Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? SUMMARY ANSWER: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints ß = 0.017, 95% CI [0.009; 0.025], bifurcation points ß = 0.012, 95% CI [0.006; 0.018], crossing points ß = 0.017, 95% CI [0.008; 0.025], vessel points ß = 0.01, 95% CI [0.002; 0.008], and total vascular length ß = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV ß = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV ß = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV ß = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV ß -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV ß = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically. LIMITATION, REASONS FOR CAUTION: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered at the Dutch Trial Register (NTR6854).

Ultrafast Transition from State-Blocking Dynamics to Electron Localization in Transition Metal ß-Tungsten.

We describe an ultrafast transition of the electronic response of optically excited transition metal ß-tungsten with few-femtosecond time resolution. The response moves from a regime where state filling of the excited carrier population around the Fermi level dominates towards localization of carriers onto the outer d orbitals. This is in contrast to previous measurements using ultrafast element-specific core-level spectroscopy enabled by attosecond transient absorption spectroscopy on transition metals such as titanium and around the transition metal atom in transition metal dichalchogenides MoTe_{2} and MoSe_{2}. This surprisingly different dynamical response for ß-tungsten can be explained by considering the electron-electron dynamics on a few-femtosecond timescale and the slower electron-phonon thermalization dynamics.

The treatment of biochemical genetic diseases: From substrate reduction to nucleic acid therapies.

Newborn screening (NBS) began a revolution in the management of biochemical genetic diseases, greatly increasing the number of patients for whom dietary therapy would be beneficial in preventing complications in phenylketonuria as well as in a few similar disorders. The advent of next generation sequencing and expansion of NBS have markedly increased the number of biochemical genetic diseases as well as the number of patients identified each year. With the avalanche of new and proposed therapies, a second wave of options for the treatment of biochemical genetic disorders has emerged. These therapies range from simple substrate reduction to enzyme replacement, and now ex vivo gene therapy with autologous cell transplantation. In some instances, it may be optimal to introduce nucleic acid therapy during the prenatal period to avoid fetopathy. However, as with any new therapy, complications may occur. It is important for physicians and other caregivers, along with ethicists, to determine what new therapies might be beneficial to the patient, and which therapies have to be avoided for those individuals who have less severe problems and for which standard treatments are available. The purpose of this review is to discuss the "Standard" treatment plans that have been in place for many years and to identify the newest and upcoming therapies, to assist the physician and other healthcare workers in making the right decisions regarding the initiation of both the "Standard" and new therapies. We have utilized several diseases to illustrate the applications of these different modalities and discussed for which disorders they may be suitable. The future is bright, but optimal care of the patient, including and especially the newborn infant, requires a deep knowledge of the disease process and careful consideration of the necessary treatment plan, not just based on the different genetic defects but also with regards to different variants within a gene itself.

The hypergonadotropic hypogonadism conundrum of classic galactosemia.

BACKGROUND: Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored. OBJECTIVE AND RATIONALE: The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage. SEARCH METHODS: In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed. OUTCOMES: A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level. WIDER IMPLICATIONS: Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathways might serve as markers of disease progression and efficiency of new treatment options.

Systematic Review - Combining Neuroprotection With Reperfusion in Acute Ischemic Stroke.

