Acceptability and Feasibility of Early Palliative Care Among Women with Advanced Epithelial Ovarian Cancer: A Randomized Controlled Pilot Study.

OBJECTIVE: To evaluate the acceptability of early palliative care (EPC) among patients with advanced ovarian cancer and to determine the feasibility of larger-scale phase III trials. METHODS: We performed a randomized controlled pilot study of adult women (>18 years) with pathologically confirmed epithelial ovarian cancer that had recurred or progressed on first-line therapy and had no immediate need for palliative care. We randomly assigned patients to either EPC or standard oncologic care (SOC), and collected patient-reported outcomes (PRO) at baseline, 3 months, and 6 months; end-of-life care quality indicators were collected at study completion. Study endpoints were rates of enrollment, EPC adherence, and PRO completion. RESULTS: Of 32 eligible patients approached, 23 enrolled (72%; 95% CI 53-86) and were randomly assigned to either EPC (n = 12) or SOC (n = 11). At baseline, participants had poor physical and emotional wellbeing, high rates of depression (65%), and understood that their disease was not curable (87%). Eleven patients (92%; 95% CI 62-100) attended their EPC consultation, and all visits took place within 4 weeks of enrollment. However, PRO completion was low due to deaths by 3 (5/23) and 6 months (9/23). CONCLUSION: Patients had accurate perceptions of their disease status, were willing to be randomly assigned to EPC, and attended scheduled appointments. However, a definitive trial in this group is not feasible without major adjustments to eligibility criteria and a multicentre, international effort. We propose that EPC be considered routinely at progression or recurrence given patients' symptom burden and clear acceptance of the intervention, as well as evidence of benefit from adequately powered trials in other malignancies.

Coping with fear of cancer recurrence among ovarian cancer survivors living in small urban and rural settings: A qualitative descriptive study.

PURPOSE: Fear of cancer recurrence (FCR) is a paramount concern among ovarian cancer survivors. Evidence shows that cancer survivors living in regional or rural areas have higher psychological morbidity; however, no known studies have explored how ovarian cancer survivors living in small urban and rural areas cope with FCR. METHODS: In this qualitative descriptive study, a semi-structured questioning process was developed in accordance with Carver et al.'s conceptualization of coping. Focus groups or 1:1 telephone interviews were used to collect data from a convenience sample of ovarian cancer survivors. Participants completed a demographic form and the Fear of Cancer Recurrence Inventory, and clinical information was extracted from hospital charts. RESULTS: The average age of participants (n = 15) was 62.8 years (Range 51-76 years) and the average time since diagnosis was 2.7 years (Range 1-19 years). Most women had elevated levels of FCR. Five themes for coping were expressed by all women: 1) health care provider support; 2) knowing, trusting, and prioritizing self; 3) finding what works; 4) uniqueness and belonging; and 5) redirecting thoughts and actions. One additional theme was expressed by most women (n = 11): 6) preparing for the future. CONCLUSION: Fear of cancer recurrence was a concern for most ovarian cancer survivors who used a variety of ways to cope. Results can be used to guide nurses' discussions with post-treatment ovarian cancer survivors or be used to inform refinement and development of resources to assist ovarian cancer survivors living in small urban and rural settings to cope with FCR.

No 370 - Prise en charge du cancer spinocellulaire de la vulve.

