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Objective: This meta-analysis aimed to evaluate the success rate of trial of labor in monochorionic diamniotic pregnancies and the impact of delivery mode on neonatal outcomes., Data Sources: Searches were performed in MEDLINE/PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the International Clinical Trials Registry Platform from the inception of each database until April 2022., Study Eligibility Criteria: Selection criteria included observational studies analyzing the delivery mode among monochorionic diamniotic gestations., Methods: All analyses were carried out using an intention-to-treat approach, evaluating women according to the delivery mode to which they were assigned in the original studies., Results: Seventeen studies met the eligibility criteria and were suitable for qualitative and quantitative analysis. In total, 4116 women were analyzed. This meta-analysis showed that trial of labor in monochorionic diamniotic pregnancies resulted in vaginal delivery of both twins in 75.5% of cases (95% confidence interval, 69.1-80.9). Failure to deliver the second twin vaginally occurred in 3.8% of cases (95% confidence interval, 2.5-5.7). In addition, the neonatal outcomes were comparable among women with monochorionic diamniotic pregnancy undergoing different planned delivery modes. Neonatal death occurred in 3.7 per 1000 cases in the planned cesarean delivery group and in 1.6 per 1000 cases in the planned vaginal delivery group. Perinatal death was observed in 7.5 per 1000 cases in the planned cesarean delivery group and in 5.8 per 1000 cases in the planned vaginal delivery group. Umbilical artery pH <7.00 occurred in 0 per 1000 cases in the planned cesarean delivery and 4.6 per 1000 cases in the planned vaginal delivery group. Neonatal intensive care unit stay of >72 hours had a prevalence of 59.7 per 1000 cases in the planned cesarean delivery and 42.8 per 1000 cases in the planned vaginal delivery group., Conclusion: This meta-analysis showed that trial of labor in monochorionic diamniotic pregnancies is successful in most cases and relatively safe, considering that neonatal and perinatal mortality and severe morbidity were comparable between the trial of labor and planned cesarean delivery groups. Therefore, the choice of planned delivery mode in twin gestations should not be made a priori., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Vaginal breech delivery (VBD) has been widely discouraged over the last two decades due to associated neonatal risks. However, many gynaecologists are still challenging this approach, at least in selected settings., Objective: To study short-term neonatal outcomes in singleton pregnancies undergoing VBD., Materials and Methods: Retrospective cohort study conducted on singleton pregnancies who delivered in breech presentation between 2012 and 2019. Neonatal complications in terms of mortality, umbilical artery (UA) pH, 5-min Apgar score, and postnatal admission to neonatal intensive care unit (NICU) were evaluated., Results: Overall, 804 breech deliveries were considered. Of these, 53.86 % had VBD, 26.62 % had emergency caesarean sections (CS) and 19.53 % had elective CS. No perinatal deaths were reported. After multivariate adjustment, VBD was associated with higher incidence of UA pH < 7.10 compared with both elective and emergency CS. No significant associations were found between VBD and UA pH < 7.00 or 5-min Apgar score < 3 or < 7. No significant differences in NICU hospitalization were observed for different modes of delivery. Gestational age was inversely correlated with UA pH < 7.00, 5-min Apgar score < 3 and < 7, and NICU hospitalization., Conclusions: VBD in an experienced setting does not increase the risk of negative short-term perinatal outcomes significantly. Gestational age was the most important risk factor for low UA pH or 5-min Apgar score and NICU hospitalization, independent of mode of delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Our primary aim was to estimate the magnitude of stage I endometrial cancer (EC) survivors that could benefit from hormonal therapy (HT). Our secondary aims were to assess EC incidence in women below 50 and below 60 over the years, and analyze the overall survival and any influencing factors. We analyzed the endometrioid EC data from the Surveillance, Epidemiology, and End Results (SEER) program according to women's age, tumor stage, and grade. We analyzed the proportions of EC survivors below 50 and below 60 years of age and stratified those age groups by race. For age distribution and survival analysis SEER, 18 registries' research data (2000-2018) were analyzed. We analyzed the SEER 12 registries' research data (1992-2019) for incidence time trends. Our investigation found a 14% and 40% cumulative prevalence of stage I EC that occurs in women below 50 or 60 years, respectively. EC's prevalence has progressively risen in recent decades, but cancer-specific mortality remains low. The increasing number of women affected by EC in premenopause or early postmenopause face an 18 years-survival rate of 96.86% and 95.73%, respectively. A significant proportion of low-grade EC survivors can potentially benefit from HT treatment, and this requires awareness of other aspects of their health or quality of life, in addition to cancer treatments.

