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Serous adenofibroma of the fallopian tube is a rare, benign tumour of the female genital tract. They are usually small, asymptomatic and incidentally diagnosed during a surgery for another gynaecological condition. This report presents an atypical case of a 17-year-old girl with a tubal serous adenofibroma that presented with a palpable mass occupying the entire abdomen accompanied by urinary symptoms. She underwent a laparoscopic surgery with drainage of 1800 mL of yellow, citrine liquid from the cyst and left salpingectomy with no complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

DICER1 mutations (somatic or germline) are associated with a variety of uncommon neoplasms including cervical and genitourinary embryonal rhabdomyosarcoma (ERMS). We report a primary ovarian and 2 primary fallopian tube ERMS occurring in 60-, 13-, and 14-year-olds, respectively. The 3 neoplasms exhibited a similar morphologic appearance being polypoid and containing edematous hypocellular areas and hypercellular foci composed of small cells with scant cytoplasm exhibiting rhabdomyoblastic differentiation (desmin, myogenin, myoD1 positive). There was cellular cartilage in all cases and extensive foci of anaplasia, eosinophilic globules, and bone/osteoid in 1 case each. All 3 neoplasms exhibited DICER1 mutations; in 1 of the tubal cases, the patient had a germline mutation and in the other 2 cases, the DICER1 mutations were somatic. Accompanying DICER1 "second hits" were identified in all cases. In 2 of the neoplasms, SALL4-positive glandular structures were present which we speculate may represent an unusual primitive "metaplastic" phenomenon. Our study adds to the literature on ERMS at unusual sites associated with DICER1 mutations. ERMS arising at such sites, especially when they contain cartilage or bone/osteoid, are especially likely to be associated with DICER1 mutations. Pathologists should be aware of this as these may be the sentinel neoplasms in patients with DICER1 syndrome and confirming a germline mutation can facilitate the screening of the individual and affected family members for other neoplasms which occur in this syndrome.

Objective: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC., Methods: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m 2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS., Results: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%)., Conclusions: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab., Competing Interests: Declaration of competing interest Dr. Duska has served on advisory boards for Astra Zeneca, Genentech, Merck, Tesaro, Morphotek. She serves on the DSMC for an Inovio trial. She has received research funding from GSK/Novartis (current trial) and Merck. Her instition has received research funding from multiple pharmaceutical companies. Dr. Secord reports research funding from pharmaceutical companies outside the submitted work; and a grant from the National Cancer Trial Network outside the submitted work. She also reports honoraria/advisory boards from Alexion, Aravive, Astex Pharmaceuticals Inc., Astra Zeneca, Clovis, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Oncoquest, Roche/Genentech, and Tesaro outside of the submitted work. Dr. Moore has served on advisory boards for Astra Zeneca, Advaxis, Clovis, Immunogen, Tesaro, Genentech/Roche, Janssen, Pfizer, Merck, Aravive, Samumed, Oncomed, VBL Therapeutics and Eisai. She serves on steering committees (not compensated) for Astra Zeneca, Tesaro, VBL Therapeutics. She has received research funding from PTC Therapeutics, Lilly, Genentech/Roche and Clovis. Dr. Brown reports personal fees from Tesaro, personal fees from Clovis, from Tempus, personal fees from AstraZeneca, personal fees from Genentech, personal fees from Olympus, personal fees from Advanced Surgical Concepts, personal fees from OncLive, outside the submitted work. The following authors report no financial interests: Dr. McGuire, Dr. Petroni, Ms Varhegyi, Dr. Barroilhet, Dr. Jelovac, Dr. Darus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Primary transitional cell carcinoma (TCC) of the fallopian tube is an extremely rare tumor., Patient Concerns: A 79-year-old woman presenting with vaginal discharge., Diagnosis: Pelvic magnetic resonance imaging revealed a predominantly solid mass with a lobulated contour, measuring 5.5 cm × 4.6 cm, in the left ovary. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. Pathological analysis revealed a high-grade TCC, measuring 7.5 cm × 4 cm, in the left fallopian tube (International Federation of Gynecology and Obstetrics stage IIB)., Intervention: Forty-three months postoperation, recurrence was diagnosed as peritoneal metastasis. The patient underwent 6 cycles of palliative chemotherapy consisting of cisplatin and gemcitabine, the recommended regimen for TCC of the urinary tract., Outcome: The patient has survived for 27 months without recurrence after palliative chemotherapy, 76 months after diagnosis., Conclusion: It is rare that primary TCC of the fallopian tube responds to a urinary tract treatment regimen for TCC, even when followed up for an extended period. More research is warranted to determine which treatment regimen will benefit patients the most.

Background We assessed the prevalence, localization, type and outcome of occult cancer at risk-reducing salpingo-oophorectomy or salpingectomy (RRSO) in asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative women. Patients and methods A retrospective analysis of all consecutive gynaecologic preventive surgeries from January 2009 to December 2015 was performed. Participants underwent genetic counselling and BRCA1/2 testing before the procedure. Data on clinical parameters, adjuvant treatment and follow-up were collected and analysed. Results One hundred and fifty-five RRSO were performed in 110 BRCA1, 35 BRCA2 carriers of pathogenic or likely pathogenic variants and 10 high-risk BRCA1/2 negative women, at the mean age of 48.3 years. Nine occult cancers (9/155, 5.8%) were identified; eight in BRCA1 positive women and one in high-risk BRCA1/2 negative woman. We identified four non-invasive serous intraepithelial tubal carcinomas (3 in BRCA1 carriers and 1 in a high-risk BRCA1/2 negative woman) and five invasive tubo-ovarian high grade serous cancers (all detected in BRCA1 carriers). Only one out of nine patients (11.1%) with occult cancer had a slightly elevated CA-125 value preoperatively. Conclusions A 5.8% prevalence of occult invasive and noninvasive tubo-ovarian serous cancer after RRSO was found in high risk asymptomatic and screen negative women. We conclude that RRSO should be performed in BRCA1/2 carriers and in high-risk BRCA1/2 negative women. Age of preventive gynaecologic surgery should be carefully planned, taking into account the completion of childbearing age and type of mutation. The results favour the tubal hypothesis of tubal origin of high grade serous ovarian and peritoneal cancer. Cytology result of peritoneal cavity washing was important for the decision making process in determining treatment. Cytology examination should be performed in all cases of RRSO. CA-125 assay did not prove to be an effective screening tool for early cancer detection in our patients.

