Non-clinical Benefits Research Articles

Quantifying non-clinical outcomes of ultra-hypofractionated breast radiotherapy in Western NSW-A narrative review.

Ultra-Hypofractionated Whole Breast Radiotherapy (U-WBRT) has been proven to be a viable treatment option for breast cancer patients receiving radiation therapy, however, due to its novelty our understanding of its non-clinical benefits is still evolving. With increasing U-WBRT selection during COVID and in rural and regional settings such as the Western New South Wales Local Health District (WNSWLHD), it's important to quantify the savings when compared to other fractionation schedules (e.g. Conventional fractionation (C-WBRT) involving 25 fractions and Moderate hypofractionation (M-WBRT) with 15 fractions.) Using literature sourced from Medline, Embase, Pubmed and reports from relevant websites and organisations this narrative review investigates quantifiable methods of assessing non-clinical benefits of U-WBRT in rural settings according to the triple bottom line philosophy. This review was able to identify a standard set of quantifiable metrics that can compare the non-clinical benefits of various fractionation schedules, with relevance to a rural setting. These include: fractionation trends, financial subsidy, average linear accelerator (Linac) minutes, hospital visits, travel time and distance, Linac energy consumption, travel and Linac carbon emissions. By identifying these metrics, non-clinical benefits between the fractionation schedules can easily be quantified and compared.

What are the challenges in the Health Technology Assessment of genetic and genomic applications?

Abstract Introduction Evaluating genetic/genomic applications (GGAs) is crucial for their implementation in clinical practice but hindered by several issues, such as rapid development processes and unclear benefits. Since these challenges lack comprehensive discussion, this study aims to identify and analyze all barriers emerged in the Health Technology Assessment (HTA) of genetic/genomic tests, filling a gap in the current literature. Methods PubMed, Scopus and Web of Science were searched to identify studies that specifically discussed any challenge or barrier in the HTA evaluation of GGAs. No restriction was applied on evaluation aspect or study type. Challenges/barriers were then grouped into the domains outlined in the EUnetHTA Core Model. A narrative synthesis of the main findings was performed. This study was supported by the EC and MUR- PNRR-M4C2-I1.3 Project PE_00000019 ‘HEAL ITALIA’. Results 19 articles were included: one third involved experts from different countries, and about 50% were author perspectives. Articles either focused on one aspect only (37%) or were more general (47%). The most challenging domain was economic aspects (69%), followed by clinical effectiveness (47%) and social impact (42%), but issues were found in all domains. The lack of a standardized HTA approach, the paucity of evidence on clinical outcomes, the challenges in capturing all health benefits, and the difficulties in identifying the healthcare pathways triggered by the test were consistently mentioned across the HTA domains. Conclusions Our study systematically summarized challenges in the HTA evaluation of GGAS, providing a thorough analysis and categorization of these issues. Various challenges surfaced, notably related to the identification of costs, as well as clinical and non-clinical benefits. There is a need for exhaustive discussion on potential solutions to facilitate the assessment process of these technologies to ultimately foster their implementation in clinical practice. Key messages • There are multiple challenges in the HTA evaluation of genetic and genomic tests in clinical practice that impact every HTA domain. • There is a need for concrete efforts in generating further evidence in relation to the definition of costs and benefits of the healthcare pathways triggered by genetic/genomic applications.

Predictive and pharmacodynamic biomarkers for combination therapy in stage III-IV melanoma: A Simon phase II trial (NCT03999749).

