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High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.

Simple Summary: Anxiety, depression and fear of cancer progression are common psychological challenges faced by women with ovarian cancer. It can affect a person's well-being, treatment compliance and quality of life. In this study, we assessed how often and how severe these concerns are 12 months after surgical treatment and if there is any association with surgical, patient and tumour factors. A total of 141 patients with advanced ovarian cancer who did not have disease progression at 12 months post-surgery completed two questionnaires. We found that a significant proportion of patients undergoing surgery for ovarian cancer experience anxiety, depression and fear of progression. It was not possible to identify a group of patients who are more affected by anxiety, depression or fear of progression. It is essential for healthcare providers to be attentive to the emotional needs of all ovarian cancer patients and provide appropriate support to help them cope with these psychological concerns effectively. Patients with ovarian cancer (OC) often experience anxiety, depression and fear of progression (FOP); however, it is unclear whether surgical complexity has a role to play. We investigated the prevalence of anxiety, depression and FOP at 12 months post-cytoreductive surgery and investigated associations with surgical complexity, patient (age, ethnicity, performance status, BMI) and tumour (stage, disease load) factors. One hundred and forty-one patients with FIGO Stage III–IV OC, who did not have disease progression at 12 months post-surgery, completed the Hospital Anxiety and Depression Scale and FOP short-form questionnaire. Patients underwent surgery with low (40.4%), intermediate (31.2%) and high (28.4%) surgical complexity scores. At 12 months post-surgery, 99 of 141 (70%) patients with advanced OC undergoing surgery experienced clinically significant anxiety, 21 of 141 (14.9%) patients experienced moderate to severe depression and 37 of 140 (26.4%) experienced dysfunctional FOP. No associations were identified between the three different surgical complexity groups with regards to anxiety, depression or FOP scores. Unsurprisingly, given the natural history of the disease, most patients with OC suffer from anxiety, depression and fear of progression after completion of first-line cancer treatment. Surgical complexity at the time of surgery is not associated with a deleterious impact on anxiety, depression or FOP for patients with OC. Patients with OC experience a profound mental health impact and should be offered mental health support throughout their cancer journey. [ABSTRACT FROM AUTHOR]

The article discusses the role of neoadjuvant chemotherapy (NAC) in advanced ovarian cancer (AOC) treatment, emphasizing the importance of surgery as a prognostic factor. It critiques the NAC/IDS approach, highlighting flaws in existing evidence and presenting the TRUST trial as a significant study involving fit patients from multiple countries. The debate surrounding NAC usage is addressed, acknowledging its benefits for specific patient populations while also recognizing potential misuse due to capacity and expertise limitations. [Extracted from the article]

Objective: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach. Design: Prospective multicentre observational study. Setting: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia. Sample: Patients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late‐stage ovarian cancer. Main Outcome Measures: Primary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality‐of‐life questionnaire (QLQ‐C30). Secondary: EORTC ovarian cancer module (OV28), progression‐free survival. Results: Patients' preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre‐surgical baseline in the EORTC QLQ‐C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high‐SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated‐measures model, there were no clinically or statistically meaningful differences in EORTC QLQ‐C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p < 0.001). The high‐SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post‐surgery, which resolved by 6–12 months. Conclusions: The global QoL of patients undergoing low‐, intermediate‐ and high‐SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery. Compared with surgery of lower complexity, extensive surgery does not result in poorer quality of life in patients with advanced ovarian cancer. Compared with surgery of lower complexity, extensive surgery does not result in poorer quality of life in patients with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types. Success in achieving cure in advanced EOC has however been limited, although significant prolongation of survival has been demonstrated. Development of novel research platforms is therefore necessary to address the rapidly advancing field of early diagnostics and therapeutics, whilst also acknowledging the significant tumour heterogeneity associated with EOC. Within available tumour models, patient-derived organoids (PDO) and explant tumour slices have demonstrated particular promise as novel ex vivo systems to model different cancer types including ovarian cancer. PDOs are organ specific 3D tumour cultures that can accurately represent the histology and genomics of their native tumour, as well as offer the possibility as models for pharmaceutical drug testing platforms, offering timing advantages and potential use as prospective personalised models to guide clinical decision-making. Such applications could maximise the benefit of drug treatments to patients on an individual level whilst minimising use of less effective, yet toxic, therapies. PDOs are likely to play a greater role in both academic research and drug development in the future and have the potential to revolutionise future patient treatment and clinical trial pathways. Similarly, ex vivo tumour slices or explants have also shown recent renewed promise in their ability to provide a fast, specific, platform for drug testing that accurately represents in vivo tumour response. Tumour explants retain tissue architecture, and thus incorporate the majority of tumour microenvironment making them an attractive method to re-capitulate in vivo conditions, again with significant timing and personalisation of treatment advantages for patients. This review will discuss the current treatment landscape and research models for EOC, their development and new advances towards the discovery of novel biomarkers or combinational therapeutic strategies to increase treatment options for women with ovarian cancer. [ABSTRACT FROM AUTHOR]

