A Prospective Study on the Progression, Recurrence, and Regression of Cervical Lesions: Assessing Various Screening Approaches.

(1) Background: The prediction of cervical lesion evolution is a challenge for clinicians. This prospective study aimed to determine and compare the predictive accuracy of cytology, HPV genotyping, and p16/Ki67 dual staining alone or in combination with personal risk factors in the prediction of progression, regression, or persistence of cervical lesions in human papillomavirus (HPV)-infected patients; (2) Methods: This prospective study included HPV-positive patients with or without cervical lesions who underwent follow-up in a private clinic. We calculated the predictive performance of individual tests (cervical cytology, HPV genotyping, CINtecPlus results, and clinical risk factors) or their combination in the prediction of cervical lesion progression, regression, and persistence; (3) Results: The highest predictive performance for the progression of cervical lesions was achieved by a model comprising a Pap smear suggestive of high-grade squamous intraepithelial lesion (HSIL), the presence of 16/18 HPV strains, a positive p16/Ki67 dual staining result along with the presence of at least three clinical risk factors, which had a sensitivity (Se) of 74.42%, a specificity of 97.92%, an area under the receiver operating curve (AUC) of 0.961, and an accuracy of 90.65%. The prediction of cervical lesion regression or persistence was modest when using individual or combined tests; (4) Conclusions: Multiple testing or new biomarkers should be used to improve HPV-positive patient surveillance, especially for cervical lesion regression or persistence prediction.

Significance of the Galectin-8 Immunohistochemical Profile in Ovarian Cancer.

Ovarian cancer (OC) still registers a high prevalence in female gynecological pathology. Given the aggressiveness of the tumor and the lack of response to conventional therapies, a current research interest is the identification of new prognostic markers. Gal-8, a member of the galectin family of molecules, involved in tumorigenesis, disease progression, and metastasis, has been assigned as a valuable tumor prognostic factor, and its inhibition may open new perspectives in cancer therapeutic management. Few studies have been carried out so far to evaluate OCs' galectin profiles. Our study aimed to characterize the Gal-8 profile in different types of ovarian neoplasia and to demonstrate its prognostic value. Our study group comprised 46 cases of OCs that were histologically and immunohistochemically investigated, introduced to Gal-8 immunoreactivity, qualitatively and semi-quantitatively evaluated, and correlated with clinicopathological characteristics. Gal-8 immunoexpression was identified in tumor epithelial cells, showing a dominant nuclear labeling, followed by cytoplasmic and mixed, nuclear, and cytoplasmic labeling. Significant differences between tumor histotypes were found in the statistical analysis between low and high Gal-8 immunoscore levels and clinicopathological features: HGSC (eng.= high-grade serous carcinoma) vs. LGSC (eng. = low-grade serous carcinoma), pathogenic types (type I vs. type II), and tumor grades. Our results reflect Gal-8 expression variability depending on the histological type and subtype, the progression stages, and the degree of differentiation of ovarian tumors, supporting its value as a prognostic factor. Our findings open perspectives for larger studies to validate our results, along with a potential Gal-8 transformation into a future therapeutic target.

Targeted Alpha Therapy: All We Need to Know about 225Ac's Physical Characteristics and Production as a Potential Theranostic Radionuclide.

The high energy of α emitters, and the strong linear energy transfer that goes along with it, lead to very efficient cell killing through DNA damage. Moreover, the degree of oxygenation and the cell cycle state have no impact on these effects. Therefore, α radioisotopes can offer a treatment choice to individuals who are not responding to ß- or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves 225Ac and its daughter nuclide 213Bi. Additionally, the 225Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying 225Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates. To boost the availability of 225Ac, along with its clinical and potential theranostic applications, this review attempts to highlight the fundamental physical properties of this α-particle-emitting isotope, as well as its existing and possible production methods.

Prolapsed Atypical Polypoid Adenomyoma-A Case Report and Literature Review.