OBJECTIF: Cette directive clinique porte sur l'évaluation clinique et la prise en charge du cancer spinocellulaire (CSC) de la vulve, plus particulièrement sur son diagnostic, sa prise en charge primaire au moyen de la chirurgie, de la radiothérapie ou de la chimiothérapie et la nécessité d'une chimiothérapie et/ou d'une radiothérapie adjuvante. Cette directive clinique ne traite pas des autres diagnostics pathologiques de cancer de la vulve. UTILISATEURS CIBLES: La première partie de ce document, qui comprend les recommandations 1 à 3, s'adresse aux gynécologues, aux obstétriciens, aux médecins de famille, aux infirmières autorisées, aux infirmières praticiennes, aux résidents et aux fournisseurs de soins généralistes; elle est axée sur la présentation et le diagnostic de la maladie, et fournit des renseignements à jour sur les chirurgies effectuées par les professionnels surspécialisés. La partie sur la prise en charge chirurgicale et le traitement des cancers avancés de la vulve s'adresse aux gynécologues oncologues, aux radio-oncologues et aux oncologues médicaux appelés à traiter les patientes aux besoins complexes. Cette directive clinique a pour but de renseigner les intervenants qui pourraient suivre ces patientes après leur traitement. POPULATION CIBLE: Femmes adultes (18 ans et plus) présentant un CSC de la vulve. Les femmes atteintes d'un cancer préinvasif ne sont pas visées par cette directive clinique. OPTIONS: Les femmes ayant reçu un diagnostic de CSC de la vulve devraient être dirigées vers un gynécologue oncologue, qui effectuera une évaluation initiale et déterminera si une chirurgie primaire, une évaluation des ganglions lymphatiques inguinaux et une radiothérapie ou une chimiothérapie adjuvante sont nécessaires. Ces femmes devraient également faire l'objet d'une discussion tenue dans le cadre d'une conférence de cas multidisciplinaire. La radiothérapie et la chimiothérapie primaires peuvent être envisagées chez les femmes qui pourraient avoir besoin d'une exentération ou d'une chirurgie radicale, comme une résection abdomino-périnéale. ÉVIDENCE: Des études pertinentes rédigées en anglais ont été repérées dans PubMed, Medline, et la Cochrane Database of Systematic Reviews à l'aide des termes suivants, seuls ou combinés : « vulva ¼, « vulvar cancer ¼, « inguinofemoral lymph node dissection ¼, « sentinel nodes ¼, « systemic chemotherapy ¼, « radiotherapy ¼, « neoadjuvant ¼, « adjuvant ¼, « primary ¼, « exenteration ¼, « survival ¼, « follow up ¼. La recherche initiale a été menée en septembre 2016, et une dernière recherche a été effectuée en mai 2017. Dans l'ordre, les données probantes pertinentes pour la sélection ont été tirées de méta-analyses, de revues systématiques, de directives cliniques, d'essais cliniques randomisés, d'études de cohortes prospectives, d'études observationnelles, de revues non systématiques, d'études de série de cas et de rapports. D'autres articles pertinents ont été ciblés au moyen d'une vérification des références des revues de la littérature retenues. Au total, 286 études ont été repérées, et 78 ont été retenues pour la présente directive. VALEURS: Le contenu et les recommandations ont été rédigés et acceptés par les auteurs principaux. La direction et le conseil de la Société de gynéco-oncologie du Canada ont examiné le contenu et soumis des commentaires, puis le Conseil d'administration de la Société des obstétriciens et gynécologues du Canada a approuvé la version finale avant publication. La qualité des données probantes a été évaluée au moyen des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) [tableau 1]. L'interprétation des recommandations fortes et faibles est décrite dans le tableau 2. Le résumé des conclusions peut être fourni sur demande. AVANTAGES, INCONVéNIENTS ET COûTS: La présente directive clinique vise à guider les médecins vers une utilisation appropriée de l'évaluation du ganglion sentinelle inguinal en cas de CSC de la vulve. Le comité encourage également la centralisation du traitement des cancers de la vulve dans des centres de traitement spécialisés. MIS-à-JOUR: Une revue des données probantes sera menée cinq ans après la publication de la présente directive clinique afin de déterminer si une mise à jour complète ou partielle s'impose. Cependant, si de nouvelles données probantes importantes sont publiées avant la fin du cycle de cinq ans, le processus pourrait être accéléré afin que certaines recommandations soient mises à jour rapidement. COMMANDITAIRES: Cette directive Clinique a été développée avec les ressources de la Société de gynécologie oncologique du Canada et de la Société des obstétriciens et gynécologues du Canada. DéCLARATIONS SOMMAIRES: RECOMMENDATIONS.