Linked article: This is a mini commentary on Marchetti et al., pp.1579–1588 in this issue. To view this article visit https://doi.org/10.1111/1471‐0528.17558. [ABSTRACT FROM AUTHOR]

The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to BRCA germline and tumor testing in patients with ovarian cancer in routine clinical practice. In particular, the group explored models of consent, quality standards identified at pathology laboratories, and experience and data from pioneering cancer centers. The group liaised with representatives from ovarian cancer charities to also identify patient perspectives that would be important to implementation. Recommendations from these consensus group deliberations are presented in this manuscript. [ABSTRACT FROM AUTHOR]

Lymphogenic spread is associated with poor prognosis in epithelial ovarian cancer (EOC), yet little is known regarding roles of non-peri-tumoural lymphatic vessels (LVs) outside the tumour microenvironment that may impact relapse. The aim of this feasibility study was to assess whether inflammatory status of the LVs and/or changes in the miRNA profile of the LVs have potential prognostic and predictive value for overall outcome and risk of relapse. Samples of macroscopically normal human lymph LVs (n = 10) were isolated from the external iliac vessels draining the pelvic region of patients undergoing debulking surgery. This was followed by quantification of the inflammatory state (low, medium and high) and presence of cancer-infiltration of each LV using immunohistochemistry. LV miRNA expression profiling was also performed, and analysed in the context of high versus low inflammation, and cancer-infiltrated versus non-cancer-infiltrated. Results were correlated with clinical outcome data including relapse with an average follow-up time of 13.3 months. The presence of a high degree of inflammation correlated significantly with patient relapse (p = 0.033). Cancer-infiltrated LVs showed a moderate but non-significant association with relapse (p = 0.07). Differential miRNA profiles were identified in cancer-infiltrated LVs and those with high versus low inflammation. In particular, several members of the let-7 family were consistently down-regulated in highly inflamed LVs (>1.8-fold, p<0.05) compared to the less inflamed ones. Down-regulation of the let-7 family appears to be associated with inflammation, but whether inflammation contributes to or is an effect of cancer-infiltration requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Primary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection. Primary Objective: To clarify the optimal timing of surgical therapy in advanced ovarian cancer. Study Hypothesis: Primary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer. Trial Design: TRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB–IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB–IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations. Major Inclusion/Exclusion Criteria: Major inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB–IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy. Primary Endpoint: Overall survival. Sample Size: 772 patients. Estimated Dates for Completing Accrual and Presenting Results: Accrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024. Trial Registration: NCT02828618. [ABSTRACT FROM AUTHOR]

Introduction: Splenectomy-induced thrombocytosis and leukocytosis may obscure the early diagnosis of post-operative infection or sepsis. In trauma patients after splenectomy, a platelet-to-white blood cell ratio of <20 has been shown to reliably differentiate post-operative sepsis from transient physiological responses. Objective: To determine whether the platelet-to-white blood cell ratio can be applied to differentiate between reactive post-operative changes and latent infection. Methods: All consecutive patients with ovarian cancer who underwent splenectomy between January 2013 and October 2018 in two large European gynecological cancer centers were retrospectively evaluated. Main outcome measures were white blood cell count, platelet count, and platelet-to-white blood cell ratio on post-operative days 1, 5, and 7. These were correlated with surgical outcome and morbidity according to the Clavien-Dindo classification. A binomial logistic regression was applied to assess the predictive value of day 5 platelet-to-white blood cell ratio, white blood cell count, and platelet count for predicting grade III post-operative sepsis. Results: Ninety-five patients with ovarian cancer (mean age 54 years, range 18–75) were identified. Seventeen patients (17.9%) developed a grade III post-operative sepsis. In all post-operative patients, mean white blood cell count on day 5 decreased (from 15.4×103/μL to 11.4×103/μL), while the mean platelet count rose (from 260.7×103/μL to 385.3×103/μL). A high platelet count (>313×103/μL) failed to show any predictive value (OR=0.94; 95% CI 0.30 to 3.0; p=0.921). A low platelet-to-white blood cell ratio (<26) (OR=3.49; 95% CI 1.18 to 10.32; p=0.0241) and high white blood cell count (>14.5×103/μL) on day 5 (OR=11.0; 95% CI 3.3 to 36.2; p<0.001) were significant for predicting sepsis. Despite a significant OR, the sensitivity and specificity were low; day 5 platelet-to-white blood cell ratio at a cut-off point of 26 achieved a sensitivity of 72% and specificity of 53% (area under the curve 0.637, 95% CI 0.480 to 0.796) in predicting grade III post-operative sepsis. Conclusions: Platelet-to-white blood cell ratio after cytoreductive surgery for ovarian cancer with splenectomy does not appear to have a strong predictive value in differentiating between sepsis and reactive splenectomy-induced changes. Leukocytosis, in combination with clinical assessment, may remain the most useful tool for prediction of sepsis after cytoreductive surgery with splenectomy. [ABSTRACT FROM AUTHOR]

