Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

COVID-19 opens the door for right iliac fossa pain treatment pathway.

INTRODUCTION: The COVID-19 pandemic has increased the risks of surgery and management of common surgical conditions has changed, with greater reliance on imaging and conservative management. The negative appendectomy rate (NAR) in the UK has previously remained high. The aim of this study was to quantify pandemic-related changes in the management of patients with suspected appendicitis, including the NAR. METHODS: A retrospective study was performed at a single high volume centre of consecutive patients aged over five years presenting to general surgery with right iliac fossa pain in two study periods: for two months before lockdown and for four months after lockdown. Pregnant patients and those with previous appendectomy, including right colonic resection, were excluded. Demographic, clinical, imaging and histological data were captured, and risk scores were calculated, stratifying patients into higher and lower risk groups. Data were analysed by age, sex and risk subgroups. RESULTS: The mean number of daily referrals with right iliac fossa pain or suspected appendicitis reduced significantly between the study periods, from 2.92 before lockdown to 2.07 after lockdown (p<0.001). Preoperative computed tomography (CT) rates increased significantly from 22.9% to 37.2% (p=0.002). The NAR did not change significantly between study periods (25.5% prior to lockdown, 11.1% following lockdown, p=0.159). Twelve (75%) out of sixteen negative appendectomies were observed in higher risk patients aged 16-45 years who did not undergo preoperative CT. The NAR in patients undergoing CT was 0%. CONCLUSIONS: Greater use of preoperative CT should be considered in risk stratified patients in order to reduce the NAR.

A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5×10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Perceived age and perceived health among a Chinese cohort: Does it mean the same thing?

BACKGROUND & AIMS: Previous investigations have aimed at investigating parameters affecting age perception on several ethnicities. Perceived health has been a newer focus on Caucasian skin, yet little is known on the skin features used to estimate the health status of Chinese women and we aimed to investigate whether these cues are the same as those used for age perception. METHODS: Age and health appearance of 276 Chinese female volunteers were estimated from their photographs by 1025 female naïve Chinese graders 20-69 years old. Models were built to predict perceived age and health from topographic, colour and biophysical measured variables, in two subsets of the studied volunteers: below and above 50 years. Machine learning-based predictive models for age and health perception were built on the collected data, and the interpretability of the models was established by measuring feature importance. RESULTS: Age perception was mostly driven by topographic features, particularly eye bags and eyelid sagging in the group below 50 years old. Wrinkles, notably from the lower part of the face and oval of the lower face, were found to be more relevant in the group above 50 years. Health appearance was primarily signalled by skin imperfections and global pigmentation in the subset below 50 years, whereas colour-related parameters and skin hydration acted as health cues for the subset above 50 years. CONCLUSION: Distinct skin features were acting as cues for age perception and/or health perception and varied per age subset. Their contribution should be borne in mind when designing products for 'younger looking skin' and 'healthier looking skin'.

OBJECTIF: Des études se sont penchées sur les paramètres cutanés influant sur la perception de l'âge, et ce sur plusieurs groups ethniques. La santé perçue quant à elle est un focus plus récent, avec des données publiées sur les peaux caucasiennes, au contraire des peaux chinoises. Nous avons donc décidé d'étudier quels sont ces paramètres cutanés influant sur la santé perçue et s'ils diffèrent de ceux utilisés dans la perception de l'âge, au sein d'un panel de femmes chinoises. MÉTHODES: L'âge et la santé cutanée de 276 femmes chinoises ont été estimés à partir de leurs photographies par un panel de 1025 évaluatrices naïves âgées de 20 à 69 ans. Des modèles ont été construits pour prédire l'âge et la santé perçus à partir de paramètres cutanés topographiques, de couleur et biophysiques, dans deux groupes d'âges différents : en dessous et au-dessus de 50 ans. Des modèles prédictifs basés sur l'apprentissage automatique (Machine learning) pour la perception de l'âge et de la santé ont été construits à partir des données collectées et l'interprétabilité des modèles a été établie en mesurant l'importance des paramètres cutanés. RÉSULTATS: Nos résultats montrent que la perception de l'âge repose principalement sur des paramètres topographiques, en particulier les poches sous les yeux et l'affaissement de la paupière, pour le groupe âgé de moins de 50 ans. Les rides, notamment celles de la partie basse du visage et le contour de la partie basse du visage se sont montrés pertinents pour estimer l'âge dans le groupe âgé de plus de 50 ans. La perception de la santé est principalement affectée par les imperfections cutanées et la pigmentation dans le groupe âgé de moins de 50 ans, tandis que des paramètres liés à la couleur et l'hydratation prennent le relais pour le groupe âgé de plus de 50 ans. CONCLUSION: Des paramètres cutanés de nature diverse sont pris en compte selon que l'on essaye d'estimer l'âge ou la santé, et ce en fonction du groupe d'âge étudié. Leur contribution doit être prise en compte lors de la conception de produits pour une «peau d'apparence plus jeune¼ et une «peau d'apparence plus saine¼.

