Acceptability of self-collected vaginal samples for human papillomavirus testing for primary cervical cancer screening: comparison of face-to-face and online recruitment modes.

BACKGROUND: This study aimed to assess the acceptability and attitudes of women towards human papillomavirus (HPV) self-sampling and compare the effectiveness of two delivery modes utilising face-to-face and online website for cervical cancer screening in Hong Kong. METHODS: Women aged 30-65 years were invited to participate by distributing the study information pamphlets at the specialist clinics of a regional acute hospital. Those who were interested in participating were given the option to join directly face-to-face or through an online website. All participants provided informed consent and received self-sampling kits and acceptability questionnaires either immediately (face-to-face) or through the post after registering at the website (online). All participants were requested to collect their own vaginal samples using a swab which was then brushed on a DNA sample storage card and returned to the hospital either in person or by post. The self-collected samples were tested for high-risk HPV using the Sentis™ HPV assay, a validated isothermal nucleic acid amplification real-time fluorescent detection assay. The primary outcome was the uptake rate of HPV self-sampling. RESULTS: Of the 1998 women recruited (1200 face-to-face, 798 online), 1377 returned their samples, giving an overall uptake rate of 68.9%. The uptake rate was significantly greater in the face-to-face mode than in the online mode (74.6% vs. 60.4%, p < 0.001). The median age of the participants was 49 years, 43.7% were never or under-screened, and 7.1% had high-risk HPV detected. Overall, 82.1% of the participants reported self-sampling convenient, and 79.3% were not embarrassed when collecting self-samples. However, only 49.8% were confident that they had collected the self-samples correctly. Most (91.1%) of the participants expressed willingness to perform self-sampling again, mostly because it was simple (79.2%) and quick (56.3%). CONCLUSIONS: HPV self-sampling can serve as an alternative primary screening method for cervical cancer in Hong Kong, especially for individuals who have not been adequately screened in the past. Both face-to-face and online website recruitment were associated with high acceptability, emphasising the potential benefits of utilising different platforms and strategies for reaching diverse populations.

Comparison of the multiples of the median of serum anti-müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case-control study.

INTRODUCTION: Chemotherapy is crucial in treating gestational trophoblastic neoplasia (GTN), but its impact on gonadotoxicity is unclear. MATERIALS AND METHODS: This case-control study included 57 GTN patients and 19 age-matched patients with molar pregnancies (MP) in 2012-2018. Multiples of the median (MoM) of the serum AMH levels were compared between the two groups, and between patients using single-agent and combination chemotherapy, at baseline, 6, 12, and 24 months after treatment. Their pregnancy outcomes were also compared. RESULTS: There was no significant difference in the MoM of serum AMH between GTN and MP groups at all time points. Single-agent chemotherapy did not adversely affect the MoM. However, those receiving combination chemotherapy had lower MoM than those receiving single-agent chemotherapy at all time points. The trend of decline from the baseline was marginally significant in patients with combination chemotherapy, but the drop was only significant at 12 months (Z = -2.69, p = 0.007) but not at 24 months (Z = -1.90; p = 0.058). Multivariable analysis revealed that combination chemotherapy did not affect the MoM. There was no significant difference in the 4-year pregnancy rate and the livebirth rate between the single-agent and combination groups who attempting pregnancy, but it took 1 year longer to achieve the first pregnancy in the combination group compared to the single-agent group (2.88 vs. 1.88 years). CONCLUSION: This study showed combination chemotherapy led to a decreasing trend of MoM of serum AMH especially at 12 months after treatment, but the drop became static at 24 months. Although pregnancy is achievable, thorough counseling is still needed in this group especially those wish to achieve pregnancy 1-2 years after treatment or with other risk factors.

Evaluation of an Isothermal Amplification HPV Assay on Self-Collected Vaginal Samples as Compared to Clinician-Collected Cervical Samples.

