Arrangement into layers and mechanobiology of multi-cell co-culture models of the uterine wall.

STUDY QUESTION: Can a co-culture of three cell types mimic the in vivo layers of the uterine wall? SUMMARY ANSWER: Three protocols tested for co-culture of endometrial epithelial cells (EEC), endometrial stromal cells (ESC), and myometrial smooth muscle cells (MSMC) led to formation of the distinct layers that are characteristic of the structure of the uterine wall in vivo. WHAT IS KNOWN ALREADY: We previously showed that a layer-by-layer co-culture of EEC and MSMC responded to peristaltic wall shear stresses (WSS) by increasing the polymerization of F-actin in both layers. Other studies showed that WSS induced significant cellular alterations in epithelial and endothelial cells. STUDY DESIGN, SIZE, DURATION: Human EEC and ESC cell lines and primary MSMC were co-cultured on a collagen-coated synthetic membrane in custom-designed wells. The co-culture model, created by seeding a mixture of all cells at once, was exposed to steady WSS of 0.5 dyne/cm2 for 10 and 30 min. PARTICIPANTS/MATERIALS, SETTING, METHODS: The co-culture of the three different cells was seeded either layer-by-layer or as a mixture of all cells at once. Validation of the models was by specific immunofluorescence staining and confocal microscopy. Alterations of the cytoskeletal F-actin in response to WSS were analyzed from the 2-dimensional confocal images through the Z-stacks following a previously published algorithm. MAIN RESULTS AND THE ROLE OF CHANCE: We generated three multi-cell in vitro models of the uterine wall with distinct layers of EEC, ESC, and MSMC that mimic the in vivo morphology. Exposure of the mixed seeding model to WSS induced increased polymerization of F-actin in all the three layers relative to the unexposed controls. Moreover, the increased polymerization of F-actin was higher (P-value < 0.05) when the length of exposure was increased from 10 to 30 min. Furthermore, the inner layers of ESC and MSMC, which are not in direct contact with the applied shearing fluid, also increased their F-actin polymerization. LARGE SCALE DATA: N/A. LIMITATIONS, RESONS FOR CAUTION: The mixed seeding co-culture model was exposed to steady WSS of one magnitude, whereas the uterus is a dynamic organ with intra-uterine peristaltic fluid motions that vary in vivo with different time-dependent magnitude. Further in vitro studies may explore the response to peristaltic WSS or other physical and/or hormonal perturbations that may mimic the spectrum of pathophysiological aspects. WIDER IMPLICATIONS OF THE FINDINGS: Numerous in vitro models were developed in order to mimic the human endometrium and endometrium-myometrium interface (EMI) region. The present co-culture models seem to be the first constructed from EEC, ESC, and MSMC on a collagen-coated synthetic membrane. These multi-cell in vitro models better represent the complex in vivo anatomy of the EMI region. The mixed seeding multi-cell in vitro model may easily be implemented in controlled studies of uterine function in reproduction and the pathogenesis of diseases. STUDY FINDING/COMPETING INTEREST(S): This study was supported in part by Tel Aviv University funds. All authors declare no conflict of interest.

Medical cannabis and its effect on oncological outcomes in patients with ovarian cancer treated with PARP inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. METHODS: The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. RESULTS: Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). CONCLUSION: Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Prognostic significance of delayed complete metabolic response on PET/CT after primary chemoradiation treatment of cervical cancer.

