RANK in cancer-associated fibroblasts: A valuable prognostic determinant for metastasis in early-stage breast cancer patients.

BACKGROUND: The molecular system of receptor activator of nuclear factor kappa-ß (RANK) and its ligand (RANKL) plays a role in a variety of physiological and pathological processes. These encompass the regulation of bone metabolism, mammary gland development, immune function, as well as their involvement and tumorigenesis. Nevertheless, limited knowledge exists regarding their function within the tumor microenvironment. METHODS AND RESULTS: We explored the significance of RANK expression in cancer-associated fibroblasts (CAFs) as a prognostic biomarker in early breast cancer patients (BCPs) by immunohistochemistry. Results reveal a significant correlation between high RANK expression in CAFs and an increased risk of metastasis (p= 0.006), shorter metastasis-free survival (MFS) [p= 0.007, OR (95%CI) = 2.290 (1.259-4.156)], and lower overall survival (OS) [p= 0.004, OR (95%CI) = 2.469 (1.343-4.541)]. Upon analyzing the phenotype of CD34(-) CAFs isolated from primary tumors in BCPs, we observed co-expression of RANK with CD105 marker by immunofluorescence and flow cytometry, characteristic of mesenchymal stem/stromal cells (MSCs), suggesting the possible cellular origin. Also RANKL-RANK system increase the OCT-4, SOX-2 and DKK-1 (dickkopf 1) gene expression in CD34(-) CAFs by RT-PCR. Moreover, this system plays a crucial role in the migration of these CD34(-) CAFs. CONCLUSIONS: These results support the clinical relevance of RANK in CAFs and propose its potential as a future therapeutic target in the treatment of early BCPs.

Post-surgery statin use contributes to favorable outcomes in patients with early breast cancer.

BACKGROUND: Statins are a group of lipid-lowering drugs with pleiotropic effects that include, but are not limited to the inhibition of cholesterol synthesis resulting in a wide range of anti-inflammatory, anti-tumor, immunomodulatory, and anti-thrombotic properties. This study aimed to determine the impact of the prior to- or after- breast surgery usage of statins on the tumor prognosis in breast cancer (BC) patients. METHODS: A cohort of patients diagnosed with early invasive ductal BC (n=301) at the Hospital Italiano de Buenos Aires, Argentina, with a minimum follow-up period of 10 years after the surgical procedure were included and stratified according to the time of use of statins and type of statin used. Then, local relapse-free survival (RFS), metastasis-free survival (MFS), bone metastasis-free survival (BMFS), visceral metastasis-free (VMFS), mixed metastasis (bone and visceral)-free survival (mix-MFS) and overall survival (OS) were analyzed. RESULTS: Statins usage after breast surgery was related with lesser metastatic occurrence (p=0.017), lower number of metastatic foci (p=0.034) and fewer dead events (p=0.041), as well as longer MFS (p=0.013) and OS (p=0.027). When stratified by the nature of statins (hydrophilic or lipophilic), only the relatively hydrophilic statin rosuvastatin (ROSU) had an impact on the increase of MFS and OS (p=0.018 and p=0.030, respectively). CONCLUSION: Post-surgery statins usage was associated with increased MFS and OS, with increased benefits of ROSU over simvastatin (SIM) or atorvastatin (ATOR). These results set the rationale for additional studies addressing the use of statins, and particularly, rosuvastatin, to improve the outcome of BC patients.

Granulomatous mastitis with erythema nodosum: A breast cancer mimicking entity.

We present the case of a 42-year-old Hispanic patient who consulted with a left breast mass that showed clinical and imaging signs of breast cancer. During preprocedural examination before needle biopsy, the patient was found to have bilateral, purplish-brown skin lesions on her lower legs, suggestive of erythema nodosum. This clinical finding raised the diagnostic suspicion of granulomatous mastitis, which was later confirmed by histopathology. Granulomatous mastitis is a rare, nonmalignant entity that should be considered in patients of childbearing age who present with a breast mass. The coexistence with erythema nodosum contributes to the clinical suspicion of granulomatous mastitis; the mechanism of this association and the optimal treatment approach remain unknown.

CD105 expression in cancer-associated fibroblasts: a biomarker for bone metastasis in early invasive ductal breast cancer patients.