No. 370-Management of Squamous Cell Cancer of the Vulva.

OBJECTIVE: This guideline reviews the clinical evaluation and management of squamous cell cancer (SCC) of the vulva with respect to diagnosis, primary surgical, radiation, or chemotherapy management and need for adjuvant treatment with chemotherapy and/or radiation therapy. Other vulvar cancer pathologic diagnoses are not included in the guideline. INTENDED USERS: The first part of this document which includes recommendations 1 through 3 is for general gynaecologists, obstetricians, family doctors, registered nurses, nurse practitioners, residents, and health care providers with a focus on the presentation, diagnosis, and updated information about surgical procedures performed by subspecialists. The surgical management and treatment of advanced vulvar cancer are intended for gynaecologic oncologists, radiation oncologists, and medical oncologists who treat these complex patients. This guideline is intended to provide information for interested parties who may follow these patients once treatment is complete. TARGET POPULATION: Adult women (18 years and older) with SCC of the vulva. Excluded from these guidelines are women with preinvasive disease. OPTIONS: Women diagnosed with SCC of the vulva should be referred to a gynaecologic oncologist for initial evaluation, consideration for primary surgery and inguinal lymph node assessment, and potentially adjuvant radiation and/or chemotherapy. All cases of vulvar cancer should have access to discussion at a multidisciplinary cancer case conference. Women who would otherwise require radical surgery such as abdominal-perineal resection or exenterative procedures may be considered for primary treatment with radiation and/or chemotherapy. EVIDENCE: For this guideline, relevant studies were searched in PubMed, Medline, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials: vulva, vulvar cancer, inguinofemoral lymph node dissection, sentinel nodes, systemic chemotherapy, radiotherapy, neoadjuvant, adjuvant, primary, exenteration, survival, follow up. The initial search was performed in September 2016 with a final literature search in May 2017. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 286, and 78 studies were included in this review. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the principal authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework (Table 1). The interpretation of strong and weak recommendations is described in Table 2. The Summary of Findings is available upon request. BENEFITS, HARMS, AND/OR COSTS: These guidelines are to encourage physicians in the appropriate use of sentinel inguinal lymph node assessment for SCC of the vulva. The committee also promotes the centralization of treatment of vulvar cancer in specialized treatment centres. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Gynecologic Oncology of Canada and the Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENTS: RECOMMENDATIONS.

STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer.

BACKGROUND: High-grade serous carcinoma (HGSC) of the ovary is predominantly diagnosed at late stages and primarily treated with debulking surgery followed by platinum/taxane-based chemotherapy. Although certain patients benefit significantly from currently used chemotherapy, there are patients who either do not respond or have an inadequate duration of response. We previously showed that tumours from chemoresistant patients have an immunosuppressed pre-existing tumour immune microenvironment with decreased expression of Type I Interferon (IFN1) genes. METHODS: Efficacy of a 'STimulator of INterferon Genes' agonist was evaluated in combination with carboplatin chemotherapy and PD-1 immune checkpoint blockade therapy in the ID8-Trp53-/- immunocompetent murine model of HGSC. RESULTS: Treatment with STING agonist led to decreased ascites accumulation and decreased tumour burden. Survival of mice treated with a combination of carboplatin, STING agonist and anti-PD-1 antibody was the longest. Tumour immune transcriptomic profiling revealed higher IFN response, antigen presentation and MHC II genes in tumours from STING agonist-treated mice compared to vehicle controls. Flow cytometry analysis revealed significantly higher intra-tumoural PD-1+ and CD69+CD62L-, CD8+ T cells in STING agonist-treated mice. CONCLUSIONS: These findings will enable rational design of clinical trials aimed at combinatorial approaches to improve chemotherapy response and survival in HGSC patients.

Multi-omics in high-grade serous ovarian cancer: Biomarkers from genome to the immunome.