This study aimed to evaluate the concordance of HPV results between the SentisTM HPV assay (Sentis) (BGI Group, Shenzhen, China), an isothermal amplification-based HPV assay, on self-collected and clinician-collected samples and the agreement of Sentis on self-collected samples with the BD OnclarityTM HPV assay (Onclarity) (Becton, Dickinson, and Company, Franklin Lakes, New Jersey, USA), a PCR-based HPV assay, on clinician-collected samples. This was a prospective study of 104 women attending the colposcopy clinic for abnormal smears. After informed consent, participants self-collected vaginal samples before having clinician-collected cervical samples. Self-collected samples underwent HPV testing with Sentis (Self-Sentis HPV) and clinician-collected samples were tested with Sentis (Clinician-Sentis HPV) and Onclarity (Clinician-Onclarity), which was used as a reference standard. The concordance was assessed using Cohen's kappa. The prevalence of HPV and the acceptability of self-sampling were also evaluated. The concordance rate between Self-Sentis HPV and Clinician-Sentis HPV was 89.8% with a kappa of 0.769. The concordance rate between Self-Sentis HPV and Clinician-Onclarity was 84.4% with a kappa of 0.643. The prevalence of HPV was 26.0% on Clinician-Onclarity, 29.3% on Clinician-Sentis HPV, and 35.6% on Self-Sentis HPV. Overall, 65% of participants would undergo self-sampling again. This was attributed to mainly not feeling embarrassed (68%) and being convenient (58%). Our study showed a substantial agreement between Self-Sentis HPV with Clinician-Sentis HPV and Clinician-Onclarity. Self-sampling was also shown to be a generally well-accepted method of screening.

The Value of Four-Quadrant Cervical Biopsy in Women with Different Colposcopic Impressions.

The aim of this study was to compare the diagnostic efficacy of colposcopic-directed biopsy and four-quadrant biopsy in detecting high-grade cervical intra-epithelial neoplasia (CIN). Women attending three women's clinics for routine cervical screening were recruited. Colposcopy was arranged for women with any cytologic abnormalities greater than atypical squamous cells of undetermined significance (ASCUS), two consecutive ASCUS results or positive HPV testing. During colposcopy, a cervical biopsy was taken from the most suspicious area, but more than one biopsy was allowed. Four-quadrant biopsies at 3, 6, 9 and 12 o'clock and an endocervical curettage were also taken in all cases. A total of 1522 colposcopies were performed in 1311 subjects from June 2010 to August 2017, with 118 cases of high-grade CIN diagnosed. Colposcopic-directed biopsy detected 50.8% of the 118 high-grade CIN, while four-quadrant biopsy detected 86.4% (p < 0.0001). Twenty-seven cases (22.9%) of high-grade CIN were diagnosed in women with normal or unsatisfactory colposcopy. Among the 64 cases with low-grade colposcopic impression, four-quadrant biopsy detected significantly more high-grade CIN (53 cases, 82.8%) than colposcopic-directed biopsy (35 cases, 56.3%) (p = 0.0011). Four-quadrant cervical biopsies should be considered for all women with an abnormal smear or positive HPV testing, especially in patients with low-grade/normal/unsatisfactory colposcopy.

Learning from mothers' success in breastfeeding maintenance: coping strategies and cues to action.

This study aimed to gain insight from mothers who were successful in breastfeeding maintenance to develop interventions for promoting breastfeeding maintenance. Following the phenomenological framework, this qualitative study recruited mothers who had maintained breastfeeding for at least 4 months for in-depth interviews. A total of 30 in-depth interviews were completed. We found that almost all participants had experienced an initial adjustment period. During this period, a social support network, personal perseverance in "trying" breastfeeding and "pumping," and adjusting expectations for breastfeeding to relieve themselves from the pressure of exclusive breastfeeding were important coping strategies. All participants then entered a stage of getting more attuned when breastfeeding was easier. During this period, seeking support from the online mother groups, deliberating medication that might affect breastfeeding, adjusting to accommodate breastfeeding and lives, and managing breastfeeding in public were the main strategies. For working mothers, despite workplace and employers' support, proactive adjustment for using the facilities and lactation breaks for breast milk expression was essential for breastfeeding continuation after returning to work. Throughout the whole journey, positive cues identified from their breastfeeding experiences that helped breastfeeding maintenance included enjoying breastfeeding, breastfeeding as a personal achievement, a healthy and thriving child, positive social feedback, bodily response, the convenience of breastfeeding, and breastfeeding as a motherhood commitment. To conclude, while mothers should be mentally prepared for the difficulties of breastfeeding, they should also be encouraged that things will always get easier as they persevere. Adjustments should be made to accommodate lives and other personal needs. Future studies should consider integrating relevant cues into existing psychosocial interventions for promoting breastfeeding maintenance.

