A systematic review of axillary nodal irradiation for the management of the axilla in patients with early-stage breast cancer.

BACKGROUND: Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings. METHODS: We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO. RESULTS: We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting. CONCLUSIONS: The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients.

Risk assessment of consumer spray products using in vitro lung surfactant function inhibition, exposure modelling and chemical analysis.

Consumer spray products release aerosols that can potentially be inhaled and reach the deep parts of the lungs. A thin layer of liquid, containing a mixture of proteins and lipids known as lung surfactant, coats the alveoli. Inhibition of lung surfactant function can lead to acute loss of lung function. We focused on two groups of spray products; 8 cleaning and 13 impregnation products, and in the context of risk assessment, used an in vitro method for assessing inhibition of lung surfactant function. Original spray-cans were used to generate aerosols to measure aerodynamic particle size distribution. We recreated a real-life exposure scenario to estimate the alveolar deposited dose. Most impregnation products inhibited lung surfactant function at the lowest aerosolization rate, whereas only two cleaning products inhibited function at the highest rates. We used inhibitory dose and estimated alveolar deposition to calculate the margin of safety (MoS). The MoS for the inhibitory products was ≤1 for the impregnation products, while much larger for the cleaning products (>880). This risk assessment focused on the risk of lung surfactant function disruption and provides knowledge on an endpoint of lung toxicity that is not investigated by the currently available OECD test guidelines.

Brain and Lung Imaging Correlation in Patients with COVID-19: Could the Severity of Lung Disease Reflect the Prevalence of Acute Abnormalities on Neuroimaging? A Global Multicenter Observational Study.

PURPOSE: Our aim was to study the association between abnormal findings on chest and brain imaging in patients with coronavirus disease 2019 (COVID-19) and neurologic symptoms. MATERIALS AND METHODS: In this retrospective, international multicenter study, we reviewed the electronic medical records and imaging of hospitalized patients with COVID-19 from March 3, 2020, to June 25, 2020. Our inclusion criteria were patients diagnosed with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection with acute neurologic manifestations and available chest CT and brain imaging. The 5 lobes of the lungs were individually scored on a scale of 0-5 (0 corresponded to no involvement and 5 corresponded to >75% involvement). A CT lung severity score was determined as the sum of lung involvement, ranging from 0 (no involvement) to 25 (maximum involvement). RESULTS: A total of 135 patients met the inclusion criteria with 132 brain CT, 36 brain MR imaging, 7 MRA of the head and neck, and 135 chest CT studies. Compared with 86 (64%) patients without acute abnormal findings on neuroimaging, 49 (36%) patients with these findings had a significantly higher mean CT lung severity score (9.9 versus 5.8, P < .001). These patients were more likely to present with ischemic stroke (40 [82%] versus 11 [13%], P < .0001) and were more likely to have either ground-glass opacities or consolidation (46 [94%] versus 73 [84%], P = .01) in the lungs. A threshold of the CT lung severity score of >8 was found to be 74% sensitive and 65% specific for acute abnormal findings on neuroimaging. The neuroimaging hallmarks of these patients were acute ischemic infarct (28%), intracranial hemorrhage (10%) including microhemorrhages (19%), and leukoencephalopathy with and/or without restricted diffusion (11%). The predominant CT chest findings were peripheral ground-glass opacities with or without consolidation. CONCLUSIONS: The CT lung disease severity score may be predictive of acute abnormalities on neuroimaging in patients with COVID-19 with neurologic manifestations. This can be used as a predictive tool in patient management to improve clinical outcome.

Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

R0 Resection Margin, A New Quality Measure in the Era of National Bowel Screening?

