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1.
Innovation (N Y) ; 3(1): 100194, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34977836

RESUMO

Immune checkpoint blockade (ICB) therapies exhibit substantial clinical benefit in different cancers, but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune features. Here, we reveal overall positive correlations among immune checkpoints and immune cell populations. Clinically, patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy, suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune response. As proof-of-concept, we demonstrated that the immune activation score (IS Δ) based on dynamic alteration of interleukins in patient plasma as early as two cycles (4-6 weeks) after starting immunotherapy can accurately predict immunotherapy efficacy. Our results reveal a systematic landscape of associations among immune features and provide a noninvasive, cost-effective, and time-efficient approach based on dynamic profiling of pre- and on-treatment plasma to predict immunotherapy efficacy.

2.
Am J Hematol ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35015316

RESUMO

Clonal hematopoiesis (CH) mutations are common among individuals without known hematologic disease. CH mutations have been associated with numerous adverse clinical outcomes across many different studies. We systematically reviewed the available literature for clinical outcomes associated with CH mutations in patients without hematologic disease. We searched PubMed, EMBASE, and Scopus for eligible studies. Three investigators independently extracted the data, and each study was verified by a second author. Risk of bias was assessed using the Newcastle-Ottawa Scale. We identified 32 studies with 56 cohorts that examine the association between CH mutations and clinical outcomes. We conducted meta-analyses comparing outcomes among individuals with and without detectable CH mutations. We conducted meta-analyses for cardiovascular diseases (nine studies; HR = 1.61, 95% CI = 1.26-2.07, p = .0002), hematologic malignancies (seven studies; HR = 5.59, 95% CI = 3.31-9.45, p < .0001), therapy-related myeloid neoplasms (four studies; HR = 7.55, 95% CI = 4.3-13.57, p < .001), and death (nine studies; HR = 1.34, 95% CI = 1.2-1.5, p < .0001). The cardiovascular disease analysis was further stratified by variant allele fraction (VAF) and gene, which showed a statistically significant association only with a VAF of ≥ 10% (HR = 1.42, 95% CI = 1.24-1.62, p < .0001), as well as statistically significant associations for each gene examined with the largest magnitude of effect found for CH mutations in JAK2 (HR = 3.5, 95% CI = 1.84-6.68, p < .0001). Analysis of the association of CH mutations with hematologic malignancy demonstrated a numeric stepwise increase in risk with increasing VAF thresholds. This analysis strongly supports the association of CH mutations with a clinically meaningful increased risk of adverse clinical outcomes among individuals without hematologic disease, particularly with increasing VAF thresholds.

3.
J Immunother Cancer ; 10(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35058327

RESUMO

BACKGROUND: To determine whether antibiotic treatment is a risk factor for immune-related adverse events (irAEs) across different patients with cancer receiving anti-PD-1/PD-L1 therapies. METHODS: The retrospective analysis includes clinical information from 767 patients with cancer treated at Hunan Cancer Hospital from 2017 to 2020. The pharmacovigilance data analysis includes individual cases of 38,705 safety reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2014 to 2020, and 25,122 cases of safety reports from the World Health Organization database VigiBase from 2014 to 2019. All cases that received anti-PD-1/PD-L1 treatment were included. Multiomics data from patients across 25 cancer types were download from The Cancer Genome Atlas. Logistic regression and propensity score algorithm was employed to calculate OR of irAEs. RESULTS: Retrospective analysis of in-house patients showed that irAE potential risks are higher in all cancer (OR 2.12, 95% CI 1.38 to 3.22, false discovery rate (FDR) adjusted-p=1.93×10-3) and patients with lung cancer (OR 3.16, 95% CI 1.67 to 5.95, FDR adjusted-p=1.93×10-3) when using antibiotics. Potential risk of irAEs in patients with lung cancer with antibiotic treatment is significantly higher in FAERS (OR 1.39, 95% CI 1.21 to 1.59; FDR adjusted-p=1.62×10-5) and VigiBase (OR 1.32, 95% CI 1.09 to 1.59, FDR adjusted-p=0.05). Mechanistically, decreased microbial diversity caused by antibiotics use may increase the irAE risk through mediating the irAE-related factors. CONCLUSIONS: Our study is the first to comprehensively demonstrate the associations of irAEs and antibiotic during anti-PD-1/PD-L1 therapy across a wide spectrum of cancers by analyzing multisource data. Administration of antibiotics should be carefully evaluated in patients with cancer treated by anti-PD-1/PD-L1 to avoid potentially increasing irAE risk.

