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Purpose:Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein.Patients and Methods:Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel.Results:The RP2D was established as ceralasertib 240 mg BD days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0–51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0–5.8), the median duration of response was 9.9 months (95% CI, 3.7–23.2), and the mOS was 7.4 months (95% CI, 5.7–11.9).Conclusions:Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.See related commentary by Ashworth, p. 4667

Supplementary Table 1. Treatment Outcomes for individual trial participants and dose cohort (N=57)

Supplementary Figure 1. Single dose ceralasertib PK. PK from patients in cohorts 1 to 4 was in line with the PK model predictions (shadowed area) built with data from other studies. Supplementary Figure 2. ATM protein expression by IHC in patients with melanoma. Supplementary Figure 3. ctDNA clearance of mutant alleles from a responder to ceralasertib+paclitaxel; example 1. ctDNA was sequenced at baseline, day 61 and day 403. Re-staging scans were performed at day 63, day 117, intermediate days at approximate 8 week intervals (not shown) and day 426 (at the time of PD). The stream plot shows rapid clearance of the mutant alleles in line with RECIST v1.1 response. Supplementary Figure 4. CtDNA clearance of mutant alleles from a responder to ceralasertib+paclitaxel; example 2. ctDNA was sequenced at baseline, day 24, day 52 and day 241. Re-staging scans were performed at day 46, day 98, intermediate days at approximate 8 week intervals (not shown) and day 235. The stream plot shows rapid clearance of the mutant alleles prior to the day of the first re-staging scan which showed a RECIST v1.1 response.

Fluorescence imaging with indocyanine green is increasingly used during lymphedema patient management. However, to date, no guidelines exist on when it should and should not be used or how it should be performed. Our objective was to have an international panel of experts identify areas of consensus and nonconsensus in current attitudes and practices in fluorescence imaging with indocyanine green use during lymphedema surgery patient management.A 2-round Delphi study was conducted involving 18 experts in the use of fluorescence imaging during lymphatic surgery, all asked to vote on 49 statements on patient preparation and contraindications (n = 7 statements), indocyanine green dosing and administration (n = 10), fluorescence imaging uses and potential advantages (n = 16), and potential disadvantages and training needs (n = 16).Consensus ultimately was reached on 40/49 statements, including consistent consensus regarding the value of fluorescence imaging with indocyanine green in almost all facets of lymphedema patient management, including early detection, assessing disease extent, preoperative work-up, surgical planning, intraoperative guidance, monitoring short- and longer-term outcomes, quality control, and resident training. All experts felt it was very safe, while 94% felt it should be part of routine care and that indocyanine green was superior to colored dyes and ultrasound. Nonetheless, there also was consensus that limited high-quality evidence remains a barrier to its widespread use and that patients should still be provided with specific information and asked to sign specific consent for both fluorescence imaging and indocyanine green.Fluorescence imaging with or without indocyanine green appears to have several roles in lymphedema prevention, diagnosis, assessment, and treatment.

BackgroundPrimary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and therapeutics. The defining criteria for one such clinical syndrome, ‘WILD syndrome’ (Warts,Immunodeficiency,Lymphoedema and anogenitalDysplasia), have previously depended on a single case report.Methods and resultsWe present 21 patients (including the first described case) with similar clinical and immunological phenotypes. All had PL affecting multiple segments, with systemic involvement (intestinal lymphangiectasia/pleural or pericardial effusions) in 70% (n=14/20). Most (n=20, 95%) had a distinctive cutaneous lymphovascular malformation on the upper anterior chest wall. Some (n=10, 48%) also had hyperpigmented lesions resembling epidermal naevi (but probably lymphatic in origin). Warts were common (n=17, 81%) and often refractory. In contrast to the previous case report, anogenital dysplasia was uncommon—only found in two further cases (total n=3, 14%). Low CD4 counts and CD4:CD8 ratios typified the syndrome (17 of 19, 89%), but monocyte counts were universally normal, unlikeGATA2deficiency.ConclusionWILD syndrome is a previously unrecognised, underdiagnosed generalised PL syndrome. Based on this case series, we redefine WILD as ‘Warts,Immunodeficiency, andLymphaticDysplasia’ and suggest specific diagnostic criteria. The essential criterion is congenital multisegmental PL in a ‘mosaic’ distribution. The major diagnostic features are recurrent warts, cutaneous lymphovascular malformations, systemic involvement (lymphatic dysplasia), genital swelling and CD4 lymphopaenia with normal monocyte counts. The absence of family history suggests a sporadic condition, and the random distribution of swelling implicates mosaic postzygotic mutation as the cause.

