Circulating Innate Lymphoid Cells Exhibit Distinctive Distribution During Normal Pregnancy

Over the past decades, the investigation of innate lymphoid cells (ILCs) has revealed their significance in successful pregnancy. Sex hormones, such as estradiol and progesterone, show specific changes during pregnancy and modulate both adaptive and innate immune systems. ILC subset distribution in peripheral blood of pregnant women and its potential association with sex hormone levels have not been well revealed. Peripheral blood was obtained from healthy non-pregnant, early-pregnant, and late-pregnant women. Radioimmunoassay was performed to measure plasma estradiol and progesterone levels. The levels of type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), type 3 ILCs (ILC3s), and total ILCs as well as estrogen and progesterone receptors of ILC2s in peripheral blood were analyzed using flow cytometry. The proportion of total ILCs and distribution of ILC subsets in peripheral blood changed dynamically during pregnancy. Compared to non-pregnant women, late-pregnant women displayed significantly higher proportion of circulating ILCs, among which ILC2s accounted for the majority in late-pregnant women while a smaller part in others, and ILC3s displayed the opposite. Plasma estradiol and progesterone levels elevated while pregnancy proceeded and the expression of their receptors in ILC2s increased consisted with the proportion of circulating ILC2s. Our work first observed the existence of progesterone receptors in human circulating ILC2s and revealed the distribution pattern of circulating ILC subsets and their interrelation with plasma sex hormone levels during pregnancy. Our results suggested that the estradiol and progesterone levels might partly influence the distribution of circulating ILC subsets and implied the interplay between circulating ILCs and pregnancy.

Sex Hormone Receptor Expression in Craniopharyngiomas and Association with Tumor Aggressiveness Characteristics

Craniopharyngiomas (CPs) are rare tumors of the sellar and suprasellar regions of embryonic origin. The primary treatment for CPs is surgery but it is often unsuccessful. Although CPs are considered benign tumors, they display a relatively high recurrence rate that might compromise quality of life. Previous studies have reported that CPs express sex hormone receptors, including estrogen and progesterone receptors. Here, we systematically analyzed estrogen receptor α (ERα) and progesterone receptor (PR) expression by immunohistochemistry in a well-characterized series of patients with CP (n = 41) and analyzed their potential association with tumor aggressiveness features. A substantial proportion of CPs displayed a marked expression of PR. However, most CPs expressed low levels of ERα. No major association between PR and ERα expression and clinical aggressiveness features was observed in CPs. Additionally, in our series, β-catenin accumulation was not related to tumor recurrence.