4.
Cancer Treat Res Commun ; 30: 100514, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35051703

RESUMO

OBJECTIVE: This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC). METHODS: Patients received cCRT (carboplatin/paclitaxel and 60 Gy/30 fractions radiotherapy); oral trametinib (7 days/week) commenced on day 1 and completed on the final day of radiotherapy. Dose-finding of trametinib was done using the time-to-event continual reassessment method (TiTE-CRM); dose levels were 0.5mg (level -1), 1mg (initial, level 1), 1.5mg (level 2), and 2mg (level 3). Progression-free (PFS) and overall survival (OS) times were also recorded. RESULTS: Fifteen patients (stage III, variety of KRAS mutations) were treated, with 1/5/4/5 at dose levels -1/1/2/3, respectively. Five patients received dose reductions (n=2, levels 2 and 3; n=1, level 1). Twelve patients completed the full cCRT course. One patient (following 12d trametinib) was taken off protocol for an unrelated/unresolved grade 1 event and later experienced grade 5 sepsis/respiratory failure. There was one grade 4 retinal detachment; grade 3 events included skin rash (n=2) and ventricular dysfunction, pneumonitis, pain, fatigue, and diarrhea (n=1 each). The final dose selected by the TiTE-CRM of trametinib was 1.5 mg. Pharmacokinetic profiles were elucidated and extensively described. At median follow-up of 70 months, median PFS was 11 months and median OS was 38 months. CONCLUSIONS: The MTD for trametinib when combined with cCRT is 1.5 mg, with encouraging preliminary outcomes. This combination merits further study to combine with consolidation durvalumab in non-metastatic KRAS mutant NSCLC.

5.
Acta Oncol ; : 1-6, 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34913815

RESUMO

PURPOSE: It is essential to evaluate the risk of occult lymph node (LN) disease in early-stage non-small cell lung cancer (NSCLC), especially because delivering stereotactic ablative radiotherapy (SABR) assumes no occult spread. This study was designed to assist clinicians in roughly quantifying this risk for cN0 NSCLC. METHODS: The National Cancer Data Base was queried for cN0 cM0 lung squamous cell or adenocarcinoma who underwent surgery and LN dissection without neoadjuvant therapy. Statistics included multivariable logistic regression to evaluate factors associated with pN + disease. RESULTS: 109,964 patients were included. For tumors with size ≤1.0, 1.1-2.0, 2.1-3.0, 3.1-4.0, 4.1-5.0, 5.1-6.0, 6.1-7.0, and >7.0 cm, the pN + rate was 4.4, 7.7, 12.9, 18.0, 20.2, 22.5, 24.4, and 26.4%, respectively. When examining patients with more complete LN dissections (defined as removal of at least 10 LNs), the respective values were 6.6, 11.5, 17.6, 25.3, 26.8, 29.7, 30.7, and 31.6%. Moderately-poorly differentiated disease and adenocarcinomas were associated with a higher rate of pN + disease (p < .001 for both). For every cm increase in tumor size, the relative occult nodal risk increased by 10-14% (p < .001). For every elapsed day from initial diagnosis, the relative risk increased by ∼1% (p < .001). Graphs with best-fit lines were created based on tumor size, histology, and differentiation to aid physicians in estimating the pN + risk. CONCLUSIONS: This nationwide study can allow clinicians to roughly estimate the rate of occult LN disease in cN0 NSCLC. These data can also assist in guiding enrollment on randomized trials of SABR ± immunotherapy, individualizing follow-up imaging surveillance, and patient counseling to avoid post-diagnosis delays.

