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Rationale and research objective: As a result of neoadjuvant chemotherapy (NAC), approximately 1/3 of clinically node positive (cN+) breast cancer patients convert to a pathologic complete response (pCR) of the axilla. Targeted Axillary Dissection appears to be most accurate to evaluate axillary treatment-response, but evidence to support this is limited. The RISAS trial was set up to determine the accuracy of sentinel lymph node biopsy (SLNB) combined with excision of the pretreatment marked positive lymph node for axillary staging after NAC in cN+ patients. Methods: This prospective, multicenter trial included cT1-4N1,2,3b patients treated with NAC. Prior to NAC, an iodine seed was placed in the pathologically confirmed positive lymph node. After NAC, all patients underwent SLNB together with excision of the marked lymph node (RISAS-procedure) followed by axillary lymph node dissection (ALND). The identification rate and the accuracy (i.e. false negative rate (FNR) and negative predictive value (NPV)) were calculated for the RISAS procedure. Assuming an FNR of 2%, a prevalence of a positive ALND of 64% and a 10% drop-out rate, a sample size of 248 patients was needed to determine non-inferiority. The NULL hypothesis of inferiority would be rejected at a significance level of 5% if the upper bound of the two-sided 90% Clopper-Pearson confidence interval of the observed FNR would be below the non-inferiority margin of 6.25%. Secondary objectives included the accuracy of the SLNB and excision of the marked lymph node separately. Results: A total of 252 pathologically proven cN+ patients provided informed consent of whom 227 underwent the RISAS procedure/Targeted Axillary Dissection (SLNB combined with excision of the marked positive lymph node). The identification rate of the RISAS procedure is 98% (223/227). Preliminary analysis shows a false negative rate of approximately 5% and a negative predictive value of approximately 91%. Furthermore, by combining SLNB with excision of the marked lymph node, both the identification rate and the accuracy are improved compared to either the SLNB alone or the excision of the marked lymph node alone. Conclusion: This prospective multicenter validation trial shows that the RISAS procedure/Targeted Axillary Dissection is most suitable in terms of identification rate and accuracy to replace ALND for axillary staging after NAC in cN+ patients. The trial was funded by the Dutch Cancer Society (KWF, grant number 2015-8023). Citation Format: Janine Simons, Thiemo JA v Nijnatten, Linetta B Koppert, Carmen C van der Pol, Paul J v Diest, Agnes Jager, David v Klaveren, Boen LR Kam, Marc BI Lobbes, Maaike de Boer, Cees Verhoef, Paul RA Sars, Harold J Heijmans, Els RM van Haaren, Wouter J Vles, Caroline ME Contant, Marian BE Menke, Leonie HM Smit, Wendy Kelder, Marike Boskamp, Ingeborg Mares-Engelberts, Ernest JT Luiten, Marjolein L Smidt. Radioactive Iodine Seed placement in the Axilla with Sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: Results of the prospective multicenter RISAS trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-10.

While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central role in injury response and tissue repair, we here suggest that multipotent stem cell therapies achieve therapeutic effect by altering the immune response to injury, thereby limiting damage due to inflammation and possibly promoting repair. These findings argue for a broader understanding of the mechanisms by which cell therapies can benefit patients., Injury to the central nervous system and ear lead to immediate neuron and hair cell loss (green), respectively. Neuron/hair cell loss continues over subsequent months, exacerbating neurological impairments. Recent studies indicate this could result from chronic inflammation and unresolved proinflammatory signals (red). Treatment with mesenchymal progenitor cells (blue) improves neuron/hair cell survival, potentially via anti‐inflammatory mechanisms.

Purpose The extended role of breast-conserving surgery (BCS) in the neoadjuvant setting may raise concerns on the oncologic safety of BCS compared to mastectomy. This study compared long-term outcomes after neoadjuvant chemotherapy (NAC) between patients treated with BCS and mastectomy. Methods All breast cancer patients treated with NAC from 2008 until 2017 at the Amphia Hospital (the Netherlands) were included. Disease-free and overall survival were compared between BCS and mastectomy with survival functions. Multivariable Cox proportional hazard regression was performed to determine prognostic variables for disease-free survival. Results 561 of 612 patients treated with NAC were eligible: 362 (64.5%) with BCS and 199 (35.5%) with mastectomy. Median follow-up was 6.8 years (0.9–11.9). Mastectomy patients had larger tumours and more frequently node-positive or lobular cancer. Unadjusted five-year disease-free survival was 90.9% for BCS versus 82.9% for mastectomy (p = .004). Unadjusted five-year overall survival was 95.3% and 85.9% (p p = .019) and triple negative disease (HR 5.946, 95% CI 2.703–13.081, p p = .027) and axilla (HR 0.332, 95% CI 0.193–0.572, p = .001) were positive predictors for disease-free survival. Mastectomy versus BCS was not a significant predictor for disease-free survival when adjusted for the former variables (unadjusted HR 2.13 (95%CI: 1.4–3.24), adjusted HR 1.31 (95%CI: 0.81–2.13)). In the BCS group, disease-free and overall survival did not differ significantly between cT1, cT2 or cT3 tumours. Conclusion BCS does not impair disease-free and overall survival in patients treated with NAC. Tumour biology and treatment response are significant prognostic indicators.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

OBJECTIVEUntreated hydrocephalus poses a significant health risk to children in the developing world. In response to this risk, global neurosurgical efforts have increasingly focused on endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) in the management of infantile hydrocephalus in low- and middle-income countries (LMICs). Here, the authors report their experience with ETV/CPC at the Hospital Bernard-Mevs/Project Medishare (HBMPM) in Port-au-Prince, Haiti.METHODSThe authors conducted a retrospective review of a series of consecutive children who had undergone ETV/CPC for hydrocephalus over a 1-year period at HBMPM. The primary outcome of interest was time to ETV/CPC failure. Univariate and multivariate analyses using a Cox proportional hazards regression were performed to identify preoperative factors that were associated with outcomes.RESULTSOf the 82 children who underwent ETV/CPC, 52.2% remained shunt free at the last follow-up (mean 6.4 months). On univariate analysis, the ETV success score (ETVSS; p = 0.002), success of the attempted ETV (p = 0.018), and bilateral CPC (p = 0.045) were associated with shunt freedom. In the multivariate models, a lower ETVSS was independently associated with a poor outcome (HR 0.072, 95% CI 0.016–0.32, p < 0.001). Two children (2.4%) died of postoperative seizures.CONCLUSIONSAs in other LMICs, ETV/CPC is an effective treatment for hydrocephalus in children in Haiti, with a low but significant risk profile. Larger multinational prospective databases may further elucidate the ideal candidate for ETV/CPC in resource-poor settings.

Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Background: The large favorable stage shift, that MRI screening causes as compared with mammography has been published recently in Lancet Oncology as well as the disadvantage of more false-positive results with MRI. Here we want to present the first results of cost and effectiveness. Methods: In twelve Dutch hospitals, 1355 women aged 30-55 years with a cumulative lifetime risk (CLTR) of ≥20% without a BRCA1/2 mutation were randomized into two groups. From January 2011 until December 2017, women in the MRI-group received yearly MRI-screening, clinical breast examination (CBE), and mammography every other year; and in the Mx-group yearly mammography and CBE. We here present cost per group as well as per detected cancer in both groups, also by age group and breast density. Cost per life year gained can be presented in December. Results: After on average 4.3 screening rounds per woman, in the MRI-group (N=674) compared to the Mx-group (N=680) more breast cancers were detected (40 versus 15, p This study was supported by funds of: the Dutch Governement ZonMw grant no. 200320002, The Dutch Cancer Society (DDHK 2009-4491), A Sisters Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting. Table 1. Characteristics of participating women, detected breast cancers, and cost according to study armParticipantsMRI-arm n=674Mx-arm n=680p-valueMean age - yr ± SD44.7 ± 6.344.7 ± 6.3Premenopausal512 (76%)505 (74%)BI-RADS density categorya A(entirely fat) B (scattered densities) C (heterogeneously dense) D (extremely dense)88 (13%) 248 (37%) 237 (35%) 98 (15%)92 (14%) 229 (34%) 243 (36%) 102 (15%)Mean age at cancer detection49,6 ± 7.150,8 ± 4,60.88No cancer - no. (%) Invasive breast cancers - no. (%) DCIS - no. (%)634 (94%) 24 (4%) 16 (2%)666 (98%) 8 (1%) 7 (1%)0.0017Median size of invasive cancers9 mm (5-14)17 mm (13-22)0.01Node positive4/24 (17%)5/8 (63%)0.023Biopsy nr.14954< 0.0001Total screening cost in FaMRIsc€ 1,094,241€ 516,440Cost per detected cancer€ 32,340€ 42,384Cost per detected ca. BIRADS A-C€ 28,945€ 39,964aDetermined by radiologists, according to the fourth ACR BI-RADS edition Citation Format: Madeleine MA Tilanus-Linthorst, H Amarens Geuzinge, Inge-Marie M Obdeijn, Emiel JT Rutgers, Ritse M Mann, Sepideh Saadatmand, Diderick BW de Roy van Zuidewijn, Robert AEM Tollenaar, Marc BI Lobbes, Margreet GEM Ausems, Martijne van 't Riet, Maartje J Hooning, Jelle Wesseling, Ingeborg Mares-Engelberts, Ernest JT Luiten, Jan C Oosterwijk, Eveline AM Heijnsdijk, Harry J de Koning. Costs and effects in the first randomized trial comparing MRI breast cancer screening with mammography in women with a familial risk: FaMRIsc [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS4-07.

The aim of our study was to identify risk factors for recanalization 6 months after coil embolization using clinical data followed by computational fluid dynamics (CFD) analysis. Methods: Firstly, clinical data of 184 patients treated with coil embolization were analyzed retrospectively. Secondly, aneurysm models for high/low recanalization risk were generated based on ROC curves and their cut-off points. Afterward, CFD was utilized to validate the results. Results: In multivariable analysis, aneurysm filling during the first embolization was an independent risk factor whilst packing density was a protective factor of recanalization after 6 months in patients with aSAH. For patients with unruptured aneurysms, packing density was found to be a protective factor whilst the aneurysm neck size was an independent risk factor. Complex flow pattern and multiple vortices were associated with aneurysm shape and were characteristic of the high recanalization risk group. Conclusions: Statistical analysis suggested that there are various factors influencing recanalization risk. Once certain values of morphometric parameters are exceeded, a complex flow with numerous vortices occurs. This phenomenon was revealed due to CFD investigations that validated our statistical research. Thus, the complex flow pattern itself can be treated as a relevant recanalization predictor.

Introduction: Various options for axillary staging after neoadjuvant systemic therapy (NST) are available for breast cancer patients with a clinically positive axillary node (cN+). This survey assessed current practices amongst breast cancer specialists.Materials and methods: A survey was performed amongst members of the European Society of Surgical Oncology and two UK-based Associations: the Association of Breast Surgery and the British Association of Surgical Oncology. The survey included 3 parts: 1. general information, 2, diagnostic work-up and 3. axillary staging after NST.Results: A total of 310 responses were collected: parts 1, 2 and 3 were fully completed by 282 (91%), 270 (87.1%) and 225 (72.6%) respondents respectively. After NST, 153/267 (57.3%) respondents currently perform ALND routinely and 114 (42.7%) respondents perform less invasive restaging of the axilla with possible omission of ALND. In the latter group, 85% does and 15% does not use nodal response seen on imaging to guide the axillary restaging procedure. Regarding respondents that do use imaging: 95% would perform a less invasive staging procedure in case of complete nodal response on imaging (63% sentinel lymph node biopsy (SLNB), excision of a previously marked positive node with SLNB (21%) and without SLNB (11%)). In case of no nodal response on imaging 77% would perform ALND.Conclusion: Current axillary staging and management practices in cN + patients after NST vary widely. To determine optimal axillary staging and management in terms of quality of life and oncologic safety, breast specialists are encouraged to include patients in clinical trials prospective registries. (C) 2019 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Between January 1, 2011, and December 31, 2016, we studied the incidence, management and outcome of high‐risk breast lesions in a consecutive series of 376,519 screens of women who received biennial screening mammography. During the 6‐year period covered by the study, the proportion of women who underwent core needle biopsy (CNB) after recall remained fairly stable, ranging from 39.2% to 48.1% (mean: 44.2%, 5,212/11,783), whereas the proportion of high‐risk lesions at CNB (i.e., flat epithelial atypia, atypical ductal hyperplasia, lobular carcinoma in situ and papillary lesions) gradually increased from 3.2% (25/775) in 2011 to 9.5% (86/901) in 2016 (p, What's new? Screening mammography aims to catch breast cancer early to reduce associated morbidity and mortality. Women with suspect findings at mammography frequently are recalled for further testing with core needle biopsy (CNB). In this investigation, the proportion of high‐risk lesions detected at CNB was found to have tripled among women in the Netherlands who underwent mammographic screening between 2011 and 2016. This increase was accompanied by an increase in lesion excision rates. Of excised lesions, little more than 14% proved to be malignant at two‐year follow‐up. The remainder of lesions exhibited benign pathology, suggesting that many women underwent potentially unnecessary surgery.

Carotid-ophthalmic aneurysms are indication for endovascular treatment. Coil embolization is associated with a high recanalization rate and thus usage of flow diverter (FD) could constitute the treatment of choice. Although implementation of FD is very effective, it carries a significant risk of complications. The goal of our study was to find a radiological recanalization marker in order to facilitate decision process which would result in fewer treatment-related complications and in this way, to personalize endovascular therapy. We made a retrospective analysis of seventy-five patients with saccular carotid-ophthalmic aneurysms treated endovascularly. Morphometric measurements were performed in CTA 3D aneurysm models. The aneurysm size and volume were measured on the base of digital subtraction angiography (DSA) images. The treatment effectiveness was determined visually using the modified Raymond Roy classification after embolization and on the 6- and 12-month follow-up DSA. Statistica 13.1 software was used. Multivariate analyses showed that the aneurysm neck size (OR 2.51; 95%CI: 1.20–5.26), aspect ratio (OR 2.60; 95%CI: 1.27–5.21) and neck to parent artery ratio (OR 2.68; 95%CI: 1.26–5.70) were risk factors for carotid-ophthalmic aneurysms recanalization after 6 months. Of those factors, aneurysm neck size remained the only significant risk factor for carotid-ophthalmic aneurysms recanalization after 12 months (OR 5.23, 95%CI: 1.71–15.93). Various factors seem to influence recanalization. Preoperatively, if the above-mentioned predictors of recanalization are present, coiling is burdened with a high recanalization rate. In those cases, FD embolization should be considered.

Introduction: We evaluated the use and value of breast surgical excision biopsies for diagnostic purposes over the last decades in women undergoing mammographic screening, either as a primary procedure or following an inconclusive percutaneous biopsy.Methods: All women with an excision biopsy among 817,656 screens, obtained from January 1997 to January 2017, were included.Results: Of 18,593 recalled women (recall rate, 2.3%) with screen-detected abnormalities, 908 (4.9%) underwent excision biopsy. Of these, 411 (45.3%) were performed as first diagnostic intervention, decreasing from 4.3 per 1000 screens in 1997-1998 to 0 per 1000 screens in 2015-2016. The remaining 497 (54.7%) excision biopsies were performed secondary to pathologic findings at percutaneous biopsy. During 1997-1998, 1.0 secondary biopsies per 1000 screens were performed, decreasing to 0.3 per 1000 in 2005-2006 and afterwards increased to 0.6 per 1000 in 2015-2016 (p = 0.003). Of all 487 secondary biopsies, 303 (61.0%) had a benign pathology outcome, increasing from 40.4% in 1997-1998 to 70.2% in 2015-2016. Of all 211 biopsies in the three most recent cohorts (2011-2016) the overall upgrade rate was 26.5%, consisting of 39 (18.5%) DCIS (27 low grade) and 17 (8.1%) invasive carcinomas.Conclusions: Although the use of excision biopsy significantly decreased over the past two decades, we observed a significant increased rate in more recent years. Since the vast majority of currently performed excision biopsies reveals a benign diagnosis or shows low grade DCIS, a secondary excision biopsy should only be considered if radiologic surveillance and repeated percutaneous biopsy continues to yield indeterminate results. (C) 2019 Elsevier Ltd. All rights reserved.