Aims: This study aimed to identify any microscopic features associated with abnormal (membranous/velamentous or marginal) placental cord insertions and to analyse their adverse neonatal outcomes., Methods: We retrospectively analysed the records-including pathological findings, clinical information and pregnancy outcomes-for 1060 singleton pregnancies, involving newborn delivered after 24 weeks of gestation., Results: Marginal cord insertions were identified in 26.60% of cases and membranous cord insertions in 2.64%. Subchorionic vessel thrombus was more prevalent in marginal or membranous insertions (0.97%) than in normal cord insertions (0.27%) (p=0.129). Intervillous thrombi (13.73% vs 8.41%, p<0.05) and chorioamnionitis (8.53% vs 5.48%, p=0.089) were more prevalent in normal cord insertions. Premature rupture of membranes was significantly more commonly associated with abnormal (marginal 15.25% and membranous 17.86%) than with normal (9.87%) insertions (p<0.05). Pre-eclampsia was more common in the group with membranous cord insertions (7.14%) than in the other groups (marginal 0.35%; normal 0.80%) (p<0.05). Marginal and membranous placental cord insertions were associated with earlier gestational age at delivery and smaller fetuses than in the group with normal insertions. Intrauterine fetal demise, cardiac malformations and pregestational diabetes were also more common among cases of abnormal cord insertions., Conclusions: Subchorionic vessel thrombus and adverse pregnancy-related outcomes were more prevalent in cases of marginal/membranous cord insertion than for normal insertions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Historically, fetal heart rate (FHR) decelerations were classified into "early", "late", and "variable" based on their relationship with uterine contractions. So far, three different putative etiologies were taken for granted. Recently, this belief, passed down through generations of birth attendants, has been questioned by physiologists. This narrative review aimed to assess the evidence on pathophysiology behind intrapartum FHR decelerations. This narrative review is based on information sourced from online peer-reviewed articles databases and recommendations from the major scientific societies in the field of obstetrics. Searches were performed in MEDLINE/PubMed, EMBASE, and Scopus and selection criteria included studies in animals and humans, where the physiology behind FHR decelerations was explored. The greater affinity for oxygen of fetal hemoglobin than the maternal, the unicity of fetal circulation, and the high anaerobic reserve of the myocardium, ensure adequate oxygenation to the fetus, under basal conditions. During acute hypoxic stress the efficiency of these mechanisms are increased because of the peripheral chemoreflex. This reflex, activated at each uterine contraction, is characterized by the simultaneous activation of two neural arms: the parasympathetic arm, which reduces the myocardial consumption of oxygen by decreasing the FHR and the sympathetic component, which promotes an intense peripheric vasoconstriction, thus centralizing the fetal blood volume. This review summarizes the evidence supporting the hypoxic origin of FHR decelerations, therefore archiving the historical belief that FHR decelerations have different etiologies, according to their shape and relationship with uterine contractions. The present review suggests that it is time to welcome the new scientific evidence and to update the CTG classification systems.

Objective: This study aimed to evaluate the effectiveness of intrapartum acute tocolysis for nonreassuring fetal heart rate tracing in decreasing the incidence of cesarean delivery. Secondary outcomes included modes of delivery other than cesarean delivery, successful acute tocolysis, time-to-delivery interval, and short-term perinatal outcomes., Data Sources: Searches were performed in MEDLINE/PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials and Reviews, ClinicalTrials.gov, and the International Clinical Trials Registry Platform from the inception of each database until February 2022., Study Eligibility Criteria: Selection criteria included randomized controlled trials of laboring patients with singleton gestations randomized to receive intrapartum acute tocolysis for nonreassuring fetal heart rate tracing, as defined by the original trial., Methods: All analyses were done using an intention-to-treat approach, evaluating women according to the treatment group to which they were randomly allocated in the original trials. A frequentist network-meta-analysis was performed., Results: Four randomized clinical trials were eligible, including 605 patients with nonreassuring fetal heart rate tracing and singleton gestations at gestational ages >32 weeks. The cesarean delivery rate was similar among patients managed with different types of acute tocolysis. Acute tocolysis, compared with emergency delivery, was associated with improved neonatal acid-base status (notably decreasing the prevalence of base deficit >12 mmol/L [beta-2 agonists odds ratio, 0.61; 95% confidence interval, 0.37-0.99] and the rate of neonatal intensive care unit admission [beta-2 agonists odds ratio, 0.42; 95% confidence interval, 0.22-0.78]) and with an increase in the time-to-delivery interval (beta-2 agonists mean difference, 17.62 minutes; 95% confidence interval, 15.66-19.58); there was no reduction of cesarean delivery rate, showing an increased rate with atosiban and beta-2 agonists., Conclusion: The cesarean delivery rate was not reduced by acute tocolysis when used for nonreassuring fetal heart rate tracing during labor. Acute tocolysis is associated with improved short-term fetal outcomes and safely increases the time-to-delivery interval., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Survivin was previously associated with tumor stage and grade in ovarian cancer and interfered with the tumor's drug sensitivity. In addition, Survivin expression was found to be regulated by the Sonic hedgehog (Shh) pathway, Krüppel-like factor (KLF) family proteins, and p53 pathway. The main aim of this study was to assess the prognostic values of immunohistochemical expression of Survivin, Klf5, Klf11, Shh, p53, p21, and Mdm2 in a cohort of high-grade ovarian serous cancers. Other aims were comparison between high- and low-grade ovarian serous cancer and between platinum-resistant and the other cases. The last aim was to assess the correlations among the immunohistochemical expression of the studied proteins. Retrospective cohort study to assess immunohistochemical expression of Survivin, Klf5, Klf11, Shh, p53, p21, and Mdm2 in a tissue microarray of primary tumor samples among 73 women affected by high-grade ovarian serous cancer and 9 by low-grade ovarian serous cancer. Klf5 and Shh cytoplasmic staining were associated with short overall survival (HR 6.38, 95% CI 2.25-18.01, P < .05 and 2.25, 95% CI 1.19-4.23, P < .05, respectively). In addition, cytoplasmic Klf5 staining, high Klf11, and p53 nuclear staining were associated with platinum resistance (P < .05). Cytoplasmic Shh score was significantly correlated to the immunohistochemical expression of Klf5, Klf11, Mdm2, and Survivin. Our data highlight the possible role of Klf5 and Shh as prognostic markers, meanwhile confirming the role of the KLF family proteins and p53 in ovarian cancer drug resistance. Moreover, Shh appeared to play an important role in the intracellular network of ovarian neoplasia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: This study aimed to compare the outcomes of preterm infants given 12 vs. 24mg of betamethasone prophylaxis to understand whether a partial course of antenatal corticosteroids (CCS) could prevent or mitigate the major preterm birth complications., Methods: This is a retrospective single-center cohort study including neonates born between 24 and 34 weeks of gestation from 2001 to 2019 at the University Hospital of Udine. The study population was divided into two groups: one group received 12mg, and another received a 24mg dose of betamethasone before the delivery. A separate analysis was performed for single and multiple pregnancies. The two groups were evaluated for various neonatal outcomes., Results: The study population included a total of 1,258 pregnancies and 1,543 neonates delivered between 24 and 34 weeks of gestation, of which 1,022 (803 single and 219 multiple pregnancies) were exposed to the complete CCS prophylaxis, whereas 236 (192 single and 44 multiple pregnancies) received the incomplete CCS prophylaxis. In single pregnancies, as for maternal characteristics, the most significant differences observed between the two groups are the following: a higher prevalence of spontaneous vaginal deliveries in the incomplete CCS prophylaxis (36.46 vs. 23.91%) and, by contrast, a higher prevalence of cesarean deliveries in the complete CCS prophylaxis group (75.72 vs. 63.02%). As for neonatal outcomes, the low Apgar score in the first and fifth min was significantly more prevalent in the incomplete CCS prophylaxis group compared with the complete CCS prophylaxis group. The group of incomplete CCS prophylaxis reported a higher occurrence of the following outcomes: IVH grade 3-4 (7.81 vs. 3.74%, p < 0.05), PVL (7.29 vs. 1.99% p < 0.05), ROP (23.96 vs. 18.06% p = 0.062), and RDS (84.38 vs. 78.83% p = 0.085). After adjusting for covariates, the complete CCS prophylaxis group in single pregnancies was significantly protective for IVH grade 3-4, PVL, and low Apgar's scores. Similar results were found in multiple pregnancies except for RDS., Discussion: This retrospective single-center cohort study found that, compared with preterm infants treated with 24mg betamethasone in utero , those given half course of betamethasone had a significantly higher prevalence of IVH grade 3-4, PVL, RDS, and lower Apgar scores at 1 and 5 min. In conclusion, the evidence from this single-center retrospective study supports the preference for the complete CCS prophylaxis in women at risk of preterm birth because of its beneficial effect on the main adverse outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xodo, Trombetta, Celante, Pittini, Driul, Cagnacci and Londero.)