PATHOGENETIC MECHANISMS OF BENIGN BREAST DISEASE DEVELOPMENT IN WOMEN OF FERTILE AGE WITH ENDOMETRIAL HYPERPLASIA

Proliferative changes in the mammary glands very often associate with gynecological diseases. It is the state of receptors for sex steroids in the tissue but not the absolute concentration of hormones in the blood that influences the development of breast and endometrial diseases. It is still unclear how the structure and properties of estrogen (ER) and progesterone (PR) receptors, associated with ESR1 and PRG gene polymorphisms, change. Thus, a new line of scientific research was the examination of microRNA role in the pathogenesis of benign breast diseases in women of fertile age with endometrial hyperplasia. It is known, that microRNAs are involved in many cellular processes, as they influence target genes. The aim of the study was to determine the prognostic significance of epigenetic markers in benign mammary dysplasia pathogenesis in women of fertile age with endometrial hyperplasia. Materials and Methods. The authors examined 69 women aged 18–49, 27 women with endometrial hyperplasia (EН) without atypia and 42 women with benign mammary dysplasia (BMD) with endometrial hyperplasia without atypia. We studied the expression levels of estrogen and progesterone receptors, and their isoform ratio in the blood serum. We also isolated miR-125b, miR-155, miR-222, and miR-429 by real-time PCR. Results. The prevalence of CC allele of the PvuII C/T polymorphism and GG allele of the Xbal A/G polymorphism in ESR1 gene estrogen receptor causes the BMD in women of fertile age with EH, leading to a decrease in ER sensitivity. Epigenetic changes at the microRNA level indicate a decrease in cell adaptiveness, an increase in their proliferative activity, and an induction of angiogenesis. High expression of miR-155, miR-222, and miR-429 indicates poor prognosis for breast cancer patients. The study of correlation of miR-155, miR-222, and miR-429 with the ESR1 estrogen receptor gene polymorphism showed, that the highest Pvull C/T (TT, TC, and CC) and Xbal A/G (AA, AG, and GG) scores were found in women of fertile age with BMD associated with EH. Conclusion. The results of the molecular genetic studies demonstrate the possibility to predict the occurrence and development of breast proliferative diseases in women of fertile age with endometrial hyperplasia. Key words: benign mammary dysplasia, endometrial hyperplasia, estrogen receptors, progesterone receptors, microRNA. Пролиферативные изменения в молочных железах очень часто возникают на фоне гинекологических заболеваний. Решающее значение в возникновении заболеваний молочных желез и эндометрия имеет не абсолютная концентрация гормонов в крови, а состояние рецепторов к половым стероидам в ткани. Остается открытым вопрос об изменении структуры и свойств эстрогеновых (ER) и прогестероновых (PR) рецепторов, связанных с наличием полиморфизмов кодирующих их генов (ESR1 и PRG). Новым направлением научного поиска стало изучение роли микроРНК в патогенезе доброкачественных заболеваний молочных желез при гиперплазии эндометрия в репродуктивном возрасте. Известно, что микроРНК участвуют во многих клеточных процессах, действуя на специфические гены-мишени. Цель исследования. Определить прогностическую значимость эпигенетических маркеров в патогенезе доброкачественной дисплазии молочных желез при гиперплазии эндометрия в репродуктивном возрасте. Материалы и методы. Было обследовано 69 женщин в возрасте 18–49 лет, из них 27 – с гиперплазией эндометрия (ГЭ) без атипии и 42 – с доброкачественной дисплазией молочных желез (ДДМЖ) при гиперплазии эндометрия без атипии. Исследовали уровни экспрессии эстрогеновых и прогестероновых рецепторов, соотношение их изоформ в сыворотке крови. Произвели выделение miR-125b, -155, - 222, -429 методом ПЦР в режиме real time. Результаты. В основе патогенеза развития ДДМЖ при ГЭ в репродуктивном возрасте лежит преобладание аллеля CC полиморфизма PvuII C/T и аллеля GG полиморфизма Xbal A/G гена ESR1 эстрогенового рецептора, что приводит к снижению чувствительности ER. Эпигенетические изменения на уровне микроРНК свидетельствуют о снижении адаптивных свойств клеток, увеличении их пролиферативной активности, индукции ангиогенеза. Высокая экспрессия miR-155, miR-222 и miR-429 является фактором плохого прогноза для больных раком молочной железы. При изучении взаимосвязи miR-155, -222 и -429 с полиморфизмом гена ESR1 эстрогенового рецептора, самые высокие показатели Pvull C/T (ТТ, ТС и СС) и Xbal A/G (АА, АG и GG) выявлены у женщин с ДДМЖ при ГЭ в репродуктивном возрасте. Выводы. На основании полученных результатов молекулярно-генетических исследований дано научное обоснование возможности прогнозирования возникновения и развития пролиферативных заболеваний молочных желез при гиперплазии эндометрия в репродуктивном возрасте. Ключевые слова: доброкачественная дисплазия молочных желез, гиперплазия эндометрия, эстрогеновые рецепторы, прогестероновые рецепторы, микроРНК.

Factors Associated with Surgery Among South Asian American and Non-Hispanic White Women with Breast Cancer

