Vitamin D Supplementation in Neonatal and Infant MIS-C Following COVID-19 Infection.

To date, the SARS-CoV-2 pandemic still represents a great clinical challenge worldwide, and effective anti-COVID-19 drugs are limited. For this reason, nutritional supplements have been investigated as adjuvant therapeutic approaches in disease management. Among such supplements, vitamin D has gained great interest, due to its immunomodulatory and anti-inflammatory actions both in adult and pediatric populations. Even if there is conflicting evidence about its prevention and/or mitigation effectiveness in SARS-CoV-2 infection, several studies demonstrated a strict correlation between hypovitaminosis D and disease severity in acute COVID-19 and MIS-C (multisystem inflammatory syndrome in children). This narrative review offers a resume of the state of the art about vitamin D's role in immunity and its clinical use in the context of the current pandemic, specially focusing on pediatric manifestations and MIS-C. It seems biologically reasonable that interventions aimed at normalizing circulating vitamin D levels could be beneficial. To help clinicians in establishing the correct prophylaxis and/or supportive therapy with vitamin D, well-designed and adequately statistically powered clinical trials involving both adult and pediatric populations are needed. Moreover, this review will also discuss the few other nutraceuticals evaluated in this context.

Implementing Enhanced Recovery After Surgery for hysterectomy in a hospital network with audit and feedback: A stepped-wedge cluster randomised trial.

OBJECTIVE: To evaluate the effectiveness of implementing the Enhanced Recovery After Surgery (ERAS) protocol in patients undergoing elective hysterectomy in a network of regional hospitals, supported by an intensive audit-and-feedback (A&F) approach. DESIGN: A multi-centre, stepped-wedge cluster randomised trial (ClinicalTrials.gov NCT04063072). SETTING: Gynaecological units in the Piemonte region, Italy. POPULATION: Patients undergoing elective hysterectomy, either for cancer or for benign conditions. METHODS: Twenty-three units (clusters), stratified by surgical volume, were randomised into four sequences. At baseline (first 3 months), standard care was continued in all units. Subsequently, the four sequences implemented the ERAS protocol successively every 3 months, after specific training. By the end of the study, each unit had a period in which standard care was maintained (control) and a period in which the protocol, supported by feedback, was applied (experimental). MAIN OUTCOME MEASURES: Length of hospital stay (LOS), without outliers (>98th percentile). RESULTS: Between September 2019 and May 2021, 2086 patients were included in the main analysis with an intention-to-treat approach: 1104 (53%) in the control period and 982 (47%) in the ERAS period. Compliance with the ERAS protocol increased from 60% in the control period to 76% in the experimental period, with an adjusted absolute difference of +13.3% (95% CI 11.6% to 15.0%). LOS, moving from 3.5 to 3.2 days, did not show a significant reduction (-0.12 days; 95% CI -0.30 to 0.07 days). No difference was observed in the occurrence of complications. CONCLUSIONS: Implementation of the ERAS protocol for hysterectomy at the regional level, supported by an A&F approach, resulted in a substantial improvement in compliance, but without meaningful effects on LOS and complications. This study confirms the effectiveness of A&F in promoting important innovations in an entire hospital network and suggests the need of a higher compliance with the ERAS protocol to obtain valuable improvements in clinical outcomes.

Impact of different follow-up regimens on health-related quality of life and costs in endometrial cancer patients: Results from the TOTEM randomized trial.

PURPOSE: To investigate whether intensive follow-up (INT) after surgery for endometrial cancer impact health-related quality of life (HRQoL) and healthcare costs compared to minimalist follow-up (MIN), in the absence of evidence supporting any benefit on 5-year overall survival. METHODS: In the TOTEM trial, HRQoL was assessed using the SF-12 and the Psychological General Well-Being (PGWB) questionnaires at baseline, after 6 and 12 months and then annually up to 5 years of follow-up. Costs were analyzed after 4 years of follow-up from a National Health Service perspective, stratified by risk level. The probability of missing data was analyzed for both endpoints. RESULTS: 1847 patients were included in the analyses. The probability of missing data was not influenced by the study arms (MIN vs INT OR: 0.97 95%CI: 0.87-1.08). Longitudinal changes in HRQoL scores did not differ between the two follow-up regimens (MIN vs INT SF-12 PCS: -0.573, CI95%: -1.31; 0.16; SF-12 MCS: -0.243, CI95%: -1.08; 0.59; PGWB: -0.057, CI95%: -0,88; 0,77). The mean cost difference between the intensive and minimalist arm was €531 for low-risk patients and €683 for high-risk patients. CONCLUSION: In the follow-up of endometrial cancer after surgery, a minimalist treatment regimen did not affect quality of life and was cost-saving in both low-risk and high-risk recurrence patients. As previous results showed no survival benefit, a minimalist approach is justified. The relevant proportion of missing data on secondary outcomes of interest could be a critical point that deserves special attention.

Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer.

Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumor cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.

Survival after sentinel lymph node biopsy for early cervical cancers: a systematic review and meta-analysis.

BACKGROUND: Sentinel lymph node biopsy represents an alternative to pelvic lymphadenectomy for lymph node staging of early-stage cervical carcinoma, but prospective evidence on long-term oncological safety of sentinel lymph node biopsy alone versus pelvic lymphadenectomy is missing. OBJECTIVE: To investigate, with this meta-analysis, the impact of sentinel lymph node biopsy alone versus pelvic lymphadenectomy on survival for patients with early-stage cervical cancer. METHODS: A systematic literature review was performed. We excluded studies in which pelvic lymphadenectomy was systematically performed after every sentinel lymph node biopsy, including only articles where pelvic lymphadenectomy was performed because sentinel lymph node biopsy was not conclusive. A meta-analysis was carried out combining 5-year disease-free survival and overall survival rates with a random and fixed effect model. Heterogeneity was tested using the Cochran Χ2 test and quantified with Higgins information I2. RESULTS: The search of databases and registers found 927 items and six articles (two retrospective and four prospective). The median time of follow-up was 34.8 months (range 13-53). Overall common effect disease-free survival was 98% while random effect disease-free survival was 94%. Overall heterogeneity was 77%. A subgroup analysis was applied, dividing studies into one group including sentinel lymph node biopsy negative data only (common effect disease-free survival 91%; random effect disease-free survival 90%), and one group with a negative and positive sentinel lymph node biopsy (common effect disease-free survival 98%; random effect disease-free survival 96%). In the analysis of overall survival, positive and negative sentinel lymph node biopsy cases were examined together (common and random effect overall survival 99%). Ultrastaging did not affect disease-free survival (common and random effect disease-free survival 92% in the ultrastaging group vs common effect disease-free survival 99% and random effect disease-free survival 96% in the non-ultrastaging group). CONCLUSIONS: Both 5-year disease-free survival and overall survival rate after sentinel lymph node biopsy alone are higher than 90% and do not differ from pelvic lymphadenectomy survival data. Ultrastaging did not impact survival.

The Use of Artificial Intelligence for Complete Cytoreduction Prediction in Epithelial Ovarian Cancer: A Narrative Review.

INTRODUCTION: In patients affected by epithelial ovarian cancer (EOC) complete cytoreduction (CC) has been associated with higher survival outcomes. Artificial intelligence (AI) systems have proved clinical benefice in different areas of healthcare. OBJECTIVE: To systematically assemble and analyze the available literature on the use of AI in patients affected by EOC to evaluate its applicability to predict CC compared to traditional statistics. MATERIAL AND METHODS: Data search was carried out through PubMed, Scopus, Ovid MEDLINE, Cochrane Library, EMBASE, international congresses and clinical trials. The main search terms were: Artificial Intelligence AND surgery/cytoreduction AND ovarian cancer. Two authors independently performed the search by October 2022 and evaluated the eligibility criteria. Studies were included when data about Artificial Intelligence and methodological data were detailed. RESULTS: A total of 1899 cases were analyzed. Survival data were reported in 2 articles: 92% of 5-years overall survival (OS) and 73% of 2-years OS. The median area under the curve (AUC) resulted 0,62. The model accuracy for surgical resection reported in two articles reported was 77,7% and 65,8% respectively while the median AUC was 0,81. On average 8 variables were inserted in the algorithms. The most used parameters were age and Ca125. DISCUSSION: AI revealed greater accuracy compared against the logistic regression models data. Survival predictive accuracy and AUC were lower for advanced ovarian cancers. One study analyzed the importance of factors predicting CC in recurrent epithelial ovarian cancer and disease free interval, retroperitoneal recurrence, residual disease at primary surgery and stage represented the main influencing factors. Surgical Complexity Scores resulted to be more useful in the algorithms than pre-operating imaging. CONCLUSION: AI showed better prognostic accuracy if compared to conventional algorithms. However further studies are needed to compare the impact of different AI methods and variables and to provide survival informations.

