Preferences and considerations for interval cytoreductive surgery in advanced ovarian cancer: The patient's perspective.

OBJECTIVE: Treatment of advanced-stage ovarian cancer contains cytoreductive surgery (CRS) and chemotherapy. Achieving successful CRS (≤ 1 cm residual disease) is prognostically important, but may not be feasible peri-operatively while still risking complications. Therefore, patients' treatment expectations are important to discuss. We investigated patient considerations for interval CRS. METHODS: Patients with advanced-stage ovarian cancer planned for interval CRS completed a questionnaire about the impact of chance of successful CRS, survival benefit and becoming care-dependent on decision-making regarding CRS. The questionnaire included a vignette study, in which patients repeatedly chose between two treatment scenarios with varying levels for chance of successful CRS, survival benefit and risk of complications including stoma. Patient preferences were analyzed, including differences between patients aged < 70 and ≥ 70 years. RESULTS: Among 85 included patients, 31 (37%) patients considered interval CRS worthwhile irrespective of survival benefit and 33 (39%) irrespective of chance of successful surgery. However, 34 patients (41%) considered interval CRS only worthwhile if survival benefit was > 12 months, while 41 (49%) thought so if chance of successful surgery was ≥ 25%. Older patients considered these factors more important. Overall, 27% considered becoming permanently dependent of home care unacceptable. In the vignette study (n = 72) risk of complications and stoma were considered less important than chance of successful CRS and survival benefit. CONCLUSION: Survival benefit, chance of successful surgery and becoming care-dependent are important factors in patient's decision for interval CRS, while risk of complications and stoma are less important. Our results are useful in shared decision-making for interval CRS in ovarian cancer.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low-grade ovarian carcinoma.

BACKGROUND: Advanced low-grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. METHODS: Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. RESULTS: Patients who had normal ER STP activity had a progression-free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. CONCLUSIONS: Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

Reflectance confocal microscopy as a non-invasive imaging tool in vulvar high-grade squamous intraepithelial lesions and lichen sclerosus: A descriptive morphological study in patients and healthy volunteers.

Incorrect and delayed diagnosis of vulvar high-grade squamous intraepithelial neoplasia (vHSIL) and lichen sclerosus (LS) increases malignant progression risks and negatively impacts prognosis and quality of life. There is a need to improve diagnosis and monitoring. Reflectance confocal microscopy is a non-invasive imaging tool that visualizes skin structures at cellular resolution. The objectives were to explore feasibility and patient acceptability of vulvar RCM imaging and to identify RCM characteristics that are discriminative for vulvar HSIL and LS. This was a prospective, cross-sectional, observational clinical trial in patients with vHSIL and LS compared to healthy volunteers. RCM images and vulvar tissue samples were obtained. Five (5) patients with vHSIL, 10 patients with LS and 10 healthy volunteers were enrolled. In total, 100 image series of vulvar skin were obtained, including lesional and nonlesional sites. The RCM technique was considered acceptable for application by patients and healthy controls. Healthy vulvar skin was characterized by a homogenous, normal honeycomb patterned epidermis and a clear epidermal-dermal junctions. Vulvar HSIL and LS displayed an atypical honeycomb pattern of the epidermis and lymphocytic influx with presence of melanophages. Distinct features specifically observed in LS included the presence of hyalinised vessels and sclerotic areas in the dermis. RCM is a non-invasive imaging technique that is feasible and clinically acceptable to apply on vulvar skin, both in patients with premalignant lesions and healthy controls. Recognition and validation of disease-specific characteristics could make reflectance confocal microscopy a clinical tool to non-invasively aid identification of vulvar premalignancies.

First step in implementation of opportunistic salpingectomy for prevention of ovarian cancer: Current care and its determinants.