6.
IEEE Sens J ; 21(21): 23971-23978, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34970084

RESUMO

We report radiatively coupled arrayed gold nanodisks on invisible substrate (AGNIS) as a cost-effective, high-performance platform for nanoplasmonic biosensing. By substrate undercut, the electric field distribution around the nanodisks has been restored to as if the nanodisks were surrounded by a single medium, thereby provides analyte accessibility to otherwise buried enhanced electric field. The AGNIS substrate has been fabricated by wafer-scale nanosphere lithography without the need for costly lithography. The LSPR blue-shifting behavior synergistically contributed by radiative coupling and substrate undercut have been investigated for the first time, which culminates in a remarkable refractive index sensitivity increase from 207 nm/RIU to 578 nm/RIU. The synergy also improves surface sensitivity to monolayer neutravidin-biotin binding from 7.4 nm to 20.3 nm with the limit of detection (LOD) of neutravidin at 50 fM, which is among the best label-free results reported to date on this specific surface binding reaction. As a potential cancer diagnostic application, extracellular vesicles such as exosomes excreted by cancer and normal cells were measured with a LOD within 112-600 (exosomes/µL), which would be sufficient in many clinical applications. Using CD9, CD63, and CD81 antibodies, label-free profiling has shown increased expression of all three surface antigens in cancer-derived exosomes. This work demonstrates, for the first time, strong synergy of arrayed radiative coupling and substrate undercut can enable economical, ultrasensitive biosensing in the visible light spectrum where high-quality, low-cost silicon detectors are readily available for point-of-care applications.

7.
Int J Part Ther ; 8(2): 17-27, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722808

RESUMO

Purpose: To assess possible differences in radiation-induced lymphocyte depletion for esophageal cancer patients being treated with the following 3 treatment modalities: intensity-modulated radiation therapy (IMRT), passive scattering proton therapy (PSPT), and intensity-modulated proton therapy (IMPT). Methods and Materials: We used 2 prediction models to estimate lymphocyte depletion based on dose distributions. Model I used a piecewise linear relationship between lymphocyte survival and voxel-by-voxel dose. Model II assumes that lymphocytes deplete exponentially as a function of total delivered dose. The models can be fitted using the weekly absolute lymphocyte counts measurements collected throughout treatment. We randomly selected 45 esophageal cancer patients treated with IMRT, PSPT, or IMPT at our institution (15 per modality) to demonstrate the fitness of the 2 models. A different group of 10 esophageal cancer patients who had received PSPT were included in this study of in silico simulations of multiple modalities. One IMRT and one IMPT plan were created, using our standards of practice for each modality, as competing plans to the existing PSPT plan for each patient. We fitted the models by PSPT plans used in treatment and predicted absolute lymphocyte counts for IMRT and IMPT plans. Results: Model validation on each modality group of patients showed good agreement between measured and predicted absolute lymphocyte counts nadirs with mean squared errors from 0.003 to 0.023 among the modalities and models. In the simulation study of IMRT and IMPT on the 10 PSPT patients, the average predicted absolute lymphocyte count (ALC) nadirs were 0.27, 0.35, and 0.37 K/µL after IMRT, PSPT, and IMPT treatments using Model I, respectively, and 0.14, 0.22, and 0.33 K/µL using Model II. Conclusions: Proton plans carried a lower predicted risk of lymphopenia after the treatment course than did photon plans. Moreover, IMPT plans outperformed PSPT in terms of predicted lymphocyte preservation.

8.
Front Oncol ; 11: 748331, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737959

RESUMO

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC.

