What Proportion of Patients with Bone and Soft Tissue Tumors Contracted Coronavirus-19 and Died From Surgical Procedures During the Initial Period of the COVID-19 Pandemic? Results From the Multicenter British Orthopaedic Oncology Society Observational Study.

BACKGROUND: Delivering uninterrupted cancer treatment to patients with musculoskeletal tumors has been essential during the rapidly evolving coronavirus 2019 (COVID-19) pandemic, as delays in management can be detrimental. Currently, the risk of contracting COVID-19 in hospitals when admitted for surgery and the susceptibility due to adjuvant therapies and associated mortality due to COVID-19 is unknown, but knowledge of these potential risks would help treating clinicians provide appropriate cancer care. QUESTIONS/PURPOSES: (1) What is the risk of hospital-acquired COVID-19 in patients with musculoskeletal tumors admitted for surgery during the initial period of the pandemic? (2) What is the associated mortality in patients with musculoskeletal tumors who have contracted COVID-19? (3) Are patients with musculoskeletal tumors who have had neoadjuvant therapy (chemotherapy or radiation) preoperatively at an increased risk of contracting COVID-19? (4) Is a higher American Society of Anesthesiologists (ASA) grade in patients with musculoskeletal tumors associated with an increased risk of contracting COVID-19 when admitted to the hospital for surgery? METHODS: This retrospective, observational study analyzed patients with musculoskeletal tumors who underwent surgery in one of eight specialist centers in the United Kingdom, which included the five designated cancer centers in England, one specialist soft tissue sarcoma center, and two centers from Scotland between March 12, 2020 and May 20, 2020. A total of 347 patients were included, with a median (range) age of 53 years (10 to 94); 60% (207 of 347) were men, and the median ASA grade was II (I to IV). These patients had a median hospital stay of 8 days (0 to 53). Eighteen percent (61 of 347) of patients had received neoadjuvant therapy (8% [27] chemotherapy, 8% [28] radiation, 2% [6] chemotherapy and radiation) preoperatively. The decision to undergo surgery was made in adherence with United Kingdom National Health Service and national orthopaedic oncology guidelines, but specific data with regard to the number of patients within each category are not known. Fifty-nine percent (204 of 347) were negative in PCR testing done 48 hours before the surgical procedure; the remaining 41% (143 of 347) were treated before preoperative PCR testing was made mandatory, but these patients were asymptomatic. All patients were followed for 30 days postoperatively, and none were lost to follow-up during that period. The primary outcome of the study was contracting COVID-19 in the hospital after admission. The secondary outcome was associated mortality after contracting COVID-19 within 30 days of the surgical procedure. In addition, we assessed whether there is any association between ASA grade or neoadjuvant treatment and the chances of contracting COVID-19 in the hospital. Electronic patient record system and simple descriptive statistics were used to analyze both outcomes. RESULTS: Four percent (12 of 347) of patients contracted COVID-19 in the hospital, and 1% (4 of 347) of patients died because of COVID-19-related complications. Patients with musculoskeletal tumors who contracted COVID-19 had increased mortality compared with patients who were asymptomatic or tested negative (odds ratio 55.33 [95% CI 10.60 to 289.01]; p < 0.001).With the numbers we had, we could not show that adjuvant therapy had any association with contracting COVID-19 while in the hospital (OR 0.94 [95% CI 0.20 to 4.38]; p = 0.93). Increased ASA grade was associated with an increased likelihood of contracting COVID-19 (OR 58 [95% CI 5 to 626]; p < 0.001). CONCLUSION: Our results show that surgeons must be mindful and inform patients that those with musculoskeletal tumors are at risk of contracting COVID-19 while admitted to the hospital and some may succumb to it. Hospital administrators and governmental agencies should be aware that operations on patients with lower ASA grade appear to have lower risk and should consider restructuring service delivery to ensure that procedures are performed in designated COVID-19-restricted sites. These measures may reduce the likelihood of patients contracting the virus in the hospital, although we cannot confirm a benefit from this study. Future studies should seek to identify factors influencing these outcomes and also compare surgical complications in those patients with and without COVID-19. LEVEL OF EVIDENCE: Level III, therapeutic study.