Abstract: In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI‐anchored tumour suppressor OPCML. Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol‐rich lipid domains, where OPCML resides. Here, phospho‐AXL is brought in proximity to the lipid domain‐restricted phosphatase PTPRG, which de‐phosphorylates the RTK/ligand complex. This prevents AXL‐mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho‐ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo. We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL‐dependent oncogenic signalling. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to develop clinically relevant and evidence-based guidelines as part of European Society of Gynaecological Oncology's mission to improve the quality of care for women with gynecological cancers across Europe. Methods: The European Society of Gynaecological Oncology council nominated an international multidisciplinary development group made of practicing clinicians who have demonstrated leadership and interest in the care of ovarian cancer (20 experts across Europe). To ensure that the statements are evidence based, the current literature identified from a systematic search has been reviewed and critically appraised. In the absence of any clear scientific evidence, judgmentwas based on the professional experience and consensus of the development group (expert agreement). The guidelines are thus based on the best available evidence and expert agreement. Before publication, the guidelines were reviewed by 66 international reviewers independent from the development group including patients representatives. Results: The guidelines cover preoperative workup, specialized multidisciplinary decision making, and surgical management of diagnosed epithelial ovarian, fallopian tube, and peritoneal cancers. The guidelines are also illustrated by algorithms. [ABSTRACT FROM AUTHOR]

The lymphatic system has a major significance in the metastatic pathways in women’s cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport. [ABSTRACT FROM AUTHOR]

Patient-related diagnostic delay has been established as an analytical category in cancer research. This category has come under critique because it postulates linear cause-and-effect explanations of delayed care-seeking. These explanations are based on a one-dimensional idea of causality that neglects the processual character and the contextual situatedness of bodily experiences and care-seeking decisions. Using a notion of causality that is both process-oriented and context-sensitive, this article aims to understand ovarian cancer patients' stories on delayed healthcare seeking. It uses data from a qualitative interview study that investigated ovarian cancer patients' illness and healthcare-seeking experiences. We suggest that the interviewees' retrospective perspective generated a multi-layered notion of diagnostic delay that differs from the definition of patient-related delay commonly used in the literature. Our analysis shows how interviewees negotiate current social discourses on health and (social) responsibility, and thereby situate themselves and their healthcare seeking within a broader socio-economic and political context. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to determine the incidence of lymph node (LN) metastases in presumed stage I-II low-grade epithelial ovarian cancer (EOC). Methods: Eligible studies were identified from MEDLINE and EMBASE (time frame, 2015–1975), that analyzed patients with clinical or radiologic presumed early-stage EOC who underwent a complete pelvic and para-aortic lymphadenectomy as part of their surgical staging. The number and site of dissected and involved LNs and the correlation with overall outcome are analyzed. The term low grade and also the older term well differentiated were used. Results: Thirteen of 978 identified studies were selected, and 13 of 75 studies were identified as eligible. A total of 1403 patients were analyzed in these 13 retrospective studies. The final International Federation of Gynecology and Obstetrics staging after completed surgical staging was I to II in 912 patients (65%). A total of 338 patients (24%) had grade 1 tumors whereas 473 patients (34%) had grade 2, and 502 patients (36%) had grade 3 tumors. Systematic lymphadenectomy was performed in 1159 patients (83%), whereof 1142 (82%) were pelvic and para-aortic LN dissections. In 185 patients (13%), an upstaging from an apparent clinical stage I-II to IIIC occurred because of LN involvement: 64 (35%) of the patients had only pelvic LNs metastases, 69 (37%) had only para-aortic LNs metastasis, and 51 (28%) had both a pelvic and para-aortic LN involvement. When analyzing only the patients with low-grade (grade 1 as the old classification) presumed early-stage disease (n = 273), only 8 patients (2.9%; range, 0–6.2) were identified with LNs metastases present. Conclusions: The incidence of occult LN metastases in apparent early-stage low-grade EOC is 2.9% in a metaanalysis of retrospective studies. Future larger-scale prospectively assessed studies with established surgical quality of the LN dissection are warranted to establish the true incidence of LN metastasis in presumed early low-grade disease. [ABSTRACT FROM AUTHOR]