Research in autonomous driving for unstructured environments suffers from a lack of semantically labeled datasets compared to its urban counterpart. Urban and unstructured outdoor environments are challenging due to the varying lighting and weather conditions during a day and across seasons. In this paper, we introduce TAS500, a novel semantic segmentation dataset for autonomous driving in unstructured environments. TAS500 offers fine-grained vegetation and terrain classes to learn drivable surfaces and natural obstacles in outdoor scenes effectively. We evaluate the performance of modern semantic segmentation models with an additional focus on their efficiency. Our experiments demonstrate the advantages of fine-grained semantic classes to improve the overall prediction accuracy, especially along the class boundaries. The dataset and pretrained model are available at mucar3.de/icpr2020-tas500., Accepted at International Conference on Pattern Recognition 2020 (ICPR). For the associated project page, see https://www.mucar3.de/icpr2020-tas500/index.html

BACKGROUND: Lymphatic endothelial cells from primary lymphedema skin have never been cultured nor characterized. A subgroup of patients with primary lymphedema undergo surgery to bring about an improvement in their quality of life. The aim of this study was to culture and characterize LECs from the skin of these patients. METHODS AND RESULTS: Lymphatic endothelial cells were isolated and cultured from the skin of patients with primary lymphedema and from normal skin. The isolated cells were compared in their ability to form microvascular networks in a three-dimensional culture medium, and in their response to treatment with vascular endothelial growth factors A, C, and D. Whole tissue transcriptional profiling was carried out on two pools of isolated lymphatic endothelial cells--one from primary lymphedema skin and the other from normal skin. Lymphatic endothelial cells from primary lymphedema skin form tubule-like structures when cultured in three-dimensional media. They respond in a similar fashion to stimulation with the vascular endothelial growth factors A, C, and D. Comparative analysis between lymphedema tissue and normal tissue (fold change >2) showed differential expression of 2793 genes (5% of all transcripts), 2184 upregulated, and 609 downregulated. Genes involved in cellular apoptosis (vascular endothelial growth inhibitor, zinc finger protein), extracellular matrix turnover (matrix metalloproteinase inhibitor-16), and type IV collagen deposition were upregulated. Various pro-inflammatory genes (interleukin-6, interleukin-8, interleukin-32, E-selectin) were downregulated. CONCLUSION: Cellular adhesion, apoptosis, and increased extracellular matrix turnover play a more prominent role in primary lymphedema than previously thought. In addition, the acute inflammatory response is attenuated as evidenced by the downregulation of various pro-inflammatory genes.This sheds further light on the interplay of the various pathological processes taking place in primary lymphedema.

Lymphatic vessels are essential for the removal of interstitial fluid and prevention of tissue edema. Lymphatic capillaries lack associated mural cells, and collecting lymphatic vessels have valves, which prevent lymph backflow. In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2. We report that Foxc2(-/-) mice show abnormal lymphatic vascular patterning, increased pericyte investment of lymphatic vessels, agenesis of valves and lymphatic dysfunction. In addition, an abnormally large proportion of skin lymphatic vessels was covered with smooth muscle cells in individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4). Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process. Our results indicate that an abnormal interaction between the lymphatic endothelial cells and pericytes, as well as valve defects, underlie the pathogenesis of LD.