9.
Med Phys ; 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34800037

RESUMO

PURPOSE: The main purpose of this work was to generate and validate the dosimetric accuracy of proton beams of dimensions that are appropriate for in vivo small animal and in vitro ultrahigh dose rate (FLASH) radiotherapy experiments using a synchrotron-based treatment delivery system. This study was performed to enable future investigations of the relevance of a spread-out Bragg peak (SOBP) under FLASH conditions. METHODS: The spill characteristics of the small field fixed horizontal beam line were modified to deliver accelerated protons in times as short as 2 ms and to control the dose delivered. A Gaussian-like transverse beam profile was transformed into a square uniform one at FLASH dose rates, while avoiding low-dose regions, a crucial requirement to protect normal tissue during FLASH irradiation. Novel beam-shaping devices were designed using Monte Carlo techniques to produce up to about 6 cm3 of uniform dose in SOBPs while maximizing the dose rate. These included a scattering foil, a conical flattening filter to maximize the flux of protons into the region of interest, energy filters, range compensators, and collimators. The shapes, sizes, and positions of the components were varied to provide the required field sizes and SOBPs. RESULTS: The designed and fabricated devices were used to produce 10-, 15-, and 20-mm diameter, circular field sizes and 10-, 15-, and 20-mm SOBP modulation widths at uniform physical dose rates of up to 375 Gy/s at the center of the SOBP and a minimum dose rate of about 255 Gy/s at the entrance, respectively, in cylindrical volumes. The flatness of lateral dose profiles at the center could be adjusted to within ±1.5% at the center of the SOBP. Assessment of systematic uncertainties, such as impact of misalignments and positioning uncertainties, was performed using simulations, and the results were used to provide appropriate adjustments to ensure high-accuracy FLASH beam delivery for both in vitro and in vivo preclinical experiments. CONCLUSIONS: It is feasible to use synchrotron-generated proton beams of sufficient dimensions for FLASH radiobiology experiments. We expect to use the system we developed to acquire in vitro and in vivo small animal FLASH radiobiology data as a function of dose, dose rate, oxygen content, and linear energy transfer to help us understand the underlying mechanisms of the FLASH phenomenon.

10.
Front Cardiovasc Med ; 8: 763930, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746270

RESUMO

Overlapping risks for cancer and cardiovascular diseases (CVD), the two leading causes of mortality worldwide, suggest a shared biology between these diseases. The role of senescence in the development of cancer and CVD has been established. However, its role as the intersection between these diseases remains unclear. Senescence was originally characterized by an irreversible cell cycle arrest after a high number of divisions, namely replicative senescence (RS). However, it is becoming clear that senescence can also be instigated by cellular stress, so-called stress-induced premature senescence (SIPS). Telomere shortening is a hallmark of RS. The contribution of telomere DNA damage and subsequent DNA damage response/repair to SIPS has also been suggested. Although cellular senescence can mediate cell cycle arrest, senescent cells can also remain metabolically active and secrete cytokines, chemokines, growth factors, and reactive oxygen species (ROS), so-called senescence-associated secretory phenotype (SASP). The involvement of SASP in both cancer and CVD has been established. In patients with cancer or CVD, SASP is induced by various stressors including cancer treatments, pro-inflammatory cytokines, and ROS. Therefore, SASP can be the intersection between cancer and CVD. Importantly, the conventional concept of senescence as the mediator of cell cycle arrest has been challenged, as it was recently reported that chemotherapy-induced senescence can reprogram senescent cancer cells to acquire "stemness" (SAS: senescence-associated stemness). SAS allows senescent cancer cells to escape cell cycle arrest with strongly enhanced clonogenic growth capacity. SAS supports senescent cells to promote both cancer and CVD, particularly in highly stressful conditions such as cancer treatments, myocardial infarction, and heart failure. As therapeutic advances have increased overlapping risk factors for cancer and CVD, to further understand their interaction may provide better prevention, earlier detection, and safer treatment. Thus, it is critical to study the mechanisms by which these senescence pathways (SAS/SASP) are induced and regulated in both cancer and CVD.

11.
Redox Biol ; 47: 102132, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34619528

RESUMO

The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors.


