Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome.

BACKGROUND: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. METHODS: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient's response to a variety of therapies in multiple cancer types without training on previous treatment response data. We study ENLIGHT in two translationally oriented scenarios: personalized oncology (PO), aimed at prioritizing treatments for a single patient, and clinical trial design (CTD), selecting the most likely responders in a patient cohort. FINDINGS: Evaluating ENLIGHT's performance on 21 blinded clinical trial datasets in the PO setting, we show that it can effectively predict a patient's treatment response across multiple therapies and cancer types. Its prediction accuracy is better than previously published transcriptomics-based signatures and is comparable with that of supervised predictors developed for specific indications and drugs. In combination with the interferon-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, ENLIGHT can potentially enhance clinical trial success for immunotherapies and other monoclonal antibodies by excluding non-responders while overall achieving more than 90% of the response rate attainable under an optimal exclusion strategy. CONCLUSIONS: ENLIGHT demonstrably enhances the ability to predict therapeutic response across multiple cancer types from the bulk tumor transcriptome. FUNDING: This research was supported in part by the Intramural Research Program, NIH and by the Israeli Innovation Authority.

Fibrolamellar carcinoma transcriptomic-based treatment prediction: complete response after nivolumab and ipilimumab.

Fibrolamellar carcinoma (FLC) is a rare cancer of the liver that most commonly affects children and young adults. There is no clear standard of care for the disease, whose response to treatment seems to be very different from that of hepatocellular carcinoma. We present a case of FLC in a patient in her mid 30s that recurred and persisted despite resection and multiple lines of treatment. Following transcriptomic analysis, a combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) led to complete remission, although common biomarkers for immune checkpoint blockade were all negative in this case. The patient is still in remission. Here, combined checkpoint blockade guided by novel transcriptomic analysis led to complete remission after failure of several lines of treatment.

Identification of drugs associated with reduced severity of COVID-19 - a case-control study in a large population.

Background: Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18 to 95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher's exact test. False discovery rate was used to adjust for multiple testing. Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI [0.058 to 0.458], p<0.001), ezetimibe (OR=0.488, 95% CI [0.377 to 0.622], p<0.001), rosuvastatin (OR=0.673, 95% CI [0.596 to 0.758], p<0.001), flecainide (OR=0.301, 95% CI [0.118 to 0.641], p<0.001), and vitamin D (OR=0.869, 95% CI [0.792 to 0.954], p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. Conclusions: Ubiquinone, ezetimibe, and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.

Fractional-Pixel CO2 Laser Treatment in Patients With Urodynamic Stress Urinary Incontinence: 1-Year Follow-Up.

BACKGROUND AND OBJECTIVES: Vaginal pixelated low power and long pulses (LPLP) CO2 laser has been suggested as an optional treatment for stress urinary incontinence (SUI) with many studies reporting short-term improvements. The objective of this study was to assess the 1-year subjective and objective efficacy of vaginal CO2 laser in women with urodynamic SUI. STUDY DESIGN/MATERIALS AND METHODS: This was a prospective multicenter study. Patients with confirmed urodynamic SUI graded as mild or moderate were included. We used three sessions of fractional pixelated CO2 laser for vaginal application and followed up the patients at 6 and 12 months. We used the following measures at follow-up: 1-hour pad test (ICS protocol), questionnaires including Pelvic Floor Distress Inventory 20 (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ), Patient Global Impression of Improvement (PGI-I), and a 3-day urinary diary. The urodynamic assessment was repeated at 6 months. RESULTS: Fifty-two patients with SUI had three laser treatments, of whom 48 completed a 6-month follow-up and 42 patients completed 12-month follow-up. No serious adverse events were recorded during the study period. A significant reduction on the 1-hour pad test was found from baseline (6.3 ± 1.6 g) to the 12-month follow-up (3.7 ± 1.4 g, P < 0.05) was found. PGI-I showed 75.0%, 61.9%, and 64.3% improvements at 3, 6, and 12 months, respectively. PFDI improved significantly and consistently from baseline until 12 months (37.2 ± 3.89 to 16.1 ± 3.7, P < 0.05). Similarly, PFIQ showed significant improvements from the first treatment up to 12 months. Urodynamic assessment at 6 months showed that 41.4% of patients had no stress incontinence. CONCLUSION: The vaginal CO2 laser was found to be effective for mild-to-moderate SUI over a follow-up period of 1 year, according to a variety of objective and subjective parameters. The wide range of parameters enables optimal patient consultation and subsequent treatment. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population.

