The value of a multimodal approach combining radical surgery and intraoperative radiotherapy in the recurrence treatment of gynecological malignancies - analysis of a large patient cohort in a tertiary care center.

BACKGROUND: Recurrent and locally advanced gynecological malignancies have a poor prognosis. In particularly, pelvic local recurrence after previous radiotherapy and/or positive resection margins during surgical treatment for recurrent disease result in low survival rates. Consequently, locoregional control is of utmost importance in this cohort of patients. The aim of this study was to analyze treatment outcomes and determine prognostic factors for patients treated with surgery and intraoperative radiotherapy (IORT) for recurrent and locally advanced gynecological malignancies. METHODS: 40 patients who underwent surgical treatment and IORT between 2010 and 2022 were eligible for inclusion. The median follow-up time was 22 months. The outcomes measured were locoregional control (LRC), overall survival (OS), and survival without distant metastases (DMFS). The Cox proportional hazards model was used for univariate and multivariate analysis to assess the impact of patient variables and treatment factors on the endpoints mentioned. The following variables were analyzed: age at surgical treatment and IORT and initial diagnosis (< 65 vs. ≥65 years, each), disease-free interval (DFI) between initial diagnosis and first recurrence, DFI to surgical treatment and IORT, grading, histology, IORT dose (≤ 13 vs. >13 Gy) and technique (high dose radiotherapy (HDR) vs. IORT using electrons, (IOERT)). Survival curves were generated using the Kaplan-Meier method. RESULTS: The mean IORT dose was 13.8 Gy (range 10-18 Gy). Cervical carcinoma was most frequently found in 27.5% of patients followed by endometrial carcinoma and vulvar carcinoma in 25% respectively. The final histopathologic results after surgery with IORT showed no residual tumour in 24 patients (60%), microscopic residual disease in 5 patients (12.5%), resection status could not be evaluated in three patients (7.5%) and the resection status was unknown in eight patients (20%). Subsequently, 27.5% of patients also received adjuvant radiotherapy of the local recurrence bed. However, after IORT, 65% of the women suffered a recurrence. Of these, the recurrences were localized: in-field 32.5%, out-of-field 22.5% and margin-of-field 12.5%. The 3- and 5-year OS was 69% and 55% respectively. The 3- and 5-year LRC was 56% respectively. The 3- and 5-year DMFS was 66% and 49%. Whereas the comparison between groups by IORT dose level (≤ 13 vs. >13 Gy) showed a non-significant trend in favor of the higher dose only for OS (p = 0.094), but not in LRC and DMFS (p > 0.05). OS and DMFS, but not LRC, differed significantly between the HDR-IORT and IOERT groups (p = 0.06 and p = 0.03,) in favor of the HDR-IORT technique. For HDR-IORT technique a trend towards superior OS and LRC was observed in the univariate analysis: HR 3.76, CI 95%: 0.95-14.881, p = 0.059 and HR 2.165 CI 95%: 0.916-5.114, p = 0.078 CONCLUSIONS: The survival rate for pelvic recurrence in gynecological malignancies remains poor and comparable with historical data from the last two decades. Particularly HDR-IORT, appears to provide a long-term oncological benefit in carefully selected patients.

Therapy Response and Survival among Patients with Gynecologic Tumors Treated with Transarterial Chemoperfusion and Transarterial Chemoembolization.

Background and Objectives: This study aimed to evaluate the tumor response relating to and survival benefit of transarterial chemoperfusion (TACP) and transarterial chemoembolization (TACE) in the treatment of patients with unresectable gynecologic tumors who are intolerant of or have a suboptimal response to chemotherapy and radiotherapy. Materials and Methods: Between January 2000 and October 2023, 75 patients diagnosed with gynecologic tumors underwent 213 TACP and 154 TACE procedures. Of these, 33 patients were treated with TACP, 20 were treated with TACE, and 22 received a combination of both therapies. A retrospective evaluation of local tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) was conducted, and survival rates were determined using the Kaplan-Meier estimator. Results: Of the total 75 patients, 50 (67%) maintained a stable course of disease until the completion of therapy, 10 (13%) had a partial response, 2 (3%) had a complete response following thermal ablation, and 13 (17%) experienced progression. Furthermore, a 6% reduction in the sum of the longest diameters and an 8% reduction in tumor volume were observed. The median overall survival was 16.15 months, while the median progression-free survival was 13.19 months. Conclusions: TACP and TACE are potential treatment options for local tumor control in patients with unresectable gynecologic tumors who are intolerant of or show a poor response to chemotherapy and radiotherapy. However, further investigation and adjustment of treatment protocols are required to improve therapy response and survival outcomes.