OBJECTIVE: To investigate the prognostic significance of near-complete metabolic response on initial follow-up PET/CT after primary chemoradiation treatment of cervical cancer. METHODS: Survival data were retrospectively compared between patients who had complete metabolic response on first follow-up PET/CT, 3 months after chemoradiation (group 1) with those who had near-complete metabolic response on first PET/CT and later showed complete metabolic response at subsequent PET/CT, 6 months or more after treatment (group 2). RESULTS: Of the 108 patients included in the final analysis, 74 (68.5%) showed complete metabolic response on initial PET/CT, 3 months after treatment, and 34 patients (31.5%) showed complete metabolic response on subsequent PET/CT, 6 months after treatment. Tumor characteristics were comparable between groups. Group 1 had higher percent of stage 1 (12% vs 0%) and lower percent of stage 4 disease (3% vs 14%) than those of group 2. Group 2 patients had significantly fewer cases of recurrences and deaths than group 1 patients (6% vs 26%, p=0.018; 0% vs 20%, p=0.003, respectively), with comparable 3-year survival rates (group 1, 90% vs group 2, 100%, p=0.31). Twelve patients had progressive disease on first follow-up PET/CT; these patients had significantly worse overall survival compared with all other patients (log-rank test, p<0.001). Younger age and delayed complete metabolic response were associated with lower chance of recurrence and death on univariate analysis. On multivariate analysis, delayed complete metabolic response remained significantly associated with no recurrence HR=0.14 (95% CI 0.25 to 0.84), p=0.031. CONCLUSIONS: Survival outcome of patients with cervical cancer who show residual 18F-fluorodeoxyglucose uptake on initial PET/CT after treatment, but reach complete metabolic response on follow-up PET/CT, is not inferior compared with survival of patients who show complete metabolic response on initial PET/CT 3 months after treatment. Watchful waiting with follow-up PET/CT seems a safe option for these patients.

Effect of BMI change on recurrence risk in patients with endometrial cancer.

OBJECTIVE: Our study aimed to explore the effect of body mass index (BMI) change on cancer recurrence risk during the routine surveillance of endometrial cancer patients. METHODS: Data on patients with endometrial adenocarcinoma that had a staging procedure and continued follow-up was retrospectively collected. We compared patients' BMI at time of surgery and during the last clinic follow-up. Univariate and multivariate analyses were performed to examine the effect of predictors on BMI change and the risk of recurrence. RESULTS: A total of 211 patients were included in the final analysis. The majority of patients had stage I disease (n=176, 89%) and endometrioid histology (n=178, 86%). Median follow-up time was 53.4 (standard deviation (SD) 40) months. The mean BMI was 30.4 kg/m2 (interquartile range (IQR) 25-34) at surgery compared with 30.9 kg/m2 (IQR 26-36) at last follow-up (p<0.001). The BMI increase was most pronounced in patients with endometroid histology that recurred, 31.6 (IQR 24-35) kg/m2 at surgery compared with 33.5 (IQR 27-36) kg/m2 at last follow-up (p=0.016). On multivariate analysis, age and BMI change were the only predictors that were significantly associated with the risk of recurrence (overall response (OR 1.07 (0.99-1.14), p=0.05, OR 1.37 (1.12-1.67), p=0.002, respectively). CONCLUSION: Patients with endometroid endometrial cancer that had an increase in BMI during follow-up were at an increased risk for cancer recurrence compared with patients that did not change or had a decrease in BMI.

Impact of COVID-19 Pandemic on Human Papillomavirus Vaccine Uptake in Israel.

OBJECTIVE: Isolation and school closure during the COVID-19 pandemic could decrease human papillomavirus (HPV) vaccination uptake and potentially increase future HPV-related morbidity among unvaccinated populations. The aim of our study was to investigate HPV vaccination rates in Israel during the pandemic. METHODS: The HPV vaccination rates were compared before and during the COVID-19 pandemic years (2020-2021). Data regarding HPV vaccination between 2015 and 2021 were extracted from the Israeli Ministry of Health online reports. Vaccination rates were compared with other childhood vaccines, given at similar ages. Israeli HPV vaccination rates were further compared with England and Australia, which have an established vaccination infrastructure. RESULTS: The average Israeli coverage of first-dose HPV vaccine was 60.2%, with significant variations from 2015 to 2021. During the pandemic years, first-dose vaccine coverage increased compared with the 3 previous years. The pandemic had also no apparent influence on other childhood vaccine uptake, even though adolescents in Israel missed many school days during this time. Average vaccine uptake in England and Australia was significantly higher than Israel ( p = .009); however, first-dose vaccination rates decreased considerably in England during 2020, to a nadir of 59%. The pandemic had little effect on HPV vaccination rates in Australia. CONCLUSIONS: Despite many school days missed, the COVID-19 pandemic did not result in a decrease in HPV vaccine uptake in Israel. The pandemic could prove a good opportunity to further educate the public regarding the importance of whole-population vaccination programs. Implementing catch-up vaccination programs may bridge "vaccination gaps" that may be caused by future pandemics.

