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Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).
BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day wereâ<â9.0, 9.0-12.9, 12.9-22.8, andâ>â22.8 ng/mL, respectively. EVE trough levels increased with increasing age (pâ<â0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, pâ=â0.01). Risk of grade 2â+âtriglycerides was increased in Q2 and Q3 vs Q1 (ORâ=â2.08; pâ=â0.02 and ORâ=â2.63; pâ=â0.002). Risk of grade 2â+ârash was increased in Q2 and Q4 vs Q1 (ORâ=â2.99; pâ=â0.01 and ORâ=â2.90; pâ=â0.02). There was also an increased risk of any grade 3â+âtox in Q2 vs Q1 (ORâ=â1.71; pâ=â0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity
New N=2 Superconformal Field Theories in Four Dimensions
New examples of N=2 supersymmetric conformal field theories are found as
fixed points of SU(2) N=2 supersymmetric QCD. Relations among the scaling
dimensions of their relevant chiral operators, global symmetries, and Higgs
branches are understood in terms of the general structure of relevant
deformations of non-trivial N=2 conformal field theories. The spectrum of
scaling dimensions found are all those compatible with relevant deformations of
a y^2 = x^3 singular curve.Comment: 17 pages, harvma
Supersymmetry and Strongly Coupled Gauge Theories
I briefly review how supersymmetry helps in the extraction of exact
nonperturbative information from field theories, and then discuss some open
problems in strongly coupled gauge theories. (Talk given at ``30 Years of
Supersymmetry'' symposium in Minneapolis, Minnesota on October 15, 2000.)Comment: 8 pages, 2 figure
Outcomes and efficacy of thoracic surgery biopsy for tumor molecular profiling in patients with advanced lung cancer
BackgroundMolecular testing of patients with advanced nonâsmall cell lung cancer for personalized therapy often is limited by insufficient specimen from nonsurgical biopsies. We measured the feasibility, patient safety, and clinical impact of thoracic surgical tumor biopsy in patients with stage IV nonâsmall cell lung cancer.MethodsThis is a single institution retrospective analysis. Patients with stage IV nonâsmall cell lung cancer undergoing elective surgical tissue biopsy for molecular analysis were evaluated from March 2011 to November 2012. Perioperative specific variables were measured.ResultsTwenty-five patients with known or suspected stage IV nonâsmall cell lung cancer undergoing surgical biopsy were identified. All cases were discussed at a multidisciplinary thoracic oncology conference or a multidisciplinary thoracic oncology clinic. Preoperative histologies included adenocarcinoma in 20 patients (80.0%) and squamous cell carcinoma in 2 patients (8.0%). Surgical procedures consisted of video-assisted thoracic surgery wedge biopsy (16, 64%), video-assisted thoracic surgery pleural biopsy (4, 16.0%), mediastinoscopy (2, 8.0%), supraclavicular/cervical lymph node excisional biopsy (3, 12.0%), and rib/chest wall resection (2, 8.0%). There were no deaths and 5 postoperative complications (20.0%). Surgery identified potentially targetable molecular information in 19 of the total patients undergoing operation (76.0%) and changed the treatment strategy in 14 patients (56.0%); 10 of the total cohort (40.0%) were enrolled into therapeutic targeted clinical trials.ConclusionsThese data suggest that thoracic surgical biopsy can be safely performed in appropriately selected patients with stage IV nonâsmall cell lung cancer and direct personalized therapy and enrollment into relevant clinical trials. Patients with advanced-stage nonâsmall cell lung cancer should be discussed in a multidisciplinary setting to determine the need and strategy for thoracic surgical biopsy for molecular analysis
The ACS Nearby Galaxy Survey Treasury IX. Constraining asymptotic giant branch evolution with old metal-poor galaxies
In an attempt to constrain evolutionary models of the asymptotic giant branch
(AGB) phase at the limit of low masses and low metallicities, we have examined
the luminosity functions and number ratio between AGB and red giant branch
(RGB) stars from a sample of resolved galaxies from the ACS Nearby Galaxy
