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Multi-modal therapies for gynecological cancers management may determine a wide range of side effects which depend on therapy-related factors and patient characteristics and comorbidities. Curative or adjuvant pelvic radiotherapy is linked with acute and late toxicity due to irradiation of organs at risk, as small and large bowel, rectum, bladder, pelvic bone, vagina and bone marrow. Successful toxicity management varies with its severity, Radiation Centre practice and experience and skills of radiation oncologists. This position paper was designed by the Italian Association of Radiation and Clinical Oncology Gynecology Study Group to provide radiation oncologists with evidence-based strategies to prevent and manage acute and late toxicities and follow-up recommendations for gynecological cancer patients submitted radiotherapy. Six workgroups of radiation oncologists with over 5 years of experience in gynecologic cancers were setup to investigate radiotherapy-related toxicities. For each topic, PubMed database was searched for relevant English language papers from January 2005 to December 2022. Titles and abstracts of results were checked to verify suitability for the document. Reference lists of selected studies and review papers were added if pertinent. Data on incidence, etiopathogenesis, prevention, treatment and follow-up of acute and late side effects for each organ at risk are presented and discussed., (© 2024. The Author(s).)

Objective: Poly (ADP-ribose) polymerase inhibitors (PARPi) have become a new standard of care for the maintenance treatment of advanced epithelial ovarian cancer. This study aims to evaluate the efficacy and safety of combining stereotactic body radiotherapy with PARPi continuation as a strategy to treat ovarian cancer oligoprogression on PARPi., Methods: This is a multicenter retrospective study including ovarian cancer patients treated with stereotactic body radiotherapy and PARPi continuation for oligoprogression under PARPi maintenance therapy between June 2012 and May 2023 in three Italian centers. PARPi treatment was continued until further disease progression or unacceptable toxicity. The primary endpoint was the next-line systemic therapy-free interval. The Kaplan-Meier method was used to assess local control, progression-free survival, and overall survival. Univariate and multivariate Cox regression analyses were performed to evaluate potential clinical outcomes predictors., Results: 46 patients were included, with a total of 89 lesions treated over 63 radiotherapy treatments. Lymph nodes were the most frequently treated lesions (80, 89.9%), followed by visceral lesions (8, 9%) and one case with a bone lesion (1.1%). Median follow-up was 25.9 months (range 2.8-122). The median next-line systemic therapy-free interval was 12.4 months (95% CI 8.3 to 19.5). A number of prior chemotherapy lines greater than five was significantly associated with a reduced next-line systemic therapy-free interval (HR 3.21, 95% CI 1.11 to 9.32, p=0.032). At the time of analysis, 32 (69.6%) patients started a new systemic therapy regimen, while 14 (30.4%) remained on the PARPi regimen. The 2-year progression-free survival, local failure-free survival, and overall survival rates were 10.7%, 78.1%, and 76.5%, respectively. Four patients (8.7%) experienced acute toxicity with G1 gastrointestinal events., Conclusion: Stereotactic body radiotherapy combined with PARPi continuation may be an effective and safe strategy for managing ovarian cancer patients with oligoprogression on PARPi maintenance therapy. Prospective research is warranted to shed more light on this approach., Competing Interests: Competing interests: BAJ-F has received speakers fees from Roche, Bayer, Janssen, Carl Zeiss, Ipsen, Accuray, Astellas, Elekta, and IBA Astra Zeneca, all outside the current project., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors that originate from adrenal medulla or extra-adrenal chromaffin cells, respectively. They produce an excess of catecholamines and their metabolites. Abnormal levels of these biomolecules have been also found in pediatric patients with neuroblastoma (NB). Due to the diurnal fluctuation, the laboratory practice recommends the determination of biogenic amines in acidified 24-h urine samples. However, the collection and acidification of specimens cannot be performed easily, especially for children. Spot urines represent an attractive alternative for the detection of catecholamines and corresponding metabolites., Methods: In our study, we enrolled 50 patients with symptoms related to PPGL and we determined the concentration values for both spot and 24-h urine samples using high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS). Since day variations of the urinary concentration are due to fluctuations in renal excretion rather than in production, we normalized the concentration of biogenic amines in spot urine and in 24-h urine collection to urinary creatinine concentration. A correlation study between the normalized levels of biogenic amines was performed using a linear regression analysis model and Pearson's correlation coefficients., Results: We obtained a good correlation of values which suggests an interchangeability of the 24-h and random urine samples. Only for epinephrine a weak correlation was determined., Conclusions: Our findings suggest that the sample collection as single spot urine may replace 24-h collection for the detection of urinary biogenic amines by HPLC/MS-MS., Competing Interests: All other authors have no conflict of interest to disclose., (Copyright 2024, Rosato et al.)

Purpose: We present a large real-world multicentric dataset of ovarian, uterine and cervical oligometastatic lesions treated with SBRT exploring efficacy and clinical outcomes. In addition, an exploratory machine learning analysis was performed., Methods: A pooled analysis of gynecological oligometastases in terms of efficacy and clinical outcomes as well an exploratory machine learning model to predict the CR to SBRT were carried out. The CR rate following radiotherapy (RT) was the study main endpoint. The secondary endpoints included the 2-year actuarial LC, DMFS, PFS, and OS., Results: 501 patients from 21 radiation oncology institutions with 846 gynecological metastases were analyzed, mainly ovarian (53.1%) and uterine metastases(32.1%).Multiple fraction radiotherapy was used in 762 metastases(90.1%).The most frequent schedule was 24 Gy in 3 fractions(13.4%). CR was observed in 538(63.7%) lesions. The Machine learning analysis showed a poor ability to find covariates strong enough to predict CR in the whole series. Analyzing them separately, in uterine cancer, if RT dose≥78.3Gy, the CR probability was 75.4%; if volume was <13.7 cc, the CR probability became 85.1%. In ovarian cancer, if the lesion was a lymph node, the CR probability was 71.4%; if volume was <17 cc, the CR probability rose to 78.4%. No covariate predicted the CR for cervical lesions. The overall 2-year actuarial LC was 79.2%, however it was 91.5% for CR and 52.5% for not CR lesions(p < 0.001). The overall 2-year DMFS, PFS and OS rate were 27.3%, 24.8% and 71.0%, with significant differences between CR and not CR., Conclusions: CR was substantially associated to patient outcomes in our series of gynecological cancer oligometastatic lesions. The ability to predict a CR through artificial intelligence could also drive treatment choices in the context of personalized oncology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Individuals with Down syndrome (DS) require more time to develop motor and/or cognitive skills. Neuromodulation is used to assist in this development. However, there is a gap in the literature on neurophysiological changes that may occur in the primary motor cortex in individuals with DS following neuromodulation., Objective: Our objective was to investigate possible neurophysiological changes in brain wave behavior of the primary motor cortex following the administration of anodal transcranial direct current stimulation combined with sensorimotor training., Methods: The study involved 12 participants with DS. EEG equipment was used to investigate brain activity. The participants received neuromodulation involving anodal tDCS for 20 minutes with a current of 1 mA combined with virtual reality (VR) training three times a week for a total of ten sessions. We analyzed EGG signals and 3D movement during a reaching movement of the dominant upper limb before and after the ten-session protocol., Results: Significant differences in event-related desynchronization and event-related synchronization of the alpha and beta rhythms were found throughout the evaluations. Brain mapping revealed reductions in power and frequency, demonstrating changes in the patterns of these rhythms in the cerebral cortex. Revealed reorganization of the behavior of alpha and beta waves, as demonstrated by distribution of synchronization and desynchronization of these waves among the regions of the brain., Conclusion: The results suggest that anodal tDCS promotes the reorganization of brain impulses, redirecting these impulses to the required regions more efficiently and contributing to better motor planning.