222 Background: The evaluation of biomarkers that predict response and immune-related adverse events (irAEs) is crucial for optimizing melanoma treatment with Immune checkpoint inhibitors (ICIs). We report predictive and pharmacodynamic biomarkers for response and irAEs using high-dimensional flow cytometry in a phase II trial combining nivolumab (3 mg/kg), ipilimumab (1 mg/ml), and the IL-6 receptor inhibitor tocilizumab (4 mg/kg) in unresectable/advanced melanoma patients. Methods: We analyzed serum and blood from melanoma patients at baseline, weeks 7 and 37, categorized them by irAE severity and clinical response. Patients were categorized based on the severity of irAEs (grades 3-5) (TOX), the absence of toxicity or grades 1-2 irAE (NT), clinical benefit (CB), and non-clinical benefit (NCB). Immune monitoring regimen included ELISA for IL-6, gp130, IL-23, osteopontin, and Luminex oncological panel (LXSAHM-22). We employed multi-parametric flow cytometry panels to examine myeloid cells, cytotoxic T cells, and checkpoint protein expression on immune cells. We processed ~1 million PBMCs per sample using various antibodies, with data acquisition performed via Sony’s ID7000 cytometer. The data underwent quality control, normalization PBMCs per patient, concatenation, dimensionality reduction, and clustering in FlowJo. Results: Among the 70 patients administered treatment, we observed a best overall response rate of 57%. Grade 3-5 irAEs occurred in 22% of patients by week 24. Patients manifesting irAEs exhibited notably higher baseline Th17 cell counts (NT=181±18 vs. Tox=311±49, p<0.01) and CD26+ Naive CD4 T-cell populations (NT=5838±801 vs. Tox=9632±1343, p<0.04), suggesting their potential role as predictive markers for toxicity. Additionally, in vitro investigations led us to identify CD26 co-stimulation as a preliminary step in TH17 cell differentiation. Key pharmacodynamic markers included a significant elevation in Treg cells (NCB=1286±71 vs. CB=1492±95, p=0.02) and reduction in serum gp130 levels (NCB=104±5 vs. CB=83±5 ng/ml, p<0.01) at week 7 in addition to IL-6 (NCB=7.5±1.5 vs. CB=4.6±1.1 pg/ml, p<0.01) and osteopontin (NCB=95±15 vs. CB=25±3 ng/ml, p<0.01) by week 37 when compared to baseline. Conclusions: Our findings suggest that Th17 cells can serve as a toxicity biomarker for combination therapy with ipilimumab, nivolumab and tocilizumab. Circulating Treg cells and serum osteopontin have emerged as promising pharmacodynamic biomarkers. Clinical trial information: NCT03999749 .

The Lindsay Leg Club® Well Leg Regime: an evidence review.

This article aims to review the scarce available evidence on the effectiveness of the Well Leg Programme within the Lindsay Leg Clubs in terms of preventing wound recurrence and improving members' wellbeing. It collates the numerical data on members' wounds and healing rates from the Lindsay Leg Club relational database and members' narratives from a qualitative service evaluation of the Lindsay Leg Clubs. Findings of the review suggest that remaining within the Well Leg regime for several months (or longer) after having had a healed ulcer seems to provide further opportunity to prevent recurrence, and may also provide non-clinical benefits, such as improved wellbeing. Based on the review of available published evidence into the effectiveness of the Well Leg regime, we conclude that there is scope for further studies, including a comparison with other existing treatment and prevention protocols.

More to Offer Than Direct Clinical Benefit: FDA's Vaccine Licensure Process Ignores Population Health and Social Determinants of Disease.

The current US Food and Drug Administration (FDA) licensure process underestimates the potential benefits of vaccines at both the individual and population levels by considering only direct clinical outcomes of vaccination. While all approved vaccines do protect the person who takes them from poor clinical outcomes for a specific infectious disease, many vaccines also have the potential to offer measurable, direct nonclinical benefits. For example, coronavirus disease 2019 (COVID-19) vaccinations for school-aged children may prevent school absenteeism. Also, by preventing infection or reducing its length and severity, some vaccines also protect-to some extent-the patient's immediate contacts from contracting the same disease. These nonclinical and population-level benefits are not considered as part of the FDA's current vaccine approval process, but they could be. We argue that the FDA's structured benefit-risk assessment framework, used for vaccine approvals, can and should consider both clinical and nonclinical benefits of vaccination when sufficient evidence exists to make an informed assessment. Including them could incentivize vaccine developers to measure additional vaccination effects, inform population health, and address health inequalities-including inequalities in the social determinants of health.

Potential clinical implications of CD4+CD26high T cells for nivolumab treated melanoma patients

BackgroundNivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients’ outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe off-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will benefit from anti-PD-1 treatment avoiding unwanted side effects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies.MethodsThe frequency distribution of peripheral blood CD26-expressing cells was investigated employing multi-parametric flow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients.ResultsCirculating CD4+CD26high T cells were significantly reduced in melanoma patients compared to healthy subjects (p = 0.001). In addition, a significant association was observed between a low baseline percentage of CD4+CD26high T cells (< 7.3%) and clinical outcomes, measured as overall survival (p = 0.010) and progression-free survival (p = 0.014). Moreover, patients with clinical benefit from nivolumab therapy had significantly higher frequencies of circulating CD4+CD26high T cells than patients with non-clinical benefit (p = 0.004) at 12 months. Also, a higher pre-treatment proportion of circulating CD4+CD26high T cells was correlated with Disease Control Rate (p = 0.014) and best Overall Response Rate (p = 0.009) at 12 months. Interestingly, after 12 weeks (W1) of nivolumab treatment, percentages of CD4+CD26high T cells were significantly higher in comparison with the frequencies measured at W0 (p < 0.0001), aligning the cell counts with the ranges seen in the blood of healthy subjects.ConclusionsOur study firstly demonstrates that peripheral blood circulating CD4+CD26high T lymphocytes represent potential biomarkers whose perturbations are associated with reduced survival and worse clinical outcomes in melanoma patients.

