Molecular changes driving low-grade serous ovarian cancer and implications for treatment.

Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway (KRAS, BRAF, and NRAS), and in genes related to the MAPK pathway (NF1/2, EIF1AX, and ERBB2). However, MAPK inhibitors have shown only modest clinical responses. Based on the discovery of CDKN2A mutations in low-grade serous ovarian cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are now being tested in clinical trials in combination with hormone therapy. Additional mutations seen in a smaller population of low-grade tumors include USP9X, ARID1A, and PIK3CA, but no specific therapies targeting them have been tested clinically. This review summarizes the clinical, pathologic, and molecular features of low-grade serous ovarian cancer as they are now understood and introduces potential therapeutic targets and new avenues for research.

Hyaluronic acid to manage radiotoxicities in gynecological cancer patients: a scoping review.

PURPOSE: This study aimed to map the use of hyaluronic acid (HA) in preventing and controlling radiotoxicity in women with gynecological cancer undergoing radiotherapy. METHODS: We conducted a scoping review of eight electronic databases: CINAHL, Cochrane CENTRAL, LILACS, PubMed, Scopus, Embase, LIVIVO, and the Web of Science Core Collection. In addition, a grey literature search was performed using Google Scholar and ProQuest Dissertations & Theses Global. A manual search was also identified additional references. The search was conducted on May 18, 2023. We included primary studies, reviews, and guidelines that discussed the use of HA to prevent and manage the toxicities resulting from gynecological radiotherapy. RESULTS: Eighteen studies were included in this scoping review, published between 2009 and 2022. There was heterogeneity in the use of HA, particularly in the method of application (moisturizing gel, vaginal ovules, spacer gel, and bladder instillations). Furthermore, the radiotoxicities varied among studies, encompassing, among others, vaginal atrophy, dryness, dyspareunia, telangiectasis, adhesions, vaginal stenosis, bleeding, hematuria, and bladder issues. Most studies addressed the potential benefits of HA in managing the signs and symptoms resulting from radiotherapy. CONCLUSION: HA has been utilized in clinical practice, in various formulations, for managing signs and symptoms in patients with gynecological cancer undergoing radiotherapy. However, further studies are necessary to thoroughly investigate the most effective method of HA application and its effectiveness in managing radiotoxicity.

An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study).

OBJECTIVE: This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. METHODS: FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. RESULTS: A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. CONCLUSION: Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.

Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer.

BACKGROUND: As an unconventional subpopulation of T lymphocytes, γδ T cells can recognize antigens independently of major histocompatibility complex restrictions. Recent studies have indicated that γδ T cells play contrasting roles in tumor microenvironments-promoting tumor progression in some cancers (eg, gallbladder and leukemia) while suppressing it in others (eg, lung and gastric). γδ T cells are mainly enriched in peripheral mucosal tissues. As the cervix is a mucosa-rich tissue, the role of γδ T cells in cervical cancer warrants further investigation. METHODS: We employed a multiomics strategy that integrated abundant data from single-cell and bulk transcriptome sequencing, whole exome sequencing, genotyping array, immunohistochemistry, and MRI. RESULTS: Heterogeneity was observed in the level of γδ T-cell infiltration in cervical cancer tissues, mainly associated with the tumor somatic mutational landscape. Definitely, γδ T cells play a beneficial role in the prognosis of patients with cervical cancer. First, γδ T cells exert direct cytotoxic effects in the tumor microenvironment of cervical cancer through the dynamic evolution of cellular states at both poles. Second, higher levels of γδ T-cell infiltration also shape the microenvironment of immune activation with cancer-suppressive properties. We found that these intricate features can be observed by MRI-based radiomics models to non-invasively assess γδ T-cell proportions in tumor tissues in patients. Importantly, patients with high infiltration levels of γδ T cells may be more amenable to immunotherapies including immune checkpoint inhibitors and autologous tumor-infiltrating lymphocyte therapies, than to chemoradiotherapy. CONCLUSIONS: γδ T cells play a beneficial role in antitumor immunity in cervical cancer. The abundance of γδ T cells in cervical cancerous tissue is associated with higher response rates to immunotherapy.

Predictors and outcomes of same day discharge after minimally invasive hysterectomy in gynecologic oncology within the National Surgical Quality Improvement Program database.

