Real Benefits For Patients Research Articles

SYST-07 PLASMA MEMBRANE PROFILING REVEALS A TARGETABLE CELL-SURFACE PHENOTYPE OF WNT-MEDULLOBLASTOMA

Abstract WNT-medulloblastoma has an excellent prognosis, with an overall survival rate of 90% among children receiving standard-of-care surgical resection, radiotherapy, and chemotherapy. While curative, this treatment is associated with major, long-term, debilitating side effects. Therefore, it is crucial we develop effective, less toxic therapies for these children. The Gilbertson lab has previously shown that WNT-medulloblastomas are devoid of a Blood-Brain-Barrier (BBB). This disruption allows large molecules such as monoclonal antibodies (mAbs) to penetrate WNT-medulloblastomas. To discover WNT-medulloblastoma specific antigens for mAb targeting, we have first generated bulk and single-cell RNA sequencing profiles of the wild-type and WNT-medulloblastoma-prone mossy-fibre progenitor lineages in the lower rhombic lip, as well as human medulloblastoma patient derived orthotopic xenograft (PDOX) tumours. We next generated plasma membrane proteome profiles of hindbrain germinal zones and WNT-medulloblastomas. Plasma Membrane Profiling (PMP) deploys an isobaric chemical labelling approach -Tandem Mass Tags (TMT) - that allows multiplexing of up to sixteen variables per mass spectrometry experiment and ex vivo TMT-labelling of primary cells. Using this approach, we have mapped the cell surface proteome of our medulloblastoma models. Interrogation of these developmental and tumour data has unmasked WNT-medulloblastoma associated antigens that are specific for prenatal brain and WNT-medulloblastoma, but that are not expressed on critical postnatal tissues. Our workflow integrates multi-omic data sets to uncover a targetable landscape on the surface of WNT-medulloblastoma cells that we have cross-validated with a large cohort of patient RNA sequencing profiles and histological samples of both mouse and human tumours. To translate this dataset to real patient benefit, we are generating high affinity antibodies of these validated cell-surface proteins for assessment in our pre-clinical mouse models. Through our comparative analyses we have additionally identified non-WNT-specific targets and thus aim to expand this approach to identifying targets in other more agressive CNS tumours and brain metastases.

Mild In Vitro Fertilisation

The case for making healthcare more sustainable is becoming increasingly urgent. Medical professionals understand the need to reduce the cost and environmental impact of our work. We also see that being creative in how we plan treatment pathways and communicate with patients can allow us to work sustainably in terms of the resources required, and in tandem, deliver real benefits for patients. Approaches that deliver ‘prevention rather than cure’ and keep medical intervention as minimally invasive as possible are often better for patients, as well as better for the environment. These concepts are particularly pertinent in the field of reproductive and women’s health, where CREATE Fertility specialise in adopting an approach that is friendly and safe. With natural and mild IVF treatment, delivered with lower doses of drugs, CREATE is able to offer women treatment that reduces risks, side effects and the burden of IVF and supports healthier outcomes for mother and baby, while maintaining outcomes. That philosophy of putting patients first and finding a more efficient way to work is at the heart of the foundation of CREATE’s ABC IVF. In the UK, and around the world, access to fertility treatment is not fair or equal. For many women and couples, cost is a major barrier and one that can stop them building the family they want. In the UK, availability of NHStreatment is variable around the country. At the time of its launch, ABC IVF was the UK’s lowest cost IVF provider, offering a lifeline to thousands of patients who would not otherwise have been able to access treatment. In women’s healthcare, alongside education, innovation and research is key, yet in the UK it is acknowledged that historically there has been a ‘male as default’ approach that has affected research and clinical trials 1 . Professor Nargund is committed to helping to work towards the UN’s sustainable development goals three (health and wellbeing), five (gender inequality), ten (reduced inequality) and thirteen (climate action) with s push to provide affordable, accessible, effective and safe fertility treatment, delivered sustainably. The work is far from over and Professor Nargund and her team remain committed to improving the outlook for women’s healthcare.

