Independent organelle and organelle-organelle interactions: essential mechanisms for malignant gynecological cancer cell survival.

Different eukaryotic cell organelles (e.g., mitochondria, endoplasmic reticulum, lysosome) are involved in various cancer processes, by dominating specific cellular activities. Organelles cooperate, such as through contact points, in complex biological activities that help the cell regulate energy metabolism, signal transduction, and membrane dynamics, which influence survival process. Herein, we review the current studies of mechanisms by which mitochondria, endoplasmic reticulum, and lysosome are related to the three major malignant gynecological cancers, and their possible therapeutic interventions and drug targets. We also discuss the similarities and differences of independent organelle and organelle-organelle interactions, and their applications to the respective gynecological cancers; mitochondrial dynamics and energy metabolism, endoplasmic reticulum dysfunction, lysosomal regulation and autophagy, organelle interactions, and organelle regulatory mechanisms of cell death play crucial roles in cancer tumorigenesis, progression, and response to therapy. Finally, we discuss the value of organelle research, its current problems, and its future directions.

Primary lymphoma of the female genital tract masquerading as gynecological malignancy.

BACKGROUND: Primary lymphoma of the female genital tract (PLFGT) is a rare malignant tumor in the female reproductive system, with a low incidence and few clinical reports. The aim of this study is to report our institutional experience with this rare malignancy and emphasize the need for increasing the awareness about PLFGT presenting with gynecologic symptoms. METHODS: The medical records of patients diagnosed with PLFGT from March 2014 to November 2022 in the First Affiliated Hospital of Wannan Medical College were reviewed. Histological classification and staging were based on the World Health Organization and Ann Arbor systems, respectively. RESULTS: There were 13 patients with diagnosis of PLFGT and the median length of follow-up was 31 months (0-102 months). The main clinical symptoms included postmenopausal vaginal bleeding, pelvic mass and abdominal pain. Serum LDH increased in 10 patients and serum CA125 elevated in 2 patients. The tumor of ovarian or uterine presented as solid masses in CT or MRI, and ascites was rare. The histological subtypes were diffuse large B-cell (n = 12) and follicular (n = 1) lymphoma. Tumors were located in ovary (n = 8), uterus (n = 3), and cervix (n = 2). According to the Ann Arbor staging system, 6 cases were classified as stage II and 7 cases were classified as stage IV, respectively. A total of 10 patients underwent surgery. Combination chemotherapy was used in 10 patients. Eight patients had tumor-free survival, 1 patient had recurrent disease, 3 patients died and 1 patient lost to follow-up. The median survival time was 32 months (1-102 months). CONCLUSION: PLFGT usually presents as gynecological symptoms and solid masses in pelvis. Surgery or biopsy was the way to obtain the pathologic diagnosis, and combination chemotherapy is the efficient method for PLFGT. Making an accurate preoperative diagnosis is of paramount importance to avoid radical gynecologic surgery.

Survival prediction in patients with gynecological cancer irradiated for brain metastases.

BACKGROUND AND PURPOSE: This large population-based, retrospective, single-center study aimed to identify prognostic factors in patients with brain metastases (BM) from gynecological cancers. MATERIAL AND METHODS: One hundred and forty four patients with BM from gynecological cancer treated with radiotherapy (RT) were identified. Primary cancer diagnosis, age, performance status, number of BM, presence of extracranial disease, and type of BM treatment were assessed. Overall survival (OS) was calculated using the Kaplan-Meier method and the Cox proportional hazards regression model was used for multivariable analysis. A prognostic index (PI) was developed based on scores from independent predictors of OS. RESULTS: Median OS for the entire study population was 6.2 months. Forty per cent of patients died within 3 months after start of RT. Primary cancer with the origin in cervix or vulva (p = 0.001),  Eastern Cooperative Oncology Group (ECOG) 3-4 (p < 0.001), and the presence of extracranial disease (p = 0.001) were associated with significantly shorter OS. The developed PI based on these factors, categorized patients into three risk groups with a median OS of 13.5, 4.0, and 2.4 months for the good, intermediate, and poor prognosis group, respectively. INTERPRETATION: Patients with BM from gynecological cancers carry a poor prognosis. We identified prognostic factors and developed a scoring tool to select patients with better or worse prognosis. Patients in the high-risk group have a particular poor prognosis, and omission of RT could be considered.

Intraepithelial tumor-infiltrating lymphocytes shape loco-regional PET/CT spread of locally advanced cervical cancer.