Superior prognostic accuracy of FIGO staging system in primary female genital tract lymphomas: A retrospective study (IELSG35).

Primary lymphoma of the female genital tract (PLFGT) is a rare type of extranodal lymphoma. In this retrospective study from the International Extranodal Lymphoma Study Group, we analyzed clinical data from 60 women diagnosed with PLFGT between 1982 and 2012. The median age was 52 years. Limited stage, as defined by the Ann Arbor and FIGO staging systems, was observed in 55% and 63% of cases, respectively. The uterus was the primary site of lymphoma in 25 cases, with the ovaries as the second most common site (n = 24). The most common histological subtype was diffuse large B-cell lymphoma (DLBCL, n = 44), followed by follicular lymphoma and marginal zone lymphoma (6 patients each). Two patients received surgery alone as first-line therapy, while 58 underwent systemic therapy, 16 following major surgery. Thirteen patients received consolidation radiotherapy and six were given central nervous system (CNS) prophylaxis. Twenty patients had disease progression or recurrence. Six patients with DLBCL (14%) experienced CNS relapse, which was the only site of recurrence in five of them. All but one patient with CNS relapse had primary ovarian involvement, and three had bulky disease; none of these patients had received CNS prophylaxis. With a median follow-up of 60 months, the median overall survival of the DLBCL cohort was approximately 13 years, with a 5-year survival rate of 77%. In multivariable analysis, advanced disease according to the FIGO system was the only parameter significantly associated with shorter overall, cause-specific, and progression-free survival in patients with DLBCL.

Trends in incidence and mortality for gynaecological cancers in Southeastern China during 2011-2020: a retrospective analysis of registry data.

OBJECTIVES: This study aimed to investigate the changes in the incidence and mortality trends of ovarian cancer (OC), cervical cancer (CC) and uterine cancer (UC) in the Fujian Province, southeastern China. DESIGN: Provincial, population-based, retrospective observational study. SETTING: Fujian province, southeastern China between 2011-2020. PARTICIPANTS: From 2011 to 2020, 6178 new cases and 2037 deaths caused by 3 gynaecological cancers were eligible for analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures were the incidence and mortality rates, including the age-standardised incidence rate (ASIR) and age-standardised mortality rate (ASMR), of three gynaecological cancers. The secondary outcome measure was the prevalence (average annual per cent changes (AAPC)). RESULTS: The incidence of all three gynaecological cancers increased from 2011 to 2020. CC had the slowest upward trend, with an AAPC of 2.54% over the period. However, it had the highest ASIR among the 3 cancers in 2020 (10.41/100 000). UC showed a rapid increase, with an AAPC of 15.15% from 2016 to 2020. While the mortality rate of UC remained stable, both CC and OC also exhibited rising trends, with the CC having the highest ASMR (3.05/100 000) in 2020. The ASMR for CC increased rapidly, with the highest AAPC of 5.51%. Conversely, changes in the ASMR for UC were not statistically significant (p=0.601). Moreover, high incidence rates were more common among perimenopausal women and older participants in the respective cancer groups where the increased mortality was observed. CONCLUSIONS: Gynaecological cancer burden remains a public health issue in Fujian Province, with an increasing incidence. Improving the healthcare system and promoting a healthy lifestyle should be highlighted to reduce the cancer burden.

Global burden of gynaecological cancers in 2022 and projections to 2050.