Background In Cambodia, the most common victims of traumatic brain injury (TBI) are men 20–30 years of age involved in motor vehicle collision. Secondary injury sustained by these patients occurs during the time period between initial insult and hospital admission. Strengthening prehospital systems for TBI in low- and middle-income countries (LMICs) such as Cambodia is therefore a key element of the development agenda for universal health equity. We report a retrospective analysis of the relationship between prehospital delays and TBI outcomes among patients from a large government hospital in Cambodia. Methods Data were collected from 3476 patients with TBI admitted to a major government hospital in Phnom Penh, Cambodia, from June 2013 to June 2018. Patients with missing data or those admitted >8 hours postinjury were excluded. Statistical analyses examined associations between injury-to-admission delay (IAD) and outcomes such as Glasgow Outcome Scale (GOS) score and length of stay (LOS). Results A total of 2125 patients with TBI (76.85% men) were included. The median age was 27 years (interquartile range, 22–37 years). Injury severity at presentation included 1406 mild (66%), 464 moderate (22%), and 240 severe cases (11%). No Glasgow Coma Scale (GCS) data were available for 15 patients (1%). We found an inverse relationship between IAD and GOS score, most evidently for mild and moderate TBI (n = 1870; 88%). Regression analysis revealed a marked decrease in GOS score at the IAD >4-hour threshold. Each 30-minute delay in IAD was correlated with >2-hour increase in LOS for mild (P Conclusions In a retrospective cohort of >2000 patients with TBI from Cambodia, we found that increasing IAD was associated with worsening outcome, especially beyond the 4-hour threshold. These data should inform development of prehospital guidelines for TBI care in LMICs.

Background: Screening guidelines for women with a family history of breast cancer without a known causative gene mutation differ per country. No randomized controlled trial has been performed to assess the optimal screening strategy for these women. Methods: In twelve centers, 1355 women aged 30–55 years with a cumulative lifetime risk of ≥20% without a BRCA1/2 mutation were randomized into two arms. From January 2011 until December 2017, women in the MRI-arm received yearly MRI-screening, clinical breast examination (CBE), and mammography every other year; and in the Mx-arm yearly mammography and CBE. Outcomes were number and stage of detected breast cancers, sensitivity, specificity and positive predictive value, and stratified by screening round and by mammographic density. Results: After on average 4.3 screening rounds per woman, in the MRI-arm (N=675) compared to the Mx-arm (N=680) more breast cancers were detected (41 versus 14, p Conclusions: In real-life practice the MRI-arm detected more, relevantly smaller, and far more often node negative tumors, and also at low density in women with a familial risk for breast cancer. Table 1Characteristics of participating women at baseline and of the detected breast cancers, according to study armParticipantsMRI-arm n=675Mx-arm n=680MRI-arm vs. Mx-arm p-valueMean age yr ± SD44.6 ± 6.244.7 ± 6.3 Premenopausal512 (76%)505 (74%) Previous Mx ≤ 2 yr536 (79 %)542 (80%) Previous Mx > 2 years ago23 ( 3%)29 ( 4%) Previous MRI ≤ 2 years ago62 ( 9%)81 (12%) Previous MRI > 2 years ago91 (14%)89 (13%) BI-RADS density category* I (entirely fat)88 (13%)92 (14%) II (scattered densities)248 (37%)229 (34%) III (heterogeneously dense)238 (35%)243 (36%) IV (extremely dense)98 (15%)102 (15%) Mean age at cancer detection49,6 ± 7.049,8 ± 4,70.74No cancer – no. (%)634 (94%)666 (98%) Invasive breast cancers – no. (%)25 (4%)7 (1%) Citation Format: Tilanus-Linthorst MM, Saadatmand S, Geuzinge AH, Rutgers EJ, Mann R, de Roy van Zuidewijn DB, Zonderland HM, Tollenaar RA, Lobbes MB, Ausems MG, van 't Riet M, Hooning MJ, Mares-Engelbert I, Luiten EJ, Heijnsdijk EA, Verhoef C, Karssemeijer N, Oosterwijk JC, Obdeijn I-M, de Koning HJ. MRI breast cancer screening compared to mammography in women with a familial risk: A multicenter randomized controlled trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-01.

BackgroundGray-scale, B-mode ultrasound (US) imaging is part of the standard clinical procedure for evaluating thyroid nodules (TNs). It is limited by its instrument- and operator-dependence and inter-observer variability. In addition, the accepted high-risk B-mode US TN features are more specific for detecting classic papillary thyroid cancer rather than the follicular variant of papillary thyroid cancer or follicular thyroid cancer. Quantitative ultrasound (QUS) is a technique that can non-invasively assess properties of tissue microarchitecture by exploiting information contained in raw ultrasonic radiofrequency (RF) echo signals that is discarded in conventional B-mode imaging. QUS provides quantitative parameter-value estimates that are a function of the properties of US scatterers and microarchitecture of the tissue. The purpose of this preliminary study was to assess the performance of QUS parameters in evaluating benign and malignant thyroid nodules.MethodsPatients from the Thyroid Health Center at the Boston Medical Center were recruited to participate. B-mode and RF data were acquired and analyzed in 225 TNs (24 malignant and 201 benign) from 208 patients. These data were acquired either before (167 nodules) or after (58 nodules) subjects underwent fine-needle biopsy (FNB). The performance of a combination of QUS parameters (CQP) was assessed and compared with the performance of B-mode risk-stratification systems.ResultsCQP produced an ROC AUC value of 0.857 ± 0.033 compared to a value of 0.887 ± 0.033 (p=0.327) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.880 ± 0.041 (p=0.367) for the American Thyroid Association (ATA) risk-stratification system. Furthermore, using a CQP threshold of 0.263 would further reduce the number of unnecessary FNBs in 44% of TNs without missing any malignant TNs. When CQP used in combination with ACR TI-RADS, a potential additional reduction of 49 to 66% in unnecessary FNBs was demonstrated.ConclusionThis preliminary study suggests that QUS may provide a method to classify TNs when used by itself or when combined with a conventional gray-scale US risk-stratification system and can potentially reduce the need to biopsy TNs.

Background Neurotrauma is a leading cause of morbidity and mortality around the world. Assessment of injury prevention and prehospital care for neurotrauma patients is necessary to improve care systems. Methods A 29-question electronic survey was developed based on the Enhancing the Quality and Transparency Of health Research (EQUATOR) checklist to assess neurotrauma policies and laws related to safety precautions. The survey was distributed to members of World Health Organization regions that were considered to be experienced medical authorities in neurosurgery and traumatic brain injury. Results There were 82 (39%) responses representing 46 countries. Almost all respondents (95.2%) were within the neurosurgical field. Of respondents, 40.2% were from high-income countries (HICs), and 59.8% were from low- and middle-income countries (LMICs). Motor vehicle accidents were reported as the leading cause of neurotrauma, followed by workplace injury and assault. Of respondents, 84.1% reported having a helmet law in their country. HICs (4.38 ± 0.78) were ranked more likely than LMICs (2.88 ± 1.34; P = 0.0001) to enforce helmet laws on a scale of 1–10. Effectiveness of helmet laws was rated as 3.94 ± 0.95 out of 10. Measures regarding prehospital care varied between HICs and LMICs. Patients in HICs were more likely to use public emergency ambulance transportation (81.8% vs. 42.9%; P = 0.0004). All prehospital personnel having emergency training was also reported to be more likely in HICs than LMICs (60.6% vs. 8.7%; P = 0.0001). Conclusions When injuries occur, timely access to neurosurgical care is critical. A focus on prehospital components of the trauma system is paramount, and policymakers can use the information presented here to implement and refine health care systems to ensure safe, timely, affordable, and equitable access to neurotrauma care.