Background: Clinical trials of neuroprotection in acute ischemic stroke (AIS) have provided disappointing results. Reperfusion may be a necessary condition for positive effects of neuroprotective treatments. This systematic review provides an overview of efficacy of neuroprotective agents in combination with reperfusion therapy in AIS. Methods: A literature search was performed on the following databases, namely PubMed, Embase, Web of Science, Cochrane Library, Emcare. All databases were searched up to September 23rd 2021. All randomized controlled trials in which patients were treated with neuroprotective strategies within 12 h of stroke onset in combination with intravenous thrombolysis (IVT), endovascular therapy (EVT), or both were included. Results: We screened 1,764 titles/abstracts and included 30 full reports of unique studies with a total of 16,160 patients. In 15 studies neuroprotectants were tested for clinical efficacy, where all patients had to receive reperfusion therapies, either IVT and/or EVT. Heterogeneity in reported outcome measures was observed. Treatment was associated with improved clinical outcome for: 1) uric acid in patients treated with EVT and IVT, 2) nerinetide in patients who underwent EVT without IVT, 3) imatinib in stroke patients treated with IVT with or without EVT, 4) remote ischemic perconditioning and IVT, and 5) high-flow normobaric oxygen treatment after EVT, with or without IVT. Conclusion: Studies specifically testing effects of neuroprotective agents in addition to IVT and/or EVT are scarce. Future neuroprotection studies should report standardized functional outcome measures and combine neuroprotective agents with reperfusion therapies in AIS or aim to include prespecified subgroup analyses for treatment with IVT and/or EVT.

Prognosis after neoadjuvant chemoradiation or chemotherapy for locally advanced gastro-oesophageal junctional adenocarcinoma.

BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.

Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

First-trimester utero-placental (vascular) development and embryonic and fetal growth: The Rotterdam periconception cohort.

INTRODUCTION: Impaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth. METHODS: In a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex. RESULTS: PV trajectories were positively associated with CRL (ßadj = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (ßadj = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (ßadj = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (ßadj = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046). DISCUSSION: First-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth.

Whole-genome sequencing for TB source investigations: principles of ethical precision public health.

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis allows rapid, accurate inferences about the sources, location and timing of transmission. However, in an era of heightened concern for personal privacy and science distrust, such inferences could result in unintended harm and undermine the public´s trust.METHODS: We held interdisciplinary stakeholder discussions and performed ethical analyses of real-world illustrative cases to identify principles that optimise benefit and mitigate harm of M. tuberculosis WGS-driven TB source investigations.RESULTS: The speed and precision with which real-time WGS can be used to associate M. tuberculosis strains with sensitive information has raised important concerns. While detailed understanding of transmission events could mitigate harm to vulnerable patients and communities when otherwise unfairly blamed for TB outbreaks, the precision of WGS can also identify transmission events resulting in social blame, fear, discrimination, individual or location stigma, and the use of defaming language by the public, politicians and scientists. Public health programmes should balance the need to safeguard privacy with public health goals, transparency and individual rights, including the right to know who infects whom or where.CONCLUSIONS: Ethical challenges raised by real-time WGS-driven TB source investigation requires public health authorities to move beyond their current legal mandate and embrace transparency, privacy and community engagement.

Management of rifampicin-resistant TB: programme indicators and care cascade analysis in South Africa.

BACKGROUND: Xpert® MTB/RIF was expected to revolutionise the management of rifampicin-resistant TB (RR-TB) by enabling rapid and decentralised diagnosis of rifampicin (RIF) resistance.METHODS: We performed a care cascade analysis for a cohort of RR-TB patients managed under programmatic conditions. Cumulative incidences of time to completion of the RR-TB care cascade steps were estimated, reasons for delay or attrition from the cascade investigated and WHO programme indicators for monitoring of RR-TB programmes calculated.RESULTS: Of 502 patients diagnosed with RR-TB using Xpert, 64% initiated multidrug-resistant TB (MDR-TB) treatment immediately, 20% after some first-line treatment, 16% never initiated MDR-TB treatment, mainly because of death (44%) or loss to follow-up (26%) soon after diagnosis. A supplementary sputum sample was collected within 14 days of treatment in 58.8% of cases. Only 63% of RR-TB cases were assessed for isoniazid resistance, and only 65% of MDR-TB cases were evaluated for pre-XDR-TB (extensively drug-resistant TB). Treatment was individualised in 57% of pre-XDR and 68% of XDR-TB patients. Only 8% completed the entire RR-TB care cascade as intended.CONCLUSION: Fidelity to the RR-TB algorithm was poor, with substantial losses at each step of the cascade, highlighting the fact that implementation of novel technologies needs to be accompanied by health system strengthening to maximise impact.