MDB-06. PLASMA MEMBRANE PROFILING REVEALS A TARGETABLE CELL-SURFACE PHENOTYPE OF WNT-MEDULLOBLASTOMA

Abstract WNT-medulloblastoma has an excellent prognosis, with an overall survival rate of 90% among children receiving standard-of-care surgical resection, radiotherapy, and chemotherapy. While curative, this treatment is associated with major, long-term, debilitating side effects. Therefore, it is crucial we develop effective, less toxic therapies for these children. The Gilbertson lab has previously shown that WNT-medulloblastomas are devoid of a Blood-Brain-Barrier (BBB). This disruption allows large molecules such as monoclonal antibodies (mAbs) to penetrate WNT-medulloblastomas. To discover WNT-medulloblastoma specific antigens for mAb targeting, we have first generated bulk and single-cell RNA sequencing profiles of the wild-type and WNT-medulloblastoma-prone mossy-fibre progenitor lineages in the lower rhombic lip, as well as human medulloblastoma patient derived orthotopic xenograft (PDOX) tumours. We next generated plasma membrane proteome profiles of hindbrain germinal zones and WNT-medulloblastomas. Plasma Membrane Profiling (PMP) deploys an isobaric chemical labelling approach -Tandem Mass Tags (TMT) - that allows multiplexing of up to sixteen variables per mass spectrometry experiment and ex vivo TMT-labelling of primary cells. Using this approach, we have mapped the cell surface proteome of our medulloblastoma models. Interrogation of these developmental and tumour data has unmasked WNT-medulloblastoma associated antigens that are specific for prenatal brain and WNT-medulloblastoma, but that are not expressed on critical postnatal tissues. Our workflow integrates multi-omic data sets to uncover a targetable landscape on the surface of WNT-medulloblastoma cells that we have cross-validated with a large cohort of patient RNA sequencing profiles and histological samples of both mouse and human tumours. To translate this dataset to real patient benefit, we are generating high affinity antibodies of these validated cell-surface proteins for assessment in our pre-clinical mouse models. mAbs directed towards essential receptors may have a therapeutic effect alone, however we will additionally modify mAbs to specifically deliver cytotoxic therapeutics - curing children whilst sparing healthy brain tissue.

Depth of radiographic response (DpR) and time to tumor regrowth (TTG) to predict overall survival following anti-VEGF therapy in recurrent glioblastoma.

2063 Background: Anti-angiogenic therapies, anti-VEGF agents, cause high radiographic response rates due to reduction in vascular permeability. However, we theorized the degree of tumor shrinkage combined with the duration of response might be a more meaningful measure of tumor control and may better reflect real patient benefit. In the current study, we investigate the association between model-derived parameters describing enhancing tumor volumetric dynamics and overall survival (OS) in recurrent glioblastoma treated with anti-VEGF therapy from multiple clinical trials. Methods: N=134 patients treated with bevacizumab +/- irinotecan (BRAIN Trial; NCT00345163) and N=121 patients treated with cabozantinib (XL184-201; NCT00704288) were used to identify potential imaging biomarkers, and N=63 patients in the bevacizumab control arm in a phase III trial (GLOBE Trial; NCT02511405) were used as a validation dataset. Enhancing tumor volumes were estimated using T1 subtraction maps, and a biexponential model was used to model tumor response ( d) and regrowth ( g) rates, as well as time to tumor regrowth ( TTG), the inflection point where the tumor stops shrinking and starts to regrow, and the depth of response ( DpR) after initiation of anti-VEGF therapy for each patient. Log-rank, univariate, and multivariable Cox regression were used to quantify the relationship of these parameters and OS. Results: Optimized thresholds based on maximum hazard ratio occurred at d =0.11 months-1 ( P=5x10-9 training; P=0.0082 validation); g=0.07 months-1 ( P=5x10-20 training; P<0.0001 validation); TTG of 3.8 months ( P=6x10-17training; P<0.0001 validation); and DpR of 11.3% ( P=0.0026 training; P=0.0177 validation). Univariate and multivariable Cox regression using these thresholds and controlling for age and baseline tumor volume confirmed that d, g, TTG, and DpR were all significant and independent predictors of OS in both phase II training and phase III validation datasets ( P<0.01). Additionally, patients exhibiting combinations of a high DpR and/or long TTG showed differential median OS, while patients with favorable diffusion MR phenotypes exhibited a longer OS and significantly longer TTG. Conclusions: Volumetric response and regrowth rates, TTG, and DpR using a biexponential model are significant and independent predictors of OS in recurrent glioblastoma treated with anti-VEGF therapy. Clinical trial information: NCT00345163 ; NCT00704288 ; NCT02511405 .