Background: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer., Methods: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants., Findings: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group., Interpretation: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD)., Competing Interests: Declaration of interests DL, YX, KH, GS, ML, PR-E, AAc, VSu, NC, AJPdSG, FCM, AR, AAy, J-YL, VSa, FZ, LG, JS, ET, KLin, RLaz, C-LC, RLam, HZ, AO, MC, SPo, TU, SPi, and LRD received funding to their institutions from MSD to support the study. DL reports consulting fees from AstraZeneca, Clovis Oncology, GSK, MSD, ImmunoGen, Genmab, Seagen, Novartis, and PharmaMar; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, ImmunoGen, GSK, Seagen, and Genmab; support for attending meetings or travel from AstraZeneca, Clovis Oncology, and GSK; participation on a data safety monitoring board or advisory board for Oncoinvest, Corcept, Sutro, AstraZeneca, ImmunoGen, GSK, Seagen, Genmab, Clovis Oncology, GSK, MSD, and PharmaMar; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for GCIG; receipt of equipment, materials, drugs, medical writing, gifts, or other services from Clovis Oncology, GSK, MSD, and PharmaMar; and other financial or non-financial interests in AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Incyte, MSD, Roche, Seagen, and Novartis. YX reports participation on a data safety monitoring board or advisory board for MSD. KH reports research contracts from Daiichi Sankyo, Eisai, MSD, and Takeda; advisory board fees from Chugai, Eisai, Takeda, MSD, Roche, Genmab, and Sanofi; honoraria from Daiichi Sankyo, AstraZeneca, Chugai, Eisai, Genmab, MSD, Takeda, Sanofi, Kyowa Kirin, and Kaken; and support for attending meetings or travel from Regeneron. GS reports grants or contracts from MSD Italia; consulting fees from Tesaro and Johnson & Johnson; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Clovis Oncology Italy. ML reports grants or contracts from MSD, AstraZeneca, and Roche; speaker fees from AstraZeneca and Roche; and meeting support from Roche. PR-E reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, Asofarma, Novartis, Janssen, and AstraZeneca; support for attending meetings or travel from Roche, Novartis, Asofarma, and AstraZeneca; and participation on a data safety monitoring board or advisory board for Pfizer, Asofarma, Bristol Myers Squibb, and AstraZeneca. NC reports participation on a data safety monitoring board or advisory board for GSK, Toray, Tarveda Therapeutics, Umoja, Kartos, Zentalis, Profound, and Novita Pharmaceuticals. AJPdSG reports consulting fees, payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events, and participation on a data safety monitoring board or advisory board for AstraZeneca, Astellas, Bayer, and Janssen; payment for expert testimony from Janssen; and support for attending meetings or travel from Janssen, MSD, and Bayer. FCM reports speaker fees from MSD, Bristol Myers Squibb, GSK, Eli Lilly, and BMS; payment for expert testimony from MSD, Janssen, GSK, Eli Lilly, and Bristol Myers Squibb; and meeting and travel support from MSD and Amgen. AR reports advisory board fees from MSD Israel. J-YL reports grants or contracts from Advenchen, Ascendis Pharma, Alkermes, AstraZeneca, BeiGene, BerGenBio, Bristol Myers Squibb, Cellid, Clovis Oncology, Eisai, Genmab, GII, GSK, ImmunoGen, Janssen, Merck, Mersana, MSD, Novartis, Onconic Therapeutics, OncoQuest, Ono, Regeneron, Roche, Seagen, Sutro, Synthon, and Takeda; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, Janssen, MSD, Roche, Takeda, and Ono. FZ reports grants or contracts, consulting fees, payment for expert testimony, support for attending meetings or travel, participation on a data safety monitoring board or advisory board, and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Daiichi Sankyo, Merck, Novartis, Genesis Pharma, and Gilead. LG reports institutional grants from GSK, Pfizer, MSD, Karyopharm, Tesaro, IMV, Alkermes, Clovis Oncology, ImmunoGen, Roche, Mersana, and AstraZeneca; consulting fees from GSK, Merck, Eisai, and Novocure; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from GSK, Merck, Eisai, Novocure, and Corcept; and support for attending meetings or travel from Corcept, GSK, AstraZeneca, and Merck. JS reports grants or contracts from Roche, MSD, GSK, Tesaro, AstraZeneca, Eisai, Merck, and Novocure; consulting fees from ImmunoGen, Incyte, GSK, AstraZeneca, Clovis Oncology, Novocure, MSD, Eisai, and Merck; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from ImmunoGen, Incyte, GSK, AstraZeneca, Clovis Oncology, Novocure, Bristol Myers Squibb, Eisai, and Novartis; support for attending meetings or travel from GSK, AstraZeneca, Roche, Novocure, ImmunoGen, Incyte, MSD, and Eisei; participation on a data safety monitoring board or advisory board for ImmunoGen, Incyte, GSK, AstraZeneca, Clovis Oncology, Novocure, Bristol Myers Squibb, MSD, Merck, Bayer, and PharmaMar; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for ENGAGE, ESGO, ASCO, ESGO, GCIG, Deutsche Stiftung Eierstockkrebs, and AGO. KLin reports grants or contracts from GSK (paid to institution); payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Eisai; and participation on a data safety monitoring board or advisory board for Eisai, MSD, Nykode, AstraZeneca, and GSK. HZ reports contracted research and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events for MSD. AO reports grants or contracts from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Roche, ImmunoGen, MSD de España, Millennium Pharmaceuticals, PharmaMar, Regeneron, and Tesaro (paid to institution); consulting fees and participation on a data safety monitoring board or advisory board from Agenus, AstraZeneca, Clovis Oncology, Corcept, Deciphera Pharmaceuticals, Eisai, Exelixis, EMD Serono, Roche, Genmab, GSK, ImmunoGen, iTeos, MSD de España, Mersana, Novocure, OncXerna Therapeutics, PharmaMar, Regeneron, Sattucklabs, Seagen, and Sutro; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from NSGO, Peerview, Peervoice, Medscape, Asociación Colombiana de Ginecológos Oncólogos, ESO, AstraZeneca, and GSK; and support for attending meetings or travel from AstraZeneca, PharmaMar, and Roche. SPo reports consulting fees from MSD, AstraZeneca, GSK, and Eisai; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events, support for attending meetings or travel, and advisory board fees from MSD, AstraZeneca, and GSK; and leadership or fiduciary role in other board, society, committee, or advocacy group for the Austrian Association of Gynecologic Oncology (unpaid). SPi reports research funding from Roche, MSD, AZ, Pfizer, and GSK; and honoraria from AZ, Roche, MSD, GSK, and PharmaMar. LRD reports research funding (paid to institution) from and acting as an expert advisor (unpaid) for Merck & Co; writing fees for expert content for UpToDate; participation on a scientific advisory board for Aadi Bioscience; and serving on the Editorial Board of the British Journal of Obstetrics and Gynaecology. KLi, KY, ST, and SMK are full-time employees of MSD and hold stock or restricted stock units in the company., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the role of dose-dense neoadjuvant chemotherapy followed by radical hysterectomy in reducing adjuvant radiotherapy in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB1-IB2/IIA1 cervical cancer with disrupted stromal ring and as an alternative to concurrent chemoradiotherapy in FIGO 2018 stages IB3/IIA2., Methods: This was a retrospective cohort study including patients with FIGO 2018 stage IB1-IIA2 cervical cancer undergoing dose-dense neoadjuvant chemotherapy at the European Institute of Oncology in Milan, Italy between July 2014 and December 2022. Weekly carboplatin (AUC2 or AUC2.7) plus paclitaxel (80 or 60 mg/m 2 , respectively) was administered for six to nine cycles. Radiological response was assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. The optimal pathological response was defined as residual tumor ≤3 mm. Kaplan-Meier curves were used to estimate survival rates. A systematic literature review on dose-dense neoadjuvant chemotherapy before surgery for cervical cancer was also performed., Results: A total of 63 patients with a median age of 42.8 years (IQR 35.3-47.9) were included: 39.7% stage IB-IB2/IIA1 and 60.3% stage IB3/IIA2. The radiological response was as follows: 81% objective response rate (17.5% complete and 63.5% partial), 17.5% stable disease, and 1.6% progressive disease. The operability rate was 92.1%. The optimal pathological response rate was 27.6%. Adjuvant radiotherapy was administered in 25.8% of cases. The median follow-up for patients who underwent radical hysterectomy was 49.7 months (IQR 16.8-67.7). The 5-year progression-free survival and overall survival were 79% (95% CI 0.63 to 0.88) and 92% (95% CI 0.80 to 0.97), respectively. Fifteen studies including 697 patients met the eligibility criteria for the systematic review. The objective response rate, operability rate, and adjuvant radiotherapy rate across studies ranged between 52.6% and 100%, 64% and 100%, and 4% and 70.6%, respectively., Conclusions: Dose-dense neoadjuvant chemotherapy before radical surgery could be a valid strategy to avoid radiotherapy in stage IB1-IIA2 cervical cancer, especially in young patients desiring to preserve overall quality of life. Prospective research is warranted to provide robust, high-quality evidence., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Vulvar carcinoma is a rather uncommon gynecological malignancy affecting elderly women and the treatment of loco-regional advanced carcinoma of the vulva (LAVC) is a challenge for both gynecologic and radiation oncologists. Definitive chemoradiation (CRT) is the treatment of choice, but with disappointing results. In this multicenter study (OLDLADY-1.1), several institutions have combined their retrospective data on LAVC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of CRT., Methods: The primary study end-point was 2-year-local control (LC), secondary end-points were 2-year-metastasis free-survival (MFS), 2-year-overall survival (OS) and the rate and severity of acute and late toxicities. Participating centers were required to fill data sets including age, stage, histology, grading as well as technical/dosimetric details of CRT. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. The toxicity was a posteriori documented through the Common Terminology Criteria for Adverse Events version 5 scale., Results: Retrospective analysis was performed on 65 patients with primary or recurrent LAVC treated at five different radiation oncology institutions covering 11-year time interval (February 2010-November 2021). Median age at diagnosis was 72 years (range 32-89). With a median follow-up of 19 months (range 1-114 months), 2-year actuarial LC, MFS and OS rate were 43.2%, 84.9% and 59.7%, respectively. In 29 patients (44%), CRT was temporarily stopped (median 5 days, range 1-53 days) due to toxicity. The treatment interruption was statistically significant at univariate analysis of factors predicting LC (p: 0.05) and OS rate (p: 0.011), and it was confirmed at the multivariate analysis for LC rate (p: 0.032). In terms of toxicity profile, no G4 event was recorded. Most adverse events were reported as grade 1 or 2. Only 14 acute G3 toxicities, all cutaneous, and 7 late G3 events (3 genitourinary, 3 cutaneous, and 1 vaginal stenosis) were recorded., Conclusion: In the context of CRT for LAVC, the present study reports encouraging results even if there is clearly room for further improvements, in terms of both treatment outcomes, toxicity and treatment interruption management., (© 2023. The Author(s).)