Inequitable access to surgical care is most conspicuous in low-income countries (LICs), such as Ethiopia, where infectious diseases, malnutrition, and other maladies consume the lion's share of the available health resources. The aim of this article was to provide an update on the current state of neurosurgery in Ethiopia and identify targets for future development of surgical capacity as a universal health coverage component in this East African nation.Publicly available data included in this report were gathered from resources published by international organizations. A PubMed search was used for a preliminary bibliometric analysis of scholarly output of neurosurgeons in Ethiopia and other low-income countries. Statistical analysis was used to determine the correlation between the number of neurosurgeons and academic productivity.Neurosurgeon density has increased20-fold from 0.0022 to 0.045 neurosurgeons per 100,000 population between 2006 and 2020. The increase in neurosurgeons was strongly correlated with an increase in total publications (P0.001) and the number of new publications per year (P = 0.003). Despite recent progress, the availability of neuroimaging equipment remains inadequate, with 38 computed tomography scanners and 11 magnetic resonance imaging machines for a population of 112.07 million. The geographic distribution of neurosurgical facilities is limited to 12 urban centers.Ethiopian neurosurgery exemplifies the profound effect of international partnerships for training local surgeons on progress in low-income countries toward improved neurosurgical capacity. Collaborations that focus on increasing the neurosurgical workforce should synchronize with efforts to enhance the availability of diagnostic and surgical equipment necessary for basic neurosurgical care.

Background: The objective of our project was to identify a late recanalization predictor in ruptured intracranial aneurysms treated with coil embolization. This goal was achieved by means of a statistical analysis followed by a computational fluid dynamics (CFD) with porous media modelling approach. Porous media CFD simulated the hemodynamics within the aneurysmal dome after coiling. Methods: Firstly, a retrospective single center analysis of 66 aneurysmal subarachnoid hemorrhage patients was conducted. The authors assessed morphometric parameters, packing density, first coil volume packing density (1st VPD) and recanalization rate on digital subtraction angiograms (DSA). The effectiveness of initial endovascular treatment was visually determined using the modified Raymond–Roy classification directly after the embolization and in a 6- and 12-month follow-up DSA. In the next step, a comparison between porous media CFD analyses and our statistical results was performed. A geometry used during numerical simulations based on a patient-specific anatomy, where the aneurysm dome was modelled as a separate, porous domain. To evaluate hemodynamic changes, CFD was utilized for a control case (without any porosity) and for a wide range of porosities that resembled 1–30% of VPD. Numerical analyses were performed in Ansys CFX solver. Results: A multivariate analysis showed that 1st VPD affected the late recanalization rate (p &lt, 0.001). Its value was significantly greater in all patients without recanalization (p &lt, 0.001). Receiver operating characteristic curves governed by the univariate analysis showed that the model for late recanalization prediction based on 1st VPD (AUC 0.94 (95%CI: 0.86–1.00) is the most important predictor of late recanalization (p &lt, 0.001). A cut-off point of 10.56% (sensitivity—0.722, specificity—0.979) was confirmed as optimal in a computational fluid dynamics analysis. The CFD results indicate that pressure at the aneurysm wall and residual flow volume (blood volume with mean fluid velocity &gt, 0.01 m/s) within the aneurysmal dome tended to asymptotically decrease when VPD exceeded 10%. Conclusions: High 1st VPD decreases the late recanalization rate in ruptured intracranial aneurysms treated with coil embolization (according to our statistical results &gt, 10.56%). We present an easy intraoperatively calculable predictor which has the potential to be used in clinical practice as a tip to improve clinical outcomes.

Background: The pathophysiology of delayed cerebral ischemia (DCI) remains unclear. One of the hypotheses suggests that reactive oxygen species play a role in its onset. Thus, we studied F2-isoprostanes (F2-IsoPs)&mdash, oxidative stress biomarkers. Our goal was to improve the early diagnosis of DCI in a non-invasive way. Methods: We conducted a prospective single center analysis of 38 aneurysmal subarachnoid hemorrhage patients. We assessed urine F2-IsoP concentration using immunoenzymatic arrays between the first and fifth day after bleeding. A correlation between urine F2-IsoP concentration and DCI occurrence was examined regarding clinical conditions and outcomes. Results: The urine F2-IsoP concentrations were greater than those in the control groups (p &lt, 0.001). The 3rd day urine F2-IsoPs concentrations were correlated with DCI occurrence (p &lt, 0.001) and long term outcomes after 12 months (p &lt, 0.001). Conclusions: High levels of urine F2-IsoPs on day 3 can herald DCI.

Purpose To spare DCIS patients from overtreatment, treatment de-escalated over the years. This study evaluates the influence of these developments on the patterns of care in the treatment of DCIS with particular interest in the use of breast conserving surgery (BCS), radiotherapy following BCS and the use and type of axillary staging. Methods In this large population-based cohort study all women, aged 50–74 years diagnosed with DCIS from January 1989 until January 2019, were analyzed per two-year cohort. Results A total of 30,417 women were diagnosed with DCIS. The proportion of patients undergoing BCS increased from 47.7% in 1995–1996 to 72.7% in 2017–2018 (p p p p p = 0.01). Conclusions This study shows a shift toward less extensive treatment. DCIS is increasingly treated with BCS and less often followed by additional radiotherapy. The absence of radiotherapy still results in excellent iRFS. Axillary surgery is increasingly omitted in DCIS patients.

Glioblastoma (GB) is the most common primary brain tumour in adults. The lack of molecular biomarker, non-specific symptoms and fast growth rate often result in a significant delay in diagnosis. Despite multimodal treatment, the prognosis remains poor. Here, we verified the hypothesis that amino acids (AA) regulating the critical metabolic pathways necessary for maintenance, growth, reproduction, and immunity of an organism, may constitute a favourable target in GB biomarker research. We measured the plasma amino acids levels in 18 GB patients and 15 controls and performed the quantitative and qualitative metabolomic analysis of free AA applying high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). We present both the raw data and the results of our statistical analysis. The majority of AA were lowered in the study group in comparison to the control group. Five of these (arginine, glutamic acid, glutamine, glycine, and histidine) differed significantly (all p 0.9). Plasma levels of leucine and phenylalanine decreased in the case of GB with lost alpha-thalassemia/mental retardation X-linked (ATRX) expression on immunohistochemistry (p = 0.003 and 0.045, respectively). We demonstrated for the first time that certain plasma-free AA levels of GB patients were significantly different from those in healthy volunteers. Target profiling of plasma-free AA, identified utilizing LC-QTOF-MS, may present prognostic value by indicating GB patients with lost ATRX expression. The on-going quest for glioma biomarkers still aims to determine the detailed metabolic profile and evaluate its impact on therapy and prognosis.