Robotic pneumonectomy

: Pneumonectomy is an extensive surgical resection sometimes required to treat centrally located lung cancer or tumor infiltrating different pulmonary lobes across fissures. For several years, this surgical procedure was performed by an open approach; more recently, with the advent of less invasive approaches [robotic-assisted surgery and video-thoracoscopic thoracic surgery (VATS)], pneumonectomy has been performed by a minimally invasive approach which showed, compared to a standard thoracotomic approach, a real benefit for patients in terms of minor morbidity, minor hospital stay together with good oncological results. In the last decade we assisted to an increasing adoption of the robotic approach in thoracic surgery mainly due to the features of this technique respect to VATS: a good magnification of the anatomic structures, a best vision, an increased degree of freedom in movements, and absence of the tremor. Many reports on thoracic robotic approach described the technique, the advantages, and reported mainly data and solid experience in performing lobectomy and segmentectomy in early-stage lung cancer but very few centers performed robotic pneumonectomy. We sought to describe in this article our experience in performing robotic pneumonectomy, reporting the indications, the surgical technique, and pros and cons of this less invasive approach.

Bench to bedside: The technology adoption pathway in healthcare

New technologies have the potential to revolutionize the way we manage health and wellbeing now and in the future. But often seen as expensive and difficult to implement, the challenge is to identify the best technology to deliver real patient benefit and support its rapid adoption to help address the funding difficulties faced by all modern healthcare systems. In this paper we consider the traditional linear model of the technology adoption pathway as it pertains to healthcare, look at common challenges faced traversing this path and suggest solutions. In so doing, we recognise the limitations of the linear model and describe our version of a more realistic, non-linear model. Throughout, we will be looking at the key role of the Clinical Engineer to successful healthcare technology adoption based on our experience of supporting medical device products through to adoption and present the key lessons we learnt along the way.

<p>Machine learning techniques in a structural and functional MRI diagnostic approach in schizophrenia: a systematic review</p>

BackgroundDiagnosis of schizophrenia (SCZ) is made exclusively clinically, since specific biomarkers that can predict the disease accurately remain unknown. Machine learning (ML) represents a promising approach that could support clinicians in the diagnosis of mental disorders.ObjectivesA systematic review, according to the PRISMA statement, was conducted to evaluate its accuracy to distinguish SCZ patients from healthy controls.MethodsWe systematically searched PubMed, Embase, MEDLINE, PsychINFO and the Cochrane Library through December 2018 using generic terms for ML techniques and SCZ without language or time restriction. Thirty-five studies were included in this review: eight of them used structural neuroimaging, twenty-six used functional neuroimaging and one both, with a minimum accuracy >60% (most of them 75–90%). Sensitivity, Specificity and accuracy were extracted from each publication or obtained directly from authors.ResultsSupport vector machine, the most frequent technique, if associated with other ML techniques achieved accuracy close to 100%. The prefrontal and temporal cortices appeared to be the most useful brain regions for the diagnosis of SCZ. ML analysis can efficiently detect significantly altered brain connectivity in patients with SCZ (eg, default mode network, visual network, sensorimotor network, frontoparietal network and salience network).ConclusionThe greater accuracy demonstrated by these predictive models and the new models resulting from the integration of multiple ML techniques will be increasingly decisive for early diagnosis and evaluation of the treatment response and to establish the prognosis of patients with SCZ. To achieve a real benefit for patients, the future challenge is to reach an accurate diagnosis not only through clinical evaluation but also with the aid of ML algorithms.

Rational use of diagnostic tests for clinical decision making.