Protection provided by COVID-19 vaccines is compromised due to waning immunity over time. This study aimed to assess the level of antibodies anti-S-RBD of SARS-CoV-2 in a cohort of healthcare workers before and, on average, one and four months after the third dose of the BNT162b2 vaccine. The determination of antibodies was carried out in serum samples using an electrochemiluminescence immunoassay (ECLIA). All 34 participants (10 males, 24 females, 19 participants <50 years old, 15 participants ≥50 years old) showed a significant antibody level increase after the booster dose. Subsequently, a significant decrease in the antibody concentration was observed, with a reduction of about 60% after 150 days from the booster. Six subjects were infected by SARS-CoV-2 after the booster and showed a significantly higher antibody concentration on average four months after the third dose compared to naïve ones. Male and female participants had a similar trend in the antibody decline, while older subjects, compared to the younger ones, had a slightly slower decrease, even if they developed a lower level of antibodies after the third dose. These findings support the importance of the booster dose and underline the need for surveillance programs to better understand the antibody kinetics and optimize vaccination strategies.

Background: Adjuvant radiotherapy (aRT) has been shown to reduce the risk of local relapse in vulvar cancer (VC). In this multicentre study (OLDLADY-1.2), several Institutions have combined their retrospective data on VC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of aRT., Methods: The primary study end-point was the 2-year-local control, secondary end-points were the 2-year-metastasis free-survival, the 2-year-overall survival and the rate and severity of acute and late toxicities. Participating centres were required to fill data sets including age, stage, tumor diameter, type of surgery, margin status, depth of invasion, histology, grading as well technical/dosimetric details of radiotherapy. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected., Results: One hundred eighty-one patients with invasive VC from 9 Institutions were retrospectively identified. The majority of patients were stage III (63%), grade 2 (62.4%) squamous carcinoma (97.2%). Positive nodes were observed in 117 patients (64.6%), moreover tumor diameter > 4 cm, positive/close margins and depth of invasion deeper than 5 mm were found in 59.1%, 38.6%, 58% of patients, respectively. Sixty-one patients (33.7%) received adjuvant chemoradiation, and 120 (66.3%) received radiotherapy alone. aRT was started 3 months after surgery in 50.8% of patients. Prescribed volumes and doses heterogeneity was recorded according to margin status and nodal disease. Overall, 42.5% locoregional recurrences were recorded. With a median follow-up of 27 months (range 1-179), the 2-year actuarial local control rate, metastasis free and overall survival were 68.7%, 84.5%, and 67.5%, respectively. In term of safety, aRT leads to a prevalence of acute skin toxicity with a low incidence of severe toxicities., Conclusions: In the context of aRT for VC the present study reports a broad spectrum of approaches which would deserve greater standardization in terms of doses, volumes and drugs used., (© 2022. Italian Society of Medical Radiology.)

Background: Stereotactic body radiotherapy (SBRT) has shown promising results in the clinical setting of oligometastatic, persistent, or recurrent disease in several malignancies including ovarian cancer., Primary Objective: The MITO-RT3/RAD trial is a prospective, multicenter phase II study aimed at identifying potential predictors of response and clinical outcome after SBRT treatment., Study Hypothesis: Radiotherapy delivered by pre-defined SBRT treatment schedules and shared constraints could improve the rate of complete response., Trial Design: All patients accrued will be treated with a radiotherapy dose in the range of 30-50 Gy by 1, 3, or 5 SBRT daily fractions to all sites of active metastatic disease according to diagnostic imaging. Schedules of treatment and dose prescription have been established before considering target sites and healthy organ dose constraints. Follow-up and monitoring of side effects will be carried out every 3 months for the first year with imaging and clinical evalutation, and every 4 months within the second year; thereafter, surveillance will be carried out every 6 months. The best response on a per lesion basis will be evaluated by computed tomographic (CT) scan, positron emission tomography/CT, or magnetic resonance imaging in case of brain lesions, every 3 months., Major Inclusion/exclusion Criteria: The study includes patients with oligometastatic, persistent, or recurrent ovarian cancer for which salvage surgery or other local therapies are not feasible due to any relative contra-indication to further systemic therapy because of serious co-morbidities, previous severe toxicity, unavailability of potentially active systemic therapy, or patient refusal., Primary Endpoint: The primary endpoint of the study is the clinical complete response rate to SBRT by imaging on a per lesion basis., Sample Size: Approximately 205 lesions will be treated (90 lymph nodes and 115 parenchyma lesions)., Estimated Dates for Completing Accrual and Presenting Results: Fifty-two centers have expressed their intention to participate. Enrollment should be completed by March 2023 and analysis will be completed in September 2023., Trial Registration: NCT04593381., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

This survey investigated prognostic factors, treatment modalities, references followed and radiation oncologists' opinions to prescribe adjuvant therapy in early intermediate-risk cervical cancer. All but one recommended pelvic radiotherapy ± vaginal boost (45%) with or without chemotherapy (20%). 88% believed other prognostic factors could integrate classic risk criteria. 66% considered chemo-radiation indicated in case of lymphovascular invasion and suboptimal node dissection, high grade, size ≥ 4 cm, non squamous histology and risk factors combination. This wide heterogeneity of treatments reflects the different guideline options due to the lack of defined indications. The need of integrating the classic prognostic factors with others factors was unanimously expressed by radiation oncologists. The best local and systemic therapy should be established through new studies. These results highlighted the need of a position paper to standardize adjuvant treatment in Italy and to design collaborative studies to clarify the controversial aspects., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The SARS-CoV-2 pandemic led to the development of various vaccines. The BNT162b2 mRNA vaccine was the first approved due to its efficacy in eliciting a humoral immunity response after the second dose. However, a decrease in the antibody concentration was observed over time. Therefore, the administration of a third dose was scheduled, primarily for frail people and workers of essential public activities. The aim of this study was to assess the level of antibodies against the spike (S) RBD of SARS-CoV-2 in healthcare workers before and after the third dose of BNT162b2 vaccine, according to sex, age, and the time interval between vaccine doses and tests. All 37 (12 males, 25 females, 19 < 50 years old, 18 ≥ 50 years old) healthcare workers recruited showed a consistent antibody titer increase after the third dose. Data analysis showed that the antibody concentration before the third dose significantly decreased as the time interval up to the test increased, and a significantly higher level was shown in young than older people. Cluster analysis revealed that young females had a higher antibody level than older females before the third dose (p < 0.05). This study indicated the benefit of the third dose of BNT162b2 vaccine and its effect on leveling up the humoral immune response.

Background: Children with Down syndrome have poorer functional and sensory skills compared to children with typical development. Virtual reality (VR) training could help improve these skills. Moreover, transcranial direct current stimulation (tDCS) has achieved promising results in terms of enhancing the effects of physical and sensory therapy by modulating cortical excitability., Methods/design: Two investigations are proposed: (1) an observational study with a convenience sample consisting of children with Down syndrome (group 1-cognitive age of 6 to 12 years according to the Wechsler Abbreviated Scale of Intelligence) and children with typical development 6 to 12 years of age (group 2). Both groups will undergo evaluations on a single day involving a three-dimensional analysis of upper limb movements, an analysis of muscle activity of the biceps and brachial triceps muscles and an analysis of visuospatial and cognitive-motor variables. (2) Analysis of clinical intervention: a pilot study and clinical trial will be conducted involving individuals with Down syndrome (cognitive age of 6 to 12 years according to the Wechsler Abbreviated Scale of Intelligence). The sample will be defined after conducting a pilot study with the same methodology as that to be used in the main study. The participants will be randomly allocated to two groups: An experimental group submitted to anodal tDCS combined with a VR game and a manual motor task and a control group submitted to sham tDCS combined with a VR game and a manual motor task. The training protocol will involve 10 sessions of active or sham tDCS during memory and motor task games. Three 20-min sessions will be held per week for a total of 10 sessions. Evaluations will be performed on three different occasions: pre-intervention, post-intervention (after 10 sessions) and follow-up (1 month after the intervention). Evaluations will consist of analyses of electroencephalographic signals, electromyographic signals of the biceps and triceps brachii, and the three-dimensional reconstruction of the reaching movement. The results will be analyzed statistically with the significance level set at 5% (p ≤ 0.05)., Discussion: The optimization of the results obtained with virtual reality training is believed to be related to the interactive experience with a wide range of activities and scenarios involving multiple sensory channels and the creation of exercises, the intensity of which can be adjusted to the needs of children. Therefore, the proposed study aims to complement the literature with further information on tDCS and VR training considering different variables to provide the scientific community with clinical data on this combination of interventions., Trial Registration: Brazilian Clinical Trials Registry (REBEC) protocol number RBR-43pk59 registered on 2019 March 27 https://ensaiosclinicos.gov.br/rg/RBR-43pk59 and Human Research Ethics Committee number 3.608.521 approved on 2019 September 30. Protocol version 2021 October 20. Any changes to the protocol will be reported to the committees and approved. Informed consent will be obtained from all participants by the clinical research coordinator and principal investigator., (© 2022. The Author(s).)