Assuntos
Doença da Artéria Coronariana , Poli(ADP-Ribose) Polimerases , Difosfato de Adenosina/metabolismo , Animais , Doença da Artéria Coronariana/metabolismo , Retroalimentação , Humanos , Camundongos , Mitocôndrias/metabolismo , Fenótipo , Fosforilação , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ribose/metabolismo
12.
JCO Clin Cancer Inform ; 5: 1044-1053, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34665662

RESUMO

PURPOSE: Radiotherapy (RT)-induced lymphopenia (RIL) is commonly associated with adverse clinical outcomes in patients with cancer. Using machine learning techniques, a retrospective study was conducted for patients with esophageal cancer treated with proton and photon therapies to characterize the principal pretreatment clinical and radiation dosimetric risk factors of grade 4 RIL (G4RIL) as well as to establish G4RIL risk profiles. METHODS: A single-institution retrospective data of 746 patients with esophageal cancer treated with photons (n = 500) and protons (n = 246) was reviewed. The primary end point of our study was G4RIL. Clustering techniques were applied to identify patient subpopulations with similar pretreatment clinical and radiation dosimetric characteristics. XGBoost was built on a training set (n = 499) to predict G4RIL risks. Predictive performance was assessed on the remaining n = 247 patients. SHapley Additive exPlanations were used to rank the importance of individual predictors. Counterfactual analyses compared patients' risk profiles assuming that they had switched modalities. RESULTS: Baseline absolute lymphocyte count and volumes of lung and spleen receiving ≥ 15 and ≥ 5 Gy, respectively, were the most important G4RIL risk determinants. The model achieved sensitivitytesting-set 0.798 and specificitytesting-set 0.667 with an area under the receiver operating characteristics curve (AUCtesting-set) of 0.783. The G4RIL risk for an average patient receiving protons increased by 19% had the patient switched to photons. Reductions in G4RIL risk were maximized with proton therapy for patients with older age, lower baseline absolute lymphocyte count, and higher lung and heart dose. CONCLUSION: G4RIL risk varies for individual patients with esophageal cancer and is modulated by radiotherapy dosimetric parameters. The framework for machine learning presented can be applied broadly to study risk determinants of other adverse events, providing the basis for adapting treatment strategies for mitigation.


Assuntos
Neoplasias Esofágicas , Linfopenia , Terapia com Prótons , Idoso , Neoplasias Esofágicas/radioterapia , Humanos , Linfopenia/diagnóstico , Linfopenia/epidemiologia , Linfopenia/etiologia , Aprendizado de Máquina , Terapia com Prótons/efeitos adversos , Estudos Retrospectivos
13.
Mol Cell ; 81(20): 4319-4332.e10, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34686316

RESUMO

Microdroplet single-cell ATAC-seq is widely used to measure chromatin accessibility, however, highly scalable and simple sample multiplexing procedures are not available. Here, we present a transposome-assisted single nucleus barcoding approach for ATAC-seq (SNuBar-ATAC) that utilizes a single oligonucleotide adaptor for multiplexing samples during the existing tagmentation step and does not require a pre-labeling procedure. The accuracy and scalability of SNuBar-ATAC was evaluated using cell line mixture experiments. We applied SNuBar-ATAC to investigate treatment-induced chromatin accessibility dynamics by multiplexing 28 mice with lung tumors that received different combinations of chemo, radiation, and targeted immunotherapy. We also applied SNuBar-ATAC to study spatial epigenetic heterogeneity by multiplexing 32 regions from a human breast tissue. Additionally, we show that SNuBar can multiplex single cell ATAC and RNA multiomic assays in cell lines and human breast tissue samples. Our data show that SNuBar is a highly accurate, easy-to-use, and scalable system for multiplexing scATAC-seq and scATAC and RNA co-assay experiments.