BACKGROUND: Until COVID-19 drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Towards this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. METHODS: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18-95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher's exact test. False discovery rate was used to adjust for multiple testing. RESULTS: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI (0.058 to 0.458), p<0.001), ezetimibe (OR=0.488, 95% CI ((0.377 to 0.622)), p<0.001), rosuvastatin (OR=0.673, 95% CI (0.596 to 0.758), p<0.001), flecainide (OR=0.301, 95% CI (0.118 to 0.641), p<0.001), and vitamin D (OR=0.869, 95% CI (0.792 to 0.954), p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. CONCLUSIONS: Ubiquinone, ezetimibe and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. FUNDING: This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.

In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression.

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.

Assessment of a double freezing approach in the management of surplus embryos in IVF.

RESEARCH QUESTION: What pregnancy rates are achieved after transfer of cryopreserved double slow-frozen embryos in IVF cycles? Patients in whom surplus thawed cleaved embryos (day 2 or 3) were grown to the blastocyst stage, re-frozen and then re-thawed for transfer (double freezing) were included. DESIGN: Data were collected on all patients who had undergone the above procedure at the IVF unit of Assuta Ramat Hachayal Hospital, Tel Aviv, during a 7-year period. For each patient in the study group, the two-consecutive, matched-by-age patients treated with frozen-thawed single blastocyst transfer were selected to form a 2:1 ratio control group. All embryos were frozen using the slow freeze protocol. RESULTS: A total of 54 patients had 70 embryos that were re-frozen at the blastocyst stage. Twenty-eight of these blastocysts were thawed and 27 underwent transfer to 25 patients. A single embryo was transferred to 23 patients and two embryos were transferred to two patients. The survival rate of the second thawing was 96.4% (27/28). Clinical pregnancy rate was 16% (4/25) and implantation rate was 14.8% (4/27). In the study group, pregnancies were achieved in 22 out of the 25 patients using IVF treatment, indicating good receptivity of the uterus. In the control group, the implantation/pregnancy rates were significantly higher (44.2% [23/52]; P < 0.01). CONCLUSION: The transfer of twice slow-frozen and thawed embryos does not seem to be a beneficial approach in the planned management of cryopreserved surplus embryos owing to the low pregnancy rate achieved after transfer of the re-frozen blastocyst embryos.

The Impact of Sperm and Egg Donation on the Risk of Pregnancy Complications.

OBJECTIVE: The aim of this study was to evaluate obstetric outcomes in relation to the extent of donor sperm exposure with and without egg donation. MATERIALS AND METHODS: This is a retrospective cohort study in a single tertiary care center. All women with a singleton pregnancy who conceived following sperm donation (SD) were included. Obstetrics and neonatal outcomes for pregnancies following single SD were compared with pregnancies following repeat SD from the same donor. In a secondary analysis, we compared pregnancy outcomes among three modes of assisted reproductive technology (intrauterine insemination [IUI-SD], in vitro fertilization [IVF-SD], and IVF sperm + egg donation [IVF-SD + ED]). RESULTS: A total of 706 pregnant women met the inclusion criteria, 243 (34.4%) following the first SD and 463 (65.6%) following repeat donations. Compared with repeat SDs, single donation was not associated with higher rates of preterm delivery (12.8 vs. 12.7%, respectively, p = 0.99), preeclampsia (7.0 vs. 6.9%, p = 0.999), and intrauterine growth restriction (4.1 vs. 3.9%, p = 0.88). Pregnancies following IVF-SD + ED had increased risk for preeclampsia (adjusted odds ratio [AOR], 3.1; 95% confidence interval [CI], 1.5-6.6), preterm labor (AOR, 2.4; 95% CI, 1.1-5.4), and cesarean section (AOR, 2.1; 95% CI, 1.0-4.3) compared with IUI-SD and IVF-SD. CONCLUSION: The extent of donor sperm exposure did not correlate with obstetrics complications, but double gamete donation was associated with increased risk for preeclampsia, preterm labor, and cesarean section.