Results of shared learning of a new magnetic seed localisation device – A UK iBRA-NET breast cancer localisation study

IntroductionShared learning is imperative in the assessment and safe implementation of new healthcare interventions. Magnetic seeds (Magseed®) potentially offer logistical benefit over wire localisation for non-palpable breast lesions but few data exist on outcomes comparing these techniques. A national registration study (iBRA-NET) was conducted to collate device outcomes. In order to share learning, thematic analysis was conducted to ascertain early clinical experiences of Magseed® and wire guided localisation and explore how learning events may be applied to improve clinical outcomes. MethodsA qualitative study of 27 oncoplastic surgeons, radiologists and physicians was conducted in January 2020 to ascertain the feasibility and challenges associated with Magseed® versus wire breast localisation surgery. Four focus groups were asked to discuss experiences, concerns and shared learning outcomes which were tabulated and analysed thematically. ResultsThree key themes were identified comparing Magseed® and wire localisation of breast lesions relating to preoperative, intraoperative and postoperative learning outcomes. Percutaneous Magseed® detection, instrument interference and potential seed or wire dislodgement were the most common issues identified. Clinician experience suggested Magseed® index lesion identification was non-inferior to wire placement and improved the patient pathway in terms of scheduling and multi-site insertion. ConclusionsProspective shared learning suggested Magseed® offered additional non-clinical benefits over wire localisation, improving the efficiency of the patient pathway. Recommendations for improving breast localisation technique, appropriate patient selection and clinical practice through shared learning are discussed that may aid other surgeons in the adoption of this relatively new technique.

Future destinations and social inclusionscoping review: how people cured of hepatitis C (HCV) using direct- acting antiviral drugs progress in a new HCV-free world.

BackgroundThere has been a paradigm shift in the treatment of Hepatitis C (HCV) from the interferon-era to direct-acting antiviral (DAA) drugs. Cure of HCV for the key risk group, those with a history of injecting drug use, may provide a range of benefits to an individual’s quality of life that can be additional to that of a clinical cure. The interferon-era provided evidence that cure of HCV can be a turning point for those who use drugs, supporting a recovery journey. There remains a question if DAAs can provide the same opportunity.MethodsWe employed a scoping review methodology to consider the additional non-clinical benefits that HCV cure may provide. We used the theoretical construct of recovery capital to consider how these benefits may support a recovery journey in the DAA-era.ResultsOur search provided 2095 articles, from which 35 were included in the analysis. We developed a thematic synthesis of the non-clinical outcomes identified based on the four over-arching themes of recovery capital: physical, cultural, social and human capital. Our review suggests that identity change is a constituent part of each of the recovery capital domains in relation to HCV treatment.ConclusionWe identified Social Identity Model Of Recovery (SIMOR) as a mechanism through which DAAs may provide non-clinical outcomes to increase recovery capital domains. Further research is required to develop an understanding of the impact a cure of HCV with DAAs may have on identity, overall health and wellbeing and social inclusion to support recovery journeys.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13011-022-00475-1.

Gut microbiota and association with clinical response to anti-PD-1 based immunotherapy combined with chemotherapy in Chinese patients with lung cancer.