Supplemental digital contents are available in the text. Objectives: The surgical management of advanced ovarian cancer involves complex surgery. Implementation of a quality management program has a major impact on survival. The goal of this work was to develop a list of quality indicators (QIs) for advanced ovarian cancer surgery that can be used to audit and improve the clinical practice. This task has been carried out under the auspices of the European Society of Gynaecologic Oncology (ESGO). Methods: Quality indicators were based on scientific evidence and/or expert consensus. A 4-step evaluation process included a systematic literature search for the identification of potential QIs and the documentation of scientific evidence, physical meetings of an ad hoc multidisciplinarity International Development Group, an internal validation of the targets and scoring system, and an external review process involving physicians and patients. Results: Ten structural, process, or outcome indicators were selected. Quality indicators 1 to 3 are related to achievement of complete cytoreduction, caseload in the center, training, and experience of the surgeon. Quality indicators 4 to 6 are related to the overall management, including active participation to clinical research, decision-making process within a structured multidisciplinary team, and preoperative workup. Quality indicator 7 addresses the high value of adequate perioperative management. Quality indicators 8 to 10 highlight the need of recording pertinent information relevant to improvement of quality. An ESGO-approved template for the operative report has been designed. Quality indicators were described using a structured format specifying what the indicator is measuring, measurability specifications, and targets. Each QI was associated with a score, and an assessment form was built. Conclusions: The ESGO quality criteria can be used for self-assessment, for institutional or governmental quality assurance programs, and for the certification of centers. Quality indicators and corresponding targets give practitioners and health administrators a quantitative basis for improving care and organizational processes in the surgical management of advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Worldwide ovarian cancer affects over 200,000 women per year. Overall survival rates are poor due to two predominate reasons. First, the majority of patients present with advanced disease creating significant difficulty with effecting disease eradication. Second, acquisition of chemotherapy resistance results in untreatable progressive disease. Advances in treatment of advanced ovarian cancer involve a spectrum of interventions including improvements in frontline debulking surgery and combination chemotherapy. Anti-angiogenic factors have been shown to have activity in frontline and recurrent disease while novel chemotherapeutic agents and targeted treatments are in development particularly for disease that is resistant to platinum-based chemotherapy. These developments aim to improve the progression-free and overall survival of women with advanced ovarian cancer [ABSTRACT FROM AUTHOR]

Purpose: Borderline tumors of the ovary (BOT) represent an entity of ovarian neoplasms with low malignant potential and excellent prognosis. Mainstay of therapy is surgery including adequate staging and complete tumor resection, possibly inducing long-term side effects, especially in premenopausal women. The aim of this study was to evaluate quality of life (QoL) and sexual function in patients treated for BOT, also with respect to treatment modalities. Methods: This prospective study was part of an ambidirectional multicentric cohort study in patients with BOT in Germany. Patients from seven centers completed three questionnaires after completion of therapy. QoL and sexual function data were correlated with treatment characteristics: surgical approach, lymphadenectomy, and fertility sparing surgery. Results: One hundred ten patients returned the questionnaires. Median follow-up was 4.0 years. The majority lived in a relationship ( n = 85, 77 %, missing n = 4), and 49 % ( n = 54, missing n = 6) were sexually active. The main reason for sexual inactivity was 'no partner' (38 %). The women had a mean global health status of 69.8 (SD 22.7; min 0, max 100), with 100 implying perfect health. Mean QoL score was 73.7 (SD 23.3, range 0 to 100). Both scores showed no difference regarding fertility preserving surgery, surgical approach, and lymphadenectomy. Sexually active women had a significantly higher QoL (78.7 vs. 67.4, p = 0.0156) and global health status (75.9 vs. 60.9, p = 0.0013) than inactive patients. Conclusions: In this prospective study, patients who had been diagnosed with BOT had a very good quality of life and global health status. Sexually inactive women stated lack of a partner as the main reason and had an inferior HRQoL compared to sexually active women. [ABSTRACT FROM AUTHOR]

Salvage surgery for patients with highly advanced or relapsed epithelial ovarian cancer (EOC) complicated by bowel obstruction and resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate surgical and clinical outcome in these highly palliative situations.We evaluated all patients with EOC who underwent salvage extraperitoneal en bloc intestinal resection with terminal ileostomy or jejunostomy resulting in SBS and total parenteral nutrition owing to bowel obstruction between May 2003 and January 2012 in our institution.Thirty-seven patients were identified (median age, 58 years; range, 22-71 years), 3 (8.1%) with primary and 34 (91.6%) with relapsed EOC. Five patients (13.5%) were platinum sensitive. Median residual intestinal length was 70 cm (range, 10-180 cm); 21 patients (56.8%) had a residual intestinal length less than 1 m. Operative 30-day mortality and major morbidity rates were 10% and 51%, respectively. Median overall survival was 5.6 months (range, 0.1-49 months). One-year and 2-year overall survival rates were 18.3% (95% confidence interval, 5.1%-31.5%) and 8.1% (95% confidence interval, 0%-18.0)%, respectively. Within a median follow-up period of 5 months (range, 0.2-49 months), 4 patients (10.8%) are still alive. No significant differences in survival were seen between patients with or without major complications, tumor residuals, or residual intestinal length of less than 1 m versus greater than 1 m.Salvage palliative surgery in EOC due to bowel obstruction resulting in SBS and in need of long-life total parenteral nutrition is associated with high morbidity rates and low overall survival. These surgeries should ideally be performed only in a multidisciplinary setting with adequate infrastructure and possibility of home care support. Conservative management should be the route of action in the absence of acute abdomen or intestinal perforation. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) recurrence constitutes a therapeutic dilemma with various novel targeted agents emerging that offer alternative treatment options. The aim of the present study was to evaluate and compare epithelial cell adhesion molecule (EpCAM) expression profiles in paired tumor samples of patients with OC relapse.EpCAM expression was analyzed by immunohistochemistry using the avidin-biotin-complex method on paraffin-embedded OC tissues obtained at primary surgery as well as on corresponding tumor samples of the same patients at relapse. The EpCAM overexpression was defined as 76% to 100% of tumor cells positively stained for EpCAM. Clinical data were collected within the Tumorbank Ovarian Cancer Network.Nineteen patients with serous OC histology were included in the study (median age at primary diagnosis, 50 years; range, 40-74 years). The majority of the patients (95%) presented with International Federation of Gynecology and Obstetrics stage III/IV, and 68.4% of the tumors were poorly differentiated. A complete macroscopic tumor resection could be achieved in 15 patients (78.9%) at diagnosis. Epithelial cell adhesion molecule overexpression was detected in 17 (89%) of the primary and 16 (84%) of the recurrent tumors (P = 1.0); hence, no significant change of the EpCAM expression profile could be identified over time.Epithelial cell adhesion molecule expression profile appears to remain stable during the course from the primary throughout the relapse of serous OC. The results indicate that EpCAM might be an interesting therapeutic target structure in serous OC. [ABSTRACT FROM AUTHOR]

