Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Perinatal Outcomes of Late Preterm Rupture of Membranes with or without Latency Antibiotics.

OBJECTIVE: This study aimed to examine whether the addition of latency antibiotics in late preterm rupture of membranes (ROM) decreases neonatal infection and increases latency. STUDY DESIGN: This retrospective two-center study was conducted at Holy Family Hospital (HFH) in Nazareth and Emek Medical Center (EMC) in Afula, on data collected between January 2017 and April 2023. HFH is the smaller institution. EMC and HFH implement similar policies regarding ROM at 340/7 to 366/7 weeks' gestation; the only difference is that a 10-day course of latency antibiotics is implemented at EMC. All women with ROM between 340/7 and 366/7 weeks' gestation who were admitted to one of the centers during the study period, and had a live fetus without major malformations, were included. The primary outcome was neonatal sepsis rate. Secondary outcomes included a composite of neonatal sepsis, mechanical ventilation ≥24 hours, and perinatal death. Additionally, gestational age at delivery and delivery mode were examined. RESULTS: Overall, 721 neonates were delivered during the study period: 534 at EMC (where latency antibiotics were administered) and 187 at HFH. The gestational age at ROM was similar (35.8 and 35.9 weeks, respectively, p = 0.14). Neonatal sepsis occurred in six (1.1%) neonates at EMC and one (0.5%) neonate at HFH (adjusted p = 0.71; OR: 1.69; 95% Confidence Interval [CI]: 0.11-27.14). The composite secondary outcome occurred in nine (1.7%) and three (1.6%) neonates at EMC and HFH, respectively (adjusted p = 0.71; OR: 0.73; 95% CI: 0.14-3.83). The gestational age at delivery was 36.1 and 36.2 weeks at EMC and HFH, respectively (mean difference: 5 h; adjusted p = 0.02). The cesarean delivery rate was 24.7% and 19.3% at EMC and HFH, respectively (adjusted p = 0.96). CONCLUSION: Latency antibiotics administered to women admitted with ROM between 340/7 and 366/7 weeks' gestation did not decrease the rate of neonatal sepsis. KEY POINTS: · Latency antibiotics in late preterm ROM does not decrease neonatal sepsis.. · Latency antibiotics in late preterm ROM does not prolong gestational age at delivery.. · Latency antibiotics in late preterm ROM does not affect the mode of delivery..

Raynaud's phenomenon as a presenting manifestation of ovarian cancer: A case report.

Raynaud's phenomenon (RP) is characterized by episodes of vasospasm affecting the hands and feet. Paraneoplastic RP, as a single presenting symptom is rarely seen in cases of ovarian cancer (OC), and thus may lead to misdiagnosis. We present a case of paraneoplastic RP in a patient with high-grade serous OC. A 66-year-old female presented with dyspnea and bilateral peripheral cyanosis involving her fingers. CA125 was elevated (423 U/mL). CT revealed a pleural effusion on the left side, suspicious omental lesions and ascites. Omental biopsy and pleural cytology demonstrated high-grade serous OC. Neoadjuvant chemotherapy (carboplatin/paclitaxel) resulted in objective improvement in finger ischemia and complete regression of vasospastic features. However, the patient's disease was refractory to post-surgical treatment and eventually she deceased of multiple organ failure. To conclude, RP may be a presenting symptom of OC. It is important to determine the underlying disease and develop an effective treatment strategy.

Evaluation of Microscopic Changes in Fallopian Tubes of BRCA Mutation Carriers by Morphometric Analysis of Histologic Slides: A Preliminary Pilot Study.