Trends in SARS-CoV-2 seroprevalence amongst urban paediatric patients compared with a nationwide cohort in the Netherlands.

Objectives: The extent of SARS-CoV-2 infection amongst children and their role in transmission remains unclear. Therefore, we aimed to estimate the SARS-CoV-2 antibody seroprevalence amongst children who presented to our hospital for non-COVID-19-related morbidity during the first and second epidemic wave in 2020 and compared these to the general Dutch paediatric population. Methods: We collected residual plasma samples from all paediatric patients (1 month-17 years of age) visiting our clinic or emergency room, who had blood drawing for various medical reasons. Samples were analysed for the presence of total antibodies against SARS-CoV-2 by Wantai ELISA. The seroprevalence in two separate periods (July-Sep 2020, and Oct-Dec 2020) was compared to regional and national data (PIENTER-Corona study, September 2020), and associations with co-morbidities were assessed. Results: A total of 209 samples in period 1 and 240 samples in period 2 were collected (median age 7.1 years, IQR 1.5-13.5). SARS-CoV-2 antibodies were detected in 4.1% and 13.8%, respectively (p< 0.001). Seroprevalence was higher compared to national paediatric data, but did not differ with regional estimates. Most children with SARS-CoV-2 antibodies were seen in the outpatient clinic for general paediatric problems with no differences in medical reasons for presentation between the two periods. Conclusions: These data confirm a rapid three-fold increase in SARS-CoV-2 seroprevalence in paediatric patients in the second half of 2020 with a trend towards a higher seroprevalence compared to randomly-selected children in a nationwide study. Underlying morbidity in children might not play an important role in acquiring SARS-CoV-2 infection.

Patient-Reported Outcome Measures May Add Value in Breast Cancer Surgery.

PURPOSE: Considering the comparable prognosis in early-stage breast cancer after breast-conserving therapy (BCT) and mastectomy, quality of life should be a focus in treatment decision(s). We retrospectively collected PROs and analyzed differences per type of surgery delivered. We aimed to obtain reference values helpful in shared decision-making. PATIENTS AND METHODS: pTis-T3N0-3M0 patients operated between January 2005 and September 2016 were eligible if: (1) no chemotherapy was administered < 6 months prior to enrolment, and (2) identical surgeries were performed in case of bilateral surgery. After consent, EQ-5D-5L, EORTC-QLQ-C30/BR23, and BREAST-Q were administered. PROs were evaluated per baseline characteristics using multivariable linear regression models. Outcomes were compared for different surgeries as well as for primary (PBC) and second primary or recurrent (SBC) breast cancer patients using analyses of variance (ANOVAs). RESULTS: The response rate was 68%. PROs in 612 PBC patients were comparable to those in 152 SBC patients. Multivariable analyses showed increasing age to be associated with lower "physical functioning" [ß - 0.259, p < 0.001] and "sexual functioning" [ß - 0.427, p < 0.001], and increasing time since surgery with less "fatigue" [ß - 1.083, p < 0.001]. Mastectomy [ß - 13.596, p = 0.003] and implant reconstruction [ß - 13.040, p = 0.007] were associated with lower "satisfaction with breast" scores than BCT. Radiation therapy was associated with lower satisfaction scores than absence of radiotherapy. DISCUSSION: PRO scores were associated with age, time since surgery, type of surgery, and radiation therapy in breast cancer patients. The scores serve as a reference value for different types of surgery in the study population and enable prospective use of PROs in shared decision-making.

Breast and Tumour Volume Measurements in Breast Cancer Patients Using 3-D Automated Breast Volume Scanner Images.