High grade serous ovarian cancer (HGSC), the most lethal and frequent type of epithelial ovarian cancer (EOC), has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC) identification and understanding of its niche regulation for improvement of therapeutic strategies. [ABSTRACT FROM AUTHOR]

To evaluate the difference in operative and clinical outcome for patients with primary advanced ovarian cancer (AOC) after optimal primary debulking surgery (PDS) versus interval debulking surgery (IDS).Tumor dissemination pattern and surgical outcome, as defined by morbidity, progression-free (PFS) survival and overall survival (OS) were systematically analyzed in AOC patients who underwent surgery in our institution between September 2000 and August 2009. Overall survival and PFS were calculated by Kaplan-Meier curves. Univariate and Cox regression analysis were performed to identify the impact of IDS on surgical outcome and survival.Overall, 372 consecutive patients with histologically proven AOC (FIGO [International Federation of Gynecology and Obstetrics] stage III/IV) were evaluated. Forty patients (10.8%) underwent IDS after a median of 5 cycles (range, 2-6 cycles) platinum- and taxane-based chemotherapy, and 332 patients (89.2%) underwent PDS. Patients who underwent IDS had a significantly lower rate of tumor involvement of the lower (78.9% vs 98.8%; P < 0.001) and middle abdomen (68.4% vs 83.1%; P = 0.044) compared with PDS patients. During IDS, a significantly higher probability for complete tumor resection occurred when compared with PDS (85% vs 58.7%; P = 0.02) by equivalent rates of operative complications (36.4% vs 36.5%; P = 1.00). However, mean PFS was significantly reduced in IDS patients (14.6 vs 33.2 months; P < 0.001). Mean OS was also higher in PDS patients, but this reached a statistical significance only when complete tumor resection was obtained (65.4 vs 37.9 months; P = 0.005). Multivariate analysis identified that IDS was associated with an unfavorable OS and PFS.It seems that PDS has a more favorable outcome than IDS on both OS and PFS in AOC patients, even though IDS leads to significantly higher rates of complete tumor resection. [ABSTRACT FROM AUTHOR]

Geriatric population life expectancy is increasing and so is the incidence of epithelial ovarian cancer (EOC) in elderly women. The aim of our study was to determine the impact of radical cytoreductive surgery, the cornerstone of clinical management in primary EOC, in this population with special regard to the associated morbidity.Through a pooled data analysis, cancer-related patient characteristics, intraoperative tumor pattern, and surgical and clinical outcomes were evaluated according to a validated documentation data collection tool. Kaplan-Meier curves were calculated for overall survival (OS). The Cox regression analysis was performed to identify independent predictors of mortality.One hundred one EOC patients older than 69 years (mean [SD] age, 75.54 [4.49] years) were evaluated. The mean (SD) follow-up period was 22.63 (22.92) months. Advanced International Federation of Gynecology and Obstetrics stage III (60.4%) was the most common tumor stage. A complete tumor resection was achieved in 45 patients (44.6%) with an associated complication rate of 40.6%. The postoperative mortality was 6%. The mean OS was 47.29 months (95% confidence interval, 36.24-58.34). The multivariate analysis identified age older than 75 years, incomplete tumor resection, and absence of adjuvant chemotherapy to negatively affect OS.Radical surgery for primary EOC obtaining complete tumor resection is associated with a significantly prolonged OS in elderly patients (≥70 years). The increased postoperative morbidity must be considered, underlining the high requirement for special interdisciplinary postoperative management in this special collective. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advances in our understanding of the stem cell potential in adult tissues have far-reaching implications for cancer research, and this creates new opportunities for the development of new therapeutic strategies. Here we outline changes in stem cell biology that characterize main gynaecological malignancies, ovarian, endometrial, and cervical cancer, and focus on specific differences between them. We highlight the importance of the local niche environment as a driver of malignant transformation in addition to mutations in key cancer-driving genes. Patient-derived organoids capture in vitro main aspects of cancer tissue architecture and stemness regulatory mechanisms, thus providing a valuable new platform for a personalized approach in the treatment of gynecological malignancies. This review summarizes the main achievement and formulates remaining open questions in this fast-evolving research field. Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches. This review revisits new findings on stemness and differentiation, considering main challenges and open questions. We focus on the role of stem cell niche and tumour microenvironment in early and metastatic stages of the disease progression and highlight the potential of patient-derived organoid models to study key events in tumour evolution, the appearance of resistance mechanisms, and as screening tools to enable personalisation of drug treatments. [ABSTRACT FROM AUTHOR]