Background: Vaccine-induced immunity is at present the main strategy to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent evidences suggested a protective effect of influenza vaccination against coronavirus disease 2019 (COVID-19) severity, while impact on the immune response to BNT162b2 messenger RNA (mRNA) vaccine is under investigation., Methods: We aimed to evaluate this aspect in a cohort of 297 healthcare workers (108 males, 189 females) after seasonal influenza vaccination compared to no-flu-vaccination. VAX+ (165 individuals; 63 males and 102 females) had tetravalent influenza vaccine, and VAX- (132 individuals; 45 males and 87 females) had no flu vaccination. Anti-spike-receptor binding domain (RBD) level was tested 15 - 70 days after BNT162b2 second inoculum., Results: Increased antibody response was observed in total VAX+ compared to VAX- (2,047.4 vs. 1,494.2 binding antibody unit (BAU)/mL, P = 0.0039), independently from gender and body mass index (BMI). Younger total individuals (< 35 years) showed significant increase of the level of binding antibodies (2,184.8 vs. 1,590.9 BAU/mL, P = 0.0038) compared to ≥ 35 years; young/old difference was lost restricting to VAX+ subgroup. Flu vaccinations appear associated to better antibody response in older individuals (P = 0.027, ≥ 35 years VAX+ vs. VAX-). A decreasing trend during time was observed for both VAX+ and VAX-, except for < 35 years VAX- individuals. Early response was higher in VAX+ compared to VAX-; however a more rapid waning was observed in VAX+ subjects., Conclusions: Our data showed better antibody response to SARS-CoV-2 vaccine in subjects already vaccinated against seasonal influenza; this may represent one of the mechanisms underlying the cross-protective effects of influenza vaccination against heterologous infections reported in recent epidemiological studies., Competing Interests: The authors declare no conflict of interest., (Copyright 2021, Greco et al.)

Objective: During 2020, medical clinical activities were dramatically modified by the coronavirus disease 2019 (COVID-19) emergency. We aim to evaluate the impact of COVID-19 on radiotherapy (RT) practice in a hub cancer center., Methods: Retrospective data collection of patients with suspected COVID-19 infection, identified by pathognomonic symptoms feedback at triage realized at the entrance to RT division. Inclusion criteria were diagnosis of oncologic disease, COVID-19-related symptoms, and signed written informed consent., Results: Between 1 March and 30 June 2020, 1,006 patients accessed our RT division for RT simulation or treatment. Forty-four patients matched inclusion criteria (4.4% of all patients): 29 women and 15 men. Seventeen patients had metastatic disease. Twenty-one patients reported fever, 6 presented dyspnea, 4 complained of ageusia and anosmia, and 3 developed conjunctivitis. Thirty-six patients underwent nasal swab, with 7 positive results. From our cohort, 4 cases of pneumonia were diagnosed with computed tomography scan imaging: 3 were related to COVID-19 infection, while the fourth was evaluated as an RT adverse event. From the entire series, 4 patients died: 3 during hospitalization in intensive care unit of complications of COVID-19 and 1 of other causes neither COVID-19 nor cancer-related., Conclusions: Cancer hub allows for safe RT practice continuation while minimizing the spread of contagion in this frail patient population. A challenge for the future will be to understand pandemic consequences in cancer natural history and manage its clinical impact.

COVID-19 pandemic led to a worldwide increase of hospitalizations for interstitial pneumonia with thrombosis complications, endothelial injury and multiorgan disease. Common CT findings include lung bilateral infiltrates, bilateral ground-glass opacities and/or consolidation whilst no current laboratory parameter consents rapidly evaluation of COVID-19 risk and disease severity. In the present work we investigated the association of sFLT-1 and CA 15.3 with endothelial damage and pulmonary fibrosis. Serum sFlt-1 has been associated with endothelial injury and sepsis severity, CA 15.3 seems an alternative marker for KL-6 for fibrotic lung diseases and pulmonary interstitial damage. We analysed 262 SARS-CoV-2 patients with differing levels of clinical severity; we found an association of serum sFlt-1 (ROC AUC 0.902, decision threshold > 90.3 pg/mL, p < 0.001 Sens. 83.9% and Spec. 86.7%) with presence, extent and severity of the disease. Moreover, CA 15.3 appeared significantly increased in COVID-19 severe lung fibrosis (ICU vs NON-ICU patients 42.6 ± 3.3 vs 25.7 ± 1.5 U/mL, p < 0.0001) and was associated with lung damage severity grade (ROC AUC 0.958, decision threshold > 24.8 U/mL, p < 0.0001, Sens. 88.4% and Spec. 91.8%). In conclusion, serum levels of sFlt-1 and CA 15.3 appeared useful tools for categorizing COVID-19 clinical stage and may represent a valid aid for clinicians to better personalise treatment., (© 2021. The Author(s).)

This review analyzes the experience and trends in external beam radiotherapy for delivering a boost in locally advanced cervical cancer, identifying whether radiation therapy modalities impact clinical outcomes with the ultimate aim of evaluating alternatives to brachytherapy. Three independent Italian radiation oncologists conducted a literature search on different external beam radiotherapy boost modalities in locally advanced cervical cancer. The search yielded 30 studies. Eight dosimetric studies, evaluating target coverage and dose to organs at risk, and nine clinical investigations, reporting clinical outcomes, were analyzed. Dosimetric studies comparing external beam radiotherapy boost with brachytherapy produced divergent results, while clinical studies were limited by their retrospective nature, heterogeneous doses, radiation schedules, volumes and techniques, diverse follow-up times, and small cohorts of patients. Evidence emerged that high-tech external beam radiotherapy seemed no better than image-guided brachytherapy for delivering a boost in locally advanced cervical cancer. Prospective clinical studies comparing high-tech external beam radiotherapy and image-guided brachytherapy should be encouraged., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial., Methods: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133., Findings: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events., Interpretation: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR., Funding: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Ovarian cancer is the most lethal gynecologic malignancy. Over 5200 new cases of this tumor are diagnosed yearly in Italy, resulting in more than 3600 deaths. In terms of molecular biology, five different ovarian cancer subtypes should be distinguished., Method: This article summarizes the evidence-based guidelines that the Italian Medical Oncology Association (AIOM) has developed with a multidisciplinary panel of experts, including pathologists, gynecologic oncologists, medical oncologists, and radiotherapists, with the support of methodologists, to help clinicians involved in the management of patients with ovarian cancer in their daily clinical practice., Results: The most relevant randomized clinical trials regarding surgery, chemotherapy, and molecularly targeted agents (bevacizumab and PARP inhibitors) in early, advanced, and recurrent disease have been critically analyzed. The levels of evidence and strength of recommendation have been reported for any issue., Conclusion: Women with a clinical suspicion of ovarian cancer should be centralized in referral centers. The BRCA test should be requested for all women with nonmucinous and nonborderline tumors, regardless of age and family history. BRCA testing could be preferentially performed on neoplastic tissue. In the presence of a positive tumor test, a genetic test should always be performed on a blood sample to differentiate between germline mutations, which require counseling and genetic testing of family members, and somatic mutations.

The emergence of coronavirus disease 2019 (COVID-19) is globally a major healthcare threat. There is little information regarding the mechanisms and roles of the humoral response in SARS-CoV-2 infection. The aim of this study was to analyze the antibody levels (IgM and IgG) by chemiluminescence immunoassay in 54 subjects positive to SARS-CoV-2 swab test in relation to their clinical status (whether asymptomatic, pauci-symptomatic or with mild, sever or critical symptoms), the time from the symptom onset, sex, age, and comorbidities. Overall, the presence of comorbidities and the age of subjects were associated with their clinical status. The IgG concentrations were significantly higher in patients who developed critical and severe symptoms and seemed to be independent from age, sex and comorbidities. IgG titers peaked around day 60, and then began gradually to drop, decreasing by approximately 50% on the 180th day, while the IgM titers progressively decreased as early as the tenth day, but they could be detected even at later time points. Despite the small number of individuals, some peculiar characteristics of the humoral response in COVID-19 emerged. We observed a high inter-individual variability, an ephemeral IgG half-life in several patients, and a persistence of IgM in others.

Introduction: During the COVID-19 pandemic, Lombardy (Northern Italy) Regional Health Council created hubs for cancer care, meant to be SARS-CoV-2-free pathways for cancer patients. The workflow of breast cancer (BC) radiotherapy (RT) in one of the hubs is presented here., Methods: Candidates to adjuvant RT during the pandemic peak of March-April 2020 were compared to those treated in the same period of 2019, and patient volume, deferral rate, and type of RT were analyzed. Statistics were calculated with χ 2 or Fisher exact tests for categorical variables, and the Wilcoxon rank test for continuous variables., Results: In March-April 2020 the BC patient volume increased by 28% compared to the same period in 2019 (scheduled patients: 175 vs. 137) and amid travel restrictions it was kept high (treated patients: 136 vs. 133), mainly due to an influx from across Lombardy. RT schemes basically did not change, being already centered on hypofractionation. The increase of median time (67 vs. 74.5 days in 2019 and 2020, respectively) to the commencement of RT for low-risk patients was clinically negligible yet statistically significant ( p = 0.03), and in line with the pertinent recommendations. No significant difference was found in the time interval between treatments and RT for high-risk patients. Concomitant chemoradiotherapy was avoided throughout the pandemic peak. Twenty-one women (13.6%) delayed either computed tomography simulation or RT commencement mainly because of COVID-19-related concerns and mobility restrictions., Conclusion: The workload for BC was high during the pandemic peak. Hubs allowed the continuation of oncologic treatments, while mitigating the strain on frontline COVID-19 hospitals., Competing Interests: M.C.L., F.C., B.A.J.-F. received honorarium fees from Accuray Inc. outside the current work. The remaining authors declare no conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)