Minimally Invasive Compared With Open Surgery in High-Risk Endometrial Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare outcomes between minimally invasive surgery and open surgery in patients with high-risk endometrial cancer. DATA SOURCES: A cohort study of all patients who underwent surgery for high-risk endometrial cancer between 1999 and 2016 at Mayo Clinic (Rochester, Minnesota) and a literature search of MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, and Scopus of all published studies until December 2020. METHODS OF STUDY SELECTION: The systematic review identified 2,332 patients (14 studies, all retrospective except a subanalysis of a randomized comparison) and the cohort study identified 542 additional patients. Articles were included if reporting original data on overall survival and disease-free survival among patients with high-risk endometrial cancer, defined as International Federation of Gynecology and Obstetrics grade 3 endometrioid, serous, clear cell, mixed histology, or uterine carcinosarcoma. Studies that did not report at least one of the main outcomes, those in which one surgical technique (robotic or laparoscopic surgery) was missing in the comparison analysis with open surgery, and case reports were excluded. Additional data were extracted from a retrospective cohort of patients from Mayo. A random-effect model was used for meta-analysis. TABULATION, INTEGRATION, AND RESULTS: This systematic review and meta-analysis was registered in PROSPERO. Literature search and data extraction were performed independently by two reviewers, as well as quality assessment using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, and the Newcastle-Ottawa Scale. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Meta-analysis showed that disease-free survival and overall survival in patients with high-risk endometrial cancer who underwent minimally invasive surgery were not statistically different from those of patients who underwent open abdominal surgery (relative risk [RR] 0.93, 95% CI 0.82-1.05, I2 20%, P=.23; and RR 0.92, 95% CI 0.77-1.11, I2 31%, P=.12, respectively). Subgroup analysis by stage (early vs advanced) did not identify a difference between surgical approaches. CONCLUSION: Minimally invasive surgery and open surgery had similar disease-free survival and overall survival in patients with high-risk endometrial cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021275535.

Fetal Brain Damage during Maternal COVID-19: Emerging Hypothesis, Mechanism, and Possible Mitigation through Maternal-Targeted Nutritional Supplementation.

The recent outbreak of the novel Coronavirus (SARS-CoV-2 or CoV-2) pandemic in 2019 and the risk of CoV-2 infection during pregnancy led the scientific community to investigate the potential negative effects of Coronavirus infection on pregnancy outcomes and fetal development. In particular, as CoV-2 neurotropism has been demonstrated in adults, recent studies suggested a possible risk of fetal brain damage and fetal brain development impairment, with consequent psychiatric manifestations in offspring of mothers affected by COronaVIrus Disease (COVID) during pregnancy. Through the understanding of CoV-2's pathogenesis and the pathways responsible for cell damage, along with the available data about neurotropic virus attitudes, different strategies have been suggested to lower the risk of neurologic disease in newborns. In this regard, the role of nutrition in mitigating fetal damages related to oxidative stress and the inflammatory environment during viral infection has been investigated, and arginine, n3PUFA, vitamins B1 and B9, choline, and flavonoids were found to be promising in and out of pregnancy. The aim of this review is to provide an overview of the current knowledge on the mechanism of fetal brain damage and the impact of nutrition in reducing inflammation related to worse neurological outcomes in the context of CoV-2 infections during pregnancy.

Use of Positron Emission Tomography for Pregnancy-Associated Cancer Assessment: A Review.