Patient-Initiated Follow-Up in Ovarian Cancer.

This study aimed to assess the feasibility of patient-initiated follow-up (PIFU) in combination with regular tumour marker monitoring as an alternative to conventional hospital follow-up for ovarian cancer survivors. Women who had recently completed treatment for ovarian cancer and had a raised pre-treatment tumour marker were recruited. Participants were allocated to PIFU (intervention group) or conventional hospital follow-up (control group) according to their own preference. Both groups had regular tumour marker monitoring. The change in fear of cancer recurrence (FCR) score as measured by the FCR inventory, and the supportive care need (SCN) scores as measured by the SCN survey at baseline and at 6 months between PIFU and hospital follow-up were compared. Out of 64 participants, 37 (58%) opted for hospital follow-up and 27 (42%) opted for PIFU. During the 6-month study period, there was no significant difference in the change of FCR between the two groups (p = 0.35). There was a significant decrease in the sexuality unmet needs score in the intervention group from baseline to 6-month FU (mean difference -8.7, 95% confidence interval -16.1 to -1.4, p = 0.02). PIFU with tumour marker monitoring is a feasible follow-up approach in ovarian cancer survivorship care. FCR and SCN were comparable between PIFU and conventional hospital follow-up.

Outcome after loop electrosurgical excision procedure for cervical high-grade squamous intraepithelial lesion.

OBJECTIVE: The dilemma in treating cervical high-grade squamous intraepithelial lesion (HSIL) is how to achieve complete excision to minimize the risk of cervical cancer while sparing the anatomy of the cervix and its ability to function during pregnancy. The optimal management for positive margins after excisional treatment is still controversial. This study was conducted to determine the clinical and histologic predictors of residual/recurrent HSIL and assess the outcome of women with positive margin. MATERIALS AND METHODS: This retrospective cohort study included 386 women who had excisional treatment for HSIL during 1st January 2012 to 31st December 2015 in a university-affiliated hospital. RESULTS: Overall, 212 (54.9%) women had negative margins and 155 (40.2%) had positive margins. The cumulative rate of residual/recurrent HSIL at 2 and 5 years was 15.7% and 16.8% respectively in positive margins and 1.8% and 5.0% respectively in negative margins (p < 0.001). Of women who had residual/recurrent HSIL, significantly more women had positive margins compared to negative margins (74.1% vs 25.9%, p = 0.001). Positive margin was significantly associated with higher rate of subsequent abnormal cervical smear (48.2% vs 28.9%, p < 0.001), requiring further colposcopy (32.1% vs 14.4%, p < 0.001) and further treatment for SIL (7.5% vs 4.8%, p < 0.001) compared to negative margin. CONCLUSION: Most women (85%) with positive margin went without residual/recurrent HSIL, of which the option of close surveillance with cytology is reasonable. Repeat excision may be considered in selected women with positive margin, endocervical glandular involvement and those who are older or unable to comply with follow-up.

A patient with relapsed high-grade serous ovarian carcinoma with somatic RAD51C mutations treated with PARPi monotherapy: a case report.

