Expression of PGRMC1 in patients with polycystic ovary syndrome and its molecular mechanism for regulating ovarian granulosa cell apoptosis and glucolipid metabolism / 中南大学学报(医学版)

OBJECTIVES@#Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases in women with reproductive age, which is associated with hyperandrogenism, insulin resistance, and ovulatory dysfunction. Progesterone receptor membrane component 1 (PGRMC1) can mediate progesterone to inhibit the apoptosis of ovarian granulosa cells and the growth of follicles, and to induce glucolipid metabolism disorder in ovarian granulosa cells, which is closely related to the occurrence and development of PCOS. This study aims to determine the expression of PGRMC1 in serum, ovarian tissue, ovarian granulosa cells, and follicular fluid in PCOS patients and non-PCOS patients, analyze the value of PGRMC1 in diagnosis and prognosis evaluation of PCOS, and investigate its molecular mechanism on ovarian granulosa cell apoptosis and glucolipid metabolism.@*METHODS@#A total of 123 patients were collected from the Department of Obstetrics and Gynecology in Guangdong Women and Children Hospital (hereinafter referred to as "our hospital") from August 2021 to March 2022 and divided into 3 groups: a PCOS pre-treatment group (n=42), a PCOS treatment group (n=36), and a control group (n=45). The level of PGRMC1 in serum was detected by enzyme linked immunosorbent assay (ELISA). The diagnostic and prognostic value of PGRMC1 was evaluated in patients with PCOS by receiver operating characteristic (ROC) curve. Sixty patients who underwent a laparoscopic surgery from the Department of Obstetrics and Gynecology in our hospital from January 2014 to December 2016 were collected and divided into a PCOS group and a control group (n=30). The expression and distribution of PGRMC1 protein in ovarian tissues were detected by immunohistochemical staining. Twenty-two patients were collected from Reproductive Medicine Center in our hospital from December 2020 to March 2021, and they divided into a PCOS group and a control group (n=11). ELISA was used to detect the level of PGRMC1 in follicular fluid; real-time RT-PCR was used to detect the expression level of PGRMC1 mRNA in ovarian granulosa cells. Human ovarian granular cell line KGN cells were divided into a scrambled group which was transfected with small interfering RNA (siRNA) without interference and a siPGRMC1 group which was transfected with specific siRNA targeting PGRMC1. The apoptotic rate of KGN cells was detected by flow cytometry. The mRNA expression levels of PGRMC1, insulin receptor (INSR), glucose transporter 4 (GLUT4), very low density lipoprotein receptor (VLDLR), and low density lipoprotein receptor (LDLR) were determined by real-time RT-PCR.@*RESULTS@#The serum level of PGRMC1 in the PCOS pre-treatment group was significantly higher than that in the control group (P<0.001), and the serum level of PGRMC1 in the PCOS treatment group was significantly lower than that in the PCOS pre-treatment group (P<0.001). The areas under curve (AUC) of PGRMC1 for the diagnosing and prognosis evaluation of PCOS were 0.923 and 0.893, respectively, and the cut-off values were 620.32 and 814.70 pg/mL, respectively. The positive staining was observed on both ovarian granulosa cells and ovarian stroma, which the staining was deepest in the ovarian granulosa cells. The average optical density of PGRMC1 in the PCOS group was significantly increased in ovarian tissue and ovarian granulosa cells than that in the control group (both P<0.05). Compared with the control group, the PGRMC1 expression levels in ovarian granulosa cells and follicular fluid in the PCOS group were significantly up-regulated (P<0.001 and P<0.01, respectively). Compared with the scrambled group, the apoptotic rate of ovarian granulosa cells was significantly increased in the siPGRMC1 group (P<0.01), the mRNA expression levels of PGRMC1 and INSR in the siPGRMC1 group were significantly down-regulated (P<0.001 and P<0.05, respectively), and the mRNA expression levels of GLUT4, VLDLR and LDLR were significantly up-regulated (all P<0.05).@*CONCLUSIONS@#Serum level of PGRMC1 is increased in PCOS patients, and decreased after standard treatment. PGRMC1 could be used as molecular marker for diagnosis and prognosis evaluation of PCOS. PGRMC1 mainly localizes in ovarian granulosa cells and might play a key role in regulating ovarian granulosa cell apoptosis and glycolipid metabolism.

Progestinas y cáncer de mama en terapia de reemplazo hormonal: cómo actúan y qué alternativas son más seguras / Progestins and breast cancer in hormone replacement therapy: how do they work, and what alternatives are safer

En algunos estudios se ha asociado a la terapia de reemplazo hormonal (TRH) con estrógenos y progestinas a un mayor riesgo de cáncer de mama que la terapia con estrógenos solos. Sin embargo, dependiendo de su naturaleza algunas progestinas serían más seguras que otras. Se buscaron y analizaron artículos atingentes al tema en las bases de datos Google Scholar, PubMed, Science, SciELO y Cochrane, introduciendo los siguientes términos: terapia de reemplazo hormonal y cáncer de mama, progestinas y cáncer de mama, receptor de progesterona. Específicamente se ha asociado a las progestinas sintéticas acetato de medroxiprogesterona, noretisterona y levonorgestrel con un mayor riesgo de cáncer de mama, no así a la progesterona natural, a la progesterona oral micronizada ni a la didrogesterona. La progesterona natural, progesterona micronizada y didrogesterona serían más seguras en TRH para evitar el desarrollo de cáncer de mama, lo que estaría dado por la mayor especificidad en su acción.

