Stabilized Radiation Pressure Acceleration and Neutron Generation in Ultrathin Deuterated Foils.

Premature relativistic transparency of ultrathin, laser-irradiated targets is recognized as an obstacle to achieving a stable radiation pressure acceleration in the "light sail" (LS) mode. Experimental data, corroborated by 2D PIC simulations, show that a few-nm thick overcoat surface layer of high Z material significantly improves ion bunching at high energies during the acceleration. This is diagnosed by simultaneous ion and neutron spectroscopy following irradiation of deuterated plastic targets. In particular, copious and directional neutron production (significantly larger than for other in-target schemes) arises, under optimal parameters, as a signature of plasma layer integrity during the acceleration.

Development and Validation of a Short Version of the Metric for the Observation of Decision-Making in Multidisciplinary Tumor Boards: MODe-Lite.

BACKGROUND: Evidence-based tools are necessary for scientifically improving the way MTBs work. Such tools are available but can be difficult to use. This study aimed to develop a robust observational assessment tool for use on cancer multidisciplinary tumor boards (MTBs) by health care professionals in everyday practice. METHODS: A retrospective cross-sectional observational study was conducted in the United Kingdom from September 2015 to July 2016. Three tumor boards from three teaching hospitals were recruited, with 44 members overall. Six weekly meetings involving 146 consecutive cases were video-recorded and scored using the validated MODe tool. Data were subjected to reliability and validity analysis in the current study to develop a shorter version of the MODe. RESULTS: Phase 1, a reduction of the original items in the MODe, was achieved through two focus group meetings with expert assessors based on previous research. The 12 original items were reduced to 6 domains, receiving full agreement by the assessors. In phase 2, the six domains were subjected to item reliability, convergent validation, and internal consistency testing against the MODe-Lite global score, the MODe global score, and the items of the MODe. Significant positive correlations were evident across all domains (p < 0.01), indicating good reliability and validity. In phase 3, feasibility and high inter-assessor reliability were achieved by two clinical assessors. Six domains measuring clinical input, holistic input, clinical collaboration, pathology, radiology, and management plan were integrated into MODe-Lite. CONCLUSIONS: As an evidence-based tool for health care professionals in everyday practice, MODe-Lite gives cancer MTBs insight into the way they work and facilitates improvements in practice.

Analysing Breast Cancer Multidisciplinary Patient Management: A Prospective Observational Evaluation of Team Clinical Decision-Making.

BACKGROUND: Multidisciplinary team (MDT)-driven cancer care is a mandatory UK national policy, widely used globally. However, few studies have examined how MDT members make decisions as a team. We report a single-centre prospective study on team working within breast cancer MDT. METHODS: This was a prospective observational study of 10 breast MDT meetings (MDM). Trained clinical observer scored quality of presented information and disciplinary contribution to case reviews in real time, using a validated tool, namely Metric for the Observation of Decision-Making. Data were analysed to evaluate quality of team working. RESULTS: Ten MDMs were observed (N = 346 patients). An average of 42 patients were discussed per MDM (range: 29-51) with an average 3 min 20 s (range: 31 s-9 min) dedicated to each patient. Management decision was made in 99% of cases. In terms of contribution to case reviews, breast care nurses scored significantly (p < 0.05) lower (M = 1.79, SD = 0.12) compared to other team members (e.g. surgeons, M = 4.65; oncologists, M = 3.07; pathologists, M = 4.51; radiologists, M = 3.21). Information on patient psychosocial aspects (M = 1.69, SD = 0.68), comorbidities (M = 1.36, SD = 0.39) and views on treatment options (M = 1.47, SD = 0.34) was also significantly (p < 0.05) less well represented compared to radiology (M = 3.62, SD = 0.77), pathology (M = 4.42, SD = 0.49) and patient history (M = 3.91, SD = 0.48). CONCLUSION: MDT evaluation via direct observation in a meeting is feasible and reliable. We found consistent levels of quality of information coverage and contribution within the team, but certain aspects could be improved. Contribution to patient review resides predominantly with surgeons, while presented patient information is largely of biomedical nature. These findings can be fed to cancer MDTs to identify potential interventions for improvement.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

Multidisciplinary cancer team meeting structure and treatment decisions: a prospective correlational study.