Background. Positron emission tomography (PET) has proven clinical utility both in the initial and relapse staging phase, but this technique is controversial during pregnancy. The objective of this review is to provide a compendium of available information on the use of PET during pregnancy. Materials and methods. A systematic literature review was conducted from 1 January 2004 until 20 May 2021. A total of 4 small series and 9 case reports consisting of 25 cases were selected. Results. During the first trimester, the fetus is most sensitive to ionization damage, so lower doses are recommended (2.6E-02 mGy/MBq). Fetal-effective doses are higher in this period and the average fetal dose (4.06 ± 3.22 mGy) remains significantly below the threshold for deterministic effects. During the second and third trimesters, recommended doses are higher (1.4E-02 mGy/MBq at 6 months, and 6.9E-03 mGy/MBq at 9 months of gestation). 18F-FDG activity was distributed to the whole fetus with a prevalence of myocardial tissue in seven cases. The use of special precautions, such as PET-magnetic resonance (MR) and urinary bladder catheterization, reduces the amount of radioactive tracer. Breastfeeding interruption is not recommended. Conclusions. 18F-FDG PET is not contraindicated in pregnancy, but multidisciplinary discussion is necessary and strict precautions are recommended.

Effectiveness of Intensive Versus Minimalist Follow-Up Regimen on Survival in Patients With Endometrial Cancer (TOTEM Study): A Randomized, Pragmatic, Parallel Group, Multicenter Trial.

PURPOSE: In the absence of clear evidence from randomized trials, the intensity of follow-up regimens after surgical treatment of endometrial cancer is highly variable in clinical practice. To reduce this uncertainty, we conducted a randomized trial to test whether an intensive (INT) versus a minimalist (MIN) follow-up regimen improves overall survival (OS) in patients undergoing operation for endometrial cancer. METHODS: The TOTEM study was a large, pragmatic randomized trial, conducted in 42 hospitals (in Italy and France) including patients surgically treated for endometrial cancer, in complete clinical remission, International Federation of Gynecology and Obstetrics stage I-IV. After stratification by center and risk of relapse (low or high), patients were randomly assigned (1:1) to INT or MIN hospital-based follow-up regimens. The study was powered to demonstrate an absolute improvement of 5% of the 5-year OS with the INT regimen. RESULTS: In total, 1,871 patients were randomly assigned between November 2008 and July 2018, and 1,847 patients (98.7%) were available for the final analysis (60% low risk). After a median follow-up of 69 months, the 5-year OS was 90.6% in the INT and 91.9% in the MIN arms (hazard ratio, 1.13, 95% CI, 0.86 to 1.50, P = .380). No differences in OS were found in subgroup analyses considering age, cancer treatment, risk of relapse, and degree of adherence of the center to the scheduled follow-up. The probability of detecting a relapse was slightly higher in the INT arm (hazard ratio, 1.17; 95% CI, 0.92 to 1.48; P = .194). CONCLUSION: An INT follow-up in endometrial cancer-treated patients does not improve OS, even in high-risk patients. According to available evidence, there is no need to routinely add vaginal cytology, laboratory, or imaging investigations to the MIN regimens used in this trial.

Response to Chemotherapy and Clinical Outcome of Patients With Recurrent Epithelial Ovarian Cancer After PARP Inhibitor Maintenance Treatment: A Multicenter Retrospective Italian Study.

BACKGROUND/AIM: To assess response rates and survival in patients with recurrent platinum-sensitive epithelial ovarian cancer (EOC) who received PARP inhibitor (PARP-i) maintenance and who subsequently underwent salvage chemotherapy for disease progression after PARPi. PATIENTS AND METHODS: This retrospective investigation analyzed 103 patients who were treated in five Italian Gynecologic centers. The PARPi used was olaparib in 46 patients, niraparib in 55, and rucaparib in 2. The interval time between the last cycle of pre- PARPi platinum-based chemotherapy and the diagnosis of progression during PARPi maintenance was defined as platinum-free interval (PFI). RESULTS: Of the 28 patients with PFI <6 months, 23 received chemotherapy (non-platinum single agent, 20; trabectedin + pegylated liposomal doxorubicin (PLD), 3). Forty-two of the 43 patients with PFI 6-12 months underwent chemotherapy (platinum-based chemotherapy,11; trabectedin + PLD, 10; non platinum-single agent, 21). Thirty-one of the 32 patients with PFI >12 months received chemotherapy (platinum-based chemotherapy, 23; trabectedin + PLD, 3; non platinum - single agent, 5). An objective response was found in 13.0%, 26.2% and 41.9 % of the patients with PFI <6 months, 6-12 months, and >12 months (p= 0.03), respectively, and the corresponding median survivals after PARPi were 8.9 months, 17.5 months and 24.1 months (p= 0.002), respectively. CONCLUSION: Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from the last platinum cycle have shown response rates ranging from 47.2% to 66%. Response rates to chemotherapy for progression after PARPi appear to be lower than those expected according to PFI.