INTRODUCTION: Opportunistic salpingectomy (OS) refers to additional removal of the fallopian tubes during abdominal surgery performed for another medical indication, as prevention for ovarian cancer. As OS has been inconsistently implemented, its clinical practice varies worldwide. To reduce this variation, insight is required into current clinical practice and its determinants. Therefore, the study aim was to determine the implementation of counseling and performance of OS between 2015 and 2018, and its patient, surgical, physician, and hospital characteristics. MATERIAL AND METHODS: Retrospective study using electronic medical records from six different Dutch hospitals: two academic, two large teaching, and two non-teaching hospitals. Patients were considered eligible for OS if they underwent elective non-obstetric abdominal surgery for a gynecological indication from January 2015 through December 2018. Primary outcomes were uptake of counseling and performance of OS. Multilevel multivariable logistic regression analyses were conducted to identify characteristics associated with OS. RESULTS: A total of 3214 patients underwent elective non-obstetric abdominal surgery for a gynecological indication and were eligible for OS. Counseling on OS increased significantly from 2.9% in 2015 to 29.4% in 2018. In this period, 440 patients were counseled on OS, of which 95.9% chose OS. Performance of OS increased significantly from 6.9% in 2015 to 44.5% in 2018. Counseling for and performance of OS were more likely in patients who had surgery by laparoscopic approach, were counseled by a gynecological resident, or had more than three contact moments before surgery. Additionally, OS was less likely in patients who had vaginal surgery. CONCLUSIONS: Although the uptake of OS increased from 2015 to 2018, the majority of patients who were eligible for OS were not counseled and did not undergo OS. Its clinical practice varies on patient, surgery, and physician characteristics. Therefore, an implementation strategy tailored to associated determinants is recommended.

Dermatoscopy and Optical Coherence Tomography in Vulvar High-Grade Squamous Intraepithelial Lesions and Lichen Sclerosus: A Prospective Observational Trial.

OBJECTIVE: This study aimed to examine potential discriminatory characteristics of dermatoscopy and dynamic optical coherence tomography (D-OCT) on vulvar high-grade squamous intraepithelial lesions (vHSIL) and lichen sclerosus (LS) compared with healthy vulvar skin. METHODS: A prospective observational clinical trial was performed in 10 healthy volunteers, 5 vHSIL and 10 LS patients. Noninvasive imaging measurements using dermatoscopy and D-OCT were obtained at several time points, including lesional and nonlesional vulvar skin. Morphologic features of vHSIL and LS were compared with healthy controls. Epidermal thickness and blood flow were determined using D-OCT. Patients reported tolerability of each study procedure, including reference vulvar biopsies. The main outcome measures were feasibility and tolerability of imaging modalities, dermatoscopy and OCT characteristics, OCT epidermal thickness and D-OCT dermal blood flow. RESULTS: The application of dermatoscopy and D-OCT is feasible and tolerable. In vHSIL, dermatoscopic warty structures were present. In LS, sclerotic areas and arborizing vessels were observed. Structural OCT in the vulvar area aligned with histology for hyperkeratosis and dermal-epidermal junction visualization. Currently, the OCT algorithm is unable to calculate the epidermal thickness of the uneven vulvar area. Dynamic optical coherence tomography showed statistically significant increased blood flow in LS patients (mean ± SD, 0.053 ± 0.029) to healthy controls (0.040 ± 0.012; p = .0024). CONCLUSIONS: The application of dermatoscopy and D-OCT is feasible and tolerable in vHSIL and LS patients. Using dermatoscopy and D-OCT, the authors describe potential characteristics to aid differentiation of diseased from healthy vulvar skin, which could complement clinical assessments.

Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium.

OBJECTIVE: To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE). METHODS: We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-ß) and canonical wingless-type MMTV integration site (Wnt) pathways. RESULTS: There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression. CONCLUSION: Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.

Primary prevention of ovarian cancer: a patient decision aid for opportunistic salpingectomy.