Will virtual multidisciplinary team meetings become the norm for musculoskeletal oncology care following the COVID-19 pandemic? - experience from a tertiary sarcoma centre.

BACKGROUND: Like with all cancers, multidisciplinary team (MDT) meetings are the norm in bone and soft tissue tumour (BST) management too. Problem in attendance of specialists due to geographical location is the one of the key barriers to effective functioning of MDTs. To overcome this problem, virtual MDTs involving videoconferencing or telemedicine have been proposed, but however this has been seldom used and tested. The COVID-19 pandemic forced the implementation of virtual MDTs in the Oxford sarcoma service in order to maintain normal service provision. We conducted a survey among the participants to evaluate its efficacy. METHODS: An online questionnaire comprising of 24 questions organised into 4 sections was circulated among all participants of the MDT after completion of 8 virtual MDTs. Opinions were sought comparing virtual MDTs to the conventional face-to-face MDTs on various aspects. A total of 36 responses were received and were evaluated. RESULTS: 72.8% were satisfied with the depth of discussion in virtual MDTs and 83.3% felt that the decision-making in diagnosis had not changed following the switch from face-to-face MDTs. About 86% reported to have all essential patient data was available to make decisions and 88.9% were satisfied with the time for discussion of patient issues over virtual platform. Three-fourths of the participants were satisfied (36.1% - highly satisfied; 38.9% - moderately satisfied) with virtual MDTs and 55.6% of them were happy to attend MDTs only by the virtual platform in the future. Regarding future, 77.8% of the participants opined that virtual MDTs would be the future of cancer care and an overwhelming majority (91.7%) felt that the present exercise would serve as a precursor to global MDTs involving specialists from abroad in the future. CONCLUSION: Our study shows that the forced switch to virtual MDTs in sarcoma care following the unprecedented COVID-19 pandemic to be a viable and effective alternative to conventional face-to-face MDTs. With effective and efficient software in place, virtual MDTs would also facilitate in forming extended MDTs in seeking opinions on complex cases from specialists abroad and can expand cancer care globally.

Producing 3D printed high-fidelity retroperitoneal models from in vivo patient data: The Oxford Method.

Macroscopic anatomy has traditionally been taught using cadaveric material, lectures and a variable amount of additional resources such as online modules. Anatomical models have also been used to assist in teaching. Of these, traditional plastic models have been shown to be effective educational tools, yet have significant drawbacks such as a lack of anatomical detail and texturisation. Three-dimensional (3D) printed models stand to solve these problems and widen access to high-quality anatomical teaching. This paper outlines the use of 3D multi-planar imaging (CT and MRI) as a framework to develop an accurate model of the retroperitoneum. CT and MRI scans were used to construct a virtual 3D model of the retroperitoneum. This was printed locally as a full-size colour model for use in medical education. We give a complete account of the processes and software used. This study is amongst the first of a series in which we will document the newly formed Oxford Library of Anatomy. This series will provide the methodology for the production of models from CT and MRI scans, and the Oxford Library of Anatomy will provide a complete series of some of the most complex anatomical areas and ones which degrade quickly when a real cadaver is being used. In our own internal experience, the models are highly accurate, reproducible and durable, as compared to prosected specimens. We hope they will form an important adjunct in the teaching of the subject.

Patient safety associated with the surgical treatment of bone and soft tissue tumours during the COVID-19 pandemic-results from an observational study at the Oxford Sarcoma Service.