In some studies, hormone replacement therapy (HRT) with estrogens and progestins has been associated with a higher risk of breast cancer than therapy with estrogens alone. However, depending on their nature, some progestins may be safer than others. This article analyzes the mode of action of progesterone in breast tissue and also the role of some progestins in the development of this pathology. Articles related to the subject were searched for and analyzed in Google Scholar, PubMed, Science, SciELO and Cochrane databases, introducing the following terms: hormone replacement therapy and breast cancer, progestins and breast cancer, progesterone receptor. Specifically, synthetic progestins medroxyprogesterone acetate, norethisterone, and levonorgestrel have been associated with an increased risk of breast cancer, but not natural progesterone, micronized oral progesterone, or dydrogesterone. Natural progesterone, micronized progesterone and dydrogesterone would be safer in HRT to prevent the development of breast cancer, which would be due to the greater specificity of their action.

Establishment and comparison of two methods to produce a rat model of mammary gland hyperplasia with hyperprolactinemia

Abstract This study aimed to establish and compare models of mammary gland hyperplasia (MGH) with hyperprolactinemia (HPRL) using two different methods. The models provide information on the relationship between mammary gland hyperplasia and associated hormones. Model A was constructed using intramuscular injections of estradiol benzoate injection (EBI), followed by progesterone (P), and then metoclopramide dihydrochloride (MDI). Model B was designed by administering MDI, follow by EBI, and then P intramuscularly. Model B showed higher MGH progression compared with model A. Notably, increase in estradiol (E2) was negatively correlated with prolactin (PRL) secretion. However, PRL levels in model B were significantly higher compared with the levels in model A. Estrogen (ER), prolactin receptor (PRLR), and progesterone receptor (PR) mRNA and protein expression levels in model B rats were positively correlated with changes in the corresponding hormone levels. However, E2, P, and PRL levels in model A showed no direct relationship with levels of the mRNAs of related hormones and protein expression levels. Our results suggest that model B is an appropriate model of MGH with HPRL that can be used to perform further studies about the interactions of the E2, P, and PRL hormones in this disorder.

Searching for the emotional roots of breast cancer: A cross-disciplinary analysis integrating psychology, Chinese medicine, and oncology biomarkers / 中西医结合学报

OBJECTIVE@#We employed a multidisciplinary approach incorporating theoretical ideas, clinical experience, psychology, physiology, traditional Chinese medicine (CM), modern practice of CM, and oncology to explore the effect of patients' repression of negative emotions and traumatic events on breast cancer (BC) pathogenesis.@*METHODS@#BC female patients, older than 18 years of age, with available pathology reports who were treated at Rabin Medical Center were recruited. All participants completed questionnaires regarding medical history, behavioral tendencies, negative emotions, trauma, symptoms, and pathology (from a CM perspective). Data on tumor characteristics were collected from the pathology reports. The associations were examined using hierarchical binary logistic regressions.@*RESULTS@#A total of 155 BC patients were enrolled. The median age was 52 years, with a range of 26-79; 95% were mothers; 28% had estrogen receptor (ER)-negative BC, 52% had progesterone receptor (PR)-negative BC, 48% had human epidermal growth factor receptor 2-negative BC, and antigen Ki-67 ≥ 20% was reported for 52% of tumors. Statistically significant associations were found between the emotional markers (sense of motherhood failure, and lack of self-fulfillment), avoidance behavior, and physical symptoms that are related to emotional repression based on CM. Significant associations were also found between variables associated with physical symptoms of emotional repression, which involves the production and accumulation of non-substantial phlegm (i.e., "high-lipid Qi-like microscopic phlegm"), avoidance behavior which unconsciously uses "high-lipid Qi-like microscopic phlegm" in order to achieve emotional repression, and tumor parameters including tumor grade, PR status, and Ki-67. Patients with higher levels of "high-lipid Qi-like microscopic phlegm" were more likely to have tumors with worse prognosis (PR-negative, higher grade, and higher Ki-67).@*CONCLUSION@#We demonstrated a relationship between emotional parameters, behavioral tendencies, CM parameters, and oncologic parameters in BC. Additional research is warranted to explore these associations and their relevance to clinical practice.

Integrated optical density analysis of the immunohistochemical expression of the progesterone receptor in the uterine endometrium of prepubertal araucana sheep / Análisis por densidad óptica integrada de la expresión inmunohistoquímica del receptor de progesterona en el endometrio uterino de ovejas prepúberes de raza araucana

SUMMARY: Progesterone receptors are expressed in the reproductive organs of adult sheep, where they regulate morphofunctional and reproductive development. However, various studies have shown the presence of these receptors in the uterus of prepubertal females. It is not clear what role these receptors have at this level of development in uterine tissue. Therefore, it is relevant as a first step in the investigation, to determine the expression and histological distribution of the progesterone receptor in prepubertal sheep in order to determine possible functions at this level of reproductive development. Immunohistochemical analysis allows visualizing the specific presence of a protein in the cellular and histological context, however, the results displayed through digital images are qualitative data and subject to the observer's criteria. In this work, a quantitative analysis method of immunohistochemical expression of the progesterone receptor in ovine endometrium is presented, using digital analysis of images, by means of integrated optical density of digital photographs of histological sections processed with immunohistochemical methods. The results show the possibility of quantitatively evaluating the expression of progesterone receptors in the endometrial stroma and prepubertal endometrial glands by applying the integrated optical density analysis of digital images.