e21005 Background: The gut microbiome has been demonstrated to be closely related to not only the occurrence of lung cancer but also its anti-PD-1 based immunotherapy and chemotherapy. There is little characteristic analysis of gut microbiota in Chinese lung cancer patients, and the impact of gut microbiota on combined anti-PD-1 treatment and chemotherapy remains unclear. Methods: Fecal samples from 22 healthy volunteers and advanced-NSCLC 21 patients who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 before and after anti-PD-1 treatment combined with chemotherapy were collected. DNA was extracted from all samples, and the V3-V4 region of the bacterial 16S rRNA gene was PCR-amplified using the Illumina sequencing platform. The study results were analyzed using bioinformatic data. Results: The composition of gut microbes in NSCLC patients and healthy people at the phylum level was roughly similar, with Firmicutes as the main phylum. However, there were significant differences in Beta diversity (P&lt;0.05). The bray_curtis principal coordinate analysis revealed a significant difference in the microbiota between patients before and after combined treatment (P&lt;0.05). According to the RECIST 1.1 criteria, the efficacy of the combination therapy was evaluated. The patients with complete remission, partial remission, or stable efficacy after 6 cycles were the clinical benefit response group (CBR, n=10), and the patients with disease progression in the efficacy evaluation were the non-clinical benefit group (NCB, n=8). The results suggested that the CBR group was enriched in Bifidobacterium_longum, Bifidobacterium_adolescentis, Bifidobacterium_bifidum, and Bifidobacterium_breve at the species level (P&lt;0.05) compared with the NCB group. Compared with the median progression-free survival (mPFS) of patients without Bifidobacterium_breve at baseline, the mPFS of patients with the kind of gut bacteria was significantly prolonged (P&lt;0.001).Specifically, mPFS without Bifidobacterium_breve group was 106 days (95% CI: 37-175), mPFS of the Bifidobacterium_breve group was Not Reached (95% CI: NC-NC). Conclusions: The clinical response of combined anti-PD-1 treatment and chemotherapy in advanced NSCLC patients was closely associated with the gut microbiome,and Bifidobacterium_breve may be effective biomarkers to predict the survival benefit of NSCLC combined therapy, which provided new therapeutic targets for modulating the response to cancer therapy.

Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers

BackgroundThe gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims...

Are operating room distractions, interruptions and disruptions associated with performance and patient safety? A systematic review and meta-analysis.

The operating room is a complex environment in which distractions, interruptions and disruptions (DIDs) are frequent. Our aim was to synthesize research on the relationships between DIDs and (i) operative duration, (ii) team performance, (iii) individual performance and (iv) patient safety outcomes in order to better understand how interventions can be designed to mitigate the negative effects of DIDs. Electronic databases (MEDLINE, Embase, CINAHL and PsycINFO) and reference lists were systematically searched. Included studies were required to report the quantitative outcomes of the association between DIDs and team performance, individual performance and patient safety. Two reviewers independently screened articles for inclusion, assessed study quality and extracted data. A random-effects meta-analysis was performed on a subset of studies reporting total operative time and DIDs. Twenty-seven studies were identified. The majority were prospective observational studies (n = 15) of moderate quality. DIDs were often defined, measured and interpreted differently in studies. DIDs were significantly associated with extended operative duration (n = 8), impaired team performance (n = 6), self-reported errors by colleagues (n = 1), surgical errors (n = 1), increased risk and incidence of surgical site infection (n = 4) and fewer patient safety checks (n = 1). A random-effects meta-analysis showed that the proportion of total operative time due to DIDs was 22.0% (95% confidence interval 15.7-29.9). DIDs in surgery are associated with a range of negative outcomes. However, significant knowledge gaps exist about the mechanisms that underlie these relationships, as well as the potential clinical and non-clinical benefits that DIDs may deliver. Available evidence indicates that interventions to reduce the negative effects of DIDs are warranted, but current evidence is not sufficient to make recommendations about potentially useful interventions.

High-throughput global transcriptional profiling to identify the STAT3 signaling pathway as a potential biomarker for immune checkpoint inhibitor resistance in metastatic/advanced urothelial carcinoma.

474 Background: Advanced/metastatic urothelial carcinoma (UC) is a significant public health burden with median overall survival of 15 months. Although, immune checkpoint inhibitors (ICI) have provided an additional second line treatment option, only 15-40% of patients will respond. There has been much effort in determining the mechanisms of immunotherapy resistance and predictive biomarkers to further improve these treatments. Methods: Pre-treatment genomic sequencing data derived from FFPE samples from the IMVIGOR210 clinical trial (n=298) was accessed for analysis. Briefly it was a single arm phase II clinical trial where advanced/metastatic UC patients refractory to platinum chemotherapy treatment received the ICI atezolizumab. This study has been published with detailed methods (PMID: 28950298). The raw sequencing data was pre-processed using standard QC measures and aligned to the human reference genome (hg38). The resulting outputs were then normalized and processed to generate the gene level counts for differential gene expression (DGE). We did DGE analysis comparing patients who had clinical benefit (CR, PR, SD) vs non-clinical benefit (ie. PD) to atezolizumab. The list of differentially expressed genes were then analyzed using various gene ontology, pathway and systems biology tools (IPA, Enrichr, and X2Kweb). Further subset analysis was done using gene-gene correlations (ie. PD-L1 and STAT3) and clinicopathologic features (eg. gender, race, smoking history). Results: Among the 298 patients in this study, there were 25 with CR, 43 with PR, 63 with SD, and 167 with PD based on clinical response to atezolizumab. Subgroup analysis for CR vs PD patients found that approximately 847 genes were differentially expressed with statistical significance (p ≤ 0.05). IPA analysis for this list of differentially expressed genes found among the top signaling pathways were “primary immunodeficiency” and “sirtuin signaling”. Further subset analysis of 39 genes (p ≤ 0.01) enriched in PD patients using Enrichr and X2kweb found that there was an overrepresentation of STAT3 signaling genes (hypergeometric p-val 6.32x104). Conclusions: Our results found that when the transcriptional profiles of CR vs PD there was differential gene expression in STAT3, primary immunodeficiency, and sirtuin signaling pathways. Of note it has been reported that STAT3 signaling can modulate immune activity and its expression is correlated with poor prognosis in urothelial carcinoma patients. These results warrant a larger study to see if STAT3 signaling is a potential biomarker for ICI resistance. If validated this may indicate that the STAT3 pathway is a potential therapeutic target to overcome ICI resistance and improve the efficacy of these agents.