Transmembrane Mucin Response in Conjunctival Epithelial Cells Exposed to Wall Shear Stresses.

Human conjunctival epithelium cells (HCEC) line the inner surface of the eyelid and cover the sclera and are continuously subjected to wall shear stresses (WSS). The effects of external forces on the conjunctival epithelium are not fully known. The conjunctival epithelium contains stratified squamous cells that synthesize the membrane-spanning mucins MUC1 and MUC16, which play important roles in protecting the ocular surface. Alterations in both gel-forming and membrane-tethered mucins occur in drying ocular surface diseases. The aim of this study was to explore the mechanobiological characteristics of transmembrane mucin secretion and cellular alterations of primary HCEC exposed to airflow-induced WSS perturbations. We exposed the HCEC to a steady WSS of 0.5 dyne/cm2 for durations of 15 and 30 min. Cytoskeletal alterations and MUC1 secretions were studied using immunohistochemically fluorescent staining with specific antibodies. We investigated for the first time an in vitro model of membrane-tethered mucin secretion by HCEC in response to WSS. The exposure of HCEC to WSS increased the polymerization of F-actin, altered the cytoskeletal shape and reduced the secretion of membrane-tethered MUC1.

The Effect of Cervical Conization on Women's' Sexual Function and Psychological Health, A Prospective Observational Study.

BACKGROUND: Diagnosis of cervical dysplasia and subsequent conization of the uterine cervix might affect women's' sexual health. AIM: To assess the effect of cervical conization on women's sexual function and psychological wellbeing. METHODS: Patients undergoing conization of the cervix were assessed before, and 6 months after conization. Assessment of sexual distress and function was done using the female sexual distress scale-revised (FSDS-r) and the female sexual function inventory (FSFI), respectively. Risk for anxiety and depression, was assessed using the Hospital Anxiety and Depression Scale (HADS). MAIN OUTCOME MEASURES: FSDS-r, FSFI and HADS scores before and after conization RESULTS: From October 2018 to March 2021, 55 patients undergoing cervical conization were recruited. No significant differences were found in FSDS-r scores before and after conization. An equal number of patients indicated having sexual distress (29 patients, 53%, before and after conization, P=1.0). No significant changes were noticed on any FSDS domains or the total FSDS score before and after conization, (26.8 vs. 26.0, p=0.461). The percent of patients that indicated an overall sexual dysfunction, increased from 49 percent before conization, to 59 percent after conization, P=0.388. A high percent of patients indicated signs of anxiety on the HADS questionnaire, both before and after conization (49% and 47%, respectively). The median anxiety and depression scores did not change after conization, p=1.0. CLINICAL IMPLICATIONS: A high percent of patients undergoing conization suffer from sexual distress, sexual dysfunction and general anxiety, both before and after conization. The conization procedure itself did not seem to effect questionnaire scores. STRENGTHS AND LIMITATIONS: This was a prospective cohort, with comprehensive assessment of female sexual and psychological wellbeing after conization. Not all subjects reported sexual intercourse prior to questionnaire completion. CONCLUSION: Gynecologists should be aware of the psychological and sexual effect of the diagnosis and treatment of cervical pre-cancerous lesions, patients should be counselled accordingly. Michaan N, Loboda N, Ochshorn I, et al., The Effect of Cervical Conization on Women's' Sexual Function and Psychological Health, A Prospective Observational Study. J Sex Med 2022;19:257-262.