Background: Primary fallopian tube carcinoma (PFTC) is a malignant tumor of the female genital tract that mostly presents intraperitoneal dissemination in clinical practice. The incidence of upper anterior mediastinal metastasis in PFTCs is extremely rare. We herein report a rare case of PFTC mediastinal metastasis after radical resection. When anterior mediastinal metastasis of an unknown origin is encountered, the possibility of PFTC should be considered., Case Presentation: A 68-year-old female who was previously diagnosed with PFTC after radical resection of a primary tumor in the fallopian tube was admitted to our department with a right anterior mediastinum mass. Radical resection of the mediastinal mass was performed, and poorly differentiated metastatic adenocarcinoma of the fallopian tube was confirmed. There was no recurrence in the 24 months after the curative operation., Conclusion: To our knowledge, no mediastinal metastasis of PFTC has been reported yet. Thus, we presented this rare case indicating the heterogeneity of this malignant disease and to draw attention to the occasional distant metastasis of PFTC in clinical practice.

Background: Primary debulking surgery (PDS) and adjuvant chemotherapy is the standard treatment for advanced ovarian, fallopian or primary peritoneal cancer. However, neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been introduced as an alternative, showing similar efficacy and decreased postoperative complications compared with PDS. Although there is still no evidence for whether three or four cycles of NAC used clinically could be adequate, reducing one cycle of NAC is expected to remove more visible tumours and thereby improve prognosis. Thus, we proposed with this study to evaluate the efficacy and safety of reducing one cycle of NAC for advanced ovarian, fallopian or primary peritoneal cancer., Methods: This study is a prospective, multi-centre, open-label, randomized phase III trial. A total of 298 patients with advanced ovarian, fallopian or primary peritoneal cancer will be recruited and randomly assigned to either three (control group) or two cycles of NAC (experimental group). After the NAC, we will conduct IDS with maximal cytoreduction and then administer the remaining three or four cycles for a total of six cycles of adjuvant chemotherapy. The primary end point is progression-free survival, and the secondary end points are time to tumour progression, overall survival, tumour response after NAC, IDS and adjuvant chemotherapy, radiologic investigation after IDS, tumour response by positron emission tomography-computed tomography after NAC, quality of life, adverse events, success rate of optimal cytoreduction, surgical complexity, postoperative complications and safety of IDS. We will assess these factors at screening, at every cycle of chemotherapy, at IDS, after the completion of chemotherapy, every 3 months for the first 2 years after the planned treatment and every 6 months thereafter for 3 years., Discussion: We hypothesize that reducing one cycle of NAC will contribute to more resection of visible tumours despite 10% reduction of optimal cytoreduction, which could improve survival. Moreover, two cycles of NAC may increase postoperative complications by 5% compared with three cycles, which may be acceptable., Trial Registration: This study has been prospectively registered at ClinicalTrials.gov on Oct. 2nd, 2018 (NCT03693248, URL: https://clinicaltrials.gov/ct2/show/NCT03693248).

Background: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab., Methods: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2 , days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2 , day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251., Findings: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage)., Interpretation: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer., Funding: F Hoffmann-La Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of ovarian, fallopian tube (FT), and peritoneal carcinoma (collectively OC). We describe rates of occult neoplasia in the largest single-institution prospective cohort of women undergoing RRSO, including those with mutations in non-BRCA homologous repair (HRR) genes., Methods: Participants undergoing RRSO enrolled in a prospective tissue bank between 1999 and 2017. Ovaries and FTs were serially sectioned in all cases. Participants had OC susceptibility gene mutations or a family history suggesting OC risk. Analyses were completed in Stata IC 15.1., Results: Of 644 women, 194 (30.1%) had mutations in BRCA1, 177 (27.5%) BRCA2, 27 (4.2%) other HRR genes, and 15 (2.3%) Lynch Syndrome-associated genes. Seventeen (2.6%) had occult neoplasms at RRSO, 15/17 (88.2%) in the FT. Of BRCA1 carriers, 14/194 (7.2%) had occult neoplasia, 8/194 (4.1%) invasive. One PALB2 and two BRCA2 carriers had intraepithelial FT neoplasms. Occult neoplasm occurred more frequently in BRCA1/2 carriers ≥45 years of age (6.5% vs 2.2%, chi square, p = .04), and 211/371 (56.9%) BRCA1/2 carriers had surgery after guideline-recommended ages. Four in 8 (50%) invasive and 2/9 (22%) intraepithelial neoplasms had positive pelvic washings. None with intraepithelial neoplasms developed recurrence or peritoneal carcinoma., Conclusions: BRCA1 carriers have the highest risk of occult neoplasia at RRSO, and the frequency increased with age. Women with BRCA1/2 mutations often have RRSO beyond recommended ages. One PALB2 carrier had FT intraepithelial neoplasia, a novel finding. Serial sectioning is critical to identifying occult neoplasia and should be performed for all risk-reducing surgeries., Competing Interests: Declaration of competing interest Dr. Elizabeth Swisher has received grant support via the National Institutes of Health, 1R01CA131965. Otherwise, there are no conflicts of interest or disclosures from any of the other authors., (Copyright © 2020. Published by Elsevier Inc.)

We report 2 cases of low-grade serous carcinoma probably arising from endosalpingiosis within inguinal lymph nodes. The neoplasms occurred in 51- and 58-yr old women in the absence of tumor within the adnexa, peritoneum or elsewhere. These represent the first reported examples of low-grade serous carcinoma arising within and confined to inguinal nodes. We review the pertinent literature regarding primary nodal low-grade serous carcinoma.

The aim of this study was to evaluate overall survival (OS) and disease-free survival (DFS) of patients with Stage 3C serous ovarian, tubal and peritoneal carcinomas. A retrospective analysis of 111 patients who underwent maximal or optimal cytoreductive surgery was performed. Patients were divided into three groups as ovarian cancer ( n  = 47), tubal cancer ( n  = 24) and peritoneal cancer ( n  = 40). Median follow-up was 30 months. There was no significant difference in DFS and OS among the groups. Complete cytoreduction was an independent prognostic factor for DFS in all groups (HR 2.3, 95% CI 1.14-4.93; p =.020). Positive peritoneal cytology (HR 2.2, 95% CI 1.02-4.78; p =.044), and retroperitoneal lymph node involvement (HR 2.3, 95% CI1.11-4.89; p =.025) were independent risk factors for decreased OS, and extended cytoreduction (HR 2.7, 95% CI 1.05-6.99; p =.039) were independent risk factors for increased OS. In conclusion, these malignancies should be considered a single entity during treatment.IMPACT STATEMENT What is already known on th is subject? Epithelial ovarian cancer is the second most common gynaecological cancer in women worldwide. There are different histological types including ovarian, tubal and peritoneal carcinomas in which malignant cells form in the tissue covering the ovary or lining the fallopian tube of peritoneum. Recent data have supported the view that these malignancies should be considered a single entity and should be treated the same way. What the results of this study add ? In the present study, we evaluated overall survival and disease-free survival of patients with Stage 3C ovarian, tubal and peritoneal cancer undergoing maximal or optimal cytoreductive surgery. We found similar oncologic outcomes in all patient groups. To the best of our knowledge, this is the first study to compare oncologic outcomes of these similar and often confused malignancies in the literature. We, therefore, believe that the present study provides additional information to the body of knowledge on this topic. What the implication s are of these findings for clinical practice and/or further research ? This study is important, as it indicates similar oncologic outcomes in patients undergoing maximal or optimal cytoreductive surgery for Stage 3C ovarian, tubal and peritoneal cancer. Based on these findings, clinicians should keep in mind that these malignancies should be considered a single clinical entity and be treated the same way. We believe that our study would pave the way for further studies regarding this subject.

Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Although outcomes have improved in recent years, there remains an unmet clinical need to understand the early pathogenesis of ovarian cancer in order to identify new diagnostic approaches and agents of chemoprevention and chemotherapy. While high grade serous ovarian cancer (HGSOC), the most abundant histotype, was initially thought to arise from the ovarian surface epithelium, there is an increasing body of evidence suggesting that HGSOC originates in the fallopian tube. With this new understanding of cell of origin, understanding of disease development requires analysis with a novel perspective. Currently, factors that drive the initiation and migration of dysplastic tubal epithelial cells from the fallopian tube to the ovary are not yet fully defined. These factors include common mutations to fallopian tube epithelial cells, as well as factors originating from both the fallopian tube and ovary which are capable of inducing transformation and dissemination in said cells. Here, we review these changes, their causative agents, and various potential means of intervention., Competing Interests: Declaration of competing interest The authors have no conflicts to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In patients with epithelial ovarian cancer, whether metastasis to para-aortic lymph nodes located cephalad to the renal veins (supra-renal PAN) should be classified as regional lymph node metastasis or distant metastasis remains controversial. This study was a preliminary retrospective evaluation of the pattern of supra-renal PAN metastasis in patients with epithelial ovarian cancer., Methods: The subjects were 25 patients with epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who underwent systematic dissection of the para-aortic nodes, including the supra-renal PAN, and pelvic lymph nodes (PLN). Patient factors, perioperative factors, the number of dissected lymph nodes, and pathological lymph node metastasis were investigated., Results: Supra-renal PAN metastasis was found in 4/25 patients (16.0%). None of the 14 patients with pT1 or pT2 disease had supra-renal PAN metastasis, while 4/11 patients (36.4%) with pT3 or ypT3 disease had such metastases. None of the patients had isolated supra-renal PAN metastasis, while patients with supra-renal PAN metastasis also had multiple metastases to the infra-renal PAN and PLN., Conclusions: In patients with epithelial ovarian cancer, supra-renal PAN metastases might be considered to be distant rather than regional metastases. Further studies are needed to better define the clinical significance of supra-renal PAN metastasis.

Purpose: In this study, the prognostic value of serum HE4 was investigated in patients with advanced ovarian, fallopian tube, and peritoneal carcinoma., Methods: Serum HE4 and CA125 levels were measured in both patients and controls, and the response of treatment and the detection of recurrence were evaluated by serum HE4 and CA125 levels in the patients., Results: The results showed that the levels of serum HE4 and CA125 were significantly higher in advanced patients than those seen in benign disease controls (p < 0.001). Compared with CA125, HE4 had higher specificity, but lower sensitivity. Furthermore, serum HE4 was closely associated with the response of treatment and recurrence, the effective response rate for therapy treatment showed by HE4 was higher than CA125, and a serum HE4 level was correlated with a sensitivity of 82.8% and a specificity of 99%, a positive predictive value (PPV) of 97.7%, and a negative predictive value (NPV) of 77.9% to show the presence of recurrence; the accuracy of HE4 for recurrence prediction after treatment was 88.6%., Conclusions: Our study indicated that serum HE4 levels are effective for diagnosis, evaluating the response of treatment and predicting recurrence in patients with advanced ovarian, fallopian tube, and peritoneal carcinoma.

Introduction: Abdominopelvic washing cytology is a common specimen evaluated for ovarian, fallopian tubal, and peritoneal cancer staging or other nongynecologic malignancies presented as metastases. We reviewed our experience in diagnosing abdominopelvic washing specimens and assessing the primary tumor types and origins of the positive abdominopelvic washings., Materials and Methods: A pathology archive database search was performed for abdominopelvic washing specimens from 2007 to 2018. The corresponding cytologic diagnoses, results of ancillary studies, clinical histories, and surgical follow-up were reviewed. The primary sites were determined based on the synoptic reports, when available., Results: A total of 5.8% (350 of 6023) of cases were positive for malignancy or neoplasm. Additionally, 1.3% (78 of 6023) were diagnosed as atypical cells. Of the 350 positive cases, 93.4% were müllerian tumors. The frequency of primary sites for müllerian tumors in descending order were: ovary, uterus, fallopian tube, peritoneum, and uncertain müllerian sites. The common ovarian tumors identified in pelvic washing in descending order were: high-grade serous carcinoma, serous borderline tumor, clear cell carcinoma, low-grade serous carcinoma, and endometrioid carcinoma. Gastrointestinal, breast, bladder, and lymphoma primaries were the 23 nongynecologic tumors identified in pelvic washings., Conclusions: Positive findings in abdominopelvic washing cytology is rare. The majority of the positive cases were from müllerian origins, with ovary and uterus as the most common sites. Endometrial adenocarcinoma, endometrioid type and ovarian high-grade serous carcinoma were the most common tumor types. Knowing prior history of malignancy, morphologic comparison with concurrent surgical cases, and performing ancillary studies are keys to improve diagnostic accuracy of abdominopelvic washings., (Copyright © 2019 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the feasibility of a novel hysteroscopic catheter to collect fallopian tube cytologic samples and to correlate cytologic findings with histopathology., Methods: This was a prospective, multicenter, single-arm pilot study. Women undergoing salpingo-oophorectomy for a pelvic mass suspicious for malignancy or for prevention of cancer for BRCA mutation carriers were recruited from 3 gynecologic oncology centers (October 2016-August 2017). Cytologic samples were collected from the fallopian tube using a novel FDA-cleared hysteroscopic catheter and evaluated by a pathologist blinded to surgical or pathologic findings. The correlation between cytologic results and final surgical pathology was assessed., Results: Of the 50 patients enrolled, 42 were eligible. Hysteroscopies were completed in 40 patients with 78 fallopian tubes, of which 65 ostia (83%) were identified. Of these, 61 (72%) were successfully catheterized resulting in 44 (68%) cytology samples adequate for further evaluation: 5 were classified as positive (3 neoplastic and 2 malignant) and 39 as negative (34 benign and 5 reactive/atypical). A comparison of cytology results with fallopian tube histopathology showed a concordance rate of 95% (42/44). Of the two samples with discordant results, both had positive cytology but negative tubal pathology, and both were stage I ovarian cancers with malignant ovary histology., Conclusions: Deployment of the device yielded an evaluable cytologic sample in 68% of cases with a high rate of concordance with histopathology. Further evaluation of the device's ability to detect malignancy in high risk populations is warranted., Competing Interests: Declaration of competing interest Sharmila Pramanik reports personal fees from nVision Medical (a Boston Scientific company) during the conduct of this study. The other authors report no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The majority of extrauterine high-grade serous carcinomas are believed to arise in the fallopian tube as serous tubal intraepithelial carcinomas. The primary mode of metastasis is intraperitoneal, and patients usually present with peritoneal carcinomatosis. Although the tubes have a rich lymphatic network, tubal lymphatic invasion is observed in only a minority of cases. Fallopian tube sections from 222 patients with advanced stage high-grade extrauterine serous carcinoma were reviewed and lymphatic invasion within the lamina propria and myosalpinx were assessed. Seventeen patients were FIGO stage II, 162 stage III, and 43 stage IV. Tubal lymphatic invasion was identified in 44 cases (19.7%). Among the cases with lymphatic invasion, nonfimbrial lamina propria, fimbrial lamina propria, and myosalpingeal lymphatic invasion were present in 23 (52%), 21 (48%), and 21 (48%), respectively. Among cases with lymphatic invasion, 16 (36%) were FIGO stage IV, while among cases without lymphatic invasion, 27 (15%) were stage IV (P=0.0014, χ). In summary, in women with advanced stage high-grade extrauterine serous carcinoma, lymphatic invasion in the fallopian tube is uncommon, and is more than twice as likely to be associated with distant metastases as compared with those without tubal lymphatic invasion.