PURPOSE: Deferring cancer surgery can have profound adverse effects including patient mortality. During the COVID-19 pandemic, departmental reorganisation and adherence to evolving guidelines enabled provision of uninterrupted surgical care to patients with bone and soft tissue tumours (BST) in need of surgery. We reviewed the outcomes of surgeries on BST during the first two months of the pandemic at one of the tertiary BST centres in the UK. MATERIALS AND METHODS: Between 12 March 2020 and 12 May 2020, 56 patients of a median age of 57 years (18-87) underwent surgery across two sites: index hospital (n = 27) and COVID-free facility (n = 29). Twenty-five (44.6%) patients were above the age of 60 years and 20 (35.7%) patients were in ASA III and ASA IV category. The decision to offer surgery was made in adherence with the guidelines issued by the NHS, BOOS and BSG. RESULTS: At a minimum follow-up of 30 days post-surgery, 54 (96.4%) patients were recovering well. Thirteen patients (23.2%) had post-operative complications which included four (7.1%) patients developing pulmonary embolism. The majority of complications (12/13 = 92.7%) occurred in ASA III and IV category patients. Four (7.1%) patients contracted COVID-19, of which three required escalation of care due to pulmonary complications and two (3.6%) died. Patients < 60 years of age had significantly less complications than those > 60 years (p < 0.001). Patients operated on in the COVID-free facility had fewer complications compared with those operated on at the index hospital (p < 0.027). CONCLUSION: In spite of the favourable results in majority of our patients, our study shows that patients with sarcoma operated at the height of the pandemic are at a risk of contracting COVID-19 and also having associated with mortality. The use of a COVID-free facility, surgery in patients < 60 60 years and in ASA I & II category are associated with better outcomes. If a second wave occurs, a serious consideration should be given to ways of minimising the risk of contracting COVID-19 in these vulnerable patients either by using COVID-free facilities or delaying treatment until peak of infection has passed.

Interband cascade Lasers with AlGaAsSb cladding layers emitting at 3.3†µm.

We investigate the impact of the growth conditions of AlGaAsSb cladding layers on the properties of interband cascade lasers (ICLs). For an optimized structure emitting at 3.3 µm, we achieve an internal quantum efficiency of 65% per stage in good agreement with conventional ICL using InAs/AlSb superlattice cladding layers, in spite of internal losses of 15 cm-1 due to higher optical losses in the n-type AlGaAsSb alloys. Finally, we report a narrow ridge ICL emitting at 3.33 µm operating in continuous wave up to 80°C that produces 1 mW/uncoated facet at 80 °C, 10 mW at 40 °C and more than 12 mW at 20°C.

Probability Steiner trees and maximum parsimony in phylogenetic analysis.

The phylogenetic tree (PT) problem has been studied by a number of researchers as an application of the Steiner tree problem, a well-known network optimisation problem. Of all the methods developed for phylogenies the maximum parsimony (MP) method is a simple and commonly used method because it relies on directly observable changes in the input nucleotide or amino acid sequences. In this paper we show that the non-uniqueness of the evolutionary pathways in the MP method leads us to consider a new model of PTs. In this so-called probability representation model, for each site a node in a PT is modelled by a probability distribution of nucleotide or amino acid states, and hence the PT at a given site is a probability Steiner tree, i.e. a Steiner tree in a high-dimensional vector space. In spite of the generality of the probability representation model, in this paper we restrict our study to constructing probability phylogenetic trees (PPT) using the parsimony criterion, as well as discussing and comparing our approach with the classical MP method. We show that for a given input set although the optimal topology as well as the total tree length of the PPT is the same as the PT constructed by the classical MP method, the inferred ancestral states and branch lengths are different and the results given by our method provide a plausible alternative to the classical ones.

The role of intraoperative cell salvage for musculoskeletal sarcoma surgery.