We report our experience in the management of a relapsed ovarian cancer patient with somatic RAD51C mutation, treated with olaparib monotherapy. The patient was diagnosed with stage 4 high-grade serous ovarian carcinoma and was treated with neoadjuvant chemotherapy, cytoreductive surgery, and postoperative chemotherapy. After a second cancer recurrence, she underwent FoundationOne CDx testing following disease progression on multiple lines of chemotherapy. Based on the FoundationOne CDx results, olaparib monotherapy was started. After 13 months of therapy, all lesions responded to the treatment, and she achieved complete response as demonstrated by normalization of the levels of CA125 and positron emission tomography-computed tomography (PET-CT). We plan to continue olaparib monotherapy until disease progression.

Association between High Diffusion-Weighted Imaging-Derived Functional Tumor Burden of Peritoneal Carcinomatosis and Overall Survival in Patients with Advanced Ovarian Carcinoma.

OBJECTIVE: To investigate the association between functional tumor burden of peritoneal carcinomatosis (PC) derived from diffusion-weighted imaging (DWI) and overall survival in patients with advanced ovarian carcinoma (OC). MATERIALS AND METHODS: This prospective study was approved by the local research ethics committee, and informed consent was obtained. Fifty patients (mean age ± standard deviation, 57 ± 12 years) with stage III-IV OC scheduled for primary or interval debulking surgery (IDS) were recruited between June 2016 and December 2021. DWI (b values: 0, 400, and 800 s/mm²) was acquired with a 16-channel phased-array torso coil. The functional PC burden on DWI was derived based on K-means clustering to discard fat, air, and normal tissue. A score similar to the surgical peritoneal cancer index was assigned to each abdominopelvic region, with additional scores assigned to the involvement of critical sites, denoted as the functional peritoneal cancer index (fPCI). The apparent diffusion coefficient (ADC) of the largest lesion was calculated. Patients were dichotomized by immediate surgical outcome into high- and low-risk groups (with and without residual disease, respectively) with subsequent survival analysis using the Kaplan-Meier curve and log-rank test. Multivariable Cox proportional hazards regression was used to evaluate the association between DWI-derived results and overall survival. RESULTS: Fifteen (30.0%) patients underwent primary debulking surgery, and 35 (70.0%) patients received neoadjuvant chemotherapy followed by IDS. Complete tumor debulking was achieved in 32 patients. Patients with residual disease after debulking surgery had reduced overall survival (p = 0.043). The fPCI/ADC was negatively associated with overall survival when accounted for clinicopathological information with a hazard ratio of 1.254 for high fPCI/ADC (95% confidence interval, 1.007-1.560; p = 0.043). CONCLUSION: A high DWI-derived functional tumor burden was associated with decreased overall survival in patients with advanced OC.

First in-human trial and prospective case series of an articulated laparoscopic camera system in minimally invasive surgery in gynecology: an IDEAL stage 1 and 2a study.

Objectives: Precision Robotics' Sirius Robotic Flexible Endoscopic System is a new, fully integrated, compact three-dimensional laparoscopic camera system with a disposable single-use flexible tip that can change its viewing direction. This IDEAL Stage 1 and 2a study assessed its safety, reliability and potential efficacy particularly for single incision laparoscopic surgery and vaginal natural orifice transluminal endoscopic surgery. Design: Prospective single-institution, single-surgeon study. Setting: The study was conducted in a multispecialty hospital. Participants: Women aged 18-70 years scheduled for gynecological laparoscopic surgery were invited to participate. An information sheet and consent was available for the women and an informed consent was obtained. Thirteen participants completed this study. Interventions: The laparoscopic procedures were done in the usual manner. The only difference was the Sirius System was used in place of the conventional laparoscope. All other procedures and instruments remained the same. Main outcome measures: Primary outcome was the proportion of women who successfully completed the intended procedure using the Sirius System without conversion to another camera system, camera users and surgeon's view and experience, and iterations and modifications to the system. Secondary outcomes were the incidence of intraoperative and postoperative complications during the first 6 weeks following surgery, and duration of surgery. Results: 85% (11/13) of women had their procedure completed successfully using the Sirius System. Two women required immediate conversion to the conventional laparoscope due to technical issues. There were no intraoperative complications. Users agreed that the improved field of view was beneficial for laparoscopic surgery. Iterative improvements were made in the imaging quality, user interface and manufacturing quality. Conclusions: Sirius System has early indications for safety and efficacy for intermediate and major minimally invasive laparoscopic procedures in gynecology. Further studies are needed to confirm it can replace a conventional laparoscope in the surgical workflow. Trial registration number: NCT05048407.