Background: Childhood neurological diseases result in neuromotor impairment, which affects selective motor control, compromising the acquisition of motor skills and functional independence. The positive results achieved with virtual reality are believed to be related to training in an interactive environment that provides a broad range of activities and scenarios with multiple sensory channels, enabling the creation of exercises at an intensity based on individual need. Therefore, a review was conducted to answer the following question: What are the possible effects of virtual reality for the pediatric population, specifically children with cerebral palsy and Down syndrome?, Objective: The objective of the present study was to conduct a systematic review of the literature to determine the possible effects of virtual reality therapy in children with cerebral palsy and Down's syndrome., Methods: The PubMed, Bireme, Scielo and PEDro electronic databases were searched in the period from January to March 2016 using the following keywords: Down syndrome and virtual reality, virtual reality and cerebral palsy, virtual reality and neuropediatrics, and Down's syndrome and virtual reality. Only randomized controlled trials published in English in the previous 10 years (2007-2016) that addressed the specific purpose of this review and achieved a score of at least 4 points on the PEDro methodological quality scale were eligible for inclusion., Results: The initial research led to the retrieval of 214 articles, which were analyzed considering the inclusion criteria. Eighteen articles were submitted to an appraisal of methodological quality using the PEDro scale, only five of which received a score of four or more points and were described in the present review. Three of the studies selected analyzed children with cerebral palsy and two analyzed children with Down syndrome. Despite the different physiopathological characteristics of the two conditions, the authors employed similar therapeutic methods and evaluations. The results of the studies demonstrated that virtual reality training either alone or combined with motor training leads to improvements in sensory-motor functions and can be used as a complement to other successful rehabilitation interventions in the two populations., Conclusion: Based on the results of the studies included in the present systematic review, despite differences in the characteristics of each population, the objectives and methods proposed by the authors were similar and virtual reality demonstrated promising effects for individuals with cerebral palsy and Down syndrome., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Management of head and neck cancers (HNC) in radiation oncology in the coronavirus disease 2019 (COVID-19) era is challenging. Aim of our work is to report organization strategies at a radiation therapy (RT) department in the first European area experiencing the COVID-19 pandemic., Methods: We focused on (a) dedicated procedures for HNC, (b) RT scheduling, and (c) health care professionals' protection applied during the COVID-19 breakdown (from March 1, 2020 to April 30, 2020)., Results: Applied procedures are reported and discussed. Forty-three patients were treated. Image-guided, intensity modulated RT was performed in all cases. Median overall treatment time was 50 (interquartile range: 47-54.25) days. RT was interrupted/delayed in seven patients (16%) for suspected COVID-19 infection. Two health professionals managing HNC patients were proven as COVID-19 positive., Conclusion: Adequate and well-timed organization allowed for the optimization of HNC patients balancing at the best of our possibilities patients' care and personnel's safety., (© 2020 Wiley Periodicals, Inc.)

Purpose: To evaluate clinical results of catheter-based interstitial high-dose-rate (HDR) brachytherapy (BT) as adjuvant treatment in previously irradiated recurrent breast cancer., Material and Methods: Between January 2011 and September 2015, 31 consecutive patients with histologically confirmed recurrent breast cancer after conservative surgery and conventional whole breast radiotherapy, were retreated with a second conservative surgical resection and reirradiated with adjuvant interstitial HDR-BT. None of the brachytherapy implant was performed during the quadrantectomy procedure. A dose of 34 Gy in 10 fractions, 2 fractions per day, with a minimal interval of 6 hours was delivered., Results: At the time of the implant, the median age of patients was 59.7 years (range, 39.3-74.9 years). The median time from first treatment until BT for local recurrence was 11.9 years (range, 2.5-27.8 years). The median interval between salvage surgery and BT was 3.6 months (range, 1-8.2 months). No acute epidermitis or soft tissue side effects higher than grade 2 were recorded, with good cosmetic results in all patients. Most of the patients presented grade 1-2 late side effects. Only one patient developed grade 3 liponecrosis. After a median follow-up of 73.7 months (range, 28.8-102.4 months), the overall survival and cancer specific survival were 87.1% and 90.3%, respectively; 5-year local control and 5-year progression-free survival rate were 90.3% and 83.9%, respectively., Conclusions: Our preliminary analysis showed that HDR-BT is a feasible treatment for partial breast reirradiation offering very low complications rate and fast procedure. Higher patients' cohort is warranted in order to define the role of this treatment modality in the breast conservative management of local recurrence., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Termedia.)

Objective: Standard treatment in locally-advanced cervical cancer is external beam radiotherapy concomitant with platinum-based chemotherapy, followed by brachytherapy. The goal of our study was to determine whether an intensity modulated radiation therapy (IMRT) boost is feasible in patients unfit for brachytherapy., Methods: We retrospectively analyzed data of 25 patients unfit for brachytherapy with median age 55 years (range, 30-82) with locally-advanced/metastatic cervical cancer who underwent external beam radiotherapy to pelvis ±para-aortic lymph nodes and sequential IMRT boost between July 2014 and December 2017. Total dose of 45-50.4 Gy in 25-28 fractions (1.8 Gy/fraction) was administered to the cervix, uterus, parametria, ovaries, vaginal tissues (based on vaginal extension), involved lymph nodes, or relevant draining lymph-nodal groups. Para-aortic nodes were included if involved at radiological staging or if common iliac nodes were positive. The IMRT boost included all residual tumor after external beam radiotherapy identified on MRI. The Kaplan-Meier method was used to calculate 2 years' overall survival, 2 years' progression-free survival, and 2 years' local control. Overall survival- and progression-free survival were calculated considering the starting of radiotherapy or neo-adjuvant chemotherapy if prescribed, while local control was calculated from the end of radiotherapy., Results: Median radiation dose to pelvis ±para-aortic lymph nodes was 50.4 Gy (45-50.4), boost treatment was homogeneously performed to a total dose of 25 Gy in five fractions every other day.After a median follow-up of 26 months (range, 4-77), tumor persistence at cervix at 6 months from the end of radiotherapy or local recurrence occurred in five women (20%), eight (32%) experienced a further distant progression (two of them had also tumor persistence). Two-year local control and overall survival rates for all stages were 78% and 67%, respectively. According to Common Terminology Criteria for Adverse Events v.4 scoring criteria, 10 patients experienced gastrointestinal and/or genitourinary grade G1-2 acute toxicity. G2 rectal late toxicity requiring laser-coagulation was registered in two patients, there were no gastrointestinal and/or genitourinary acute or late toxicities≥G3., Conclusion: The combination of external beam radiotherapy and brachytherapy remains the standard of care, however our preliminary data show the feasibility of IMRT boost in terms of toxicity with promising results in terms of local control and overall survival., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recent studies have reported improvement of outcomes (progression-free survival, overall survival, and prolongation of androgen deprivation treatment-free survival) with stereotactic body radiotherapy (SBRT) in non-small cell lung cancer and prostate cancer. The aim of this retrospective, multicenter study (MITO RT-01) was to define activity and safety of SBRT in a very large, real-world data set of patients with metastatic, persistent, and recurrent ovarian cancer (MPR-OC)., Materials and Methods: The endpoints of the study were the rate of complete response (CR) to SBRT and the 24-month actuarial local control (LC) rate on "per-lesion" basis. The secondary endpoints were acute and late toxicities and the 24-month actuarial late toxicity-free survival. Objective response rate (ORR) included CR and partial response (PR). Clinical benefit (CB) included ORR and stable disease (SD). Toxicity was evaluated by the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) and Common Terminology Criteria for Adverse Events (CTCAE) scales, according to center policy. Logistic and Cox regression were used for the uni- and multivariate analysis of factors predicting clinical CR and actuarial outcomes., Results: CR, PR, and SD were observed in 291 (65.2%), 106 (23.8%), and 33 (7.4%) lesions, giving a rate of CB of 96.4%. Patient aged ≤60 years, planning target volume (PTV) ≤18 cm 3 , lymph node disease, and biologically effective dose α/β10 > 70 Gy were associated with higher chance of CR in the multivariate analysis. With a median follow-up of 22 months (range, 3-120), the 24-month actuarial LC rate was 81.9%. Achievement of CR and total dose >25 Gy were associated with better LC rate in the multivariate analysis. Mild toxicity was experienced in 54 (20.7%) patients; of 63 side effects, 48 were grade 1, and 15 were grade 2. The 24-month late toxicity-free survival rate was 95.1%., Conclusions: This study confirms the activity and safety of SBRT in patients with MPR-OC and identifies clinical and treatment parameters able to predict CR and LC rate., Implications for Practice: This study aimed to define activity and safety of stereotactic body radiotherapy (SBRT) in a very large, real life data set of patients with metastatic, persistent, recurrent ovarian cancer (MPR-OC). Patient age <60 years, PTV <18 cm 3 , lymph node disease, and biologically effective dose α/β10 >70 Gy were associated with higher chance of complete response (CR). Achievement of CR and total dose >25 Gy were associated with better local control (LC) rate. Mild toxicity was experienced in 20.7% of patients. In conclusion, this study confirms the activity and safety of SBRT in MPR-OC patients and identifies clinical and treatment parameters able to predict CR and LC rate., (© AlphaMed Press 2019.)