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial.

BACKGROUND: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen. PATIENTS AND METHODS: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13. RESULTS: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. CONCLUSIONS: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. CLINICAL TRIALS NUMBER: NCT02763579.

Ageing profiles of Caucasian and Chinese cohorts - focus on hands skin.

OBJECTIVE: In spite of hand care being a dynamic segment of skin care, hands skin physiology has been receiving little attention in comparison to facial skin. In the present study, we aimed at gathering a comprehensive set of skin data from the dorsal part of the hand to study age related-changes in two ethnic groups (Caucasian and Chinese). METHODS: Skin topographic, skin colour/colour heterogeneities, skin chromophores and skin biophysical measurements of 116 Caucasian and Chinese female volunteers aged 30-65 years old were collected in Ireland and in China as part of a cross-sectional study. RESULTS: Topographic alterations happened at both micro and macro scales with a noticeable delay in the onset of 10 years for the Chinese cohort. Similar evolution of skin colour with ageing was observed between the two cohorts and strong dissimilarities were seen when it came to colour heterogeneities and melanin hyper concentration, with a 20-year delay in severity for the Chinese cohort. A similar sharp drop of skin hydration occurred when reaching the 60's regardless of the group and substantial differences were recorded for skin biomechanical properties of the skin. CONCLUSION: These results provide additional insights about hand skin physiology in relation to ageing and ethnic differences, especially when put into perspective with what is currently known about facial ageing. This research yield additional material for hand cream product rationale and strategies for mitigating the appearance of ageing hands.

OBJECTIF: Même si le soin pour les mains demeure un segment dynamique en termes de ventes de produits cosmétiques, peu d'études se sont penchées sur la physiologie de la peau des mains en comparaison du visage. Le but de cette étude est d'élucider les changements de la partie dorsale de la main induits par le vieillissement, au sein de deux groupes ethniques (Caucasienne et Chinoise). METHODES: Des mesures de la topographie, de couleur et de distribution de la couleur, de chromophores et des propriétés biophysiques de la peau de la main ont été collectées sur 116 sujets féminins d'origine caucasienne ou chinoise, âgées entre 30 et 65 ans, en Irlande et en Chine dans le cadre d'une étude cross-sectionnelle. RESULTATS: Des altérations de la topographie de la peau ont été observés à plusieurs échelles, micro et macroscopique, avec néanmoins un délai de 10 ans dans la détérioration de la peau en faveur du panel Chinois. Au niveau de la couleur, des évolutions similaires ont été mesurées dans les deux panels, avec cependant de fortes dissimilarités pour ce qui est de la distribution de la couleur de la peau et de l'hyperconcentration de mélanine, avec des changements retardés de 20 ans en faveur du panel d'origine chinoise. Un déclin d'hydratation significatif s'est produit à partir de la soixantaine dans les deux panels étudiés tandis que des différences flagrantes ont été relevées en ce qui concerne les propriétés biomécaniques de la peau. CONCLUSION: Ces résultats offre des données supplémentaires sur la physiologie de la peau des mains lors du vieillissement cutané et sur les différences à prendre en compte entre deux groupes ethniques très distincts, surtout si l'on considère les différences avec le vieillissement du visage. Cette étude fournit un support additionnel pour la conception de crèmes pour les mains et les stratégies à mettre en place pour atténuer l'apparence de mains âgées.

Antera 3D capabilities for pore measurements.

BACKGROUND: The cause of enlarged pores remains obscure but still remains of concern for women. To complement subjective methods, bioengineered methods are needed for quantification of pores visibility following treatments. The study objective was to demonstrate the suitability of pore measurements from the Antera 3D. MATERIAL AND METHODS: Pore measurements were collected on 22 female volunteers aged 18-65 years with the Antera 3D, the DermaTOP and image analysis on photographs. Additionally, 4 raters graded pore size on photographs on a scale 0-5. Repeatability of Antera 3D parameters was ascertained and the benefit of a pore minimizer product on the cheek was assessed on a sub panel of seven female volunteers. RESULTS: Pore parameters using the Antera were shown to depict pore severity similar to raters on photographs, except for Max Depth. Mean pore volume, mean pore area and count were moderately correlated with DermaTOP parameters (up to r = .50). No relationship was seen between the Antera 3D and pore visibility analysis on photographs. The most repeatable parameters were found to be mean pore volume, mean pore area and max depth, especially for the small and medium filters. The benefits of a pore minimizer product were the most striking for mean pore volume and mean pore area when using the small filter for analysis, rather than the medium/large ones. CONCLUSION: Pore measurements with the Antera 3D represent a reliable tool for efficacy and field studies, with an emphasis of the small filter for analysis for the mean pore volume/mean pore area parameters.