BACKGROUND: The efficacy and safety of cell salvage for musculoskeletal sarcoma surgery have not been reported, and concerns over re-infusion of tumour cells remain. This study aims to i) describe the intra-operative blood loss and cell salvage reinfusion volumes for lower limb sarcoma and pelvic sarcoma procedures ii) and explore whether there is evidence of tumour cells in reinfused blood. METHODS: Retrospective analysis of 109 consecutive surgical procedures for biopsy-proven sarcoma or bone metastasis performed between 1 July 2015 and 30 October 2019. Salvaged blood was processed and reinfused when intraoperative blood loss exceeded 500 ml. Primary bone tumour (n = 86(79%)) and metastasis (n = 23(21%) constituted the study group and surgeries were classified under hemipelvectomy (n = 43(39%)), lower limb endoprosthesis replacement (LLE) (n = 50(46%)) and wide excision surgery (WE) (n = 16(15%)). Microscopic examination of imprint cytology of leuco-depletion(LD) filters, and peripheral smear examination was performed for reinfused blood. RESULTS: Median (IQR) intra-operative blood loss was 1750 (600-3000) ml for hemipelvectomy, 850 (600-1200) ml for LLE, and 1000 (550-2000) ml for WE. Salvaged blood was re-infused in 102 of 109 (94%) patients. The mean (SD) volume of re-infusion was 445(4 2 5) ml for hemipelvectomy, 206(1 3 1) ml for LLE, and 184(1 0 6) ml for WE. In total, 64 of 109 (59%) patients received an allogeneic red blood transfusion within 72 h of surgery. Cytology analysis of imprints taken from the filtered blood available in 95(87%) patients and peripheral smear examination of reinfused blood available in 32(29%) patients did not reveal evidence of tumour cells on microscopic examination of any samples. CONCLUSION: Our study demonstrates that musculoskeletal sarcoma surgery is associated with significant blood loss, and cell salvage permits reinfusion of autologous blood in most patients. The cytological analysis did not reveal evidence of tumour cells in reinfused blood, consistent with other studies where cell salvage is used for cancer surgery.

Distinct roles of lymphotoxin alpha and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells.

In mice deficient in either lymphotoxin alpha (LT-alpha) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-alpha and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-alpha-deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-alpha-expressing cells required to establish organized FDC are derived from BM. The role of LT-alpha in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)-deficient BM cells into LT-alpha-deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-alpha-deficient recipient. Thus, expression of LT-alpha in the BM-derived cells, but not in the non-BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I-deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non-BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I-deficient BM was able to restore FDC organization and GC formation in LT-alpha-deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-alpha-expressing BM-derived cells and by TNFR-I-expressing non-BM-derived cells.

Service delivery during the COVID-19 pandemic: Experience from The Oxford Bone Tumour and Soft Tissue Sarcoma service.

The COVID-19 (Coronavirus disease 2019) pandemic has caused an unprecedented strain on healthcare systems across the globe. Apart from being a major hurdle to delivery of basic healthcare services, this may be associated with potential harm for cancer patients. Usually being immunocompromised, cancer patients are at a higher risk of contracting the disease and with hospitals being a potential source of the infection, an urgent need to reorganise the structure of delivery of cancer care is essential. Cancer departments must balance patient care whilst also minimising transmission among patients and healthcare professionals. The Oxford Sarcoma Service was re-structured based on the guidelines issued by the National Health Service (NHS) and the British Orthopaedic Oncology Society (BOOS) to deliver unhindered care to patients. Prioritising patients who needed urgent surgery, weighing the risk-benefit ratio while delivering adjuvant treatments and conducting regular virtual multi-disciplinary team (MDT) meetings combined with personal protection equipment (PPE) usage by all involved healthcare workers were salient features in terms of ensuring the delivery of effective care during the COVID-19 pandemic. Our new model of modus operandi during this global crisis was effective in delivering high standard of care to patients and might serve as a guide to similar units managing bone and soft tissue tumours.

Analysis of throwing power for megasonic assisted electrodeposition of copper inside THVs.

The deposition of increased volumes of Cu down an interconnect through-hole via (THV) of a Printed Circuit Board (PCB) is highly desirable for the fabrication of increasing component density and PCB stacks. A quality metric, called micro-throwing power, characterises the volume of Cu that can be deposited within a THV. In this paper, we analyse the influence of 1 ± 0.05 MHz megasonic (MS) assisted agitation applied to copper (Cu) electroplating baths on the micro-throwing ability of a standard, non-filling Cu electroplating solution. Our results indicate that megasonic agitation is shown to increase the Cu deposition volume within a THV by 45% for an increase of MS pressure from 225 W to 450 W, highlighting the significance of acoustic pressure as a key parameter to control MS THV plating volume. Bulk fluid flow rate within a 500 L plating tank is shown to increase by 150% due to Eckhart acoustic streaming mechanisms, compared to existing bath agitation techniques and panel movement. From MS plating experiments and COMSOLTM finite element acoustic scattering simulations, transducer orientation is shown to influence plating performance, with higher-order acoustic resonant modes forming within THVs identified as the cause. Simulations indicate that higher potential acoustic energy was coupled into a 0.200 mm diameter THV cavity, width-to-length aspect ratio (ar): 8:1, than a larger cavity of diameter 0.475 mm, ar 3.4:1. The maximum acoustic energy coupled into THV cavity is observed for a wavefront propagating along the axis of the cavity entrance, indicating an ideal alignment for the MS plating setup.

