitância Elétrica , Condutividade Elétrica , Mamoplastia , Micro-Ondas/uso terapêutico , Feminino , HumanosRESUMO
The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%.
Assuntos
Neoplasias da Mama/fisiopatologia , Mama/fisiopatologia , Micro-Ondas , Modelos Biológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Simulação por Computador , Impedância Elétrica , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The frequency-dependent complex moduli of human uterine tissue have been characterized. Quantification of the modulus is required for developing uterine ultrasound elastography as a viable imaging modality for diagnosing and monitoring causes for abnormal uterine bleeding and enlargement, as well assessing the integrity of uterine and cervical tissue. The complex modulus was measured in samples from hysterectomies of 24 patients ranging in age from 31 to 79 years. Measurements were done under small compressions of either 1 or 2%, at low pre-compression values (either 1 or 2%), and over a frequency range of 0.1-100 Hz. Modulus values of cervical tissue monotonically increased from approximately 30-90 kPa over the frequency range. Normal uterine tissue possessed modulus values over the same range, while leiomyomas, or uterine fibroids, exhibited values ranging from approximately 60-220 kPa.
Assuntos
Colo do Útero/diagnóstico por imagem , Doenças Uterinas/diagnóstico , Útero/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Histerectomia , Leiomioma/diagnóstico , Leiomioma/diagnóstico por imagem , Pessoa de Meia-Idade , Modelos Anatômicos , Modelos Estatísticos , Ultrassonografia , Doenças Uterinas/diagnóstico por imagem , Útero/patologiaRESUMO
BACKGROUND: Estrogen receptor beta (ERß) is expressed by 50% to 80% of triple-negative breast cancers (TNBC). Agonism of ERß has antiproliferative effects in TNBC cells expressing ERß. This phase 2 study evaluated single-agent high-dose estradiol in patients with advanced TNBC. PATIENTS AND METHODS: Adult women with measurable advanced TNBC were treated with estradiol 10 mg oral 3 times daily provided continuously for 28-day cycles. A Simon optimal 2-stage design was used. The primary end point was objective response (OR). Secondary end points included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB, and PFS by ERß status were also examined. RESULTS: Seventeen evaluable women were enrolled. Median age was 58 years (range, 34-90 years); the median number of prior systemic therapies was 2 (range, 0-6). One patient had a confirmed partial response (OR rate, 5.9%) and remained on the study for > 24 weeks. Three patients had stable disease, with one lasting more than 16 weeks. ERß expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ERß-positive patients and 0% (0 of 4) in ERß-negative patients (P = 1). PFS was poor (median, 1.9 months) and not statistically significantly different between ERß-positive versus -negative patients. No new adverse events from estradiol were identified. The study closed after the first stage as a result of limited responses in these unselected patients. CONCLUSION: In unselected TNBC, high-dose estradiol has limited efficacy. However, further evaluation of ERß selective agonists in TNBC selected by ERß expression may be warranted.
Assuntos
Estradiol/administração & dosagem , Estradiol/uso terapêutico , Receptor beta de Estrogênio/agonistas , Estrogênios/uso terapêutico , Terapia de Alvo Molecular , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Esquema de Medicação , Término Precoce de Ensaios Clínicos , Estradiol/efeitos adversos , Receptor beta de Estrogênio/metabolismo , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , WisconsinRESUMO
Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple-negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase 1 (HPRT1), suggesting an elevated gene-dosage of HPRT1 in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy. Mol Cancer Ther; 15(1); 48-59. ©2015 AACR.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Descoberta de Drogas , Poliploidia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzoquinonas/química , Benzoquinonas/farmacologia , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Cariótipo , Prognóstico , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Ultrasound elastography is envisioned as an optional modality to augment standard ultrasound B-mode imaging and is a promising technique to aid in detecting uterine masses which cause abnormal uterine bleeding in both pre- and post-menopausal women. In order to determine the effectiveness of strain imaging, mechanical testing to establish the elastic contrast between normal uterine tissue and stiffer masses such as leiomyomas (fibroids) and between softer pathologies such as uterine cancer and adenomyosis has to be performed. In this paper, we evaluate the stiffness of normal uterine tissue, leiomyomas, and endometrial cancers using a EnduraTEC ElectroForce (ELF) system. We quantify the viscoelastic characteristics of uterine tissue and associated pathologies globally by using two mechanical testing approaches, namely a dynamic and a quasi-static (ramp testing) approach. For dynamic testing, 21 samples obtained from 18 patients were tested. The testing frequencies were set to 1, 10, 20, and 30 Hz. We also report on stiffness variations with pre-compression from 1% to 6% for testing at 2%, 3%, and 4% strain amplitude. Our results show that human uterine tissue stiffness is both dependent on percent pre-compression and testing frequencies. For ramp testing, 20 samples obtained from 14 patients were used. A constant strain rate of 0.1% was applied and comparable results to dynamic testing were obtained. The mean modulus contrast at 2% amplitude between normal uterine tissue (the background) and leiomyomas was 2.29 and 2.17, and between the background and cancer was 0.47 and 0.39 for dynamic and ramp testing, respectively.
Assuntos
Neoplasias do Endométrio/fisiopatologia , Leiomioma/fisiopatologia , Útero/fisiologia , Adulto , Elasticidade , Feminino , Humanos , Pressão , Estresse Mecânico , ViscosidadeRESUMO
The authors report, to the best of their knowledge, the first case of lumbosacral choristoma of breast origin, presenting in a young girl with lumbosacral lipomyelomeningocele. Although choristomas are considered to be benign, the regrowth of this mass when the patient was 15 and 16 years of age, and its involvement in the conus medullaris and cauda equina, warranted 2 additional resections with spinal cordotomy resulting in cessation of any further growth. The authors describe the case and provide a review of pertinent literature and a discussion of the mechanisms involving the development and growth of this lesion.
Assuntos
Mama , Coristoma/diagnóstico , Meningomielocele/diagnóstico , Doenças da Coluna Vertebral/diagnóstico , Adolescente , Criança , Coristoma/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Vértebras Lombares , Imageamento por Ressonância Magnética , Sacro , Doenças da Coluna Vertebral/cirurgiaRESUMO
Three-dimensional impedance maps (3DZMs) are virtual volumes of acoustic impedance values constructed from histology to represent tissue microstructure acoustically. From the 3DZM, the ultrasonic backscattered power spectrum can be predicted and model based scatterer properties, such as effective scatterer diameter (ESD), can be estimated. Additionally, the 3DZM can be exploited to visualize and identify possible scattering sites, which may aid in the development of more effective scattering models to better represent the ultrasonic interaction with underlying tissue microstructure. In this study, 3DZMs were created from a set of human fibroadenoma samples. ESD estimates were made assuming a fluid-filled sphere form factor model from 3DZMs of volume 300×300×300 µm. For a collection of 33 independent human fibroadenoma tissue samples, the ESD was estimated to be 111±40.7 µm. The 3DZMs were then investigated visually to identify possible scattering sources which conformed to the estimated model scatterer dimensions. This estimation technique allowed a better understanding of the spatial distribution and variability of the estimates throughout the volume.