OBJECTIVE: To assess trends over time of same day discharge after minimally invasive hysterectomy in oncology, identify perioperative factors influencing same day discharge, and evaluate 30 day postoperative morbidity. METHODS: A retrospective cohort of elective minimally invasive hysterectomies performed for gynecologic oncologic indications between January 2013 and December 2021 was identified using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Clinical and surgical characteristics, length of stay, and 30 day postoperative complications were captured. Clinical and surgical factors affecting same day discharge rate and impact of same day discharge on postoperative outcomes were evaluated using χ2 tests and logistic regression. RESULTS: Patients undergoing minimally invasive hysterectomy (n=32 823) had a same day discharge rate of 34.5% over the 9 year period, increasing from 15.5% in 2013 to 55.1% in 2021. The rate of patients discharged on postoperative day 1 decreased from 76.4% to 41.4% over this period. On multivariable analysis, same day discharge decreased with: age 70-79 years (odds ratio (OR) 0.80) and ≥80 years (OR 0.42); body mass index 40-49.9 kg/m2 (OR 0.89) and ≥50 kg/m2 (OR 0.67); patient comorbidities, including hypertension (OR 0.85), chronic steroid use (OR 0.74), bleeding disorder (OR 0.54), anemia (OR 0.89), and hypoalbuminemia (OR 0.76); and surgical time >90th percentile (OR 0.40) (all p<0.05). Lymphadenectomy did not impact the same day discharge rate (unadjusted OR 1.03, p=0.22). Same day discharge had no effect on 30 day postoperative composite morbidity (OR 0.91, p=0.20), and was associated with fewer readmissions (OR 0.75, p=0.005). Age 70-79 years (OR 1.07, p=0.435) and age ≥80 years (OR 1.11, p=0.504) did not increase postoperative morbidity. However, body mass index categories 40-49.9 kg/m2 (OR 1.28, 95% CI 1.08 to 1.51) and ≥50 kg/m2 (OR 1.60, 95% CI 1.27 to 2.01) were associated with greater 30 day composite morbidity. CONCLUSION: In this study, same day discharge following minimally invasive hysterectomy for oncologic indications was safe, and rates are rising among all age and body mass index categories. Quality improvement initiatives are needed at oncology centers to promote early discharge after minimally invasive gynecologic oncology surgery.

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review.

BACKGROUND: Endometrial cancers with more than one molecular feature-POLE mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'. OBJECTIVE: To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. METHODS: Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. RESULTS: Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. TP53 sequencing allowed the detection of additional 7 (18.9%) multiple classifiers with normal p53 immunostaining. The incidence of multiple classifiers ranged from 1.8% to 9.8% in 10 published studies including >100 patients. When only p53 immunohistochemistry was performed, the highest incidence was 3.9%. CONCLUSIONS: The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and TP53 sequencing.

Prognostic significance of delayed complete metabolic response on PET/CT after primary chemoradiation treatment of cervical cancer.

OBJECTIVE: To investigate the prognostic significance of near-complete metabolic response on initial follow-up PET/CT after primary chemoradiation treatment of cervical cancer. METHODS: Survival data were retrospectively compared between patients who had complete metabolic response on first follow-up PET/CT, 3 months after chemoradiation (group 1) with those who had near-complete metabolic response on first PET/CT and later showed complete metabolic response at subsequent PET/CT, 6 months or more after treatment (group 2). RESULTS: Of the 108 patients included in the final analysis, 74 (68.5%) showed complete metabolic response on initial PET/CT, 3 months after treatment, and 34 patients (31.5%) showed complete metabolic response on subsequent PET/CT, 6 months after treatment. Tumor characteristics were comparable between groups. Group 1 had higher percent of stage 1 (12% vs 0%) and lower percent of stage 4 disease (3% vs 14%) than those of group 2. Group 2 patients had significantly fewer cases of recurrences and deaths than group 1 patients (6% vs 26%, p=0.018; 0% vs 20%, p=0.003, respectively), with comparable 3-year survival rates (group 1, 90% vs group 2, 100%, p=0.31). Twelve patients had progressive disease on first follow-up PET/CT; these patients had significantly worse overall survival compared with all other patients (log-rank test, p<0.001). Younger age and delayed complete metabolic response were associated with lower chance of recurrence and death on univariate analysis. On multivariate analysis, delayed complete metabolic response remained significantly associated with no recurrence HR=0.14 (95% CI 0.25 to 0.84), p=0.031. CONCLUSIONS: Survival outcome of patients with cervical cancer who show residual 18F-fluorodeoxyglucose uptake on initial PET/CT after treatment, but reach complete metabolic response on follow-up PET/CT, is not inferior compared with survival of patients who show complete metabolic response on initial PET/CT 3 months after treatment. Watchful waiting with follow-up PET/CT seems a safe option for these patients.

Advanced ovarian yolk sac tumor: upfront surgery or neoadjuvant chemotherapy followed by interval debulking?