BACKGROUND: Data suggest an association between positron emission tomography/CT (PET/CT) metabolic metrics and tumor microenvironment in several malignancies, and a potential role of PET/CT to monitor response to immunotherapy. OBJECTIVE: To evaluate the correlation between tumor loco-regional extension and tumor-infiltrating lymphocyte infiltration in locally advanced cervical cancer prior to concurrent chemo-radiotherapy.The secondary objective was to assess the association between tumor-infiltrating lymphocytes and PET/CT metabolic metrics. METHODS: Patients with locally advanced cervical cancer and negative para-aortic extensions on PET/CT were included. Two senior nuclear medicine physicians specializing in gynecologic oncology reviewed all PET/CT exams, and extracted tumor maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis, as well as pelvic lymph node involvement. One senior gynecologic oncology pathologist assessed intraepithelial tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes. Intraepithelial tumor-infiltrating lymphocytes were categorized following previous studies as <1% and >1%. The cut-off for stromal tumor-infiltrating lymphocytes was chosen empirically: intermediate <60% and high >60%. RESULTS: 86 patients were included. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with tumor metabolic metrics. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with maximum standard uptake value (p=0.16), or metabolic tumor volume (p=0.19). Tumors with <1% intraepithelial tumor-infiltrating lymphocytes score were associated with a higher MRI tumor size (≥ median) (63.3% vs 39.3%, p=0.04). Patients with pelvic lymph node uptake were significantly more frequent in patients with high stromal tumor-infiltrating lymphocytes score (≥60%) (61.5% vs 31.7%, p=0.009). CONCLUSIONS: Poor or absent intraepithelial tumor-infiltrating lymphocytes were associated with more advanced disease at diagnosis and larger tumor size. Tumor-infiltrating lymphocytes were not associated with tumor metabolic activity. Intraepithelial and stroma tumor-infiltrating lymphocytes are not redundant and should be assessed separately. Further work is needed to evaluate the association between tumor metabolic profile and immune populations, including different T-cell subtypes for patient selection for immunotherapy strategies.

Trends in gynecologic cancer in Japan: incidence from 1980 to 2019 and mortality from 1981 to 2021.

BACKGROUND: In Japan, comprehensive cancer statistics data have been collected through national cancer registries, but these data are rarely summarized and reported in research articles. METHODS: Here, we compiled the national registry data on malignant tumors originating from gynecologic organs (ovary, corpus uteri, cervix uteri) in Japan. RESULTS: The number of new patients in 2019 was 13,380, 17,880, and 10,879, respectively, and the number of deaths in 2021 was 5081, 2741, and 2894, respectively. Compared with 40 years ago, the incidence of ovarian cancer has tripled, the incidence of uterine corpus cancer (mainly endometrial cancer) has increased eightfold, the mortality rate of uterine corpus cancer has tripled, and the incidence of cervical intraepithelial cancer has increased ninefold in data standardized by the world population. Compared with the United States, the incidence rate of ovarian cancer has overtaken and the mortality rate of uterine corpus cancer is the same, while both the incidence and mortality rates of cervical cancer are higher in Japan. CONCLUSION: The incidence of gynecologic cancer is increasing significantly in Japan.

Gynecological Cancers and Microbiota Dynamics: Insights into Pathogenesis and Therapy.

In recent years, the relationship between the microbiota and various aspects of health has become a focal point of scientific investigation. Although the most studied microbiota concern the gastrointestinal tract, recently, the interest has also been extended to other body districts. Female genital tract dysbiosis and its possible impact on pathologies such as endometriosis, polycystic ovary syndrome (PCOS), pelvic inflammatory disease (PID), and gynecological cancers have been unveiled. The incursion of pathogenic microbes alters the ecological equilibrium of the vagina, triggering inflammation and compromising immune defense, potentially fostering an environment conducive to cancer development. The most common types of gynecological cancer include cervical, endometrial, and ovarian cancer, which occur in women of any age but especially in postmenopausal women. Several studies highlighted that a low presence of lactobacilli at the vaginal level, and consequently, in related areas (such as the endometrium and ovary), correlates with a higher risk of gynecological pathology and likely contributes to increased incidence and worse prognosis of gynecological cancers. The complex interplay between microbial communities and the development, progression, and treatment of gynecologic malignancies is a burgeoning field not yet fully understood. The intricate crosstalk between the gut microbiota and systemic inflammation introduces a new dimension to our understanding of gynecologic cancers. The objective of this review is to focus attention on the association between vaginal microbiota and gynecological malignancies and provide detailed knowledge for future diagnostic and therapeutic strategies.