Abstract 3189: Dynamics characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire during immune checkpoint blockade in cancer

Abstract Introduction: Immune checkpoint blockade (ICB) targeted to CTLA-4, PD-1, and PD-L1 can promote anti-tumor T cell immunity and clinical responses. Tracking the dynamic changes of the T Cell Repertoire (TCR) can reflect the evolution of the immune system in tumor immunotherapy patients, predict the immune response to ICB, and provide high-value information for clinical monitoring of immune function status of cancer patients to make effective clinical decisions. The purpose of this study was to explore the correlation between the peripheral blood TCR repertoire dynamic changes and the immune response of patients with anti-PD-1/PD-L1, and to accurately guide the individualized treatment of immunotherapy. Methods: To comprehensively profile the TCR repertoire, high-throughput sequencing was used to identify hypervariable rearrangements of complementarity determining region 3 (CDR3) of the TCR β chain in peripheral blood samples from 31 advanced solid tumors (most were non-small cell lung cancer) patients treated with immune checkpoint blockade. The blood samples were obtained at baseline of treatment with PD-1/PD-L1 antibody, one to two additional blood samples were obtained during treatment to assess dynamic changes. Shannon-Wiener index was used to identify the diversity of TCR receptor. D50 index was used to account for diversity from the cumulative 50% of the total CDR3s counted in the sample. Results:Shannon-Wiener index at baseline was higher in durable clinical benefit (CB) group than non-clinical benefit (NCB) group (p value = 0.0040) treated with anti-PD1/PD-L1, and significantly increased in CB group ( p value = 0.031). There is a significant correlation between D50 index and clinical benefit during treatment (p value = 0.025). The higher the D50 index, the more likely it is to have durable clinical benefit. Significant difference in progression-free survival (PFS) rate was identified between the D50 high and D50 low groups (p value = 0.037). We validated this result in an independent cohort of NSCLC patients treated with anti-PD1/PD-L1(N=12). Conclusions:This study revealed the dynamic changes of peripheral blood T cell receptor beta-chain repertoire in patients with solid tumors before and during anti-PD1/PD-L1 treatment. This study found that baseline TCR diversity was associated with clinical efficacy. Patients with durable clinical benefit had an increased overall diversity of TCR. The D50 index of the sample during treatment can reflect whether the patient could benefit from anti-PD1/PD-L1 treatment or not, and was a significant prognostic factor for progression-free (PFS). These analyses provide that the peripheral blood TCR repertoire parameters may be useful for prognosis prediction and rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors. Citation Format: Ye Li, Jiaqian Wang, Shengjie Sun, Liangliang Wu, YunXiao Zhang, Guoqing Zhang, Xiaoting Li, Shunchang Jiao. Dynamics characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire during immune checkpoint blockade in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3189.

Abstract 2002: Assessment of the co-localization between PD-L1 positive macrophages and PD-1 positive cells is associated with benefit from PD-1 axis immunotherapy in NSCLC