RESUMEN: Los receptores de progesterona se expresan en los órganos reproductores de ovejas adultas, donde regulan el desarrollo morfofuncional y reproductivo. Sin embargo, diversos estudios han demostrado la presencia de estos receptores en útero de hembras prepúberes. No está claro, el papel que estos receptores tienen en este nivel de desarrollo en tejido uterino. Por lo que, es relevante como primer paso en la investigación, determinar la expresión y distribución histológica del receptor de progesterona en ovejas prepúberes con el fin determinar posibles funciones en este nivel de desarrollo reproductivo. El análisis inmuno- histoquímico permite visualizar la presencia específica de una proteína en el contexto celular e histológico, sin embargo, los resultados visualizados a través de imágenes digitales, son datos cualitativos y sujeto al criterio del observador. En este trabajo se presenta un método de análisis cuantitativo de expresión inmunohistoquímica del receptor de progesterona en endometrio ovino, utilizando análisis digital de imágenes, mediante densidad óptica integrada de fotografías digitales de cortes histológicos procesados con métodos inmunohistoquímicos. Los resultados muestran la posibilidad de evaluar cuantitativamente la expresión de los receptores de progesterona en el estroma endometrial y las glándulas endometriales prepúberes aplicando el análisis de densidad óptica integrado de imágenes digitales.

Evaluation of progesterone receptor expression in low- and high-grade astrocytomas

SUMMARY OBJECTIVE: Gliomas are tumors originating from glial cells. Gliomas are the most common primary neoplasms of the central nervous system, with astrocytomas being the most prevalent glioma subtype. Progesterone regulates several reproductive processes, such as ovulation and sexual behavior, and influences neuronal excitability, learning, and the neoplastic proliferation of glial cells. Progesterone functions mainly by interacting with intracellular progesterone receptors to modify the expression of the genes involved in cell proliferation, angiogenesis, and epidermal growth factor production. As not many studies on the hormone receptors in glial tumors have been reported, the objective of this study was to evaluate the expression of these proteins in astrocytomas and to determine whether their expression levels vary according to the tumor grade. METHODS: This was a retrospective study using glial tumor paraffin blocks obtained from the São Marcos Hospital Pathology Department archives. Forty cases were divided equally into two groups, based on histological types and the World Health Organization criteria (low- and high-grade tumors). Progesterone receptor expression was analyzed by immunohistochemistry. The data were statistically analyzed using the Mann-Whitney U test and Spearman's correlation coefficient; results with p<0.05 were considered statistically significant. RESULTS: There were no statistically significant differences between the mean nuclear progesterone receptor expression of low-grade (0.1495) and high-grade (0.0937) astrocytomas (p=0.2). CONCLUSION: Progesterone receptors are present in both low- and high-grade gliomas; however, there is no significant difference in the levels of progesterone receptor expression between the tumor grades.

Rol del receptor de progesterona como factor pronóstico de recidiva en cáncer de mama / Role of the progesterone receptor as a pronostic factor for breast cáncer recurrence

Introducción: las pacientes con cáncer de mama con receptores hormonales positivos mantienen una tasa de recurrencia significativa durante el seguimiento prolongado. La predicción del patrón de recurrencia puede ayudar en el desarrollo de estrategias específicas de vigilancia y tratamiento en pacientes con cáncer de mama. Material y método: estudio analítico observacional, de cohorte retrospectivo en el cual se analizaron los datos de 203 pacientes del Hospital J. M. Penna en el periodo comprendido entre enero de 2005 y enero 2015. Objetivo: el objetivo principal de este trabajo es evaluar la asociación que existe entre los receptores de progesterona (RP) negativos (0%) con probabilidad de recaída local y a distancia luego del tratamiento del cáncer de mama. Resultados: las pacientes con RP negativo mostraron mayor edad que las pacientes con RP positivo (61,24+/-12,4 años vs 57+/-13.7; p=0,0480), menor porcentaje de pacientes premopáusicas (17,54% vs 35,62%; p=0,012); y también una mayor tendencia de compromiso ganglionar axilar (36,9% vs 26,,5%; p=0,098). En el análisis multivariado no se observó que el estatus negativo en los RP sea un factor de riesgo independiente para recidiva local (OR=1,28; IC95%=0,44-3,68), recidiva en forma independiente menor SLE (OR=1,18, IC95%0,52-2,64). Conclusiones: en esta población no se logró demostrar asociación significativa independiente de otros factores entre el estatus negativo de los RP y la supervivencia libre de enfermedad en las pacientes operadas de cáncer de mama. El análisis de los resultados nos demuestra la necesidad de realizar nuevos estudios, con un mayor número de pacientes y mayor tiempo de seguimiento, para dilucidar el real papel del RP

Introduction: patients with breast cancer with positive hormone receptors maintain a significant recurrence rate during prolonged follow-up. Predicting the pattern of recurrence can aid in the development of specific surveillance and treatment strategies in patients with breast cancer. Material and method: observational, retrospective cohort analytic study that analyzed the data of 2003 patients of Hospital José María Penna between january 2005 and january 2015. Objetive: the main objetive of this stydy is to evaluate the correlation that exists between negative (0%) progesterone receptors (PR) and the likelihood of local and distant relapse after treatment of breast cancer. Results: patients with negative PR showed greater age than patients with positive PR (61.24+/-12.4 years old vs 57+/-13.7; p=0,048), lower percentage of postmenopausal patients (17.54% vs 35.62&; p=0.012), and also a greater tendency of axillary lymph node involvement (36.9% vs 26.5%; p=0.098). In the multivariate analysis it was not observed that the negative status in the PR is an independent risk factor for local recurrence (OR 1.28; CI95% 0.44 - 3.68), distant recurrence (OR 1.33; CI95% 0.55 - 3.21), or a factor that conditions independently lower DFS (OR 1.18; CI95% 0.52 - 2.64). Conclusions: in this population it was not possible to demonstrate significant correlation independent of other factors between the negative status of PR and the disease-free survival in patients who underwent surgery for breast cancer. The analysis of the results shows the need to carry out new studies, with a larger number of patients and longer follow-up time, to understand the real role PR plays.