BACKGROUND: Anecdotally, organizational factors appear to have an effect on the quality of decision-making in the multidisciplinary team (MDT) meeting. We assess the effect of the number of team-members present, number and order of cases, and the timing of meetings on the process of decision-making in MDT meetings. METHODS: Between December 2009 and January 2010, data were prospectively collected on treatment decisions, meeting characteristics, quality of information, and teamworking for all cases discussed at a London-based MDT meeting. Variables measured using a validated assessment tool (MDT MODe) and correlational analyses were performed. RESULTS: Treatment decisions were reached in 254 of 298 (85%) cases. Cases toward the end of meetings were associated with lower rates of decision-making, information quality, and teamworking (r = -0.15 to -0.37). Increased number of cases per meeting and team members in attendance were associated with better information and teamworking (r = 0.29-0.43). More time per case was associated with improved teamworking (r = 0.16). A positive correlation was obtained between ability to reach decisions and improved information and teamworking (r = 0.36-0.54; all P ≤ 0.001). CONCLUSIONS: Organizational factors related to the structure of the MDT meeting are associated with variation in the likelihood of reaching a treatment decision. Further research is required to establish causation and to modify such factors in order to improve the quality of cancer care.

Facilitators and barriers to teamworking and patient centeredness in multidisciplinary cancer teams: findings of a national study.

BACKGROUND: Multidisciplinary teams (MDTs) are the standard means of making clinical decisions in surgical oncology. The aim of this study was to explore the views of MDT members regarding contribution to the MDT, representation of patients' views, and dealing with disagreements in MDT meetings-issues that affect clinical decision making, but have not previously been addressed. METHODS: Responses to open questions from a 2009 national survey of MDT members about effective MDT working in the United Kingdom were analyzed for content. Emergent themes were identified and tabulated, and verbatim quotes were extracted to validate and illustrate themes. RESULTS: Free-text responses from 1,636 MDT members were analyzed. Key themes were: (1) the importance of nontechnical skills, organizational support, and good relationships between team members for effective teamworking; (2) recording of disagreements (potentially sharing them with patients) and the importance of patient-centered information in relation to team decision making; (3) the central role of clinical nurse specialists as the patient's advocates, complementing the role of physicians in relation to patient centeredness. CONCLUSIONS: Developing team members' nontechnical skills and providing organizational support are necessary to help ensure that MDTs are delivering high-quality, patient-centered care. Recording dissent in decision making within the MDT is an important element, which should be defined further. The question of how best to represent the patient in MDT meetings also requires further exploration.

Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases.

The discovery that some melanoma tumours harbour mutations in the BRAF gene (e.g. V600E) and the subsequent development of specific BRAF inhibitors have greatly improved the treatment of metastatic melanoma. Resistance of tumour cells to BRAF inhibitors is reduced by the addition of an MEK inhibitor; both BRAF and MEK inhibitors have been reported to produce a variety of dermatological toxic effects. Benign naevi often harbour BRAF mutations but few reports exist that document the response of naevus cells to BRAF inhibition. We report sarcoidal-type granulomatous inflammation in two patients with metastatic melanoma undergoing treatment with combination BRAF and MEK inhibitor therapy. This inflammation manifested in one patient as a nonspecific papular eruption; in the other, in association with clinical regression of multiple benign-appearing naevi during the course of therapy. The significance of sarcoidal-type inflammation occurring during treatment of metastatic melanoma with a combination of BRAF and MEK inhibitors is unclear. Its association with the clinical regression of benign-appearing naevi suggests a possible exaggerated inflammatory response to degenerating naevus cells in these lesions.