Background: The incidence and mortality of gynaecological cancers can significantly impact women's quality of life and increase the health care burden for organisations globally. The objective of this study was to evaluate global inequalities in the incidence and mortality of gynaecological cancers in 2022, based on The Global Cancer Observatory (GLOBOCAN) 2022 estimates. The future burden of gynaecological cancers (GCs) in 2050 was also projected. Methods: Data regarding to the total cases and deaths related to gynaecological cancer, as well as cases and deaths pertaining to different subtypes of GCs, gathered from the GLOBOCAN database for the year 2022. Predictions for the number of cases and deaths in the year 2050 were derived from global demographic projections, categorised by world region and Human Development Index (HDI). Results: In 2022, there were 1 473 427 new cases of GCs and 680 372 deaths. The incidence of gynecological cancer reached 30.3 per 100 000, and the mortality rate hit 13.2 per 100 000. The age-standardised incidence of GCs in Eastern Africa is higher than 50 per 100 000, whereas the age-standardised incidence in Northern Africa is 17.1 per 100 000. The highest mortality rates were found in East Africa (ASMR (age-standardised mortality rates) of 35.3 per 100 000) and the lowest in Australia and New Zealand (ASMR of 8.1 per 100 000). These are related to the endemic areas of HIV and HPV. Very High HDI countries had the highest incidence of GCs, with ASIR (age-standardised incidence rates) of 34.8 per 100 000, and low HDI countries had the second highest incidence rate, with an ASIR of 33.0 per 100 000. Eswatini had the highest incidence and mortality (105.4 per 100 000; 71.1 per 100 000) and Yemen the lowest (5.8 per 100 000; 4.4 per 100 000). If the current trends in morbidity and mortality are maintained, number of new cases and deaths from female reproductive tract tumours is projected to increase over the next two decades. Conclusions: In 2022, gynaecological cancers accounted for 1 473 427 new cases and 680 372 deaths globally, with significant regional disparities in incidence and mortality rates. The highest rates were observed in Eastern Africa and countries with very high and low HDI, with Eswatini recording the most severe statistics. If current trends continue, the number of new cases and deaths from gynaecological cancers is expected to rise over the next two decades, highlighting the urgent need for effective interventions.

Long-Term Survival Trend of Gynecological Cancer: A Systematic Review of Population-Based Cancer Registration Data.

Gynecological cancer significantly affect the health of women. This review aimed to describe the global patterns and trends in the survival of patients with gynecological cancers. We searched PubMed, Embase, Web of Science, SinoMed, and SEER for survival analyses of cancer registration data of cervical, endometrial, and ovarian cancers published between 1980 and 2022. Globally, the highest 5-year observed survival rate for cervical cancer was 76.5% in Anshan, Liaoning, China (2008-2017). The 5-year observed survival rates of endometrial and ovarian cancers were higher in Finland (1995-1999, 82.5%) and Singapore (1988-1992, 62.0%). The 5-year relative survival rate of cervical cancer patients was higher in Haining, Zhejiang, China (2011-2014, 85.8%). Korea ranked first at 89.0% and 64.5% for endometrial and ovarian cancers, respectively. Survival rates have improved for cervical, endometrial, and ovarian cancers. Patients aged ≥ 75 years and those with advanced-stage disease had the worst 5-year survival rates. Survival rates were better for squamous cell carcinoma in cervical cancer, for endometrial carcinoma and mucinous adenocarcinoma in endometrial cancer, and for germ cell and sex-cord stromal tumors in ovarian cancer. Over the past four decades, the survival rates of gynecological cancers have increased globally, with notable increases in cervical and endometrial cancers. Survival rates are higher in developed countries, with a slow-growing trend. Future studies should focus on improving survival, especially in ovarian cancer patients.

Clinical characteristics and outcome of early-stage diffuse large B cell lymphoma of female genital track: A retrospective study of the Hellenic cooperative lymphoma group.

Involvement of female genital track (FGT) by diffuse large B cell lymphoma (DLBCL) represents an extremely rare diagnosis. Especially data regarding early-stage disease (i.e., IE, IIE) is very limited. Importantly, previous studies showed controversial results about the risk of central nervous system (CNS) relapse in this entity. Herein, we describe one of the largest reported real-world series of patients with early-stage FGT DLBCL aiming to investigate the clinicopathological characteristics, response to therapy and survival outcomes in the era of immunochemotherapy. We analyzed 21 consecutive patients with biopsy proven DLBCL from uterus or ovary classified as stage IE or IIE out of 1905 newly diagnosed DLBCL patients (1.1%). Uterine and ovarian localization was observed in 14 and seven patients, respectively. Median age was 66 years (range 33-96); 9/21 (43%) were <55 years. Regarding Cell of Origin DLBCL subtype, Germinal Center B-cell subtype was found in seven patients, non-GCB in 10 and non-classified in 4 patients. Median follow-up was 57 months and 5-year overall survival, lymphoma specific survival and Freedom from Progression were 78%, 89% and 90%, respectively. There was no correlation of patients' characteristics with survival parameters. Interestingly, none of the patients experienced CNS relapse. Our results indicate that localized FGT DLBCL exhibits a good prognosis and may not increase the risk for secondary CNS involvement.