Integrin alpha subunit ratios, cytoplasmic domains, and growth factor synergy regulate muscle proliferation and differentiation.

The role of integrins in muscle differentiation was addressed by ectopic expression of integrin alpha subunits in primary quail skeletal muscle, a culture system particularly amenable to efficient transfection and expression of exogenous genes. Ectopic expression of either the human alpha5 subunit or the chicken alpha6 subunit produced contrasting phenotypes. The alpha5-transfected myoblasts remain in the proliferative phase and are differentiation inhibited even in confluent cultures. In contrast, myoblasts that overexpress the alpha6 subunit exhibit inhibited proliferation and substantial differentiation. Antisense suppression of endogenous quail alpha6 expression inhibits myoblast differentiation resulting in sustained proliferation. These effects of ectopic alpha subunit expression are mediated, to a large extent, by the cytoplasmic domains. Ectopic expression of chimeric alpha subunits, alpha5ex/6cyto and alpha6ex/5cyto, produced phenotypes opposite to those observed with ectopic alpha5 or alpha6 expression. Myoblasts that express alpha5ex/6cyto show decreased proliferation while differentiation is partially restored. In contrast, the alpha6ex/5cyto transfectants remain in the proliferative phase unless allowed to become confluent for at least 24 h. Furthermore, expression of human alpha5 subunit cytoplasmic domain truncations, before and after the conserved GFFKR motif, shows that this sequence is important in alpha5 regulation of differentiation. Ectopic alpha5 and alpha6 expression also results in contrasting responses to the mitogenic effects of serum growth factors. Myoblasts expressing the human alpha5 subunit differentiate only in the absence of serum while differentiation of untransfected and alpha6-transfected myoblasts is insensitive to serum concentration. Addition of individual, exogenous growth factors to alpha5-transfected myoblasts results in unique responses that differ from their effects on untransfected cells. Both bFGF or TGFbeta inhibit the serum-free differentiation of alpha5-transfected myoblasts, but differ in that bFGF stimulates proliferation whereas TGF-beta inhibits it. Insulin or TGF-alpha promote proliferation and differentiation of alpha5-transfected myoblasts; however, insulin alters myotube morphology. TGF-alpha or PDGF-BB enhance muscle alpha-actinin organization into myofibrils, which is impaired in differentiated alpha5 cultures. With the exception of TGF-alpha, these growth factor effects are not apparent in untransfected myoblasts. Finally, myoblast survival under serum-free conditions is enhanced by ectopic alpha5 expression only in the presence of bFGF and insulin while TGF-alpha and TGF-beta promote survival of untransfected myoblasts. Our observations demonstrate (1) a specificity for integrin alpha subunits in regulating myoblast proliferation and differentiation; (2) that the ratio of integrin expression can affect the decision to proliferate or differentiate; (3) a role for the alpha subunit cytoplasmic domain in mediating proliferative and differentiative signals; and (4) the regulation of proliferation, differentiation, cytoskeletal assembly, and cell survival depend critically on the expression levels of different integrins and the growth factor environment in which the cells reside.

Room air dilution of heliox given by facemask.