BACKGROUND: The resection volume in relation to the breast volume is known to influence cosmetic outcome following breast-conserving therapy. It was hypothesised that three-dimensional ultrasonography (3-D US) could be used to preoperatively assess breast and tumour volume and show high association with histopathological measurements. METHODS: Breast volume by the 3D-US was compared to the water displacement method (WDM), mastectomy specimen weight, 3-D MRI and three different calculations for breast volume on mammography. Tumour volume by the 3-D US was compared to the histopathological tumour volume and 3-D MRI. Relatedness was based on the intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (95% CI). Bland-Altman plots were used to graphically display the agreement for the different assessment techniques. All measurements were performed by one observer. RESULTS: A total of 36 patients were included, 20 and 23 for the evaluation of breast and tumour volume (ductal invasive carcinomas), respectively. 3-D US breast volume showed 'excellent' association with WDM, ICC 0.92 [95% CI (0.80-0.97)]. 3-D US tumour volume showed a 'excellent' association with histopathological tumour volume, ICC 0.78 [95% CI (0.55-0.91)]. Bland-Altman plots showed an increased overestimation in lager tumour volumes measured by 3-D MRI compared to histopathological volume. CONCLUSIONS: 3-D US showed a high association with gold standard WDM for the preoperative assessment of breast volume and the histopathological measurement of tumour volume. 3-D US is an patient-friendly preoperative available technique to calculate both breast volume and tumour volume. Volume measurements are promising in outcome prediction of intended breast-conserving treatment.

The design, production and clinical application of 3D patient-specific implants with drilling guides for acetabular surgery.

An innovative procedure for the development of 3D patient-specific implants with drilling guides for acetabular fracture surgery is presented. By using CT data and 3D surgical planning software, a virtual model of the fractured pelvis was created. During this process the fracture was virtually reduced. Based on the reduced fracture model, patient-specific titanium plates including polyamide drilling guides were designed, 3D printed and milled for intra-operative use. One of the advantages of this procedure is that the personalised plates could be tailored to both the shape of the pelvis and the type of fracture. The optimal screw directions and sizes were predetermined in the 3D model. The virtual plan was translated towards the surgical procedure by using the surgical guides and patient-specific osteosynthesis. Besides the description of the newly developed multi-disciplinary workflow, a clinical case example is presented to demonstrate that this technique is feasible and promising for the operative treatment of complex acetabular fractures.

Focally positive margins in breast conserving surgery: Predictors, residual disease, and local recurrence.

BACKGROUND: Re-excision after breast conserving surgery (BCS) for invasive breast cancer (IBC) can be omitted for focally positive margins in the Netherlands, but this guideline is not routinely followed. Focally positive and extensively positive margins have rarely been studied separately and compared to negative margins regarding clinicopathological predictors, residual disease incidence, and local recurrence. METHODS: All females with BCS for Tis-T3, without neo-adjuvant chemotherapy between 2005 and 2014 at one university hospital were included. Clinicopathological and follow-up information was collected from electronic patient records. Index tumor samples from all patients with re-excision were reviewed by one pathologist. Margins were classified as negative (≥2 mm width), close (<2 mm width), focally positive (≤4 mm length of tumor touching inked margin), or extensively positive (>4 mm length). RESULTS: From 499 patients included, 212 (43%) had negative, 161 (32%) had close, 59 (12%) had focally positive, and 67 (13%) had extensively positive margins. Increasingly involved margins were associated with lobular type, tumor size, and adjacent DCIS in IBC patients and lesion size in purely DCIS patients. In IBC patients, 17%, 49%, and 77% had re-excision after close, focally positive, and extensively positive margins and residual disease incidence was 55%, 50%, and 70% respectively. In purely DCIS patients, 26 (65%), 13 (87%), and 16 (94%) had re-excision after close, focally positive, and extensively positive margins and residual disease incidence was 39%, 46%, and 90% respectively. CONCLUSION: Incidence of residual disease after focally positive margins was not different from close margins, but was significantly higher after extensively positive margins. We recommend quantifying extent of margin involvement in all pathology reports.