Ovarian reserve after uterine artery embolization in women with morbidly adherent placenta: A cohort study.

OBJECTIVE: To evaluate ovarian reserve in women after preservative cesarean delivery using uterine artery embolization due to morbidly adherent placenta. STUDY DESIGN: A historical cohort study including all women admitted to a single tertiary care center, with morbidly adherent placenta that had preservative cesarean delivery with bilateral uterine artery embolization. Inclusion criteria included gestational age >24 weeks, singleton pregnancy and placenta increta / percreta. Exclusion criteria included maternal age > 43 years old and cesarean hysterectomy. Control group included women attending the infertility clinic due to male factor or single women conceiving via sperm donation, matched by age. Blood samples were collected on day 2-5 of menstruations for hormonal profile and Anti Mullarian Hormone (AMH) levels. Primary outcome was ovarian reserve evaluated by the levels of AMH. RESULTS: 59 women underwent preservative cesarean delivery using uterine artery embolization during the study period. 21 women met inclusion criteria (33.9%) and were matched controls (n = 40). Circulating levels of E2 and FSH did not differ significantly between the two groups (p = 0.665, p = 0.396, respectively). AMH was lower in the study group (median 0.8 IQR 0.44-1.80) compared to the controls (median 2.08 IQR 1.68-3.71) (p = 0.001). This finding was consistent in linear multivariate regression analysis where the group of cesarean delivery using bilateral artery embolization due to placenta accrete was significantly predictive for the levels of AMH (B = -1.308, p = 0.012). CONCLUSION: Women post preservative cesarean delivery using uterine artery embolization due to placenta accrete have lower ovarian reserve compare to controls matched by age.

Quantitative assessment of physical activity in pregnant women with sonographic short cervix and the risk for preterm delivery: A prospective pilot study.

OBJECTIVE: Bed rest or activity restriction is a common obstetrical practice, despite a paucity of data to support its efficacy. The aim of this study was to determine whether physical activity, as assessed by a smart band activity tracker, is associated with preterm birth in pregnant women at high risk for preterm delivery. METHODS: This was a pilot prospective cohort study including pregnant women at high risk for preterm delivery between 24 and 32 weeks-of-gestation. Physical activity level was assessed by smart band activity. Patients with sonographic short cervical length (≤ 20 mm) were asked to wear the smart band activity tracker continuously for at least one week, including one weekend. Both physicians and patients were blinded to the data stored in the smart band activity tracker. No specific recommendations were given to participants as to the level or intensity of physical activity. The primary outcome was the rate of preterm birth (< 37 weeks-of-gestation). Secondary outcomes included the rate of delivery before 34 weeks of gestation and neonatal outcome. Parametric and nonparametric statistics were used for analysis. RESULTS: Study population included 49 pregnant women: 37 women (75.7%) delivered preterm and 12 (24.5%) delivered at or after 37 weeks-of-gestation. The median steps per day was significantly lower in patients who delivered preterm (3576, IQR: 2478-4775 vs. 4554, IQR: 3632-6337, p = 0.02). Regression analysis revealed that the median number of steps per day was independently inversely associated with preterm birth, after adjustment for maternal age, body mass index, gestational age at recruitment, cervical length, cervical dilatation and plurality. CONCLUSION: This pilot study represents the first quantitative assessment of the association between physical activity and preterm birth. The results of this pilot study do not support the efficacy of decreased physical activity in the prevention of preterm birth in patients with sonographic short cervical length.

Sonographic large fetal head circumference and risk of cesarean delivery.