Association of Chemotherapy Timing in Pregnancy With Congenital Malformation.

Importance: Chemotherapy during the first trimester of pregnancy should be avoided owing to the risk of congenital malformations. However, the precise gestational age at which chemotherapy can be initiated safely remains unclear. Objective: To assess congenital malformation rates associated with gestational age at initiation of chemotherapy among pregnant women with cancer. Design, Setting, and Participants: This multicenter cohort study evaluated all pregnant women who received chemotherapy between 1977 and 2019 registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. Data were analyzed from February 15 to June 2, 2020. Exposures: Cancer treatment with chemotherapy during pregnancy. Main Outcomes and Measures: Analysis was focused on major and minor structural malformations in offspring, defined by EUROCAT, detected during pregnancy or at birth. Results: A total of 755 women in the INCIP database who underwent cancer treatment with chemotherapy during pregnancy were included in analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Among offspring, the major congenital malformation rate was 3.6% (95% CI, 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%). Chemotherapy exposure prior to 12 weeks gestational age was associated with a high rate of major congenital malformations, at 21.7% (95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after gestational age 12 weeks, the frequency of major congenital malformations was 3.0% (95% CI, 1.9%-4.6%), which was similar to the expected rates in the general population. Minor malformations were comparable when exposure occurred before or after gestational age 12 weeks (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy prior to 12 weeks gestation, 17 (58.6%) were not aware of pregnancy, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate their pregnancy (3 women [10.3%]). Conclusions and Relevance: This cohort study found that chemotherapy was associated with an increased risk of major congenital malformations only in the first 12 weeks of pregnancy. The risk of congenital malformations when chemotherapy was administered during the first trimester and the high number of incidental pregnancies during cancer treatment in the INCIP registry underscore the importance of contraceptive advice and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer.

Adjuvant chemotherapy in early-stage endometrioid endometrial cancer with >50% myometrial invasion and negative lymph nodes.

OBJECTIVE: The role of adjuvant chemotherapy as an addition or alternative to radiotherapy for early-stage high-risk endometrioid endometrial cancer is controversial. This study aimed to investigate the role of adjuvant chemotherapy in early-stage high-risk endometrioid endometrial cancer. METHODS: We identified patients with stage I or II endometrioid grade 2 or 3 endometrial cancer with myometrial invasion >50% and negative lymph nodes after pelvic with or without para-aortic lymphadenectomy at four institutions (USA and Italy). Associations between chemotherapy and cause-specific and recurrence-free survival were assessed with Cox proportional hazards models. Hematogenous, peritoneal, and lymphatic recurrences were defined as 'non-vaginal'. RESULTS: We identified 329 patients of mean (SD) age 66.4 (9.8) years. The median follow-up among those alive was 84 (IQR 44-133) months. The 5-year cause-specific survival was 86.1% (95% CI 82.0% to 90.4%) and the 5-year recurrence-free survival was 82.2% (95% CI 77.9% to 86.8%). Stage II (vs stage IB) was associated with poorer cause-specific and recurrence-free survival. A total of 58 (90.6%) of 64 patients who had chemotherapy had 4-6 cycles of platinum-based regimen. In adjusted analysis, we did not observe a statistically significant improvement in cause-specific survival (HR 0.34; 95% CI 0.11 to 1.03; p=0.06) or non-vaginal recurrence-free survival (HR 0.36; 95% CI 0.12 to 1.08; p=0.07) with adjuvant chemotherapy. Sixteen of 18 lymphatic recurrences (88.9%; 3/5 pelvic, all 13 para-aortic) were observed in the 265 patients who did not receive adjuvant chemotherapy. Among stage II patients, no deaths (100% 5-year recurrence-free survival) were observed in the eight patients who received adjuvant chemotherapy compared with 66% 5-year recurrence-free survival in the 34 patients who did not. CONCLUSION: Although we observed that adjuvant chemotherapy was associated with improved oncologic outcomes in early-stage high-risk endometrioid endometrial cancer, the associations did not meet conventional levels of statistical significance. Further research is warranted in this relatively uncommon subgroup of patients.