BACKGROUND: The discovery of the fallopian tube epithelium as the origin of high-grade serous ovarian cancer has brought a new option for ovarian cancer prevention. The fallopian tubes have no known function after completion of childbearing and can be removed to reduce the lifetime risk of ovarian cancer. Although the lifetime risk in the general population does not justify preventive surgery in itself, salpingectomy can be performed during abdominal surgery for other indications, also known as an opportunistic salpingectomy. The popularity of opportunistic salpingectomy is increasing worldwide; however, the variation between gynecologists and hospitals in their advice on opportunistic salpingectomy occurs because of the remaining uncertainty of evidence. Therefore, whether a woman can make her own decision depends on the hospital or gynecologist she visits. We aimed to lower this practice variation by providing standardized and unbiased counseling material. OBJECTIVE: We aimed to develop and test a patient decision aid for opportunistic salpingectomy in women undergoing pelvic gynecologic surgery to either retain the ovaries or opt for sterilization. STUDY DESIGN: We followed a systematic development process based on the International Patient Decision Aid Standards. Data were collected between June 2019 and June 2020, using both qualitative and quantitative methods. The development process that occurred in collaboration with patients and healthcare professionals was overseen by a multidisciplinary steering group and was divided into 4 phases: (1) assessment of decisional needs using individual telephone interviews and questionnaires; (2) development of content and format based on decisional needs, current literature, and guidelines; (3) alpha testing and the first revision round; and (4) alpha testing and the second revision round. RESULTS: An outline of the patient decision aid was developed on the basis of decisional needs, current literature, and guidelines. It became clear that the decision aid should consist of 2 separate paths: one with information specifically for salpingectomy in addition to abdominal surgery and one for salpingectomy as a sterilization method. Both paths contained information on the anatomy and function of ovaries and fallopian tubes, risk reduction of ovarian cancer, and potential benefits and risks of opportunistic salpingectomy. Moreover, the sterilization path contains information on various sterilization methods and risks of unwanted pregnancy. The patient decision aid was developed as an online tool that includes information chapters, a knowledge quiz, consideration statements, and a summary detailing the patient's preferences and considerations. Adjustments were made following alpha testing round 1. The improved patient decision aid was subjected to usability tests (alpha testing round 2), in which it scored an "excellent" in tests with patients and a "good" in tests with gynecologists. Furthermore, our patient decision aid met the requirements of 45 of 49 applicable items from the International Patient Decision Aid Standards criteria. CONCLUSION: In collaboration with patients and healthcare professionals, a patient decision aid was developed on opportunistic salpingectomy and salpingectomy as a sterilization method. Both patients and gynecologists believed it is a useful tool that supports patients in making an informed decision whether to undergo an opportunistic salpingectomy and supports the counseling process by gynecologists.

Cyclic activity of signal transduction pathways in fimbrial epithelium of the human fallopian tube.

INTRODUCTION: The local environment of the fallopian tube represents the optimal conditions for reproductive processes. To maintain tissue homeostasis, signal transduction pathways are thought to play a pivotal role. Enhancing our understanding of functional signal transduction pathway activity is important to be able to clarify the role of aberrant signal transduction pathway activity leading to female subfertility and other tubal diseases. Therefore, in this study we investigate the influence of the hormonal cycle on the activity of key signal transduction pathways in the fimbrial epithelium of morphologically normal fallopian tubes. MATERIAL AND METHODS: We included healthy pre- (n = 17) and postmenopausal (n = 8) patients who had surgical interventions for benign gynecologic conditions. Histologic sections of the fallopian tubes were reviewed by two pathologists and, for the premenopausal patients, hormone serum levels and sections of the endometrium were examined to determine the hormonal phase (early follicular [n = 4], late follicular [n = 3], early luteal [n = 5], late luteal [n = 5]). After laser capture microdissection, total mRNA was extracted from the fimbrial epithelium and real-time quantitative reverse transcription-PCR was performed to determine functional signal transduction pathway activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor-beta (TGF-ß) and canonical wingless-type MMTV integration site (Wnt) pathways. RESULTS: The early luteal phase demonstrated high AR and ER pathway activity in comparison with the late luteal phase (p = 0.016 and p = 0.032, respectively) and low PI3K activity compared with the late follicular phase (p = 0.036), whereas the late luteal phase showed low activity of HH and Wnt compared with the early follicular phase (both p = 0.016). Signal transduction pathway activity in fimbrial epithelium from postmenopausal patients was most similar to the early follicular and/or late luteal phase with regard to the AR, ER and PI3K pathways. Wnt pathway activity in postmenopausal patients was comparable to the late follicular and early luteal phase. We observed no differences in HH and TGF-ß pathway activity between pre- and postmenopausal samples. The cyclic changes in signal transduction pathway activity suggest a stage-specific function which may affect the morphology and physiology of the human fallopian tube. CONCLUSIONS: We demonstrated cyclic changes in activity of the AR, ER, PI3K, HH and Wnt pathways throughout the hormonal cycle.

The effectiveness of monotherapy with PI3K/AKT/mTOR pathway inhibitors in ovarian cancer: A meta-analysis.