Epithelial proliferations in the fallopian tube have been characterized by some as stem cell outgrowths (SCOUTs) and divided into type I and type II. Type II SCOUTs exhibit diffuse cellular beta-catenin nuclear staining (β-catenin), implying a CTNNB1 mutation. SCOUTs are more common in perimenopausal and postmenopausal women and are associated with ovarian cancer but have not been linked directly to malignancy. We analyzed type II SCOUTs in various gynecologic conditions, and searched for endometrioid atypical hyperplasias (tubal endometrioid intraepithelial neoplasia) or adenocarcinomas in the tube. β-catenin SCOUT frequency in cases of neoplasia was 66.7% per case and 30.7% per nonfimbrial cross-section for uterine endometrioid carcinomas versus 25% and 13.3% for controls, respectively (P=0.02 and 0.09). Multiple (3 or more) β-catenin SCOUTs in a single section were uncommon; 6 of 9 were associated with a carcinoma or proliferative lesion in the endometrium. Tubal endometrioid intraepithelial neoplasia/atypical hyperplasia displayed complex growth, including focal cribriform growth patterns and squamous morules. Two cases of type II SCOUTs associated with tubal endometrioid intraepithelial neoplasia/atypical hyperplasia and/or adenocarcinomas in the fallopian tube were identified, both of which coexisted with a separate endometrioid adenocarcinoma, one with bilateral ovarian endometrioid adenocarcinomas. Both benign and neoplastic tubal lesions were β-catenin. This report is the first to link components of a unique β-catenin endometrioid carcinogenic sequence in the fallopian tube. It further emphasizes the multifocal nature of endometrioid neoplasia in the female genital tract and poses questions regarding the frequency and biologic underpinnings of β-catenin proliferations in the oviduct.

Robust preclinical models of ovarian high-grade serous carcinoma (HGSC) are needed to advance our understanding of HGSC pathogenesis and to test novel strategies aimed at improving clinical outcomes for women with the disease. Genetically engineered mouse models of HGSC recapitulating the likely cell of origin (fallopian tube), underlying genetic defects, histology, and biologic behavior of human HGSCs have been developed. However, the degree to which the mouse tumors acquire the somatic genomic changes, gene expression profiles, and immune microenvironment that characterize human HGSCs remains unclear. We used integrated molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1 , and Nf1 ( BPRN ) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features. Targeted DNA sequencing showed the mouse BPRN tumors, but not endometrioid carcinoma-like tumors based on different genetic defects (e.g., Apc and Pten ), acquire somatic mutations and widespread copy number alterations similar to those observed in human HGSCs. RNA sequencing showed the mouse HGSCs most closely resemble the so-called immunoreactive and mesenchymal subsets of human HGSCs. A combined immuno-genomic analysis demonstrated the immune microenvironment of BPRN tumors models key aspects of tumor-immune dynamics in the immunoreactive and mesenchymal subtypes of human HGSC, with enrichment of immunosuppressive cell subsets such as myeloid-derived suppressor cells and regulatory T cells. The findings further validate the BPRN model as a robust preclinical experimental platform to address current barriers to improved prevention, diagnosis, and treatment of this often lethal cancer. SIGNIFICANCE: The acquired gene mutations, broad genomic alterations, and gene expression and immune cell-tumor axis changes in a mouse model of oviductal serous carcinoma closely mirror those of human tubo-ovarian high-grade serous carcinoma., (©2019 American Association for Cancer Research.)

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC., Competing Interests: Declaration of Interests A.A.A., C.Y., and Z.H. filed a patent application for the use of the 52-gene panel for predicting the prognosis in ovarian cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Bevacizumab and gemcitabine are key drugs for treating recurrent epithelial ovarian cancer. However, information about the combination of bevacizumab and gemcitabine is insufficient. We conducted a phase II study to assess the feasibility, clinical activity, and toxicity of this combination chemotherapy., Methods: This study included women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer who received one to three regimens of platinum-based chemotherapy between April 1, 2015 and December 31, 2018. The patients received bevacizumab 15 mg/kg intravenously on day 1 and gemcitabine 1000 mg/m 2 intravenously on days 1 and 8 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of three cycles of chemotherapy. This study was registered in the University Medical Information Network (UMIN) Clinical Trials Registry (UMIN000016619)., Results: Among the 19 patients, 18 (95%) received ≥3 and 9 (47%) received ≥6 cycles of the study therapy. The objective response rate was 42% (complete response of 16% and partial response of 26%), and the clinical control rate was 84%. Hematological toxicity included neutropenia grade 3/4 in 9 patients (47%), anemia grade 3/4 in 2 (11%), and thrombocytopenia grade 3/4 in 1 (5%). One patient (5%) had grade 3 hypertension, and 1 (5%) had grade 3 protein urea. Possibly related grade 3 pulmonary toxicity was observed in 1 patient. Three patients needed dose reduction of gemcitabine to 800 mg/m 2 due to treatment delay by 15 to 21 days on day1. There was no treatment delay more than 14 days on day 8. The median progression-free survival duration was 5.1 months and median overall survival duration was 21.3 months., Conclusion: The combination chemotherapy with gemcitabine and bevacizumab was feasible, effective and safe. This combination chemotherapy may be explored in a further randomized trial.