Atypical polypoid adenomyoma (APAM) is a rare polypoid benign tumor of the uterus that causes irregular vaginal bleeding in women of reproductive age. It has the potential for malignant transformation, but it does not metastasize. APAM may coexist with endometrial hyperplasia and adenocarcinoma, usually leading to misdiagnosis. Histopathologically, it is a biphasic tumor, represented by the endometrioid glands with a complex histoarchitecture, with sometimes squamous morular metaplasia or cytologic atypia, interspersed with a fibromyomatous stroma. This tumor has a high incidence of recurrence. We present a very rare case of a 21-year-old patient, a virgin, without a significant medical history, with a bleeding mass occupying the vagina. The mass was excised using forceps, scissors, and a suture of the visible pedicle. After a four-year follow-up and no additional medical treatment, no relapse was observed. Given the risk of recurrence and progression, APAM might be treated via a hysterectomy in patients with no desire for pregnancy. Due to a lower recurrence rate, the conservative treatment of atypical polypoid adenomyoma performed via an operative hysteroscopy represents the best choice. Previously diagnosed in hysterectomy specimens, with the introduction of better-performing indirect imaging techniques, adenomyosis is a clinical entity that has the possibility of being diagnosed in the presurgical stage.

Off the Beaten Path in Oncology: Active Brown Adipose Tissue by Virtue of Molecular Imaging.

Brown Adipose Tissue (BAT) is considered beneficial in diabetes and obesity, but it can also have negative effects such as its implication in tumours' pathogenesis and the development of Cancer-induced Cachexia. Since 18F-FDG PET/CT is a common molecular imaging modality used in cancer assessment, we aim to study the 18F-FDG BAT biodistribution in oncological patients and look for possible correlations between BAT activity and different malignancies as well as the patient's weight status. After analysing the total number of oncological 18F-FDG PET/CT scans between 2017 and 2021, we selected patients with active BAT. Based on their BMI, the selected patients were divided into nonobese (NO) vs. overweight and obese (OOB). OOB SUVmaxlean body mass(LBM) had the highest mean values in supraclavicular, latero-cervical, and paravertebral vs. mediastinal and latero-thoracic localisations in NO. BMI was positively correlated with latero-cervical and supraclavicular SUVmax(LBM) but negatively correlated with latero-thoracic and abdominal SUVmax(LBM). Considering the age of the patients, SUVmax(LBM) decreases in the latero-cervical, paravertebral, and abdominal regions. In addition, the males presented lower SUVmax(LBM) values. SUVmax(LBM) was not affected by the treatment strategy or the oncological diagnosis. To conclude, it is mandatory to take into consideration the BAT particularities and effects on weight status in order to optimise the clinical management of oncological patients.

The significance of immune microenvironment in patients with endometriosis.

Endometriosis represents an estrogen-dependent disease of the female reproductive system and intra- and extraperitoneal regions, with chronic feature. Currently, immune cells, such as macrophages and lymphocytes, are considered to play a pivotal role in angiogenesis and invasion of endometriotic cells through matrix remodeling. Additionally, various studies have revealed the role of E-cadherin, ß-catenin, along with steroid hormone receptors in endometriosis development. In this context, our study aimed to analyze the relationship between the cellular immune profile and E-cadherin, ß-catenin, estrogen receptor alpha (ERα), and progesterone receptor (PR) immunoexpression in endometriosis tissues, along with an analysis of the possible association between serological parameters and immunohistochemical (IHC) markers. The study included 53 patients diagnosed with ovarian or cutaneous abdominal wall endometriosis, which have been investigated by routine histology, immunohistochemistry, and serum analysis. The IHC exam showed an increased density of cluster of differentiation (CD)4+ T-cells, CD8+ T-cells, and CD68+ macrophages, along with variable increased expressions of E-cadherin, ß-catenin, ERα, and PR. Statistical analysis revealed an intense positive correlation between CD68 and PR expression (p<0.05), without any other statistically significant correlations between IHC markers or between IHC and serological markers. Our study supports that endometriosis is an immune-dependent disease characterized by an abnormal morphological profile of T-cells and macrophages in endometriotic implants. Our study provides additional data useful in the understanding the immune milieu of endometriosis in the context of its complex pathogenic molecular mechanism. Further research is needed to develop new immunological therapeutic approaches, like immune checkpoint inhibitors administration or T-cell-targeted immunotherapy in these patients.

Kisspeptin Variations in Patients with Polycystic Ovary Syndrome-A Prospective Case Control Study.