To assist clinicians to make adequate interpretation of scientific evidence from studies that evaluate diagnostic tests in order to allow their rational use in clinical practice. This is a narrative review focused on the main concepts, study designs, the adequate interpretation of the diagnostic accuracy data, and making inferences about the impact of diagnostic testing in clinical practice. Most of the literature that evaluates the performance of diagnostic tests uses cross-sectional design. Randomized clinical trials, in which diagnostic strategies are compared, are scarce. Cross-sectional studies measure diagnostic accuracy outcomes that are considered indirect and insufficient to define the real benefit for patients. Among the accuracy outcomes, the positive and negative likelihood ratios are the most useful for clinical management. Variations in the study's cross-sectional design, which may add bias to the results, as well as other domains that contribute to decreasing the reliability of the findings, are discussed, as well as how to extrapolate such accuracy findings on impact and consequences considered important for the patient. Aspects of costs, time to obtain results, patients' preferences and values should preferably be considered in decision making. Knowing the methodology of diagnostic accuracy studies is fundamental, but not sufficient, for the rational use of diagnostic tests. There is a need to balance the desirable and undesirable consequences of tests results for the patients in order to favor a rational decision-making approach about which tests should be recommended in clinical practice.

Education care in patients with psychiatric disorders in France: Psychoeducation or therapeutic patient education?

Psychoeducation and therapeutic patient education can be effectively included in treatments for patients with psychiatric disorders. These two effective educational therapies have the common purpose of improving disorder-related morbidity, compliance with treatment and patients' quality of life. While they have different methods of application, both teach patients to play an active role in their own care. However, it is still critical to combine them for care of patients with psychiatric and addiction disorders in a manner that allows for specificity. To do this, the differences between psychoeducation and therapeutic patient education must be considered, and their potential for the management of patients with psychiatric and addiction disorders must be determined. In our article, we review the literature concerning therapeutic education programs for patients and discuss the literature based on the experiences of psychiatrists trained in these therapies. Despite rather nonrestrictive guidelines, and after reviewing numerous studies, we found that psychoeducation seems to be rarely used in psychiatry. The use of therapeutic patient education programs for psychiatric patients has doubled in four years but still accounts for less than 4% of validated programs in France. Only 154 programs were developed in 1175 public psychiatric facilities in 2016. Therapeutic patient education has a legal framework and recommendations, which make it suitable for inclusion in care and in the training of care providers. The rigor in the development of therapeutic patient education programs and the requirement for training and financial support reinforce the need for their establishment in healthcare institutions. As such, they could help to modify professional practices and the culture of care in mental health fields. There is a place for therapeutic patient education in psychiatry as it provides a real benefit for patients. It could modify care practices and costs, and is suitable for patients with psychiatric or addiction disorders by helping them play an active role in their care, thereby improving treatment outcomes and quality of life.

Expert Panel Discusses the Importance of Systems Medicine

Expert Panel Discusses the Importance of Systems Medicine

Upcoming translational challenges for uveal melanoma.

The past few years have witnessed major advances in the understanding of the molecular landscape of uveal melanoma (UM). The discovery of a mutational background that is completely different from the one of skin melanoma has granted to UM a stand-alone status. The absence of effective therapy for metastatic disease offers now a chessboard for targeted therapy but at the same time urges preclinical science to develop accordingly, to guide the use of economical resources to the best profit of patients. This review describes the current knowledge on the biology of this disease and discusses the challenges that must be undertaken to translate this knowledge into real benefit for patients.

Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias

BackgroundThe effectiveness of intra-articular hyaluronic acid (IAHA) injection for knee osteoarthritis (KOA) is debated.ObjectivesTo evaluate the effect of IAHA for patients with KOA by analysing data from trials of IAHA...

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

There is a need for research to understand and improve health systems for rare diseases in order to ensure that new, efficacious therapies developed through basic and early translational science lead to real benefits for patients. Such research must (i) focus on appropriate patient-oriented outcomes, (ii) include robust study designs that can accommodate real-world decision priorities, and (iii) involve effective stakeholder-engagement strategies. For transformative therapies, study outcomes will need to shift toward longer-term goals in recognition of success in preventing catastrophic outcomes. For incremental therapies, outcomes should be selected in recognition of the impact of care on quality of life for patients and families. To generate new evidence, we suggest that hybrid study designs integrating elements of practice-based observational research and pragmatic trials hold the most promise for addressing priorities such as minimizing bias, accounting for cointerventions, identifying long-term impacts, and considering clinical heterogeneity. To effectively engage with stakeholders, a knowledge exchange infrastructure is needed to foster collaboration among patients with rare diseases and their families, health-care providers, researchers, and policy decision makers. A key priority for these groups must be collaboration toward a shared understanding of the outcomes that are of most relevance to the facilitation of patient-centered care.