The chemotherapy response score (CRS) is used to score histopathologic response to neoadjuvant chemotherapy (NACT) of patients with extrauterine high-grade serous carcinoma. This study was undertaken to determine if the CRS in the omentum, adnexa or when combined correlates with (1) progression-free survival (PFS) or overall survival (OS), (2) laparoscopic score of abdominal disease, (3) Cancer antigen 125 levels, (4) BRCA status, and (5) platinum-resistant disease. A total of 158 cases were retrospectively collected that received NACT between April 2013 and February 2018 at a single institution. The 3-tier Böhm CRS system was applied to the omentum and adnexa. Survival outcomes between scored subgroups were analyzed using Cox proportional hazards regression. Spearman rank correlation analyses were used to assess CRS and clinical data. A total of 119 cases were treated only with carboplatin/paclitaxel. Omental CRS was: 1 (23 cases, 19.3%), 2 (65 cases, 54.6%), and 3 (31 cases, 26.1%), whereas adnexal CRS was: 1 (50 cases, 42%), 2 (48 cases, 40.3%) and 3 (21 cases, 17.6%). The omental CRS was significantly associated with PFS as a 2-tier score (hazard ratio [HR]=0.612, 95% confidence interval [CI]: 0.378-0.989, P=0.045) but not associated with the PFS using the 3-tier score or with OS using either system. Adnexal CRS was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.49, 95% CI: 0.263-0.914, P=0.025) and 2-tier scores (HR=0.535, 95% CI: 0.297-0.963, P=0.037). The combined score was not associated with OS but was significantly associated with PFS using the 3-tier (HR=0.348, 95% CI: 0.137-0.88, P=0.026) and 2-tier scores (HR=0.364, 95% CI: 0.148-0.896, P=0.028). No CRS system used associated with laparoscopic assessment of disease. CRS in the omentum had no significant association with platinum resistance; however, the adnexal CRS 1/2 were 3 times as likely to develop platinum resistance compared with CRS 3 (relative risk=3.94, 95% CI: 1.03-15.09, P=0.046). The CRS, when used on the omentum, adnexa, and as a combined score, was significantly associated with PFS but not with OS. Adnexal CRS 1/2 are more likely to develop platinum-resistant disease. Therefore, the use of this pathology parameter may be useful for clinical management.

Increasingly, high-grade serous carcinomas (HGSCs) of fallopian tube/ovarian origin are managed initially with neoadjuvant chemotherapy (NACT) and pre-treatment diagnosis is often based upon relatively limited core biopsy and/or cytology specimens. Endometrial HGSC can also present with adnexal and peritoneal metastasis, thus mimicking a primary tubo-ovarian neoplasm, but the role of NACT in these cases is less established. Immunohistochemistry has been considered useful in this distinction but with a wide range of reported findings in the literature. In this study we have examined tumour growth patterns and the expression p16, Ki-67, WT1, PAX2, HER2, ER-α, ER-β, PR, and BAF250a in 18 tubo-ovarian and 14 endometrial HGSCs, comparing the findings in primary and omental sites. Metastatic tubo-ovarian carcinomas demonstrated significantly more varied architectural patterns than metastatic endometrial HGSCs (median 2.5 versus 1). None of the immunohistochemical markers proved completely reliable but only endometrial HGSC were WT1 negative (7/14 metastatic tumours) or demonstrated over-expression of HER2 (2/14 cases). Micropapillary tumour elements more often showed retained PAX2 and WT1 expression, low Ki-67 labelling, and (in endometrial tumours) PR staining. Diverse architectural patterns suggest tubo-ovarian origin in a metastatic HGSC. Immunohistochemical results should be cautiously interpreted, particularly in small specimens., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

A 0.2-cm intramural focus composed predominantly of myelocytes and metamyelocytes, many CD3+, CD43+ T-lymphocytes, scanty CD20+ B-lymphocytes, rare mast cells, but no eosinophils or myeloblasts was incidentally found in a ligation specimen of the left fallopian tube. The myeloid cells were positive for chloroacetate esterase, myeloperoxidase, myeloid marker BM2, and CD43, and they were negative for CD30, CD34, CD117, ERG, and TDT. The findings in the left fallopian tube were consistent with the diagnosis of differentiated myeloid sarcoma. The right fallopian tube was normal. No hematologic abnormalities were found elsewhere in the body. Curiously, the patient remains free of any hematologic abnormality for 18 years despite absence of treatment.

Objective: To compare the germline BRCA1 and BRCA2 mutation ( gBRCA ) status in women with high-grade serous tubo-ovarian and primary peritoneal carcinoma with and without serous tubal intra-epithelial carcinomas (serous tubal intra-epithelial carcinoma-positive vs serous tubal intra-epithelial carcinoma-negative)., Materials and Methods: A retrospective study was performed of patients in Western Australia diagnosed with high-grade serous tubo-ovarian and primary peritoneal carcinoma and referred for genetic counseling and gBRCA testing from July 1, 2014 to June 30, 2017. Histopathology reports were reviewed to ascertain whether serous tubal intra-epithelial carcinoma was present. Personal or family gBRCA status, family history, age at diagnosis, mode of treatment (neoadjuvant chemotherapy vs primary surgery), and stage were also recorded., Results: A total of 269 women with high-grade serous tubo-ovarian and primary peritoneal carcinoma were referred for genetic counseling and testing. 114 patients were excluded because the serous tubal intra-epithelial carcinoma status was not assessable or because patients did not attend for genetic assessment. 155 patients (55 serous tubal intra-epithelial carcinoma-positive and 100 serous tubal intra-epithelial carcinoma-negative) underwent genetic testing. gBRCA mutations were found in 27.8% of serous tubal intra-epithelial carcinoma-positive patients compared with 14.0% of serous tubal intra-epithelial carcinoma-negative patients (p=0.094). Of those found to have a gBRCA mutation, 89.7% reported a positive personal or family history of BRCA -related cancers., Conclusions: The gBRCA mutation detection rate in serous tubal intra-epithelial carcinoma-positive patients was nearly double that of serous tubal intra-epithelial carcinoma-negative patients. Factors such as a positive family history of BRCA -related cancers were seen at a higher proportion in the mutation positive women., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The introduction of genomic studies has enabled assessment of the clonality of synchronous tumours involving the ovary and other sites in the female genital tract in a definitive way. This has led to the abandonment of conventional approaches to primary site assignment, and the recognition that most such synchronous neoplasms are clonally related single tumours with metastatic spread, rather than independent primary tumours. These discoveries have implications for diagnostic practice, analogous to the gradual change over the last few decades in our approach to mucinous neoplasms of the ovary metastatic from the gastrointestinal tract. In this review, we first examine the routes of metastasis to the ovary, and then discuss the diagnostic and clinical implications of concurrent ovarian carcinomas arising in combination with endometrial, endocervical and tubal carcinomas. It is proposed that cases of primary low-grade endometrioid endometrial carcinoma with a secondary unilateral ovarian tumour, both with indolent characteristics, may be classified as 'FIGO stage IIIA-simulating independent primary tumours', with a comment that conservative management would be appropriate. It should be recognised that human papillomavirus-associated endocervical adenocarcinomas may result in synchronous or metachronous ovarian metastases that appear to be unrelated to the primary tumour, and that these may be managed conservatively in the absence of other sites of disease. In cases of tubo-ovarian high-grade serous carcinoma, tubal intraepithelial or contralateral adnexal involvement should count as a pelvic disease site for staging purposes., (© 2019 John Wiley & Sons Ltd.)