Mutations in MKKS cause Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with locus heterogeneity. None of the 'responsible' genes have previously been identified. Some BBS cases (approximately 10%) remain unassigned to the five previously mapped loci. McKusick-Kaufma syndrome (MKS) includes hydrometrocolpos, postaxial polydactyly and congenital heart disease, and is also inherited in an autosomal recessive manner. We ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa (RP), obesity and polydactyly. The probands were from families unsuitable for linkage because of family size. We found MKKS mutations in four typical BBS probands (Table 1). The first is a 13-year-old Hispanic girl with severe RP, PAP, mental retardation and obesity (BMI >40). She was a compound heterozygote for a missense (1042GA, G52D) and a nonsense (1679TA, Y264stop) mutation in exon 3. Cloning and sequencing of the separate alleles confirmed that the mutations were present in trans. A second BBS proband (from Newfoundland), born to consanguineous parents, was homozygous for two deletions (1316delC and 1324-1326delGTA) in exon 3, predicting a frameshift. An affected brother was also homozygous for the deletions, whereas an unaffected sibling had two normal copies of MKKS. Both the proband and her affected brother had RP, PAP, mild mental retardation, morbid obesity (BMI >50 and 37, respectively), lobulated kidneys with prominent calyces and diabetes mellitus (diagnosed at ages 33 and 30, respectively). A deceased sister (DNA unavailable) had similar phenotypic features (RP with blindness by age 13, BMI >45, abnormal glucose tolerance test and IQ=64, vaginal atresia and syndactyly of both feet). Both parents and the maternal grandfather were heterozygous for the deletions. Genotyping with markers from the MKKS region confirmed homozygosity at 20p12 in both affected individuals.

Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1-5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.

Multidisciplinary team working across different tumour types: analysis of a national survey.

BACKGROUND: Using data from a national survey, this study aimed to address whether the current model for multidisciplinary team (MDT) working is appropriate for all tumour types. PATIENTS AND METHODS: Responses to the 2009 National Cancer Action Team national survey were analysed by tumour type. Differences indicate lack of consensus between MDT members in different tumour types. RESULTS: One thousand one hundred and forty-one respondents from breast, gynaecological, colorectal, upper gastrointestinal, urological, head and neck, haematological and lung MDTs were included. One hundred and sixteen of 136 statements demonstrated consensus between respondents in different tumour types. There were no differences regarding the infrastructure for meetings and team governance. Significant consensus was seen for team characteristics, and respondents disagreed regarding certain aspects of meeting organisations and logistics, and patient-centred decision making. Haematology MDT members were outliers in relation to the clinical decision-making process, and lung MDT members disagreed with other tumour types regarding treating patients with advanced disease. CONCLUSIONS: This analysis reveals strong consensus between MDT members from different tumour types, while also identifying areas that require a more tailored approach, such as the clinical decision-making process, and preparation for and the organisation of MDT meetings. Policymakers should remain sensitive to the needs of health care teams working in individual tumour types.

Development and evaluation of a checklist to support decision making in cancer multidisciplinary team meetings: MDT-QuIC.

BACKGROUND: The quality of decision-making in cancer multidisciplinary team (MDT) meetings is variable, which can result in suboptimal clinical decision making. We developed MDT-QuIC, an evidence-based tool to support clinical decision making by MDTs, which was evaluated by key users. METHODS: Following a literature review, factors important for high-quality clinical decision making were listed and then converted into a preliminary checklist by clinical and safety experts. Attitudes of MDT members toward the tool were evaluated via an online survey, before adjustments were made giving rise to a final version: MDT-QuIC. RESULTS: The checklist was evaluated by 175 MDT members (surgeons = 38, oncologists = 40, specialist nurses = 62, and MDT coordinators = 35). Attitudes toward the checklist were generally positive (P < 0.001, 1-sample t test), although nurses were more positive than other groups regarding whether the checklist would improve their contribution in MDT meetings (P < 0.001, Mann-Whitney U test). Participants thought that the checklist could be used to prepare cases for MDT meetings, to structure and guide case discussions, or as a record of MDT discussion. Regarding who could use the checklist, 70% thought it should be used by the MDT chair, 54% by the MDT coordinator, and 38% thought all MDT members should use it. CONCLUSION: We have developed and validated an evidence-based tool to support the quality of MDT decision making. MDT members were positive about the checklist and felt it may help to structure discussion, improve inclusivity, and patient centeredness. Further research is needed to assess its effect on patient care and outcomes.