Cáncer de mama localmente avanzado. Neoadyuvancia: indicaciones y seguimiento / Locally advanced breast carcinoma. Neoadjuvant treatment: indications and follow up

El cáncer de mama localmente avanzado (CMLA) se manifiesta con grandes tumores (T3-4) y/o gran carga adenopática (N 1-2-3), sin metástasis a distancia e incluye estadios clínicos: II b, III a, III b y III c. La quimioterapia neoadyuvante (QTNA) es el tratamiento inicial para gran parte de las pacientes con CMLA y está indicada en pacientes con cáncer de mama operable e inoperable. Este tratamiento presenta algunas ventajas como la reducción del tamaño del tumor primario (downstaging) y de ganglios positivos, permitiendo así más cirugías conservadoras, y la medición directa de la sensibilidad de las células tumorales. Un rol similar cumple la terapia endocrina neoadyuvante en tumores con receptores de estrógeno (RE) y receptores de progesterona (RP) positivos, al demostrar beneficios en reducción del volumen tumoral. Los anticuerpos monoclonales anti Her2 asociados a la QTNA aumentan la efectividad de esta última. La respuesta del CMLA a la neoadyuvancia se evalúa con la clínica y el estudio histológico de la pieza quirúrgica, con esta última, se monitorea enfermedad residual a través de la respuesta patológica completa (RCp) que es un importante factor pronóstico de la sobrevida libre de enfermedad (SLE) como de la sobrevida global (SG). El carcinoma mamario inflamatorio (CMI) posee distintas características clínicas, epidemiológicas y biológicas donde el tratamiento de inicio es la QTNA.

Immunohistochemical and clinicopathologic features of estrogen receptor-negative, progesterone receptor-positive, HER-2 negative breast carcinomas

SUMMARY OBJECTIVE: Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. METHODS: Tumors estrogen receptor -/progesterone receptor +, Her-2 - from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. RESULTS: Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. CONCLUSION: Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.

Comparação entre expressão de receptores hormonais e de HER-2 entre células tumorais circulantes e metástases de câncer de mama / Comparison of hormonal receptor expression and HER2 status in circulating tumor cells and breast cancer metastases

Introdução: O câncer de mama é a neoplasia mais comum em mulheres. A maioria deles é diagnosticada em estágios iniciais, quando o tratamento visa a cura. Mas apesar dos avanços no tratamento, metástases à distância podem ocorrer. A biópsia das lesões metastáticas é recomendada para confirmar o status do receptor de estrogênio (RE), receptor de progesterona (RP) e receptor do fator de crescimento epidérmico humano 2 (HER2), por ocorrerem discrepâncias nesses padrões entre tumores primários e metástases em até 40% dos casos. As células tumorais circulantes (CTCs) estão relacionadas às evoluções clínicas do câncer de mama e podem potencialmente desempenhar um papel substituto aos procedimentos invasivos de rebiópsia de metástase. A tecnologia ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, França) não é usualmente empregada para detectar CTCs em pacientes com câncer de mama, embora seja reconhecida como uma ferramenta útil em alguns outros tumores. Existem dados emergentes de que a caracterização da expressão proteica das CTC pode refinar seu valor prognóstico. Sabe-se que o fator de transformação de crescimento (TGF-ß) desempenha um papel na progressão e invasividade do câncer de mama. Objetivos: Comparar a expressão de RE, RP e HER2 em tumores primários, CTCs, metástases e avaliar a expressão do receptor TGF-ß tipo 1 (TGF-ß RI) em CTCs como fator prognóstico para sobrevida global. Metodologia: Estudo realizado no A.C.Camargo Cancer Center, Brasil. As amostras de sangue foram coletadas antes da biópsia guiada por tomografia computadorizada de lesões metastáticas suspeitas e processadas pela metodologia ISET®. Os níveis de expressão proteica das CTCs foram comparados aos de tumores primários e metástases e correlacionados aos resultados clínicos. Todos os dados clínicopatológicos foram obtidos dos prontuários médicos. Resultados: Dos 39 pacientes inicialmente incluídos, 27 tiveram tanto a biópsia de metástases quanto a coleta de sangue e foram considerados para análise. As taxas de concordância para a expressão de RE, RP e HER2 entre tumores primários e metástases foram altas. Não foi observada nenhuma perda de expressão de HER2 nas metástases e os tumores triplo negativos mantiveram o mesmo padrão em todas as metástases (p <0,0001). Quando as metástases e CTCs foram classificadas como triplo negativo (TN) ou não ­ TN, as CTCs determinaram alta especificidade (93%), acurácia (84,2%) e valor preditivo negativo (88%). A sobrevida global mediana de pacientes sem expressão de TGF-ß RI em CTCs foi de 42,6 x 20,8 meses para os positivos, clinicamente relevante, porém sem significância estatística (p> 0,05). Conclusões: No câncer de mama, o papel das CTCs detectadas pelo ISET® ainda não está estabelecido. Com este estudo, sugerimos que esta metodologia possa ser útil para avaliar metástases em casos de tumores não TN, assim como a expressão de TGF-ß RI em CTCs, o que pode impactar a sobrevida. Devido à limitação da amostra, estudos futuros devem se concentrar em subtipos específicos de câncer de mama, ampliando a coorte.