Objectives Paramedics routinely make critical decisions about the most appropriate care to deliver in a complex system characterized by significant variation in patient case-mix, care pathways and linked service providers. There has been little research carried out in the ambulance service to identify areas of risk associated with decisions about patient care. The aim of this study was to explore systemic influences on decision making by paramedics relating to care transitions to identify potential risk factors. Methods An exploratory multi-method qualitative study was conducted in three English National Health Service (NHS) Ambulance Service Trusts, focusing on decision making by paramedic and specialist paramedic staff. Researchers observed 57 staff across 34 shifts. Ten staff completed digital diaries and three focus groups were conducted with 21 staff. Results Nine types of decision were identified, ranging from emergency department conveyance and specialist emergency pathways to non-conveyance. Seven overarching systemic influences and risk factors potentially influencing decision making were identified: demand; performance priorities; access to care options; risk tolerance; training and development; communication and feedback and resources. Conclusions Use of multiple methods provided a consistent picture of key systemic influences and potential risk factors. The study highlighted the increased complexity of paramedic decisions and multi-level system influences that may exacerbate risk. The findings have implications at the level of individual NHS Ambulance Service Trusts (e.g. ensuring an appropriately skilled workforce to manage diverse patient needs and reduce emergency department conveyance) and at the wider prehospital emergency care system level (e.g. ensuring access to appropriate patient care options as alternatives to the emergency department).

Background As part of a study examining systemic influences on conveyance decisions by paramedics and potential threats to patient safety, stakeholder workshops were conducted with three Ambulance Service Trusts in England. The study identified seven overarching systemic influences: demand; priorities; access to care; risk tolerance; training, communication and resources. The aim of the workshops was to elicit feedback on the findings and identify perceived areas for future intervention and research. Attendees were also asked to rank the seven threats to patient safety in terms of their perceived importance for future attention. Methods A total of 45 individuals attended across all the workshops, 28 ambulance service staff and 17 service user representatives. Discussions were audio-recorded, transcribed and thematically analysed. A paper based paired comparison approach was used to produce an ordinal ranking to illustrate the relative prioritisation of issues. Analysis included testing for internal consistency and between-rater agreement for this relatively small sample. Findings The two highest ranking priorities were training and development, as well as access to care. The areas for intervention identified represent what attendees perceived as feasible to undertake and relate to: care options; cross boundary working; managing demand; staff development; information and feedback; and commissioning decisions. Perceived areas for research specifically address conveyance decisions and potential threats to patient safety. 17 areas for research were proposed that directly relate to six of the systemic threats to patient safety. Conclusions Feedback workshops were effective in the validation of findings as well as providing an opportunity to identify priorities for future interventions and research. They also facilitated discussion between a variety of Ambulance Service staff and service user representatives. Ongoing collaboration between members of the research team has enabled some of the research recommendations to be explored as part of a mutually agreed research agenda.

BACKGROUND. Obesity is considered a risk factor for the development of breast cancer-related lymphedema of the arm and as a poor prognostic factor in response to lymphedema treatment. The objective of this study was to examine weight reduction as a treatment for breast cancer-related lymphedema. METHODS. Twenty-one women with breast cancer-related lymphedema were randomized either to receive dietary advice for weight reduction or to receive a booklet on general healthy eating. They were monitored for 12 weeks. RESULTS. The primary outcome measure was arm volume at 12 weeks. The results indicated a significant reduction in swollen arm volume at the end of the 12-week period (P = .003) in the intervention weight-reduction group. There was a significant reduction in body weight (P = .02) and body mass index (P = .016) in the weight-reduction group at the end of the 12-week study period. CONCLUSIONS. Weight loss achieved by dietary advice to reduce energy intake can reduce breast cancer-related lymphedema significantly. Cancer 2007. © 2007 American Cancer Society.

Decisions made by ambulance staff are often time-critical and based on limited information. Wrong decisions could have serious consequences for patients but little is known about areas of risk associated with decisions about patient care. We aimed to examine system influences on decision making in the ambulance service setting focusing on paramedic roles.