Survival analysis of gynecological cancers in Southeast China, 2011-2020: A population-based study.

PURPOSE: To analyze the survival outcomes of female patients with cervical, uterine, and ovarian cancers in Southeast China (Fujian Province) from 2011 to 2020 and to provide a reference basis for prognostic evaluation and prevention of gynecological malignancies. METHODS: The data of 5823 patients with cervical, uterine, and ovarian cancers registered in the Fujian Provincial Cancer Prevention and Control System from 2011 to 2020 were enrolled for survival analysis and further stratified by age at diagnosis and township. Survival time was calculated up to March 30, 2022, and relative survival (RS) and age-standardized RS were calculated according to the International Cancer Survival Standards (ICSS). RESULTS: During 2011-2015, the 5-year RS for cervical, uterine, and ovarian cancers were 64.3 %, 64.2 %, and 44.7 %, respectively, while the age-standardized 5-year RS were 56.8 %, 47.9 %, and 27.9 %, respectively. During 2016-2020, the 5-year RS for cervical, uterine, and ovarian cancers were 72.3 %, 78.9 %, and 50.8 %, respectively, while the age-standardized 5-year RS were 64.5 %, 54.6 %, and 34.2 %, respectively. The 5-year RS for cervical and ovarian cancer all declined with age, while the 5-year RS for uterine cancer was highest at 45-54 years and lowest at 75 years. In addition, survival rates were broadly higher in urban than rural areas. CONCLUSION: Survival rates for cervical, uterine, and ovarian cancers have generally increased in the population covered by the Fujian Cancer Registry. However, survival rates remain lower than in developed countries. Emphasis should be placed on gynecological cancer screening and the introduction of effective treatments to improve survival rates for gynecological cancers.

Gynaecological cancer-related deaths in a tertiary hospital: A four-year retrospective review.

The aim of this study is to describe the profile, causes of death, and associated complications among women who died with a diagnosis of gynecological cancer during a four-year period in a gynae oncology unit in a tertiary hospital. The study is based on a retrospective review of clinical records of patients. There were 368 gynecological cancer admissions during the study period and 51 gynecological cancer-related deaths (13.8%); however, only 48 (13%) of the 51 files were available for analysis. The mean age of the women who died was 52.7 years (SD ±16.92). Most of the women who died were South African citizens (41, 85%), black (44, 91.7%) and unemployed (37, 77.1%). The most common comorbidities were hypertension and HIV which occurred at similar frequencies (20, 41.7%), followed by diabetes mellitus (7, 14,6%). The three most common cancers were cervical (18, 37.5%), ovarian (13, 27.1%), and endometrial (12, 25,0%). All women who died (48, 100%) had some form of cancer-related complications on admission to the hospital. The most common complication at presentation was obstructive uropathy (16, 31.3%) followed by ascites (11, 21.6%) and pleural effusion (8, 15.8%). Just less than half of the patients (22, 45.8%) received palliative treatment due to advanced-stage disease, and the remainder, (20, 41.6%) and (5, 10.4%) surgical and radiation therapy, respectively. The surgical procedure performed was staging laparotomy for ovarian and endometrial cancer (19, 95%) and radical hysterectomy and lymph node dissection for operatable cervical cancer (01, 5%). Forty-nine complications were recorded among the 20 women who underwent surgical treatment. The most common complications were sepsis and hemorrhage followed by organ injury.