Importance For women with a 20% or more familial risk of breast cancer without a known BRCA1/2 (BRCA1, OMIM; and BRCA2, OMIM) or TP53 (OMIM) variant, screening guidelines vary substantially, and cost-effectiveness analyses are scarce.Objective To assess the cost-effectiveness of magnetic resonance imaging (MRI) screening strategies for women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant.Design, Setting, and Participants In this economic evaluation, conducted from February 1, 2019, to May 25, 2020, microsimulation modeling was used to estimate costs and effectiveness on a lifetime horizon from age 25 years until death of MRI screening among a cohort of 10 million Dutch women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. A Dutch screening setting was modeled. Most data were obtained from the randomized Familial MRI Screening (FaMRIsc) trial, which included Dutch women aged 30 to 55 years. A health care payer perspective was applied.Interventions Several screening protocols with varying ages and intervals including those of the randomized FaMRIsc trial, consisting of the mammography (Mx) protocol (annual mammography and clinical breast examination) and the MRI protocol (annual MRI and clinical breast examination plus biennial mammography).MAIN OUTCOMES AND MEASURES Costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated and discounted by 3%. A threshold of (sic)22 000 (US $24 795.87) per QALY was applied.RESULTS This economic evaluation modeling study estimated that, on a lifetime horizon per 1000 women with the Mx protocol of the FaMRIsc trial, 346 breast cancers would be detected, and 49 women were estimated to die from breast cancer, resulting in 22 885 QALYs and total costs of (sic)7 084 767 (US $7 985 134.61). The MRI protocol resulted in 79 additional QALYs and additional (sic)2 657 266 (US $2 994 964.65). Magnetic resonance imaging performed only every 18 months between the ages of 35 and 60 years followed by the national screening program was considered optimal, with an ICER of (sic)21 380 (US $24 097.08) compared with the previous nondominated strategy in the ranking, when applying the National Institute for Health and Care Excellence threshold. Annual screening alternating MRI and mammography between the ages of 35 and 60 years, followed by the national screening program, gave similar outcomes. Higher thresholds would favor annual MRI screening. The ICER was most sensitive to the unit cost of MRI and the utility value for ductal carcinoma in situ and localized breast cancer.CONCLUSIONS AND RELEVANCE This study suggests that MRI screening every 18 months between the ages of 35 and 60 years for women with a family history of breast cancer is cost-effective within the National Institute for Health and Care Excellence threshold for all densities. Higher thresholds would favor annual MRI screening. These outcomes support a change of current screening guidelines for this specific risk group and support MRI screening.

Purpose We assessed the uptake of fertility preservation (FP), recovery of ovarian function (OFR) after chemotherapy, live birth after breast cancer, and breast cancer outcomes in women with early-stage breast cancer. Methods Women aged below 41 years and referred to our center for FP counseling between 2008 and 2015 were included. Data on patient and tumor characteristics, ovarian function, cryopreservation (embryo/oocyte) and transfer, live birth, and disease-free survival were collected. Kaplan–Meier analyses were performed for time-to-event analyses including competing risk analyses, and patients with versus without FP were compared using the logrank test. Results Of 118 counseled women with a median age of 31 years (range 19–40), 34 (29%) chose FP. Women who chose FP had less often children, more often a male partner and more often favorable tumor characteristics. The 5-year OFR rate was 92% for the total group of counseled patients. In total, 26 women gave birth. The 5-year live birth rate was 27% for the total group of counseled patients. Only three women applied for transfer of their cryopreserved embryo(s), in two combined with preimplantation genetic diagnosis (PGD) because of BRCA1-mutation carrier ship. The 5-year disease-free survival rate was 91% versus 88%, for patients with versus without FP (P = 0.42). Conclusions Remarkably, most women achieved OFR, probably related to the young age at diagnosis. Most pregnancies occurred spontaneously, two of three women applied for embryo transfer because of the opportunity to apply for PGD.

PURPOSE Tumor boards, clinical practice guidelines, and cancer registries are intertwined cancer care quality instruments. Standardized structured reporting has been proposed as a solution to improve clinical documentation, while facilitating data reuse for secondary purposes. This study describes the implementation and evaluation of a national standard for tumor board reporting for breast cancer on the basis of the clinical practice guideline and the potential for reusing clinical data for the Netherlands Cancer Registry (NCR). METHODS Previously, a national information standard for breast cancer was derived from the corresponding Dutch clinical practice guideline. Using data items from the information standard, we developed three different tumor board forms: preoperative, postoperative, and postneoadjuvant-postoperative. The forms were implemented in Amphia Hospital’s electronic health record. Quality of clinical documentation and workload before and after implementation were compared. RESULTS Both draft and final tumor board reports were collected from 27 and 31 patients in baseline and effect measurements, respectively. Completeness of final reports increased from 39.5% to 45.4% ( P = .04). The workload for tumor board preparation and discussion did not change significantly. Standardized tumor board reports included 50% (61/122) of the data items carried in the NCR. An automated process was developed to upload information captured in tumor board reports to the NCR database. CONCLUSION This study shows implementation of a national standard for tumor board reports improves quality of clinical documentation, without increasing clinical workload. Simultaneously, our work enables data reuse for secondary purposes like cancer registration.

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidizedNAT8LmRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain hampers myelin integrity making neuronal axons more susceptible to damage, which contributes in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.

Background In the early days of neurosurgery, extradural haemorrhages (EDHs) contributed to a high mortality rate after craniotomies. Almost a century ago, Walter Dandy reported dural tenting sutures as an effective way to prevent postoperative EDH. Over time, his technique gained in popularity and significance to finally become a neurosurgical standard. Yet, several retrospective reports and one prospective report have questioned the ongoing need for dural tenting sutures. Dandy’s explanation that the haemostasis observed under hypotensive conditions is deceiving and eventually causes EDH may be obsolete. Today, proper intra- and postoperative care, including maintenance of normovolemia and normotension and the use of modern haemostatic agents, may be sufficient for effective haemostasis. Thus, there is a fundamental need to evaluate the necessity of dural tenting sutures in a solid, unbiased, evidence-based manner. Methods This study is designed as a randomised, multicentre, double-blinded, controlled interventional trial with 1:1 allocation. About one half of the participants will undergo craniotomy without dural tenting sutures and will be considered an intervention group. The other half will undergo craniotomy with these sutures. Both groups will be followed clinically and radiologically. The primary outcome is reoperation due to extradural haematoma. Secondary outcomes aim to evaluate the impact of dural tenting sutures on mortality, readmission risk, postoperative headaches, size of extradural collection, cerebrospinal fluid leak risk and the presence of any new neurological deficit. The study protocol follows the SPIRIT 2013 statement. Discussion It is possible that many neurosurgeons around the globe are tenting the dura in elective craniotomies which brings no benefit and only extends the operation. Unfortunately, there is not enough data to support or reject this technique in modern neurosurgery. This is the first study that may produce strong, evidence-based recommendations on using dural tenting sutures. Trial registration, ethics and dissemination The Bioethics Committee of the Medical University of Warsaw approved the study protocol (KB/106/2018). The trial is registered at http://www.clinicaltrials.gov (NCT03658941) on September 6, 2018. The findings of this trial will be submitted to a peer-reviewed neurosurgical journal. Abstracts will be submitted to relevant national and international conferences. Trial status Protocol version and date: version 1.5, 14.01.2020 First recruitment: September 7, 2018 Estimated recruitment completion: September 1, 2021

To evaluate correlation between the lateral ventricle ratio (LVR) and the risk of conservative treatment failure (CTF) among patients with acute subdural hematoma (ASDH) after non-severe traumatic brain injury (TBI), we retrieved from the hospital database and performed a retrospective analysis of 1339 cases with TBI treated during the 2008-2016 period.112 patients with ASDH, GCS≥ 9 and initial conservative treatment were enrolled. They were divided according to the final treatment method applied (surgical or conservative). Clinical and radiological data was evaluated. We used ROC curve analysis and multivariate logistic regression model to identify risk factors of CTF.LVR higher than 1.48 calculated on admission CT scans was the strongest predictor of CTF, with sensitivity of 78.9% and specificity of 93.5% (AUC: 0.774-0.994). LVR, prolonged prothrombin time and coexisting traumatic subarachnoid hemorrhage were independent risk factors.Despite limitations, study results support the view that patients after non-severe TBI with ASDH and with lateral ventricle asymmetry, defined as LVR 1.48, require surgical treatment. LVR seems to be indirect, but still the closest method to quantify intracranial compliance. Thus, in the selected group of patients without clinical symptoms of critically diminished compensatory reserve, LVR could indicate those who need a surgical decompression.