OBJECTIVE: To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current PI3K/AKT/mTOR biomarkers on therapy response. METHODS: A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events. RESULTS: We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20-44%) and ORR of 3% (95% CI 0-6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23-62%) and 27% (95% CI 14-42%), P = 0.217). To better reflect true patient benefit, we excluded SD <6 months as a beneficial outcome which resulted in a pooled CBR of 7% (95% CI 2-13%). The overall proportion of patients with drug-related grade 3 and 4 adverse events was 36%. CONCLUSIONS: The efficacy of monotherapy with PI3K/AKT/mTOR inhibitors in advanced recurrent ovarian cancer patients is limited to a small subgroup and selection of patients with the use of current biomarkers did not improved the CBR significantly. Given the toxicity profile, we suggest that current treatment with PI3K/AKT/mTOR inhibitors should not be initiated unless in clinical trials. Furthermore, improved biomarkers to measure functional PI3K/AKT/mTOR pathway activity are needed to optimize patient selection.

FOXL2 and TERT promoter mutation detection in circulating tumor DNA of adult granulosa cell tumors as biomarker for disease monitoring.

OBJECTIVE: Adult granulosa cell tumors (aGCTs) represent a rare, hormonally active subtype of ovarian cancer that has a tendency to relapse late and repeatedly. Current serum hormone markers are inaccurate in reflecting tumor burden in a subset of aGCT patients, indicating the need for a novel biomarker. We investigated the presence of circulating tumor DNA (ctDNA) harboring a FOXL2 or TERT promoter mutation in serial plasma samples of aGCT patients to determine its clinical value for monitoring disease. METHODS: In a national multicenter study, plasma samples (n = 110) were prospectively collected from 21 patients with primary (n = 3) or recurrent (n = 18) aGCT harboring a FOXL2 402C > G and/or TERT (C228T or C250T) promoter mutation. Circulating cell-free DNA was extracted and assessed for ctDNA containing one of either mutations using droplet digital PCR (ddPCR). Fractional abundance of FOXL2 mutant and TERT mutant ctDNA was correlated with clinical parameters. RESULTS: FOXL2 mutant ctDNA was found in plasma of 11 out of 14 patients (78.6%) with aGCT with a confirmed FOXL2 mutation. TERT C228T or TERT C250T mutant ctDNA was detected in plasma of 4 of 10 (40%) and 1 of 2 patients, respectively. Both FOXL2 mutant ctDNA and TERT promoter mutant ctDNA levels correlated with disease progression and treatment response in the majority of patients. CONCLUSIONS: FOXL2 mutant ctDNA was present in the majority of aGCT patients and TERT promoter mutant ctDNA has been identified in a smaller subset of patients. Both FOXL2 and TERT mutant ctDNA detection may have clinical value in disease monitoring.

Salvage surgery for patients with residual disease after chemoradiation therapy for locally advanced cervical cancer: A systematic review on indication, complications, and survival.

INTRODUCTION: Standard treatment for locally advanced cervical cancer is chemoradiation therapy. Treatment with chemoradiation therapy harbors a risk of local residual disease, which can be curatively treated with salvage surgery, but the risk of complications following surgical procedures in radiated tissue is not negligible. The presence of residual disease can be radiologically and/or histologically diagnosed. The objective of this study is to describe studies that report on salvage surgery for patients with locally advanced cervical cancer after primary treatment with chemoradiation therapy. Therefore, we assessed the method of determining the presence of residual disease, the risk of complications, and the survival rate after salvage surgery. MATERIAL AND METHODS: PubMed, EMBASE, and the Cochrane database were searched from inception up to 6 March 2020. Titles and abstracts were independently assessed by two researchers. Studies were eligible for inclusion when patients had locally advanced cervical cancer with radiologically suspected or histologically confirmed residual disease after chemoradiation therapy, diagnosed with a CT, MRI, or PET-CT scan, or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. Methodological quality of the articles was independently assessed by two researchers with the Newcastle-Ottawa scale. RESULTS: Of the 2963 screened articles, six studies were included, representing 220 women. A total of 175 patients were treated with salvage surgery, of whom 27%-100% had residual disease on the surgery specimen. Of the 161 patients treated with salvage surgery based on positive biopsy results, 72%-100% showed residual disease on the surgery specimen. Of the 44 patients treated with salvage surgery based on suspected residual disease on radiology, 27%-48% showed residual disease on the salvage surgery specimen. A total of 105 complications were registered in 175 patients treated with salvage surgery. The overall survival rate after salvage surgery was 69% (mean follow-up period of 24.9 months). CONCLUSIONS: It is necessary to confirm residual disease by biopsy before performing salvage surgery in patients with locally advanced cervical cancer primarily treated with chemoradiation therapy. Salvage surgery only based on radiologically suspected residual disease should be avoided to prevent unnecessary surgery and complications.