A simplified fascial model of pelvic anatomical surgery: going beyond parametrium-centered surgical anatomy.

The classical surgical anatomy of the female pelvis is limited by its gynecological oncological focus on the parametrium and burdened by its modeling based on personal techniques of different surgeons. However, surgical treatment of pelvic diseases, spreading beyond the anatomical area of origin, requires extra-regional procedures and a thorough pelvic anatomical knowledge. This study evaluated the feasibility of a comprehensive and simplified model of pelvic retroperitoneal compartmentalization, based on anatomical rather than surgical anatomical structures. Such a model aims at providing an easier, holistic approach useful for clinical, surgical and educational purposes. Six fresh-frozen female pelves were macroscopically and systematically dissected. Three superficial structures, i.e., the obliterated umbilical artery, the ureter and the sacrouterine ligament, were identified as the landmarks of 3 deeper fascial-ligamentous structures, i.e., the umbilicovesical fascia, the urogenital-hypogastric fascia and the sacropubic ligament. The retroperitoneal areolar tissue was then gently teased away, exposing the compartments delimited by these deep fascial structures. Four compartments were identified as a result of the intrapelvic development of the umbilicovesical fascia along the obliterated umbilical artery, the urogenital-hypogastric fascia along the mesoureter and the sacropubic ligaments. The retroperitoneal compartments were named: parietal, laterally to the umbilicovesical fascia; vascular, between the two fasciae; neural, medially to the urogenital-hypogastric fascia and visceral between the sacropubic ligaments. The study provides the scientific rational for a model of pelvic retroperitoneal anatomy based on identifiable anatomical structures and suitable for surgical planning and training.

Missing data in longitudinal studies: Comparison of multiple imputation methods in a real clinical setting.

RATIONALE, AIMS, AND OBJECTIVES: Missing data represent a challenge in longitudinal studies. The aim of the study is to compare the performance of the multivariate normal imputation and the fully conditional specification methods, using real data set with missing data partially completed 2 years later. METHOD: The data used came from an ongoing randomized controlled trial with 5-year follow-up. At a certain time, we observed a number of patients with missing data and a number of patients whose data were unobserved because they were not yet eligible for a given follow-up. Both unobserved and missing data were imputed. The imputed unobserved data were compared with the corresponding real information obtained 2 years later. RESULTS: Both imputation methods showed similar performance on the accuracy measures and produced minimally biased estimates. CONCLUSION: Despite the large number of repeated measures with intermittent missing data and the non-normal multivariate distribution of data, both methods performed well and was not possible to determine which was better.

Renal and Bladder Cancer During Pregnancy: A Review of 47 Cases and Literature-based Recommendations for Management.

OBJECTIVE: To provide contemporary gestational age-specific recommendations for management, a retrospective series of patients with renal or bladder cancer during pregnancy is reported. METHODS: Obstetric and oncological data of pregnant patients with a diagnosis of renal or bladder cancer were selected from the worldwide registry of the International Network of Cancer, Infertility and Pregnancy. In addition, the literature was reviewed for recent case reports since last reviews in 2014 for renal cancer and 2004 for bladder cancer. RESULTS: International Network of Cancer, Infertility and Pregnancy registered 22 cases (14 renal cancer and 8 bladder cancer), diagnosed between 1999 and 2017, and the literature reported 15 cases with renal cancer and 10 cases with bladder cancer between 2004 and 2019. Most common symptoms for renal and bladder cancer were pain (28%) and hematuria (66%), respectively. In more than half of the patients, surgical treatment was performed during pregnancy. Preterm deliveries were mostly medically induced (12 of 17, 71%) and all patients with a planned delivery before 34 weeks had advanced cancer. For renal and bladder cancer respectively, 79% and 87% of patients obtained complete remission. Advanced cancer stages had worse prognosis; 3 of 7 patients with known follow-up deceased within 15 months after diagnosis. CONCLUSION: Gestational age at diagnosis determines further management of renal and bladder cancers during pregnancy. Advanced stages challenge decision-making. The maternal needs for immediate treatment, and the neonatal risks including the impact of a preterm delivery should be discussed in a multidisciplinary setting while respecting the patient's autonomy.