Le but de cette étude est de décrire le profil, les causes de décès et les complications associées chez les femmes décédées avec un diagnostic de cancer gynécologique au cours d'une période de quatre ans dans une unité de gynécologie-oncologie d'un hôpital tertiaire. L'étude est basée sur une revue rétrospective des dossiers cliniques des patients. Il y a eu 368 admissions pour cancer décès liés au cancer gynécologique 51 décès d'origine gynécologique (13,8 %) ; cependant, seulement 48 (13 %) des 51 dossiers étaient disponibles pour analyse. L'âge moyen des femmes décédées était de 52,7 ans (ET ± 16,92). La plupart des femmes décédées étaient des citoyennes sud-africaines (41, 85 %), noires (44, 91,7 %) et au chômage (37, 77,1 %). Les comorbidités les plus courantes étaient l'hypertension et le VIH, qui survenaient à des fréquences similaires (20, 41,7 %), suivis du diabète sucré (7, 14,6 %). Les trois cancers les plus courants étaient le cancer du col de l'utérus (18, 37,5 %), de l'ovaire (13, 27,1 %) et de l'endomètre (12, 25,0 %). Toutes les femmes décédées (48, 100 %) ont présenté une forme ou une autre de complications liées au cancer lors de leur admission à l'hôpital. La complication la plus fréquente lors de la présentation était l'uropathie obstructive (16, 31,3 %), suivie de l'ascite (11, 21,6 %) et de l'épanchement pleural (8, 15,8 %). Un peu moins de la moitié des patients (22, 45,8 %) ont reçu un traitement palliatif en raison d'un stade avancé de la maladie, et le reste (20, 41,6 %) et (5, 10,4 %), une chirurgie et une radiothérapie, respectivement. L'intervention chirurgicale réalisée était une laparotomie de stadification pour un cancer de l'ovaire et de l'endomètre (19, 95 %) et une hystérectomie radicale et un curage ganglionnaire pour un cancer du col de l'utérus opérable (01, 5 %). Quarante-neuf complications ont été enregistrées parmi les 20 femmes ayant bénéficié d'un traitement chirurgical. Les complications les plus courantes étaient la septicémie et l'hémorragie, suivies de lésions organiques.

Stereotactic Ablative Radiotherapy for Gynecological Oligometastatic and Oligoprogessive Tumors.

Importance: The role of stereotactic ablative radiotherapy (SABR) for gynecologic malignant tumors has yet to be clearly defined despite recent clinical uptake. Objective: To evaluate the outcomes of SABR in patients with oligometastatic and oligoprogressive gynecologic cancers. Design, Setting, and Participants: In this retrospective pooled analysis, patients with oligometastatic and oligoprogressive gynecologic cancers receiving SABR at 5 institutions from Canada and the US were studied. Data were collected from January 2011 to December 2020, and data were analyzed from January to December 2023. Exposure: Stereotactic ablative radiotherapy. Main Outcomes and Measures: Cumulative incidence of local and distant recurrence, chemotherapy-free survival (CFS), and overall survival (OS) probabilities after SABR were calculated using Kaplan-Meier methods. Univariable and multivariable analysis was conducted using Cox regression methods. Results: A total of 215 patients with 320 lesions meeting criteria were included in the analysis; the median (range) age at primary diagnosis was 59 (23-86) years. The median (range) follow-up from SABR was 18.5 (0.1-124.5) months. The primary site included the endometrium (n = 107), ovary (n = 64), cervix (n = 30), and vulva or vagina (n = 14). Local cumulative incidence of recurrence was 13.7% (95% CI, 9.4-18.9) and 18.5% (95% CI, 13.2-24.5) at 1 and 5 years, respectively. Distant cumulative incidence of recurrence was 48.5% (95% CI, 41.4-55.1) and 73.1% (95% CI, 66.0-79.0) at 1 and 5 years, respectively. OS was 75.7% (95% CI, 69.2-81.1) and 33.1% (95% CI, 25.3-41.1) at 1 and 5 years, respectively. The median CFS was 21.7 months (95% CI, 15.4-29.9). On multivariable analysis, local recurrence was significantly associated with nodal metastasis, lesion size, biologically effective dose, treatment indication, institution, and primary disease type. Distant progression-free survival was associated with nodal targets and lesion size. OS and CFS were significantly associated with lesion size. Conclusions and Relevance: In this study, SABR appeared to have excellent local control with minimal toxic effects in this large patient group, and certain patients may achieve durable distant control and OS as well. It may be possible to delay time to chemotherapy in select patient subtypes and therefore reduce associated toxic effects. Prospective multicenter trials will be critical to establish which characteristics procure the greatest benefit from SABR use and to define the ideal time to implement SABR with other oncologic treatments.

Associations between race and ethnicity and treatment setting among gynecologic cancer patients.