South Asian American (SA) women are diagnosed with more aggressive breast cancer than non-Hispanic White (NHW) women. Understanding the factors associated with the types of surgery received by these women sheds light on disease management in these culturally distinct populations. We used data on age at diagnosis, stage, grade, estrogen and progesterone receptors, and surgery from 4,590 SA and 429,030 NHW breast cancer cases in the Surveillance, Epidemiology and End Results (SEER) program. We used logistic regression with surgery as the binary outcome (subcutaneous, total, or radical mastectomy (STRM) versus partial mastectomy, no, unknown or other (PNUM)) and included additive effects of all the variables and interactions of age, stage, grade, and estrogen and progesterone receptors with race/ethnicity. Type I error of 5% was used to assess statistical significance of the effects. SA were significantly more likely than NHW cases to receive STRM relative to PNUM surgery among women diagnosed at or after age 50 years and having localized stage disease (Odds Ratio (OR) = 1.27, 95% Confidence Interval (CI) = 1.06 – 1.52). Further, SA were significantly less likely than NHW cases to receive STRM relative to PNUM surgery among those diagnosed before age 50 years and having regional or distant stage disease (OR = 0.75, 95% CI = 0.59 – 0.95 for age at diagnosis < 40 years; OR = 0.77, 95% CI = 0.62 – 0.95 for age at diagnosis 40-49 years). The type of surgery received by SA and NHW women differ according to age at diagnosis and disease stage. KEYWORDS: Breast Cancer; Surgery; Cancer Health Equity; Disease Characteristics; South Asian American; Non-Hispanic White; Logistic Regression; Interaction

α-Fetoprotein-Producing Endometrial Carcinoma Is Associated With Fetal Gut-Like and/or Hepatoid Morphology, Lymphovascular Infiltration, TP53 Abnormalities, and Poor Prognosis: Five Cases and Literature Review

The clinicopathological, immunohistochemical, and molecular characteristics of α-fetoprotein (AFP)-producing endometrial carcinoma (AFP+ EC) are poorly understood. From 284 cases of endometrial carcinoma in our pathology archive, we identified five cases (1.8%) of AFP+ EC with fetal gut–like (4/5) and/or hepatoid (2/5) morphology. All cases exhibited lymphovascular infiltration. In addition, 24 cases of endometrial carcinoma with elevated serum AFP levels were retrieved from the literature. The patient age ranged from 44 to 86 years (median: 63). Of 26 cases whose FIGO (International Federation of Gynecology and Obstetrics) stage and follow-up information was available (mean follow-up 24 months), 15 were stage I or II and 11 were stage III or IV. Even in stage I or II disease, death or relapse occurred in more than half of the patients (8/15). Detailed analysis of our five cases revealed that, on immunohistochemistry, AFP+ EC was positive for SALL4 (4/5), AFP (3/5), and HNF1β (4/5) in &gt;50% of neoplastic cells and negative for estrogen and progesterone receptors (5/5), PAX8 (4/5), and napsin A (5/5). Four cases exhibited aberrant p53 immunohistochemistry and were confirmed to harbor TP53 mutations by direct sequencing. No mutation was found in POLE, CTNNB1, or KRAS. In conclusion, AFP+ EC merits recognition as a distinct subtype of endometrial carcinoma, which occurs in 1.8% of endometrial carcinoma cases, are associated with TP53 abnormalities, exhibit lymphovascular infiltration, and can show distant metastasis even when treated in early stage.

Endometrial Stromal Expression of ER, PR, and B-Catenin Toward Differentiating Hyperplasia Diagnoses

Background. The interpretation of histopathological changes of endometrial hyperplasia with or without atypia can be challenging. We aim to investigate the role of specific immunohistochemical markers in the endometrial stroma to classify endometrial hyperplasia in difficult cases. Methods and Results. We retrospectively reviewed and reclassified (WHO 2014): 47 specimens with endometrial hyperplasia without atypia, 33 with atypical hyperplasia (AH), and 13 endometrioid adenocarcinomas. We performed IHC for B-catenin, E-cadherin, p16, estrogen receptors and progesterone receptors, and B-cell lymphoma 2 (BCL2). Percentage of positive stromal cells was calculated. B-catenin was equally expressed in the stroma of both hyperplasia and AH (mean 60%, 50%; P = .17) and was absent from adenocarcinoma (0%, hyperplasia vs adenocarcinoma; P < .0001, AH vs adenocarcinoma; P < .0001). E-cadherin was not expressed in the stroma of any lesion, while p16 expression levels were not statistically different (hyperplasia vs AH; P = .46, hyperplasia vs adenocarcinoma; P = .22, AH vs adenocarcinoma; P = .48). Estrogen and progesterone were highly identified in stromal cells of hyperplasia (80%) and diminished in AH (respectively, at 30% and 60%, hyperplasia vs AH; P < .0001), and in adenocarcinoma (0% and 40%, respectively). Finally, BCL2 was not differentially expressed (hyperplasia vs AH; P = .33, hyperplasia vs adenocarcinoma; P = .17, AH vs adenocarcinoma; P = .36). Conclusion. Estrogen and progesterone were strongly expressed in stroma exclusively of hyperplasia, while B-catenin was particularly expressed in hyperplasia and AH. Use of these markers can be useful in the differential diagnosis of hyperplasia from AH, and AH from adenocarcinoma in challenging cases.