OBJECTIVES: To measure the extent of dilution of helium-oxygen (heliox) by room air when given via high concentration reservoir mask to spontaneously breathing subjects. Substantial dilution of heliox by room air under these circumstances might alter its physical properties sufficiently to negate any potential clinical benefit in obstructive respiratory failure. DESIGN: Healthy volunteers breathing different concentrations of helium in oxygen via two different masks in a randomised crossover design. SETTING: Operating theatre in a university hospital. PATIENTS AND PARTICIPANTS: Six healthy volunteers. INTERVENTIONS: The concentrations of helium, nitrogen and oxygen were measured in the trachea of each volunteer using a mass spectrometer during normal breathing, hyperventilation and hypoventilation. MEASUREMENTS AND RESULTS: During normal breathing of Heliox21 (79% helium) via a standard non-rebreathe reservoir mask, within subject median percentage tracheal helium was 37.2% (range 29.3-52.2%) and nitrogen was 41.7% (27.4-49.4%). Air entrainment was affected by changes in breathing pattern: tracheal nitrogen concentration was greater during hyperventilation (55.4%; range 49.4-63.5%) and less during hypoventilation (33.1%; range 24.6-39.6%, p=0.043). Tracheal nitrogen could be almost completely abolished by administering heliox via a tightly fitting cushioned facemask, even during hyperventilation (2.2%; range 0.6-6.1%, p=0.028). CONCLUSIONS: Heliox administration via a standard high-concentration reservoir mask leads to significant dilution by room air. For the full potential benefits of heliox to be realised in spontaneously breathing patients, it should be administered via a system that achieves a gas tight seal, with no leaks between the delivery device and the surroundings.

Copper electroplating of PCB interconnects using megasonic acoustic streaming.

In this research experimental and simulated analysis investigates the influence of megasonic (MS; 1 ±â€¯0.05 MHz) acoustic-assisted electroplating techniques, with respect to the fabrication of through-hole via (THV) and blind-via (BV) interconnects for the Printed Circuit Board (PCB) industry. MS plating of copper down THV and BV interconnects was shown to produce measurable benefits such as increased connectivity throughout a PCB and cost savings. More specifically, a 700% increase of copper plating rate was demonstrated for THVs of 175 µm diameter and depth-to-width aspect ratio (ar) of 5.7:1, compared with electrodeposition under no-agitation conditions. For BVs, a 60% average increase in copper thickness deposition in 150 µm and 200 µm, ar 1:1, was demonstrated against plating under standard manufacturing conditions including bubble agitation and panel movement. Finite element modelling simulations of acoustic scattering revealed 1st harmonic influence for plating rate enhancement.

How do cytotoxic lymphocytes kill their targets?

CD8+ cytotoxic lymphocytes, natural killer cells and lymphokine-activated killer cells depend primarily on the perforin/granzyme system to kill their targets, while CD4+ T cells utilize Fas and other mechanisms to induce cell death. The molecular mechanisms used by these pathways to induce target cell apoptosis may converge on common death substrates.

Growth inhibition of a rat colon tumor by L-canavanine.

The effects of L-canavanine, a higher plant nonprotein amino acid, on the growth of a rat colon carcinoma were assessed. The 1 and 10% lethal dose values following a single s.c. injection in Fischer rats were 4.75 and 5.57 g/kg, respectively. Rats received s.c. injections of a 10% (w/v) tumor cell suspension. When the tumors reached a size of 500 to 1000 mm3, the rats received canavanine, 2.0 g/kg or 3.0 g/kg s.c. daily for 5 or daily for 9 days. Control animals received a 0.9% NaCl solution. Administration of canavanine, 2.0 g/kg for 5 days produced a treated versus control of 23%; the treated versus control for 9 days was 14%. The 3.0-g/kg dosing regimen resulted in a treated versus control value of -13% after 5 days and -8% after 9 days. The negative values indicated regression of the tumor. The reduction in tumor volume, expressed as the percentage of regression, was 22% in animals receiving canavanine, 3.0 g/kg daily for 5 days and 60% in the 3.0-g/kg-daily-for-9-days treatment group. Cumulative toxicity caused death in 2 of 5 animals in the 3.0-g/kg-for-9-days treatment group; the average weight loss was 31%. The 3.0-g/kg-for-5-days treatment also produced undesirable cumulative toxicity as indicated by a weight loss of 19%. Cumulative toxicity was reduced greatly when canavanine was administered at a dose level of 2.0 g/kg for 5 days (weight loss of 13%). Analysis of the relationship of caloric deprivation to tumor growth reduction established that canavanine-mediated curtailment of tumor growth was not caused by reduced food intake and its associated loss in body weight. Histological examination of tissues from rats receiving canavanine, 2.0 or 3.0 g/kg daily for 5 or 9 days failed to reveal lesions in any of the examined tissues, except for varying degrees of pancreatic acinar atrophy. All other tissues appeared normal. The white and red blood cell values of canavanine-treated rats were also normal following 1, 3, or 6 injections of canavanine, 2.0 or 3.0 g/kg. The results indicated that canavanine induced marked growth inhibition of the rat colon carcinoma. Our experiments also disclosed that further studies must be conducted to optimize the dosing schedule to enhance drug efficacy and to reduce its cumulative toxicity.