Abstract Background: The immune checkpoint target PD-L1 has been found to be highly expressed in macrophages and immune cell PD-L1 expression is associated with response to therapy in multiple tumor types. Here, we examine the co-localization between PD-L1 and its receptor PD-1 and especially in macrophages, using interaction analysis to determine whether this co-localization carries the predictive value of PD-1 axis therapy in NSCLC. Methods: We utilized two quantitative immunofluorescence (QIF) platforms (AQUA analysis with the PM2000 platform and InForm analysis with R studio with the Perkin Elmer Polaris Automated Quantitative Pathology Imaging System platform) and assessed the co-localization between PD-L1 and PD-1 both in the stroma and specifically in macrophages by phenotyping each cell. Co-localization was confirmed with high resolution images using confocal microscopy. The PD-1/L1 co-localization was measured using the 5-plex QIF panel including PD-1, PD-L1, CD68, cytokeratin, and DAPI. This panel was performed on three retrospective Yale NSCLC cohorts (1 PD-1 axis immunotherapy treated cohort with 62 cases and 2 non-immunotherapy treated cohort with 457 cases) represented in tissue microarrays. Results: PD-1/L1 co-localization measured by AQUA analysis was significantly associated with response to PD-1 axis therapy using overall survival as the endpoint(P=0.0176) but it was not prognostic in standard of care treated patients. PD-1/L1 co-localization was found to also co-localize with CD68. The co-localized signal of PD-1/L1 was 69.5% in CD68 expressing macrophages and 30.5% in other, CD68 negative cells. Phenotyping by InForm analysis showed that patients with clinical benefit had a significantly shorter distance of nearest neighbor between PD-1 positive cells and PD-L1/CD68 double positive cells as compared to non-clinical benefit group (P=0.03). However, no difference was found between two response groups for the distance between PD-1 positive and PD-L1/cytokeratin double positive cells. Conclusion: The association between PD-1/L1 co-localization and clinical outcome to PD-1 axis therapy infers the biological significance of the immune inhibition release by checkpoint inhibitors. Similar to previous work on melanoma (Johnson et al, CCR 2018), we find that PD-1/L1 co-localization is associated with clinical benefit in NSCLC. In addition, work shows this co-localization predominantly occurs in CD68 positive macrophages and the clinical benefit is associated with CD68 cell expressed PD-L1 instead of cytokeratin cell expressed PD-L1, confirming our previous work showing PD-L1 expression in CD68 positive cells is associated with immune checkpoint inhibitor benefit (Liu et al, CCR 2019). Citation Format: Yuting Liu, Jon Zugazagoitia, Kurt A. Schalper, Roy S. Herbst, David L. Rimm. Assessment of the co-localization between PD-L1 positive macrophages and PD-1 positive cells is associated with benefit from PD-1 axis immunotherapy in NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2002.

The personal utility and uptake of genomic sequencing in pediatric and adult conditions: eliciting societal preferences with three discrete choice experiments

PurposeTo estimate the personal utility and uptake of genomic sequencing (GS) across pediatric and adult-onset genetic conditions. MethodsThree discrete choice experiment (DCE) surveys were designed and administered to separate representative samples of the Australian public. Bayesian D-efficient explicit partial profile designs were used. Choice data were analyzed using a panel error component random parameter logit model. ResultsOverall, 1913 participants completed the pediatric (n=533), symptomatic adult (n=700) and at-risk adult (n=680) surveys. The willingness-to-pay for GS information in pediatric conditions was estimated at $5470–$15,250 (US$3830–$10,675) depending on the benefits of genomic information. Uptake ranged between 60% and 81%. For symptomatic adults, the value of GS was estimated at $1573–$8102 (US$1100–$5671) and uptake at 34–82%. For at-risk adults, GS was valued at $2036–$5004 (US$1425–$3503) and uptake was predicted at 35–61%. ConclusionThere is substantial personal utility in GS, particularly for pediatric conditions. Personal utility increased as the perceived benefits of genomic information increased. The clinical and regulatory context, and individuals’ sociodemographic and attitudinal characteristics influenced the value and uptake of GS. Society values highly the diagnostic, clinical, and nonclinical benefits of GS. The personal utility of GS should be considered in health-care decision-making.

MRI characteristics predict the efficacy of meloxicam treatment in patients with desmoid-type fibromatosis.

This study aimed to determine the clinical significance of MRI characteristics as a possible predictor of responsiveness to meloxicam treatment in patients with desmoid-type fibromatosis (DF). Additionally, it analysed the correlation between CTNNB1 mutation status and signal intensity of MRI. Forty-six patients consecutively treated with meloxicam composed this study. The low-intensity area (LIA) on T2-weighted MRI was determined. We divided patients into two groups based on the efficacy of meloxicam: a clinical benefit group (CB group, including CR: complete response; PR: partial response; and SD: stable disease) and non-clinical benefit group (NB group, including PD: progressive disease). Correlations of the efficacy with LIA and CTNNB1 mutation status with LIA were investigated. In total, 11, 17 and 18 patients showed PR, SD and PD, respectively. The mean LIA ratio before treatment was significantly higher (P<0.001) in the CB group than in the NB group. For predicting the efficacy, sensitivity was 68%, and specificity was 89% when setting the cut-off value as 20% for LIA. Mean changes in the LIA ratio before and after treatment were significantly higher (P=0.01) in the CB group than in the NB group. Mean LIA ratio before treatment was significantly lower (P<0.001) in the S45F mutation group than in the other mutation group. In multivariate analysis, the LIA ratio before treatment was a significant predictor of responsiveness (P=0.02). MRI characteristics were a useful predictor of the efficacy of meloxicam in DF patients. It may be possible to predict the clinical outcome more accurately when combined with other factors, such as CTNNB1 mutantion status.