Background: The role of radiotherapy and brachytherapy in the management of locally advanced cervical and endometrial cancer is well established. However, in some cases, intracavitary brachytherapy (ICBRT) is not recommended or cannot be carried out. We aimed to investigate whether external-beam irradiation delivered by means of intensity-modulated radiation therapy (IMRT) might replace ICBRT in gynaecological cancer when the standard ICBRT boost delivering cannot be administered for technical or clinical reasons., Materials and Methods: Fifteen already delivered treatments for gynaecological cancer patients were analysed. The treatments were performed through 3-dimensional conformal radiotherapy (3D-CRT) to the whole-pelvis up to the dose of 45-50.4 Gy followed by a boost dose administered with ICBRT in high-dose-rate or pulsed-dose-rate modality. For each patient, IMRT plans were elaborated to mimic the ICBRT. We analysed the ICBRT boost versus IMRT boost in terms of dosimetric and radiobiological aspects., Results: Mean conformity index value calculated on boost volume was 0.73 for ICBRT and 0.97 for IMRT. Mean conformation number was 0.24 for ICBRT boost and 0.78 for IMRT boost. Mean normal tissue complication probability (NTCP) values for 3D-CRT plus ICBRT and for IMRT (pelvis plus boost) were, respectively, 28% and 5% for rectum; 1.5% and 0.1% for urinary bladder and 8.9% and 6.1% for bowel., Conclusions: Our findings suggest that IMRT may represent a viable alternative in delivering the boost in patients diagnosed with gynaecological cancer not amenable to ICBRT., Competing Interests: Nothing to declare., (© the authors; licensee ecancermedicalscience.)

Purpose: To analyse the survival outcomes and toxicity profile of patients treated with pulsed-dose-rate (PDR) brachytherapy (BT) after intensity-modulated radiation therapy (IMRT) for uterine cervical cancer in a single institution., Material and Methods: Between March 2011 and December 2014, 50 patients with histologically proven stages IB1-IVB cervical cancer were treated with IMRT followed by PDR-BT boost. Radiation treatment consisted of IMRT to pelvic with or without paraaortic lymph nodes to a total dose of 45-50.4 Gy. Weekly concomitant chemotherapy was administered to 45 patients. PDR-BT boost was delivered with a median dose of 30 Gy to the high-risk clinical target volume (HR-CTV) after a median time of 14 days since IMRT. Acute and late toxicity were evaluated by Radiation Therapy Oncology Group (RTOG) - European Organization for Research and Treatment of Cancer (EORTC) scoring criteria and Subjective Objective Management Analytic-Late Effects of Normal Tissues (SOMA-LENT) criteria., Results: Two patients had tumour persistence at 6 months after the end of BT. After a median follow-up of 33 months, 6 distant metastases with or without regional relapse were observed. The 1- and 5-year progression-free survival was 83% (95% CI: 69-91%) and 76% (95% CI: 61-86%), whereas the 3- and 5-year overall survival was 91% (95% CI: 78-97%) and 76% (95% CI: 56-88%), respectively. Urinary and rectal toxicity higher than grade 2 was observed in 6.3% and 17% of patients, respectively. Five patients (10.6%) had grade 4 gastrointestinal toxicity requiring colostomy., Conclusions: Our study confirms that the combination of IMRT and PDR-BT can be considered an effective treatment for cervical cancer, ensuring high local control, despite the high percentage of locally advanced disease., (Copyright © 2019 Termedia.)

Purpose: To evaluate whether perfusion and diffusion parameters from staging MR in ovarian cancer (OC) patients may predict the presence of residual tumor at surgery and the progression-free survival (PFS) in 12 months., Materials and Methods: Patients who are from a single institution, candidate for OC to cytoreductive surgery and undergoing MR for staging purposes were included in this study. Inclusion criteria were: preoperative MR including diffusion-weighted imaging (DWI) and perfusion dynamic contrast-enhanced (DCE) sequence; cytoreductive surgery performed within a month from MR; and minimum follow-up of 12 months. Patients' characteristics including the presence of residual tumor at surgery (R0 or R1) and relapse within 12 months from surgery were recorded. DWI parameters included apparent diffusion coefficient (ADC) of the largest ovarian mass (O-ADC) and normalized ovarian ADC as a ratio between ovarian ADC and muscle ADC (M-ADC). DCE quantitative parameters included were descriptors of tumor vascular properties such as forward and backward transfer constants, plasma volume and volume of extracellular space. Statistical analysis was performed, and p values < 0.05 were considered significant., Results: Forty-nine patients were included. M-ADC showed a slightly significant association with the presence of residual tumor at surgery. None of the other functional parameters showed either difference between R0 and R1 patients or association with PFS in the first 12 months., Conclusions: This preliminary study demonstrated a slightly significant association between normalized ovarian ADC and the presence of residual tumor at surgery. The other perfusion and diffusion parameters were not significant for the endpoints of this study.

Soil transmitted helminthiasis (STHs) are endemic in Nepal but since the country territory is extremely heterogeneous, a multidisciplinary assessment is required to evaluate the risk of infection in different areas. Prevalence data were retrieved with systematic literature search and geographical coordinates were assigned to each survey site. Spatial stratification was then implemented considering land use and ecological parameters. STH transmission boundaries were tested after reference criteria and elevation was evaluated as additional predictor: the elevation threshold of 3057 m above sea level is demarking the STH transmission limit. Areas above this threshold are safe, but since lodging in at-risk sites is a compulsory stopover for international travelers, STH risk exposure should be considered for every travel to the country., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To report in-vivo dosimetry in the infraclavicular region, a potential site of a cardiac implantable electronic device (CIED) and to evaluate the absorbed dose from intraoperative radiotherapy with electrons (ELIOT)., Methods: 27 non-cardiopathic breast cancer (BC) patients without CIED received quadrantectomy and ELIOT as partial breast irradiation. Before delivering ELIOT, two catheters, each containing eight thermoluminescent dosimeters (TLDs), were positioned in the infraclavicular region. TLDs internal catheter was located deep in the tumor bed while the external catheter was placed on patient's skin., Results: Data were available for 24/27 patients. The absorbed doses were referred to the dose of 21 Gy. Values measured by the external catheter were low, although statistically significant higher doses were found close to the applicator (mean values 0.26-0.49 Gy). External TLD doses in proximity of the applicator were lower than those detected by their internal counterparts. Values measured by the internal catheter TLDs varied according to the distance from the applicator while no correlation with tumor site and beam energy was found. The distance from the applicator to deliver < 2 Gy to a CIED was 2 cm, while from 2.5 cm the dose measured in all the patients became negligible., Conclusions: This dosimetric study provided data to support the clinical use of ELIOT in BC patients having CIEDs as long as the suggested minimum safe distance of 2.5 cm is taken from the RT field in case of ELIOT single dose of 21 Gy, in the energy range of 6-10 MeV.

Introduction: Recovering the ability to walk is an important goal of physical therapy for patients who have survived cerebrovascular accident (stroke). Orthotics can provide a reduction in plantar flexion of the ankle, leading to greater stability in the stance phase of the gait cycle. Postural insoles can be used to reorganize the tone of muscle chains, which exerts an influence on postural control through correction reflexes. The aim of the present study was to perform kinematic and spatiotemporal analyses of gait in stroke survivors with hemiparesis during postural insole usage., Material and Methods: Twenty stroke victims were randomly divided into two groups: 12 in the experimental group, who used insoles with corrective elements specifically designed for equinovarus foot, and eight in the control group, who used placebo insoles with no corrective elements. Both groups were also submitted to conventional physical therapy. The subjects were analyzed immediately following insole placement and after three months of insole usage. The SMART-D 140 ® system (BTS Engineering) with eight cameras sensitive to infrared light and the 32-channel SMART-D INTEGRATED WORKSTATION ® were used for the three-dimensional gait evaluation., Results: Significant improvements were found in kinematic range of movement in the ankle and knee as well as gains in ankle dorsiflexion and knee flexion in the experimental group in comparison to the control group after three months of using the insoles., Conclusion: Postural insoles offer significant benefits to stroke survivors regarding the kinematics of gait, as evidenced by gains in ankle dorsiflexion and knee flexion after three months of usage in combination with conventional physical therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate stereotactic body radiation therapy (SBRT) for metachronous oligometastatic ovarian cancer patients in terms of local control, delay of systemic treatment, survival outcomes, and toxicity., Methods and Materials: Retrospective data collection from a single institution was performed. The inclusion criteria were as follows: (1) oligorecurrent or oligoprogressive disease in ovarian cancer patients during or after systemic therapy; (2) surgery or other local therapies not feasible; and (3) relative contraindication to systemic therapy for reasons such as unavailability of additional chemotherapy lines or refusal of the patient. Tumor response and toxicity were evaluated using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. A new systemic therapy regimen was started after an SBRT treatment course in 57 of 109 cases (52.3%). Local progression-free survival, progression-free survival, and overall survival were calculated via the Kaplan-Meier method. The systemic treatment-free interval was calculated in cases without concomitant systemic therapy., Results: Between May 2012 and December 2016, 82 patients (156 lesions) underwent SBRT with a median dose of 24 Gy in 3 fractions. The median follow-up period was 17.4 months. Patients received a median of 3 systemic therapy regimens prior to SBRT. Concomitant systemic therapy was performed for 29 lesions (18.6%). Among 152 evaluable lesions, a complete radiologic response, partial response, stabilization, and progressive disease were observed in 91 (60%), 26 (17%), 24 (16%), and 11 (7%), respectively. No grade 3 or 4 acute or late toxicities were observed. The median systemic treatment-free interval after SBRT was 7.4 months, and 1 of 3 patients was disease free at 1 year after SBRT. The actuarial 2-year local progression-free survival, progression-free survival, and overall survival rates were 68%, 18%, and 71%, respectively. The pattern of failure was predominantly out of field., Conclusions: SBRT for oligometastatic ovarian cancer showed good local control and a good toxicity profile. It might be an appealing alternative to other invasive local therapies to delay systemic therapy in the case of chemorefractory disease or intolerance to systemic agents., (Copyright © 2018. Published by Elsevier Inc.)