Patients' and professionals' perspectives on implementation of opportunistic salpingectomy: a mixed-method study.

BACKGROUND: To prevent ovarian cancer, several international societies have issued guidelines which recommend to discuss opportunistic salpingectomy with women undergoing pelvic surgery after completion of childbearing. The opportunistic salpingectomy refers to the additional removal of Fallopian tubes during pelvic surgery for another indication to reduce the risk of developing ovarian cancer. These recommendations emphasize the importance of counselling on benefits and risks of opportunistic salpingectomy but offer no guidance on their implementation in daily practice. The lack of a tailored implementation strategy has resulted in a wide variation in current practice. To reduce this practice variation, we identified influencing factors on implementing opportunistic salpingectomy from patients' and professionals' perspectives. METHODS: We conducted a mixed-method study between 2019 and 2020 throughout the Netherlands. In a qualitative phase, we conducted interviews with gynecologic patients (N = 11) and their professionals (N = 20) to explore barriers and facilitators, using an interview guide. In the quantitative phase, we quantified these barriers and facilitators among patients who underwent a hysterectomy or sterilization and were counselled on the opportunistic salpingectomy (N = 77), and members of the Dutch Society of Obstetrics and Gynecology (N = 204), using questionnaires. For both phases, barriers and facilitators were classified into the following domains: innovation, patient, healthcare professional, social setting, organization, and economic and political context. RESULTS: For patients, main barriers were lack of knowledge about: the existence of the opportunistic salpingectomy (45%), size of the surgery (44%) and its associated possible disadvantages (37%). In addition, patients attributed their reluctance to concerns about the removal of healthy organs (46%). For professionals, main barriers were: patients' lack of knowledge of the size of surgery (85%) and its associated possible disadvantages (77%), the gap in evidence on long term risks and benefits (43%), the lack of feasibility in certain patients and during vaginal surgery (66%). Both patients (41%) and professionals (67%) identified the need for counselling material as facilitator. CONCLUSION: To reduce the variety in care regarding opportunistic salpingectomy, consensus and uniform counselling is needed. Including the opportunistic salpingectomy in gynecological guidelines and a decision aid for counselling could serve as tools to facilitate implementation.

Development of the Patient's Experience and Attitude Colposcopy Eindhoven Questionnaire (PEACE-q).

BACKGROUND: No validated instruments for the evaluation of patient satisfaction in colposcopy do exist. Therefore, this study reports on the development of a Patient's Experience and Attitude to Colposcopy questionnaire. METHODS: Patients who recently received colposcopy participated in a focus group. A panel of experts evaluated the transcriptions and agreed on a 15-item draft questionnaire. The draft questionnaire was completed by 68 women who subsequently came for a colposcopy. For construct validation, Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were performed as well as reliability analysis. Concurrent validity was assessed with the 4-item Patient Health questionnaire (PHQ-4). RESULTS: Construct validation resulted in an 8-item patient perception scale with good psychometric properties (Cronbach's alpha: 0.76) and excellent model fit. Two subscales could be discriminated: patient procedure perception scale (alpha: 0.89) and caregiver attitude perception scale (alpha: 0.71). Both subscales intercorrelated moderately (r = 0.28, p = 0.045). The subscale patient perception correlated significantly with the PHQ-4 scale and its anxiety subscale, not with the depression subscale. CONCLUSIONS: We developed a Patient's Experience and Attitude to Colposcopy questionnaire with adequate psychometric properties. Future application in out-patient clinics should further evaluate its clinical relevance.