Simple Summary: Implementing intraoperative assessment of sentinel lymph nodes by one-step nucleic acid amplification in early breast cancer can reduce the surgical burden to the patient and the costs to the health system. However, only limited data are available in terms of long-term disease-free survival and overall survival. Therefore, this study aims to compare disease-free survival and overall survival between one-step nucleic acid amplification, frozen section, and definitive histology. These results could impact the healthcare community, adding further proof to the body of evidence supporting the broader adoption of this innovative technology that enables a safe reduction in patient surgical burden and healthcare costs., Background: The one-step nucleic acid amplification (OSNA) system is a novel molecular technique, which consents to quick intraoperative detection of sentinel lymph node metastases by the amplification of cytokeratin 19 mRNA. Our study aims to evaluate the OSNA method in comparison with frozen section (FS) and definitive histological examination of the sentinel lymph node biopsy among early breast cancer patients considering disease-free survival (DFS) and overall survival (OS)., Methods: In this study, we included all women who underwent sentinel lymph node biopsy (SLNB) for breast cancers classified as TNM stage I and II in our center between January 2005 and January 2017, and the follow-up was collected up to January 2019. We divided patients among three groups based on SLNB evaluation: definitive histological examination, intra-operative FS, or OSNA., Results: We included 2412 SLNBs: 727 by definitive histological examination, 697 by FS, and 988 by OSNA. Isolated tumor cells were found in 2.32% of cases, micrometastasis in 9.12%, and macrometastases in 13.64%. Surgical procedure duration was significantly shorter in OSNA than in FS (42.1 minutes ±5.1 vs. 70.1 minutes ±10.5, p <0.05). No significant differences have been observed among the three groups regarding OS, DSF, cumulative local, or distant metastases. In particular 5-year DFS was 96.38% in definitive histology (95% C.I. 95.02-97.75%), 96.37% in FS (95% C.I. 94.98-97.78%), and 96.51% in OSNA group (95% C.I. 95.32-97.72%)., Conclusions: No difference in OS and DFS was found comparing OSNA, FS, and definitive histology. Furthermore, reduced operative time was found in the OSNA group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bertozzi, Londero, Bulfoni, Seriau, Agakiza, Pasqualucci, Andretta, Orsaria, Mariuzzi and Cedolini.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: Our aim was to assess diagnostic accuracy in the prediction of small for gestational age (SGA <10th centile) and fetal growth restricted (FGR) (SGA <3rd centile) fetuses using three different sonographic methods in pregnancies at increased risk of fetal growth restriction: 1) fetal abdominal circumference (AC) z-scores, 2) estimated fetal weight (EFW) z-scores according to postnatal reference standard; 3) EFW z-scores according to a prenatal reference standard., Methods: Singleton pregnancies at increased risk of fetal growth restriction seen in two university hospitals between 2014 and 2015 were studied retrospectively. EFW was calculated using formulas proposed by the INTERGROWTH-21st project and Hadlock; data derived from publications by the INTEGROWTH-twenty-first century project and Hadlock were used to calculate z-scores (AC and EFW). The accuracy of different methods was calculated and compared., Results: The study group included 406 patients. Prenatal standard EFW z-scores derived from INTERGROWTH-21st project and Hadlock and co-workers performed similarly and were more accurate in identifying SGA infants than using AC z-scores or a postnatal reference standard. The subgroups analysis demonstrated that EFW prenatal standard was more or similarly accurate compared to other methods across all subgroups, defined by gestational age and birth weight., Conclusions: Prenatal standard EFW z-scores derived from either INTERGROWTH-21 st project or Hadlock and co-workers publications demonstrated a statistically significant advantage over other biometric methods in the diagnosis of SGA fetuses., (© 2022. The Author(s).)