Introduction: Breast cancer (BC) is the most common neoplasm in women. Most of BC are diagnosed in early stages, when treatment aims cure. Despite advances in BC treatment, distant metastases may develop. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, due to discrepancies in these patterns between primary tumors/metastasis in up to 40% of cases. Circulating Tumor Cells (CTCs) are related to breast cancer outcomes and could potentially play a role surrogating invasive procedures of metastasis rebiopsy. ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, France) technology is not currently employed to detect CTCs in breast cancer patients, although recognized as a useful tool in some other tumors. There are emerging data that characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-ß play a role in progression/invasiveness of BC. Objectives: To compare ER, PR and HER2 expression in primary tumors, CTCs, metastases and to evaluate TGF-ß type 1 receptor (TGF- ß RI) expression in CTCs as prognostic factor for overall survival. Methods: Study conducted at the A.C.Camargo Cancer Center, Brazil. Blood samples were processed in ISET® before computed tomography­guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases and correlated to clinical outcomes. All clinicopathological data were obtained from medical records. Results: From the 39 patients initially included, 27 had both biopsy of metastases and blood collection and were considered for analysis. Concordance rates for ER, PR and HER2 expression between primary tumors/metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern in all triplenegative (TN) tumors (p <0.0001) were observed. When metastases/CTCs were classified as TN/non­TN, CTCs showed high specificity (93%), accuracy (84.2%) and negative predictive value (88%). The median overall survival of patients with no TGF-ß RI expression in CTCs was 42.6 x 20.8 months for positive ones, clinically relevant but not statistically significant (p>0.05). Conclusions: In BC, the role of CTCs detected by ISET® is not yet established. Here, we could suggest that this methodology may be useful to evaluate metastasis in non-TN cases as also TGF-ß RI expression in CTCs, which may impact survival. Due to sample limitation, future studies must focus on specific subtypes of BC, expanding the cohort.

Clinical information and management status of de novo stage IV breast cancer patients: a Chinese multicenter investigation (CSBrS-002) / 中华医学杂志(英文版)

BACKGROUND@#Although de novo stage IV breast cancer is so far incurable, it has entered an era of individualized treatment and chronic disease management. Based on systemic treatment, whether the surgical resection of primary or metastatic foci of de novo stage IV breast cancer can bring survival benefits is currently controversial. We aimed to explore the clinicopathological factors and current status of the management of de novo stage IV breast cancer in China to provide a reference for clinical decisions.@*METHODS@#Based on the assistance of Chinese Society of Breast Surgery, a retrospective study was conducted to analyze the clinical data of patients with de novo stage IV breast cancer in 33 centers from January 2017 to December 2018. The relationship between basic characteristic (age, menstrual status, family history, reproductive history, pathological type, estrogen receptor [ER] status, progesterone receptor [PR] status, human epidermal growth factor receptor 2 [HER2] status, Ki-67 percentage, and molecular subtype), and metastasis sites (lung metastasis, liver metastasis, and bone metastasis) was examined by Pearson Chi-square tests.@*RESULTS@#A total of 468 patients with de novo stage IV breast cancer were enrolled. The median age of the enrolled patients was 51.5 years. The most common pathological type of primary lesion was invasive carcinoma (97.1%). Luminal A, luminal B, HER2 overexpressing, and triple-negative subtypes accounted for 14.3%, 51.8%, 22.1%, and 11.8% of all cases, respectively. Age, PR status, and HER2 status were correlated with lung metastasis (χ2 = 6.576, 4.117, and 8.643 and P = 0.037, 0.043, and 0.003, respectively). Pathological type, ER status, PR status, and molecular subtype were correlated with bone metastasis (χ2 = 5.117, 37.511, 5.224, and 11.603 and P = 0.024, <0.001, 0.022, and 0.009, respectively). Age, PR status, HER2 status, Ki-67 percentage, and molecular subtype were correlated with liver metastasis (χ2 = 11.153, 13.378, 10.692, 21.206, and 17.684 and P = 0.004, <0.001, 0.001, <0.001, and 0.001, respectively). Combined treatment with paclitaxel and anthracycline was the most common first-line chemotherapy regimen for patients with de novo stage IV breast cancer (51.7%). Overall, 91.5% of patients used paclitaxel-containing regimens. Moreover, 59.3% of hormone receptor-positive patients underwent endocrine therapy.@*CONCLUSIONS@#In 2018, 1.07% of patients from all studied centers were diagnosed with de novo stage IV breast cancer. This study indicated that 95.1% of patients received systemic therapy and 54.2% of patients underwent surgical removal of the primary lesion in China.