Current treatment strategies for primary epithelial ovarian cancer (EOC) have significantly evolved, and the value of complete cytoreduction has not yet been reassessed. The study aimed to investigate the impact of residual disease after cytoreductive surgery for EOC on survival outcomes within the recent paradigm of frontline ovarian cancer treatment. We searched relevant literature from the MEDLINE, Embase, and Cochrane Library databases to identify randomized controlled trials and prospective clinical trials of primary EOC published between 1 January 2000 and 22 September 2022. To evaluate the impact of postoperative residual tumors on progression-free survival (PFS) and OS, we constructed a linear regression model for log-transformed median PFS and OS. Patients who did or did not receive first-line maintenance therapy were examined. A total of 97 trials with 43,260 patients were included:2476 received poly(ADP-ribose) polymerase (PARP) inhibitors and 6587 received bevacizumab. Multivariable analysis of the linear regression model of all studies revealed that the median OS increased by 12.97% for every 10% increase in complete cytoreduction rates, independent of the use of systemic maintenance. In the subgroup analysis of patients receiving maintenance therapies, the effect of complete tumor clearance was potentiated, with a median OS increase of 19.13% for every 10% increase in complete cytoreduction rates. Total macroscopic tumor clearance at the initial presentation of EOC significantly prolongs OS. Our results establish the importance of complete surgical cytoreduction, even after the introduction of recent advances in frontline treatment for EOC. • Treatment strategies for primary EOC have evolved, but complete cytoreduction's value remains unassessed. • 97 trials, 43,260 patients, studied residual disease impact on EOC survival after surgery in this meta-analysis. • 10% rise in complete cytoreduction rate linked to a 12.97% increase in median log overall survival. [ABSTRACT FROM AUTHOR]

Objective: To acquire a comprehensive assessment of the current status of implementation of Enhanced Recovery After Surgery (ERAS) protocols across Europe. Methods: The survey was launched by The European Network of Young Gynecologic Oncologists (ENYGO). A 45‐item survey was disseminated online through the European Society of Gynecological Oncology (ESGO) Network database. Results: A total of 116 ESGO centers participated in the survey between December 2020 and June 2021. Overall, 80 (70%) centers reported that ERAS was implemented at their institution: 63% reported a length of stay (LOS) for advanced ovarian cancer surgery between 5 and 7 days; 57 (81%) centers reported a LOS between 2 and 4 days in patients who underwent an early‐stage gynecologic cancer surgery. The ERAS items with high reported compliance (>75% "normally‐always") included deep vein thrombosis prophylaxis (89%), antibiotic prophylaxis (79%), prevention of hypothermia (55%), and early mobilization (55%). The ERAS items that were poorly adhered to (less than 50%) included early removal of urinary catheter (33%), and avoidance of drains (25%). Conclusion: This survey shows broad implementation of ERAS protocols across Europe; however, a wide variation in adherence to the various ERAS protocol items was reported. Synopsis: There is broad implementation of the ERAS protocols across European centers, but a wide variation in adherence to the various ERAS protocol items was reported. [ABSTRACT FROM AUTHOR]

The value of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery (CRS) for epithelial ovarian cancer (EOC) is controversial and its use remains experimental in most national and international guidelines. We wished to systematically evaluate all available evidence. A comprehensive review of data from MEDLINE, EMBASE, and Cochrane Library databases was conducted from the first report on HIPEC in EOC till April 3, 2022. Progression-free survival (PFS) and overall survival (OS) were compared between the HIPEC and control groups. This meta-analysis was registered with PROSPERO (CRD42021265810). Fifteen studies (10 case-control studies and 5 randomized controlled trials [RCTs]) were included in the present meta-analysis. Based on the time interval between the last systemic chemotherapy exposure and timing of CRS +/− HIPEC, all studies and patients' cohorts we classified into recent (<6 months; n = 9 studies/patients cohorts) and non-recent (≥6 months, n = 8 studies/patients cohorts) chemotherapy exposure groups. In the recent chemotherapy exposure group, HIPEC was associated with improvement of both PFS (HR, 0.585; 95% CI, 0.422–0.811) and OS (HR, 0.519; 95% CI, 0.346–0.777). On the contrary, in the non-recent chemotherapy exposure group, HIPEC failed to significantly affect PFS (HR, 1.037; 95% CI, 0.684–1.571) or OS (HR, 0.932; 95% CI, 0.607–1.430). Consistent results were observed in subsequent sensitivity analyses. Our present meta-analysis demonstrates that the value of HIPEC at CRS for EOC appears to depend on the timing of the last systemic chemotherapy exposure. Future trials are awaited to define the role of HIPEC in EOC. • The value of HIPEC at cytoreductive surgery for ovarian cancer remains controversial in most guidelines. • A total of 15 studies of 1861 patients contributed data for meta-analysis. • In the study, the value of HIPEC appears to depend on the timing of the last systemic chemotherapy exposure. [ABSTRACT FROM AUTHOR]