Background: Breast cancer chemoresistance is attributed to a wide variety of mechanisms, including autophagy. Transcription factor EB (TFEB) has been recently identified and characterized as one major regulator of autophagy and lysosomal genesis., Objective: This study aims to evaluate the prognostic impact of TFEB and its pathway in breast cancer chemoresistance., Methods: This retrospective study analyzes the expression of TFEB, CARM1, SIRT1, and Beclin-1 and the methylation of PITX2 in breast carcinoma. A group of breast cancer patients treated with chemotherapy, who relapsed within 12 months from treatment initiation, were compared to a sub-cohort of chemo-treated patients who did not recur within 12 months of follow-up. The expression of TFEB, CARM1, SIRT1, and Belcin-1 was analyzed using immunohistochemistry or RT-PCR on formalin-fixed paraffin-embedded samples. PITX2 methylation was tested with the diagnostic CE-marked kit Therascreen PITX2 RGQ PCR. In the final model, 136 cases of chemo-treated breast cancer were included., Results: A higher TFEB and Beclin-1 expression correlate with shorter survival in patients with chemo-treated invasive breast cancer (respectively HR 3.46, CI.95 1.27-9.47, p < 0.05 and 7.11, CI.95 2.54-19.9). TFEB, CARM1, and SIRT1 are positively correlated with Beclin-1. The protein expression of SIRT1 is significantly associated with TFEB and CARM1 so that a very low SIRT1 expression (lower than the first quartile of the H-score distribution) correlates with a low expression of TFEB and CARM1 and with longer survival. SIRT1 seems to have a lower H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. Beclin-1 and TFEB seem to have a higher H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. PITX2 methylation analysis was feasible only in 65% of the selected samples, but no significant differences between cases and controls were found, and there was also no correlation with the expression of the TFEB pathway., Conclusions: TFEB, SIRT1, and Beclin-1 seem to have a potential prognostic significance in patients with chemo-treated breast cancer, likely because of their role in the regulation of autophagy. In addition, no correlation between TFEB and PITX2 methylation was found, likely because they perform two different roles within the autophagy process., (© 2021. The Author(s).)

Objective: Accelerated placental maturation is regarded as a sign of vascular malperfusion and is often interpreted as a compensatory response by the placenta. In vitro embryo culture affects placental development. This study assessed placental maturation in spontaneous conceived and in vitro conceived pregnancies., Methods: Retrospective cohort study on a single center between 2014 and 2017. For this study, preterm placentas of singleton pregnancies between 24 and 36 weeks were considered. Routine placental examinations were retrospectively reviewed., Results: During the considered period, 423 placentas of singleton pregnancies were assessed. Three hundred ninety-six placentas were from spontaneous conception and 20 from in vitro fertilization and embryo transfer (IVF/ET). IVF/ET was significantly associated with accelerated villous maturation (AVM) and distal villous hypoplasia (DVH) (P<0.05)., Conclusions: Placental AVM and DVH were significantly associated with in vitro fertilization in singleton pregnancies. This result supports the hypothesis that AVM is a compensatory response by the placenta to improve its transport capacity in specific settings such as in vitro fertilization., Competing Interests: None., (IJCEP Copyright © 2021.)

Background: The aim of this study was to retrospectively analyze the prevalence of severe preeclampsia and low sodium (PALS) among the pregnant population admitted at the University Hospital of Udine in the past 4 years and to compare these data with the current literature., Methods: Only women with a diagnosis of preeclampsia were included. According to the lowest sodium level measured either 5 days before or 5 days after delivery, patients were divided in two groups: women with hyponatremia (<135 mmol/L; severe <120 mmol/L) and women with normonatremia (>135 mmol/L). Moreover, a search literature was performed., Results: Of 59 patients with preeclampsia, 20 (34%) had hyponatremia. Only one case (1.6%) of severe maternal hyponatremia (sodium level 117 mmol/L) in the setting of preeclampsia was identified. After literature search, a total of 22 manuscripts including 60 case reports of PALS were identified. The lowest sodium level was 113 mmol/L, at 25 weeks of gestation. In most cases hyponatremia was treated with fluid restriction. In only 5 cases hyponatremia was treated with a saline hypertonic solution. Hyponatremia resolution, when reported, occurred in about 48 h. Sodium level in neonates ranged from 118 and 128 mmol/L., Conclusions: PALS may occur in about a third of women with severe preeclampsia. Severe maternal hyponatremia should be treated with fluid restriction and with hypertonic saline solution. Moreover neonatologists should be alerted in order to treat the neonate for the best outcome., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Krüppel-like factors (KLFs) are transcription factors with the ability to mediate cross-talk with signaling pathways involved in cell proliferation control, apoptosis, migration, and differentiation. They also appear to influence steroid hormone signaling through transcriptional networks involving steroid hormone receptors and members of the nuclear receptor family of transcription factors. Our study aims to evaluate the potential prognostic role of KLF5, KLF9, and KLF11 in endometrial cancer, and their correlation with hormonal receptor status and cellular proliferation., Materials and Methods: Retrospective observational study on cases of endometrioid endometrial adenocarcinoma collected in the period January 2000-December 2011 at the University of Udine. Formalin-fixed, paraffin-embedded tissue samples were all submitted to tissue microarray immunohistochemical study. A survival analysis was performed., Results: One hundred forty seven patients were included in the study with a mean age at surgery of 65.6 years (±10.2). 80.3% of endometrial malignancies were classified as stage FIGO I (118/147). Radiation therapy and chemotherapy were administered in 62.3% (91/146) and 6.2% (9/145) of patients respectively. Five-year overall survival and disease-free survival resulted 85.4% (95% CI, 79.8-91.4%) and 79.4% (95% CI, 73.0-86.4%) respectively. A high Ki-67, cytoplasmatic KLF5 (HR 4.72, CI.95 1.61-13.89, p < 0.05), and nuclear KLF11 (HR 3.04, CI.95 0.99-9.36, p = 0.053) scores correlated with a shorter overall survival. In addition, a high nuclear KLF11 (HR 2.59, CI.95 1.13-5.95, p < 0.05) score correlated with a shorter disease-free survival., Conclusions: In patients affected by endometrioid endometrial carcinoma, higher staining levels of KLF5 and KLF11 correlated with a poorer prognosis. However, further studies are required in order to better clarify the role of KLFs in the natural history of endometrial cancer.