Wrinkle and roughness measurement by the Antera 3D and its application for evaluation of cosmetic products.

BACKGROUND: Skin topographic measurements are of paramount importance in the field of dermo-cosmetic evaluation. The aim of this study was to investigate how the Antera 3D, a multi-purpose handheld camera, correlates with other topographic techniques and changes in skin topography following the use of a cosmetic product. METHODS: Skin topographic measurements were collected on 26 female volunteers aged 45-70 years with the Antera 3D, the DermaTOP and image analysis on parallel-polarized pictures. Different filters for analysis from the Antera 3D were investigated for repeatability, correlations with other imaging techniques and ability to detect improvements of skin topography following application of a serum. RESULTS: Most of Antera 3D parameters were found to be strongly correlated with the DermaTOP parameters. No association was found between the Antera 3D parameters and measurements on parallel-polarized photographs. The measurements repeatability was comparable among the different filters for analysis, with the exception of wrinkle max depth and roughness Rt. Following a single application of a tightening serum, both Antera 3D wrinkles and texture parameters were able to record significant improvements, with the best improvements observed with the large filter. CONCLUSION: The Antera 3D demonstrated its relevance for cosmetic product evaluation. We also provide recommendations for the analysis based on our findings.

Meta-analysis on anticoagulation and prevention of thrombosis and mortality among patients with lung cancer.

BACKGROUND: Venous thromboembolism (Wickham et al., 2012 [1]) is a leading cause of morbidity and mortality among patients with cancer; however, primary thromboprophylaxis is not routinely recommended. We performed a systematic review and meta-analysis of randomized control trials (RCTs) to measure the impact of primary VTE prevention and its effect on mortality among patients with lung cancer. METHODS: With assistance from a master librarian, we searched Ovid, Scopus, DARE, CINAHL, MEDLINE, EMBASE, EBM reviews-Cochrane database of systematic reviews, EBM reviews-ACP journal, and EBM Reviews-Databases for relevant studies following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included articles addressing the role of anticoagulation in patients with lung cancer for primary VTE prevention for outpatients. The clinical outcomes were VTE occurrence, all-cause mortality, major and clinically relevant non-major bleeding. The results are presented as odds ratio (OR) and data were analyzed using R and R META package (Version 0.8-2, Author: Guido Schwarzer). RESULTS: Eleven studies with 5107 patients were included for the final analysis. We found 50% lower VTE occurrence in the prophylaxis group with low molecular weight heparin (LMWH) (OR: 0.50; 95% Confidence Interval (CI): 0.38-0.66; I2: 0%) without an increased bleeding risk (OR: 2.03; 95% CI: 0.78-5.25; I2: 71.1%). We found a mortality benefit when we grouped all VTE prevention modalities [LMWH, Warfarin, unfractionated heparin (UFH)] (OR: 0.75; 95% CI: 0.58-0.96; I2: 18.4%), but no significant difference when LMWH (OR: 0.74; 95% CI: 0.49-1.11; I2: 56.9%) and warfarin were analyzed individually (OR: 0.75; 95% CI: 0.47-1.21; I2: 0%). We found higher odds of bleeding combining all treatment modalities (OR: 3.06; 95% CI: 1.64-5.72; I2: 64.4%) with the greatest occurrence in the warfarin group (OR: 5.42; 95% CI: 3.48-8.45; I2: 45.7%). CONCLUSION: Primary VTE prophylaxis with LMWH reduces the occurrence of VTE among ambulatory patients with lung cancer, without apparent increase in bleeding risk. There is a measurable mortality benefit of anticoagulation strategies that remains elusive when the analysis is restricted to a single agent.

Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRß fusions and may benefit from targeted therapy. PATIENT AND METHODS: We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. RESULTS: The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. CONCLUSIONS: In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.

Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer.

BACKGROUND: The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. EXPERIMENTAL DESIGN: Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ(2) or Fisher's exact test were used for analysis. RESULTS: We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). CONCLUSIONS: We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.

Predictors of active cancer thromboembolic outcomes: validation of the Khorana score among patients with lung cancer.