OBJECTIVE: To compare surgery and survival outcomes between neoadjuvant chemotherapy and primary debulking surgery in patients with advanced ovarian yolk sac tumor. METHODS: In this retrospective cohort analysis, patients with stage III to IV ovarian yolk sac tumor or mixed germ cell tumors containing yolk sac tumor elements, and who underwent surgery at Peking Union Medical College Hospital between January 2011 and December 2021, were identified. Patient characteristics, treatment, and survival data were analyzed between the two groups. RESULTS: A total of 40 patients were enrolled: 19 patients received neoadjuvant chemotherapy followed by interval surgery, and 21 patients were treated with primary debulking surgery. After neoadjuvant chemotherapy, the surgical conditions of patients were improved. All patients achieved cytoreduction to R0 or R1 at interval surgery. No statistical difference was found in 3-year disease-free survival and overall survival between the neoadjuvant chemotherapy group and the primary debulking surgery group (log rank p=0.4 and 0.94). Patients had less blood loss (328.4 vs 1285.7 mL, p=0.029), lower transfusion volume (1044.4 vs 3066.7 mL, p=0.011), and fewer peri-operative complications (15.8% vs 47.6%, p=0.032) at the interval debulking surgery after neoadjuvant chemotherapy compared with patients who underwent primary debulking surgery. CONCLUSION: For patients with advanced-stage ovarian yolk sac tumor, neoadjuvant chemotherapy followed by interval surgery is an alternative option, especially for those who cannot tolerate the primary debulking surgery because of high tumor burden and vulnerable status.

Gestational choriocarcinoma.

Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.

Predicting resectable disease in relapsed epithelial ovarian cancer by using whole-body diffusion-weighted MRI.

OBJECTIVE: To determine the diagnostic value of whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to predict resectable disease at the time of secondary cytoreductive surgery for relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months. METHODS: A retrospective cohort study between January 2012 and December 2021 in a tertiary referral hospital. Inclusion criteria were: (a) first recurrence of epithelial ovarian cancer; (b) platinum-free interval of ≥6 months; (c) intent to perform secondary cytoreductive surgery with complete macroscopic resection; and (d) WB-DWI/MRI was performed.Diagnostic tests of WB-DWI/MRI for predicting complete resection during secondary cytoreductive surgery are calculated as well as the progression-free and overall survival of the patients with a WB-DWI/MRI scan that showed resectable disease or not. RESULTS: In total, 238 patients could be identified, of whom 123 (51.7%) underwent secondary cytoreductive surgery. WB-DWI/MRI predicted resectable disease with a sensitivity of 93.6% (95% confidence interval [CI] 87.3% to 96.9%), specificity of 93.0% (95% CI 87.3% to 96.3%), and an accuracy of 93.3% (95% CI 89.3% to 96.1%). The positive predictive value was 91.9% (95% CI 85.3% to 95.7%).Prediction of resectable disease by WB-DWI/MRI correlated with improved progression-free survival (median 19 months vs 9 months; hazard ratio [HR] for progression 0.36; 95% CI 0.26 to 0.50) and overall survival (median 75 months vs 28 months; HR for death 0.33; 95% CI 0.23 to 0.47). CONCLUSION: WB-DWI/MRI accurately predicts resectable disease in patients with a platinum-free interval of ≥6 months at the time of secondary cytoreductive surgery and could be of complementary value to the currently used models.

Timing of HPV vaccination as adjuvant treatment of CIN2+ recurrence in women undergoing surgical excision: a meta-analysis and meta-regression.

OBJECTIVE: The main aim was to determine the overall vaccine effectiveness (VE) against recurrent cervical intraepithelial neoplasia grade 2 or worse (CIN2+) including specific VE associated with timing of human papillomavirus (HPV) vaccination using data from published studies. DESIGN: Meta-analysis and meta-regression. DATA SOURCES: A computerised literature search was undertaken using the MEDLINE, EMBASE, International Pharmaceutical Abstracts, Derwent Drug File, ProQuest Science and Technology, Cochrane and MedRxiv databases. To be eligible, the studies, with no language restrictions, had to be published between 1 January 2001 and 25 May 2023. REVIEW METHODS: Included were studies with an unvaccinated reference group that assessed CIN2+ recurrence irrespective of the HPV genotype in women undergoing conisation provided. The present study was carried out in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology guidelines. The risk of study bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. The Grading of Recommendations Assessment, Development, and Evaluation guidelines were used to assess the strength of evidence for the primary outcome. Data synthesis was conducted using meta-analysis and meta-regression. RESULTS: Out of a total of 14 322 publications, 20 studies with a total of 21 estimates were included. The overall VE against recurrent CIN2+ irrespective of the HPV genotype achieved 69.5% (95% CI: 54.7% to 79.5%). While the HPV vaccine valency, follow-up duration, type of study including its risk of bias had no effect on VE, the highest VE of 78.1% (95% CI: 68.7% to 84.7%) was reported for women receiving their first dose not earlier than the day of excision. This outcome was supported by additional analyses and a VE prediction interval ranging from 67.1% to 85.4%. CONCLUSIONS: The outcome of this meta-analysis and meta-regression convincingly showed the beneficial effect of post-excisional HPV vaccination against CIN2+ recurrence. Studies published to date have been unable to determine whether or not vaccination, completed or initiated before conisation, would be associated with more favourable results. PROSPERO REGISTRATION NUMBER: CRD42022353530.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer.