Background and objectives: Kisspeptin, also named metastin, showed important roles in initiating the secretion of gonadotropin-releasing hormone (GnRH) and is an essential factor in the development of polycystic ovaries syndrome (PCOS). Several research studies noticed associations between kisspeptin levels and patients with anovulatory cycles due to PCOS with an increased LH/FSH ratio. The aim of our study was to bring scientific evidence regarding the correlation between high kisspeptin and luteinizing hormone values in subfertile women due to PCOS. Materials and Methods: A prospective case-control study was conducted in "Elena Doamna" Hospital of Obstetrics and Gynecology between 4 January 2021 and 1 March 2022. All patients agreed to participate in our study, had ages between 18 and 45 years old, and had a body mass index between 18.5 and 30 kg/m2. The study group consisted of subfertile patients with PCOS and menstrual disturbances, including amenorrhea or oligomenorrhea. The control group consisted of healthy patients with ovulatory cycles and no other reproductive or endocrinology pathologies. During the follicular phase of their menstrual cycle, patients had blood samples taken with the dosage of kisspeptin, LH, FSH, estradiol, insulin, glycemic levels, testosterone, and prolactin. Pelvic ultrasounds and clinical examinations were performed as well. Results: Significant differences were observed in kisspeptin, LH, FSH, and estradiol levels between patients with PCOS and the control group. After the univariate analysis, PCOS was significantly associated with increased kisspeptin, increased LH, and decreased FSH. There was no significant association between PCOS, estradiol, prolactin, and insulin. Conclusions: kisspeptin serum values are higher in subfertile PCOS patients, supporting the hypothesis that an over-stimulation of the KISS1 system might cause the hyper-stimulation of the HPG-axis.

BMI-1 Expression Heterogeneity in Endometriosis-Related and Non-Endometriotic Ovarian Carcinoma.

BMI-1 is a key component of stem cells, which are essential for normal organ development and cell phenotype maintenance. BMI-1 expression is deregulated in cancer, resulting in the alteration of chromatin and gene transcription repression. The cellular signaling pathway that governs BMI-1 action in the ovarian carcinogenesis sequences is incompletely deciphered. In this study, we set out to analyze the immunohistochemical (IHC) BMI-1 expression in two different groups: endometriosis-related ovarian carcinoma (EOC) and non-endometriotic ovarian carcinoma (NEOC), aiming to identify the differences in its tissue profile. METHODS: BMI-1 IHC expression has been individually quantified in epithelial and in stromal components by using adapted scores systems. Statistical analysis was performed to analyze the relationship between BMI-1 epithelial and stromal profile in each group and between groups and its correlation with classical clinicopathological characteristics. RESULTS: BMI-1 expression in epithelial tumor cells was mostly low or negative in the EOC group, and predominantly positive in the NEOC group. Moreover, the stromal BMI-1 expression was variable in the EOC group, whereas in the NEOC group, stromal BMI-1 expression was mainly strong. We noted statistically significant differences between the epithelial and stromal BMI-1 profiles in each group and between the two ovarian carcinoma (OC) groups. CONCLUSIONS: Our study provides solid evidence for a different BMI-1 expression in EOC and NEOC, corresponding to the differences in their etiopathogeny. The reported differences in the BMI-1 expression of EOC and NEOC need to be further validated in a larger and homogenous cohort of study.

Insights into molecular pathways of endometriosis and endometriosis-related ovarian carcinoma.