TUmor-volume to breast-volume RAtio for improving COSmetic results in breast cancer patients (TURACOS); a randomized controlled trial.

BACKGROUND: Cosmetic result following breast conserving surgery (BCS) for cancer influences quality of life and psychosocial functioning in breast cancer patients. A preoperative prediction of expected cosmetic result following BCS is not (yet) standard clinical practice and therefore the choice for either mastectomy or BCS is still subjective. Recently, we showed that tumour volume to breast volume ratio as well as tumour location in the breast are independent predictors of superior cosmetic result following BCS. Implementation of a prediction model including both factors, has not been studied in a prospective manner. This study aims to improve cosmetic outcome by implementation of a prediction model in the treatment decision making for breast cancer patients opting for BCS. METHODS/DESIGN: Multicentre, single-blinded, randomized controlled trial comparing standard preoperative work-up to a preoperative work-up with addition of the prediction model. Tumour volume to breast volume ratio and tumour location in the breast will be used to predict cosmetic outcome in invasive breast cancer patients opting for BCS. Three dimensional (3D)-ultrasonography will be used to measure the tumour volume to breast volume ratio needed for the prediction model. Sample size was estimated based on a 14% improvement in incidence of superior cosmetic result one year after BCS (71% in the control group versus 85% in the intervention group). Primarily cosmetic outcome will be evaluated by a 6-member independent panel. Secondary endpoints include; (1) patient reported outcome measured by BREAST-Q, EORTC-QLQ-C30/BR23 and EQ-5D-5 L (2) cosmetic outcome as assessed through the BCCT.core software, (3) radiation-induced reaction (4) surgical treatment performed, (5) pathological result and (6) cost-effectiveness. Follow-up data will be collected for 3 years after surgery or finishing radiotherapy. DISCUSSION: This randomized controlled trial examines the value of a preoperative prediction model for the treatment-decision making. It aims for a superior cosmetic result in breast cancer patients opting for BCS. We expect improvement of patients' quality of life and psychosocial functioning in a cost-effective way. TRIAL REGISTRATION: Prospectively registered, February 17th 2015, at 'Nederlands Trialregister - NTR4997 '.

[An evidence-update on the prospective relationship between childhood sedentary behaviour and biomedical health indicators: a systematic review and meta-analysis]. / Gezondheidseffecten van veel zitten tijdens de jeugd.

This systematic review and meta-analysis summarizes the evidence on the prospective relationship between childhood sedentary behaviour and biomedical health indicators, overall and stratified by type of sedentary behaviour (TV viewing, computer use/games, screen time and objective sedentary time).

Validation of the Oral Survey-B System for Electronic Data Capture in National Oral Health Surveys.

The aims of the present study were to incorporate and to validate the electronic capture of participant-related outcomes into the Oral Survey-B System, which was originally developed for the electronic capture of clinical data. The validation process compared the performances of electronic and handwritten data captures. The hypothesis of noninferiority would be established if participants performed electronic data capture of the questionnaire survey with an effectiveness of at least 95% of that of handwritten data capture. In this multicenter, randomized, one-period crossover study design, participants (n = 261) were allocated to start with either electronic or handwritten data capture. The incorporation of the electronic self-completed questionnaire into the Oral Survey-B System was successful. The validation of the electronic questionnaire was performed by participants aged from 18 to 75 years. The interrater reliability of participants performing electronic and handwritten data capture of nonclinical assessments per questionnaire and per entry showed a kappa value of 0.72 (95% CI: 0.53-0.94). The noninferiority of electronic data capture in relation to that of the handwritten data capture and transfer was shown (p < 0.0001; 95% CI: 1.47-2.99). In conclusion, the electronic capture of participant-related outcomes with the Oral Survey-B System, originally designed for capture of clinical data, was validated. The electronic data capture was accurate and limited the number of errors. The participants were able to perform electronic data capture effectively, supporting its implementation in further National Oral Health Surveys. With the consideration of participant preference and time savings, this could lead to the implementation of electronic data capture worldwide in National Oral Health Surveys.