Aims To determine the completeness of polyp resection (i.e. achieving an R0 margin) and its relation with Endoscopists, histopathologist, size, location and technique of polypectomy in an NSS cohort. The definition of R0 margin is complete macroscopic resection with a negative microscopic margin at polypectomy. Method NCCS (National Colon Cancer Screening) colonoscopies are offered to bowel cancer screening patients after a positive faecal immunochemical test (FIT) test in a Joint Advisory Group (JAG) accredited Gastrointestinal Endoscopy centre. We histologically evaluated the polyp margins for complete resection, which was defined as the absence of adenomatous or hyperplastic tissue in the resected polyp margins in a cohort of faecal immunochemical test positive patients. Results A total of 186 consecutive NCCS colonoscopies out of a total of 542 performed between 2013 and 2017 were included in this study. Of the polyps excised 152(27%) had a R0 margin histologically, and 30(5%) had involvement of the margin. Surprisingly in 373(67%) of polyps pathologists were unable to assess the margin. Conclusion Achieving an R0 margin should be a key performance indicator for endoscopists performing polypectomy. At the same time more studies on polyp margins are recommended.

Neoadjuvant radiotherapy in rectal cancer - less is more?

AIM: There is significant international variation in the use of neoadjuvant radiation prior to total mesorectal excision. The MERCURY group advocate selective neoadjuvant chemoradiotherapy (CRT). We have performed a retrospective, single-centre study of patients treated with CRT, where only the circumferential resection margin is threatened, with the aim of identifying whether a more selective approach to CRT provides acceptable local relapse rates (LRRs). METHOD: All consecutive patients who underwent radical surgery for rectal adenocarcinoma over a 5-year period (2007-2012) in the Oxford University Trust were considered. Electronic hospital systems were reviewed to obtain patient and tumour demographics, treatment and follow-up information. All patients were classified into risk categories according to National Institute for Health and Care Excellence guidance. Data were analysed using Microsoft Excel and R. RESULTS: Two hundred and seventy-two patients were identified: 123, 89 and 60 in the high-, intermediate- and low-risk categories, respectively. Seventy-nine per cent of those in the high-risk group, 6% in the intermediate and 5% in the low-risk group underwent CRT. The overall 5-year LRR and distant recurrence rate (DRR) were 5.2% and 17.8%, respectively. The 5-year LRR for those who went straight to surgery was 2.0% and for those who had neoadjuvant CRT it was 7.4%. The DRR for these two groups was 8.5% and 18.9%, respectively. CONCLUSION: Our series demonstrates that the use of CRT only in margin-threatening tumours, results in an exceptionally low LRR for those without margin-threatening disease. In routine clinical care, this strategy can minimize the significant morbidity of multimodal treatment and allow earlier introduction of systemic therapy to minimize distant recurrence.

Ultra-high resolution and multi-shell diffusion MRI of intact ex vivo human brains using kT-dSTEAM at 9.4T.

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B1+) inhomogeneities, specially at ultra-high field (UHF, 7T and higher). To overcome these issues, it is necessary to tailor ex vivo diffusion-weighted sequences specifically for high resolution and high diffusion-weighting. Here, we present kT-dSTEAM, which achieves B1+ homogenization across whole human brain specimens using parallel transmit (pTx) on a 9.4T MR system. We use kT-dSTEAM to obtain multi-shell high b-value and high resolution diffusion-weighted data in ex vivo whole human brains. Isotropic whole brain data can be acquired at high b-value (6000-8000 s/mm2) at high resolution (1000 µm) and at moderate b-value (3000 s/mm2) at ultra-high isotropic resolution (400 µm). As an illustration of the advantages of the ultra-high resolution, tractography across the WM/GM border shows less of the unwanted gyral crown bias, and more high-curvature paths connecting the sulcal wall than at lower resolution. The kT-dSTEAM also allows for acquisition of T1 and T2 weighted images suitable for estimating quantitative T1 and T2 maps. Finally, multi-shell analysis of kT-dSTEAM data at variable mixing time (TM) is shown as an approach for ex vivo data analysis which is adapted to the strengths of STEAM diffusion-weighting. Here, we use this gain for multi-orientation modelling and crossing-fiber tractography. We show that multi-shell data allows superior multiple orientation tractography of known crossing fiber structures in the brain stem.

Variations in antibiotic use across India: multi-centre study through Global Point Prevalence survey.