Clinical and X-ray characteristics for expressions of different receptors in patients with breast cancer / 中南大学学报(医学版)

OBJECTIVES@#Clarifying the expression of breast cancer receptor is the key to clinical treatment for breast cancer. This study aims to explore the correlation between X-ray and clinical characteristics of 4 molecular subtypes and their receptor types of breast cancer.@*METHODS@#A total of 439 breast cancer patients who confirmed by pathology and performed X-ray examination were enrolled. The X-ray and clinical characteristics of 4 molecular subtypes and the expression of their receptors were analyzed.@*RESULTS@#Luminal A type showed the highest proportion of spiculate masses, and the lowest calcification score, showing significant difference with other 3 subtypes (all @*CONCLUSIONS@#Four molecular subtypes of breast cancer and their receptor expressions are correlated with X-ray and clinical characteristics, which can provide a basis for clinical diagnosis and treatment.

Survival rates of advanced estrogen-receptor positive breast cancer. Analysis of 211 cases

ABSTRACT Background: About 80% of breast cancer (BC) cases express estrogen receptor (ER), which has been correlated with good prognosis and response to estrogen deprivation Aim: To characterize ER positive advanced BC (ABC) patients treated at our institution assessing the impact of clinical pre-sentation (stage IV, de novo disease at diagnosis versus systemic recurrence) and BC subtype on survival rates. Material and Methods: We evaluated 211 ER+ advanced BC (ABC) patients, treated between 1997 and 2017. Results: The median overall survival (OS) was 37 months. Median OS for the period 1997/2006 and 2007/2017 were 33 and 42 months, respectively (p = 0.47). Luminal A, ABC stage IV disease at diagnosis displayed better OS rates than Luminal B stage IV tumors (100 and 32 months respectively, p < 0.01). Conclusions: Clinical presentation (stage IV vs. systemic recurrence) and tumor subtype are key determinants of OS in ABC.

Antecedentes: Casi el 80% de los casos de cáncer de mama (CM) son positivos para receptores de estrógenos (RE+). Éstos se caracterizan por una mejor sobrevida y respuesta a terapia endocrina. Objetivo: Caracterizar a pacientes con CM avanzado (CMA), RE+, y determinar sobrevida según presentación clínica y subtipos. Material y Métodos: Analizamos en nuestra base de datos los antecedentes de 211 pacientes con CMA RE+, tratados en nuestra institución en el período 1997-2017. Se evaluó el impacto de la presentación clínica (estadio IV al diagnóstico, enfermedad de novo, versus recurrencia sistémica) y subtipo de CM, en los niveles de sobrevida. Resultados: La mediana de sobrevida global (SG) fue de 37 meses. La mediana de SG para el período 1997/2006 y 2007/2017 fue de 33 y 42 meses; respectivamente (p = 0,47). Pacientes con CMA, estadio IV, Luminal A al momento del diagnóstico mostraron mejores tasas de SG frente al estadio IV del Luminal B (100 y 32 meses respectivamente (p < 0,01). Conclusiones: La presentación clínica (estadio IV, de novo, versus recurrencia sistémica) y subtipo son determinantes clave de la SG en CMA.

Progesterone and estrogen receptor expression by canine cutaneous soft tissue sarcomas / Expressão de receptores para progesterona e estrógeno em sarcomas de tecidos moles cutâneos em cães

Canine soft tissue sarcomas (STS) comprise a heterogeneous group of malignancies that share similar histopathological features, a low to moderate recurrence rate and low metastatic potential. In human medicine, the expression of estrogen receptors (ER) and progesterone receptors (PR) in sarcomas has been studied to search for prognostic factors and new treatment targets. Similar studies have yet to be conducted in veterinary medicine. The objective of this study was therefore to investigate by immunohistochemistry (IHC) the ER and PR expression in a series of 80 cutaneous and subcutaneous sarcomas in dogs with histopathological features of peripheral nerve sheath tumor (PNST) and perivascular wall tumor (PWT). All cases were positive for PR and negative for ER. Tumors of high malignancy grade (grade III) exhibited higher PR expression than low-grade tumors (grade I). Tumors with mitotic activity greater than 9 mitotic figures/10 high power fields also exhibited higher PR expression. In addition, there was a positive correlation between cell proliferation (Ki67) and PR expression. Therefore, it is possible that progesterone plays a greater role than estrogen in the pathogenesis of these tumors. Future studies should explore the potential for selective progesterone receptor modulators as therapeutic agents in canine STS, as well as evaluating PR expression as a predictor of prognosis.(AU)

Sarcomas de tecidos moles (STM) caninos compreendem um grupo heterogêneo de neoplasias malignas, que apresentam alterações histopatológicas similares, baixa a moderada taxa de recorrência e baixo potencial metastático. Em medicina humana, a expressão de receptor para estrógeno (RE) e receptor para progesterona (RP) nos sarcomas tem sido estudada, visando a busca por fatores prognósticos e novos alvos para tratamentos. Na medicina veterinária, ainda não foram realizados estudos similares. O objetivo deste trabalho foi investigar por imuno-histoquímica a expressão de RE e RP em uma série de 80 sarcomas cutâneos e subcutâneos de cães, com características histopatológicas de tumor de bainha de nervo periférico e tumor de parede perivascular. Todos os casos foram positivos para RP e negativos para RE. Tumores de alto grau de malignidade (grau III) exibiram maior expressão deste receptor que os tumores de baixo grau (grau I). Tumores com atividade mitótica maior que 9 figuras mitóticas/10 campos de grande aumento também exibiram maior expressão do RP. Em adição, houve correlação positiva entre o índice de proliferação celular (Ki67) e a expressão de RP. Assim, é possível que a progesterona desempenhe maior papel que o estrógeno na patogênese desses tumores. Futuros trabalhos poderão explorar o potencial dos moduladores seletivos de RP como agente terapêutico em STM caninos, bem como avaliar a expressão de RP como preditiva de prognóstico.(AU)