Mutations in BRCA genes increase the risk of ovarian cancer, yet no method for early diagnosis is available. Some serous ovarian tumors are hypothesized to stem from cells of the fallopian tube fimbria. Using a novel method of computerized morphometry of the fimbrial epithelium, this study aimed to detect morphologic differences in noncancerous fimbriae between BRCA mutation carriers and noncarriers, and between healthy and serous ovarian cancer patients. Twenty-four fimbriae from healthy women (13 BRCA+, 11 BRCA-) and 21 fimbriae from women with serous ovarian cancer (10 BRCA+, 11 BRCA-), all reported as "normal" by hematoxylin and eosin examination, were subjected to computerized histomorphometric analysis. A Fast Fourier Transformation was applied to images of fimbrial epithelium and the Fast Fourier Transformation 2-dimensional frequency maps were subsequently quantified for nuclear orientation and planar distribution by a cooccurrence matrix analysis. Additional analysis of nuclear contour was applied to the fimbriae of the healthy women. Among the healthy women, significant differences were found in morphometric characteristics between the BRCA mutation carriers and noncarriers. Among the women with ovarian cancer, no significant differences were found between BRCA mutation carriers and noncarriers. Between healthy women and those with ovarian cancer, significant differences were detected, regardless of BRCA mutational status. A novel method, which combined Fast Fourier Transformation with cooccurrence matrix analysis, demonstrated differences in morphometric characteristics in the fimbriae between healthy and ovarian cancer patients, and between BRCA mutation carriers and noncarriers. The clinical significance of these observations should be investigated.

Minimizing pain medication use and its associated costs following robotic surgery.

INTRODUCTION: Minimally invasive surgery (MIS) has been associated with diminished postoperative pain and analgesia requirements. The objective of the current study was to evaluate the use of analgesia in the post-operative period following robotic surgery for endometrial cancer. METHODS: All consecutive patients who underwent robotic surgery for the treatment of endometrial cancer were included in this study. The timing, dose, and type of analgesics administered postoperatively were recorded from patients' electronic medical record. Data was compared to a matched historical cohort of patients who underwent laparotomy before the introduction of the robotic program. RESULTS: Only eight patients (2.4%, 5 during the first 25 cases and 3 following mini-laparotomy) received patient-controlled analgesia (PCA) following robotic surgery. Most patients' pain was alleviated by over-the-counter analgesics (acetaminophen, non-steroidal anti-inflammatories). In comparison to laparotomy, patients who underwent robotic surgery required significantly less opioids (71mg vs. 12mg IV morphine, p<0.0001) and non-opioids (4810mg vs. 2151mg acetaminophen, 1892 vs. 377mg ibuprofen, and 1470mg vs. 393mg naproxen; all p<0.0001). CONCLUSION: Patients require less analgesics (opioids and non-opioids) following robotic surgery in comparison to conventional laparotomy, including the elderly and the obese. The diminished pain medication use is associated with some cost savings.

Pharmacological treatment of ectopic pregnancy: Accuracy, safety and cost-effectiveness of day 1-7 ß-hCG measurements.

OBJECTIVE: The aim of the present study was to compare accuracy, safety and cost-effectiveness of three ß-hCG measurements protocols, applied in managing ectopic pregnancies (EP) with methotrexate (MTX): (1) day 1 to 7 ß-hCG levels, (2) day 1 to 4 ß-hCG levels and (3) day 4 to 7 ß-hCG levels. METHODS: Cost-minimization analysis (CMA) based on a retrospective study of patients treated with single-dose MTX for EP, was evaluated at a single institution between January 2001 to May 2021. Successful MTX treatment was defined as no surgical intervention. We evaluated safety by analyzing cases of day 4 interventions and cases of inconsistency between the different protocols. Predicting accuracy was assessed by the area under the receiver operating characteristic (AUC) curve. RESULTS: A total of 229 patients with single dose MTX treatment were included. Overall, 184 (80.3%) patients were treated successfully with a single dose of MTX. For days 1 and 7 the optimal cutoff point was 7% reduction in ß-hCG levels with sensitivity, specificity and PPV of 76.6% (69.9-82.5, 95% CI), 75.5% (60.5-87.1, 95% CI) and 92.8% (88.4-95.6, 95% CI), respectively. There was no significant difference between the protocols' AUC. None of the patients had any change of management during their day 4 visit in our 20 years of records. The cost for each visit day (day 4 and 7) was calculated with a total cost of 251 USD per patient. CONCLUSION: Patients treated with MTX for EP, measurement of day 1 and day 7 ß-hCG serum levels has a cost minimization advantage and is not inferior to the traditional protocol for predictive accuracy and safety.

Fourier transformation based texture analysis for differentiating between hyperplastic polyps and sessile serrated adenomas.