Background The neurosurgical literature rarely describes managing open head injuries caused by machetes, although this is a common head injury in developing countries. We present our experience managing cranial machete injuries in Nicaragua over a 5-year period. Methods A retrospective chart review identified patients admitted to a neurosurgery service for cranial machete injury. Results Among 51 patients studied, the majority (n = 42, 82%) presented with mild neurologic deficits (Glasgow Coma Scale score ≥14). Nondepressed skull fracture (25/37, 68%) was the most common injury identified on skull radiography, and pneumocephalus (15/29, 52%) was the most common injury identified with computed tomography. Overall, 38 patients (75%) underwent surgical intervention for 1 or more conditions, including laceration length ≥10 cm (n = 20), open intracranial wound (n = 8), pneumocephalus (n = 7), cerebral contusion (n = 6), intracranial hemorrhage (n = 5), and depressed fracture (n = 5). All patients received aggressive antibiotic therapy. Patients without intracranial injury received a 7-day course of intravenous ceftriaxone, followed by a 10-day course of oral ciprofloxacin. Patients with violation of the dura received a 7- to 14-day course of intravenous metronidazole, ceftriaxone, and vancomycin, followed by a 10-day course of oral ciprofloxacin. Postoperative complications included a visible skull defect (n = 6), infection (n = 3), and unspecified neurologic (n = 2) and mixed (n = 1) complications. At discharge, most patients had only minimal disabilities (47/51, 92%). In-hospital mortality rate was zero. Conclusions An aggressive approach to managing open head injury caused by machete yields good outcomes, with the majority of patients experiencing minimal disability at hospital discharge and a low rate of infection.

BACKGROUND AND OBJECTIVES Sensorineural hearing loss (SNHL) in children is associated with neurocognitive morbidity. The cause of SNHL is a loss of hair cells in the organ of Corti. There are currently no reparative treatments for SNHL. Numerous studies suggest that cord blood mononuclear cells (human umbilical cord blood, hUCB) allow at least partial restoration of SNHL by enabling repair of a damaged organ of Corti. Our objective is to determine if hUCB is a safe treatment for moderate to severe acquired SNHL in children. Subjects and. METHODS Eleven children aged 6 months to 6 years with moderate to severe acquired SNHL were treated with intravenous autologous hUCB. The cell dose ranged from 8 to 30 million cells/kg body weight. Safety was assessed by measuring systemic hemodynamics during hUCB infusion. Infusion-related toxicity was evaluated by measuring neurologic, hepatic, renal and pulmonary function before and after infusion. Auditory function, auditory verbal language assessments and MRI with diffusion tensor imaging (DTI) were obtained before and after treatment. RESULTS All patients survived, and there were no adverse events. No infusionrelated changes in hemodynamics occurred. No infusion-related toxicity was recorded. Five subjects experienced a reduction in auditory brainstem response (ABR) thresholds. Four of those 5 subjects also experienced an improvement in cochlear nerve latencies. Comparison of MRI with DTI sequences obtained before and after treatment revealed increased fractional anisotropy in the primary auditory cortex in three of five subjects with reduced ABR thresholds. Statistically significant (p

BACKGROUND Resection of meningiomas in older adults is associated with increased complications and postoperative functional deficits. Extent of peritumoral edema (PTE), which has been associated with surgical prognosis, may represent a preoperative risk marker for poorer outcomes in older adults. OBJECTIVE To quantitatively evaluate the relationship between preoperative PTE and postresection outcomes in older meningioma patients. METHODS One hundred twelve older meningioma patients (age ≥ 60) with evidence of PTE on MRI were reviewed. Extent of PTE, measured as a ratio of edema to tumor volume (edema index, EI) using semiautomatic image-processing software, was correlated with postresection outcomes. Other preoperative factors were included as covariates in multivariate analyses. Results were compared to matched nonedema older patients. Receiver operating characteristic (ROC) curve analysis was performed to identify cut-off EI values to predict postoperative outcomes. RESULTS EI was associated with functional decline (as measured by Karnofsky Performance Status, KPS) at 6 mo, 1, 2 yr, and most recent follow-up (Ps

The initial management of atypical meningiomas poses a distinct clinical challenge in that treatment protocols have not been fully established, and outcomes, especially differences by patient age, have not been broadly measured. The National Cancer Database (NCDB) allows for analysis of a large, diverse patient population to determine clinical parameters and survival outcomes based on the initial treatment of patients with atypical meningiomas.Analysis of the NCDB yielded 3611 atypical meningioma patients treated between 2008 and 2012. Principal treatment paradigms included surgery with or without radiation. Survival estimates were calculated using Kaplan-Meier curves stratified by age at diagnosis for each treatment paradigm. Subset analysis was performed for socio-economic factors.Overall 5-year survival rate was 77.6% and declined with increasing patient age (p 0.0001). Five-year survival for patients ≤ 45 years undergoing surgery alone was 89.3 vs. 44.4% for those 75 years (p 0.0001). For patients undergoing surgery with adjuvant radiation, 5-year survival was 93.7% in those ≤ 45 years and 54.1% in those 75 years (p 0.0001). Use of adjuvant radiation was stable over time. Private-insured patients were more likely to receive adjuvant radiation (p = 0.0001).Patients treated for atypical meningioma have high rates of 5-year survival. A marginal survival benefit of adjuvant radiation was observed for patients 55 and 75 years, while patients between 55 and 75 years tended to have slightly improved survival with surgery alone. Though surgery remains the standard of care in the primary treatment of atypical meningioma, the decision to administer radiation post-operatively has remained controversial.

Treatment of breast cancer is complex and multidisciplinary by nature, with protocols that are updated continuously. During preoperative multidisciplinary team meetings, regularly there is discussion between team members regarding optimal timing and type of breast reconstruction, due to conflicting interests of oncological and reconstructive treatments. Therefore, a multidisciplinary, evidence-based guideline for breast reconstruction in women undergoing breast conserving therapy or mastectomy for breast cancer, or following prophylactic mastectomy was developed by a multidisciplinary working group. The guideline was drafted in accordance with the AGREE II instrument, designed to assess the quality of guidelines with broad international support. For the recommendations, scientific evidence was considered together with other key aspects, such as working group member expertise, patient preferences, costs, availability of facilities and/or organizational aspects. Recommendations provide an answer to the primary questions, and are based on the best scientific evidence available together with the most important considerations by the working group. In accordance with the GRADE method, the level of scientific evidence and the importance given to considerations by the working group jointly determined the strength of the recommendation. The guideline aims to provide practical guidance for plastic surgeons and other members of the multidisciplinary breast cancer team. The implementation of the present breast reconstruction guideline may contribute to optimizing the delivery of care and support for breast reconstruction patients, it may stimulate evidence-based plastic surgery, it may reduce undesirable variation in clinical practice between health care providers, and improve the overall quality of life of breast reconstruction patients. (c) 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Background The role of isoprostanes in cerebral vasospasm (CVS) following aneurysmal subarachnoid hemorrhage (aSAH) is controversial. Recent studies have suggested that the level of isoprostanes in cerebrospinal fluid could play a role in outcomes of patients with aSAH. We measured concentration of urinary F 2 -isoprostanes (F 2 -IsoPs), which is simple and noninvasive. Methods A prospective analysis was performed of clinical data and urine samples of 20 patients with aSAH who underwent microsurgical clipping of the aneurysmal neck between May 2016 and January 2017. The role of F 2 -IsoPs as a CVS biomarker was analyzed with regard to clinical conditions of patients. Outcome was assessed at discharge and 1-month and 4-month follow-up using the Glasgow Outcome Scale and modified Rankin Scale. Results The concentration of urinary F 2 -IsoPs was significantly greater in patients with aSAH than in healthy control subjects ( P 2 -IsoP levels on day 3 after aSAH were associated with development of CVS ( P = 0.015) and worse neurologic performance after 1 month ( P = 0.042) and 4 months ( P = 0.027). The prognostic value of urinary F 2 -IsoPs on day 3 in terms of CVS was found to be high (area under the curve 0.864, 95% confidence interval 0.691–1.000). Conclusions Urinary F 2 -IsoPs may be used as a noninvasive prognostic biochemical marker in patients with aSAH. F 2 -IsoP levels in urine may have significant implications in pathogenesis of CVS.