Prostate-Specific Membrane Antigen PET/CT Detection of Prostate Cancer Metastasis to Thyroid and Cricoid Cartilages.

ABSTRACT: Prostate-specific membrane antigen (PSMA) PET/CT has revolutionized the imaging of prostate cancer. Historically, prostate cancer metastasis to thyroid and cricoid cartilages was thought to be exceedingly rare, with only a few reported cases in the literature. Prostate cancer metastasis to the laryngeal cartilages was detected in 4 of 221 patients who underwent imaging with 18 F-PSMA (Pylarify) or 68 Ga-PSMA (Illuccix) PET/CT for initial staging of high-risk prostate cancer or restaging evaluation in the setting of biochemical recurrence from April 2022 through October 2023. The increased sensitivity and specificity of PSMA PET/CT allow for the detection of previously occult metastatic disease.

Interplay between LncRNA/miRNA and TGF-ß Signaling in the Tumorigenesis of Gynecological Cancer.

Gynecologic cancers are among the most common malignancies with aggressive features and poor prognosis. Tumorigenesis in gynecologic cancers is a complicated process that is influenced by multiple factors, including genetic mutations that activate various oncogenic signaling pathways, including the TGF-ß pathway. Aberrant activation of TGF-ß signaling is correlated with tumor recurrence and metastasis. It has been shown that non-coding RNAs (ncRNAs) have crucial effects on cancer cell proliferation, migration, and metastasis. Upregulation of various ncRNAs, including long non-coding RNAs (lncRNA) and microRNAs (miRNAs), has been reported in several tumors, like cervical, ovarian, and endometrial cancers, but their cellular mechanisms remain to be investigated. Thus, recognizing the role of ncRNAs in regulating the TGF-ß pathway may provide novel strategies for better treatment of cancer patients. The present study summarizes recent findings on the role of ncRNAs in regulating the TGF-ß signaling involved in tumor progression and metastasis in gynecologic cancers.

The prognostic impact of peritoneal tumour DNA in gastrointestinal and gynaecological malignancies: a systematic review.

Peritoneal metastases from various abdominal cancer types are common and carry poor prognosis. The presence of peritoneal disease upstages cancer diagnosis and alters disease trajectory and treatment pathway in many cancer types. Therefore, accurate and timely detection of peritoneal disease is crucial. The current practice of diagnostic laparoscopy and peritoneal lavage cytology (PLC) in detecting peritoneal disease has variable sensitivity. The significant proportion of peritoneal recurrence seen during follow-up in patients where initial PLC was negative indicates the ongoing need for a better diagnostic tool for detecting clinically occult peritoneal disease, especially peritoneal micro-metastases. Advancement in liquid biopsy has allowed the development and use of peritoneal tumour DNA (ptDNA) as a cancer-specific biomarker within the peritoneum, and the presence of ptDNA may be a surrogate marker for early peritoneal metastases. A growing body of literature on ptDNA in different cancer types portends promising results. Here, we conduct a systematic review to evaluate the prognostic impact of ptDNA in various cancer types and discuss its potential future clinical applications, with a focus on gastrointestinal and gynaecological malignancies.

Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: Annual Patient Report for 2020 and Annual Treatment Report for 2015.

AIM: To provide information including the trend of gynecological malignancies in Japan, we hereby present the annual patient report for 2020 and the Annual Treatment Report for 2015, on the outcomes of patients who started treatment in 2015. METHODS: The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry, where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment with gynecologic malignancies was initiated in 2020 were analyzed retrospectively. Survival of the patients who started treatment with cervical, endometrial, and ovarian cancer in 2015 was analyzed by using the Kaplan-Meier, log-rank, and Wilcoxson tests. RESULTS: Treatment was initiated in 2020 for 7689 patients with cervical cancer, 13 113 with endometrial cancer, 8004 with ovarian, tubal, and peritoneal cancer, 2152 with ovarian borderline tumors, and with the others (260 vulvar cancer, 157 vaginal cancer, 464 uterine sarcoma, 50 uterine adenosarcoma, 136 trophoblastic diseases). This clinicopathological information was summarized as the patient annual report. The 5-year survival rates of the patients with cervical cancer were 92.3%, 76.2%, 56.5%, and 32.2% for Stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 93.9%, 87.6%, 71.4%, and 29.3% for Stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 91.7%, 80.6%, 50.8%, and 39.7% for Stages I, II, III, and IV, respectively. CONCLUSION: The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan.

Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer.

BACKGROUND: Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. METHODS: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. RESULTS: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. CONCLUSION: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.

The Role and Applications of Exosomes in Gynecological Cancer: A Review.

Exosomes are phospholipid bilayer vesicles that are released by all types of cells, containing proteins, lipids, and nucleic acids such as DNAs and RNAs. Exosomes can be transferred between cells and play a variety of physiological and pathological regulatory functions. Noncoding RNAs, including micro RNAs, long noncoding RNAs, and circular RNAs, are the most studied biomolecules from exosomes and more and more studies found that noncoding RNAs play an important role in the diagnosis, prognosis, and treatment of diseases, including various types of cancer. Gynecological malignancies such as ovarian, endometrial, and cervical cancer seriously threaten women's life. Therefore, this article reviews the roles and applications of exosomes in gynecological malignancies, including the promotion or inhibition of tumor progression and regulation of tumor microenvironments, and as potential therapeutic targets for treating gynecological cancers.

Increased absolute lymphocyte count, increased absolute neutrophil count and low platelet to lymphocyte ratio as predicting factors in the superior disease control of refractory/relapsing gynecologic malignancies with anti PD-1 therapy: 10 years of experience in a single institution.

OBJECTIVE: Immune checkpoint inhibitors are rapidly being used in solid and hematologic malignancies, including gynecologic cancers. The high mortality and relapsing rates of advanced gynecologic malignancies remain a challenging issue. This study aimed to identify the predicting factors associated with survival prognosis and disease control in patients with refractory/relapsing (R/R) gynecologic malignancies receiving anti PD-1 therapy. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 49 patients diagnosed with R/R gynecologic malignancies between July 2012 and June 2019 in Chang Gung Memorial Hospital, Taiwan. Among the 49 patients, 6 were excluded due to incomplete medical records or not receiving anti PD-1 therapy. The remaining 43 patients were further divided into responsive and non-responsive groups according to disease control for predicting prognostic factor analysis. RESULTS: For the 43 cases, the median age at diagnosis and disease follow-up length were 54 years and 29 months, respectively. Among them, 23 (53%) were categorized into the responsive group, and the remaining 20 (47%) were categorized into the non-responsive group. The mortality rates were 17% and 25% in the responsive and non-responsive groups, respectively. The responsive group had significantly higher absolute lymphocyte count (ALC), higher absolute neutrophil count (ANC) and low platelet to lymphocyte ratio (PLR) than the non-responsive group. A superior long-term survival trend was also observed in the responsive group, but the difference was not statistically significant. CONCLUSIONS: This study reinforced the hypothesis that high ALC, high ANC and low PLR are associated with superior disease control in patients with R/R gynecologic malignancies receiving anti PD-1 therapy.

Ovarian preservation in gynecologic oncology: current indications and techniques.

PURPOSE OF REVIEW: Early menopause represents a relevant clinical issue for women. Nevertheless, this issue should be balanced with the risks of ovarian metastasis, ovarian recurrence, and the risk of recurrence in hormone-sensitive gynecological cancers. The purpose of this review was to provide an overview on current indications and techniques of ovarian preservation in patients with gynecological cancers. RECENT FINDINGS: The potential discussion about ovarian conservation could be proposed to patients with FIGO-stage IA grade 1-2 endometrioid endometrial cancer aged 40 years or less, FIGO-stage IB1-IB2 node-negative cervical cancer with squamous cell carcinoma and HPV-associated adenocarcinoma, FIGO-stage IA-IC grade 1-2 serous, endometrioid, mucinous expansile pattern ovarian cancer, any stage germ cell ovarian tumors, and FIGO-stage IA sex cord-stromal tumors. Technique to perform ovarian transposition in cervix cancer is also reported. SUMMARY: Ovarian conservation is a surgical approach that involves preserving one or both ovaries during the treatment of gynecologic cancers. This approach has gained popularity in recent years, as it offers several benefits to the patient, including the preservation of hormonal function and fertility. The decision to perform ovarian conservation depends on several factors, such as the stage and type of cancer, the patient's age, fertility desire, and should be carefully discussed with patients.

Profile of gynecological cancers in a tertiary hospital, Eastern Nigeria.