Survey Treasury (ANGST). This database provides HST optical photometry together
with maps of completeness, photometric errors, and star formation histories for
dozens of galaxies within 4 Mpc. We select 12 galaxies characterized by
predominantly metal-poor populations as indicated by a very steep and blue RGB,
and which do not present any indication of recent star formation in their
color--magnitude diagrams. Thousands of AGB stars brighter than the tip of the
RGB (TRGB) are present in the sample (between 60 and 400 per galaxy), hence the
Poisson noise has little impact in our measurements of the AGB/RGB ratio. We
model the photometric data with a few sets of thermally pulsing AGB (TP-AGB)
evolutionary models with different prescriptions for the mass loss. This
technique allows us to set stringent constraints to the TP-AGB models of
low-mass metal-poor stars (with M<1.5 Msun, [Fe/H]<~-1.0). Indeed, those which
satisfactorily reproduce the observed AGB/RGB ratios have TP-AGB lifetimes
between 1.2 and 1.8 Myr, and finish their nuclear burning lives with masses
between 0.51 and 0.55 Msun. This is also in good agreement with recent
observations of white dwarf masses in the M4 old globular cluster. These
constraints can be added to those already derived from Magellanic Cloud star
clusters as important mileposts in the arduous process of calibrating AGB
evolutionary models.Comment: To appear in ApJ, a version with better resolution is in
http://stev.oapd.inaf.it/~lgirardi/rgbagb.pd
23 Validation of PD-L1 dynamic expression on extracellular vesicles as a predictor of response to immune-checkpoint inhibitors and survival in non-small cell lung cancer patients
BackgroundImmune-checkpoint inhibitors (ICIs) revolutionized the treatment of advanced non-small cell lung cancer (NSCLC).1â3 To date, tissue PD-L1 immunohistochemistry is one of the leading biomarkers for prediction of ICIs response but has several limitations.4 5Extracellular vesicles (EVs) are cell-derived structures involved in cell communication and represent a potential minimally invasive alternative to predicting ICI response.6â9 Based on this and our preliminary results presented at SITC 2020,10 we hypothesize that EV PD-L1 predicts response to ICIs in NSCLC.MethodsThis study evaluates an exploratory cohort of advanced/metastatic NSCLC patients receiving ICIs (cohort A) and a validation cohort receiving Pembrolizumab+docetaxel or docetaxel alone (PROLUNG Phase 2 randomized trial) (cohort B).11 Plasma samples were collected pre-treatment (T1) and at 3 treatment cycles (T2) (figure 1A). Response was assessed by computed-tomography scan at 3 (cohort A) and 6â8 treatment cycles (cohort B) according to mono- or chemotherapy combination therapy. Patients were classified as responders (partial, stable, or complete response) or non-responders (progressive disease) by RECISTv1.1.12 EVs were isolated by serial ultracentrifugation and characterized following ISEV recommendations.13,14 Tissue PD-L1 expression was measured by standardized immunohistochemistry (SP263, 22C3, or 28â8 clones)5 and EV PD-L1 expression by immunoblot and its ratio was calculated as EV PD-L1 T2/T1. Cut-offs from the exploratory cohort were applied to the validation cohort, being EV PD-L1 ratio <0.85 = Low.ResultsPaired samples from 30 ICIs, 23 pembrolizumab+docetaxel, and 15 docetaxel treated patients were analyzed. In cohort A, non-responders showed higher EV PD-L1 ratio than responders (p=0.012) (figure 1B) with an area-under-the-curve (AUC) of 77.3%, 83.3% sensitivity, and 61.1% specificity, while the tissue PD-L1 was not predictive (AUC=50%). As a validation, pembrolizumab+docetaxel treated non-responders showed higher EV PD-L1 ratio (p=0.036) than responders with an AUC=69.3%, sensitivity=75%, and specificity=63.6%, outperforming the tissue PD-L1 (figure 1C). No statistically significant differences were observed in the docetaxel group (p=0.885). Moreover, ICIs patients with higher EV PD-L1 ratio showed shorter progression-free survival (PFS) (HR=0.30, p=0.066) and overall survival (OS) (HR=0.17, p=0.016) (figure 1D) which was also observed in the pembrolizumab+docetaxel cohort with shorter PFS (HR=0.12, p=0.004) and OS (HR=0.23, p=0.010) (figure 