Developing and testing TEAM (Team Evaluation and Assessment Measure), a self-assessment tool to improve cancer multidisciplinary teamwork.

BACKGROUND: Cancer multidisciplinary teams (MDTs) are well established worldwide and are an expensive resource yet no standardised tools exist to measure performance. We aimed to develop and test an MDT self-assessment tool underpinned by literature review and consensus from over 2000 UK MDT members about the "characteristics of an effective MDT." METHODS: Questionnaire items relating to all characteristics of MDTs (particularly Leadership and Chairing; Teamworking and Culture; Patient-centred care; Clinical decision-making process; and Organisation and administration during meetings) were developed by an expert panel. Acceptability, feasibility and psychometric properties were tested by online completion of the questionnaire by 23 MDTs from 4 UK NHS Trusts followed by interviews with 74 team members including members from all teams and nonresponders. 10 of the MDTs also completed questionnaires that directly translated each characteristic to an item (for the five domains above) to test content validity. RESULTS: A total of 47 items were created, each rated for agreement on a 5-point scale. A total of 329 (52 %) of 637 team members completed the questionnaire, including representation from medical, nursing and clerical MDT members. Responses correlated well with domain-specific questionnaires (r > 0.67, p = 0.01), most domain-scales had acceptable internal consistency (Cronbach alpha > 0.60), and good item discrimination (majority of items r < 0.20). Team members were positive about its value. CONCLUSIONS: Self-assessment of team performance using this tool may support MDT development.

Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 mutation.

The lifetime risk of developing colorectal cancer (CRC) in Lynch syndrome (LS) carriers is very high. To determine the impact of colonoscopic screening in 54 male and 98 female MSH2 mutation carriers, outcomes were compared with 94 males and 76 females who were not screened. CRC incidence and survival in the screened group were compared to that expected, derived from the non-screened group. To correct for survivor bias, controls were matched for age at entry into screening and also for gender. In males, median age to CRC was 58 years, whereas expected was 47 years (p = 0.000), and median survival was 66 years vs 62 years (p = 0.034). In screened females, median age to CRC was 79 years compared to 57 years in the non-screened group (p = 0.000), and median survival was 80 years compared with expected of 63 years (p = 0.001). Twenty percent of males and 7% of females developed an interval CRC within 2 years of previous colonoscopy. Although colonoscopic screening was associated with decreased CRC risk and better survival, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to 1 year and improving quality of colonoscopy.

Calibration of BAS-TR image plate response to GeV gold ions.

The response of the BAS-TR image plate (IP) was absolutely calibrated using a CR-39 track detector for high linear energy transfer Au ions up to ∼1.6 GeV (8.2 MeV/nucleon), accelerated by high-power lasers. The calibration was carried out by employing a high-resolution Thomson parabola spectrometer, which allowed resolving Au ions with closely spaced ionization states up to 58+. A response function was obtained by fitting the photo-stimulated luminescence per Au ion for different ion energies, which is broadly in agreement with that expected from ion stopping in the active layer of the IP. This calibration would allow quantifying the ion energy spectra for high energy Au ions, which is important for further investigation of the laser-based acceleration of heavy ion beams.

Absolute calibration of Fujifilm BAS-TR image plate response to laser driven protons up to 40 MeV.

Image plates (IPs) are a popular detector in the field of laser driven ion acceleration, owing to their high dynamic range and reusability. An absolute calibration of these detectors to laser-driven protons in the routinely produced tens of MeV energy range is, therefore, essential. In this paper, the response of Fujifilm BAS-TR IPs to 1-40 MeV protons is calibrated by employing the detectors in high resolution Thomson parabola spectrometers in conjunction with a CR-39 nuclear track detector to determine absolute proton numbers. While CR-39 was placed in front of the image plate for lower energy protons, it was placed behind the image plate for energies above 10 MeV using suitable metal filters sandwiched between the image plate and CR-39 to select specific energies. The measured response agrees well with previously reported calibrations as well as standard models of IP response, providing, for the first time, an absolute calibration over a large range of proton energies of relevance to current experiments.