BACKGROUND: Endometriosis is a benign estrogen-dependent gynecological disease involving components of the female genital tract (uterus, Fallopian tubes, ovaries, large, round, and utero-sacral ligaments) and intra- and extraperitoneal regions. Since the moment of its etiopathogeny has been identified, the intrinsic capacity of endometriosis malignant transformation has been hypothesized. PATIENTS, MATERIALS AND METHODS: Our study included a total number of 50 patients diagnosed with endometriosis (31 cases) and endometriosis-related ovarian carcinoma (EOC) (19 cases). A clinicopathological and immunohistochemical study directed towards the detection of atypical transition lesions and the similitudes in epithelial-mesenchymal transition (EMT) phenomenon [E-cadherin∕ß-catenin∕cytokeratin 18 (CK18)], apoptosis [B-cell lymphoma 2 (Bcl-2)∕Bcl-2-associated X (Bax)], and hormonal dynamics mirrored by the immunoexpression of estrogen receptor (ER) and progesterone receptor (PR) in endometriosis and EOC glands and stroma has been performed. RESULTS: Our study showed a higher immunoexpression of CK18 and E-cadherin in endometriosis than in neoplastic counterparts, while ß-catenin had a stronger immunoexpression in tumors compared with endometriotic areas, with statistically significant differences between the studied groups. Bcl-2∕Bax higher rate in endometriosis had a statistically significant association to a more aggressive tumor behavior (p=0.020). ER immunoexpression was stronger in endometriosis, with less negative scores compared to EOC, while PR immunoexpression was stronger in endometriosis, with a lower percent of negative scores compared to EOC. PR immunostaining was correlated to ovarian location of endometriosis (p=0.004) and tumor grade of EOC (p=0.027). Stromal ER and PR immunoexpression has been significantly lower in endometriosis in comparison to tumor stroma (p=0.001) and PR stromal immunoexpression had been higher in more differentiated tumors compared to less differentiated types (p=0.005). CONCLUSIONS: Our study supports that endometriosis is a precursor of EOC by the identification and the coexistence of both lesions in the investigated cases, the identification of intermediate lesions, as well as the expression of EMT immunomarkers, along with apoptosis and steroid receptors immunoexpression.

The endometrial regeneration frontiers: from mechanisms to applications in regenerative medicine.

The endometrium is a unique and remarkable tissue characterized by a constant regeneration activity and this has been speculative for scientists, regarding its mechanism, regulatory factors, and their significance for fertility and endometrial pathology. Relatively recent scientific progresses due to genomics, proteomics, and transcriptomics have changed the knowledge in respect with endometrial regeneration and uterine-derived diseases. Our review is designed to highlight the recent progresses in understanding the endometrial physiology and its alterations involvement in uterine-derived diseases, addressing the current paradigm regarding endometrial regeneration, based on endometrial regenerative cells. In an attempt to explain the complex process of endometrial regeneration, different mechanisms have been proposed during time, from proliferation of basal glandular cells, to mesenchymal-epithelial transition, and lately to differentiation of stromal cells, based on endometrial regenerative cells or stem cells. Their unlimited potential of reconstruction of any type of tissue has been demonstrated and is currently in different trial stages in cell-based therapies of regenerative medicine, opening promising perspectives in severe or lethal diseases, by exploitation of stem cells. Currently, beside uterine acquired diseases and infertility, endometrial stem cells have been tested in a large spectrum of clinical applications. The great potential of endometrial cells for cell therapies arise from their accessibility, completely xeno-free derivation, allogenic use, possibility of large-scale therapeutic doses production, safety, reproducibility, and chance to overcome the drawbacks associated with autologous therapies. In order to overcome hostile environment of an injured tissue, the association of endometrial stem cells with other cells or added medium opens the perspective of specific combination available as standardized therapeutic means in the next future.

Endometriosis - insights into a multifaceted entity.

Firstly described at the end of nineteenth century, endometriosis remains an enigmatic disease, from etio-pathogenesis to specific markers of diagnosis and its ability to associate with malignancies. Our review has been designed from a historical perspective and steps up to an updated understanding of the disease, facilitated by relatively recent molecular and genetic progresses. Although the histopathological diagnosis is relatively simple, the therapy is difficult or ineffective. Experimental models have been extremely useful as they reproduce the human disease and allow the testing of different potential modulators or treatment options. Due to molecular resemblance to carcinogenesis, applications of anti-cancer agents are currently under scrutiny. The desired goal of an efficient therapy against symptomatic disease, along with associated infertility and malignancies, needs a deeper insight into the complex mechanisms involved in endometriosis initiation, development, and progres-sion. Current trends in genomic and proteomic approaches are useful for a more accurate classification and for the identification of new therapeutic targets.

Preliminary results of the first cervical cancer screening programme in the North Eastern region of Romania.

