The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation ...of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.
ObjectivesTo improve the experiences of people from diverse cultural backgrounds, there has been an increased emphasis on strengthening cultural awareness and competence in healthcare contexts. The ...aim of this focus-group based study was to explore how professionals in cancer care experience their encounters with migrant cancer patients with a focus on how they work with cultural diversity in their everyday practice, and the personal, interpersonal and institutional dimensions therein.DesignThis paper draws on qualitative data from eight focus groups held in three local health districts in major metropolitan areas of Australia. Participants were health professionals (n=57) working with migrants in cancer care, including multicultural community workers, allied health workers, doctors and nurses. Focus group discussions were audio recorded and transcribed in full. Data were analysed using the framework approach and supported by NVivo V.11 qualitative data analysis software.ResultsFour findings were derived from the analysis: (1) culture as merely one aspect of complex personhood; (2) managing culture at the intersection of institutional, professional and personal values; (3) balancing professional values with patient values and beliefs, and building trust and respect; and (4) the importance of time and everyday relations for generating understanding and intimacy, and for achieving culturally competent care.ConclusionsThe findings reveal: how culture is often misconstrued as manageable in isolation; the importance of a renewed emphasis on culture as interpersonal and institutional in character; and the importance of prioritising the development of quality relationships requiring additional time and resource investments in migrant patients for enacting effective intercultural care.
What does migrancy mean for personhood, and how does this flow through caring relations? Drawing on life history interviews and photo elicitation with 43 people who identify as migrants and live with ...cancer, here we argue for the significance of recognising complex personhood as it inflects illness and care. Drawing on social science theory around temporalities, moralities and belonging, we assemble a series of cross-cutting themes at the intersection of personhood and care; relations that transcend cultural origins yet are vividly illustrated in relation to migrant pasts. In seeking a multidimensional view of personhood, we attend to the intersecting layers of complexity that make up care in this context vis-a-vis an emphasis on forms of difference, vulnerability and otherness. In this way, we develop an approach to personhood and care that broadens the lens on migrancy and cancer, but also, one that speaks to the importance of recognition of complexity and how it shapes care more generally.
The neurotrophic tyrosine kinase receptor type 2 (Ntrk2, also known as TrkB) and its ligands brain derived neurotrophic factor (Bdnf), neurotrophin-4 (NT-4/5), and neurotrophin-3 (NT-3) are known ...primarily for their multiple effects on neuronal differentiation and survival. Here, we provide evidence that Ntrk2 plays a role in the pathologic remodeling of the spleen that accompanies chronic infection. We show that in Leishmania donovani-infected mice, Ntrk2 is aberrantly expressed on splenic endothelial cells and that new maturing blood vessels within the white pulp are intimately associated with F4/80(hi)CD11b(lo)CD11c(+) macrophages that express Bdnf and NT-4/5 and have pro-angiogenic potential in vitro. Furthermore, administration of the small molecule Ntrk2 antagonist ANA-12 to infected mice significantly inhibited white pulp neovascularization but had no effect on red pulp vascular remodeling. We believe this to be the first evidence of the Ntrk2/neurotrophin pathway driving pathogen-induced vascular remodeling in lymphoid tissue. These studies highlight the therapeutic potential of modulating this pathway to inhibit pathological angiogenesis.
Purpose To determine whether a virtual reality (VR) arthroscopy simulator or benchtop (BT) arthroscopy simulator showed superiority as a training tool. Methods Arthroscopic novices were randomized to ...a training program on a BT or a VR knee arthroscopy simulator. The VR simulator provided user performance feedback. Individuals performed a diagnostic arthroscopy on both simulators before and after the training program. Performance was assessed using wireless objective motion analysis and a global rating scale. Results The groups (8 in the VR group, 9 in the BT group) were well matched at baseline across all parameters ( P > .05). Training on each simulator resulted in significant performance improvements across all parameters ( P < .05). BT training conferred a significant improvement in all parameters when trainees were reassessed on the VR simulator ( P < .05). In contrast, VR training did not confer improvement in performance when trainees were reassessed on the BT simulator ( P > .05). BT-trained subjects outperformed VR-trained subjects in all parameters during final assessments on the BT simulator ( P < .05). There was no difference in objective performance between VR-trained and BT-trained subjects on final VR simulator wireless objective motion analysis assessment ( P > .05). Conclusions Both simulators delivered improvements in arthroscopic skills. BT training led to skills that readily transferred to the VR simulator. Skills acquired after VR training did not transfer as readily to the BT simulator. Despite trainees receiving automated metric feedback from the VR simulator, the results suggest a greater gain in psychomotor skills for BT training. Further work is required to determine if this finding persists in the operating room. Clinical Relevance This study suggests that there are differences in skills acquired on different simulators and skills learnt on some simulators may be more transferable. Further work in identifying user feedback metrics that enhance learning is also required.
Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited ...for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines.
To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied.
Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice.
Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 85.7% vs 2 males 11.8%) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 71.8%) and HS Quality of Life score (13 92.9%), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 69.2%).
An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.
Background. Confidence in one's ability to perform a given task can be a stronger predictor of performance than skill itself. There are currently no measures to assess confidence with manual ...wheelchair use. The objective of this study was to develop and assess the content validity of the Wheelchair Use Confidence Scale (WheelCon-M).
Method. A two-phase mixed-methods design was used. Semi-structured interviews were conducted to generate items, followed by a Delphi survey for item selection. Persons who use a wheelchair, health care professionals, and researchers participated in both phases of the study.
Results. An 84-item WheelCon-M was developed based on the qualitative data. After the Delphi survey, a final 62-item WheelCon-M was composed of the following six areas (number of items per area): Negotiating the Physical Environment (33 items), Activities Performed using a Manual Wheelchair (11 items), Knowledge and Problem Solving (6 items), Advocacy (4 items), Managing Social Situations (5 items) and Managing Emotions (3 items).
Conclusion. This article reports the development and content validation of the WheelCon-M. As a scale to measure confidence with wheelchair use was not available prior to this work, clinicians now have a method of identifying individuals who have low confidence with wheelchair use.
Introduction:
With the advent of complex treatment techniques like volumetric modulated arc therapy, there has been increasing interest in treatment planning technologies aimed at reducing planning ...time. One of these such technologies is auto-planning, which is an automated planning module within Pinnacle3. This study seeks to retrospectively evaluate the dosimetric quality of auto-planning-derived treatment plans as they compare to manual plans for intact prostate, prostate and lymph nodes, and brain treatment sites.
Materials and Methods:
Previous clinical plans were used to generate site-specific auto-planning templates. These templates were used to compare the 3 evaluated treatment sites. Plans were replanned using auto-planning and compared to the clinically delivered plans. For the planning target volume, the following metrics were evaluated: homogeneity index, conformity index, D2cc, Dmean, D2%, D98%, and multiple dose fall-off parameters. For the organs at risk, D2cc, Dmean, and organ-specific clinical metrics were evaluated. Statistical differences were evaluated using a Wilcoxon paired signed-rank test with a significance level of 0.05. Statistically significant (P < 0.05) differences were noted in organs at risk sparing.
Results:
For the prostate, there was as much as 6.8% reduction in bladder Dmean and 23.5% reduction in penile bulb Dmean. For the prostate + lymph nodes, decreases in Dmean values ranging from 4.1% in the small bowel to 22.3% in the right femoral head were observed. For brain, significant improvements were observed in Dmax and Dmean to most organs at risk.
Conclusion:
Our study showed improved organs at risk sparing in most organs while maintaining planning target volume coverage. Overall, auto-planning can generate plans that delivered the same target coverage as the clinical plans but offered significant reductions in mean dose to organs at risk.
Purpose:
The use of radiation as a treatment modality for skin cancer has increased significantly over the last decade with standardized applicators. Utilizing 3D printing, the ability to make ...applicators specifically designed for each patient’s anatomy has become economically feasible. With this in mind it was the aim of this study to determine the dosimetric accuracy of a 3-D printed HDR brachytherapy applicator for the skin.
Methods:
A CT reference image was used to generate a custom applicator based on an anthropomorphic head and neck phantom. To create the applicator a 1cm expansion anteriorly with 0.5cmX0.5cm trenches on the outer surface that were spaced 1cm sup-inf to accommodate standard 6F flexible catheters. The applicator was printed using PLA material using a printrbot simple printer. A treatment plan optimized to deliver a clinically representative volume was created in Oncentra and delivered with a nucletron afterloader. Measurements were made using TLDs and EBT3 gafchromic film that were placed between the applicator and the phantom’s forehead. An additional piece of film was also used to qualitatively asses the dose distribution in the transverse plane. Using a standard vaginal cylinder and bolus, a standardized curve correlating TLD and film exposure-to-radiation dose was established by irradiating film to known doses (200,500,700 cGy) at a 3.5 cm radius distance.
Results:
Evaluated TLDs showed the absolute dose delivered to the skin surface using the 3-D printed bolus was 615cGy±6%, with a mean predicted TPS value in the measured area of 617.5±7%. Additionally, planar dose distributions had good qualitative agreement with calculated TPS isodoses.
Conclusion:
This work demonstrates patient specific 3-D printed HDR brachytherapy applicators for skin cancer treatments are practical and accurate in TPS calculations but additional measurements are needed to verify additional sites and dose at depth.
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