BACKGROUND: Persistently high rates of cesarean deliveries are cause for concern for physicians, patients, and health systems. Prelabor assessment might be refined by identifying factors that help predict an individual patient's risk of cesarean delivery. Such factors may contribute to patient safety and satisfaction as well as health system planning and resource allocation. In an earlier study, neonatal head circumference was shown to be more strongly associated with delivery mode and other outcome measures than neonatal birthweight. OBJECTIVE: In the present study we aimed to evaluate the association of sonographically measured fetal head circumference measured within 1 week of delivery with delivery mode. STUDY DESIGN: This was a multicenter electronic medical record-based study of birth outcomes of primiparous women with term (37-42 weeks) singleton fetuses presenting for ultrasound with fetal biometry within 1 week of delivery. Fetal head circumference and estimated fetal weight were correlated with maternal background, obstetric, and neonatal outcome parameters. Elective cesarean deliveries were excluded. Multinomial regression analysis provided adjusted odds ratios for instrumental delivery and unplanned cesarean delivery when the fetal head circumference was ≥35 cm or estimated fetal weight ≥3900 g, while controlling for possible confounders. RESULTS: In all, 11,500 cases were collected; 906 elective cesarean deliveries were excluded. A fetal head circumference ≥35 cm increased the risk for unplanned cesarean delivery: 174 fetuses with fetal head circumference ≥35 cm (32%) were delivered by cesarean, vs 1712 (17%) when fetal head circumference <35 cm (odds ratio, 2.49; 95% confidence interval, 2.04-3.03). A fetal head circumference ≥35 cm increased the risk of instrumental delivery (odds ratio, 1.48; 95% confidence interval, 1.16-1.88), while estimated fetal weight ≥3900 g tended to reduce it (nonsignificant). Multinomial regression analysis showed that fetal head circumference ≥35 cm increased the risk of unplanned cesarean delivery by an adjusted odds ratio of 1.75 (95% confidence interval, 1.4-2.18) controlling for gestational age, fetal gender, and epidural anesthesia. The rate of prolonged second stage of labor was significantly increased when either the fetal head circumference was ≥35 cm or the estimated fetal weight ≥3900 g, from 22.7% in the total cohort to 31.0%. A fetal head circumference ≥35 cm was associated with a higher rate of 5-minute Apgar score ≤7: 9 (1.7%) vs 63 (0.6%) of infants with fetal head circumference <35 cm (P = .01). The rate among fetuses with an estimated fetal weight ≥3900 g was not significantly increased. The rate of admission to the neonatal intensive care unit did not differ among the groups. CONCLUSION: Sonographic fetal head circumference ≥35 cm, measured within 1 week of delivery, is an independent risk factor for unplanned cesarean delivery but not instrumental delivery. Both fetal head circumference ≥35 cm and estimated fetal weight ≥3900 g significantly increased the risk of a prolonged second stage of labor. Fetal head circumference measurement in the last days before delivery may be an important adjunct to estimated fetal weight in labor management.

First delivery in a leukemia survivor after transplantation of cryopreserved ovarian tissue, evaluated for leukemia cells contamination.

OBJECTIVE: To describe a successful autologous ovarian tissue re-transplantation in a sterile leukemia survivor after evaluation for minimal residual disease and provide a review of the current literature. DESIGN: Presentation of a carefully designed workup taken to evaluate tissue for minimal residual disease, its limitations, and applicability to other patients. To date, there have not been any publications of auto-transplantations in leukemia survivors, owing to an estimated high risk for malignancy induction. SETTING: Large tertiary hospital. PATIENT(S): A 19-year-old acute myeloid leukemia patient underwent ovarian tissue cryopreservation during complete remission before bone marrow transplantation. After prolonged amenorrhea, the patient desired pregnancy. Laboratory tests showed antimüllerian hormone <0.1 ng/mL and FSH 116 mIU/mL. Ultrasound revealed no ovarian follicles. INTERVENTION(S): Ovarian tissue cryopreservation and auto-transplantation. Histology, immunohistochemistry, FISH, next-generation sequencing, and xenotransplantation were done to evaluate thawed tissue samples for the presence of leukemia cells. MAIN OUTCOME MEASURE(S): Evidence for leukemia cells in thawed ovarian tissue, reproductive outcomes and live birth after transplantation, and leukemia-free survival. RESULT(S): Histology was negative for leukemia cells. Three severe combined immunodeficiency mice, grafted with tissue fragments, were followed for 6 months and showed no macroscopic/microscopic signs for leukemia. Fluorescence in situ hybridization for disease-specific gene rearrangement resulted in a read below the probe's cut-off. A next-generation sequencing panel of genes implicated in myeloproliferative disorders did not reveal any significant molecular event. Transplantation was performed, followed by ovarian stimulation and IVF, resulting in the delivery of healthy newborn. More than 2 years have elapsed since transplantation, and the patient is leukemia free. CONCLUSION(S): Harvesting during complete remission, combined with intense tissue evaluation before transplantation, allowed a safe, successful transplantation in an acute myeloid leukemia survivor.