The aim of the present study was to perform a review of the literature on current quantitative clinical methods for the evaluation of upper limb movements in children and adolescents with Down syndrome, with a focus on describing the variables, protocols, motor function and motor control., Methods: A survey of PubMed, Scielo, BVS Bireme and PEDro databases using the following key words: upper limb and EMG and Down syndrome; upper limb and kinematics and Down syndrome; upper limb and motion analysis and Down syndrome; movement and upper limb and Down syndrome; upper limb and Down syndrome; reach and Down syndrome., Results: In all, 344 articles and five were selected to compose the present systematic review. No standardization was found among the studies analyzed with regard to data collection, data processing or procedures for the evaluation of the variables., Conclusion: A kinematic evaluation is effective for the discussion of the results, but methodological differences among the studies and inconsistent results exert a negative influence on clinical interpretations and the possibility of reproducibility. The standardization of an upper limb movement evaluation protocol using kinematic analysis is important, as it would provide the basis for comparable, reproducible results and facilitate the planning of treatment interventions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To evaluate inter-fraction tumor localization errors (TE) in the RapidArc® treatment of pelvic cancers based on CBCT. Appropriate CTV-to PTV margins in a non-IGRT scenario have been proposed., Methods: Data of 928 patients with prostate, gynecological, and rectum/anal canal cancers were retrospectively analyzed to determine systematic and random localization errors. Two protocols were used: daily online IGRT (d-IGRT) and weekly IGRT. The latter consisted in acquiring a CBCT for the first 3 fractions and subsequently once a week. TE for patients who underwent d-IGRT protocol were calculated using either all CBCTs or the first 3., Results: The systematic (and random) TE in the AP, LL, and SI direction were: for prostate bed 2.7(3.2), 2.3(2.8) and 1.9(2.2) mm; for prostate 4.2(3.1), 2.9(2.8) and 2.3(2.2) mm; for gynecological 3.0(3.6), 2.4(2.7) and 2.3(2.5) mm; for rectum 2.8(2.8), 2.4(2.8) and 2.3(2.5) mm; for anal canal 3.1(3.3), 2.1(2.5) and 2.2(2.7) mm. CTV-to-PTV margins determined from all CBCTs were 14 mm in the AP, 10 mm in the LL and 9-9.5 mm in the SI directions for the prostate and the gynecological groups and 9.5-10.5 mm in AP, 9 mm in LL and 8-10 mm in the SI direction for the prostate bed and the rectum/anal canal groups. If assessed on the basis of the first 3 CBCTs, the calculated CTV-to-PTV margins were slightly larger., Conclusions: without IGRT, large CTV-to-PTV margins up to 15 mm are required to account for inter-fraction tumor localization errors. Daily IGRT should be used for all hypo-fractionated treatments to reduce margins and avoid increased toxicity to critical organs., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effects of gait training with virtual reality (VR) on walking distance and physical fitness in individuals with Parkinson's Disease (PD)., Methods: Thirty-seven individuals with PD participated in this prospective, randomized, controlled clinical trial. They were randomly allocated to a control group submitted to conventional training (n = 12), a treadmill group submitted to gait training on a treadmill (n = 13) and a VR group submitted to gait training using the XboxTM (n = 12). Clinical measures, gait variables and the Six-Minute Walk Test (6MWT) were evaluated: pre-intervention, after one intervention session, post-intervention and follow up (30 days after intervention)., Results: The VR and treadmill groups travelled longer distances on the 6MWT and had faster gait speed in comparison to the control group. The VR and treadmill groups demonstrated an increase in pre-6MWT HR. The VR group had more intense HR after the first session and throughout training, but these gains were not maintained at the follow-up., Conclusion: The present findings demonstrate that gait training with a VR program is as effective as treadmill training with regard to gains in walking distance and improvements in temporal gait variables in individuals with PD.

Purpose: To assess the best electrode position of transcranial direct current stimulation combined with treadmill training in children with unilateral spastic cerebral palsy., Methods: Thirty children with cerebral palsy were randomly allocated to 3 groups: (1) treadmill training combined with anodal electrode positioned over the primary motor cortex in the region of the dominant hemisphere and the cathode positioned in the supraorbital region contralateral to anode; (2) sham anodal transcranial direct current stimulation over the primary motor cortex and sham cathode over the contralateral supraorbital region combined with treadmill training; (3) treadmill training combined with the anodal electrode positioned over the primary motor cortex in the region of the injured hemisphere and the cathode positioned contralateral to anode over the primary motor cortex. Evaluations of gait, balance, quality of life, and electromyographic activity were performed., Discussion: This is the protocol for an intervention study investigating electrode position to achieve improved function.

Background: The aim of this study was to confirm our preliminary results with in vivo dosimetry in non-pregnant breast cancer patients receiving electron beam intraoperative radiotherapy (ELIOT) and to report on the first treatment in a pregnant woman., Patients and Methods: Following our previous experience, 5 non-pregnant patients receiving ELIOT to the tumor bed after breast-conserving surgery (BCS) were studied with thermoluminescent dosimeters positioned in the subdiaphragmatic region, within the uterus, and in the ovarian region. In December 2011, the first pregnant breast cancer patient underwent BCS and ELIOT (21 Gy at 90% isodose) during the 15th week of gestation., Results: The mean dose to the subdiaphragmatic external region in the 5 non-pregnant patients was 5.57 mGy, while pelvic measurements were below 1 mGy. The actual dosimetry of the pregnant patient showed a mean subdiaphragmatic dose of 4.34 mGy, a mean suprapubic dose of 1.64 mGy, and mean ovarian doses of 1.48 mGy (right-sided) and 1.44 mGy (left-sided). The expected dose to the fetus was estimated as 0.84 mGy (0.004% of the prescribed dose)., Conclusion: ELIOT as an anticipated boost to the breast could be considered in pregnant women in the early second trimester, postponing whole-breast irradiation after delivery.

Aim: To ascertain whether cholestasis affects the expression of two CYP3A isoforms (CYP3A1 and CYP3A2) and of pregnane X receptor (PXR) and constitutive androstane receptor (CAR)., Methods: Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3A1 and CYP3A2 were assessed by means of qRT-PCR and Western blot, respectively. Alterations in CYP3A activity were measured by calculating the kinetic parameters of 4-OH and 1'-OH-midazolam hydroxylation, marker reactions for CYP3A enzymes., Results: The mRNA and protein expression of CYP3A1 increased significantly in mild cholestasis ( P < 0.01). At variance, mRNA and protein expression of CYP3A2 didn't change in mild cholestasis, whereas the expression and activity of both CYP3A1 and CYP3A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR., Conclusion: Early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3A-mediated liver detoxification., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to report.