Peritoneal carcinomatosis after risk-reducing surgery in BRCA1/2 mutation carriers.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for BRCA1/2 mutation carriers because of their increased risk of ovarian carcinoma. Despite RRSO, metachronous peritoneal carcinomatosis occasionally is diagnosed. METHODS: The literature was searched for BRCA1/2 mutation carriers with peritoneal carcinomatosis after risk-reducing surgery. The authors were asked for additional data. Clinical and histopathological data were descriptively analyzed. Cases were compared with a single-institution control cohort. RESULTS: Of 36 cases, 86.1% concerned BRCA1 mutation carriers. The median age of the patients was 52 years (range, 30-71 years) at the time of risk-reducing surgery and 60 years (range, 37-75 years) at the time of diagnosis of peritoneal carcinomatosis. The median interval between the 2 events was 54.5 months (range, 11-292 months). Peritoneal carcinomatosis was mostly high-grade serous carcinoma. Histopathological details of the RRSO specimens were retrieved in 8 cases; 5 (62.5%) were found to have serous tubal intraepithelial carcinoma and 1 had epithelial atypia. Cases were older (P = .025) at the time of risk-reducing surgery and harbored more serous tubal intraepithelial carcinomas (P<.001) compared with women from the control cohort. CONCLUSIONS: Metachronous peritoneal carcinomatosis after risk-reducing surgery occurs predominantly in BRCA1 mutation carriers, usually within 5 years. Data have suggested that surgery at a younger age lowers the rates of peritoneal carcinomatosis. These data can be used in the gynecologic counseling of BRCA1/2 mutation carriers. RRSO should include complete salpingectomy. Detailed histopathological examination of specimens removed during RRSO is essential. Cancer 2018;124:952-9. © 2018 American Cancer Society.

Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80-96% but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. METHODS: A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40-45 (BRCA1) or 45-50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed. DISCUSSION: The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02321228 ).

Endoscopic full-thickness resection of a solitary ovarian carcinoma colorectal metastasis.

A woman in her 70s with a medical history of recurrent ovarian carcinoma was referred to the gastroenterologist because of rectal blood loss. Colonoscopy revealed a spontaneously bleeding lesion, which was not a typical colorectal carcinoma by optical diagnosis. Biopsies confirmed the diagnosis of recurrence of the former ovarian carcinoma. The patient was not eligible for surgical resection due to former abdominal surgery and she declined chemotherapy due to severe side effects earlier. After a multidisciplinary team consultation, she was treated with endoscopic full-thickness resection (eFTR). This is a minimally invasive resection technique for removal of challenging colorectal lesions. The patient has recovered well and 2 years after the metastasis resection with eFTR there still have been no signs of recurrent malignancy.

Analysis of computer-aided diagnostics in the preoperative diagnosis of ovarian cancer: a systematic review.

OBJECTIVES: Different noninvasive imaging methods to predict the chance of malignancy of ovarian tumors are available. However, their predictive value is limited due to subjectivity of the reviewer. Therefore, more objective prediction models are needed. Computer-aided diagnostics (CAD) could be such a model, since it lacks bias that comes with currently used models. In this study, we evaluated the available data on CAD in predicting the chance of malignancy of ovarian tumors. METHODS: We searched for all published studies investigating diagnostic accuracy of CAD based on ultrasound, CT and MRI in pre-surgical patients with an ovarian tumor compared to reference standards. RESULTS: In thirty-one included studies, extracted features from three different imaging techniques were used in different mathematical models. All studies assessed CAD based on machine learning on ultrasound, CT scan and MRI scan images. Per imaging method, subsequently ultrasound, CT and MRI, sensitivities ranged from 40.3 to 100%; 84.6-100% and 66.7-100% and specificities ranged from 76.3-100%; 69-100% and 77.8-100%. Results could not be pooled, due to broad heterogeneity. Although the majority of studies report high performances, they are at considerable risk of overfitting due to the absence of an independent test set. CONCLUSION: Based on this literature review, different CAD for ultrasound, CT scans and MRI scans seem promising to aid physicians in assessing ovarian tumors through their objective and potentially cost-effective character. However, performance should be evaluated per imaging technique. Prospective and larger datasets with external validation are desired to make their results generalizable.

Cytoreductive Surgery with the PlasmaJet Improved Quality-of-Life for Advanced Stage Ovarian Cancer Patients.