Epithelial ovarian cancer (EOC) is a lethal gynaecological disease that imposes significant burden on health care and patient quality of life. High-grade serous carcinoma of the ovary (HGSC) is the most prevalent histological type of EOC. A vast majority of HGSC cases are diagnosed at late stages of the disease, limiting the opportunity for clinical intervention and resulting in a 10-year survival rate of <20%. Recent innovations in high-throughput molecular analysis of patient-derived specimens may address these clinical challenges by providing an enhanced understanding of the molecular aetiology of ovarian cancer, in addition to offering several opportunities for rational biomarker and targeted therapy discovery. In this review, we highlight the most significant contributions of omics approaches and how the advent of immunomics can aid in personalized combination chemo-immunotherapy in ovarian cancer treatment. We further provide insights into immunogenomic correlates of pre-treatment tumour immune microenvironment and some of the potential interpretations of immunomic data that require further validation, based on stromal and immune contributions to biomarker signatures. We believe a comprehensive integrative approach via meta-analysis of large ovarian cancer molecular profiling data sets is urgently needed to define robust prognostic and predictive classifiers of disease progression and treatment response. These investigations will inform rationalized biomarker-driven combination chemo-immunotherapy trials for improving response and survival of ovarian cancer patients.

No. 344-Opportunistic Salpingectomy and Other Methods of Risk Reduction for Ovarian/Fallopian Tube/Peritoneal Cancer in the General Population.

OBJECTIVE: This guideline reviews the potential benefits of opportunistic salpingectomy to prevent the development of high grade serous cancers (HGSC) of the ovary/fallopian tube/peritoneum based on current evidence supporting the fallopian tube origin of disease. INTENDED USERS: Gynaecologists, obstetricians, family doctors, registered nurses, nurse practitioners, residents, and health care providers. TARGET POPULATION: Adult women (18 and older): OPTIONS: Women considering hysterectomy who wish to retain their ovaries in situ have traditionally also retained their fallopian tubes. In addition, women undergoing permanent surgical sterilization have usually undergone tubal ligation using various methods rather than undergoing surgical removal of the entire fallopian tube. EVIDENCE: For the sections "Evidence Supporting the Hypothesis That HGSC Originates in the Fallopian Tube" and "Current Literature on the Effects and Safety of Opportunistic Salpingectomy," relevant studies were searched in PubMed, Medline, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials: "high grade serous cancers ovary," "fallopian tube," "peritoneum," "opportunistic salpingectomy," "epithelial ovarian cancers," "origin," "tubal carcinoma in situ," "BRCA mutation," "prophylactic salpingectomy," "inflammation," "clear cell," and "endometrioid." The initial search was performed in March 2015 with a final literature search in March 2016. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. The total number of studies identified was 458, and 56 studies were included in this review. For the section "Other Factors Influencing the Risk of Developing "Ovarian" Cancers" a general Medline search was carried out using the terms "ovarian neoplasm" and "prevention." The search included papers published from December 2005 to March 2016. Meta-analyses were preferentially selected except where no such review was found. Additional searches for each subheading were also conducted (e.g., "ovarian neoplasm" and "tubal ligation.") Additional significant articles were identified through cross-referencing the identified reviews. For the search for "ovarian neoplasm" and "prevention," 10 meta-analyses were identified. For the search for "ovarian neoplasm" and "tubal ligation," an additional 4 meta-analyses were identified. VALIDATION METHODS: The content and recommendations were drafted and agreed on by the principal authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the SOGC approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation methodology framework (Table 1). The interpretation of strong and weak recommendations is described in Table 2. The summary of findings is available on request. BENEFITS, HARMS, AND/OR COSTS: The addition of opportunistic salpingectomy to a planned hysterectomy or permanent sterilization did not increase rates of hospital readmission (OR 0.91, 95% CI 0.75 to 1.10 and OR 0.8, 95% CI 0.56 to 1.21, respectively) or blood transfusions (OR 0.86, 95% CI 0.67 to 1.10 and OR 0.75, 95% CI 0.32 to 1.73, respectively) but did increase the overall operating time (by 16 minutes and 10 minutes, respectively) in a retrospective review of 43 931 women. The risk of repeat surgery for tubal pathology among women with retained fallopian tubes after hysterectomy was at least doubled (OR 2.13, 95% CI 1.88 to 2.42 in a population-based study of 170 000 women). If general gynaecologists were to consider removal of fallopian tubes at the time of every hysterectomy and sterilization procedure with referral of all patients with HGSC for hereditary cancer counselling and genetic testing, experts project a potential reduction in the rate of HGSC by 40% over the next 20 years. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Gynecologic Oncology of Canada and SOGC. SUMMARY STATEMENTS: RECOMMENDATIONS.