Prognostic and predictive value of combined HE-4 and CA-125 biomarkers during chemotherapy in patients with epithelial ovarian cancer.

INTRODUCTION: At present there is no predictive value univocally associated with the success of chemotherapy. Biomarkers produced by ovarian cancer (HE4 and Ca125) could have a good prognostic significance. The aim of this study is to prove the ability of biomarkers to identify patients with the highest risk of non-optimal response during the chemotherapy, and to predict which patients will most likely develop recurrence of disease. METHODS: We analyzed 78 patients with epithelial ovarian cancers who underwent surgery in the biennium 2016-2017. All the patients underwent chemotherapy after surgery or interval debulking surgery following neoadjuvant therapy. Serum levels of HE4 and Ca125 were measured at diagnosis and at each cycle of chemotherapy. We established the degree of response to the treatment by computed tomography scan, and the patients were followed up (median: 10 months). The parameters of progression-free survival and disease-free survival were related to serum levels of biomarkers. RESULTS: Both CA125 and HE4 values became negative at the fourth cycle in the patients with good response to chemotherapy. HE4 increased earlier than Ca125. The parameters that best correlated with a long progression-free survival were: negativization of the marker after the third cycle of chemotherapy (HE4: odds ratio (OR) 5.5; Ca125: OR 9.1) and biomarker serum levels lower than the mean value in the affected population at the time of diagnosis (HE4: OR 3.4; Ca125: OR 3.7). CONCLUSIONS: We can conclude that the monitoring of HE4 and Ca125 during chemotherapy, especially at the third cycle, is recommended, because their variation is a good prognostic factor.

Ultrasound and clinical characteristics of uterine smooth muscle tumors of uncertain malignant potential (STUMPs).

OBJECTIVE(S): Smooth muscle tumors of uncertain malignant potential are rare uterine neoplasms. Their identification through imaging is still limited due to the few available descriptions in the scientific literature. The objective of this paper is to provide clinical and ultrasound features that could support an early identification of these neoplasms. STUDY DESIGN: We retrospectively evaluated preoperative sonographic data of patients receiving a histopathological diagnosis of smooth muscle tumors of uncertain malignant potential between 2014 and 2019 at the S. Anna Hospital (Turin, Italy), a tertiary gynecological center. Tumors were characterized on the basis of ultrasound images using terms and definitions according to the morphological uterus sonographic assessment group. RESULTS: A total of fourteen patients with smooth muscle tumors of uncertain malignant potential (20 lesions, including 18 pure and 2 with associated leiomyosarcoma) were identified. The median age was 47 years (range 28-77) and nine (64%) patients were of reproductive age. Six patients (43%) were asymptomatic, two (14%) presented with abdominal pain, two (14 %) with menorrhagia and four (29%) with both symptoms. Two (14%) patients developed local recurrences as uterine smooth muscle tumor of uncertain malignant potential and leiomyosarcoma, respectively. At ultrasound imaging, nine (69%) smooth muscle tumors of uncertain malignant potential were poorly or moderately vascularized and nine (82%) showed both circumferential and intra-lesional flows. Only three (15%) showed shadowing. The outlines were well-defined in seventeen cases (85%) and most (90%) showed isoechoic or mixed echogenicity with microcystic anechoic areas in fourteen (70%) of cases. CONCLUSION(S): Sonographic features of smooth muscle tumors of uncertain malignant potential may vary and a pathognomonic description has not been recognized. However, the identification of single or multiple lesions with specific ultrasound features should raise the suspicion of tumors of uncertain malignant potential. These features include isoechogenicity or mixed echogenicity, regular borders, presence of internal microcystic and anechoic areas, circumferential and intralesional vascularization ranging from minimal to high and absence of shadowing.