Percutaneous Coronary Interventions for Chronic Total Occlusions: More Benefit for the Patient or for the Interventionist's Ego?

Chronic total occlusions (CTOs) represent a common lesion subset observed in patients who undergo coronary angiography. During the past decade, the interest of the interventionist community in CTOs has exponentially grown with fast advancement in dedicated equipment and techniques, which has resulted in high rates of procedural success and low rates of complications. Although different observational studies have shown that CTO revascularization was associated with good clinical outcome, its real benefit for patients remains to be determined, particularly in the absence of randomized trials. In addition, compared with non-CTO lesions, the American and European guidelines downgraded percutaneous coronary intervention in the setting of CTOs. In this viewpoint, we try to identify patients who would benefit from CTO recanalization, and discuss the issues that might improve the appropriateness of CTO percutaneous coronary intervention.

Anxious wait for patients and big pharma

Anxious wait for patients and big pharma

P74 Follow-up Of Lung Cancer Patients Post Surgery

Rationale Over 50% of patients undergoing surgery for lung cancer die from recurrence or a second episode of lung cancer within 5 yrs.1 There is little evidence based guidelines regarding the follow up of post surgical resection. Most follow up with physical examination and plain radiographs. Few recommend follow up with CTs. Within Mid Yorkshire NHS trust, patients are followed up post-operatively for 5 years. In the initial 2 years CTs are performed at 3, 12 and 24 months and chest radiographs at 3 to 6 monthly intervals for 5 years. The aim of this study was to assess the benefits of cross sectional imaging. Methods A retrospective analysis was conducted of 109 patients undergoing surgery for lung cancer within Mid Yorkshire NHS hospital trust between 2009 and 2012. Results 109 patients were included in total (42% female). Types of surgery were lobectomy (80%), wedge resection (10%) and pneumonectomy (10%) Recurrence occurred in 37% of patients (85% pulmonary). 60% of recurrences were adenocarcinomas and 33% squamous cell carcinomas. The majority of patients were asymptomatic (78%). Dyspnoea was the most frequent symptom (19%). The most commonly staged tumour was 1B (pT2A 53%, pN0 50%). 53% of recurrences were identified at the 3 month post-operative CT, 8% at 6 months, 28% at 12 months and 3% at 24 months. Chest radiographs identified recurrence at 6 (3%), 9 (3%) 18 (3%) and 21 months (3%). Total mortality within the recurrence group was 25%. 54% of patients had treatment with curative intent (surgery; 23% radiotherapy; 18% chemotherapy 8%; chemoradiotherapy 5%). 23% received palliative treatment, chemotherapy/ radiotherapy. Conclusions There are substantial benefits of imaging in identifying recurrences in cancer patients. The post-operative CT imaging at 3 and 12 months is advantageous as they identified 53% and 28% of the recurrences respectively. However, the benefit of regular chest radiographs and surveillance CT at 24 months is questionable as they were less effective. Reference Egerman U, Jaeggi K, Habicht JM, Perruchoud AP, Dalugen P, Soler M. Regular follow-up after curative resection of nonsmall cell lung cancer: a real benefit for patients? Eur Respir J 2002 Mar;19(3):464–8

The Effects of Palliative Chemotherapy in Metastatic Colorectal Cancer Patients With an ECOG Performance Status of 3 and 4