Incidence of endometrial carcinoma in patients with endometrial intraepithelial neoplasia versus atypical endometrial polyp.

ObjectiveOur study's primary aim was to compare the incidence of endometrial carcinoma in patients with a presurgical diagnosis of endometrial intraepithelial neoplasia confined to the endometrium (EIN-E) versus endometrial intraepithelial neoplasia confined to a polyp (EIN-P). Our secondary aim was to examine the difference in pathological features, prognostic risk groups and sentinel lymph node involvement between the two groups. METHODS: We conducted a retrospective cohort study between January 2014 and December 2020 in a tertiary university-affiliated medical center. The study considered the characteristics of women who underwent hysterectomy with sentinel lymph node dissection for endometrial intraepithelial neoplasia (EIN). We compared EIN-E diagnosed by endometrial sampling via dilatation curettage or hysteroscopic curettage vs EIN-P. A multivariate logistic regression analysis was used to assess risk factors for endometrial cancer. RESULTS: Eighty-eight women were included in the study, of those, 50 were women with EIN-P (EIN-P group) and 38 were women with EIN following an endometrial biopsy (EIN-E group).The median age was 57.5 years (range; 52-68) in the EIN-P group as compared with 63 years (range; 53-71) in the EIN-E group (p=0.47). Eighty-nine percent of the women in the EIN-E group presented with abnormal uterine bleeding whereas 46% of the women in the EIN-P group were asymptomatic (p=0.001). Pathology results following hysterectomy revealed concurrent endometrial carcinoma in 26% of women in the EIN-P group compared with 47% of women in the EIN-E group (p=0.038). Multivariate analysis showed that endometrial cancer was significantly less common in the EIN-P group (overall response (OR)=0.3 95% confidence interval (CI)=0.1-0.9, p=0.03). Eighty-four percent of cancers were grade one in the EIN-P group compared with 50% in the EIN-E group (p=0.048). CONCLUSIONS: Concurrent endometrial cancer is less frequent with EIN-P than with EIN-E. The high incidence of endometrial carcinoma in both groups supports the current advice to perform hysterectomy for post-menopausal women. Our data does not support performing sentinel lymph node dissection for EIN-P that was completely resected. The benefit of sentinel lymph node dissection for women with pre-operative EIN-E is yet to be determined.

Recurrent Dysplasia After a Loop Electrosurgical Excision Procedure: Local Versus General Anesthesia.

OBJECTIVE: This study aimed to compare the rates of positive specimen margins and postconization recurrent dysplasia between loop electrosurgical excision procedures (LEEPs) performed under general anesthesia (GA) and LEEP under local anesthesia (LA). METHODS: This retrospective cohort study included all consecutive women who underwent LEEP between 2011 and 2019. Collected data included demographics, LEEP indication, cone dimensions, and margin involvement as well as recurrence rate. Women who had undergone previous conization, cold-knife conization, or those who were lost to follow-up during the first 2 years after the procedure were excluded. RESULTS: Overall, 71 women who underwent LEEP under GA and 75 women under LA were included. Demographic characteristics were similar between the groups, as were the rates of preceding abnormal cytology and high-grade dysplasia before conization. Although cone depth and volume were higher for LEEP specimens done under GA compared with LA, the rate of positive specimen margins was comparable both for the endocervical margin (16/71 [22.5%] vs 16/75 [21.3%], respectively; p = .861) and the ectocervical margin (14/71 [19.7%] vs 11/75 [14.7%], respectively; p = .418). During the first 2 years after conization, the rates of high-grade dysplasia (cervical intraepithelial neoplasia ≥ 2) in repeat biopsy and the need for repeat conization were also not significantly different between the GA and LA groups (4.2% vs 1.3%, p = .356; 7.0% vs 9.3%, p = .614, respectively). CONCLUSIONS: Anesthesia mode does not seem to affect the rate of positive LEEP margins and the need for repeat conization. Our study findings suggest that LA should be preferred instead of GA in LEEP.