Each year in the United States and Canada, thousands of individuals seek medical care for a burn injury. Some individuals are burned significantly enough they require treatment at specialized burn care facilities. Most of these injuries are preventable. This article presents an historical perspective related to burn prevention and elements of successful burn prevention programs and explores ways in which the plastic surgeon can promote burn prevention through education, advocacy, and the legislative process. Prevention efforts undertaken by the surgeon can increase awareness, ensure a safe environment, and reduce burn injuries.

Introduction : Ectopic sphenoid sinus pituitary adenoma is a rare tumour originating from embryologic remnants of Rathke’s pouch. Although it is considered a clinically benign neoplasm, necrosis is encountered in 25% of cases and it can invade adjacent bone structures. Aims : To establish clinical, radiological and histopathological features of ectopic sphenoid sinus pituitary adenoma. Material and methods: Analysis of three cases: two females and one man, aged 61-70. Results : One patient presented with a unilateral hearing loss, the other two with headache and vertigo. They all suffered from type 2 diabetes mellitus. Neurological examination revealed no abnormality. Radiological imaging showed a sphenoid sinus space-occupying soft-tissue lesion with bone erosion in 2 cases and empty sella in 2 patients whereas one had a normal pituitary gland. All were operated on via the transnasal approach. Total resection was achieved in one patient and subtotal in two; in two cases we observed intact sellar dura and in one intact sellar floor. Histopathology showed immunoreactivity for synaptophysin in all cases and cytokeratin in two. The Ki-67 index was less than 2%. Immunohistochemical staining demonstrated growth hormone cells in all cases whereas prolactin and adrenocorticotropin in two. The patients were discharged home in good condition with no neurological deficits. Conclusions : Ectopic sphenoid sinus pituitary adenoma should always be considered in differential diagnosis of sphenoid sinus lesion in the elderly, especially in coexistence with empty sella or type 2 diabetes mellitus. Since ectopic sphenoid sinus pituitary adenoma is a benign lesion, surgical removal is an effective treatment.

We describe a case of an intradural extramedullary inflammatory myofibroblastic tumor of the cervical spine. A 56-year-old woman presented with progressive neck pain, radiating to the right scapula, without any neurologic deficit. Magnetic resonance imaging showed an intradural extramedullary tumor with a dural tail sign, located at the C3–T1 segment with homogeneous contrast enhancement. The patient was operated on for a suspected meningioma. Pathologic examination showed fibrosis and inflammation with infiltration of B and T lymphocytes accompanied by plasmocytes, macrophages, and myofibroblast oocytes. We present the clinical course and review of the literature.

Background Marking the axilla with radioactive iodine seed and sentinel lymph node (SLN) biopsy have been proposed for axillary staging after neoadjuvant systemic therapy in clinically node‐positive breast cancer. This study evaluated the identification rate and detection of residual disease with combined excision of pretreatment‐positive marked lymph nodes (MLNs) together with SLNs. Methods This was a multicentre retrospective analysis of patients with clinically node‐positive breast cancer undergoing neoadjuvant systemic therapy and the combination procedure (with or without axillary lymph node dissection). The identification rate and detection of axillary residual disease were calculated for the combination procedure, and for MLNs and SLNs separately. Results At least one MLN and/or SLN(s) were identified by the combination procedure in 138 of 139 patients (identification rate 99·3 per cent). The identification rate was 92·8 per cent for MLNs alone and 87·8 per cent for SLNs alone. In 88 of 139 patients (63·3 per cent) residual axillary disease was detected by the combination procedure. Residual disease was shown only in the MLN in 20 of 88 patients (23 per cent) and only in the SLN in ten of 88 (11 per cent), whereas both the MLN and SLN contained residual disease in the remainder (58 of 88, 66 per cent). Conclusion Excision of the pretreatment‐positive MLN together with SLNs after neoadjuvant systemic therapy in patients with clinically node‐positive disease resulted in a higher identification rate and improved detection of residual axillary disease., Replacing axillary lymph node dissection with less invasive axillary staging procedures in patients with clinically node‐positive breast cancer treated with neoadjuvant systemic therapy is debated. Implementation of several different less invasive procedures is ongoing at some centres. In this cohort, the identification rate and detection of residual disease of combined excision of the pretreatment‐positive marked lymph node with the sentinel lymph nodes were evaluated, and compared with excising only the marked lymph node or the sentinel lymph nodes alone. Combination superior

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.

Objective Traumatic brain injury (TBI) remains a major cause of morbidity and mortality worldwide. The prognostic value of skull fracture (SF) remains to be clearly defined. To evaluate the need for neurosurgical intervention and determine the risk factors of conservative treatment failure (CTF), we retrieved from the hospital database the records of patients with SF after TBI. Methods We analyzed 146 consecutive patients (mean age: 49.8 ± 17.5 years) treated at the department of neurosurgery in a 5-year period. Clinical data, radiologic reports, and laboratory results were evaluated retrospectively. Results A total of 63% of patients were treated conservatively, 21.9% were operated on immediately, and 15.1% experienced CTF. Overall, 73.3% had a favorable outcome; the mortality rate was 13%. Intracranial bleeding occurred in 96.6% of cases, basilar SF in 61%, and cerebrospinal fluid (CSF) leak in 2.8%. The independent risk factors for outcome were Glasgow Coma Scale (GCS) score, age, and platelet count (PCT). The independent risk factors for CTF were epidural hematoma, subdural hematoma, mass effect, edema, international normalized ratio, PCT, mean platelet volume, and CSF leakage. The consensus decision tree algorithm used at the accident and emergency department indicated patients with no need for neurosurgical intervention with an accuracy of 91.7%, sensitivity of 88.9%, and featured the importance of mass effect, GCS, and epidural hematoma. Conclusions Tests included in the complete blood count appeared useful for predicting the course in patients with SF, although the most important factors were age and neurologic status, as well as radiologic findings. Our decision tree requires further validation before it can be used in everyday practice.

Background: Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk. Methods: In this multicentre, randomised, controlled trial done in 12 hospitals in the Netherlands, women were eligible to participate if they were aged 30–55 years and had a cumulative lifetime breast cancer risk of at least 20% because of a familial predisposition, but were BRCA1, BRCA2, and TP53 wild-type. Participants who were breast-feeding, pregnant, had a previous breast cancer screen, or had a previous a diagnosis of ductal carcinoma in situ were eligible, but those with a previously diagnosed invasive carcinoma were excluded. Participants were randomly allocated (1:1) to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group). Randomisation was done via a web-based system and stratified by centre. Women who did not provide consent for randomisation could give consent for registration if they followed either the mammography group protocol or the MRI group protocol in a joint decision with their physician. Results from the registration group were only used in the analyses stratified by breast density. Primary outcomes were number, size, and nodal status of detected breast cancers. Analyses were done by intention to treat. This trial is registered with the Netherlands Trial Register, number NL2661. Findings: Between Jan 1, 2011, and Dec 31, 2017, 1355 women provided consent for randomisation and 231 for registration. 675 of 1355 women were randomly allocated to the MRI group and 680 to the mammography group. 218 of 231 women opting to be in a registration group were in the mammography registration group and 13 were in the MRI registration group. The mean number of screening rounds per woman was 4·3 (SD 1·76). More breast cancers were detected in the MRI group than in the mammography group (40 vs 15; p=0·0017). Invasive cancers (24 in the MRI group and eight in the mammography group) were smaller in the MRI group than in the mammography group (median size 9 mm [5–14] vs 17 mm [13–22]; p=0·010) and less frequently node positive (four [17%] of 24 vs five [63%] of eight; p=0·023). Tumour stages of the cancers detected at incident rounds were significantly earlier in the MRI group (12 [48%] of 25 in the MRI group vs one [7%] of 15 in the mammography group were stage T1a and T1b cancers; one (4%) of 25 in the MRI group and two (13%) of 15 in the mammography group were stage T2 or higher; p=0·035) and node-positive tumours were less frequent (two [11%] of 18 in the MRI group vs five [63%] of eight in the mammography group; p=0·014). All seven tumours stage T2 or higher were in the two highest breast density categories (breast imaging reporting and data system categories C and D; p=0·0077) One patient died from breast cancer during follow-up (mammography registration group). Interpretation: MRI screening detected cancers at an earlier stage than mammography. The lower number of late-stage cancers identified in incident rounds might reduce the use of adjuvant chemotherapy and decrease breast cancer-related mortality. However, the advantages of the MRI screening approach might be at the cost of more false-positive results, especially at high breast density. Funding: Dutch Government ZonMw, Dutch Cancer Society, A Sister's Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting.