14.
Lancet Oncol ; 22(10): 1448-1457, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34529930

RESUMO

BACKGROUND: A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND). METHODS: This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992. FINDINGS: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis. INTERPRETATION: Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended. FUNDING: Varian Medical Systems and US National Cancer Institute (National Institutes of Health).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Radiocirurgia , Cirurgia Torácica Vídeoassistida , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pneumonectomia/efeitos adversos , Pneumonectomia/mortalidade , Intervalo Livre de Progressão , Estudos Prospectivos , Radiocirurgia/efeitos adversos , Radiocirurgia/mortalidade , Texas , Cirurgia Torácica Vídeoassistida/efeitos adversos , Cirurgia Torácica Vídeoassistida/mortalidade , Fatores de Tempo
15.
Radiother Oncol ; 164: 27-36, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34534613

RESUMO

Esophageal cancer remains one of the leading causes of death from cancer across the world despite advances in multimodality therapy. Although early-stage disease can often be treated surgically, the current state of the art for locally advanced disease is concurrent chemoradiation, followed by surgery whenever possible. The uniform midline tumor location puts a strong importance on the need for precise delivery of radiation that would minimize dose to the heart and lungs, and the biophysical properties of proton beam makes this modality potential ideal for esophageal cancer treatment. This review covers the current state of knowledge of proton therapy for esophageal cancer, focusing on published retrospective single- and multi-institutional clinical studies, and emerging data from prospective clinical trials, that support the benefit of protons vs photon-based radiation in reducing postoperative complications, cardiac toxicity, and severe radiation induced immune suppression, which may improve survival outcomes for patients. In addition, we discuss the incorporation of immunotherapy to the curative management of esophageal cancers in the not-too-distant future. However, there is still a lack of high-level evidence to support proton therapy in the treatment of esophageal cancer, and proton therapy has its limitations in clinical application. It is expected to see the results of future large-scale randomized clinical trials and the continuous improvement of proton radiotherapy technology.

16.
Int J Radiat Oncol Biol Phys ; 111(5): e27-e37, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34348174

RESUMO

PURPOSE: The combination of cytotoxic chemotherapy with radiation therapy (CRT) has resulted in significant improvements in clinical outcomes for patients with many locally advanced unresectable cancers. Only a small proportion of patients achieve pathologic complete responses to CRT; combination of CRT with targeted agents offers the promise of further improving treatment responses. However, numerous clinical trials have failed to show an improvement in clinical outcomes with the addition of targeted agents. To increase the accessibility of our screening method and accelerate the pace at which novel combinations with CRT are identified and incorporated into standard practices for treatments, we report details on screening method optimization, data generation, and downstream data analysis. METHODS: In part, the gap in translation to large, expensive, and ultimately unsuccessful clinical trials reflects the shortcomings of inconsistently designed, executed, and reported preclinical data on which these studies are based. In an effort to standardize the selection of agents for future clinical testing, we have designed, optimized and validated a high throughput, high content, clonogenic assay platform for step-wise progression of preclinical studies from in vitro to in vivo in non-small cell lung cancer and pancreatic ductal adenocarcinoma. RESULTS: This highly stable in vitro method was standardized for identification of the most promising CTEP drugs that could best be combined with CRT from among as screen of multiple agents tested in an unbiased manner using 96-well plates. The methodology lends itself to seamless testing of multiple agents in a similar fashion allowing cross-comparisons, evaluation of CRT, or radiation therapy alone, and testing multiple concentrations of test agents sequenced at different times before and after radiation. The method identified Trametinib as a strong CRT sensitizer in KRAS-mutant non-small cell lung cancer and pancreatic ductal adenocarcinoma cell lines. This platform has enabled the screening and identification of several chemoradiation sensitizers. CONCLUSIONS: High throughput, high content clonogenic drug screening assay allows for the rapid identification of targets and agents to be translated to the clinic to help improve the effectiveness of current standard of care CRT in various solid tumors.