No 344-Salpingectomie opportuniste et autres méthodes pour réduire le risque de cancer de l'ovaire, de la trompe de Fallope et du péritoine dans la population générale.

OBJECTIF: La présente directive clinique examine les avantages potentiels de la salpingectomie opportuniste pour prévenir le développement du cancer séreux de grade élevé de l'ovaire, de la trompe de Fallope et du péritoine à la lumière de données probantes actuelles selon lesquelles ce type de cancer prendrait naissance dans la trompe de Fallope. UTILISATEURS CIBLES: Gynécologues, obstétriciens, médecins de famille, infirmières autorisées, infirmières praticiennes, résidents et fournisseurs de soins de santé. POPULATION CIBLE: Femmes adultes (18 ans et plus) : OPTIONS: Les femmes envisageant une hystérectomie et souhaitant conserver leurs ovaires conservent généralement aussi leurs trompes de Fallope. De plus, celles qui subissent une chirurgie de stérilisation permanente subissent habituellement aussi une ligature des trompes selon des méthodes variées plutôt qu'un retrait chirurgical complet des trompes. RéSULTATS: Les sections « Données probantes appuyant l'hypothèse selon laquelle les CSGE prendraient naissance dans la trompe de Fallope ¼ et « Articles récents sur les répercussions et la sûreté de la salpingectomie opportuniste ¼ reposent sur des études pertinentes rédigées en anglais, qui ont été repérées dans PubMed, Medline et la Cochrane Database of Systematic Reviews à l'aide des termes suivants, seuls ou combinés : high grade serous cancers ovary, fallopian tube, peritoneum, opportunistic salpingectomy, epithelial ovarian cancers, origin, tubal carcinoma in situ, BRCA mutation, prophylactic salpingectomy, inflammation, clear cell et endometrioid. La recherche initiale a été menée en mars 2015, et une dernière recherche a été effectuée en mars 2016. Dans l'ordre, les données probantes pertinentes ont été tirées de méta-analyses, de revues de la littérature, de directives, d'essais cliniques randomisés, d'études de cohorte prospectives, d'études d'observation, de revues non systématiques, d'études de série de cas ainsi que de rapports. Au total, 458 études ont été repérées, et 56 ont été retenues pour la présente directive. Pour la section « Autres facteurs influant sur le risque de développer un cancer de ″l'ovaire″ ¼, une recherche générale a été effectuée dans Medline à partir des termes ovarian neoplasm et prevention. Ont été inclus dans cette recherche des articles rédigés entre décembre 2005 et mars 2016. Les méta-analyses ont été privilégiées lorsque possible. Des recherches supplémentaires ont également été menées pour chaque sous-descripteurs (p. ex., ovarian neoplasm et tubal ligation). D'autres articles pertinents ont été ciblés au moyen d'une vérification des références des revues de la littérature retenues. Les termes ovarian neoplasm et prevention ont permis de repérer 10 méta-analyses; les termes ovarian neoplasm et tubal ligation, 4 méta-analyses. MéTHODES DE VALIDATION: Le contenu et les recommandations ont été rédigés et acceptés par les auteurs principaux. La direction et le conseil de la Société de gynéco-oncologie du Canada ont examiné le contenu et soumis des commentaires, puis le Conseil d'administration de la SOGC a approuvé la version finale avant publication. La qualité des données probantes a été évaluée à partir des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) (tableau 1). L'interprétation des recommandations solides et conditionnelles est décrite dans le tableau 2. Le résumé des conclusions peut être fourni sur demande. AVANTAGES, INCONVéNIENTS ET COûTS: L'ajout d'une salpingectomie opportuniste à une hystérectomie ou à une procédure de stérilisation permanente prévue n'a pas entraîné une augmentation des taux de réadmission à l'hôpital (RC : 0,91; IC à 95 % : 0,75-1, 10 et RC : 0,8; IC à 95 % : 0,56-1,21, respectivement) ou de transfusion sanguine (RC : 0,86; IC à 95 % : 0,67-1,10 et RC : 0,75; IC à 95 % : 0,32-1,73, respectivement), mais il a entraîné une hausse de la durée des opérations (de 16 minutes et de 10 minutes, respectivement) selon une étude rétrospective portant sur 43 931 femmes. Le risque de subir des interventions répétées pour une pathologie tubaire chez les femmes ayant conservé leurs trompes de Fallope après une hystérectomie était au moins deux fois plus élevé (RC : 2,13; IC à 95 % : 1,88-2,42, selon une étude fondée sur une population de 170 000 femmes). Selon des experts, si les gynécologues généralistes envisageaient systématiquement de retirer les trompes de Fallope lors d'une hystérectomie ou d'une procédure de stérilisation et d'aiguiller toutes les patientes aux prises avec un CSGE vers une consultation en oncologie génétique et un dépistage génétique, le taux de CSGE pourrait diminuer de 40 % au cours des 20 prochaines années. MISE à JOUR DE DIRECTIVES CLINIQUES: Une revue des données probantes sera menée cinq ans après la publication de la présente directive clinique afin de déterminer si une mise à jour complète ou partielle s'impose. Cependant, si de nouvelles données probantes importantes sont publiées avant la fin du cycle de cinq ans, le processus pourrait être accéléré afin que certaines recommandations soient mises à jour rapidement. PARRAINS: La présente directive clinique a été élaborée à l'aide de ressources financées par la Société de gynéco-oncologie du Canada et la SOGC. DéCLARATIONS SOMMAIRES: RECOMMANDATIONS.

CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer.

OBJECTIVE: We recently established that high STAT1 expression and associated T helper type I tumour immune microenvironment (TME) are prognostic and chemotherapy response predictive biomarkers in high-grade serous ovarian cancer (HGSC). STAT1 induced chemokine CXCL10 is key to the recruitment of lymphocytes in the TME and is significantly highly expressed in the tumours from patients with longer survival. In the current study we therefore aimed to elucidate the role CXCL10 in disease progression and tumour immune transcriptomic alterations using the ID8 syngeneic murine model of HGSC. METHODS: ID8 ovarian cancer cells were engineered for stable knockdown (KD) and overexpression (OX) of CXCL10. The OX and KD cell line derivatives, along with their respective vector controls, were implanted in immunocompetent C57BL/6 mice via intra-peritoneal injections. At end point, immune transcriptomic profiling of tumour tissues and multiplex cytokine profiling of ascites, was performed. Effect of CXCL10 expression on the tumour vasculature and tumour cell proliferation was evaluated by CD31 and Ki67 immunostaining, respectively. RESULTS: Increased CXCL10 expression led to decreased tumour burden and malignant ascites accumulation in the ID8 syngeneic murine model of HGSC. The ascites levels of IL-6 and VEGF were significantly reduced in OX mice compared to the vector controls. The OX tumours also showed reduced vasculature (CD31) and proliferative index (Ki67) compared to the control tumours. Significantly higher expression of genes associated with antigen processing, apoptosis and T cell function was observed in OX tumours compared to the controls. Reduced CXCL10 expression in tumours from KD mice led to increased ascites accumulation and disease progression compared to the controls. CONCLUSION: CXCL10 is a positive determinant of anti-tumour immune responses in HGSC TME and disease progression. These findings are foundational for future translational studies aimed at improving treatment response and survival in HGSC patients, via exploiting the TME.

