PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma.

BACKGROUND: Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better. METHODS: We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals. RESULTS: We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy. CONCLUSION: We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.

A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.

INTRODUCTION: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy. METHODS: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment. RESULTS: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified. CONCLUSIONS: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments. METHODS: Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated. RESULTS: Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. CONCLUSION: Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies.

EHA evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies.

OBJECTIVE: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. RESULTS: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. CONCLUSIONS: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials.

Comparative Assessment of Clinical Benefit Using the ESMO-Magnitude of Clinical Benefit Scale Version 1.1 and the ASCO Value Framework Net Health Benefit Score.

PURPOSE: To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies. METHODS: The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance. RESULTS: The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman's rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity. CONCLUSION: The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales.

Report on the status of women occupying leadership roles in oncology.

BACKGROUND: While the global workforce is approaching gender parity, women occupy a small number of management level positions across most professions, including healthcare. Although the inclusion of women into the membership of many oncology societies has increased, the under-representation of women in leadership roles within international and national oncology societies remains relatively consistent. Moreover, the exact status of women participating as board members or presidents of oncology societies or as speakers at oncology congresses was undocumented to date. METHODS: The database used in this analysis was derived from data collection performed by the European Society for Medical Oncology for the years 2015-2016 and data analyses performed using the Statistical Analysis Software V.9.3 and R language for statistical computing V.3.4.0 by Frontier Science Foundation-Hellas. The literature search was performed by the authors. RESULTS: We report the presence of a gender gap within oncology. Results regarding the under-representation of women occupying leadership roles in oncology show female participation as members of the board or presidents of national and international oncology societies and as invited speakers at oncology congresses remains below 50% in the majority of societies included in this analysis. Women in leadership positions of societies was associated with a higher percentage of female invited speakers at these societies' congresses (p=0.006). CONCLUSION: The full contribution that can be attained from using the potential of women in leadership roles is currently under-realised. Examples of how gender and minority participation in organisations improves outcomes and creativity are provided from science, clinical practice and industry that show outcomes are greatly improved by collective participation of both men and women. Although there are programmes in place in many oncology organisations to improve this disparity, the gender gap is still there. Ongoing discussion may help to create more awareness in the effort to accelerate the advancement of women within oncology.

Gender-related challenges facing oncologists: the results of the ESMO Women for Oncology Committee survey.

BACKGROUND: Although women account for a growing proportion of the oncology workforce, there is evidence they are under-represented in leadership roles. To gain further insights into this issue and extend understanding of gender challenges, the European Society for Medical Oncology Women for Oncology (W4O) Committee undertook a survey of female and male oncologists in 2016. DESIGN: The 2016 W4O questionnaire included questions on (1) Demographics and professional environment, (2) Gender impact on career development, (3) Challenges for career progression and inappropriate behaviour experienced in the workplace, (4) Barriers for gender parity and (5) The gender gap. Between July and September 2016, the online survey was available to male and female clinical and academic oncology healthcare professionals in the EU and internationally. RESULTS: Responses were analysed from 462 oncologists, of whom 76.7 % were women. Of female respondents, 45.5 % had a managerial or leadership role, compared with 65 % of male respondents (p<0.001). Men were more likely to have leadership roles, even in clinical teams with more women than men. Women respondents were more likely to consider their gender had a major impact on their career than men: 35.9 % vs 20.9 % (p<0.001). The biggest challenge to career progression for women was work and family balance (64.2%). Of female respondents, 14.4 % believed there had been significant or major progress in closing the gender pay gap compared with 39.3 % of men (p<0.001). Of female participants, 37.7 % reported they had encountered unwanted sexual comments by a superior or colleague. CONCLUSIONS: New initiatives are needed to address under-representation of women oncologists in leadership roles, including greater and concrete promotion of work-life balance, development and leadership training for women, and more support for flexible working. The fact that over a third of women in the survey had encountered unwanted sexual comments at work is of great concern and must be urgently addressed.

Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry - Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort.

INTRODUCTION: Phosphatase and tensin homolog (PTEN) loss is frequently observed in NSCLC and associated with both phosphoinositide 3-kinase activation and tumoral immunosuppression. PTEN immunohistochemistry is a valuable readout, but lacks standardized staining protocol and cutoff value. METHODS: After an external quality assessment using SP218, 138G6 and 6H2.1 anti-PTEN antibodies, scored on webbook and tissue microarray, the European Thoracic Oncology Platform cohort samples (n = 2245 NSCLC patients, 8980 tissue microarray cores) were stained with SP218. All cores were H-scored by pathologists and by computerized pixel-based intensity measurements calibrated by pathologists. RESULTS: All three antibodies differentiated six PTEN+ versus six PTEN- cases on external quality assessment. For 138G6 and SP218, high sensitivity and specificity was found for all H-score threshold values including prospectively defined 0, calculated 8 (pathologists), and calculated 5 (computer). High concordance among pathologists in setting computer-based intensities and between pathologists and computer in H-scoring was observed. Because of over-integration of the human eye, pixel-based computer H-scores were overall 54% lower. For all cutoff values, PTEN- was associated with smoking history, squamous cell histology, and higher tumor stage (p < 0.001). In adenocarcinomas, PTEN- was associated with poor survival. CONCLUSION: Calibration of immunoreactivity intensities by pathologists following computerized H-score measurements has the potential to improve reproducibility and homogeneity of biomarker detection regarding epitope validation in multicenter studies.

Evaluation of NGS and RT-PCR Methods for ALK Rearrangement in European NSCLC Patients: Results from the European Thoracic Oncology Platform Lungscape Project.

INTRODUCTION: The reported prevalence of ALK receptor tyrosine kinase gene (ALK) rearrangement in NSCLC ranges from 2% to 7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proved to be a reproducible and sensitive technique. Reverse-transcriptase polymerase chain reaction (RT-PCR) has also been advocated, and most recently, the advent of targeted next-generation sequencing (NGS) for ALK and other fusions has become possible. This study compares anaplastic lymphoma kinase (ALK) evaluation with all four techniques in resected NSCLC from the large European Thoracic Oncology Platform Lungscape cohort. METHODS: A total of 96 cases from the European Thoracic Oncology Platform Lungscape iBiobank, with any ALK immunoreactivity were examined by FISH, central RT-PCR, and NGS. An H-score higher than 120 defines IHC positivity. RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers covered the most frequent ALK translocations. For NGS, the Oncomine Solid Tumour Fusion Transcript Kit (Thermo Fisher Scientific, Waltham, MA) was used. The concordance was assessed using the Cohen κ coefficient (two-sided α ≤ 5%). RESULTS: NGS provided results for 77 of the 95 cases tested (81.1%), whereas RT-PCR provided results for 77 of 96 (80.2%). Concordance occurred in 55 cases of the 60 cases tested with all four methods (43 ALK negative and 12 ALK positive). Using ALK copositivity for IHC and FISH as the criterion standard, we derived a sensitivity for RT-PCR/NGS of 70.0%/85.0%, with a specificity of 87.1%/79.0%. When either RT-PCR or NGS was combined with IHC, the sensitivity remained the same, whereas the specificity increased to 88.7% and 83.9% respectively. CONCLUSION: NGS evaluation with the Oncomine Solid Tumour Fusion transcript kit and RT-PCR proved to have high sensitivity and specificity, advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed by using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact.

Migration levels of PVC plasticisers: Effect of ionising radiation treatment.