Biomechanics of Early Life in the Female Reproductive Tract.

Early human life that starts at the onset of fertilization and ends with implantation of the embryo in the uterine wall is the foundation for a successful pregnancy. The different stages during this period require biomechanical mechanisms, which are mostly unknown due to difficulties to conduct in vivo studies in humans.

Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three-Weekly Schedule in First-Line Treatment of Ovarian Cancer.

BACKGROUND: Conventional first-line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5-6) with paclitaxel (175 mg/m2 ) every 3 weeks (PC-3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC-3W with a modified protocol of weekly paclitaxel 80 mg/m2 and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28-day cycle (i.e., with 1 week off-treatment [PC-W]). MATERIALS AND METHODS: Medical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity. RESULTS: PC-3W was administered to 402 patients (median age, 60.5 years) and PC-W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III-IV. Notwithstanding a higher proportion of residual disease and older patients in the PC-W group, median progression-free survival was 21.4 months and 13.2 months for PC-W and PC-3W, respectively; median overall survival was 75.2 and 54.0 months for PC-W and PC-3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC-W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC-W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia. CONCLUSION: PC-W is as active and better tolerated than the standard PC-3W regimen. PC-W may serve as an alternative option for elderly or frail patients. IMPLICATIONS FOR PRACTICE: Weekly scheduling of paclitaxel 80 mg/m2 and carboplatin AUC2, administered on days 1, 8, and 15 in a 28-day cycle (PC-W) for first-line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m2 ) every 3 weeks (PC-3W). It is possible that the weekly holiday on day 21 in the PC-W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC-3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.

Preimplantation genetic testing for BRCA gene mutation carriers: a cost effectiveness analysis.

BACKGROUND: Gynecologic oncologists should be aware of the option of conception through IVF/PGT-M for families with high BRCA related morbidity or mortality. Our objective was to investigate the cost-effectiveness of preimplantation genetic testing for selection and transfer of BRCA negative embryo in BRCA mutation carriers compared to natural conception. METHODS: Cost-effectiveness of two strategies, conception through IVF/PGT-M and BRCA negative embryo transfer versus natural conception with a 50% chance of BRCA positive newborn for BRCA mutation carriers was compared using a Markovian process decision analysis model. Costs of the two strategies were compared using quality adjusted life years (QALYs'). All costs were discounted at 3%. Incremental cost effectiveness ratio (ICER) compared to willingness to pay threshold was used for cost-effectiveness analysis. RESULTS: IVF/ PGT-M is cost-effective with an ICER of 150,219 new Israeli Shekels, per QALY gained (equivalent to 44,480 USD), at a 3% discount rate. CONCLUSIONS: IVF/ PGT-M and BRCA negative embryo transfer compared to natural conception among BRCA positive parents is cost effective and may be offered for selected couples with high BRCA mutation related morbidity or mortality. Our results could impact decisions regarding conception among BRCA positive couples and health care providers.

Cardiac Function and Hemodynamic Changes during Minimally Invasive Hysterectomy with Pneumoperitoneum and Steep Trendelenburg Position for Patients with Endometrial Cancer Who Are Obese.