STAT1-associated intratumoural TH1 immunity predicts chemotherapy resistance in high-grade serous ovarian cancer.

High-grade serous ovarian carcinoma (HGSC) accounts for 70% of all epithelial ovarian cancers but clinical management is challenged by a lack of accurate prognostic and predictive biomarkers of chemotherapy response. This study evaluated the role of Signal Transducer and Activator of Transcription 1 (STAT1) as an independent prognostic and predictive biomarker and its correlation with intratumoural CD8+ T cells in a second independent biomarker validation study. Tumour STAT1 expression and intratumoural CD8+ T cell infiltration were assessed by immunohistochemistry as a multicentre validation study conducted on 734 chemotherapy-naïve HGSCs. NanoString-based profiling was performed to correlate expression of STAT1 target genes CXCL9, CXCL10 and CXCL11 with CD8A transcript expression in 143 primary tumours. Multiplexed cytokine analysis of pre-treatment plasma from resistant and sensitive patients was performed to assess systemic levels of STAT1-induced cytokines. STAT1 was validated as a prognostic and predictive biomarker in both univariate and multivariate models and its expression correlated significantly with intra-epithelial CD8+ T cell infiltration in HGSC. STAT1 levels increased the prognostic and predictive value of intratumoural CD8+ T cells, confirming their synergistic role as biomarkers in HGSC. In addition, expression of STAT1 target genes (CXCL9, CXCL10 and CXCL11) correlated significantly with levels of, and CD8A transcripts from intratumoural CD8+ T cells within the resistant and sensitive tumours. Our findings provide compelling evidence that high levels of STAT1, STAT1-induced chemokines and CD8+ T cells correlate with improved chemotherapy response in HGSC. These results identify STAT1 and its target genes as novel biomarkers of chemosensitivity in HGSC. These findings provide new translational opportunities for patient stratification for immunotherapies based on emerging biomarkers of inflammation in HGSC. An improved understanding of the role of interferon-inducible genes will be foundational for developing immunomodulatory therapies in ovarian cancer.

Current state of biomarkers in ovarian cancer prognosis.

High-grade serous ovarian cancer remains one of the most lethal malignancies in women. Despite recent advances in surgical and pharmaceutical therapies, survival rates remain poor. A major impediment in management of this disease, that continues to contribute to poor overall survival rates, is resistance to standard carboplatin-paclitaxel combination chemotherapies. In addition to tumor cell intrinsic mechanisms leading to drug resistance, there is increasing awareness of the crucial role of the tumor microenvironment in mediating natural immune defense mechanisms and selective pressures that appear to facilitate chemotherapy sensitivity. We provide an overview of some of the promising new genetic and immunological biomarkers in ovarian cancer and discuss their biology and their likely clinical utility in future ovarian cancer management.

Gastrointestinal stromal tumor presenting as a recurrent vaginal mass.

Gastrointestinal stromal tumors are CD117 (c-Kit)-positive mesenchymal neoplasms with histologic and ultrastructural features of the interstitial cell of Cajal. While tumors outside of the gastrointestinal tract have been described, to our knowledge the case we present is the first such case in the vagina. We describe a 75-year-old woman with a recurrent vaginal gastrointestinal stromal tumor without apparent rectal involvement. This tumor was characterized by short intersecting fascicles of spindled cells, focal necrosis, and 12 to 15 mitoses per 50 high-power fields. Immunohistochemistry revealed diffuse cytoplasmic positivity for CD117 (c-Kit), CD34, vimentin, and h-caldesmon. Tumor cells were negative for S100, desmin, actin, and CAM 5.2. The differential diagnosis in this case included a vaginal smooth muscle tumor. While histologically similar to a smooth muscle neoplasm, the immunohistochemical profile ruled out smooth muscle differentiation. Gastrointestinal stromal tumor should be considered in the differential diagnosis of vaginal mesenchymal neoplasms.