Colorectal cancer (CRC) is the third most common type of cancer. One major pathway involved in the development of CRC is the serrated pathway. Colorectal polyps can be divided in benign, like small hyperplastic polyps and premalignant polyps, like the sessile serrated adenomas (SSA) that has a significant potential of malignant transformation. The morphological similarity between these types of polyp, not-infrequently raises diagnostic difficulties. This study aimed to morphologically differentiate between hyperplastic polyps (HP) and SSAs by using automated computerized texture analysis of Fourier transformed histological images. Thirty images of HP and 58 images of SSA were analyzed by computerized texture analysis. A fast Fourier transformation was applied to the images. The Fourier frequency plots were further transformed into gray level co-occurrence matrices and four textural variables were extracted: entropy, correlation, contrast, and homogeneity. Our study is the first to combine this type of analysis for automated classification of colonic neoplasia. The results were analyzed using statistical and neural network (NNET) classification models. The predictive values of these classifiers were compared. The statistical regression algorithm presented a sensitivity of 95% to detect the SSA and a specificity of 80% to detect the HP. The NNET analysis was superior to the statistical analysis displaying a classification accuracy of 100%. The results of this study have confirmed the hypothesis that Fourier based texture image analysis is helpful in differentiating between HP and SSA. RESEARCH HIGHLIGHTS: Colorectal polyps can be divided in benign, like hyperplastic polyps (HP) and premalignant, like the sessile serrated adenomas (SSA). There is a high morphologic similarity between these two types of polyp that not-infrequently raises diagnostic difficulties. The results of our morphometric analysis that were used to build a neural network based model of prediction of the polyp types, have a great clinical importance of identifying SSA polyps which have significant potential of malignant progression as compared to HP.

Computerized morphometry analysis of epithelial fimbriae nuclear symmetry in BRCA carriers may identify patients at risk for developing ovarian cancer.

Serous ovarian tumors may originate in epithelial cells of the fallopian tubes. Computerized morphometry was able to find significant alterations in the fallopian tube epithelium of healthy BRCA carriers. The purpose of this study was to identify a subgroup of BRCA carriers that may be at risk of developing serous ovarian cancer by evaluation of the epithelial nuclear symmetry in the fallopian tubes. Four groups of patients were analyzed; healthy patients, ovarian cancer patients, BRCA carriers, and BRCA noncarriers. All fallopian tubes appeared normal by H&E examination. The ImageProPlus software was used to assess the nuclear symmetry of 65 fimbriae epithelium cells and an artificial neural network algorithm aided in detecting a subpopulation among fimbriae of healthy BRCA carriers at risk for ovarian cancer. Significant differences were found between healthy patients and ovarian cancer patients, and between BRCA carriers and noncarriers. The algorithm was able to accurately predict BRCA carriers with associated ovarian cancer based on fallopian tube nuclear symmetry characteristics. These results reinforce the hypothesis that fimbriae epithelial cells of BRCA carriers may undergo early-stage changes that could predict the risk of progression toward malignancy.

The impact of radiation therapy on vaginal biomechanical properties.

OBJECTIVE: In women with cervical cancer (CC), treatment with radiation causes changes in vaginal biomechanical properties, anatomy and function. The aims of the current study were to objectively assess effects of radiotherapy (RT) on vaginal elasticity, wall mobility and contraction strength; and to evaluate associations of these changes with sexual function. STUDY DESIGN: This prospective cohort study was approved by our Institutional Review Board. Between May 2018 and June 2020, women with CC who were candidates for RT were eligible to participate. Participants underwent vaginal tactile imaging (VTI) evaluation and were asked to fill the Female Sexual Function Index (FSFI) questionnaire at the time of first RT session and at a 6-month post-treatment follow up visit. Women who underwent radical hysterectomy, or had pelvic side-wall, pelvic or distant organ metastasis were not included. RESULTS: A total of 25 women with locally advanced CC were included in the final analysis. The mean age was 39 ± 2.7 years, the mean BMI was 24.8 ± 2.2 kg/m2 and the median parity was 2 (range: 1-5). Following RT, the mean scores for vaginal elasticity and vaginal tightening were significantly lower than at pre-treatment: 11.3 ± 2.5 vs. 28.3 ± 9, P < 0.0001 and 2.6 ± 0.7 vs. 16.7 ± 3, P < 0.0001, respectively. Following RT, significant decreases were demonstrated in vaginal wall mobility and pelvic muscle contraction strength: from 1.77 ± 0.34 to 0.36 ± 0.15, P < 0.0001 and from 2.55 ± 0.48 to 0.52 ± 0.23, P < 0.0001, respectively. Compared to pre-treatment, post-RT vaginal length was significantly shorter (3.30 ± 0.22 vs. 7.64 ± 0.63, P = 0.0023) and sexual intercourse frequency significantly lower: 1 (range 1-2) vs. 2 (range 1-4), P = 0.014). The mean total FSFI score was significantly lower following RT (6.7 ± 1 vs. 14.5 ± 2.7, P < 0.0001). CONCLUSIONS: Women with locally advanced CC who have been treated with RT exhibit persistent vaginal biomechanical changes that compromise sexual activity and result in considerable distress.