The objective of the present study was to define and validate an anastomotic leak prognostic score based on previously described and reported anastomotic leak risk factors (OVA-LEAK: https://n9.cl/ova-leakscore) and to establish if the use of OVA-LEAK score is better than clinical criteria (surgeon's choice) selecting anastomosis to be protected with a diverting ileostomy. This is a retrospective, multicentre cohort study that included patients who underwent cytoreductive surgery for primary advanced or relapsed ovarian cancer with colorectal resection and anastomosis between January 2011 and June 2021. Data from patients already included in the previous predictive model were not considered in the present analysis. To validate the performance of our logistic regression model, we used the OVA-LEAK formula (Annex I: https://n9.cl/ova-leakscore) for estimating leakage probabilities in a new independent cohort. Then, receiver operating characteristic (ROC) analysis was performed and area under the curve (AUC) was used to measure the performance of the model. Additionally, the Brier score was also estimated. 95% confidence intervals (CI) for each of the estimated performance measures were also calculated. 848 out of 1159 recruited patients were finally included in the multivariable logistic regression model validation. The AUC of the new cohort was 0.63 for predicting anastomotic leak. Considering a cut-off point of 22.1% to be 'positive' (to get a leak) this would provide a sensitivity of 0.45, specificity of 0.80, positive predictive value of 0.09 and negative predictive value of 0.97 for anastomotic leak. If we consider this cut-off point to select patients at risk of leak for bowel diversion, up to 22.5% of the sampled patients would undergo a diverting ileostomy and 47% (18/40) of the anastomotic leaks would be 'protected' with the stoma. Nevertheless, if we consider only the 'clinical criteria' for performing or not a diverting ileostomy, only 12.5% (5/40) of the leaks would be 'protected' with a stoma, with a rate of diverting ileostomy of up to 24.3%. Compared with subjective clinical criteria, the use of a predictive model for anastomotic leak improves the selection of patients who would benefit from a diverting ileostomy without increasing the rate of stoma use. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is associated with high mortality rates. Surgical outcome is one of the most important prognostic factors. There are no valid biomarkers to identify which patients may benefit from a primary debulking approach. Our study aimed to discover and validate a predictive panel for surgical outcome of residual tumor mass after first-line debulking surgery. Firstly, "In silico" analysis of publicly available datasets identified 200 genes as predictors for surgical outcome. The top selected genes were then validated using the novel Nanostring method, which was applied for the first time for this particular research objective. 225 primary ovarian cancer patients with well annotated clinical data and a complete debulking rate of 60% were compiled for a clinical cohort. The 14 best rated genes were then validated through the cohort, using immunohistochemistry testing. Lastly, we used our biomarker expression data to predict the presence of miliary carcinomatosis patterns. The Nanostring analysis identified 37 genes differentially expressed between optimal and suboptimal debulked patients (p < 0.05). The immunohistochemistry validated the top 14 genes, reaching an AUC Ø0.650. The analysis for the prediction of miliary carcinomatosis patterns reached an AUC of Ø0.797. The tissue-based biomarkers in our analysis could not reliably predict post-operative residual tumor. Patient and non-patient-associated co-factors, surgical skills, and center experience remain the main determining factors when considering the surgical outcome at primary debulking in high-grade serous ovarian cancer patients. • Predictive tools for the surgical outcome of patients with ovarian cancer are needed. • To establish predictive tools a large and defined patient cohort is needed. • Techniques like Nanostring and Immunohistochemistry can be used to select biomarkers. • A predictive gene panel using Nanostring technique was tried but was not successful. • A gene signature for diffuse peritoneal carcinomatosis could be described. [ABSTRACT FROM AUTHOR]

Abstract Objective Evaluate postoperative hepatic-function in patients with advanced ovarian cancer (OC) who underwent extensive right upper-quadrant (RUQ) cytoreduction in primary, relapsed or interval settings. Methods We retrospectively reviewed all patients with OC who underwent liver resection, mobilization and/or diaphragmatic-stripping between 01/2013 and 12/2016. Postoperative liver enzyme function (LFTs), assessed by alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin (Bil), was correlated with postoperative complications. Results 132 patients were identified. 81 patients (61%) underwent upfront, 25(19%) interval and 26(20%) secondary cytoreduction. The surgical procedures were right diaphragmatic peritoneal stripping (81/132;61%), full-thickness resection (42/132;32%), liver-capsule resection (85/132;64%), porta-hepatis tumor resection (11/132;8%) and partial hepatectomy (5/132;4%). 74%(98/132) of patients increased their LFTs postoperatively with a peak at 24-hours. Highest ALT median was 1.7-fold of upper normal limit (UNL), with the highest ALT value rising up to 28-fold UNL on the 1st postoperative day (PoD)(range 6–1792 IU/L). Median value of highest ALP was within normal, with the highest ALP value rising up to 4-fold UNL on PoD 5(range 22–512 IU/L). Median value of highest Bilirubin level was also within normal, with highest Bilirubin level rising up to 6-fold UNL on PoD 5(range: 2–120 μmol/L). Mean LFT-normalization time was 7 days (range: 3–14 days). No significant morbidity was directly linked to LFT deterioration, apart from one case (0.8%) of fatal fulminant hepatic-failure. Conclusion RUQ-cytoreduction is almost always associated with a transient LFT-increase, with no significant clinical implications and spontaneous normalization within the first postoperative week. Due to the existing risk of fulminant liver failure, albeit rare and difficult to predict, postoperatively elevated LFTs should be monitored, until normalization. Large prospective studies are required to assess the predictive value of LFTs and other risk factors for postoperative hepatic failure in patients with OC undergoing extensive RUQ-cytoreduction. Highlights • Right upper abdominal cytoreduction is associated with transient liver-transaminases increase. • Liver function tests normalize spontaneously postoperatively without intervention. • There is a small postoperative risk of fulminant hepatic failure. [ABSTRACT FROM AUTHOR]