Human Papillomavirus Self-Sampling for Primary Cervical Cancer Screening in Under-Screened Women in Hong Kong during the COVID-19 Pandemic.

The aim of this study was to assess the effectiveness of HPV self-sampling for cervical cancer screening and the best means of service delivery, with a specific focus on under-screened women, particularly during the COVID-19 pandemic. Using three arms of service delivery (social media, school outreach and underserved outreach), we recruited under-screened women aged 30-65 years from two population groups: the general public and specific underserved communities, from whom self-sampled specimens and optional clinician-sampled cervical specimens were obtained for HPV testing. A total of 521 self-sampling kits were distributed, of which 321 were returned, giving an overall uptake rate of 61.6%. The response rate was higher in the face-to-face underserved outreach (65.5%) compared to social media (22.8%) and school outreach (18.2%). The concordance for HPV detection between self-sampled and clinician-sampled specimens was 90.2% [95% confidence interval (CI) 85.1-93.8%; Cohen's kappa 0.59 (95% CI 0.42-0.75)]. Overall, 89.2% of women were willing to have self-sampling again. In conclusion, HPV self-sampling is an effective method for cervical cancer screening and can be considered as an option, particularly in women who are reluctant or unable to attend regular screening. Various service deliveries could be considered to increase participation in cervical cancer screening.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

Role of adjuvant and post-surgical treatment in gynaecological cancer.

Adjuvant and post-operative therapy aimed at reducing the risk of disease recurrence and improving potential for cure can be broadly categorised into systemic and locoregional treatment. For epithelial ovarian cancer, cytoreductive surgery and platinum-based chemotherapy is the mainstay management. Maintenance therapy with PARPi is a state-of-the-art option for women with advanced disease following complete or partial response to first-line platinum-based chemotherapy, particularly those with BRCA mutations. Adjuvant treatment for endometrial cancer depends mostly on FIGO staging and histopathological risk factors. For cervical cancer, adjuvant chemoradiation is indicated after surgery in women with close or positive resection margins and positive nodes. Generally, recommendations for adjuvant therapy should be individualised and reviewed at the multidisciplinary tumour board meeting, and the decision for adjuvant therapy should be balanced with treatment toxicity. The overview of the role of adjuvant and post-surgical treatment in gynaecological cancers will be discussed in this chapter.

Olaparib dose re-escalation in ovarian cancer patients who experienced severe and/or uncommon adverse events: A case series.

AIM: Few real-world studies have reported detailed management and dose adjustment strategies of adverse events (AEs) of ovarian cancer (OC) patients treated with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib. This case series aimed to describe olaparib AEs in Chinese OC patients in real-life settings and to explore dose modification strategies. METHODS: We conducted a detailed examination of the clinical records of OC patients who were treated with olaparib at the Gynecologic Oncology Unit in Hong Kong from September 2015 to December 2019, including baseline characteristics, treatment outcomes, AEs, and management strategies, particularly dose modifications. RESULTS: Nineteen patients were included, with a median olaparib treatment duration of 12 (range: 3-30) months. For recurrent platinum-sensitive cases (n = 16), the median progression-free survival was 16.0 months (95% confidence interval: 9.5-22.5). Eighteen (95%) patients experienced AE(s) of any grade, including four (21%) who experienced grade ≥3 AE(s). The most common AEs were as follows: nonhematologic fatigue (68%), nausea (42%), vomiting (26%), decreased appetite (26%), dyspepsia (21%), dizziness (21%), anemia (37%), neutropenia (26%), and thrombocytopenia (21%). Four specific cases involving anemia, lower limb lymphedema, myeloid neoplasm, and erythema nodosum are discussed separately. Eight patients required dose interruption or reduction due to AEs, of which five patients attempted and tolerated dose re-escalation. CONCLUSION: In this study, most AEs were mild, but rare AEs were observed. In OC patients, olaparib AE management with dose reductions followed by re-escalations was feasible, including for anemia.