INTRODUCTION: Racial and ethnic disparities in gynecologic cancer care have been documented. Treatment at academic facilities is associated with improved survival, yet no study has examined independent associations between race and ethnicity with facility type among gynecologic cancer patients. MATERIALS & METHODS: We used the National Cancer Database and identified 484,455 gynecologic cancer (cervix, ovarian, uterine) patients diagnosed between 2004 and 2020. Facility type was dichotomized as academic vs. non-academic, and we used logistic regression to estimate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between race and ethnicity and facility type. Secondarily, we examined joint effects of race and ethnicity and facility type on overall survival using Cox proportional hazards regression. RESULTS: We observed higher odds of treatment at academic (vs. non-academic) facilities among American Indian/Alaska Native (OR = 1.42, 95% CI = 1.28-1.57), Asian (OR = 1.64, 95% CI = 1.59-1.70), Black (OR = 1.69, 95% CI = 1.65-1.72), Hispanic (OR = 1.70, 95% CI = 1.66-1.75), Native Hawaiian/Pacific Islander (OR = 1.74, 95% CI = 1.57-1.93), and other race (OR = 1.29, 95% CI = 1.20-1.40) patients compared with White patients. In the joint effects survival analysis with White, academic facility-treated patients as the reference group, Asian, Hispanic, and other race patients treated at academic or non-academic facilities had improved overall survival. Conversely, Black patients treated at academic facilities [Hazard Ratio (HR) = 1.10, 95% CI = 1.07-1.12] or non-academic facilities (HR = 1.19, 95% CI = 1.16-1.21) had worse survival. DISCUSSION: Minoritized gynecologic cancer patients were more likely than White patients to receive treatment at academic facilities. Importantly, survival outcomes among patients receiving care at academic institutions differed by race, requiring research to investigate intra-facility survival disparities.

A systematic review and meta-analysis on mortality rate following total pelvic exenteration in cancer patients.

BACKGROUND: Total pelvic exenteration (TPE), an en bloc resection is an ultraradical operation for malignancies, and refers to the removal of organs inside the pelvis, including female reproductive organs, lower urological organs and involved parts of the digestive system. The aim of this meta-analysis is to estimate the intra-operative mortality, in-hospital mortality, 30- and 90-day mortality rate and overall mortality rate (MR) following TPE in colorectal, gynecological, urological, and miscellaneous cancers. METHODS: This is a systematic review and meta-analysis in which three international databases including Medline through PubMed, Scopus and Web of Science on November 2023 were searched. To screen and select relevant studies, retrieved articles were entered into Endnote software. The required information was extracted from the full text of the retrieved articles by the authors. Effect measures in this study was the intra-operative, in-hospital, and 90-day and overall MR following TPE. All analyzes are performed using Stata software version 16 (Stata Corp, College Station, TX). RESULTS: In this systematic review, 1751 primary studies retrieved, of which 98 articles (5343 cases) entered into this systematic review. The overall mortality rate was 30.57% in colorectal cancers, 25.5% in gynecological cancers and 12.42% in Miscellaneous. The highest rate of mortality is related to the overall mortality rate of colorectal cancers. The MR in open surgeries was higher than in minimally invasive surgeries, and also in primary advanced cancers, it was higher than in recurrent cancers. CONCLUSION: In conclusion, it can be said that performing TPE in a specialized surgical center with careful patient eligibility evaluation is a viable option for advanced malignancies of the pelvic organs.

Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers.

Cancer cells with DNA repair defects (e.g., BRCA1/2 mutant cells) are vulnerable to PARP inhibitors (PARPi) due to induction of synthetic lethality. However, recent clinical evidence has shown that PARPi can prevent the growth of some cancers irrespective of their BRCA1/2 status, suggesting alternative mechanisms of action. We previously discovered one such mechanism in breast cancer involving DDX21, an RNA helicase that localizes to the nucleoli of cells and is a target of PARP1. We have now extended this observation in endometrial and ovarian cancers and provided links to patient outcomes. When PARP1-mediated ADPRylation of DDX21 is inhibited by niraparib, DDX21 is mislocalized to the nucleoplasm resulting in decreased rDNA transcription, which leads to a reduction in ribosome biogenesis, protein translation, and ultimately endometrial and ovarian cancer cell growth. High PARP1 expression was associated with high nucleolar localization of DDX21 in both cancers. High nucleolar DDX21 negatively correlated with calculated IC50s for niraparib. By studying endometrial cancer patient samples, we were able to show that high DDX21 nucleolar localization was significantly associated with decreased survival. Our study suggests that the use of PARPi as a cancer therapeutic can be expanded to further types of cancers and that DDX21 localization can potentially be used as a prognostic factor and as a biomarker for response to PARPi. SIGNIFICANCE: Currently, there are no reliable biomarkers for response to PARPi outside of homologous recombination deficiency. Herein we present a unique potential biomarker, with clear functional understanding of the molecular mechanism by which DDX21 nucleolar localization can predict response to PARPi.