The ADNEX model to triage adnexal masses: An external validation study and comparison with the IOTA two-step strategy and subjective assessment by an experienced ultrasound operator.

OBJECTIVES: The ADNEX (Assessment of Different NEoplasias in the adneXa) model was developed using parameters collected by experienced (level III) ultrasound examiners. Our primary aim was to externally validate the ADNEX model. Then, the discriminatory performance of ADNEX was compared with the two-step strategy and subjective assessment by an experienced ultrasound operator. METHODS: Between February 2013 and January 2017, all patients who were scheduled for surgery for an adnexal mass at the Sant'Anna Hospital in Turin were enrolled in this study. Preoperative transvaginal sonography was performed, and the two-step strategy was applied for triage of the adnexal mass. Two ultrasound examiners, IOTA certified, applied the ADNEX model to all the collected masses based on the ultrasound reports. Finally, an experienced operator assigned the subjective assessment based on recorded ultrasound images. The discrimination and calibration performance of ADNEX were evaluated. The AUC was calculated for the basic discrimination between benign and malignant tumours. In addition, AUCs were computed for each pair of tumour types using the conditional risk method. RESULTS: A total of 577 patients were included in the analysis: the overall prevalence of malignancy was 25 %. With ADNEX, the AUC to differentiate between benign and malignant masses was 0.9111 (95 % CI 0. 8788-0.9389). At risk cut-offs of 1%, 10 % and 30 %, sensitivities were 100 %, 89.6 % and 79.2 %, respectively, and specificities were 2.8 %, 76.2 % and 89.6 %, respectively. Discrimination between benign and stage II-IV tumours was good (AUC 0.935). The model had the most difficulties discriminating between borderline and stage I tumours (AUC 0.666), and between stages II-IV invasive and secondary metastatic tumours (AUC 0.736). The polytomous discrimination index (PDI) was 0.61 for ADNEX, whereas PDI for random performance would be 0.25. ADNEX proved to be equally or more accurate than the subjective assessment or the two-step strategy in the discrimination between benign and malignant adnexal masses. CONCLUSIONS: the ADNEX model could probably be successfully applied when an expert examiner is not available and, therefore both a subjective assessment and the two-step strategy cannot be performed.

Impact of cancer in the management of delivery: 10 years of variations.

Importance: The active-during-pregnancy-cancer (ADPC) is a condition that complicates the 0.1% of pregnancies. Abortion, preterm delivery and cesarean section (CS) are common attitudes for these patients, because of scarcity of evidence-based studies. Not-active-during-pregnancy-cancer (NADPC) is an increasing medical problem. The fertility of young girls survived to neoplasia is significantly lower compared to general population and there are increased rates of low birth weight and preterm birth.Objective: To analyze the impact that the pregnancy-related neoplastic disease has on management of deliveries in the decade 2006-2015.Material and methods: In this observational study, we collected obstetric and oncological data about 205 patients bearing a history of cancer related to pregnancy between January 2006 and September 2016 from Sant'Anna Hospital database archive in Turin. The entire population was divided in 59 patients with ADPC and 146 patients with NADPC because it was cured before starting the gestation. Three ADPC and three NADPC patients who completed their pregnancy in the year 2016 were excluded from the 10 years 2006-2015 trends realization. All in situ and invasive cancers were considered.Results: In ADPC patients, we registered 3.4% miscarriage and 15.3% iatrogenic abortion. The type of delivery was vaginal (22%) and CS (59.3%). Induction of labor was 14.6%, elective CS was 68.8%: the indication for these procedures was 78.6% oncological. The average gestational age was 35.5 weeks. In NADPC patients, we registered 9.6% miscarriage and 8.2% iatrogenic abortion. The type of delivery was vaginal (43.2%) and CS (39%). Induction of labor was 11.7%, elective CS was 36.7%: the indication for these procedures was 77.5% obstetrical. The average gestational age was 38.3 weeks.Conclusions: Ten-year trends in ADPC and NADPC patients showed an increase of induced deliveries and a decrease in elective CS. We observed not significant reduction of gestational age and birth weight. A contemporary decrease of oncological indications for CS in the two populations was reported.