Applying economic models to estimate local economic benefits of improved coverage of early intervention for psychosis.

Early Intervention Psychosis Services (EIPS) for people experiencing First Episode Psychosis (FEP) offer important clinical and non-clinical benefits over standard care. Similarly, intervention for Clinical High Risk for Psychosis state (CHR-P) can prevent psychosis, ameliorate symptoms and have non-clinical benefits. This study aimed to estimate associated local economic benefits of FEP and CHR-P services compared with standard care. Across four south London boroughs, proportion of annual number of new cases of FEP and CHR-P seen by early intervention services was estimated. Economic modelling conducted for England's mental health strategy was applied to estimate local economic impacts of current and improved service provision. Across four London boroughs during 2011/2012, proportion of 15-34 year olds with FEP seen by EIPS was 100.2% assuming 80/100 000 annual incidence whereas proportion with CHR-P seen by CHR-P services was 4.1% assuming 200/100 000 annual incidence. Application of economic modelling suggests that provision of EIPS to reach all new FEP cases each year would free up resources of £13.1m over 10 years including £2.0m to National Health Service (NHS) after the first year. Scaling up to reach all new CHR-P cases each year would free up resources of £19.7m over 10 years with an estimated 10-year cost of implementation gap for each 1 year cohort of £18.9m. An earlier related briefing resulted in increased funding for EIPS and new CHR-P services despite overall cuts to mental health services. Estimation of local economic impacts of FEP and CHR-P services was associated with improved investment in such services.

Caring and curing: Considering the effects of hepatitis C pharmaceuticalisation in relation to non-clinical treatment outcomes

BackgroundThe development of simplified and effective hepatitis C (HCV) pharmaceuticals enables treatment scale up among the most marginalised. This potentiates a promise of viral elimination at the population level but also individual level clinical and non-clinical benefits. Reports of transformative non-clinical outcomes, such as changes in self-worth and substance use, are primarily associated with arduous interferon-based treatments that necessitate intensive care relationships. We consider the implications of simplified treatment provision in the era of direct acting antivirals (DAAs) for the realisation of non-clinical benefits. MethodsWe draw on qualitative data from ethnographic observations and longitudinal interviews with people receiving (n = 22) and providing (n = 10) HCV treatment in London during a transition in HCV biomedicine. First generation DAAs in conjunction with interferon were standard of care for most of this time, with the promise of simplified treatment provision on the horizon. FindingsPatient accounts of care accentuate the transformative value of interferon-based HCV treatment derived through non-clinical benefits linked to identity and lifestyle change. Such care is constituted as extending beyond the virus and its biomedical effects, with nurse specialists positioned as vital to this care being realised. Provider accounts emphasise the increased pharmaceuticalisation of HCV treatment; whereby care shifts from the facilitation of therapeutic relationships to pharmaceutical access. ConclusionHCV care in the interferon-era affords identity transformations for those receiving and providing treatment. Biomedical promise linked to the increasing pharmaceuticalisation of HCV treatment has disruptive potential, shifting how care is practised and potentially the realisation of non-clinical treatment outcomes.