Migration levels of commercial plasticisers [di-(2-ethylhexyl) adipate (DEHA) and acetyl tributyl citrate (ATBC)] from polyvinyl chloride (PVC) film into the EU specified aqueous food simulants (distilled water, 3% w/v acetic acid and 10% v/v ethanol) were monitored as a function of time. Migration testing was carried out at 40°C for 10days (EEC, 1993). Determination of the analytes was performed by applying the analytical methodology based on surfactant (Triton X-114) mediated extraction prior to gas chromatographic-flame ionisation detection (GC-FID) recently proposed by our group. The study focuses on the determination of the effect of gamma radiation on plasticiser migration into the selected simulants. PVC cling film used was subjected to ionising treatment with a [(60)Co] source at doses equal to 5, 15 and 25kGy. DEHA and ATBC migration into the EU aqueous simulating solvents was limited, yielding final concentrations in the respective ranges 10-100µg/l and 171-422µg/l; hence, ATBC demonstrated a stronger interaction with all three simulants compared to DEHA. Migration data, with respect to ATBC, showed that the most aggressive simulant seemed to be the 10% ethanol, while in the case of DEHA the 3% aqueous acetic acid exhibited the highest extraction efficiency; distilled water demonstrated the lowest migration in both cases. With regard to PVC treatment with gamma rays, high radiation doses up to 25kGy produced a statistically significant (p<0.05) effect on the migration of both plasticisers.

Migration of di(2-ethylhexyl) adipate and acetyltributyl citrate plasticizers from food-grade PVC film into sweetened sesame paste (halawa tehineh): kinetic and penetration study.

Food-grade polyvinyl chloride (PVC) cling-film containing 5.3% (w/w) di(2-ethylhexyl) adipate (DEHA) and 3.0% (w/w) acetyltributyl citrate (ATBC) plasticizers was used to wrap halawa tehineh (halva) samples. Samples were split into two groups and stored at 25+/-1 degrees C. One group was analyzed for DEHA and ATBC content at intervals between 0.5 and 240h of contact (kinetic study) and a second group was cut into slices (1.5mm thick) after 240h of halva/PVC contact and was analyzed for DEHA and ATBC content (penetration study). Determination of both plasticizers was performed using a direct gas chromatographic (GC) method after extraction of DEHA from halva samples. DEHA readily migrated into halva samples: the equilibrium amount of DEHA in halva (3.31mg/dm(2) film or 81.4mg/kg halva) corresponding to a loss of 54.7% (w/w) DEHA from PVC film. This value is slightly higher than the limit of 3mg/dm(2) of film surface set by the European Union for DEHA. The equilibrium amount of ATBC in halva was 1.46mg/dm(2) (36.1mg/kg) corresponding to a loss of 42.7% ATBC from PVC film. With regard to the penetration of both placticizers into halva samples, migration of DEHA was detectable up to the 7th slice beneath the surface of halva (total depth 10.5mm) while the migration of ATBC was detectable up to the 5th slice (total depth 7.5mm).

Determination of diethylhexyladipate and acetyltributylcitrate in aqueous extracts after cloud point extraction coupled with microwave assisted back extraction and gas chromatographic separation.

The determination of commercial plasticizers (di-(2-ethylhexyl)adipate (DEHA) and acetyl tributyl citrate (ATBC)) in aqueous solutions is described. The newly proposed technique of applying microwaves to cloud point extracts in order to enable combination with gas chromatographic analysis has been used for this purpose. Both plasticizers were entrapped in the micelles of the non-ionic surfactant Triton X-114 and removed from the bulk phase by centrifugation. Micellization was enhanced by increasing the ionic strength of the solution with concentrated NaCl. Extraction recoveries of the proposed method were over 95% for water and 3% (w/v) aqueous acetic acid and over 85% for 10% (v/v) aqueous ethanol, respectively. The calibration curves obtained, following the proposed methodology have a linear range between 50 and 2000 microg/L for each analyte while the detection limits were as low as 15 and 19 microg/L for DEHA and ATBC, respectively, with an RSD below 5% even for low concentrations. As an analytical demonstration the proposed methodology was applied for the determination of the migration levels of the selected plasticizers from a PVC food packaging film into aqueous simulants.