STUDY OBJECTIVE: To assess the effect of carbon dioxide (CO2) pneumoperitoneum and steep Trendelenburg position on patients' cardiac function and hemodynamics during minimally invasive staging surgery for endometrial cancer. DESIGN: Single-center prospective longitudinal study. SETTING: University-affiliated tertiary hospital. PATIENTS: Patients with endometrial cancer undergoing minimally invasive surgery. INTERVENTIONS: After consent, the patients' hemodynamic parameters were assessed by the Non-Invasive Cardiac System (NI Medical, Petah Tikva, Israel) at 5 time points: before general anesthesia, after induction of general anesthesia, after CO2 insufflation of the peritoneum, after steep Trendelenburg position, and at the end of surgery. MEASUREMENTS AND MAIN RESULTS: Twenty-three women were recruited. The median age of the patients was 68 years (interquartile range [IQR] 62-75), with a median body mass index of 34.9 kg/m2 (IQR 31.2-39.5) and an American Society of Anesthesiologists score ≥2. The initial median mean arterial pressure was 108 mmHg (IQR 101-113), and the baseline median cardiac output was 7.2 L/min (IQR 5.6-8.7). The median mean arterial pressure significantly decreased by 18% after insufflation (p = .001), again after Trendelenburg position (p = .003), and did not fully recover at the end of surgery in comparison with the preanesthesia baseline (p = .001). The median stroke volume significantly decreased by 17% after insufflation compared with the baseline (p = .01) and then gradually recovered to the baseline levels by the end of surgery. The median cardiac power significantly decreased by 35% after insufflation (0.009), remained low during Trendelenburg position (p = .009), and recovered by the end of surgery to 18% below the baseline levels (p = .035). CONCLUSION: Significant hemodynamic changes occur during minimally invasive staging surgery for endometrial cancer. CO2 insufflation is accompanied by the most dramatic hemodynamic deterioration during surgery, and this does not get affected much with Trendelenburg. Knowledge of the hemodynamic values of women classified as high risk when using a noninvasive technique during surgery is obtainable and may assist both surgeon and anesthesiologist to ensure a safer procedure.

The effect of age at immigration on cervical cancer incidence: a population-based cohort study of 1 486 438 Israeli women.

OBJECTIVE: To clarify the effect of mass migration from a high-risk area (former Soviet Union) to a low-risk area (Israel) on cervical cancer incidence and mortality in Israel and the modifying effect of age at immigration. METHODS: All women who immigrated to Israel from the former Soviet Union between January 1, 1990 and December 31, 2000 (N=345 202) and all Jewish Israeli-born women who were 0-80 years old on January 1, 1990 (N=1 141 236) were included. Follow-up ended at December 31, 2010 or date of death or date of cervical cancer diagnosis, whatever occurred earlier. Crossing data from the computerized population registry of the Ministry of Interior, the Israel National Cancer Registry and the Central Bureau of Statistics, cervical cancer incidence and mortality and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI) were calculated. RESULTS: 1595 new cases (crude incidence rate 29.71: 100 000 person years) of cervical cancer were diagnosed in immigrants as compared with 6159 cases (crude incidence rate 27.21: 100 000 person years) diagnosed in Israel-born Jewish women. Immigration at an age older than 12 years was hazardous (aHR 1.27, 95% CI 1.19 to 1.35; P<0.001) while immigration at a younger age was protective (aHR 0.62, 95% CI 0.51 to 0.75; P<0.001) for cervical cancer incidence compared with native Israeli women. Cervical cancer mortality was also significantly higher in immigrants compared with Israel-born women with incidence density rates of 1.15 and 0.35 per 100 person years, respectively (P<0.0001). CONCLUSIONS: Factors related to the acquired causes of the disease at the country of origin are probably at the root of the low incidence of cervical cancer in Israel. Adult immigrants from the former Soviet Union should be managed as a high-risk group.

Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements.

Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti-carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined. In this study we describe novel and potentially genotoxic Que activities in suppressing non-homologous end joining and homologous recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA-PK, ATM and PI3K signalling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII-independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs. Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values.

[HORMONE REPLACEMENT THERAPY AFTER GYNECOLOGICAL MALIGNANCIES].