Checkpoint Inhibitors in Gynecological Malignancies: Are we There Yet?

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the field of oncology. For many cancer types, treatment paradigms have changed, as immunotherapy is increasingly being integrated into frontline standard-of-care treatments and producing meaningful and prolonged responses. This has inspired an avalanche of clinical trials studying ICIs in all types of malignancies, including gynecological cancers. Ovarian and endometrial cancers are characterized by DNA damage repair defects, either via disruption of the homologous recombination DNA repair mechanism in the former or via defects in the mismatch repair (MMR) pathway in the latter, which lead to a high load of neoantigens in both. Cervical cancer is dependent on the expression of human papillomavirus (HPV) proteins, which induce an immune response. Regardless, clinical trials testing ICIs in gynecological malignancies have initially led to disappointing results. Despite durable responses in some patients, overall response rates have been dismal. Nevertheless, in recent years, with the development of better predictive tumor biomarkers, such as microsatellite instability for endometrial cancer and programmed death ligand 1 for cervical cancer, ICIs have found their way into routine treatments for patients with advanced-stage disease. ICI-based combinations, although adding toxicity, have further improved response rates, and new combinations are currently being tested in clinical trials, as are other immunotherapy modalities, such as adoptive cell transfer and HPV-based vaccines. This review summarizes current clinical evidence supporting the use of immunotherapy in gynecological malignancies and describes studies in progress, with a focus on ICIs and predictive response biomarkers.

Can morphometric analysis of the fallopian tube fimbria predict the presence of uterine papillary serous carcinoma (UPSC)?

Uterine serous papillary carcinoma (UPSC) is an aggressive tumor, often diagnosed as a metastatic disease and characterized by a high recurrence rate and poor prognosis. UPSC represents a distinct subtype of endometrial cancer which is different in clinical and pathological behaviors from endometrioid endometrial carcinoma (EEC) and resembles more to serous ovarian carcinoma. Since tumors of serous papillary of the ovary are hypothesized to stem from cells of the fallopian tube's fimbria, we hypothesized that UPSC may also origin in the fallopian tubes. In our previous study, using a novel method of computerized morphometry of the fimbrial epithelium we have found significant differences between fimbriae of healthy women and serous ovarian cancer patients. In this study we showed the presence of morphologic differences between twenty-four fimbriae from healthy women, and twenty six fimbriae from uterus cancer (13 from UPSC patients and 13 from EEC patients). All fimbriae reported by the pathologist as "normal" were subjected to a computerized histomorphometric analysis. Two-step method of computerized histomorphometry, i.e. Fast Fourier transformation (FFT) followed by a co-occurrence matrix analysis and an additional analysis of the nuclear symmetry of the tubal fimbrial epithelium were applied. Using these novel methods, we were able to show differences in the morphometric characteristics of the fimbriae in UPSC patients compared to EEC and healthy patients. It is yet to be determined the clinical significance of this observation.

Recurrent ascites due to oral contraceptives and pregnancy.

BACKGROUND: Ascites during pregnancy is a rare disorder with wide differential diagnosis. CASE: We report on 8 years of follow-up of a patient suffering from recurrent episodes of ascites following oral contraceptive use and during both her pregnancies. Each ascitic event resulted in spontaneous recovery. CONCLUSION: The mechanism underlying our patient's fluid shift remains an enigma. We hypothesize that during her pregnancy and when oral contraceptives were administered, high levels of endogenous or exogenous sex hormones led to increased permeability and fluid displacement.