Objective To determine whether cranial metrics consistently differed between patients with moyamoya and age-, sex-, and race-matched controls. Methods Patients diagnosed with moyamoya disease by cerebral angiogram were obtained from a prospectively collected database through the Department of Neurosurgery at the University of Kansas Medical Center. Control patients matched by decade of age, sex, and race were collected through a deidentified hospital database by International Classification of Diseases-9 and 10 codes for ischemic stroke to identify patients with computed tomography angiograms. Imaging studies for both groups were analyzed to obtain 6 skull metrics: maximum anterior to posterior distance, maximum biparietal distance, bregma to occiput distance, right carotid canal diameter (CCD), left CCD, and cephalic index. Results Forty-five patients were identified in each cohort. Measurements of mean anterior to posterior skull diameter, mean biparietal skull diameter, bregma to occiput distances, and calculated cephalic index did not demonstrate a statistically significant difference between patients with moyamoya and control patients. Right carotid canal mean diameter was 4.8 mm for the moyamoya group and 5.4 mm for the control group, with a significant raw mean difference of −0.61 mm (95% confidence interval, −0.95 to −0.27). Left CCD was 4.7 mm for the moyamoya group and 5.5 mm for the control group, resulting in a significant raw mean difference of −0.76 mm (95% confidence interval, −1.09 to −0.43). Conclusions This study identified 2 skull parameters as statistically different in patients with moyamoya compared with a matched control group of patients with ischemic stroke: right CCD and left CCD.

INTRODUCTION: Thyroid cancer is the most common endocrine malignancy. While thyroid nodules (TN) can been seen in up to 50% of the adult population, only about 5 percent of the nodules are malignant. Currently, management of TN involves risk stratification prior to biopsy using B-mode grey-scale ultrasound (US) characteristics including echogenicity, micro- and macrocalcifications, and margins. A less-subjective method of TN evaluation, shear wave elastography, has been evaluated but both the grey-scale classification and elastography are subject to operator and machine variability. This study assesses the use of quantitative ultrasound (QUS) to differentiate between malignant and benign thyroid nodules. B-mode appearance based on the radiofrequency (RF) signal envelope and discards much of the information in the RF signal. QUS uses the normalized power spectrum and extracts discarded RF signal information to obtain parameters that reflect scatterer size, concentration and relative acoustic impedance. The advantage of using QUS is that the parameter values reflect the microarchitecture (

Background: In 1 of 3 patients with initial lymph node-positive (cN(+)) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax-pCR). This urges the need for a less-invasive axillary staging method. Recently introduced less-invasive procedures have been insufficient in accurately identifying ax-pCR. Therefore, we propose a novel less-invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB). Patients and Methods: In the present open single-arm multicenter validation study, 225 cN(+) (biopsy-proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine-125 seed before NAC. After NAC completion, this iodine-125 seed-marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false-negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported. Conclusion: The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN(+) patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax-pCR confirmed using the RISAS procedure.

Gentamicin is an aminoglycoside antibiotic that is used in clinical, organismic, and agricultural applications to combat gram-negative, aerobic bacteria. The clinical use of gentamicin is widely linked to various toxicities, but there is a void in our knowledge about the neuromodulatory or neurotoxicity effects of gentamicin. This investigation explored the electrophysiologic effects of gentamicin on GABAergic pharmacological profiles in spontaneously active neuronal networks in vitro derived from auditory cortices of E16 mouse embryos and grown on microelectrode arrays. Using the GABAA agonist muscimol as the test substance, responses from networks to dose titrations of muscimol were compared in the presence and absence of 100µM gentamicin (the recommended concentration for cell culture conditions). Spike-rate based EC50 values were generated using sigmoidal fit concentration response curves (CRCs). Exposure to 100µM gentamicin exhibited a muscimol EC50±S.E.M. of 80±6nM (n=10). The EC50 value obtained in the absence of gentamicin was 124±11nM (n=10). The 35% increase in potency suggests network sensitization to muscimol in the presence of gentamicin. Action potential (AP) waveform analyses of neurons exposed to gentamicin demonstrated a concentration-dependent decrease in AP amplitudes (extracellular recordings), possibly reflecting gentamicin effects on voltage-gated ion channels. These in vitro results reveal alteration of pharmacological responses by antibiotics that could have significant influence on the behavior and performance of animals.

Background: The epidemic of lethal prescription opioid overdose is one of the most pressing public health problems in the United States. In an ambulatory clinic setting, current practice guidelines suggest that health care providers should screen patient's aberrant drug-related behaviors. Given the difficulty of predicting which patients on chronic opioid therapy (COT) will experience opioid overdose, a new paradigm of harm reduction is called for. In previous studies, naloxone, an opioid antagonist, was given only to high-risk patients. However, if naloxone is co-prescribed in a Universal Precautions manner for all patients receiving COT, this may have a significant impact on intentional and unintentional opioid overdose deaths. Methods: Adult patients treated with COT for chronic noncancer pain are eligible study participants at the University of New Mexico Pain Center. The primary goal of this 1-year study was to develop an efficient Universal Precautions model for co-prescribing of naloxone with COT in the ambulatory clinic setting. Outcome measures included demographic data, detailed medical and substance use history, current morphine equivalent dose (MED), other “high-risk” medications used, and opioid misuse risk. Results: One hundred and sixty-four patients were enrolled in this study. All subjects were educated about the risks of opioid overdose and provided naloxone rescue kits. No overdoses occurred in the study population. Follow-up data illustrated that approximately 57% of the cohort had depressive disorder, the median MED was 90 mg/day, and the median Current Opioid Misuse Measure score (COMM) was 5.0. Conclusions: The ambulatory co-prescribing of naloxone in a Universal Precautions model for all patients prescribed COT can be adopted as a useful public health intervention. This study illustrates a model that can be used to educate patients, caregivers, and an interdisciplinary team of health care professionals in an academic medical center.

Axillary reverse mapping (ARM) is a technique by which the lymphatic drainage of the upper extremity that traverses the axillary region can be differentiated from the lymphatic drainage of the breast during axillary lymph node dissection (ALND). Adding this procedure to ALND may reduce upper extremity lymphedema by preserving upper extremity drainage. This review of the current literature on the ARM procedure discusses the feasibility, safety and relevance of this technique. A PubMed literature search was performed until 12 August 2015. A total of 31 studies were included in this review. The studies indicated that the ARM procedure adequately identifies the upper extremity lymph nodes and lymphatics in the axillary basin using blue dye or fluorescence. Preservation of ARM lymph nodes and corresponding lymphatics was proven to be oncologically safe in clinically node-negative breast cancer patients with metastatic lymph node involvement in the sentinel lymph node (SLN) who are advised to undergo a completion ALND. The ARM procedure is technically feasible with a high visualisation rate using blue dye or fluorescence. ALND combined with ARM can be regarded as a promising surgical refinement in order to reduce the incidence of upper extremity lymphedema in selected groups of patients.