A Survey of the Non-clinical Benefits of EBVM

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;This study aims to add non-clinical benefits to the virtues for adopting Evidence-based Veterinary Medicine (EBVM). The objective is to quantify the commercial benefits of EBVM through an online survey of veterinary professionals, giving clear indications of the key areas of non-clinical benefits of EBVM. Further, the study aims to outline barriers to the wider implementation of EBVM and find preferred ways of overcoming those barriers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; A PICO-based literature review (Hauser and Jackson, 2016) found that while there are some papers suggesting a link between the practice of EBVM and better non-clinical benefits such as client satisfaction, a single study, focusing on the non-clinical benefits of EBVM, had yet to be conducted. This study builds on the findings of an exploratory study (Jackson and Hauser, 2017) outlining key areas of non-clinical benefits of EBVM: increased client satisfaction and retention, improved reputation, confidence, as well as employee engagement.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Evidentiary value:&lt;/strong&gt; This online survey of veterinary professionals (n=407) provides evidence for practitioners, universities and other veterinary staff regarding the non-clinical benefits of EBVM, the barriers to a wider adoption of the practice and ways of overcoming those barriers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The online survey of veterinary professionals was conducted during September – October 2016 and contained 23 questions. Survey participation was voluntary and the data used for analysis were de-identified.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; The survey responses of 407 veterinary professionals provide quantitative evidence of how EBVM is put into practice, how EBVM is perceived to impact client behaviour and employee engagement, what the barriers are to practising EBVM and how these could be overcome. Key findings are that veterinary professionals are more likely to practise EBVM if they have been taught how to do so at vet school. EBVM is a way to provide value to and build trust with clients. Survey respondents who practise EBVM are more likely to find their workplace inspiring and to be an intellectual challenge and the main barriers to EBVM are: time and access to information. Respondents, especially those who were employees suggested overcoming these barriers through attending journal clubs and other training opportunities.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The study provides the view of veterinary professionals on the non-clinical benefits of EBVM, the barriers to wider implementation and ways of overcoming those barriers. Further research is needed to obtain the perspective of clients and more detailed cost effectiveness analyses could shed more light on specific practices of EBVM.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Application:&lt;/strong&gt; Findings are applicable to universities, veterinarians and vet nurses seeking to increase the practice of EBVM. The ultimate beneficiaries are those vets who seek additional non-clinical reasons for the adoption of EBVM in their practice.&lt;/p&gt;&lt;br /&gt; &lt;img src="https://www.veterinaryevidence.org/rcvskmod/icons/oa-icon.jpg" alt="Open Access" /&gt; &lt;img src="https://www.veterinaryevidence.org/rcvskmod/icons/pr-icon.jpg" alt="Peer Reviewed" /&gt;

An Exploratory Study Investigating the Non-Clinical Benefits of Evidence-Based Veterinary Medicine

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;As little prior research exists about the non-clinical benefits of evidence-based veterinary medicine (EBVM), this exploratory study was conducted to identify non-clinical benefits of EBVM to veterinary practices, as well as highlighting the barriers to further implementation, and ways to overcome them.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; A PICO-based literature review (Hauser and Jackson, 2016) was conducted to establish current knowledge about the non-clinical benefits of EBVM. It found that while there are some papers suggesting a link between the practice of EBVM and better non-clinical benefits such as client satisfaction and client retention, a single study, focusing on the non-clinical benefits of EBVM, had yet to be conducted.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Evidentiary value:&lt;/strong&gt; This exploratory study provides a solid basis for the further development of a confirmatory study of the themes identified in the interviews. The impact on practice from our findings is significant as it details the key areas where the use of EBVM can yield commercial benefits from the perspective of a group of EBVM experts via interview. It is entirely possible that international veterinary environments which mirror that of the UK will find this research beneficial.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Due to the paucity of data about the non-clinical benefits of EBVM, an exploratory, qualitative approach was taken to this research in order to build a platform for further confirmatory, quantitative investigation (Zikmund, 2003). In February and March 2016 interviews with 16 RCVS Knowledge Group chairs&lt;a name="_ftnref1" href="#_ftn1"&gt;&lt;/a&gt;[1] were conducted. The interview guide contained broad, open-ended questions to explore existing tacit knowledge about the non-commercial benefits of EBVM. The interviews were audio recorded and transcribed &lt;em&gt;verbatim&lt;/em&gt; and subsequently analysed using NVivo 11 software.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; This qualitative enquiry showed that the key areas where the use of EBVM can yield non-clinical benefits are through increased client satisfaction and retention, improved reputation and confidence of the veterinarian, as well as employee engagement. In order to yield these benefits the two main barriers, time and resources, need to be overcome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The themes highlighted in this paper provide a solid, real world base for further, quantitative study of the non-clinical benefits of practising EBVM. &lt;/p&gt;&lt;p&gt;&lt;strong&gt;Application:&lt;/strong&gt; The results of this research are applicable to practicing veterinarians, nurses and other practice staff. It is clear that practising EBVM not only leads to better clinical outcomes, but can also result in commercial benefits, such as better client retention and employee engagement&lt;/p&gt;&lt;br /&gt; &lt;img src="https://www.veterinaryevidence.org/rcvskmod/icons/oa-icon.jpg" alt="Open Access" /&gt; &lt;img src="https://www.veterinaryevidence.org/rcvskmod/icons/pr-icon.jpg" alt="Peer Reviewed" /&gt;