[Prenatal imaging of the Meckel-Gruber syndrome].

A 32 years old woman, gravida 2 para 1, presented at 27 + 5 weeks' gestation with a large fetal head for the gestational age, an occipital encephalocele and ventriculomegaly. Both fetal kidneys were large, echogenic and multicystic, but oligohydramnion was not observed. Post-axial polydactyly of the fetal feet was demonstrated. The Meckel-Gruber syndrome was diagnosed, but termination of pregnancy was declined. Three weeks later, the patient spontaneously delivered an 1890 grams live-born female. The newborn died 2 days later in the neonate intensive care unit.

IGF1R tyrosine kinase inhibitor enhances the cytotoxic effect of methyl jasmonate in endometrial cancer.

The present study evaluated the cytotoxic activity of methyl jasmonate (MJ) in endometrial cancer cells and examined the hypothesis that the apoptotic and anti-proliferative actions of MJ in these cell lines can be enhanced by co-targeting the insulin-like growth factor-1 receptor (IGF1R) signaling pathway. MJ had a potent pro-apoptotic effect and exhibited significant toxicity in all cell lines tested. MJ in combination with NVP-AEW541, a selective IGF1R tyrosine kinase inhibitor, had significantly increased cytotoxicity. MJ decreased IGF1R phosphorylation, however, it enhanced AKT phosphorylation and abolished the anti-apoptotic effect of IGF1. These findings suggest that combined IGF1R inhibitor and MJ administration may constitute an attractive modality for treating endometrial cancer.

PET/CT in gynecologic cancer: present applications and future prospects--a clinician's perspective.

This article briefly reviews the epidemiology, diagnosis, and treatment of the common gynecologic malignancies, with an emphasis on the shortcomings of current clinical practice. The persistent need to achieve early diagnosis, adjust proper treatment, enhance surveillance, and improve the outcome of these patients has led to the development of new diagnostic modalities. Novel tools such as 18F-fluorodeoxyglucose PET/CT should aim at enhancing the clinician's ability to make critical decisions in treating difficult scenarios.

PET/CT in Gynecologic Cancer: Present Applications and Future Prospects-A Clinician's Perspective.

This article briefly reviews the epidemiology, diagnosis, and treatment of the common gynecologic malignancies, with an emphasis on the shortcomings of current clinical practice. The persistent need to achieve early diagnosis, adjust proper treatment, enhance surveillance, and improve the outcome of these patients has led to the development of new diagnostic modalities. Novel tools such as 18F-fluorodeoxyglucose PET/CT should aim at enhancing the clinician's ability to make critical decisions in treating difficult scenarios.

Nomogram of maxillary bone length in normal pregnancies.

OBJECTIVE: The aim of this study was to define normal ultrasonographic growth of the fetal maxillary bone throughout pregnancy as a basis for further studies and as normative data for assessing deviations in growth. METHODS: A prospective cross-sectional study was performed. Consecutive routine biometric measurements and fetal organ scans were obtained from patients undergoing elective fetal anatomic surveys. Special attention was paid to the profile view of the fetal face, and the maxillary bone was identified and measured. RESULTS: Three hundred twenty-seven fetuses between 13 and 40 weeks' gestation were scanned. The maxillary bone is seen as a rodlike structure; it is a part of the facial skeleton that allows the opening and closing of the pharynx. A linear growth function was observed across gestational age (GA), and first-degree correlation was found to exist between GA and the maxillary bone (r = .645; P < .0001; y = 7.78 + 0.18 x GA). Significant correlation was also found between the maxillary bone and biparietal diameter (BPD) (r = 0.652; P > .0001; y = 8.36 + 0.66 x BPD), head circumference (HC) (r = .645; P < .0001; y = 8.39 + 0.18 x HC), femoral bone length (FBL) (r = .640; P < .0001; y = 9.28 + 0.7 x FBL), and abdominal circumference (AC) (r = .640; P < .0001; y = 8.91 + 0.17 x AC). CONCLUSIONS: Normative data for ultrasonographic measurements of the fetal maxillary bone throughout pregnancy are provided. These data potentially allow the prenatal diagnosis of abnormal maxillary bone length.