Does antenatal steroids treatment prior to elective cesarean section at 34-37 weeks of gestation reduce neonatal morbidity? Evidence from a case control study.

OBJECTIVE: To determine whether antenatal corticosteroids administration prior to an elective cesarean section (ECS) at 34-37 weeks gestation is associated with improved neonatal outcome. MATERIALS AND METHODS: A case control study of women with singleton pregnancies who underwent ECS between 34 and 37 weeks of gestation including two groups: (1) study group in which patients were treated with betamethasone prior to ECS (n = 58) and (2) control group matched for gestational age at delivery in which patients did not receive betamethasone (n = 107). Neonatal measures including respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), oxygen requirement, admission to the special care unit, hypoglycemia, hyperbilirubinemia and length of hospitalization were determined in both groups. Composite respiratory morbidity was defined as the presence of either RDS, TTN, mechanical ventilation or oxygen requirement. RESULTS: There was no significant difference in the rate of composite respiratory morbidity nor its components between patients with and without betamethasone treatment (25.9 vs. 25.2%, respectively, p = 0.9). CONCLUSION: Antenatal treatment with corticosteroids prior to ECS at 34-37 weeks of gestation did not result in significant reduction in neonatal respiratory morbidity in our cohort of patients.

Sonographic Signs of Adenomyosis Are Prevalent in Women Undergoing Surgery for Endometriosis and May Suggest a Higher Risk of Infertility.

OBJECTIVES: To determine the prevalence of ultrasound features suggestive of adenomyosis in women undergoing surgery for endometriosis compared with a control group of healthy women without endometriosis. METHODS: Retrospective case-control study comparing women with intractable pain or infertility, who underwent transvaginal ultrasound and subsequent laparoscopic surgery, with a control group of healthy women without a previous history of endometriosis. A diagnosis of adenomyosis on TVUS was made based on asymmetrical myometrial thickening, linear striations, myometrial cysts, hyperechoic islands, irregular endometrial-myometrial junction, parallel shadowing, and localized adenomyomas and analyzed for one sign and for three or more signs. RESULTS: The study and control groups included 94 and 60 women, respectively. In the study group, women were younger and had more dysmenorrhea and infertility symptoms. The presence of any sonographic feature of adenomyosis, as well as three or more signs, was found to be more prevalent in the study group, which persisted after controlling for age, for all features but linear striations. Women in the study group who had five or more sonographic features of adenomyosis had more than a threefold risk of suffering from infertility (OR = 3.19, p = 0.015, 95% CI; 1.25-8.17). There was no association with disease severity at surgery. CONCLUSIONS: Sonographic features of adenomyosis are more prevalent in women undergoing surgery for endometriosis compared to healthy controls. Women with more than five features had an increased risk of infertility.

Applying a statistical method in transvaginal ultrasound training: lessons from the learning curve cumulative summation test (LC-CUSUM) for endometriosis mapping.