Quality improvement in multidisciplinary cancer teams: an investigation of teamwork and clinical decision-making and cross-validation of assessments.

PURPOSE: Teamworking and clinical decision-making are important in multidisciplinary cancer teams (MDTs). Our objective is to assess the quality of information presentation and MDT members' contribution to decision-making via expert observation and self-report, aiming to cross-validate the two methods and assess the insight of MDT members into their own team performance. MATERIALS AND METHODS: Behaviors were scored using (i) a validated observational tool employing Likert scales with objective anchors, and (ii) a 29-question online self-report tool. Data were collected from observation of 164 cases in five MDTs, and 47 surveys from MDT members (response rate 70%). Presentation of information (case history, radiological, pathological, comorbidities, psychosocial, and patients' views) and quality of contribution to decision-making of MDT members (surgeons, oncologists, radiologists, pathologists, nurses, and MDT coordinators) were analyzed via descriptive statistics and the Jonckheere-Terpstra test. Correlation between observational and self-report assessments was assessed with Spearman's correlations. RESULTS: Quality of information presentation: Case histories and radiology information rated highest; patients' views and comorbidities/psychosocial issues rated lowest (observed: Z = 14.80, P ≤ 0.001; self-report: Z = 3.70, P < 0.001). Contribution to decision-making: Surgeons and oncologists rated highest, nurses and MDT coordinators rated lowest, and others in between (observed: Z = 20.00, P ≤ 0.001; self-report: Z = 8.10, P < 0.001). Correlations between observational and self-report assessments: Median Spearman's rho = 0.74 (range = 0.66-0.91; P < 0.05). CONCLUSIONS: The quality of teamworking and clinical decision-making in MDTs can reliably be assessed using observational and self-report metrics. MDT members have good insight into their own team performance. Such robust assessment methods could provide the basis of a toolkit for MDT team evaluation and improvement.

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. METHODS: Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. RESULTS: 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). CONCLUSIONS: Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

Laser-driven fast electron collimation in targets with resistivity boundary.

We demonstrate experimentally that the relativistic electron flow in a dense plasma can be efficiently confined and guided in targets exhibiting a high-resistivity-core-low-resistivity-cladding structure analogous to optical waveguides. The relativistic electron beam is shown to be confined to an area of the order of the core diameter (50 µm), which has the potential to substantially enhance the coupling efficiency of electrons to the compressed fusion fuel in the Fast Ignitor fusion in full-scale fusion experiments.

Enhanced spatial resolution of Eljen-204 plastic scintillators for use in rep-rated proton diagnostics.

A pixelated scintillator has been designed, fabricated, and tested using a laser-accelerated proton source for use in proton diagnostics at rep-rated laser facilities. The work presented here demonstrates the enhanced spatial resolution of thin, organic scintillators through a novel pixelation technique. Experimental measurements using laser-generated protons incident onto 130 µm-thick scintillators indicate a >20% reduction in the scintillator point spread function (PSF) for the detectors tested. The best performing pixelated detector reduced the ∼200 µm PSF of the stock material to ∼150 µm. The fabrication technique may be tailored to reduce the pixel size and achieve higher spatial resolutions.

Genetic mapping of a locus predisposing to human colorectal cancer.

Genetic linkage analysis was used to determine whether a specific chromosomal locus could be implicated in families with a history of early onset cancer but with no other unique features. Close linkage of disease to anonymous microsatellite markers on chromosome 2 was demonstrated in two large kindreds. The pairwise lod scores for linkage to marker D2S123 in these kindreds were 6.39 and 1.45 at zero recombination, and multipoint linkage with flanking markers resulted in lod scores of 6.47 and 6.01. These results prove the existence of a genetically determined predisposition to colorectal cancer that has important ramifications for understanding and preventing this disease.