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.

A Rare Case of Hepatocellular Carcinoma Recurrence in Ovarian Site after 12 Years Mimicking a Hepatoid Adenocarcinoma: Case Report.

Hepatoid carcinoma of the ovary (HCO) is a tumor that resembles, both histologically and cytologically, hepatocarcinoma (HCC) in a patient with a non-cirrhotic liver not involved by the disease. Hepatoid carcinoma is an extremely rare histologic subtype of ovarian cancer and should be distinguished from metastatic HCC. Here, we report the rare case of a 67-year-old woman with ovarian recurrence of HCC 12 years after first diagnosis. The patient was being followed by oncologists because she had been diagnosed with HCV-related HCC (Edmonson and Stainer grade 2, pT2 N0 M0, G2, V1) in 2009. She had undergone surgery for enlarged left hepatectomy to the 4th hepatic segment with cholecystectomy and subsequent placement of a Kehr drain. The preoperative alpha-fetoprotein (AFP) level was 8600 ng/mL, while the postoperative value was only 2.7 ng/mL. At the first diagnosis, no other localizations of the disease, including the genital tract, were found. At the time of recurrence, however, the patient was completely asymptomatic: her liver function was within normal limits with negative blood indices, except for an increased blood dosage of AFP (467 ng/mL), and CA125, which became borderline (37.4 IU/mL). The oncologist placed an indication for a thoracic abdominal CT scan, which showed that the residual liver was free of disease, and the presence of a formation with a solid-cystic appearance and some calcifications at the left adnexal site. The radiological findings were confirmed on level II gynecological ultrasound. The patient then underwent a radical surgery of hysterectomy, bilateral oophorectomy, pelvic peritonectomy, and omentectomy by a laparotomic approach, with the sending of intraoperative extemporaneous histological examination on the annexus site of the tumor mass, obtaining RT = 0. Currently, the patient continues her gyneco-oncology follow-up simultaneously clinically, in laboratory, and instrumentally every 4 months. Our study currently represents the longest elapsed time interval between first diagnosis and disease recurrence, as evidenced by current data in the literature. This was a rather unique and difficult clinical case because of the rarity of the disease, the lack of scientific evidence, and the difficulty in differentiating the primary hepatoid phenotype of the ovary from an ovarian metastasis of HCC. Several multidisciplinary meetings for proper interpretation of clinical and anamnestic data, with the aid of immunohistochemistry (IHC) on histological slides were essential for case management.

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer.

BACKGROUND: High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function of BRCA1 and PTENgenes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency. METHODS: Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53 -/-; Pten -/- and ID8-Trp53 -/-; Brca1 -/-, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy. RESULTS: Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1-deficient cells; further, tumors from mice injected with Pten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation. CONCLUSIONS: This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.

Utilisation of hospital-based specialist palliative care in patients with gynaecological cancer: Temporal trends, predictors and association with high-intensity end-of-life care.

OBJECTIVE: To examine hospital-based specialist palliative care (SPC) utilisation among patients with gynaecological cancer, including temporal trends, predictors and associations with high-intensity end-of-life care. METHODS: We conducted a nationwide registry-based study for all patients dying from gynaecological cancer in Denmark during 2010-2016. We estimated the proportions of patients receiving SPC by year of death and used regression analyses to examine predictors of SPC utilisation. Use of high-intensity end-of-life care according to SPC utilisation was compared by regression analyses adjusting for type of gynaecological cancer, year of death, age, comorbidities, residential region, marital/cohabitation status, income level and migrant status. RESULTS: Among 4502 patients dying from gynaecological cancer, the proportion of patients receiving SPC increased from 24.2% in 2010 to 50.7% in 2016. Young age, three or more comorbidities, residence outside the Capital Region and being immigrant/descendant were associated with increased SPC utilisation, whereas income, cancer type and stage were not. SPC was associated with lower high-intensity end-of-life care utilisation. Particularly, when compared with patients not receiving SPC, patients who accessed SPC >30 days before death had 88% lower risk of intensive care unit admissions within 30 days before death (adjusted relative risk: 0.12 (95% CI: 0.06; 0.24)) and 96% lower risk of surgery within 14 days before death (adjusted relative risk: 0.04 (95% CI: 0.01; 0.31)). CONCLUSIONS: Among patients dying from gynaecological cancer, SPC utilisation increased over time and age, comorbidities, residential region and migrant status were associated with access to SPC. Furthermore, SPC was associated with lower use of high-intensity end-of-life care.