BACKGROUND: Methods available for assessing the learning curve, such as a predefined number of procedures or direct mentoring are lacking. Our aim was to describe the use of a statistical method to identify the minimal training length of an experienced sonographer, newly trained in deep infiltrating endometriosis (DIE) mapping by evaluating the learning curve of transvaginal ultrasound (TVUS) in the preoperative assessment of endometriosis. METHODS: A retrospective study in a tertiary referral center for endometriosis. Reports and stored data from TVUS scans performed by one operator with training in general gynecological ultrasound, but not in endometriosis mapping, were analyzed retrospectively for patients who subsequently underwent laparoscopy, which served as a reference standard. The performance of TVUS was assessed for the following sites: endometriomas, bladder, vagina, pouch of Douglas, bowel and uterosacral ligaments, and correlated with laparoscopic findings. Sensitivity, specificity, PPV, NPV, and accuracy were calculated, and the operator's diagnostic performance was assessed using the learning curve cumulative summation test (LC-CUSUM). RESULTS: Data from 94 women were available for analysis. The learning curve using the LC-CUSUM graph showed that the sonographer reached the predefined level of proficiency in detecting endometriosis lesions after 20, 26, 32, 31, 38, and 44 examinations for endometriomas, bladder nodules, vaginal nodules, pouch of Douglas obliteration, bowel nodules, and uterosacral ligament nodules, respectively. CONCLUSIONS: LC-CUSUM allows monitoring of individual performance during the learning process of new methodologies. This study shows that a sonographer trained in general gynecologic ultrasonography, who devotes time to learn TVUS for DIE mapping, can achieve proficiency for diagnosing the major types of endometriotic lesions after examining less than 50 patients who subsequently undergo surgery in a training setting.

Feasibility and efficacy of repeated hysteroscopic cesarean niche resection.

OBJECTIVE: Cesarean-induced niche can cause symptoms such as abnormal postmenstrual bleeding, pain and associated infertility. Hysteroscopic niche resection is usually a successful treatment, but can result in a failure to improve symptoms or symptoms can recur. In the present study we aim to evaluate the feasibility, effectiveness, and safety of a second hysteroscopic niche resection for patients in whom an initial hysteroscopic resection failed to improve symptoms. STUDY DESIGN: This retrospective cohort study (Canadian Task Force classification II-2) hospital tell hashomer (tertiary center) included all patients who underwent a second hysteroscopic niche resection between 2011 and 2015. MEASUREMENTS: Fertility,obstetric outcomes, clinical outcome and complications were compared between the first surgery and the second RESULTS: Eight patients underwent a second hysteroscopy after failure of the first hysteroscopy to resolve symptoms or after recurrence of symptoms. Abnormal uterine bleeding (AUB) was the most common symptom, occurring in all patients. The average number of days of bleeding per cycle were significantly reduced following the second surgery [14.50 (range 8-21days) vs 11.75 (range 8-20days), respectivelyp=0.009]. The second surgery improved symptoms in 6 out of the 8 patients with AUB and 1 of 2 patients with pain. There were no significant differences in fertility and obstetric outcomes between the first and the second surgery and no complications were reported during any of the surgeries. CONCLUSION: Reintervention with a second hysteroscopic niche resection is both feasible and effective treatment option following a failed first attempt or recurrence of symptoms. The second surgery improved symptoms, especially AUB, with no consequent detrimental effect on obstetric outcomes on our series.

Pre-implantation genetic diagnosis-should we use ICSI for all?

OBJECTIVE: Intracytoplasmic sperm injection (ICSI) is commonly used during pre-implantation genetic diagnosis (PGD) in vitro fertilization (IVF), aiming to eliminate the risk of contamination from extraneous sperm DNA. Recently, ICSI "overuse" in non-male infertility has been doubted, since it does not offer an advantage over IVF. Prompted by the aforementioned observations, we sought to assess the accuracy of IVF vs ICSI in PGD cases, as might be reflected by a difference in the prevalence of discarded embryos as a consequent of parental contamination. METHODS: Cohort-historical study of all consecutive patients admitted to the IVF-PGD program in a large tertiary center. The percentages of complete, incomplete diagnosis, PCR failure, abnormal embryos, and the contamination rate with paternal DNA in the IVF-only and the ICSI-only groups. We reviewed the computerized files of all consecutive women admitted to our IVF for a PGD-PCR cycle. Patients were divided accordingly into three groups: an IVF group-where all the oocytes underwent IVF only, an ICSI group-where all oocytes underwent ICSI, and a mixed group-where sibling oocytes underwent both IVF and ICSI. The laboratory data and the genetic diagnostic results were collected and compared between the different insemination groups. RESULTS: Nine-hundred and twenty-seven patients underwent IVF-PGD cycles in our program, 315 in the IVF group, 565 in the ICSI group, and 47 in the mixed group. No differences were observed in fertilization rates, the percentage of embryos available for biopsy, and the percentages of complete, incomplete diagnosis, PCR failure, or abnormal embryos, between the IVF-only and the ICSI-only groups and between the IVF and the ICSI of sibling oocytes in the mixed group. Moreover, contamination with paternal DNA, through contamination with sperm cells, was negligible. Not one single case of misdiagnosis was encountered during the study period. CONCLUSION: It might be therefore concluded that IVF should be the preferred insemination methods in PGD cycles, and ICSI should be indicated only in cases of male-factor infertility.