Background We compared survival outcomes and risk of venous thromboembolism (VTE) among patients with advanced and early-stage ovarian clear cell carcinoma (OCCC) and serous ovarian carcinoma (SOC), as well as potential links with interleukin-6 (IL-6) levels. Methods A multicenter case-control study was conducted in 370 patients with OCCC and 938 with SOC. In a subset of 200 cases, pretreatment plasma IL-6 levels were examined. Findings Patients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P < 0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2 pg/mL and early-stage SOC 5.0 pg/mL, P = 0.006). Advanced OCCC (hazard ratio [HR] 3.38, P < 0.0001), thrombocytosis (HR 1.42, P = 0.032) and elevated IL-6 (HR 8.90, P = 0.046) were independent predictors of VTE. In multivariate analysis, patients with advanced OCCC had significantly poorer 5-year progression-free and overall survival rates than those with advanced SOC ( P < 0.01), and thrombocytosis was an independent predictor of decreased survival outcomes ( P < 0.01). Elevated IL-6 levels led to poorer 2-year progression-free survival rates in patients with OCCC (50% versus 87.5%, HR 4.89, P = 0.016) than in those with SOC (24.9% versus 40.8%, HR 1.40, P = 0.07). Interpretation Advanced OCCC is associated with an increased incidence of VTE and decreased survival outcomes, which has major implications for clinical management of OCCC. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a malignant entity typically diagnosed in advanced stages, with concomitant poor prognosis. Delayed healthcare seeking is commonly explained by the ‘vague’ character of the disease's symptoms combined with a lack of awareness among patients. However, research on the social contexts of ovarian cancer patients' pre-diagnostic illness experiences and healthcare seeking is scarce. To explore these topics, we initiated a qualitative interview study guided by the principles of grounded theory and based on interviews with 42 ovarian cancer patients. The study was conducted in Germany from September 2011 to February 2013. Our analysis illustrates how, in the narratives, the interviewees struggled to balance specific bodily sensations with aspects of their life-worlds prior to consulting a biomedical professional. We propose a three-phase model to capture these experiences and demonstrate how the developments of pre-diagnostic sensations were catalysed by the dynamic and complex interplay of the sensations with a variety of individual and socio-cultural factors. To conceptualize these interplays, we introduce the analytical notion of a triggering process, and we elaborate on the different ways in which such a process conditioned the transformation of a sensation into a symptom and decisions to seek healthcare. We finally discuss our findings both in relation to current research on sensations, symptoms and healthcare seeking and in their relevance for understanding diagnostic delays in ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate the diagnostic performance of the IOTA (International Ovarian Tumor Analysis group) (clinically oriented three-step strategy for preoperative characterization of ovarian masses when ultrasonography is performed by examiners with different background training and experience. Methods: A 27-month prospective multicenter cross-sectional study was performed. 36 level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardized approach. Step one uses simple descriptors (SD), step two ultrasound simple rules (SR) and step three subjective assessment of ultrasound images (SA) by examiners. The final outcome was findings at surgery and the histological diagnosis of surgically removed masses. Results: 1165 women with adnexal masses underwent transvaginal ultrasonography, 301 had surgery. Prevalence of malignancy was 31% (n=92). SD were able to classify 46% of the masses into benign or malignant (step one), with a sensitivity of 93% and specificity of 97%. Applying SD followed by SR to residual unclassified masses by SD enabled 89% of all masses (n=268) to be classified with a sensitivity 95% of and specificity of 95%. SA was then used to evaluate the rest of the masses. Compared to the risk of malignancy index (RMI), the sensitivity and specificity for the three-step (SD+SR+SA) strategy were 93% (95% CI: 86–97%) and 92% (95% CI: 87–95%) vs. 72% (95% CI: 62–80%) and 95% (95% CI: 91–97%) for RMI, respectively. Conclusion: The IOTA three-step strategy shows good test performance on external validation in the hands of ultrasonography examiners with different background training and experience. This performance is considerably better than the RMI. [Copyright &y& Elsevier]