A recent phase II clinical trial showed increased progression-free survival in patients with HER2-positive endometrial serous carcinoma receiving trastuzumab in addition to carboplatin-paclitaxel chemotherapy. Similar to endometrial serous carcinomas, carcinosarcomas of the female genital tract have a dismal prognosis and could potentially benefit from new targeted therapeutic approaches. We aimed to systematically evaluate the characteristics of HER2 expression/amplification in gynecologic carcinosarcomas using standardized staining methods and scoring criteria. Tumors from 80 patients (65 uterine, 15 tubo-ovarian) were included, containing a serous (60%), endometrioid (10%), clear cell (3%), undifferentiated (3%), neuroendocrine (1%), or mixed (24%) carcinoma, and either a homologous (46%), or a heterologous (54%) sarcoma component. HER2 scores were assigned to both components per the 2007 and 2013 ASCO/CAP breast scoring criteria. A total of 13 cases (12 uterine, 1 ovarian, 16%) were HER2 positive (either by immunohistochemistry or FISH) using the 2013 criteria, while only 10 cases (9 uterine, 1 ovarian, 13%) were HER2 positive per the 2007 criteria. Nine cases showed a change in their HER2 immunohistochemical score between the two scoring systems, including two cases with a change in the overall HER2 status from negative (2007) to positive (2013). Heterogeneity of HER2 protein expression was observed in 38% of HER2-positive tumors, and a lateral/basolateral membranous staining pattern was common. The sarcoma component showed 2+, equivocal HER2 expression in five cases, one of which also demonstrated HER2 amplification by FISH. All HER2-positive carcinosarcomas had either a serous or a mixed carcinoma component, and all but one HER2-positive tumors were of uterine primaries. Our study demonstrates that gynecologic carcinosarcomas share similarities in their HER2 expression/amplification profiles to endometrial serous carcinomas, which should be taken into account when assessing their HER2 status to ensure appropriate patient selection for potential targeted HER2-based therapies in the future.

Background: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC., Methods: A phase I, 3 + 3 dose escalation evaluated dose-limiting toxicities (DLTs) in cycles 1-2. Once <2/6 patients experienced a DLT, that dose level expanded to evaluate feasibility over 4 cycles. This study opened 10/2009 and closed 8/2016. Eligible patients had untreated, stage II-IV EOC. Veliparib was added either continuous (day 1-21) or intermittent (day - 2 to 5) during 6 cycles of chemotherapy. Three chemotherapy backbones were evaluated (2 intravenous (q3week and weekly) and 1 intraperitoneal (IP)) all inclusive of bevacizumab with and as maintenance to 22 cycles., Findings: Dose evaluations for 424 treated patients were available. Regimen 1 (q3 week), continuous (Reg1c) the maximum tolerated dose (MTD) was 250 mg veliparib BID and feasible dose was 150 mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250 mg BID. For Reg2c (weekly paclitaxel) the MTD and feasible dose were 150 mg BID. For Reg2i the MTD and feasible dose were 250 and 150 mg BID. For Reg3c (IP) the MTD and feasible dose were 150 mg BID and for Reg3i (IP), the MTD and feasible dose were 400 mg and 300 mg BID., Interpretation: The feasible dose for Reg1c, 2c, 2i and 3c was 150 mg po BID. For Reg1i and 3i the dose was pushed to 250 and 300 mg po BID respectively. There is no apparent difference in efficacy between continuous and intermittent dosing indicating that the higher doses achieved in intermittent dosing may not be needed. (NCT00989651)., Funding: National Cancer Institute., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer., Methods: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m 2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m 2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m 2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3)., Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m 2 in group 1; 1233 mg/m 2 in group 2; 1274 mg/m 2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups., Interpretation: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations., Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Early-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity., Methods: From 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity., Results: Of 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71-1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively., Conclusions: Vaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches., Trial Registration: NCT00857545., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5 + OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.

High-grade serous ovarian carcinoma commonly arises from fallopian tube secretory epithelium and is characterized by a high level of chromosomal instability. To model the acquisition of aneuploidy during early carcinogenesis, chromosome missegregation was induced in immortalized tubal epithelial cells, which proved acutely detrimental to cellular fitness. The phenotype was characterized by accumulation of misfolded proteins, activation of the unfolded protein response (UPR), decreased protein synthesis, and enhanced vulnerability to proteasome inhibition. However, chromosome missegregation also resulted in heightened transformation potential, assessed by colony formation in soft agar. Ovarian cancer cells retained intrinsic sensitivity to proteasome inhibitors under adherent culture conditions, but acquired resistance as spheroids (recapitulating their native configuration in ascites) by downregulating protein synthesis via mTORC1 suppression. Loss of PTEN drove constitutive mTORC1 activity, enhanced proteotoxic stress, as evidenced by UPR induction, and resensitized tumor spheroids to proteasome inhibition both in vitro and in vivo . In cohorts of primary ovarian carcinomas, mTORC1 and UPR signaling pathways were closely associated. These results implicate attenuation of protein synthesis as a protective mechanism in tumor spheroids, which may explain the overall poor response to bortezomib in clinical trials of patients with advanced ovarian cancer. However, patients with PTEN-deficient tumors may represent a subpopulation potentially amenable to treatment with proteasome inhibitors or other therapeutic agents that disrupt protein homeostasis. SIGNIFICANCE: Chromosome instability and protein synthesis are important factors that determine the efficacy of proteotoxic stress-inducing agents, such as proteasome inhibitors, in the treatment of ovarian cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5536/F1.large.jpg., (©2019 American Association for Cancer Research.)