Introduction: Bone metastasis is one of the causes that mainly decrease survival in patients with advanced breast cancer. Therefore, it is essential to find prognostic markers for the occurrence of this type of metastasis during the early stage of the disease. Currently, cancer-associated fibroblasts, which represent 80% of the fibroblasts present in the tumor microenvironment, are an interesting target for studying new biomarkers and developing alternative therapies. This study evaluated the prognostic significance of the CD105 expression in cancer-associated fibroblasts in early breast cancer patients. Methods: Immunohistochemistry was used to assess CD105 expression in invasive ductal breast carcinomas (n = 342), analyzing its association with clinical and pathological characteristics. Results: High CD105 expression in cancer-associated fibroblasts was associated with an increased risk of metastatic occurrence (p = 0.0003), particularly bone metastasis (p = 0.0005). Furthermore, high CD105 expression was associated with shorter metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0002, 0.0006, and 0.0002, respectively). CD105 expression also constituted an independent prognostic factor for metastasis-free survival, bone metastasis-free survival, and overall survival (p = 0.0003, 0.0006, and 0.0001, respectively). Discussion: The high CD105 expression in cancer-associated fibroblasts is an independent prognostic marker for bone metastasis in early breast cancer patients. Therefore, the evaluation of CD105(+) CAFs could be crucial to stratify BCPs based on their individual risk profile for the development of BM, enhancing treatment strategies and outcomes.

Radioterapia intraoperatoria de la mama con intrabeam, experiencia de la Unidad de Mastología del Hospital Italiano de Buenos Aires / Intraoperative radiotherapy of the breast with intrabeam, experience of the Mastology Unit of the Italian Hospital of Buenos Aires

Objetivo: La radioterapia intraoperatoria (IORT) es la radioterapia que se administra directamente al lecho tumoral. Existen varias modalidades de IORT. La empleada en nuestro centro es la que utiliza el dispositivo Intrabeam, el cual a través de rayos X de baja energía y un aplicador esférico que se adapta al lecho tumoral, permite la administración de la radiación a los tejidos con mayor riesgo de recidiva. Presentamos nuestra experiencia inicial de IORT con el dispositivo Intrabeam. Material y método: Se seleccionaron 51 pacientes con cáncer de mama para IORT con Intrabeam ® según protocolo TARGIT-A, desde febrero 2021 hasta mayo 2022. Los indicaciones fueron: pacientes mayores a 45 años, con tumores unifocales, < 3 cm de diámetro, luminales A o B, con axila clínica e imagenológicamente negativa. También se incluyen pacientes con carcinoma intraductal, de bajo grado o de grado intermedio. Resultados: La edad media fue de 66 años. Según el examen histológico definitivo, el tamaño tumoral promedio fue de 11.9 mm, con 95% de las pacientes con tumores menores a 2 cm. El 82.3% de nuestras pacientes completaron su tratamiento radiante sólo con la radioterapia intraoperatoria, pero en 9 casos (17.6%) fue necesario agregar radioterapia externa del volumen mamario. 10 pacientes (25.6%) tuvieron complicaciones, 2 casos fueron seromas que precisaron varias aspiraciones para su resolución. El resultado estético es muy bueno. Conclusiones: La IORT con Intrabeam es una alternativa segura y bien tolerada frente a la radioterapia externa en pacientes seleccionadas, con un buen resultado estético a corto plazo(AU)

Objetive: Intraoperative radiation therapy (IORT) is a radiation therapy delivered directly to the tumor bed. There are several modalities of IORT. The one used in our center is the one that uses the Intrabeam device, which through low-energy X-rays and a spherical applicator that adapts to the tumor bed, allows the administration of radiation to the tissues with the highest risk of recurrence. We present our initial experience with the Intrabeam device at our center. Material and method: From February 2021 to May 2022, 51 patients with breast cáncer were selected for IORT with Intrabeam® according to the TARGIT-A protocol. The indications were: patients older than 45 years, with unifocal tumors, < 3 cm in diameter, luminal A or B, with negative clinical and imaging axilla. Patients with intraductal, low-grade or intermediate-grade carcinoma were also included. Results: The mean age was 66 years. According to the definitive histological examination, the average tumor size was 11.9 mm, 95% of the patients with tumors smaller than 2 cm. 82.3% of our patients completed their radiant treatment with intraoperative radiotherapy alone, but in 9 cases (17.6%) it was necessary to add external radiotherapy of the breast volume. 10 patients (25.6%) had complications, 2 cases were seromas that required several aspirations for their resolution. The aesthetic result is very good. Conclusions: IORT with Intrabeam is a safe and well tolerated alternative versus external radiotherapy in selected patients and provides a good shortterm aesthetic result(AU)