The aim of the study was to assess antimicrobial prescribing patterns, and variation in practice, in India. A point prevalence survey (PPS) was conducted in October to December 2017 in 16 tertiary care hospitals across India. The survey included all inpatients receiving an antimicrobial on the day of PPS and collected data were analysed using a web-based application of the University of Antwerp. In all, 1750 patients were surveyed, of whom 1005 were receiving a total of 1578 antimicrobials. Among the antimicrobials prescribed, 26.87% were for community-acquired infections; 19.20% for hospital-acquired infections; 17.24% for medical prophylaxis; 28.70% for surgical prophylaxis; and 7.99% for other or undetermined reasons. Antibiotic prescribing quality indicators, such as reason in notes and post-prescription review score, were low. This PPS showed widespread antibiotic usage, underlining the need for antibiotic stewardship to promote evidence-based practice.

Spectral and Structural Variations of Biomimetic Light-Harvesting Nanotubes.

Bioinspired, self-assembled nanotubes have been investigated by low-temperature, polarization-resolved single-tube spectroscopy. These assemblies are based on zinc chlorin monomers and are considered as model systems that resemble the secondary structural elements in the natural light-harvesting systems of green (non)sulfur bacteria. Compared to the natural systems, the spectral parameters extracted from the single-nanotube spectra feature distributions with significantly smaller widths, which is ascribed to a tremendous reduction of structural heterogeneity in the artificial systems. Employing quantum chemical molecular modeling the spectra of individual nanotubes can be explained consistently only for a molecular packing model that is fundamentally different from those considered so far for the natural systems. Subsequent theoretical simulations reveal that the remaining spectral variations between single nanotubes can be traced back to small variations of the mutual orientations of the monomer transition dipole moments that are far beyond the resolving power of high-resolution electron microscopy imaging techniques.

High Performance Bi-2212 Round Wires Made with Recent Powders.

Multifilamentary Bi2Sr2CaCu2Ox (Bi-2212) wire made by the powder-in-tube technique is the only high temperature superconductor made in the round shape preferred by magnet builders. The critical current density (J C ) of Bi-2212 round wire was improved significantly by the development of overpressure heat treatment in the past few years. Bi-2212 wire is commercially available in multiple architectures and kilometer-long pieces and a very promising conductor for very high field NMR and accelerator magnets. We studied the effects of precursor powder and heat treatment conditions on the superconducting properties and microstructure of recent Bi-2212 wires. Short samples of recent wire with optimized overpressure processing showed J C (4.2 K, 15 T) = 6640 A/mm2 and J C (4.2 K, 30 T) = 4670 A/mm2, which correspond to engineering critical current densities J E (4.2 K, 15 T) = 1320 A/mm2 and J E (4.2 K, 30 T) = 930 A/mm2.

Screening for vision-threatening diabetic retinopathy in South India: comparing portable non-mydriatic and standard fundus cameras and clinical exam.

PurposeTo evaluate the sensitivity and specificity of a portable non-mydriatic fundus camera to diagnose vision-threatening diabetic retinopathy (VTDR).Patients and methodsA prospective, single-site, comparative instrument validation study was undertaken at the Aravind Eye Care System. Overall, 155 subjects with and without diabetes were recruited. Images from 275 eyes were obtained with the (1) non-mydriatic Smartscope, (2) mydriatic Smartscope, and (3) mydriatic table-top camera of the macular, nasal, and superotemporal fields. A retina specialist performed a dilated fundus examination (DFE), (reference standard). Two masked retina specialists graded the images. Sensitivity and specificity to detect VTDR with the undilated Smartscope was calculated compared to DFE.ResultsGraders 1 and 2 had a sensitivity of 93% (95% confidence interval (CI): 87-97%) and 88% (95% CI: 81-93%) and a specificity of 84% (95% CI: 77-89%) and 90% (95% CI: 84-94%), respectively, in diagnosing VTDR with the undilated Smartscope compared to DFE. Compared with the dilated Topcon images, graders 1 and 2 had sensitivity of 88% (95% CI: 81-93%) and 82% (95% CI: 73-88%) and specificity of 99% (95% CI: 96-100%) and 99% (95% CI: 95-100%).ConclusionsRemote graders had high sensitivity and specificity in diagnosing VTDR with undilated Smartscope images, suggesting utility where portability is a necessity.