INTRODUCTION: Treatment of gynecological malignancies can cause an abrupt onset of menopausal symptoms along with associated long term morbidity. Hormone replacement therapy (HRT) is the most effective treatment to alleviate these symptoms but the safety of HRT among gynecologic oncology patients remains controversial. We conducted a review of the published literature on the risk of recurrent disease among gynecologic cancer patients using HRT. Our research revealed a shortage of prospective, randomized trials on this important subject. The current evidence, mainly cohort studies, did not find an increased risk of recurrence for endometrial cancer in women with early stage disease or increased risk for recurrent ovarian epithelial cancer among HRT users after oncological treatment. Vulvar cancer and most cases of cervical cancer are presumably hormone independent malignancies and the small number of published works did not find an increased risk of recurrence among HRT users. In summary, according to current literature, there is no clear contraindication to HRT among gynecological cancer patients. Treatment should be individualized and the lack of good evidence, along with the advantages and possible disadvantages of this treatment, should be discussed with patients.

Weekly carboplatin with paclitaxel compared to standard three-weekly treatment in advanced epithelial ovarian carcinoma--a retrospective study.

OBJECTIVE: To retrospectively compare primary treatment with weekly carboplatin/paclitaxel (PC-W) to the standard 3-weekly carboplatin/paclitaxel (PC-3 W) in women with advanced epithelial ovarian cancer, tubal carcinoma and primary peritoneal carcinoma. METHODS: Medical records were assessed for age, stage of disease, tumor histology and grade, BRCA mutation status, and platinum sensitivity. Patients were treated with either paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every three weeks (PC-3 W; 133 patients), or with weekly paclitaxel (80 mg/m(2)) and weekly carboplatin (AUC 2) on days 1, 8, and 15 every 28 days (PC-W; 267 patients). RESULTS: Patient baseline characteristics were similar in both groups. Median overall survival (OS) was similar for PC-W and PC-3 W (64.5 months vs. 61.5 months), but PC-W had longer median progression-free survival [PFS: 27.4 months (95% CI, 22.7-31.4) vs. 19.5 months (95% CI, 15.6-22.2) for PC-3 W, p = 0.0024] and a longer median platinum-free interval [PFI: 22.1 months (95% CI, 16.0-24.5) vs. 14.2 months (95% CI, 10.7-17.2) for PC-3 W, p = 0.0075]. PC-W showed a significantly higher response rate (86.4% vs. 77.9% for PC-3 W, p = 0.0435). Multivariate analysis including for age at diagnosis, stage of disease, optimal debulking, histology, BRCA status, pretreatment CA-125 and PFI revealed that the PC-W women had lower risk of death (HR = 0.587, 95% CI, 0.402-0.857, p = 0.0058), lower risk of disease progression (HR = 0.494, 95% CI, 0.359-0.680, p < 0.0001), higher 2- and 3-year survival rates, and decreased grade II hair loss, neuropathy and thrombocytopenia compared with the PC-3 W women. CONCLUSION: The PC-W protocol improved PFS and had a similar OS as PC-3W.

The combination of gemcitabine and carboplatin shows similar efficacy in the treatment of platinum-resistant and platinum-sensitive recurrent epithelial ovarian cancer patients.

The aim of this study was to evaluate progression-free survival, overall survival (OS), response rate (RR), and clinical benefit in recurrent ovarian cancer patients treated with gemcitabine and carboplatin and to compare the outcome among platinum-resistant and platinum-sensitive patients. A retrospective study using the medical records of patients diagnosed and treated for recurrent epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma with gemcitabine and carboplatin from 2005 through 2012 at the Tel Aviv Sourasky Medical Center. The treatment regimen was carboplatin (area under the curve=5) administered on day 1 and gemcitabine 850 mg/m administered on days 1 and 8 in a 21-day cycle. Seventy patients with a median age of 57 years (range: 38-86) were included in the study. Most patients (94.3%) were initially diagnosed with stage III-IV disease and 44.3% had platinum-sensitive disease. Median progression-free survival in platinum-sensitive patients was 6.3 months [95% confidence interval (CI): 4.3-8.3] and 6.3 months (95% CI: 4.6-7.9) in platinum-resistant patients. Median overall survival was 15.8 months (95% CI: 13.6-18.1) in the platinum-sensitive patients and 18.4 months (95% CI: 10.0-27.8) in the platinum-resistant patients. Platinum-sensitive patients had a RR of 43.2% and platinum-resistant patients had a RR of 39.1%. The clinical benefit was 70.5% in platinum-sensitive patients and 65.2% in platinum-resistant patients. Overall treatment had a favorable safety profile. Gemcitabine and carboplatin demonstrate moderate toxicity with similar efficacy in both platinum-sensitive and platinum-resistant epithelial ovarian cancer, suggesting reversal of platinum resistance by gemcitabine.