In-office Hysteroscopic Extraction of Intrauterine Devices in Pregnant Patients Who Underwent Prior Ultrasound-guided Extraction Failure.

STUDY OBJECTIVE: To determine an effective method of intrauterine device (IUD) retrieval from pregnant women who had previous unsuccessful ultrasound-guided IUD extraction failure. DESIGN: A retrospective cohort study (Canadian task force classification II-1). SETTING: A gynecology department of an outpatient clinic. PATIENTS: Pregnant patients in their first trimester with IUD in situ who underwent prior unsuccessful ultrasound-guided IUD extraction. INTERVENTIONS: Hysteroscopic IUD extraction guided by transabdominal ultrasound. MEASUREMENTS AND MAIN RESULTS: Between 2011 and 2014, 7 of 8 pregnant patients who had undergone previous failed attempts at IUD retrieval via ultrasound guidance underwent successful removal via ultrasound-guided hysteroscopy performed without anesthesia. The sole patient with extraction failure was in her 12th week of pregnancy, and the procedure was concluded to avoid risk to the fetus. Minimal vaginal bleeding was experienced by 2 patients after the procedure. Seven of 8 patients delivered at term without any obstetric complications. One patient had a miscarriage in her 8th week of pregnancy, 2 weeks after successful IUD removal. CONCLUSION: A novel, easy outpatient hysteroscopic technique without anesthesia is presented in case of failure of previous ultrasound-guided IUD removal in early pregnancy. Results are encouraging in this difficult context.

The Yield of Abdominal Ultrasound in the Evaluation of Elevated Liver Enzymes during the Second and the Third Trimester of Pregnancy.

AIMS: To determine the clinical yield of abdominal ultrasound in the evaluation of elevated liver enzymes (ELEs) in the second and the third trimester of pregnancy. METHODS: A retrospective cohort study including all pregnant women admitted to a single tertiary care center was conducted between April 2011 and January 2015 with ELE. Inclusion criteria included gestational age above 24 weeks and ELEs, abdominal ultrasound report, and live fetus. Exclusion criteria included known maternal liver disease, structural or chromosomal fetal anomalies, and positive serology for viral hepatitis. All patients underwent abdominal ultrasound. A significant finding of this study led to a change in treatment. RESULTS: One hundred and twenty patients (41.8%) met inclusion criteria: 93 (77.5%) had a normal scan and 27 (22.5%) had abnormal findings. Significant ultrasound findings were found only in 2 (1.6%) patients: gallstones in the common bile duct and suspected autoimmune hepatitis. There were no significant differences between patients with and without ultrasound findings in the rate of cholestasis of pregnancy, preeclampsia, chronic hypertension, and gestation diabetes. CONCLUSION: Abdominal ultrasound examination in this population has a low clinical yield. The decision to perform an abdominal ultrasound must be individualized based on the obstetric history, clinical findings, and the level of liver enzymes.

Trial of labour after caesarean (TOLAC) is associated with increased risk for instrumental delivery.

We compared the rates of instrumental delivery in a cohort of nulliparous women at term (n = 19,416), to primiparous women who attempted labour after prior caesarean (TOLAC) (n = 1747). The rate of instrumental deliveries was higher in the TOLAC group compared to nulliparous gravidas (17.3 vs. 15% respectively, p = 0.001). The difference was more prominent for women who eventually had successful vaginal delivery (TOLAC: 23.9% vs. CONTROLS: 17.1%, p < 0.0001 respectively). Based on our results, previous caesarean whether urgent or elective was associated with an increased risk of instrumental delivery in the subsequent pregnancy.