Assessment of secular trends of three major gynecologic cancers burden and attributable risk factors from 1990 to 2019: an age period cohort analysis.

BACKGROUND: This study aims to assess the long-term trends in the burden of three major gynecologic cancers(GCs) stratified by social-demographic status across the world from 1990 to 2019. To assess the trends of risk factor attributed mortality, and to examine the specific effects of age, period, cohort behind them in different regions. METHODS: We extracted data on the mortality, disability-adjusted life years(DALYs), and age-standardized rates(ASRs) of cervical cancer(CC), uterine cancer(UC), and ovarian cancer(OC) related to risks from 1990 to 2019, as GCs burden measures. Age-period-cohort analysis was used to analyze trends in attributable mortality rates. RESULTS: The number of deaths and DALYs for CC, UC and OC increased since 1990 worldwide, while the ASDRs decreased. Regionally, the ASDR of CC was the highest in low SDI region at 15.05(11.92, 18.46) per 100,000 in 2019, while the ASDRs of UC and OC were highest in high SDI region at 2.52(2.32,2.64), and 5.67(5.16,6.09). The risk of CC death caused by unsafe sex increased with age and then gradually stabilized, with regional differences. The period effect of CC death attributed to smoking showed a downward trend. The cohort effect of UC death attributed to high BMI decreased in each region, especially in the early period in middle, low-middle and low SDI areas. CONCLUSIONS: Global secular trends of attributed mortality for the three GCs and their age, period, and cohort effects may reflect the diagnosis and treatment progress, rapid socioeconomic transitions, concomitant changes in lifestyle and behavioral patterns in different developing regions. Prevention and controllable measures should be carried out according to the epidemic status in different countries, raising awareness of risk factors to reduce future burden.

Pelvic Exenteration - Past, Present and Future.

Background: Bearing in mind that the open procedure is already validated by multiple studies, the article aims to prove that pelvic exenteration performed in a minimally invasive fashion might offer better survival and to potentially identify prognostic factors for the outcome of these patients. Material and Methods: Data regarding past and present classifications and surgical indications are presented. Patient data were collected retrospectively. Results: The most frequent diseases treated with pelvic exenteration, in terms of the hystological type, were gynecological malignancy and squamous cell carcinoma. Recurrent pelvic disease was found in 68.2% of patients. R0 resection was achieved in 72.7% of patients in the MI group, and in 73.7% of patients in the OP group. Peri-operative morbidity was reported to be 56.6% for open surgery, and 18.1% for minimally invasive. Average DFS was 20.15 months, ranging from 1.5 to 70.3 months, while the OS was calculated to be 38.1 months (0.33 1508) up until November 2023. Conclusion: Pelvic exenteration is a continuously improving surgical procedure, open approach being favored to minimally invasive one. On the other hand, hospitalization and morbidity are reduced when choosing the latter. R0 and lymph node status are important predictors for overall survival, as well as major early postoperative complications. All in all, pelvic exenteration is still a promising surgical procedure to extend cancer patients lives.

The challenge of survivors of gynecological carcinomas: a retrospective study on occurrence of second tumors.

OBJECTIVE: To clarify the epidemiologic characteristics and risk of other tumors in survivors of gynecological tumors. MATERIALS AND METHODS: This is a retrospective study based on the Surveillance, Epidemiology, and End Results database (SEER). RESULTS: The morbidity of other malignant tumors in patients with gynecological cancer was 8.07%. The most common subsequent tumors are breast, lung, colorectal, thyroid, and bladder cancers. Taking the incidence rate of the general population as reference, the second tumor with the highest relative risk in patients with cervical cancer is vulvar cancer. Bladder cancer is the second tumor with the highest relative risk value both in patients with corpus and ovarian cancer. The median period from the diagnosis of the initial tumor to the diagnosis of the second tumor was 5 years. Most patients with other tumors following gynecological cancer showed worse prognosis than patients with gynecological tumors only. However, thyroid cancer following ovarian cancer is a protective factor in survival. CONCLUSION: Patients with gynecological tumors have a significantly higher risk of malignant tumors in other systems compared to ordinary population. It is necessary to be vigilant against subsequent high-risk tumors and tumors with poor prognosis within 5 years of initial diagnosis.