Preliminary measurements of the edge magnetic field pitch from 2-D Doppler backscattering in MAST and NSTX-U (invited).

The Synthetic Aperture Microwave Imaging (SAMI) system is a novel diagnostic consisting of an array of 8 independently phased antennas. At any one time, SAMI operates at one of the 16 frequencies in the range 10-34.5 GHz. The imaging beam is steered in software post-shot to create a picture of the entire emission surface. In SAMI's active probing mode of operation, the plasma edge is illuminated with a monochromatic source and SAMI reconstructs an image of the Doppler back-scattered (DBS) signal. By assuming that density fluctuations are extended along magnetic field lines, and knowing that the strongest back-scattered signals are directed perpendicular to the density fluctuations, SAMI's 2-D DBS imaging capability can be used to measure the pitch of the edge magnetic field. In this paper, we present preliminary pitch angle measurements obtained by SAMI on the Mega Amp Spherical Tokamak (MAST) at Culham Centre for Fusion Energy and on the National Spherical Torus Experiment Upgrade at Princeton Plasma Physics Laboratory. The results demonstrate encouraging agreement between SAMI and other independent measurements.

Modifications to the synthetic aperture microwave imaging diagnostic.

The synthetic aperture microwave imaging diagnostic has been operating on the MAST experiment since 2011. It has provided the first 2D images of B-X-O mode conversion windows and showed the feasibility of conducting 2D Doppler back-scattering experiments. The diagnostic heavily relies on field programmable gate arrays to conduct its work. Recent successes and newly gained experience with the diagnostic have led us to modify it. The enhancements will enable pitch angle profile measurements, O and X mode separation, and the continuous acquisition of 2D DBS data. The diagnostic has also been installed on the NSTX-U and is acquiring data since May 2016.

Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition.

Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR(+) ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR(+) B-ALL.

Pilot study of low-dose interleukin-11 in patients with bone marrow failure.

PURPOSE: Interleukin-11 (IL-11) is a thrombopoietic cytokine that attenuates postchemotherapy thrombocytopenia at doses of 50 microg/kg/d subcutaneously. Very little is known about the activity of IL-11 in patients with bone marrow failure states. PATIENTS AND METHODS: Our preliminary experience with IL-11 at doses of 50 microg/kg/d suggested that patients with bone marrow failure developed significant peripheral and pulmonary edema after the prolonged dosing necessary for treating these conditions. We, therefore, initiated a study of low-dose IL-11 (starting dose, 10 microg/kg/d). RESULTS: Sixteen patients were assessable for response. Six patients had diploid cytogenetics; the others had a variety of chromosomal abnormalities. Six (38%) of 16 patients showed a platelet response to IL-11, and two had a multilineage response (to IL-11 alone, n = 1; to IL-11 plus G-CSF and erythropoietin, n = 1). The median increase in peak platelet counts was 95 x 10(9)/L above baseline in the responders (range, increase of 55 x 10(9)/L to 130 x 10(9)/L above baseline). Responders included five of 11 patients with myelodysplasia and one of four patients with aplastic anemia. Response durations were 12, 13, 14+, 25, 30, and 30+ weeks. Side effects of IL-11 were mild (peripheral edema, n = 7; conjunctival injection, n = 7; myalgia, n = 1; all grade 1). Seven patients had no side effects. CONCLUSION: Our pilot study suggests that administration of low-dose IL-11 (10 microg/kg/d) can raise platelet counts without significant toxicity in selected thrombocytopenic patients with bone marrow failure.