BACKGROUND: Knowledge of quality-of-life after cytoreductive surgery is important to counsel patients with advanced-stage epithelial ovarian cancer prior to surgery. The aim of this study was to determine whether the use of the PlasmaJet Surgical device during cytoreductive surgery has an effect on the quality-of-life of patients with advanced epithelial ovarian cancer. METHODS: Data included in this prospective observational study were derived from the PlaComOv study, in which patients with advanced epithelial ovarian cancer were randomly assigned to have cytoreductive surgery with or without adjuvant use of the PlasmaJet. Quality-of-life was measured before surgery and one, six, 12, and 24 months after surgery with three questionnaires: the EORTC QLQ-C30, QLQ-OV28, and EQ-5D-5L. RESULTS: Between 2018 and 2020, 326 patients were enrolled in the trial. The overall response rate was high, with the lowest response rate at 24 months of 77%. At 6 months, quality-of-life was higher in the intervention group (95%CI 0.009; 0.081, p = 0.045). At 12 months, quality-of-life was higher in the intervention group with fewer symptoms of fatigue, appetite loss, and diarrhea (95%CI 0.6; 10,0, p = 0.027); similarly, patients in the intervention group reported a better body image (95%CI -14.2; -3.0, p = 0.003) and a higher score on the visual analog scale (95%CI 1.99; 11.15, p = 0.005). At 24 months postoperatively, no further difference was found between the two groups except for pain (95%CI -12.9; -0.8, p = 0.027) and body image (95%CI -13.808; -0.733, p = 0.029). A higher quality-of-life in the intervention group was partially explained by the mediator 'surgery outcome'. CONCLUSIONS: This study demonstrated knowledge of patients' quality-of-life until two years after cytoreductive surgery. The use of the PlasmaJet Surgical device during cytoreductive surgery leads to a higher quality-of-life than conventional surgery with electrocoagulation alone. Even after adjustment for the mediator of surgical outcome, a higher quality-of-life was seen in patients who had surgery with the use of the PlasmaJet device.

The vulvar microbiome in lichen sclerosus and high-grade intraepithelial lesions.

Background: The role of the vulvar microbiome in the development of (pre)malignant vulvar disease is scarcely investigated. The aim of this exploratory study was to analyze vulvar microbiome composition in lichen sclerosus (LS) and vulvar high-grade squamous intraepithelial lesions (HSIL) compared to healthy controls. Methods: Women with vulvar lichen sclerosus (n = 10), HSIL (n = 5) and healthy controls (n = 10) were included. Swabs were collected from the vulva, vagina and anal region for microbiome characterization by metagenomic shotgun sequencing. Both lesional and non-lesional sites were examined. Biophysical assessments included trans-epidermal water loss for evaluation of the vulvar skin barrier function and vulvar and vaginal pH measurements. Results: Healthy vulvar skin resembled vaginal, anal and skin-like microbiome composition, including the genera Prevotella, Lactobacillus, Gardnerella, Staphylococcus, Cutibacterium, and Corynebacterium. Significant differences were observed in diversity between vulvar skin of healthy controls and LS patients. Compared to the healthy vulvar skin, vulvar microbiome composition of both LS and vulvar HSIL patients was characterized by significantly higher proportions of, respectively, Papillomaviridae (p = 0.045) and Alphapapillomavirus (p = 0.002). In contrast, the Prevotella genus (p = 0.031) and Bacteroidales orders (p = 0.038) were significantly less abundant in LS, as was the Actinobacteria class (p = 0.040) in vulvar HSIL. While bacteria and viruses were most abundant, fungal and archaeal taxa were scarcely observed. Trans-epidermal water loss was higher in vulvar HSIL compared to healthy vulvar skin (p = 0.043). Conclusion: This study is the first to examine the vulvar microbiome through metagenomic shotgun sequencing in LS and HSIL patients. Diseased vulvar skin presents a distinct signature compared to healthy vulvar skin with respect to bacterial and viral fractions of the microbiome. Key findings include the presence of papillomaviruses in LS as well as in vulvar HSIL, although LS is generally considered an HPV-independent risk factor for vulvar dysplasia. This exploratory study provides clues to the etiology of vulvar premalignancies and may act as a steppingstone for expanding the knowledge on potential drivers of disease progression.