Biomarkers Changes after Neoadjuvant Chemotherapy in Breast Cancer: A Seven-Year Single Institution Experience

The adoption of neoadjuvant chemotherapy (NACT) for breast cancer (BC) is increasing. The need to repeat the biomarkers on a residual tumor after NACT is still a matter of debate. We verified estrogen receptors (ER), progesterone receptors (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) status changes impact in a retrospective monocentric series of 265 BCs undergoing NACT. All biomarkers changed with an overall tendency toward a reduced expression. Changes in PR and Ki67 were statistically significant (p = 0.001). Ki67 changed in 114/265 (43.0%) cases, PR in 44/265 (16.6%), ER in 31/265 (11.7%) and HER2 in 26/265 (9.8%). Overall, intrinsic subtype changed in 72/265 (27.2%) cases after NACT, and 10/265 (3.8%) cases switched to a different adjuvant therapy accordingly. Luminal subtypes changed most frequently (66/175; 31.7%) but with less impact on therapy (5/175; 2.8%). Only 3 of 58 triple-negative BCs (5.2%) changed their intrinsic subtype, but all of them switched treatment. No correlation was found between intrinsic subtype changes and clinicopathological features. To conclude, biomarkers changes with prognostic implications occurred in all BC intrinsic subtypes, albeit they impacted therapy mostly in HER2 negative and/or hormone receptors negative BCs. Biomarkers retesting after NACT is important to improve both tailored adjuvant therapies and prognostication of patients.

Possibilities of PET/CT with 18F-PSMA-1007 in the Diagnosis of Triple Negative Breast Cancer: a Case Study

Breast cancer (BC) is one of the most common cancers and the leading cause of cancer death in women. Triple negative breast cancer (TNBC) is a specific subtype of breast cancer that does not express estrogen receptors (ER), progesterone receptors (RP) or human epidermal growth factor receptor-2 (HER-2), has certain clinical features, a tendency to relapses and poor prognosis. Various studies demonstrate that prostate-specific antigen (PSA) is not strictly specific for prostate cancer, and can be produced by other tumor pathologies. In routine practice, PET/CT for TNBC is performed with 18F-FDG. However PET/CT with 18F-PSMA-1007 can be used as the method of choice with high theranostic potential. Here is a clinical case of a patient with TNBC who underwent PET/CT with 18F-FDG and 18F-PSMA-1007.

Immunotherapy for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by extensive tumor heterogeneity at both the pathologic and molecular levels, particularly accelerated aggressiveness, and terrible metastasis. It is responsible for the increased mortality of breast cancer patients. Due to the negative expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2, the progress of targeted therapy has been hindered. Higher immune response in TNBCs than for other breast cancer types makes immunotherapy suitable for TNBC therapy. At present, promising treatments in immunotherapy of TNBC include immune checkpoints (ICs) blockade therapy, adoptive T-cell immunotherapy, and tumor vaccine immunotherapy. In addition, nanomedicines exhibit great potential in cancer therapy through the enhanced permeability and retention (EPR) effect. Immunotherapy-involved combination therapy may exert synergistic effects by combining with other treatments, such as traditional chemotherapy and new treatments, including photodynamic therapy (PTT), photodynamic therapy (PDT), and sonodynamic therapy (SDT). This review focuses on introducing the principles and latest development as well as progress in using nanocarriers as drug-delivery systems for the immunotherapy of TNBC.