Corrigendum: FXYD5/Dysadherin, a biomarker of endometrial cancer myometrial invasion and aggressiveness: its relationship with TGF-ß1 and NF-κB pathways.

[This corrects the article DOI: 10.3389/fonc.2019.01306.].

Characterization of Ovarian Granulosa Cell Tumors using Magnetic Resonance Imaging.

Purpose: To identify the MRI features that aid in the characterization of ovarian granulosa cell tumors. Materials and methods: 11 MR pelvis of an adult woman with pathology-proven ovarian granulosa cell tumors with surgical pathology.We evaluated the patient's age, Ca-125, size, laterality, and with MRI features such as indirect signs (i.e., thickened endometrium > 0.9 cm), morphology (cystic, solid-cystic, or solid), subacute hemorrhage, T2 signal (low or intermediate-to-high), restricted diffusion (B values: 0, 50, 1000 sec/mm3/ADC), and dynamic enhancement (intense or similar to myometrium). Also, the presence of ascites, peritoneal implants, or adenopathy. Results: The final cohort included 11 women with a surgical-pathological diagnosis of granulosa cell tumors. The median age was 52.4 years (range, 17-80). The Ca-125 level was with a median within normal limits. The median size was 9.4 cm. Most cases were unilateral (81.8%) and more frequent on the left (54.5%). MRI Analysis: 36.4% had endometrial thickening. Ovarian granulosa cell tumors were polymorphous: cystic (54.6%), mixed solid-cystic (9.1%), and solid (36.3%). Most GC had intermediate to high signal on T2 (90.9%), restricted diffusion (81.8%), intense enhancement (81.8%), and 36.4% had intraparenchymal bleeding. 9.1% had associated implants/adenopathy/ascites at diagnosis. Conclusion: The MRI features characteristic of ovarian granulosa cell tumors were the polymorphous morphology, an intense enhancement to the myometrium, restricted diffusion, and the presence of intraparenchymal hemorrhage.

CD1a- and CD83-positive dendritic cells as prognostic markers of metastasis development in early breast cancer patients.

PURPOSE: Dendritic cells (DCs) are the most potent antigen-presenting cells that play a major role in initiating the antitumor immune response in different types of cancer. However, the prognostic significance of the accumulation of these cells in human early breast tumors is not totally clear. The aim of this study is to evaluate the prognostic relevance of CD1a( +) and CD83( +) dendritic cells in early breast cancer patients. METHODS: We conducted immunohistochemical assays to determine the number of stromal CD1a( +) and CD83( +) DCs in primary tumors from early invasive ductal breast cancer patients, and analyzed their association with clinico-pathological characteristics. RESULTS: Patients with high CD1a( +) DC number had lower risk of bone metastatic occurrence, as well as, longer disease-free survival (DFS), bone metastasis-free survival (BMFS) and overall survival (OS). Moreover, CD1a( +) DC number was an independent prognostic factor for BMFS and OS. In contrast, we found that patients with high number of CD83( +) DCs had lower risk of mix (bone and visceral)-metastatic occurrence. Likewise, these patients presented better prognosis with longer DFS, mix-MFS and OS. Furthermore, CD83( +) DC number was an independent prognostic factor for DFS and OS. CONCLUSION: The quantification of the stromal infiltration of DCs expressing CD1a or CD83 in early invasive breast cancer patients serves to indicate the prognostic risk of developing metastasis in a specific site.

Breast lactating adenoma, an example of the utility of the radiological-pathological correlation.

Lactating adenomas are benign breast tumors, of which etiology, pathogenesis, and management are not yet fully evident in the literature. The primary goal of the radiological evaluation is to make the differential diagnosis with malignant conditions. We present a case of a 34-year-old pregnant woman referred to our service with a progressively increasing mass in the right breast, in whom the histopathology was consistent with a lactating adenoma.