Background: Atypical polypoid adenomyoma (APA) is a rare uterine tumor typically found in fertile age and associated with infertility. Among young nullipara women, conservative treatment is proposed despite the high recurrence rate and the association with endometrial cancer.Our aim was to assess the risk of recurrence with different conservative treatments in fertile ages and the prevalence of malignant or pre-malignant associated lesions to better address an adequate patient counselling when treatment modalities are discussed., Methods: This study is a systematic review and meta-analysis of case reports and case series about APA management and follow-up. A literature search was carried from Medline and Scopus for studies published from January 1, 1980 to December 31, 2018., Results: We included 46 observational studies and 296 cases in fertile women. The prevalence of APA relapse was 44% (CI.95 33-57%) and was lower in cases treated with operative hysteroscopy (22%; CI.95 11-39%) than in cases treated with blind curettage and polypectomy (38%; CI.95 15-67%). The prevalence of the concomitant or during the follow-up diagnosis of endometrial carcinoma was 16% (CI.95 9-29%). The risk of cancer development during follow-up was significantly less in cases treated with histeroscopy (10.56% new cumulative diagnosis at 5 years follow up; CI.95 0-23.7%) than blind curettage and polypectomy (35.5% new cumulative diagnosis at 5 years; CI.95 11.65-52.92%; P < .05). Medical treatment with medroxyprogesterone acetate after surgery does not reduce APA recurrence. Pregnancy was observed in 79% cases in which the desire was expressed., Conclusion: This review suggests that conservative treatment performed by operative hysteroscopy is the optimal choice because it lowers the risk of recurrence, improves the accuracy of concomitant carcinoma or hyperplasia diagnosis, and leaves the possibility of future pregnancies.

Purpose:  The human aorta stores strain energy in the distended wall during systole through the extracellular matrix of the tunica media that could be influenced by blood pressure, flow, or increased peripheral resistance. In intrauterine growth restriction (IUGR) fetuses, the increased aorta intima media thickness (aIMT) could reflect a different extracellular matrix composition and, therefore, functionality. The aim of this study was to analyze the resistance to flow in the fetal descending aorta and its relation to aIMT and systolic and diastolic fetal abdominal aorta diameters in IUGR fetuses and controls., Materials and Methods: This is a prospective case control study of single pregnancies collected at a tertiary center for feto-maternal medicine in Northeast Italy. An IUGR group as cases and a group of fetuses appropriate for gestational age (AGA) as controls were included., Results:  We found a greater PI of the fetal abdominal aorta in the IUGR group (1.82) than in the AGA group (1.21) (p < 0.05). The change between the systolic and diastolic fetal abdominal aorta diameters was significantly greater in IUGR fetuses (0.10 mm (IQR 0.07 - 0.28)) than in the AGA group (0.04 mm (0.03 - 0.05)) (p < 0.05). In the IUGR group aIMT was significantly correlated with peak systolic velocity (PSV) and systolic-diastolic aorta diameter change, while these two correlations were not found in the control group., Conclusion:  The change between the systolic and diastolic fetal abdominal aorta diameters in IUGR cases during the early third trimester of pregnancy was significantly increased and aIMT in the IUGR group was significantly correlated to systolic-diastolic diameter change and PSV, probably reflecting aortic wall adaptation to blood flow changes in IUGR fetuses., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Oncoplastic breast surgery originated in order to improve the esthetic result of breast-conserving surgery (BCS). Autologous free dermal fat graft (FDFG) is an emerging oncoplastic technique to improve the cosmetic outcome of breast-conserving surgery., Objectives: The aim of this study was to analyze our experience with FDFGs in breast reconstruction after breast-conserving surgery. Oncological outcomes, surgical complications and cosmetic results were considered., Material and Methods: This retrospective chart review study considered all consecutive oncoplastic breast treatment by means of FDFG reconstruction during the period between September 2011 and September 2012 in our Clinic of Surgery (University of Udine, Italy). The data collected included patient and tumor characteristics and outcomes (cosmetic and oncological)., Results: During the study period, 37 women were treated by breast cancer surgery and immediate breast reconstruction by FDFG. At a 3-year follow-up, we found no cases of recurrence among breast cancer patients treated by FDFG; at a 18-month follow-up, we found a prevalence of 75.0% of women extremely satisfied with their oncoplastic surgery and a high prevalence of excellent or good cosmetic outcomes (70.3%) according to objective and subjective cosmetic assessment., Conclusions: Immediate breast reconstruction by FDFG after BCS in a population selected for a low risk of breast cancer recurrence seems to be an oncologically safe option, with a good cosmetic outcome and a high prevalence of women satisfied with the treatment.

Endometriosis is an inflammatory disease characterized by the presence of ectopic endometrial tissue outside the uterus. A diffuse infiltration of mast cells (MCs) is observed throughout endometriotic lesions, but little is known about how these cells contribute to the network of molecules that modulate the growth of ectopic endometrial implants and promote endometriosis-associated inflammation. The aryl hydrocarbon receptor (AhR), a transcription factor known to respond to environmental toxins and endogenous compounds, is present in MCs. In response to AhR activation, MCs produce IL-17 and reactive oxygen species, highlighting the potential impact of AhR ligands on inflammation via MCs. Here, we investigated the possibility that endometrial MCs promote an inflammatory microenvironment by sensing AhR ligands, thus sustaining endometriosis development. Using human endometriotic tissue (ET) samples, we performed the following experiments: (i) examined the cytokine expression profile; (ii) counted AhR-expressing MCs; (iii) verified the phenotype of AhR-expressing MCs to establish whether MCs have a tolerogenic (IL-10-positive) or inflammatory (IL-17-positive) phenotype; (iv) measured the presence of AhR ligands (tryptophan-derived kynurenine) and tryptophan-metabolizing enzymes (indoleamine 2,3-dioxygenase 1 (IDO1)); (v) treated ET organ cultures with an AhR antagonist in vitro to measure changes in the cytokine milieu; and (vi) measured the growth of endometrial stromal cells cultured with AhR-activated MC-conditioned medium. We found that ET tissue was conducive to cytokine production, orchestrating chronic inflammation and a population of AhR-expressing MCs that are both IL-17 and IL-10-positive. ET was rich in IDO1 and the AhR-ligand kynurenine compared with control tissue, possibly promoting MC activation through AhR. ET was susceptible to treatment with an AhR antagonist, and endometrial stromal cell growth was improved in the presence of soluble factors released by MCs on AhR activation. These results suggest a new mechanistic role of MCs in the pathogenesis of endometriosis., Competing Interests: The authors declare no conflict of interest.