UNLABELLED: Essentials Venous thromboembolism (VTE) prevention strategies require effective risk assessment models. We sought to validate the Khorana Risk Score (KRS) in patients with lung cancer. A high KRS was not predictive of VTE but was independently associated with all-cause mortality. Our findings stress the need for a lung cancer-specific VTE risk assessment model. SUMMARY: Objectives Lung cancer is strongly associated with venous thromboembolism (VTE), but primary prevention against VTE is not a validated management strategy. Risk assessment models will be necessary for efficient implementation of preventative strategies. Materials and methods Utilizing a prospectively collected lung cancer database, we aimed to validate the Khorana Risk Score (KRS) in the prediction of VTE among patients with lung cancer. VTE events were retrospectively identified by reviewers unaware of the clinical prediction score calculation. The association between KRS and the risk of VTE was examined using cumulative incidence function with competing risk models. Mortality prediction was evaluated as a secondary outcome. Results We included 719 patients in our review. The patients were predominantly older men with non-small cell lung cancer and 40% had metastatic disease at inception. The median follow-up was 15.2 months. There were 83 VTEs (11.5%) and 568 (78.8%) patients died. A high KRS (cumulative incidence, 12.4%; 95% confidence interval [CI], 6.4-20.5%) was not associated with VTE compared with an intermediate score (cumulative incidence, 12.1%; 95% confidence interval, 9.5-15.0%) in both univariate and multivariable analyses. However, a high KRS was a predictor of mortality (hazard ratio, 1.7; 95% CI, 1.4-2.2). Conclusions Among patients with lung cancer, the KRS did not stratify the patients at the highest risk of VTE. Improved risk stratification methods are needed for this group of patients prior to implementing a primary prevention strategy.

Implications of Programmed Cell Death 1 Ligand 1 Heterogeneity in the Selection of Patients With Non-Small Cell Lung Cancer to Receive Immunotherapy.

The use of programmed cell death 1 ligand 1 (PD-L1) as a predictive biomarker to select patients to receive programmed cell death 1 (PD-1) or PD-L1 inhibitors in non-small cell lung cancer (NSCLC) is limited by the definitions of positivity, interassay agreement, and intra- and intertumoral heterogeneity of expression. Although PD-L1 expression enriches for responses, the lack of expression does not exclude clinical benefit.

Prospective evaluation of protein C and factor VIII in prediction of cancer-associated thrombosis.

Venous thromboembolism (VTE) is a preventable disease, yet it is one of the leading causes of death among patients with cancer. Improving risk stratification mechanisms will allow us to personalize thrombo-prophylaxis strategies. We sought to evaluate Collagen and Thrombin Activated Platelets (COAT-platelets) as well as protein C and factor VIII as biomarkers predictive of cancer-associated thrombosis in a prospective cohort of patients with cancer. Protein C was selected as a candidate based on bioinformatics prediction. Blood samples were collected before chemotherapy. All specimen processing was blinded to clinical data. Surveillance and adjudication of the main outcome of VTE was performed for up to 1 year. We used Cox proportional hazard regression to measure the association of biomarkers and incident events using SAS 9.2 for all statistical analysis. Death was modeled as a competing event. Among 241 patients followed for an average of 10.4 months, 15% died and 13% developed a VTE. COAT-platelets were not predictive of VTE. Low levels of pre-chemotherapy protein C (<118%) (HR 2.5; 95% CI 1.1-5.5) and high baseline factor VIII (>261% I) (HR 3.0; 95% CI 1.1-8.0) were predictive of VTE after adjusting for age, Khorana prediction risk, metastatic disease and D dimer. In addition, low protein C was predictive of overall mortality independent of age, metastatic disease and functional status (HR 2.8; 95% CI 1.3-6.0). Addition of these biomarkers to cancer-VTE risk prediction models may add to risk stratification and patient selection to optimize thrombo-prophylaxis.

Severe hepatic dysfunction is associated with venous thromboembolic events in phase 1 clinical trials.

INTRODUCTION: Venous thromboembolic events (VTEs) are a significant cause of death in patients with cancer. The incidence of VTE is not well characterized in early phase clinical trials of novel antineoplastic agents, or in hepatic dysfunction studies designed for patients with varying degrees of liver test abnormalities. We compared the incidences of VTE in phase 1 clinical trials (P1CTs) and hepatic dysfunction trials (HDCTs) sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) of the United States. MATERIALS & METHODS: We reviewed individual patient records of 1841 subjects for symptomatic VTE diagnosed while on study: 1328 subjects on 42 P1CTs, and 513 subjects on 9 HDCTs. The NCI's Organ Dysfunction Working Group definitions were used to categorize patients. The incidences of VTEs between patients were compared by the Chi square test. Confounders were evaluated with the Cochran-Mantel-Haenszel method. RESULTS & CONCLUSIONS: There were 43 VTEs identified among all subjects (2.3%). There were significantly more VTE observed in the subjects on P1CTs (n=38, 2.9%) than in the subjects on HDCTs (n=5, 1.0%; RR 0.341, 95% 0.13-0.86, p=0.015). For patients on HDCTs, those with severe dysfunction had a high incidence of VTE (RR 10.5 (1.12-93.6), p=0.021) that remained significant in a multivariate model. VTEs were observed less frequently in patients who were enrolled in HDCT than those who were enrolled in P1CT; however, patients with severe hepatic dysfunction were more likely to experience VTE. Severe liver test abnormalities may not be protective against VTE in patients with malignancies receiving chemotherapy.