Treatment Interruptions and Mortality Among Puerto Rican Women With Gynecologic Cancers in Puerto Rico After Hurricanes Irma and María: A Retrospective Cohort Study.

OBJECTIVE: Cancer patients are among the most vulnerable populations during and after a disaster. We evaluated the impact of treatment interruption on the survival of women with gynecologic cancer in Puerto Rico following Hurricanes Irma and María. METHODS: A retrospective cohort study among a clinic-based sample of women with gynecological cancer diagnosed between January 2016 and September 2017 (n = 112) was done. Women were followed from their diagnosis until December 2019, to assess vital status. Kaplan-Meier survival curves and Cox proportional hazards models were performed. RESULTS: Mean age was 56 (± 12.3) years; corpus uteri (58.9%) was the most common gynecologic cancer. Predominant treatments were surgery (91.1%) and chemotherapy (44.6%). Overall, 75.9% were receiving treatment before the hurricanes, 16.1% experienced treatment interruptions, and 8.9% died during the follow-up period. Factors associated with treatment interruption in bivariate analysis included younger age (≤55 years), having regional/distant disease, and receiving > 1 cancer treatment (P < 0.05). Crude analysis revealed an increased risk of death among women with treatment interruption (HR: 3.88, 95% CI: 1.09-13.77), persisting after adjusting for age and cancer stage (HR: 2.49, 95% CI: 0.69-9.01). CONCLUSIONS: Findings underscore the detrimental impact of treatment interruption on cancer survival in the aftermath of hurricanes, emphasizing the need for emergency response plans for this vulnerable population.

Obesity paradox: is a high body mass index positively influencing survival outcomes in gynecological cancers? A systematic review and meta-analysis.

OBJECTIVE: Obesity represents an exponentially growing preventable disease leading to different health complications, particularly when associated with cancer. In recent years, however, an 'obesity paradox' has been hypothesized where obese individuals affected by cancer counterintuitively show better survival rates. The aim of this systematic review and meta-analysis is to assess whether the prognosis in gynecological malignancies is positively influenced by obesity. METHODS: This study adheres to PRISMA guidelines and is registered with PROSPERO. Studies reporting the impact of a body mass index (BMI) of >30 kg/m2 compared with <30 kg/m2 in patients with gynecological cancers listed in PubMed, Google Scholar and ClinicalTrials.gov were included in the analysis. The Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2) was used for quality assessment of the selected articles. RESULTS: Twenty-one studies were identified for the meta-analysis, including 14 108 patients with cervical, ovarian, or endometrial cancer. There was no benefit in 5-year overall survival for obese patients compared with non-obese patients (OR 1.2, 95% CI 1.00 to 1.44, p=0.05; I2=71%). When pooling for cancer sub-groups, there were no statistically significant differences in 5-year overall survival in patients with cervical cancer and 5-year overall survival and progression-free survival in patients with ovarian cancer. For obese women diagnosed with endometrial cancer, a significant decrease of 44% in 5-year overall survival (p=0.01) was found, with no significant difference in 5-year disease-free survival (p=0.78). CONCLUSION: According to the results of the present meta-analysis, a BMI of ≥30 kg/m2 does not have a positive prognostic effect on survival compared with a BMI of <30 kg/m2 in women diagnosed with gynecological cancers. The existence of the 'obesity paradox' in other fields, however, suggests the importance of further investigations with prospective studies.

The prognostic value of MEK pathway-associated estrogen receptor signaling activity for female cancers.

BACKGROUND: Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness. METHODS: Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data. RESULTS: We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers. CONCLUSION: This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.

Clinical and Genomic Landscape of RAS Mutations in Gynecologic Cancers.

PURPOSE: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. EXPERIMENTAL DESIGN: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model. RESULTS: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5-12.0) vs. 5.5 years (95% CI, 4.6-6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis. CONCLUSIONS: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.