17.
Int J Radiat Oncol Biol Phys ; 111(5): e63-e74, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34343607

RESUMO

The development of molecular targeted drugs with radiation and chemotherapy is critically important for improving the outcomes of patients with hard-to-treat, potentially curable cancers. However, too many preclinical studies have not translated into successful radiation oncology trials. Major contributing factors to this insufficiency include poor reproducibility of preclinical data, inadequate preclinical modeling of intertumoral genomic heterogeneity that influences treatment sensitivity in the clinic, and a reliance on tumor growth delay instead of local control (TCD50) endpoints. There exists an urgent need to overcome these barriers to facilitate successful clinical translation of targeted radiosensitizers. To this end, we have used 3-dimensional (3D) cell culture assays to better model tumor behavior in vivo. Examples of successful prediction of in vivo effects with these 3D assays include radiosensitization of head and neck cancers by inhibiting epidermal growth factor receptor or focal adhesion kinase signaling, and radioresistance associated with oncogenic mutation of KRAS. To address the issue of tumor heterogeneity, we leveraged institutional resources that allow high-throughput 3D screening of radiation combinations with small-molecule inhibitors across genomically characterized cell lines from lung, head and neck, and pancreatic cancers. This high-throughput screen is expected to uncover genomic biomarkers that will inform the successful clinical translation of targeted agents from the National Cancer Institute Cancer Therapy Evaluation Program portfolio and other sources. Screening "hits" need to be subjected to refinement studies that include clonogenic assays, addition of disease-specific chemotherapeutics, target/biomarker validation, and integration of patient-derived tumor models. The chemoradiosensitizing activities of the most promising drugs should be confirmed in TCD50 assays in xenograft models with or without relevant biomarker and using clinically relevant radiation fractionation. We predict that appropriately validated and biomarker-directed targeted therapies will have a higher likelihood than past efforts of being successfully incorporated into the standard management of hard-to-treat tumors.

18.
Semin Radiat Oncol ; 31(4): 274-285, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34455983

RESUMO

In multiple anatomic sites, patients with cancers associated with the Human Papillomavirus (HPV) experience better locoregional control and overall survival after radiotherapy and/or chemoradiotherapy than patients with HPV-negative cancers. These improved outcomes suggest that relatively unique biological features in HPV-positive cancers may increase sensitivity to DNA damaging agents as well as an impaired DNA damage response. This review will address potential biological mechanisms driving this increased sensitivity of HPV-positive cancer to radiation and/or chemotherapy. This review will discuss the clinical and preclinical observations that support the intrinsic radiosensitivity and/or chemosensitivity of HPV-positive cancers. Furthermore, this review will highlight the molecular mechanisms for increased radiation sensitivity using the classical "4 Rs" of radiobiology: repair, reassortment, repopulation, and reoxygenation. First, HPV-positive cancers have increased DNA damage due to increased oxidative stress and impaired DNA damage repair due to the altered activity TP53, p16, TIP60, and other repair proteins. Second, irradiated HPV-positive cancer cells display increased G2/M arrest leading to reassortment of cancer cells in more radiosensitive phases of the cell cycle. In addition, HPV-positive cancers have less radioresistant cancer stem cell subpopulations that may limit their repopulation during radiotherapy. Finally, HPV-positive cancers may also have less hypoxic tumor microenvironments that make these cancers more sensitive to radiation than HPV-negative cells. We will also discuss extrinsic immune and microenvironmental factors enriched in HPV-positive cancers that facilities responses to radiation. Therefore, these potential biological mechanisms may underpin the improved clinical outcomes often observed in these virally induced cancers.

19.
Radiother Oncol ; 163: 192-198, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34453954

RESUMO

BACKGROUND: The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia. METHODS: Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy ("extended-CROSS") and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir < 0.2 µL). The secondary outcome measures were the prediction model's external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan-Meier analysis. RESULTS: A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (p < 0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70-0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (p = 0.045). CONCLUSION: The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia-mitigating strategies.

20.
Int J Radiat Oncol Biol Phys ; 111(5): 1131-1139, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34454045

RESUMO

Radiation therapy is a major treatment modality used in > 60% of cancer patients as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. Although cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiation therapy alone is modest. There is a need to enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biological pathways are known to enhance the effectiveness of radiation therapy, there is currently a paucity of drugs approved for use in combination. Several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiation therapy, but the results of these trials have been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in an appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This article provides an overview of the opportunities and challenges of developing therapeutics to combine with radiation therapy, and some guidance toward preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long term.

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