BackgroundAlthough chemotherapy is standard for patients with mCRC and ECOG PS of 0/1, the real benefit for patients with ECOG PS > 2 remains uncertain, because they are generally excluded from clinical trials. Our objectives were to compare the survival and safety of ECOG PS 3/4 patients who were administered chemotherapy with those who received BSC only. Patients and MethodsWe retrospectively analyzed all consecutive mCRC patients who started first-line chemotherapy at our institution in a 4-year period. A multivariable Cox regression model was used to adjust for prognostic factors and logistic regression, to identify predictive factors of Grade 3/4 toxicity. ResultsFrom June 2008 to June 2012, 240 consecutive patients were included: 100 (41.7%) had an ECOG PS of 0/1, 75 (31.3%) ECOG PS of 2, and 65 (27%) ECOG PS of 3/4. Median survival for patients treated with chemotherapy was 18.4 months for patients with ECOG PS of 0/1, 10.8 months for those with ECOG PS of 2, and 6.8 months for patients with ECOG PS of 3/4. Among those with ECOG PS of 3/4, chemotherapy use led to a nonsignificant survival gain (median, 6.8 vs. 2.3 months for BSC; P = .13). Factors significantly associated with worse survival in an adjusted analysis were right-sided tumors (hazard ratio [HR], 2.97; P = .005) and ECOG PS status (ECOG PS 2 vs. 0/1; HR, 1.67; P = .025, and ECOG PS 3/4 vs. 0/1; HR, 2.67; P < .0001). The rate of Grade ≥ 3 toxicities during the first cycle did not differ significantly across ECOG groups; likely because 40% of ECOG PS 3/4 patients received upfront dose-reduced therapy. The rates of treatment-related hospitalization were similar across all ECOG groups. All deaths were disease-associated. ConclusionOur retrospective study suggests that chemotherapy might benefit selected mCRC patients with poor PS. With up-front dose reduction and close monitoring for toxicity, the risk of serious adverse events is minimized.

Patient safety and beyond: what should we expect from microneedle arrays in the transdermal delivery arena?

Research based upon microneedle (MN) arrays has intensified recently. While the initial focus was on biomolecules, the field has expanded to include delivery of conventional small-molecule drugs whose water solubility currently precludes transdermal administration. Much success has been achieved, with peptides, proteins, vaccines, antibodies and even particulates delivered by MN in therapeutic/prophylactic doses. Recent innovations have focused on enhanced formulation design, scalable manufacture and extension of exploitation to minimally invasive patient monitoring, ocular delivery and enhanced administration of cosmeceuticals. Only two MN-based drug/vaccine delivery products are currently marketed, partially due to limitations with older MN designs based upon silicon and metal. Even the more promising polymeric MN have raised a number of regulatory and manufacturability queries that the field must address. MN arrays have tremendous potential to yield real benefits for patients and industry and, through diligence, innovation and collaboration, this will begin to be realised over the next 3-5 years.

Current Readings: Status of Robotic Cardiac Surgery

Robotic surgery has been applied to various fields in cardiac surgery. Despite excellent results published in the literature, critics have questioned procedure reproducibility, increased cost, and the real patient benefit. We reviewed 5 recent articles to show that robotic cardiac surgery likely will play an important role in the new era of cardiac surgery.

First year prognosis of patients hospitalized in an acute geriatric ward with a known dementia or newly diagnosed

In France, only a third of demented patients have an established diagnostic of dementia. Hospitalization is often an opportunity to perform a diagnostic of dementia. Real benefits for patients of such a diagnostic process are unknown. The objective of the study was to observe prognosis of elderly patients hospitalized in geriatric courses in terms of mortality, hospitalization rate and entry into an institution. This was a monocentric prospective study with a one-year follow-up of 90 patients hospitalized in an acute geriatric ward with either dementia known by general practitioner, either diagnosed during the hospitalization according to DSM IV criteria. A one year follow-up by phone has been conducted. From a consecutive set of 159 inpatients for 18 weeks, we included in this study 49 patients with a known dementia (group 1, mean age 85.7±4.6 years, mean Mini-mental state examination (MMSE) score 12.4±6.2) and 41 patients with dementia diagnosed during hospitalization (group 2, mean age 88.4±6.4 years, mean MMSE score 16.1±6.5). Differences between the two groups were significant for age (p<0.03) and MMSE score (p<0.02). One-year mortality rate was near 30% in the 2 groups. Rate of institutionalization was 33% in group 1 and 49% in group 2 (not statistically significant). There was a significant difference in number of days spent at home between group 1 and group 2, respectively 190.9±159.9 days vs 111.1±148.1 days (p<0.03). Demented patients previously diagnosed lived longer at home at one year than patients newly diagnosed. These results tend to support the diagnosis of dementia in very elderly patients with multiple comorbidities. Conditions of living at home, in particular the quality of life, should be the object of further studies.