Extra-uterine endometrial stromal sarcoma arising from deep infiltrating endometriosis.

We present a compelling case of a 45-year-old female with a history of endometriosis and leiomyomas, who presented to her gynecologist with chronic pelvic pain complaints. Both a transvaginal ultrasound (US) and an MRI (magnetic resonance imaging) were ordered. The US demonstrated multiple uterine lesions, likely fibroids, and an endometrioma within the right ovary. The MRI of the pelvis with and without gadolinium identified a mass within the right ovary with homogenous intermediate T2-signal, restricted diffusion, and delayed enhancement relative to the myometrium. Several irregular-shaped lesions were also noted within the external myometrium, anterior pelvic wall, and the peritoneum, which were intermediate signal on T2-weighted images, restricted diffusion, and an enhancement pattern similar to the myometrium. The patient underwent a right adnexectomy. The histopathology findings were consistent with a low-grade endometrial stromal sarcoma (low grade-ESS) arising from the endometrial stroma of the right ovary. A debulking surgery confirmed the involvement of external myometrium, anterior pelvic wall, and the peritoneum secondary to a low-grade ESS without the endometrial cavity's involvement. The underlying hypothesis is that the endometriosis stroma from extra-uterine structures such as the right ovary, pelvic and anterior peritoneum, and external myometrium may have subsequently resulted in a low-grade ESS. Low-grade extra-uterine ESS without endometrial involvement is a rare entity. Based on our literature search, this is one of the few reports covering the radiological features of low-grade extra-uterine ESS arising outside the uterus with a concomitant deep infiltrating endometriosis, but without the involvement of the endometrial cavity.

Measurement of tumor size in early cervical cancer: an ever-evolving paradigm.

The major tenets in accurately assessing tumor size in patients with early stage cervical cancer currently include physical examination, imaging studies, and pathologic evaluation. It is estimated that when comparing clinical stage based on physical examination and final pathology, the concordance diminishes as stage increases: 85.4%, 77.4%, 35.3%, and 20.5% for stage IB1, IB2, IIA, and IIB, respectively. Vaginal involvement and larger tumor diameter are considered the main causes of stage inaccuracy. When considering imaging studies, magnetic resonance imaging (MRI) provides the highest level of accuracy in the assessment of cervical tumor size. Its accuracy in determining tumor location within the cervix is approximately 91% and in predicting tumor size 93%. MRI imaging is also significantly more accurate in measuring tumor size, delineating cervical tumor boundaries, and local tumor extension when compared with computed tomography (CT) scan. When comparing with pelvic ultrasound, the accuracy of both imaging techniques (MRI and pelvic ultrasound) in the assessment of tumor size in small versus large tumors is comparable. Pertaining to pathology, the depth of invasion should be measured by convention from the nearest surface epithelium, which equates to tumor thickness. In the setting where tumor is found both in the conization and hysterectomy specimen, the horizontal extent should be measured by summing the maximum horizontal measurement in the different specimens and the depth of invasion measured as the maximum depth in either specimen. A new pattern-based classification for endocervical adenocarcinomas recommends the description of patterns of invasion for human papillomavirus (HPV)-related adenocarcinomas as this is associated with differing risks of lymph node involvement.

Placental site trophoblastic disease.

A case study of a 38-year-old woman with a diagnosis of placental site trophoblastic tumor is presented. The patient had a 22-month history of amenorrhea since her last pregnancy, and a dilation and curettage procedure was performed after a 3.1×2.4×2.8 cm endometrial echogenic lesion was visualized on a pelvic ultrasound. When the diagnosis of placental site trophoblastic tumor was made by histopathologic and immunohistochemical analysis, complementary examinations including including pelvic magnetic resonance imaging (MRI) and a chest computed tomography (CT) were done. There was no evidence of disease outside the uterus, and a laparoscopic hysterectomy with bilateral salpingectomy was performed. After a surveillance period of 12 months, no disease recurrence was identified. Best imaging studies, treatment options, and proper surveillance for these type of tumors are discussed alongside the case study.