OBJECTIVE: Cervical cancer represents a major health problem in Romania. A national population-based cervical cancer screening programme was launched in 2012. The aims of the study were to assess the participation rate and to estimate the prevalence of epithelial cell abnormalities in the first four years of the programme in North Eastern Romania. METHODS: The participation rate, representing the proportion of eligible women screened in the programme, was evaluated for 2012-2016. The prevalence of cytological abnormalities was estimated by age group and calendar year. RESULTS: Of 107,968 Pap smears taken, 312 were unsatisfactory (0.3%). The number of smears decreased by year. The participation rate over the four years was 16.9%. Of the 107,656 satisfactory smears, 6.5% were positive for squamous and/or glandular lesion, among which 0.5% contained high-grade squamous intraepithelial or worse lesions. CONCLUSION: The participation rate in the first four years of the programme was low. The effectiveness of the screening programme should be improved by attendance monitoring of the target population, and follow-up of screen-positive women. Measures should be taken to raise coverage and assure quality at all steps of the screening chain. The data collected should include all screening tests from both opportunistic and organized settings.

Immunohistochemical significance of ER alpha, inhibin A, calretinin, and Ki67 expression in granulosa cell ovarian tumors.

Adult granulosa cell tumors (AGCTs) have a heterogeneous morphology and an unpredictable behavior, which can lead to a misinterpreted diagnosis. The aim of our study was to assess the immunoexpression of estrogen receptor (ER) alpha, Ki67, calretinin, and inhibin A in AGCTs, in order to evaluate their value in diagnosis and prognosis of this type of tumor. Immunohistochemical stainings for these markers were performed in 21 cases of AGCTs. The immunopositivity evaluation of calretinin and inhibin A was scored according to the percentage of staining intensity and the extent of positive cells, of ER alpha was scored based on the percentage of positive cells, and Ki67 score was recorded as the percentage of positively stained nuclei across the tumor, without taking in consideration the staining intensity. ER was positive in nine cases, Ki67 was expressed in 12 cases, calretinin showed positive immunoreactivity in 16 cases, and inhibin A was positive in 14 cases. Stromal cells presented also immunopositivity for inhibin A and calretinin in the negative cases. ER alpha and calretinin immunoexpression can help in identification of cell components of AGCT. Our results regarding Ki67 expression emphasize the potential utility of this marker in tumor behavior prediction. Inhibin A immunopositivity has an important value in AGCT diagnosis, in association to the other evaluated markers. Additional studies are needed to identify new specific and sensitive markers for AGCT or, at least, of a panel of markers which might contribute to a more accurate characterization of these tumors.

An update on the biological markers of endometriosis.

INTRODUCTION: Endometriosis is a disease that affects 7-10% of reproductive-age women. When its diagnosis is delayed, its management becomes more difficult. Both for earlier detection and for therapeutic follow-up, discovering noninvasive biological markers with good specificity for this disease is a promising aspect of its research. We analyzed the recent data in the literature regarding these markers to determine which were worth following. EVIDENCE ACQUISITION: This literature review focused on medical data reported in the last 6 years (2011-2016). After identifying articles in PubMed, an analysis of the type of data and level of evidence provided was performed. The selected articles were compared and conclusions regarding the specific markers addressed. EVIDENCE SYNTHESIS: Of the 255 articles identified that reported human studies, we had access to the full text for 169 of them. We selected 71 prospective studies to include in our analysis. The studies were divided based on the primary marker studied: 22 analyzed inflammatory and immunological markers, 9 adhesivity and migration markers, 18 genetic polymorphisms, 7 oxidative stress, 4 micro-RNA circulating fragments, and 11 other biological markers (hormonal receptors, leukocytes, and others). CONCLUSIONS: CA 125 remains the most recommended marker for suspicion of endometriosis and follow-up. Other markers, such as CA 19-9, CA 72-4, and endometrial cells in peripheral blood, have more value for differentiating endometriosis from other pathologies, while circulating micro-RNA could help clarify the endometrial stem cell's implication in its pathogeny. Finally, other new urinary markers could be used in early diagnostic and screening strategies.

TREATMENT OF METABOLIC ALTERATIONS IN POLYCYSTIC OVARY SYNDROME.

Polycystic ovary syndrome is a common endocrinopathy characterized by oligo ovulation or anovulation, signs of androgen excess and multiple small ovarian cysts. It includes various metabolic abnormalities: insulin resistance, hyperinsulinemia, impaired glucose tolerance, visceral obesity, inflammation and endothelial dysfunction, hypertension and dyslipidemia. All these metabolic abnormalities have long-term implications. Treatment should be individualized and must not address a single sign or symptom. Studies are still needed to determine the benefits and the associated risks of the medication now available to practitioners.