Objective: To investigate the relationship between the precursors of high grade serous ovarian cancer (HGSOC) and the characteristics of patients with a low HGSOC risk in terms of the effects of pregnancy., Methods: We prospectively examined consecutive cases in which the bilateral fallopian tubes were removed during benign gynecological or obstetric surgery and assessed the relationship between the patient characteristics, including parity and pregnancy, and the incidence of HGSOC precursors. All the fallopian tubes were examined by applying the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) Protocol., Results: Of the 113 patients enrolled, 67 were gynecological and 46 were obstetric. The p53 signature was identified in 21 patients. No other precursors were identified. In a comparison of the p53 signature-positive and negative groups, parous women and pregnant women were significantly fewer in the p53 signature-positive group (53% vs. 86%, p=0.002, 10% vs. 47%, p=0.001, respectively). Current pregnancy was also associated with a significantly lower incidence of the p53 signature after multivariate adjustment (odds ratio [OR]=0.112; 95% confidence interval [95% CI]=0.017-0.731; p=0.022). Among gynecological patients, parous women were fewer in the p53 signature-positive group on univariate (47% vs. 73%, p=0.047) and multivariate analysis (OR=0.252; 95% CI=0.069-0.911; p=0.036). No other characteristics were associated with p53 signature positivity., Conclusions: The incidence of the p53 signature was significantly lower in parous women and pregnant women. This decreased incidence of early phase serous carcinogenesis may be one of the possible mechanisms underlying HGSOC risk reduction among parous women., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objective: In patients with recurrent ovarian cancer (ROC) in whom surgery is likely to render them disease-free, it is unclear whether secondary cytoreductive surgery (SCS) combined with chemotherapy is superior to chemotherapy alone. The aim of this study was to evaluate the 2 treatment options in Tian-model low-risk patients., Methods: We retrospectively reviewed 118 ROC cases treated in our hospital between 2004 and 2016. Of these, 52 platinum-sensitive cases were classified as low-risk (complete resection anticipated) using the Tian model. Prognostic factors were assessed with univariate and multivariate analysis using Cox's regression model. Progression-free survival (PFS) and overall survival (OS) were compared in patients treated with SCS plus chemotherapy (SCS group) and those treated with chemotherapy alone (chemotherapy group), using a propensity-score-based matching method., Results: By multivariate analysis, the only factor associated with better OS was SCS. PFS and OS were significantly longer in the SCS group compared to the chemotherapy group in the matched cohort (median PFS: 21.7 vs. 15.1 months, p=0.027 and median OS: 91.4 vs. 33.4 months, p=0.008, respectively). In cases with multiple-site recurrence, the SCS group also showed significantly longer OS than the chemotherapy group (median 91.4 vs. 34.8 months, p=0.022). In almost all SCS cases, cooperation was required from other departments, and operation time was lengthy (median 323 minutes); however, no serious complications occurred., Conclusion: SCS combined with chemotherapy results in better PFS and OS than chemotherapy alone in first platinum-sensitive ROC patients categorized as low-risk by Tian's model., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Background: To assess late toxicity, quality of life and oncological outcome after consolidative whole abdominal radiotherapy (WART) following cytoreductive surgery and carboplatin/paclitaxel chemotherapy in high risk patients with advanced ovarian cancer FIGO stage III using IMRT (Intensity modulated radiation therapy)., Methods: The OVAR-IMRT-02 study is a multi-center single-arm phase-II-trial. Twenty patients with optimally debulked ovarian cancer stage FIGO III with complete remission after chemotherapy were treated with intensity modulated WART. A total dose of 30 Gy in 20 fractions was applied to the entire peritoneal cavity. Primary endpoint was treatment tolerability; secondary objectives were acute and chronic toxicities, quality of life, rates of therapy disruption/abortion, progression-free survival (PFS) and overall survival (OS)., Results: All patients completed treatment and 10/20 patients (50%) reached the final study follow-up of 36 months. Late side effects consisted of °1-°2 lower limb edema (44.5%), with one patient (5.6%) showing °3 edema. Three patients (16.7%) showed elevated gamma-Glutamyltransferase. There were no severe late side effects regarding renal or hepatic function or any gastrointestinal toxicity greater than °2. During WART, mean global health status decreased by 18.1 points (95%-CI: 7.1-29.0), but completely normalized after 6 months. The same trend was observed for the function scale scores. Kaplan-Meier-estimated 1-, 2- and 3-year PFS was 74, 51 and 40%, respectively. 1-, 2- and 3-year OS was 89, 83 and 83%, respectively., Conclusions: Intensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute and late toxicity and minor impact on long-term quality of life. Together with the promising results for PFS and OS, intensity modulated WART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer., Trial Registration: The study is registered with ClinicalTrials.gov ( NCT01180504 ). Registered 12 August 2010 - retrospectively registered.

Most high-grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal-type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal-type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi-lineage differentiation and can form glands with tubal-type epithelium. We used double transgenic Ovgp1-iCreER T2 ;R26R LSL-eYFP mice, which express an eYFP reporter protein in OVGP1-positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post-TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM-treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post-TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM-treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre-pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease., Objective: To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes., Study Design: Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated., Results: Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001)., Conclusion: Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Papillomas of the fallopian tube are exceedingly rare benign tumors, and only very few cases have been reported in the literature. Clinically, they may present as a mass lesion or occur without symptoms. Histomorphologically, they are papillary tumors covered by nonatypical epithelium with occasional ciliated or goblet cells growing in the lumen, and they are most frequently located in the infundibular region of the fallopian tube. They require a number of differential diagnostic evaluations and can be mistaken for either other benign tumors or malignant neoplasms. Because of their rare occurrence, molecular data about this entity have been lacking so far. Herein, a case of a papilloma with a BRAF (c.1799T>A) mutation (V600E) in a 45-yr-old woman with tumor-like dilation of the fallopian tube is presented.

Background/aim: We aimed to demonstrate the use of next-generation sequencing (NGS) to confirm the presence of tumor protein 53 (TP53) mutations in tubo-ovarian and peritoneal high-grade serous carcinoma (HGSC) with a wild-type p53 immunostaining pattern and investigate whether the TP53 mutational status is altered by chemotherapy., Materials and Methods: A commercial NGS panel comprising 171 genes was used to analyze the genetic profiles of 15 HGSC samples. Paired specimens obtained before and after chemotherapy were available for four patients., Results: All examined samples exhibited TP53 mutations. For all the patients who underwent neoadjuvant or postoperative adjuvant chemotherapy, TP53 mutations identified in samples obtained after chemotherapy were the same as those detected in pre-chemotherapeutic samples., Conclusion: HGSCs exhibit TP53 mutations even though a subset of HGSCs displayed a wild-type p53 immunostaining pattern. Chemotherapy does not affect the TP53 mutational status in HGSC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Serous tubal intraepithelial carcinoma (STIC) is found in 10% to 60% of cases of tuboovarian high-grade serous carcinoma (HGSC) and is presumed to be the site of origin, linking many HGSCs to the fallopian tube. Bilateral STIC is present in ∼20% of cases. Because clonal Tp53 mutations are a defining feature of HGSC, including their associated STICs, we analyzed 4 cases of bilateral serous tubal intraepithelial neoplasia (STIN), including STIC and Tp53-mutated serous tubal intraepithelial lesions (STILs), associated with HGSC to determine whether they contained the same or different p53 mutations. Extracted DNA from STINs, concurrent HGSCs and control tissues was analyzed for mutations in all exons of Tp53. Sequencing was successful in 3 of the 4 cases, and an identical Tp53 mutation was detected in the HGSC and bilateral STINs in 2 of these 3 cases. One STIN was morphologically a STIL. These findings confirm that a subset of bilateral STINs share the same Tp53 mutation, implying that at least one of the STINs is an intraepithelial metastasis from either the contralateral STIN or HGSC. This study complements others addressing the multiple origins of STIN in the setting of existing HGSC. It further underscores the fact that potential overlap in biologic behavior between STILs and STICs as well as timing and direction of metastatic spread has yet to be resolved.