High resolution anatomical and quantitative MRI of the entire human occipital lobe ex vivo at 9.4T.

Several magnetic resonance imaging (MRI) contrasts are sensitive to myelin content in gray matter in vivo which has ignited ambitions of MRI-based in vivo cortical histology. Ultra-high field (UHF) MRI, at fields of 7T and beyond, is crucial to provide the resolution and contrast needed to sample contrasts over the depth of the cortex and get closer to layer resolved imaging. Ex vivo MRI of human post mortem samples is an important stepping stone to investigate MRI contrast in the cortex, validate it against histology techniques applied in situ to the same tissue, and investigate the resolutions needed to translate ex vivo findings to in vivo UHF MRI. Here, we investigate key technology to extend such UHF studies to large human brain samples while maintaining high resolution, which allows investigation of the layered architecture of several cortical areas over their entire 3D extent and their complete borders where architecture changes. A 16 channel cylindrical phased array radiofrequency (RF) receive coil was constructed to image a large post mortem occipital lobe sample (~80×80×80mm3) in a wide-bore 9.4T human scanner with the aim of achieving high-resolution anatomical and quantitative MR images. Compared with a human head coil at 9.4T, the maximum Signal-to-Noise ratio (SNR) was increased by a factor of about five in the peripheral cortex. Although the transmit profile with a circularly polarized transmit mode at 9.4T is relatively inhomogeneous over the large sample, this challenge was successfully resolved with parallel transmit using the kT-points method. Using this setup, we achieved 60µm anatomical images for the entire occipital lobe showing increased spatial definition of cortical details compared to lower resolutions. In addition, we were able to achieve sufficient control over SNR, B0 and B1 homogeneity and multi-contrast sampling to perform quantitative T2* mapping over the same volume at 200µm. Markov Chain Monte Carlo sampling provided maximum posterior estimates of quantitative T2* and their uncertainty, allowing delineation of the stria of Gennari over the entire length and width of the calcarine sulcus. We discuss how custom RF receive coil arrays built to specific large post mortem sample sizes can provide a platform for UHF cortical layer-specific quantitative MRI over large fields of view.

Patients' preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial: what makes it worthwhile?

Background: We sought to determine the survival benefits that patients judged sufficient to warrant adjuvant therapy with sorafenib for 1 year, or for 3 years after resection of renal cell carcinoma in the SORCE trial. Methods: SORCE participants from all sites in Australia and New Zealand, and selected sites in the UK, completed a validated preferences questionnaire at months 0, 3, 15, and 42 to elicit the minimum survival benefits they judged sufficient to warrant adjuvant sorafenib for 1 year (versus observation), or for 3 years (versus 1 year). The questionnaires used reference survival times of 5 and 15 years; and reference survival rates at 5 years of 65% and 85%. Results: The 233 participants had a median age of 57 years (range 29-78) and 71% were male. For 1 year of sorafenib versus no adjuvant therapy, the median benefits in survival times judged sufficient to warrant treatment were an extra 9 months beyond 5 years and an extra 1 year beyond 15 years; the median benefit in survival rates were an extra 4% beyond 65% and an extra 3% beyond 85% at 5 years. For 3 years of sorafenib versus 1 year of sorafenib, the median benefit in survival time judged sufficient to warrant extended treatment was an extra 1 year beyond both 5 and 15 years. Participants randomly allocated to treatment with sorafenib judged larger benefits necessary than those allocated to placebo. Participants' preferences were not associated with their baseline characteristics or the interval from randomisation. Conclusion: Most participants judged an extra year of survival necessary to warrant 1 year of adjuvant sorafenib worthwhile, and an additional year of survival to warrant extending the duration of sorafenib from 1 to 3 years. Patients' preferences are important in shared decision making. SORCE trial clinical trials number: NCT00492258.

Description of a multi-university education and collaborative care child psychiatry access program: New York State's CAP PC.