FXYD5/Dysadherin, a Biomarker of Endometrial Cancer Myometrial Invasion and Aggressiveness: Its Relationship With TGF-ß1 and NF-κB Pathways.

Objective: Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Methods: FXYD5/Dys messenger RNA (mRNA) levels were determined in EC tissue and UA biopsies. FXYD5/Dys expression was evaluated in EC RNAseq data from The Cancer Genome Atlas (TCGA) and GENEVESTIGATOR tools. FXYD5/Dys impact on E-cadherin expression and cell behavior was assessed in EC Hec1a cells treated with transforming growth factor (TGF)-ß1, stably transfected with ETV5, and transiently transfected with FXYD5/Dys small interfering RNA (siRNA) or pcDNA3-FXYD5/Dys plasmid. Results: FXYD5/Dys was associated with EC aggressiveness, finding high mRNA levels in tumors depicting MI > 50%, Grade 3, and intermediate/high risk of recurrence. FXYD5/Dys was highly expressed at the tumor invasive front compared to the superficial area. Most results were recapitulated in UA biopsies. FXYD5/Dys modulation in Hec1a cells altered cell migration/adhesion and E-cadherin expression. TGF-ß1 treatment of Hec1a cells induced FXYD5/Dys expression. TCGA-UCEC RNAseq analysis revealed a positive correlation between FXYD5/Dys, TGF-ß1, and plasminogen activator inhibitor (PAI)-1 mRNA levels. FXYD5/Dys induced nuclear factor (NF)-κB pathway activation in Hec1a cells. FXYD5/Dys mRNA levels positively correlated with transcriptional activation of NF-κB p65-regulated genes. Survival analysis revealed patient segregation into low- and high-risk groups, the latter depicting the highest FXYD5/Dys, PAI-1, tumor necrosis factor (TNF)-α, and TGF-ß1 mRNA levels and shorter survival rates. Conclusion: FXYD5/Dys is a novel biomarker of EC progression related to TGF-ß1 and NF-κB pathways that collectively promote tumor dissemination and result in poor patient prognosis.

Localización radioguiada de lesiones no palpables y ganglio centinela en estadios iniciales de Cáncer de Mama (snoll). Primera experiencia en el Hospital Italiano de Buenos Aires / Radioguided non-palpable lesion localization and sentinel lymph node mapping (snoll) at early breast carcinoma. First experience at Hospital Italiano de Buenos Aires

Introducción Actualmente, entre un 25 y un 35% de los cánceres de mama se diagnostican como lesiones no palpables. La detección de lesiones cada vez más pequeñas exige el desarrollo de nuevas técnicas prequirúrgicas de marcación y localización. Presentamos la experiencia del Hospital Italiano de Buenos Aires con la técnica de localización radioguiada de lesiones no palpables y ganglio centinela (snoll). Objetivos El objetivo de este trabajo es describir las características clínico-patológicas de las pacientes sometidas a dicha técnica y las ventajas, desventajas, complicaciones y resultados en términos de márgenes libres, tasa de retumorectomías, volumen tumoral resecado y tiempo quirúrgico. Material y método Se trata de un estudio observacional, retrospectivo. Se incluyeron todas las pacientes con carcinomas no palpables en quienes se llevó a cabo la técnica de snoll entre el 1 de agosto de 2016 y el 4 de mayo de 2017. Resultados Se incluyó un total de 25 pacientes, todas con diagnóstico previo de carcinoma de mama invasor a través de una punción histológica. Utilizando la técnica snoll, se logró identificar la lesión de mama en el 96% de las pacientes. En el 100% de las pacientes, los márgenes quirúrgicos estaban libres de lesión, por lo que no se realizaron retumorectomías. Se identificó el 100% de los ganglios centinelas, 76% mediante la técnica snoll y 24% mediante la inyección previa del colorante Azul Patente. Conclusiones La técnica snoll demostró ser una técnica sencilla, que mejora el confort de la paciente y que presenta resultados comparables con las técnicas tradicionales. Si bien se trata de una primera experiencia, son alentadores los resultados en términos de márgenes libres, tiempo quirúrgico y volumen resecados.