To evaluate the expression of markers correlated with cellular senescence and DNA damage (8-hydroxy-2'-deoxy-guanosine (8-OHdG), p53, p21, APE1/Ref-1 (APE1), interleukin (IL-6 and IL-8) in placentas from healthy and pathologic pregnancies. This retrospective study considered a placental tissue micro-array containing 92 controls from different gestational ages and 158 pathological cases including preeclampsia (PE), HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), small for gestational age (SGA) fetuses, and intrauterine growth restriction (IUGR) occurring at different gestational ages. In this study, we demonstrated a significant influence of gestational age on the expression in the trophoblast of 8-OHdG, p53, p21, APE1, and IL-6. In placentas of cases affected by PE, HELLP, or IUGR, there was an increased expression of 8-OHdG, p53, APE1, and IL-6 compared to controls (only IL-8 was significantly decreased in cases). In both groups of pathology between 22- and 34-week gestation and after 34-week gestation, APE1 levels were higher in the trophoblast of women affected by hypertensive disorders of pregnancy than women carrying an IUGR fetus. The cytoplasmic expression of 8-OHdG was increased in placentas in IUGR cases compared to PE or HELLP pregnancies. In cases after 34-week gestation, p21 was higher in SGA and IUGR than in controls and late PE. Moreover, p53 was increased after 34-week gestation in IUGR pregnancies. Placentas from pathological pregnancies had an altered expression of 8-OHdG, p53, p21, APE1, IL-6, and IL-8. The alterations of intracellular pathways involving these elements may be the cause or the consequence of placental dysfunction, but in any case reflect an impaired placental function, possibly due to increased aging velocity in pathologic cases.

Aim: To determine the accuracy of cervical elastography in predicting labor induction success., Materials and Methods: A systematic search, review, and meta-analysis of observational studies published in English language between January 2000 and October 2014 was performed. It included studies considering cervix sonoelastography as the index test and successful labor or vaginal delivery as the reference standard. As cervix length and Bishop score were considered comparator tests, the quality of the included studies was assessed using quality assessment tool for diagnostic accuracy studies (QUADAS) tool., Results: A total of four studies assessing 323 women before medical induction of labor were included. Cervical elastography, cervical length, and Bishop score showed a diagnostic odds ratio (DOR) with 95% confidence interval (CI) for successful labor prediction of 3.50 (1.93-6.35), 3.35 (1.94-5.77), and 1.45 (0.33-6.41), respectively. In addition, cervical elastography, cervical length, and Bishop score showed a DOR with 95% CI for successful vaginal delivery prediction of 5.24 (3.23-8.50), 4.94 (2.72-8.98), and 4.62 (0.69-30.94), respectively. Considering the summary of receiver operating characteristic curves we show that cervical elastography or length are similarly reliable, and both are more reliable to predict successful labor than the Bishop score. Two studies were excluded because it was not possible to retrieve data for the meta-analysis. Among the excluded studies, one found no significant contribution from elastography for prediction of successful labor induction., Conclusions: Even though there is a limited number of studies included and the heterogeneity of the methods used, cervical elastography seems to be a promising tool for predicting successful labor induction and vaginal delivery in women treated by medical induction of labor.

Two vaccines focused on the prevention of HPV-related diseases have been introduced in the last decade, the quadrivalent vaccine Gardasil and the bivalent vaccine Cervarix. They are targeted to prevent precancerous and cancerous lesions not only of the cervix, but also of the vulva, vagina, anal and head-neck region. Furthermore, the protection of the quadrivalent vaccine Gardasil includes also genital warts and recurrent respiratory Papillomatosis, two benign conditions with high socio-economic impact. Although their efficacy in reducing the burden of HPV-related pathologies has been already documented, second-generation HPV vaccines are being developed in order to overcome major limitations, above all the cost of production, distribution and acceptance, thus promoting an easier access to vaccination, especially in developing countries. Recently a new multivalent VLP vaccine active against nine HPV subtypes, called Gardasil 9 (Merck & Co., Inc., Whitehouse Station, NJ, USA), has been approved, showing promising preliminary results. In this article, we outline the strategies adopted for second-generation HPV vaccine engineering, the latest HPV vaccines available at this time, as well as those currently in development.

Peritoneal metastasis from breast cancer is a serious and deadly condition only limited considered in the literature. Our aim was to study prevalence, risk factors, and prognosis of breast cancer peritoneal metastasis. We retrospectively analyzed 3096 women with a diagnosis of invasive breast cancer. We took into consideration presence and localization of breast cancer distant metastasis as well as the possible risk factors and survival from the diagnosis of the breast cancer metastasis. The prevalence of breast cancer peritoneal metastases was 0.7 % (22/3096), representing the 7.6 % (22/289) of women affected by distant metastases. Moreover, independent risk factors for breast cancer peritoneal metastases resulted high grading, lobular invasive histology, and advanced T and N stage at diagnosis. Overall survival after metastasis diagnosis was shorter in women affected by peritoneal metastases or brain metastases in comparison to other metastatic women. Breast cancer peritoneal metastases were uncommon but not rare events with a poor prognosis after standard treatments.