1E). EV PD-L1 ratio did not predict survival in docetaxel-treated patients.Abstract 23 Figure 1(A) Study design and methodology. (B) EV PD-L1 ratio predicts response to ICIs in 30 NSCLC patients from the discovery cohort A and outperforms tissue PD-L1. (C) EV PD-L1 ratio is predictive for response to pembrolizumab+docetaxel in 23 NSCLC patients but not in 15 patients receiving docetaxel alone from cohort B. (D) Higher EV PD-L1 ratio predicts shorter PFS and OS in 30 patients from the discovery cohort A treated with ICIs. (E) Higher EV PD-L1 ratio is associated with shorter PFS and OS in 23 patients treated with pembrolizumab+docetaxel but not in patients treated with docetaxel alone. Abbreviations: CT: Computed tomography, EV: Extracellular vesicle; HR: Hazard Ratio; ICIs: Immune-checkpoint Inhibitors; IHC: Immunohistochemistry; NR: Non-Responders; OS: Overall Survival; p: p-value; PFS: Progression-free survival; R: Responders [Created with BioRender].ConclusionsWe demonstrated that treatment-associated changes in EV PD-L1 levels are predictive of response and survival in advanced NSCLC patients treated with ICIs. This model, if confirmed in a large prospective cohort, could have important clinical implications, guiding treatment decisions and improving the outcome of patients receiving ICIs.AcknowledgementsWe would like to extend our gratitude to the all the patients that participated in the study.ReferencesBorghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous NonâSmall-Cell Lung Cancer. N Engl J Med 2015;373:1627â39.Herbst RS, Baas P, Kim DW, Felip E, PĂ©rez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540â50.Ruiz-Patiño A, Arrieta O, Cardona AF, MartĂn C, Raez LE, Zatarain-BarrĂłn ZL, et al. Immunotherapy at any line of treatment improves survival in patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP). Thorac Cancer 2020;11:353â61.Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 2021;18:345â362.Hirsch FR, McElhinny A, Stanforth D, Ranger-Moore J, Jansson M, Kulangara K, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thorac Oncol 2017;12:208â222.Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 2019;177:414â427.e13.Cordonnier M, Nardin C, Chanteloup G, Derangere V, Algros MP, Arnould L, et al. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J Extracell Vesicles 2020;9:1710899.Del Re M, Cucchiara F, Rofi E, Fontanelli L, Petrini I, Gri N, et al. A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC. Cancer Immunol Immunother 2020;70:1667â1678.Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382â6.10 de Miguel Perez D, Russo A, Gunasekaran M, Cardona A, Lapidus R, Cooper B, et al. 31 Dynamic change of PD-L1 expression on extracellular vesicles predicts response to immune-checkpoint inhibitors in non-small cell lung cancer patients. 2020J Immunother Cancer;8(Suppl 3):A30âA30.Arrieta O, BarrĂłn F, RamĂrez-Tirado LA, Zatarain-BarrĂłn ZL, Cardona AF, DĂaz-GarcĂa D, et al. Efficacy and safety of pembrolizumab plus docetaxel vs docetaxel alone in patients with previously treated advanced nonâsmall cell lung cancer: the PROLUNG phase 2 randomized clinical trial. 2020JAMA Oncol;6:856â864.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 2009Eur J Cancer;45:228â47.Reclusa P, Verstraelen P, Taverna S, Gunasekaran M, Pucci M, Pintelon I, et al. Improving extracellular vesicles visualization: From static to motion. 2020Sci Rep;10:6494.ThĂ©ry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. 2018J Extracell Vesicles;7:1535750Ethics ApprovalPatients consented to Institutional Review Boardâapproved protocol, A.O. Pappardo, Messina, Italy for cohort A and Thoracic Oncology Unit, Instituto Nacional de CancerologĂa (INCan), MĂ©xico City, MĂ©xico in case of the cohort B. Biological material was transferred to the University of Maryland School of Medicine, Baltimore for EV analysis under signed MTA between institutions MTA/2020â13111 & MTA/2020â13113
Cetuximab Plus Carboplatin and Paclitaxel With or Without Bevacizumab Versus Carboplatin and Paclitaxel With or Without Bevacizumab in Advanced NSCLC (SWOG S0819): A Randomised, Phase 3 Study
Background
EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.