Introduction Currently, about 25 to 35% of all breast tumors are diagnosed at a nonpalpable stage. The increasing ability to detect small lesions consequently demands the development of novel technology for preoperative lesion identification and intraoperative localization. In this study, we present our initial experience using Sentinel Node Occult Lesion Localization (snoll) at the Hospital Italiano de Buenos Aires. Objectives The objective of this study is to describe clinical and pathological characteristics of patients who were submitted to snoll technique and the advantages and disadvantages, complications and results in terms of tumor-free margins, subsequent surgery rate, total specimen volume and surgical time. Materials and method This is a retrospective, observational study. We included all patients with non-palpable breast cancer who were submitted to surgery and snoll technique between August 1st, 2016 and March 14th, 2017. Results A total of 25 patients were included in this study. All patients had previous diagnosis of invasive breast cancer by core needle biopsy. The breast lesion was correctly identified in 96% of patients through snoll. Surgical margins were tumor-free in all patients. No patients required subsequent surgery. All sentinel nodes were correctly identified. In 76% of cases, snoll was sufficient and in 24% additional injection of patent blue was required. Conclusions In our experience, snoll has proven to be a simple technique that improves patient comfort and shows comparable results when compared to traditional identification methods. Although these are our initial results, we believe our findings to be promising in terms of adequacy of margins, surgical time and total specimen volume.

Impacto del Score de Recurrencia de 21 genes en la indicación de tratamiento sistémico adyuvante: nuestra experiencia en el Hospital Italiano de Buenos Aires / Impact of the Recurrence Score on clinical decision-making about chemotherapy in the adjuvant setting: our experience at Hospital Italiano of Buenos Aires (Argentina)

Introducción Las plataformas genómicas han tomado gran relevancia como factores pronósticos y predictivos para definir tratamiento adyuvante en pacientes con cáncer de mama. Su uso permitiría discriminar un subgrupo de pacientes en quienes la indicación de quimioterapia podría ofrecer más morbilidad que verdadero beneficio. Objetivos Describir las características de las pacientes en quienes se utilizó la plataforma Oncotype DX® y evaluar el impacto del Score de Recurrencia (Recurrence Score) como herramienta de decisión para la indicación de adyuvancia. Material y método Se consideraron pacientes operadas entre 2013 y 2017 en el Hospital Italiano de Buenos Aires, Argentina, con diagnóstico de carcinoma invasor primario de mama de subtipo Luminal A o B, her2neu negativas. Se seleccionaron los casos en los que se solicitó Oncotype DX® y se describieron sus características clínicas e histológicas. Resultados Se utilizó Oncotype DX® en 47 pacientes con cáncer de mama invasor. En el 48,9% se obtuvo un Recurrence Score de riesgo bajo, en el 40,4% de riesgo intermedio y en el 10,6% de riesgo alto. En 22 casos (46,8%) consideramos que hubo un cambio de conducta en la indicación de adyuvancia. Conclusiones En nuestra experiencia, hemos visto que la plataforma genómica Oncotype DX® sería una herramienta útil para definir tratamiento adyuvante en tumores de tipo Luminal, her2neu negativo.

Introduction Over the past decade, gene expression assays have become relevant prognostic factors for guiding clinical decision-making in patients with breast cancer. Their use allows to discriminate which patients are most likely to benefit from chemotherapy in the adjuvant setting, avoiding unnecessary toxicity. Objectives To describe the clinical and pathologic characteristics of patients in whom Oncotype DX® was used as a prognostic factor and assess the impact of the Recurrence Score on clinical decision-making. Materials and method Patients who underwent surgery at the Hospital Italiano de Buenos Aires, Argentina, between 2013 and 2017 for Estrogen-Receptor positive (er+), her2neu negative primary breast cancer were considered eligible. We evaluated the cases in which Oncotype DX® was ordered and described the clinical and pathologic characteristics, as well as whether Recurrence Score (rs) modified the prescription of adjuvant therapy. Results Oncotype DX® was performed in 47 patients. The distribution of patients according to rs was as follows: low risk rs 48,9%, intermediate risk 40,4% and high risk 10,6%. We considered that adjuvant therapy decision was modified after rs in 22 patients (46,8%). Conclusions Oncotype DX® and its resulting Recurrence Score appear to be a clinically useful tool for decision-making in the adjuvant setting for patients with er+, her2neu negative breast cancer.