Cytoreduction surgery with hyperthermic intraperitoneal chemotherapy in recurrent ovarian cancer improves progression-free survival, especially in BRCA-positive patients- a case-control study.

BACKGROUND: Approximately 70% of women diagnosed with advanced-stage ovarian cancer experience disease recurrence. Survival data were compared between a group of recurrent epithelial ovarian cancer (rEOC) patients treated by cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) and a matched group of rEOC patients treated by systemic chemotherapy only (without surgery). Treatment outcome in relation to the patients' BRCA status was compared. METHODS: Twenty-seven rEOC patients treated by cytoreduction and HIPEC were selected from our database and matched (1:3) with 84 rEOC patients treated with chemotherapy only. Progression-free survival (PFS) and overall survival (OS) in the two groups were analyzed and compared. RESULTS: The estimated median PFS was 15 months in the HIPEC group and 6 months in the systemic chemotherapy group (P = 0.001). The median OS following HIPEC treatment has not been reached, since more than 70% of the women were alive at the time of analysis. The 5-year survival rate was significantly higher in the HIPEC treated patients compared to that of the controls (79% vs. 45%, P = 0.016). BRCA status did not affect PFS. CONCLUSIONS: HIPEC after surgical cytoreduction in patients with rEOC appears beneficial compared to systemic chemotherapy treatment alone. The benefit is even greater in BRCA mutation carriers.

Human Papilloma Virus Typing as a Triage Tool for Women with Postcoital Bleeding: A Retrospective Cohort Study.

Objective: To investigate the performance of human papilloma virus (HPV) typing as a triage tool in the management of patients with postcoital bleeding (PCB). Methods: All patients referred for colposcopy at a cervical pathology clinic of a nationwide health insurance organization, due to PCB and had a preceding high-risk HPV (hrHPV) test between 2018 and 2020, were retrospectively located. Demographic and pathologic data were collected from electronic medical files. Sensitivity, specificity, and negative and positive predictive value of hrHPV test according to final pathology were calculated. Results: Three hundred ninety patients referred for colposcopy due to PCB with a preceding hrHPV test were located. HrHPV-positive patients were significantly younger (33.7 ± 10 vs. 37.2 ± 9, p < 0.006) with a higher proportion of nulliparous, nonmarried, and smokers compared with hrHPV-negative patients (75% vs. 47%, p < 0.001; 75.4% vs. 45.1%, p < 0.001; and 24.6% vs. 12.8%, p < 0.028, respectively). No case of high-grade cervical intraepithelial neoplasia (CIN2/3) was identified among hrHPV-negative patients. The sensitivity and NPV of the hrHPV test for high-grade cervical lesions were both 100%, decreasing to 36% and 95%, respectively, for any cervical dysplasia (CIN1/CIN2/CIN3). Adding cytology to HPV typing had a negligible effect on test performance. At univariate analysis, age, HPV vaccine status, nulliparity, and positive HPV typing were independently associated with cervical dysplasia. At multivariate analysis, only positive HPV typing remained significantly associated with cervical dysplasia (hazard ratio 2.75, confidence interval 1.1-6.5, p = 0.023). Conclusion: A negative HPV test even in the presence of PCB may rule out cervical dysplasia with extremely high accuracy and may save unnecessary colposcopies.