Objective: The aim of the study was to analyze the clinicopathologic features, the survival rate, and the prognostic factors of women with unexpected primary fallopian tube carcinoma diagnosed during gynecological operations., Materials and Methods: We reviewed medical records of patients with unexpected primary fallopian tube carcinoma at the Obstetrics and Gynecology Hospital of Fudan University between January 2004 to December 2017. The survival analysis was based on the Kaplan-Meier method, and the results were compared using the log-rank test. Cox regression analysis was used to determine factors affecting survival., Results: Sixty-seven patients with unexpected primary fallopian tube carcinoma were identified. The 5-year overall survival was 49.7%, the mean overall survival was 64 months [95% confidence interval (CI) 54-74], and the median overall survival was 59 months (95% CI 49-69). The mean follow-up time was 53.9 months (range 5-141 months). The most common clinical presentation was adnexal mass (38.8%), followed by vaginal bleeding (16.4%) and no specific symptom (13.4%). Cytoreductive surgery was performed initially in 57 (85.1%) patients. Residual disease was optimal in 56 (83.6%) patients and suboptimal in 11 (16.4%) patients. The histological subtype was predominantly the serous type (88.1%). 44 patients (65.7%) were diagnosed at Stage I/II postoperatively. 23 (34.3%) patients were in Stage III/IV. 51 patients (76.1%) had gone through laparoscopic surgery, 16 patients (23.9%) were performed laparotomy. Univariate analyses on overall survival revealed that only the International Federation of Gynecology and Obstetrics (FIGO)stage [p < 0.001; Hazard Ratio (HR), 6.433; 95% CI, 2.274-18.199], residual tumor (p = 0.014; HR, 4.957; 95% CI, 1.378-17.831) were significant prognostic factor. Pelvic lymphadenectomy did not show association with overall survival in our univariate or multivariate analyses. After an observation period of 70 months, we found an increased overall survival in the group of without lymphadenectomy., Conclusions: The diagnosis of primary fallopian tube carcinoma is rarely considered preoperatively. The early stage and optimal debulking surgery with residual tumor ≤1 cm are important independent factors to improve patients' prognosis. However, there were no statistically significant correlations between lymphadenectomy and prognosis. The value of lymph node sampling or dissection needs to be reconsidered., (Copyright © 2019. Published by Elsevier B.V.)

This case describes a 69-year-old woman, who presented with rapidly progressive cerebellar symptoms and unintentional weight loss. Full neurological assessment excluded space-occupying lesions, vascular accidents and infection. Surprisingly, a chest, abdomen and pelvis CT showed a left hemipelvis mass, which was subsequently biopsied. A high-grade serous carcinoma of tubo-ovarian origin was found, diagnosing paraneoplastic cerebellar degeneration (PCD) secondary to this. The exact mechanism is not known, but is thought to be immune-mediated. In cases of PCD, after cancer treatment, the neurological disability stabilises to a severe level and will unfortunately be lifelong. Our patient continues to make great progress with intensive rehabilitation for her ongoing balance issues. Early recognition of PCD can lead to a prompt diagnosis of the underlying malignancy and hence subsequent management. This can at least limit the extent of the neurological disability of the disease and increase the survival rate from cancer., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ovarian carcinomas sometimes grow in the pelvic cavity, adhering firmly to the pelvic sidewall. These cases are often considered as inoperable or result in the incomplete resection because the tumors are not mobile. We performed en bloc resection of the tumors along with the entire internal iliac vessel system to achieve complete resection., Methods: Twenty of 237 consecutive patients with FIGO stage II-IV ovarian, fallopian tubal, or primary peritoneal carcinoma who underwent cytoreductive surgery at Chiba University Hospital between January 2008 and December 2016 had locally advanced tumors adhered firmly to the pelvic sidewall. We performed isolation of the tumors from the pelvic sidewall using the following procedure: the trunk of internal iliac vessels, the obturator vessels, the inferior gluteal and internal pudendal vessels were isolated and divided. The tumor together with the entire internal iliac vessel system was isolated from the sacral nerve plexus and piriform muscle. We examined the surgical outcomes, perioperative complications, and prognosis for the patients who underwent this procedure., Results: All patients successfully underwent complete resection, resulting in no gross residual disease in the pelvic cavity. There was no mortality within 90 days postoperatively. Two patients had Grade IIIb complications, comprising wound dehiscence and vesicovaginal fistula. Recurrence occurred in nine of the patients. However, no recurrence was observed in the pelvic sidewall. The median progression-free survival was 43 months., Conclusions: Removal of the entire internal iliac vessel system is feasible for the complete resection of locally advanced ovarian carcinomas adhered firmly to the pelvic sidewall.

Objective: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT., Methods: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS)., Results: 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027)., Conclusions: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.

Background . Ovarian carcinosarcomas are rare aggressive biphasic tumors. Evidence suggests that these tumors are monoclonal and that the sarcoma component is derived from a stem cell undergoing divergent differentiation. Currently, there remains a paucity of data regarding its origin, with few reports suggesting an association with serous tubal intraepithelial carcinoma (STIC) by immunohistochemistry and genetics. Objective . We sought to determine the relationship of carcinosarcoma to high-grade serous carcinoma and STIC by investigating for similar mutation signatures through next-generation sequencing. Methodology. A case of carcinosarcoma with associated high-grade serous carcinoma and STIC was macrodissected, and next-generation sequencing was performed on each component separately. Results. The STIC, high-grade serous carcinoma component, and chondrosarcoma component were all diffusely positive for p53 and p16 by immunohistochemistry. Next-generation sequencing demonstrated an identical TP53 gene c.376-1G>A 5' splice site pathogenic mutation in all 3 components. Conclusions . Our findings suggest that carcinosarcomas may also originate from the fallopian tube.

Ten-eleven translocation methylcytosine dioxygenase-1, TET1, takes part in active DNA demethylation. However, our understanding of DNA demethylation in cancer biology and its clinical significance remain limited. This study showed that TET1 expression correlated with poor survival in advanced-stage epithelial ovarian carcinoma (EOC), and with cell migration, anchorage-independent growth, cancer stemness, and tumorigenicity. In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), a currently accepted type II EOC precursor, and inversely correlated with TP53 mutations. Moreover, TET1 could demethylate the epigenome and activate multiple oncogenic pathways, including an immunomodulation network having casein kinase II subunit alpha (CK2α) as a hub. Patients with TET1 high CK2α high EOCs had the worst outcomes, and TET1-expressing EOCs were more sensitive to a CK2 inhibitor, both in vitro and in vivo. Our findings uncover the oncogenic and poor prognostic roles of TET1 in EOC and suggest an unexplored role of epigenetic reprogramming in early ovarian carcinogenesis. Moreover, the immunomodulator CK2α represents a promising new therapeutic target, warranting clinical trials of the tolerable CK2 inhibitor, CX4945, for precision medicine against EOC. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)