OBJECTIVE: Although, child mental health problems are widespread, few get adequate treatment, and there is a severe shortage of child psychiatrists. To address this public health need many states have adopted collaborative care programs to assist primary care to better assess and manage pediatric mental health concerns. This report adds to the small literature on collaborative care programs and describes one large program that covers most of New York state. PROGRAM DESCRIPTION: CAP PC, a component program of New York State's Office of Mental Health (OMH) Project TEACH, has provided education and consultation support to primary care providers covering most of New York state since 2010. The program is uniquely a five medical school collaboration with hubs at each that share one toll free number and work together to provide education and consultation support services to PCPs. METHODS: The program developed a clinical communications record to track information about all consultations which forms the basis of much of this report. 2-week surveys following consultations, annual surveys, and pre- and post-educational program evaluations have also been used to measure the success of the program. RESULTS: CAP PC has grown over the 6years of the program and has provided 8013 phone consultations to over 1500 PCPs. The program synergistically provided 17,523 CME credits of educational programming to 1200 PCPs. PCP users of the program report very high levels of satisfaction and self reported growth in confidence. CONCLUSIONS: CAP PC demonstrates that large-scale collaborative consultation models for primary care are feasible to implement, popular with PCPs, and can be sustained. The program supports increased access to child mental health services in primary care and provides child psychiatric expertise for patients who would otherwise have none.

Evidence of dengue and chikungunya virus co-infection and circulation of multiple dengue serotypes in a recent Indian outbreak.

In India, dengue endemic areas overlap with chikungunya-affected areas and both the viruses are transmitted by same vector, Aedes aegypti - thereby increasing opportunity of co-infection by both viruses. Present study was carried out to understand the DENV-CHIKV infection dynamics during recent outbreaks in eastern India (West Bengal state) and its implication on disease manifestations. Blood was collected from 326 symptomatic febrile patients. Patients' serum was subjected to serological diagnosis for presence of anti-dengue-IgM, anti-chikungunya-IgM antibodies and dengue-NS1 antigen by ELISA. Viral RNA was extracted, and presence of dengue virus (DENV) and chikungunya virus (CHIKV) genome, their viral load (VL), and serotype among infected patients' plasma was determined by real-time qRT-PCR. Statistical analysis was performed by using EPI INFO software. DENV and CHIKV were detected in 54% and 33% of symptomatic patients respectively, among whom 23% were harboring both viruses. WHO classified warning signs were detected among 64% DENV patients and 61% DENV-CHIKV double-infected patients. Patients with warning signs always had much higher DEN VL than those without warning signs. Hemorrhagic manifestation and abdominal pain was found in significantly higher frequency among patients with high dengue VL (>10,000 copies/ml). DENV2 was the most predominant serotype among monotypic dengue patients, whereas DENV2-DENV4 combination was most prevalent among patients infected with dual dengue serotypes. This study indicated that DENV-CHIKV double infection and high dengue VL contributed towards severe disease manifestations among infected patients. DENV2 and DENV2-DENV4 combination were the most prevalent serotype(s) found in current outbreak.

Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3.

Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1-/- mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

Chimeric antigen receptors for treatment of glioblastoma: a practical review of challenges and ways to overcome them.

Glioblastoma (GBM) is by far the most common and the most aggressive of all the primary brain malignancies. No curative therapy exists, and median life expectancy hovers at around 1 year after diagnosis, with a minute fraction surviving beyond 5 years. The difficulty in treating GBM lies in the cancer's protected niche within the blood-brain barrier and the heterogeneity of the cancer cells, which possess varying degrees of susceptibility to various common modalities of treatment. Over time, it is the tumor heterogeneity of GBM and the ability of the cancer stem cells to evolve in response treatment that renders the cancer refractory to conventional treatment. Therefore, research has increasingly focused on treatment that incorporates knowledge of GBM molecular biology to therapeutic strategies. One type of therapy that shows great promise is the area of T-cell immunotherapy to target GBM-specific tumor antigens. One attractive strategy is to use T cells that have undergone genetic modification to express a chimeric antigen receptor capable of interacting with tumor antigens. In this article, we will review chimeric antigen receptor T-cell therapy, their advantages, drawbacks, challenges facing their use and how those challenges may be overcome.