Shear-Wave Elastography of the Breast: Added Value of a Quality Map in Diagnosis and Prediction of the Biological Characteristics of Breast Cancer

Multi-center investigation of the clinical and pathological characteristics of inflammatory breast cancer based on Chinese Society of Breast Surgery (CSBrs-007) / 中华医学杂志(英文版)

BACKGROUND@#Inflammatory breast cancer (IBC) is an aggressive type of cancer with poor prognosis and outcomes. This study aimed to investigate clinicopathological features, molecular characteristics, and treatments among Chinese patients diagnosed with IBC.@*METHODS@#We collected data of 95 patients with IBC who were treated by members of the Chinese Society of Breast Surgery, from January 2017 to December 2018. The data, including demographic characteristics, pathological findings, surgical methods, systemic treatment plans, and follow-up, were obtained using a uniform electronic questionnaire. The clinicopathological features of different molecular types in patients without distant metastases were compared using the Kruskal-Wallis (H) test followed by post hoc analyses.@*RESULTS@#Lymph node metastasis was noted in 75.8% of all patients, while distant metastasis was noted in 21.4%. Pathological findings indicated invasive ductal and lobular carcinomas in 86.8% and 5.3% of cases, respectively. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (41.5%) and HR-/HER2+ (20.1%) were the most common biologic subtypes, followed by HR+/HER2+ (19.1%) and HR-/HER2- (19.1%). Stage III IBC was treated via pre-operative neoadjuvant chemotherapy in 87.7% of the cases, predominantly using anthracycline and taxanes. A total of 91.9% of patients underwent surgical treatment. Among them, 77.0% of the patients underwent modified radical mastectomy, 8.1% of whom also underwent immediate breast reconstruction. The Kruskal-Wallis test revealed that the efficacy of chemotherapy significantly differed among those with HR+/HER2- and HR-/HER2- tumors (adjusted P = 0.008), and Ki-67 expression significantly differed in HR-/HER2+ and HR+/HER2+ molecular subtypes (adjusted P = 0.008).@*CONCLUSION@#Our study provides novel insight into clinicopathological characteristics and treatment status among patients with IBC in China, and might provide a direction and basis for further studies.@*TRIAL REGISTRATION@#chictr.org.cn, No. ChiCTR1900027179; http://www.chictr.org.cn/showprojen.aspx?proj=45030.

Association of menopausal status, expression of progesterone receptor and ki67 to the clinical response to neoadjuvant chemotherapy in luminal breast cancer / Associação de status menopausal, expressão de receptor de progesterona e de Ki67 à resposta clínica à quimioterapia neoadjuvante no câncer luminal de mama

Abstract Objective To identify the biomarkers of response to neoadjuvant chemotherapy in early luminal breast cancer. Methods A cross-sectional study that included all patients with early or locallyadvanced luminal breast cancer submitted to neoadjuvant chemotherapy between 2013 and 2014. Demographic, clinic and pathologic data were retrieved from patient records. The expressions of the estrogen receptor (ER), the progesterone receptor (PR), and Ki67 were analyzed by immunohistochemistry (IHC). The status of the human epidermal growth factor receptor 2 (HER2) was evaluated by IHC and fluorescent in situ hybridization (FISH). Independent predictors of clinic and pathologic response were evaluated by stepwise logistic regression models and receiver operating characteristic (ROC) curve analysis. Results Out of 298 patients identified, 115 were included in the analysis. Clinical complete response (cCR) was observed in 43.4% of the patients (49/113), and pathologic complete response (pCR) was observed in 7.1% (8/115) of the patients. The independent predictors of cCR were premenopausal status (p < 0.001), low PR expression (≤ 50% versus > 50%; p = 0.048), and Ki67 expression ≥ 14% (versus < 14%; p = 0.01). Patients with cCR were more commonly submitted to breast conserving surgery (34.7% versus 7.8%; p < 0.001). Increasing cut-off points for Ki67 expression were associated with an increase in specificity and a decrease in sensitivity to identify patients with cCR. Conclusion Premenopausal status, lower PR expression and higher Ki67 expression were associated with a higher rate of cCR to neoadjuvant chemotherapy in luminal breast cancer.

Resumo Objetivo Identificar biomarcadores de resposta à quimioterapia neoadjuvante em câncer luminal de mama. Métodos Estudo transversal em que foram incluídas todas as pacientes com câncer luminal de mama em estádio inicial ou localmente avançado que foram submetidas a quimioterapia neoadjuvante nos anos de 2013 e 2014. Dados demográficos, clínicos e patológicos foram obtidos de prontuários médicos. As expressões de receptor de estrogênio (RE), de receptor de progesterona (RP), e de Ki67 foram avaliadas por imuno-histoquímica (IHQ). A expressão do receptor tipo 2 do fator de crescimento epidérmico humano (human epidermal growth factor receptor 2, HER2) foi avaliada por IHQ e hibridização in situ por imunofluorescência (HISI). Análises de regressão logística e de curva de característica de operação do receptor (COR) foram usadas para investigar fatores preditivos independentes de resposta clínica e patológica. Resultados De 298 pacientes identificadas, 115 foram incluídas na análise. Resposta clínica completa (RCc) foi observada em 43.4% das pacientes (49/113), e resposta patológica completa (RPc), em 7.1% (8/115). Os fatores preditivos independentes de RCc foram status menopausal (p < 0.001), baixa expressão de RP (≤ 50% versus > 50%; p = 0.048), e expressão de Ki67 ≥ 14% (versus < 14%; p = 0.01). Pacientes com RCc apresentaram maior probabilidade de serem submetidas a cirurgia conservadora da mama (34.7% versus 7.8%; p < 0.001). Aumento no ponto de corte para expressão de Ki67 foi associado a aumento da especificidade e redução da sensibilidade na identificação de pacientes com RCc. Conclusão Status premenopausal, baixa expressão de RP e maior expressão de Ki67 estiveram associados a maior taxa de RCc à quimioterapia neoadjuvante no câncer luminal de mama.