Introduction: there is a great diversity in the profile of cancers in the world. This study set out to analyze the profile of gynecological cancer in Federal University Teaching Hospital, Owerri, [FUTHO] (former Federal Medical Centre, Owerri, Imo state, Nigeria). Methods: this was a retrospective cross sectional descriptive study of the records of women admitted in the gynecological ward in FUTHO from January 2020 to November 2022. It was analyzed using SPSS version 23.0 and reported in simple percentages for categorical variables and measures of central tendency for quantitative variables. Results: a total of 1,378 gynecological patients were admitted into the Gynaecological ward of the hospital, out of which 242 (17.6%) were cancer cases. The most common cancer over the three years in review, was ovarian, 81 (33.5%), followed by cervical, 66 (27.3%), endometrial, 65 (26.8%), choriocarcinoma, 22 (9.1%), vulvar, 6 (2.5%) and vagina, 2 (0.8%). The most common gynecological cancers in this study is very different from previous reports from Nigeria and other African countries. The pattern looks like that seen in developed countries where endometrial and ovarian cancers top the list. Conclusion: this report shows a possible change in lifestyle and improved access to cervical cancer prevention strategies. It is also assumed that all the facilities who have recorded cervical cancer as the most common cancer can actually have a similar result as ours if a more current review is done.

Utility of TRPS1 immunohistochemistry in confirming breast carcinoma: Emphasis on staining in triple-negative breast cancers and gynecologic tumors.

OBJECTIVES: Our aim was to explore the performance of TRPS1 as an immunohistochemical diagnostic marker; find the optimal conditions for its use in breast carcinomas, especially triple-negative breast cancers (TNBCs); and compare its results in carcinomas of a select few organ sites, with an emphasis on gynecologic tumors. METHODS: Tissue microarrays from breast carcinomas (n = 197), endometrial adenocarcinomas (n = 69), ovarian tumors (n = 250), vulvar squamous cell carcinomas (n = 97), pancreatic ductal adenocarcinomas (n = 20), and gastric adenocarcinomas (n = 12) were stained with TRPS1 using 2 different conditions (protocol 1: high pH; protocol 2: low pH). Breast carcinomas consisted of hormone receptor (HR)-positive/ERBB2 (formerly HER2 or HER2/neu)-negative (n = 53) samples, HR-positive/ERBB2-positive (n = 6) samples, and TNBCs (n = 138). RESULTS: Comparing TRPS1 results in breast carcinomas vs tumors from other organ sites, the sensitivity of TRPS1 was 91% and 87%, respectively, while the specificity was 66% and 74% for protocol 1 and 2, respectively. For TNBCs vs gynecologic tumors, the sensitivity of TRPS1 was 89% and 85%, respectively, while the specificity was 65% and 73%, respectively. CONCLUSIONS: TRPS1 stains approximately 90% of breast carcinomas but also up to 71% of endometrial carcinomas, albeit with a weaker median expression. Our data show that although TRPS1 is a highly sensitive marker for TNBCs, it is not as highly specific as previously reported.

Imaging of Endometrial Cancer.

Endometrial cancer is the most common gynecologic cancer in the United States and Europe, with an increasing incidence rate in high-income countries. MR imaging is recommended for treatment planning because it provides critical information on the extent of myometrial and cervical invasion, extrauterine spread, and lymph node status, all of which are important in the selection of the most appropriate therapy. This article highlights the added value of imaging, focused on MR imaging, in the assessment of endometrial cancer and summarizes the role of MR imaging for endometrial cancer risk stratification and management.

PET/MRI in Gynecologic Malignancy.

Patients with gynecologic malignancies often require a multimodality imaging approach for initial staging, treatment response assessment, and surveillance. MRI imaging and PET are two well-established and widely accepted modalities in this setting. Although PET and MRI imaging are often acquired separately on two platforms (a PET/computed tomography [CT] and an MRI imaging scanner), hybrid PET/MRI scanners offer the potential for comprehensive disease assessment in one visit. Gynecologic malignancies have been one of the most successful areas for implementation of PET/MRI. This article provides an overview of the role of this platform in the care of patients with gynecologic malignancies.

MR Imaging of Gynecologic Tumors: Pearls, Pitfalls, and Tumor Mimics.

MR imaging is the modality of choice for the pre-treatment evaluation of patients with gynecologic malignancies, given its excellent soft tissue contrast and multi-planar capability. However, it is not without pitfalls. Challenges can be encountered in the assessment of the infiltration of myometrium, vagina, cervical stroma, and parametria, which are crucial prognostic factors for endometrial and cervical cancers. Other challenges can be encountered in the distinction between solid and non-solid tissue and in the identification of peritoneal carcinomatosis for the sonographically indeterminate adnexal mass.