Benefits of preoperative MRI in breast cancer surgery studied in a large population-based cancer registry.

BACKGROUND: Although evidence for the benefits of preoperative MRI in breast cancer is lacking, use of MRI is increasing and characterized by large interhospital variation. The aim of the study was to evaluate MRI use and surgical outcomes retrospectively. METHODS: Women with invasive breast cancer (pT1-3) or ductal carcinoma in situ (DCIS), diagnosed in 2011-2013, were selected from the Netherlands Cancer Registry and subdivided into the following groups: invasive cancer, high-grade DCIS, non-palpable cancer, age 40 years or less, and invasive lobular cancer. Associations between preoperative MRI use and initial mastectomy, resection margin after breast-conserving surgery (BCS), re-excision after BCS, and final mastectomy were analysed. RESULTS: In total, 5514 women were included in the study; 1637 (34·1 per cent) of 4801 women with invasive cancer and 150 (21·0 per cent) of 713 with DCIS had preoperative MRI. Positive resection margins were found in 18·1 per cent women who had MRI and in 15·1 per cent of those who did not (adjusted odds ratio (OR) 1·20, 95 per cent c.i. 1·00 to 1·45), with no differences in subgroups. Re-excision rates were 9·8 per cent in the MRI group and 7·2 per cent in the no-MRI group (adjusted OR 1·33, 1·04 to 1·70), with no differences in subgroups. In the MRI group, 38·8 per cent of patients ultimately underwent mastectomy, compared with 24·2 per cent in the no-MRI group (adjusted OR 2·13, 1·87 to 2·41). This difference was not found for patients aged 40 years or less, or for those diagnosed with lobular cancer. CONCLUSION: No subgroup was identified in which preoperative MRI influenced the risk of margin involvement or re-excision rate after BCS. MRI was significantly associated with more extensive surgery, except in patients aged 40 years or less and those with invasive lobular cancer. These results suggest that use of preoperative MRI should be more targeted, and that general, widespread use be discouraged.

Image quality and cancer visibility of T2-weighted magnetic resonance imaging of the prostate at 7 Tesla.

OBJECTIVES: To assess the image quality of T2-weighted (T2w) magnetic resonance imaging of the prostate and the visibility of prostate cancer at 7 Tesla (T). MATERIALS & METHODS: Seventeen prostate cancer patients underwent T2w imaging at 7T with only an external transmit/receive array coil. Three radiologists independently scored images for image quality, visibility of anatomical structures, and presence of artefacts. Krippendorff's alpha and weighted kappa statistics were used to assess inter-observer agreement. Visibility of prostate cancer lesions was assessed by directly linking the T2w images to the confirmed location of prostate cancer on histopathology. RESULTS: T2w imaging at 7T was achievable with 'satisfactory' (3/5) to 'good' (4/5) quality. Visibility of anatomical structures was predominantly scored as 'satisfactory' (3/5) and 'good' (4/5). If artefacts were present, they were mostly motion artefacts and, to a lesser extent, aliasing artefacts and noise. Krippendorff's analysis revealed an α = 0.44 between three readers for the overall image quality scores. Clinically significant cancer lesions in both peripheral zone and transition zone were visible at 7T. CONCLUSION: T2w imaging with satisfactory to good quality can be routinely acquired, and cancer lesions were visible in patients with prostate cancer at 7T using only an external transmit/receive body array coil. KEY POINTS: • Satisfactory to good T2-weighted image quality of the prostate is achievable at 7T. • Periprostatic lipids appear hypo-intense compared to healthy peripheral zone tissue at 7T. • Prostate cancer is visible on T2-weighted MRI at 7T.