Surgery including fertility-sparing treatment of GTD.

Gestational trophoblastic disease (GTD) consists of a spectrum of diseases, including hydatidiform moles, invasive mole, metastatic mole, choriocarcinoma, placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). GTD is a relatively uncommon disease occurring in women of reproductive age, with high cure rates. Primary treatment of hydatidiform moles includes uterine evacuation, followed by close monitoring of serial hCG levels to detect for post-molar gestational trophoblastic neoplasia (GTN). In patients with GTN, the main therapy consists of chemotherapy, although some surgical procedures are important in selected patients to achieve curing. Hysterectomy is the mainstay treatment for PSTT or ETT and may be considered in selected patients for management of hydatidiform mole and malignant GTN especially in chemoresistant disease. Resection of metastatic lesions such as in the lung or brain can be considered in selected patients with isolated chemoresistant tumour. Surgical treatment of GTD will be discussed in this chapter.

Tamoxifen use in recurrent ovarian cancer in a Chinese population: A 15 -year clinical experience in a tertiary referral center.

AIM: To review the clinical use and the effectiveness of tamoxifen in patients with advanced or recurrent ovarian cancer. METHODS: A retrospective review of clinical records was conducted in patients who received tamoxifen for the treatment of ovarian cancer between 2002 and 2016. We reviewed the clinical setting that it was given, duration of use, patients' tolerability, clinical benefit and progression-free survival. We also attempted to identify predictive markers for response. RESULTS: A total of 92 patients received tamoxifen during this 15-year period. The patients received a median of 2.5 lines of chemotherapy before switching to tamoxifen, and they remained on tamoxifen for a median of 5.6 months (range 0-85 months), with 24 patients receiving it for more than 12 months. Seventy-six patients continued on tamoxifen for more than 2 months. In this group, 75 patients had an evaluable response, either by CA 125 or clinically and clinical benefit rate (defined as complete, partial response and static disease) was seen in 42 patients (56%), with majority of patients having static disease. The median progression-free survival was 5.3 months (95% confidence interval, 2.6-8.1). Tamoxifen was well tolerated. Hormone receptor status was not demonstrated to predict response. CONCLUSION: Patients with advanced ovarian cancer who have failed previous lines of chemotherapy may achieve static disease with tamoxifen with minimal side effects. Tamoxifen may still have a role in the era of molecular target therapy.

Nurse-led follow-up in survivorship care of gynaecological malignancies-A randomised controlled trial.

OBJECTIVE: To assess clinical and psychosocial outcomes of nurse-led follow-up in survivorship care of gynaecological malignancies. METHODS: Women with endometrial or ovarian cancer who were attending regular post-treatment follow-up at a tertiary referral centre were randomised into two groups-group-1: telephone follow-up by nurses and group-2: gynaecologists-led clinic follow-up. Women in group-1 were asked about their symptoms and quality of life (QoL) by nurses. Women in group-2 were followed up by gynaecologists and underwent symptom reviews and physical examinations. All ovarian cancer patients in both groups also had CA125 measured. All recruited women completed a QoL questionnaire (EORTC QLQ-C30), HADS-anxiety questionnaire and symptom checklist. RESULTS: 385 women (215 with endometrial and 170 with ovarian cancer) were randomised. There was no significant difference in the detection of recurrence according to the two follow-up protocols. However, women in the nurse-led arm scored higher on emotional (p = 0.023) and cognitive functioning (p = 0.012). Those in the gynaecologist-led arm scored higher on the HADS-anxiety scale (p = 0.001) and were more likely to report symptoms. CONCLUSIONS: Our results demonstrate a preliminary non-inferiority of nurse-led follow-up, with improved psychological morbidity and QoL. Thus, nurse-led follow-up can be considered an effective substitute for hospital-based care.

PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5ß1 integrin and JNK/IL-8 signaling.

Ovarian cancer is the most lethal gynecological malignancies owing to the lack of definitive symptoms until development of widespread metastases. Identification of novel prognostic and therapeutic targets is therefore an urgent need to improve survival. Here, we demonstrated high expression of the mitochondrial gatekeeping enzyme, pyruvate dehydrogenase kinase 1 (PDK1), in both clinical samples and cell lines of ovarian cancer. PDK1 expression was significantly associated with metastasis, reduced chemosensitivity, and poor overall and disease-free survival, and further highlighted as an independent prognostic factor. Silencing of PDK1 retarded lactate production, ovarian cancer cell adhesion, migration, invasion, and angiogenesis, and consequently metastasis, concomitant with decreased α5ß1 integrin expression. Phospho-kinase array profiling and RNA sequencing analyses further revealed reduction of JNK activation and IL-8 expression in PDK1-depleted cells. Conversely, PDK1 overexpression promoted cell adhesion via modulation of α5ß1 integrins, along with cell migration, invasion, and angiogenesis through activation of JNK/IL-8 signaling. PDK1 depletion additionally hindered tumor growth and dissemination in nude mice in vivo. Importantly, PDK1 levels were upregulated upon treatment with conditioned medium from omental tissues, which in turn promoted metastasis. Our findings suggest that PDK1, which is regulated by the tumor microenvironment, controls lactate production and promotes ovarian cancer cell metastasis via modulation of α5ß1 integrin and JNK/IL-8 signaling. To our knowledge, this is the first report to demonstrate an association between PDK1 and survival in patients with ovarian cancer, supporting its efficacy as a valuable prognostic marker and therapeutic molecular target for the disease.

Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells.

Ovarian cancer is an intra-abdominal tumor in which the presence of ascites facilitates metastatic dissemination, and associated with poor prognosis. However, the significance of metabolic alterations in ovarian cancer cells in the ascites microenvironment remains unclear. Here we show ovarian cancer cells exhibited increased aggressiveness in ascites microenvironment via reprogramming of lipid metabolism. High lipid metabolic activities are found in ovarian cancer cells when cultured in the ascites microenvironment, indicating a metabolic shift from aerobic glycolysis to ß-oxidation and lipogenesis. The reduced AMP-activated protein kinase (AMPK) activity due to the feedback effect of high energy production led to the activation of its downstream signaling, which in turn, enhanced the cancer growth. The combined treatment of low toxic AMPK activators, the transforming growth factor beta-activated kinase 1 (TAK1) and fatty acid synthase (FASN) inhibitors synergistically impair oncogenic augmentation of ovarian cancer. Collectively, targeting lipid metabolism signaling axis impede ovarian cancer peritoneal metastases.

A Case Series of Five Patients With Pure or Mixed Gestational Epithelioid Trophoblastic Tumors and a Literature Review on Mixed Tumors.

OBJECTIVES: To review the clinicopathologic features of five patients with epithelioid trophoblastic tumor (ETT). METHODS: Characteristics of patients diagnosed with ETT in 2000 to 2012 were reviewed. RESULTS: Among 190 patients with gestational trophoblastic neoplasia (GTN), two had pure ETT and three had mixed ETT and choriocarcinoma. The median age was 32.5 years. All the patients had localized disease in the uterus. One patient with pure ETT had a recurrence in the ureter 6 years after the initial treatment. Another patient with pure ETT had two full-term deliveries after fertility-sparing surgery. The three patients with mixed tumors had chemotherapy for GTN before their diseases were completely treated by hysterectomy. At a median follow-up of 102 months, all patients survived. CONCLUSIONS: ETT is indolent. Recurrence can happen, but the risk factors are not clear. When patients with GTN fail to respond to chemotherapy, the possibility of mixed GTN should be considered.