Introduction: The role of ductal carcinoma in situ (DCIS) component on the outcome of invasive breast cancer is not yet completely clear. Our study aims to assess the impact of the presence and quantity of DCIS component on the outcome of patients operated for invasive breast cancer., Materials and Methods: We collected retrospective data about patients operated at their breast for invasive cancer between 2007 and 2012, focusing on the presence of DCIS component. Then, we divided patients into four groups based on the quantity of DCIS component as follows: not found (group A), minimal (group B, <25%), extensive (group C, 25-75%), and prevalent (group D, >75%). We further defined "extensive intraductal component" (EIC) groups C and D together., Results: DCIS component was associated with young age, familial history of breast cancer and worse biological characteristics, including high grading, higher prevalence of Her2/Neu overexpression, hormone receptors negativity, comedo-like necrosis and multifocality/multicentricity. Despite the unfavorable prognostic factors, invasive cancers associated with EIC were frequently treated with radical surgery and resulted to have long disease-free survival and low local recurrence rate. In patients with DCIS component (groups B, C, and D) the extension of this component resulted indirectly correlated with local recurrence rate, tumor lymphovascular invasion, and lymphnode extracapsular invasion. The highest prevalence of local recurrences was found in group B, which tended to be less frequently treated with radical surgery than group D (P<0.05) and C (P=n.s.)., Conclusions: Different clinical and tumor features among invasive breast cancer with and without DCIS component indicate that they are distinct entities probably originating by different pathways that deserve to be studied. Furthermore, the controversial results about the management of cancer with minimal intraductal component require further studies in order to reduce local recurrence.

Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy., Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)., Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean±SD: TTR 3.96±0.89 μmol/L vs. 4.68±1.21 μmol/L, RBP4 1.13±0.25 μmol/L vs. 1.33±0.38 μmol/L and ROH 1.33±0.17 μmol/L vs. 1.62±0.29 μmol/L, p<0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p<0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95% CI 0.87-0.98, p<0.05)., Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM.

Background: Infection with high-risk human papillomavirus (HPV) is linked to a sub-group of squamous cell oropharyngeal tumors (OPSCC). Our aim was to compare an HPV Polymerase Chain Reaction (PCR) assay and p16(INK4A) expression status by immunohistochemistry (IHC) as a surrogate marker., Materials and Methods: This was a retrospective study considering patients affected by squamous cell oropharyngeal tumors. All included samples were processed for IHC for p16(INK4A) and tested by PCR for detection of HPV DNA and HPV genotyping., Results: A total of 84 patients affected by squamous cell oropharyngeal tumors were included and tested. A significant positive correlation was found between HPV PCR and p16(INK4A) IHC but the agreement was poor (k coefficient of 0.25). In fact, the sensitivity of p16(INK4A) IHC positivity in detecting HPV PCR positivity was low (28.21%, 95% confidence interval=16.54% - 43.78%)., Conclusion: Positivity of p16(INK4A) by IHC had a low sensitivity in detecting HPV DNA and our results suggest the need at least to test p16(INK4A) IHC- negative samples using HPV PCR to increase detection accuracy and provide valuable information for the clinical management of these patients., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The necessity of complete axillary lymph node dissection (CALND) after sentinel lymph node biopsy (SLNB) for women with sentinel lymph node metastases is a matter of debate because non-sentinel lymph nodes after CALND contain no further metastases in about 50 % of cases. Our study aims to determine the applicability in our setting of two different validated nomograms to predict axillary lymph node status after SLNB., Methods: We collected data about all women who underwent SLNB in our Department of Surgery from 2007 to 2010, focusing on tumor, patient, and breast characteristics. Data was analyzed by R (version 2.15.2); p < 0.05 was considered significant., Results: Among 511 women who underwent SLNB, 126 received CALND due to sentinel lymph node metastasis, and 73.0 % of these had no further metastatic non-sentinel lymph node. The area under the receiver operating characteristic (ROC) curves for the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram and the Tenon score were 78.5 % (95 % CI 70.1-86.8 %) and 77.0 % (95 % CI 67.9-86.0 %) (p = 0.678), respectively., Conclusions: Both the MSKCC nomogram and the Tenon score were predictive for the axillary non-sentinel lymph node status by SLNB. The MSKCC nomogram was the more accurate of the two and the Tenon score was the easier one to apply.

Aim: To evaluate the influence on feasibility and reliability of quantitative tissue Doppler imaging (TDI)-based cervical elastography of the cycle phase and of the derivative pitch (DP) selected during tissue strain (TS) calculation across all three trimesters of pregnancy., Materials and Methods: The pilot study included 17 patients collected between the 12th and the 42nd week of gestation. The TS was measured by a single operator by quantitative elastography. The influence of DP values (5, 10, 15, and 20 mm) and phase (compression versus relaxation) was tested after a cycle of freehand compression and relaxation of the cervix through the vaginal probe. Feasibility and intra-operator intraclass correlation coefficient (ICC) agreement for strain measurement were also evaluated for every setting used., Results: TS values were inversely correlated with DP and were slightly higher if measured during a compression phase. TDI-based cervical elastography was feasible in all cases. Reliability for the process of strain calculation of different raw datasets was very good (ICC agreement ranging between 0.79 and 0.87), while excellent considering the same raw dataset (ICC agreement ranging between 0.93 and 0.95)., Conclusions: The DP and cycle phase influenced the strain values calculated. Nonetheless, TDI-based cervical elastography was feasible and reliable for all the settings considered.

Objective: To test the immunohistochemical staining pattern of some mismatch repair (MMR) system proteins in endometriotic tissue (ET) and eutopic endometrium., Methods: This was a retrospective study conducted at the Pathology and Obstetrics and Gynecology Departments of the Udine University Hospital. We analyzed 528 samples obtained from 246 patients affected by endometriosis and 71 samples from 71 patients with normal endometrium. A tissue microarray model was used to analyze the immunohistochemical expression of MMR system proteins., Results: Significant loss of MMR proteins was found in the stromal component of ETs. We found MSH2 to be expressed at a higher level than any other MMR system proteins in eutopic endometrium and ETs, to be significantly correlated to Ki-67 expression in both stromal and glandular components of ETs, and to be expressed at a significantly higher level in ETs than in eutopic endometrium. When considering the subgroup of endometriosis with high recurrence rate and glandular cytoplasmic staining for aurora A kinase, we found MMR proteins expressed at a significantly higher level in these ETs than in other ETs and eutopic endometrium of unaffected women., Conclusions: We found significant loss of MMR proteins (known to be associated with microsatellite instability) in the stromal component of ETs. The group of ETs with glandular cytoplasmic staining for aurora A kinase had higher MMR protein expression, suggesting an increased activity of this system. Our result suggests a novel role of increased MSH2 expression in cellular proliferation of endometriosis.