Purpose: To investigate the local outcome of patients after accelerated partial breast irradiation with intraoperative electrons (IORT) for invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC)., Methods and Materials: From 1999 to 2007, 2173 patients were treated with breast-conserving surgery and IORT (21 Gy/1 fraction) as the sole local treatment: 252 patients with ILC (11.6%) were compared with 1921 patients with IDC in terms of local control., Results: Compared with the IDC subgroup, patients with ILC had a low-risk profile and were more hormone responsive. The 5- and 10-year in-breast tumor reappearance (IBTR) rates were 5.5% and 14.4%, respectively, for the IDC group and 7.5% and 21.8%, respectively, for the ILC group (log-rank P=.03). The excess risk of IBTR associated with ILC was particularly high for small tumors (≤1 cm: hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.03-4.85), elderly patients (60-69 years: HR, 2.27; 95% CI, 1.11-4.63; ≥70 years: HR, 3.28; 95% CI, 1.08-10.0), low-grade tumors (grade 1: HR, 3.50; 95% CI, 1.05-11.7), and luminal A molecular subtype (HR, 3.18; 95% CI, 1.49-6.77). Among the ILC histologic variants, no difference between classic and nonclassic subgroups was observed, although the signet ring cell and solid variants had the worst local control., Conclusions: Despite a favorable tumor profile, accelerated partial breast irradiation with IORT led to a higher incidence of IBTRs in patients with ILC compared with those with IDC. Our institutional experience emphasized the importance of the size of the irradiation field, pointing to the use of larger collimators, even when dealing with small tumors, to improve local control., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Down syndrome results in neuromotor impairment that affects selective motor control, compromising the acquisition of motor skills and functional independence. The aim of the proposed study is to evaluate and compare the effects of multiple-monopolar anodal transcranial direct current stimulation and sham stimulation over the primary motor cortex during upper limb motor training involving virtual reality on motor control, muscle activity, cerebral activity and functional independence., Methods and Analysis: A randomised, controlled, double-blind, clinical trial is proposed. The calculation of the sample size will be defined based on the results of a pilot study involving the same methods. The participants will be randomly allocated to two groups. Evaluations will be conducted before and after the intervention as well as 1 month after the end of the intervention process. At each evaluation, three-dimensional analysis of upper limb movement muscle activity will be measured using electromyography, cerebral activity will be measured using an electroencephalogram system and intellectual capacity will be assessed using the Wechsler Intelligence Scale for Children. Virtual reality training will be performed three times a week (one 20 min session per day) for a total of 10 sessions. During the protocol, transcranial stimulation will be administered concomitantly to upper limb motor training. The results will be analysed statistically, with a p value≤0.05 considered indicative of statistical significance., Ethical Aspects and Publicity: The present study received approval from the Institutional Review Board of Universidade Nove de Julho (Sao Paulo,Brazil) under process number 1.540.113 and is registered with the Brazilian Registry of Clinical Trials (N° RBR3PHPXB). The participating institutions have presented a declaration of participation. The volunteers will be permitted to drop out of the study at any time with no negative repercussions. The results will be published and will contribute evidence regarding the use of this type of intervention on children., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Epidemiology of Neisseria meningitidis has been changing since the introduction of universal vaccination programmes against meningococcal serogroup C (MenC) and meningococcal serogroup B (MenB) has now become dominant. This study aimed to analyse the cases reported in institutional data recording systems to estimate the burden of invasive meningococcal diseases (IMDs) and assess the effectiveness of surveillance in Veneto region (Italy)., Methods: Analysis was performed from 2007 to 2014 on data recorded in different systems: Mandatory Notification System, National Surveillance of Invasive Bacterial Diseases System and Laboratories Surveillance System (LSS), which were pooled into a combined surveillance system (CSS) and hospital discharge records (HDRs). A capture-recapture method was used and completeness of each source estimated. Number of cases with IMD by source of information and year, incidence of IMD by age group, case fatality rate (CFR) and distribution of meningococcal serogroups by year were also analysed., Results: Combining the four data systems enabled the identification of 179 confirmed cases with IMD, achieving an overall sensitivity of 94.7% (95% CI: 90.8% to 98.8%), while it was 76.7% (95% CI: 73.6% to 80.1%) for CSS and 77.2% (95% CI: 74.1% to 80.6%) for HDRs. Typing of isolates was done in 80% of cases, and 95.2% of the typed cases were provided by LSS. Serogroup B was confirmed in 50.3% of cases. The estimated IMD notification rate (cases with IMD diagnosed and reported to the surveillance systems) was 0.48/100 000 population, and incidence peaked at 6.2/100 000 in children aged <1 year old (60.9% due to MenB), and increased slightly in the age group between 15 and 19 years (1.1/100 000). A CFR of 14% was recorded (8.7% in paediatric age)., Conclusions: Quality of surveillance systems relies on case ascertainment based on serological characterisation of the circulating strains by microbiology laboratories. All available sources should be routinely combined to improve the epidemiology of IMD and the information used by public health departments to conduct timely preventive measures., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The authors' aim was to investigate the effects of continuous transcranial direct current stimulation (tDCS) combined with virtual reality training on static and functional balance in children with cerebral palsy (CP). Twenty children with CP (6 girls and 14 boys; M age = 7 years 6 months ± 2 years) were randomly allocated to two groups. The experimental group received active tDCS and the control group received sham stimulation during the 10 sessions of virtual reality mobility training protocols. The children were evaluated on 3 occasions (preintervention, postintervention, and 1-month follow-up). Static balance was evaluated using a force plate under 4 conditions: feet on force plate with (a) eyes open and (b) with eyes closed, and feet on foam mat with (c) eyes open and (d) with eyes closed. Functional balance was evaluated using the Pediatric Balance Scale and the Timed Up and Go Test. The analyses demonstrated statistically significant postintervention and follow-up effects favoring the experimental group over the control group with regard to the Pediatric Balance Scale, Timed Up and Go Test, and area of oscillation of the center of pressure when standing on the force plate with eyes open. The present findings suggest that tDCS can potentiate the effects of virtual reality training on static and functional balance among children with CP.

Purpose: Mathematical modeling is a powerful and flexible method to investigate complex phenomena. It discloses the possibility of reproducing expensive as well as invasive experiments in a safe environment with limited costs. This makes it suitable to mimic tumor evolution and response to radiotherapy although the reliability of the results remains an issue. Complexity reduction is therefore a critical aspect in order to be able to compare model outcomes to clinical data. Among the factors affecting treatment efficacy, tumor oxygenation is known to play a key role in radiotherapy response. In this work, we aim at relating the oxygenation dynamics, predicted by a macroscale model trained on tumor volumetric data of uterine cervical cancer patients, to vascularization and blood flux indices assessed on Ultrasound Doppler images., Methods: We propose a macroscale model of tumor evolution based on three dynamics, namely active portion, necrotic portion, and oxygenation. The model parameters were assessed on the volume size of seven cervical cancer patients administered with 28 fractions of intensity modulated radiation therapy (IMRT) (1.8 Gy/fraction). For each patient, five Doppler ultrasound tests were acquired before, during, and after the treatment. The lesion was manually contoured by an expert physician using 4D View ® (General Electric Company - Fairfield, Connecticut, United States), which automatically provided the overall tumor volume size along with three vascularization and/or blood flow indices. Volume data only were fed to the model for training purpose, while the predicted oxygenation was compared a posteriori to the measured Doppler indices., Results: The model was able to fit the tumor volume evolution within 8% error (range: 3-8%). A strong correlation between the intrapatient longitudinal indices from Doppler measurements and oxygen predicted by the model (about 90% or above) was found in three cases. Two patients showed an average correlation value (50-70%) and the remaining two presented poor correlations. The latter patients were the ones featuring the smallest tumor reduction throughout the treatment, typical of hypoxic conditions. Moreover, the average oxygenation value predicted by the model was close to the average vascularization-flow index (average difference: 7%)., Conclusions: The results suggest that the modeled relation between tumor evolution and oxygen dynamics was reasonable enough to provide realistic oxygenation curves in five cases (correlation greater than 50%) out of seven. In case of nonresponsive tumors, the model failed in predicting the oxygenation trend while succeeded in reproducing the average oxygenation value according to the mean vascularization-flow index. Despite the need for deeper investigations, the outcomes of the present work support the hypothesis that a simple macroscale model of tumor response to radiotherapy is able to predict the tumor oxygenation. The possibility of an objective and quantitative validation on imaging data discloses the possibility to translate them as decision support tools in clinical practice and to move a step forward in the treatment personalization., (© 2017 American Association of Physicists in Medicine.)

Background: Stroke is one of the main causes of disability among adults., Objective: The aim of the present study was to analyze the effect of postural insoles on static balance in individuals with stroke., Methods: Twenty-four strokes survivors with hemiparesis were recruited from the rehabilitation clinics of the university and randomly allocated to two groups: experimental and control group. The subjects were analyzed for stabilometry, immediately following insole placement and after three months of insole usage, with eyes open and eyes closed., Results: A significant difference was found immediately after postural insole placement regarding anteroposterior range of movement (p < 0.05). Moreover, significant reductions were found in the inter-group analysis after three months of insole usage., Conclusion: Based on the present findings, postural insoles combined with conventional physical therapy offer significant benefits regarding static postural control among stroke victims after three months of use, as demonstrated by computerized stabilometry., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To prospectively assess whether choline levels and Apparent Diffusion Coefficient (ADC) values within cervical cancers before, during, and after non-surgical therapy are predictive of tumour response., Patients and Methods: Patients undergoing MR examination for staging of cervical cancer, candidate for non-surgical therapy, were prospectively enrolled. According to the status at the end of therapies, patients were divided into responders and non-responders. The final outcome after a 5-year follow-up was classified as No Evidence of Disease (NED) or Progression of Disease (PD). Baseline values of mean ADC and Cho/H2O were compared between responders and non-responders, as well as between patients with NED and PD. The percent variation of ADC and Cho/H2O values over time was compared. P values <0.05 were considered significant., Results: 16 patients were included. There was no significant difference at baseline between responders (n = 12) and non-responders (n = 4), nor between NED (n = 11) PD patients (n = 5), in ADC values and Cho/H2O ratio. There was no significant difference in percent variation of ADC values and of Cho/H2O, comparing responders and non-responders. There was a significant increase in absolute values of ADC from the initial to mid-therapy MRI (p = 0.0001), while Cho/H2O was stable (p value: 0.61). In the four non-responders, the ADC increase was not significant (p value: 0.25), while it was significant in the 11 responders (p value: 0.001). Values of spectroscopy were stable in both responders and non-responders., Conclusions: High increases of ADC values from baseline to mid-therapy MR reflect response to therapies. There were no significant variations in choline/water ratios over time.

Background: The aim of the proposed study is to perform a comparative analysis of functional training effects for the paretic upper limb with and without transcranial direct current stimulation over the primary motor cortex in children with spastic hemiparetic cerebral palsy., Methods: The sample will comprise 34 individuals with spastic hemiparetic cerebral palsy, 6 to 16 years old, classified at level I, II, or III of the Manual Ability Classification System. Participants will be randomly allocated to two groups: (1) functional training of the paretic upper limb combined with anodic transcranial stimulation; (2) functional training of the paretic upper limb combined with sham transcranial stimulation. Evaluation will involve three-dimensional movement analysis and electromyography using the SMART-D 140® system (BTS Engineering) and the FREEEMG® system (BTS Engineering), the Quality of Upper Extremity Skills Test, to assess functional mobility, the Portable Device and Ashworth Scale, to measure movement resistance and spasticity, and the Pediatric Evaluation of Disability Inventory, to evaluate performance. Functional reach training of the paretic upper limb will include a range of manual activities using educational toys associated with an induced constraint of the non-paretic limb during the training. Training will be performed in five weekly 20-minute sessions for two weeks. Transcranial stimulation over the primary motor cortex will be performed during the training sessions at an intensity of 1 mA. Findings will be analyzed statistically considering a 5 % significance level (P ≤ 0.05)., Discussion: This paper presents a detailed description of a prospective, randomized, controlled, double-blind, clinical trial designed to demonstrate the effects of combining transcranial direct current stimulation over the primary motor cortex and functional training of the paretic limb in children with cerebral palsy classified at level I, II, or III of the Manual Ability Classification System. The results will be published and evidence found may contribute to the use of transcranial stimulation for this population., Trial Registration: ReBEC RBR-6V4Y3K . Registered on 11 February 2015.