Carcinoma ductal in situ de la mama con características apocrinas: reporte de un caso / Ductal carcinoma in situ of the breast with apocrine characteristics: case report

Resumen Se presenta el caso de una femenina de 69 años con un carcinoma ductal in situ de la mama, el cual presentaba diferenciación apocrina y alto grado nuclear. La forma de presentación clínica se hizo patente en forma de microcalcificaciones detectadas en la mamografía, y corroboradas histológicamente como comedonecrosis. La diferenciación apocrina se comprobó por medio de tinciones de inmunohistoquímica. El diagnóstico se realizó en una biopsia excisional, pero dado a que uno de los márgenes se encontraba comprometido, la paciente se sometió posteriormente a una mastectomía.

Abstract We present the case of a 69 year old female diagnosed with a ductal in situ carcinoma of the breast. The tumor had apocrine differentiation and a high nuclear grade. The clinical presentation corresponded to microcalcifications detected on mammography, which were histologically patent in the form of comedo type necrosis. The aforementioned apocrine differentiation was reassured using the aid of immunohistochemistry. The biopsy was an excisional biopsy, but due to positive quirurgical margins, the patient was later reintervened for total mastectomy.

Omitting Adjuvant Radiotherapy for Hormone Receptor‒Positive Early-Stage Breast Cancer in Old Age: A Propensity Score Matched SEER Analysis / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to investigate the non-inferiority of omitting radiotherapy (RT) after breast-conserving surgery (BCS) for hormone receptor (HR)‒positive T1N0 breast cancer in elderly women. MATERIALS AND METHODS: From 2004 to 2014, HR-positive T1N0 breast cancer patients aged 50 years or older and receiving BCS were retrieved from the Surveillance, Epidemiology, and End RESULTS: 18 database. After propensity score matching between the no-RT and RT groups, univariate and multivariate analyses were performed. Identified prognostic factors were used to stratify the risk groups. In each risk group, 10-year cancer-specific survival (CSS) rates were compared between the no-RT and RT groups. RESULTS: After propensity score matching, the numbers of patients in the no-RT and RT groups were both 18,586. For patients who satisfied both a tumor size of 1-10 mm and a tumor grade of 1-2, omitting RT did not decrease the CSS rate at any age group, ranging from ≥ 50 to ≥ 85 years; for patients aged ≥ 50 years, the 10-year CSS rates in the no-RT and RT groups were 97.2% and 96.8%, respectively (adjusted hazard ratio, 0.862; p=0.312). However, for patients with a tumor size of 11-20 mm or tumor grade of 3-4, RT significantly increased the CSS rate irrespective of age. CONCLUSION: RT after BCS for HR-positive T1N0 breast cancer in elderly women might be omitted without causing a decrease in the CSS rate, but only in patients who satisfy both a small tumor size (≤ 10 mm) and low tumor grade (1-2).

The prognostic significance of estrogen and progesterone receptors in grade I and II endometrioid endometrial adenocarcinoma: hormone receptors in risk stratification / 부인종양

OBJECTIVES: Although patients with grade I and II endometrioid endometrial adenocarcinoma (EEA) are considered with good prognosis, among them 15%–25% died in 5 years. It is still unknown whether integrating estrogen receptor (ER) and progesterone receptor (PR) into clinical risk stratification can help select high-risk patients with grade I–II EEA. This study was to investigate the prognostic value of ER and PR double negativity (ER/PR loss) in grade I–II EEA, and the association between ER/PR loss and The Cancer Genome Atlas (TCGA) classification. METHODS: ER and PR were assessed by immunohistochemistry on hysterectomy specimens of 903 patients with grade I–II EEA. ER and PR negativity were determined when < 1% tumor nuclei were stained. Gene expression data were obtained from the TCGA research network. RESULTS: Compared with ER or PR positive patients (n=868), patients with ER/PR loss (n=35) had deeper myometrial infiltration (p=0.012), severer FIGO stage (p=0.004), and higher rate of pelvic lymph node metastasis (p=0.020). In univariate analysis, ER/PR loss correlated with a shorter progression-free survival (PFS; hazard ratio [HR]=5.25; 95% confidence interval [CI]=2.21–12.52) and overall survival (OS; HR=7.59; 95% CI=2.55–22.60). In multivariate analysis, ER/PR loss independently predicted poor PFS (HR=3.77; 95% CI=1.60–10.14) and OS (HR=5.56; 95% CI=1.37–22.55) for all patients, and poor PFS for patients in stage IA (n=695; HR=5.54; 95% CI=1.28–23.89) and stage II–IV (n=129; HR=5.77; 95% CI=1.57–21.27). No association was found between ER/PR loss and TCGA classification. CONCLUSION: Integrating ER/PR evaluation into clinical risk stratification may improve prognosis for grade I–II EEA patients.