Background: The role of surgical therapy in patients with liver metastases from neuroendocrine tumors (NETs) is unclear. In this study, the results obtained with curative or palliative resection, by reviewing recent literature and performing a meta-analysis, were examined., Materials and Methods: A systematic review and meta-analysis of observational studies published between January 1990 and October 2013 were performed. Studies that evaluated the different survival between patients treated by curative or palliative surgical resection of hepatic metastases from NETs were considered. The collected studies were evaluated for heterogeneity, publication bias, and quality. To calculate the pooled hazard ratio (HR) estimate and the 95% confidence interval (95% CI), a fixed-effects model was applied., Results: After the literature search, 2,546 studies were found and, among 38 potentially eligible studies, 3 were considered. We did not find a significant longer survival in patients treated with curative surgical resection of hepatic metastases when compared to palliative hepatic resection HR 0.40 (95% CI: 0.14-1.11). In one study, palliative resection of hepatic metastases significantly increased survival when compared to embolization., Conclusions: Curative and also palliative surgery of NETs liver metastases may improve survival outcome. However, further randomized clinical trials are needed to elucidate this argument.

Introduction: Breast cancer screening is known to reduce mortality. In the present study, we analyzed the prevalence of breast cancers detected through screening, before and after introduction of an organized screening, and we evaluated the overall survival of these patients in comparison with women with an extrascreening imaging-detected breast cancer or those with palpable breast cancers., Materials and Methods: We collected data about all women who underwent a breast operation for cancer in our department between 2001 and 2008, focusing on type of tumor diagnosis, tumor characteristics, therapies administered, and patient outcome in terms of overall survival, and recurrences. Data was analyzed by R (version 2.15.2), and P < .05 was considered significant., Results: Among the 2070 cases of invasive breast cancer we considered, 157 were detected by regional mammographic screening (group A), 843 by extrascreening breast imaging (group B: 507 by mammography and 336 by ultrasound), and 1070 by extrascreening breast objective examination (group C). The 5-year overall survival in groups A, B, and C were, respectively, 99% (95% CI, 98%-100%), 98% (95% CI, 97%-99%), and 91% (95% CI, 90%-93%), with a significant difference between the first 2 groups and the third (P < .05) and a trend between groups A and B (P = .081)., Conclusion: The diagnosis of invasive breast cancer with screening in our population resulted in a survival gain at 5 years from the diagnosis, but a longer follow-up is necessary to confirm this data., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The present study evaluates the accuracy of computed tomographic (CT) scan and positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET)/CT for the quantification of peritoneal carcinomatosis (PC) in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were retrospectively collected for 58 patients, who were considered for CRS and HIPEC. The predictability, sensitivity, specificity and accuracy values of FDG-PET/CT and CT were tested. Preoperative CT and FDG-PET/CT failed to detect PC in 9% and 17% of cases, respectively, with a sensitivity of 91% and 82%, a specificity of 33% and 67%, an area under the curve (AUC) of 62% and 74% and a negative likelihood ratio of 0.27 (CI.95 0.07-1.09) and 0.27 (CI.95 0.11-0.62), respectively (p=0.469). Both techniques showed a high prevalence of PC extent underestimation (CT 47% and FDG-PET/CT 43% of cases). Small bowel involvement and optimal CRS had a prevalence of 60% and 76%, respectively, and both the CT and FDG-PET/CT imaging techniques were inaccurate at predicting them (AUC 53% and 52% for small bowel involvement, and 63% and 58% for optimal CRS, respectively). In conclusion both CT and FDG-PET/CT had low preoperative staging reliability for PC, and this can strongly influence the ability to implement the correct treatment strategy for patients with PC.

Sentinel lymph node biopsy (SLNB) completely changed the impact of breast surgery on patients psycho-physical wellness, reducing morbidity associated with complete axillary lymph node dissection (CALND) while granting an adequate breast cancer staging. We reviewed our experience with the SLNB in a University Clinic. We collected data about all breast cancer patients submitted to SLNB from 2002 to 2010, and analyzed them with R (version 2.15.2), considering significant p<0.05. We performed 615 SLNBs on 607 patients, with a mean age of 59.86 (±10.76). Sentinel node detection rate resulted 99,7%, with a mean number of biopsied nodes of 1.64 (±0.67), axillary localization in 98% of cases, and negative intraoperative histological finding in the 86.2% of cases. Prevalence of ITCs, micrometastasis, macrometastasis and pericapsular metastasis resulted respectively 0.6%, 4.9%, 7.5% and 8.8%. Among women who received CALND, mean number of examined nodes was 16.36 (±6.19) and mean number of metastatic non-sentinel nodes was 0.97 in case of micrometastasis, 2.65 in case of macrometastasis, and up to 9.88 when pericapsular invasion was described. To conclude, our data confirm the role of nodal metastasis size in the prediction of non-sentinel node involvement, but further studies are required in order to better assess the role of ITCs and micrometastasis in the diagnostic and therapeutic management of breast cancer, with the final aim to reduce the surgical complications of axilla demolition when unnecessary.

Paget disease is a rare disorder of the skin of the vulva, comprising less than 1% of vulvar neoplasms. Surgical excision is considered the standard of care. While the invasive variant of Paget disease is rare, frequent local recurrences from non-invasive disease, which are inoperable, constitute a major clinical problem. In this article we report on a 71-year-old patient with recurrent disease treated successfully with imiquimod cream. Symptoms such as local itching subsided shortly after initiation of treatment. Four weeks later, first signs of resolution could be demonstrated colposcopically. Within 8 weeks, complete clinical remission was achieved. Thus, topical imiquimod is not only effective as treatment of vulvar intraepithelial neoplasia, but may also be used for selected patients with recurrent Paget disease as an alternative to repeat surgical interventions.