Methods
We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m 2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m 2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712).
Findings
Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9â39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75â1·12; p=0·40; median 5·4 months [95% CI 4·5â5·7] vs 4·8 months [3·9â5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83â1·04; p=0·22; median 10·9 months [95% CI 9·5â12·0] vs 9·2 months [8·7â10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36â0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46â1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78â1·40; p=0·77; and 1·02, 0·77â1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68â1·14; p=0·34; and 0·99, 0·78â1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85â1·17; p=0·97; and 1·03, 0·88â1·20; p=0·69; respectively). The most common grade 3â4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [\u3c 1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group.
Interpretation
Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation
La vesĂcula extracelular TGF-ÎČ basal es un biomarcador predictivo de la respuesta a los inhibidores del punto de control inmunitario y de la supervivencia en el cĂĄncer de pulmĂłn no microcĂtico
Antecedentes: Los inhibidores de los puntos de control inmunitarios (ICI) son una estrategia terapĂ©utica eficaz que mejora la supervivencia de los pacientes con cĂĄncer de pulmĂłn en comparaciĂłn con los tratamientos convencionales. terapĂ©utica eficaz que mejora la supervivencia de los pacientes con cĂĄncer de pulmĂłn en comparaciĂłn con los tratamientos convencionales. Sin embargo, se necesitan biomarcadores predictivos novedosos para estratificar quĂ© pacientes obtienen un beneficio clĂnico, ya que el histolĂłgico PD-L1, actualmente utilizado y altamente heterogĂ©neo, ha mostrado una baja precisiĂłn. La biopsia lĂquida es el anĂĄlisis de biomarcadores en fluidos corporales y representa una herramienta mĂnimamente invasiva que puede utilizarse para monitorizar la evoluciĂłn del tumor y los efectos del tratamiento, reduciendo potencialmente los sesgos asociados a la heterogeneidad tumoral asociada a las biopsias de tejidos. En este contexto citoquinas, como el factor de crecimiento transformante-ÎČ (TGF-ÎČ), pueden encontrarse libres en circulaciĂłn en la sangre y empaquetadas en vesĂculas extracelulares (VE), que tienen un tropismo de administraciĂłn especĂfico y pueden afectar a la interacciĂłn entre el tumor y el sistema inmunitario. El TGF-ÎČ es una citocina inmunosupresora que desempeña un papel crucial en el escape inmunitario de los tumores, la resistencia al tratamiento y la metĂĄstasis. AsĂ pues, nuestro objetivo era evaluar el valor predictivo predictivo del TGF-ÎČ circulante y EV en pacientes con cĂĄncer de pulmĂłn no microcĂtico que reciben ICI.Background: Immuneâcheckpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PDâL1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factorâÎČ (TGFâÎČ), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGFâÎČ is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGFâÎČ in patients with nonâsmallâcell lung cancer receiving ICIs
Extrahepatic Anomalies in Infants With Biliary Atresia: Results of a Large Prospective North American Multicenter Study
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100275/1/hep26512.pd
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