Summary Background Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of ...disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival. Methods In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation. First-line therapy was four or more cycles of platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK rearrangements, respectively. Patients were randomly assigned (1:1) to either local consolidative therapy (chemoradiotherapy or resection of all lesions) with or without subsequent maintenance treatment or to maintenance treatment alone, which could be observation only. Maintenance treatment was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic treatment. Randomisation was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, CNS metastases, intrathoracic nodal status, and EGFR and ALK status. The primary endpoint was progression-free survival analysed in all patients who were treated and had at least one post-baseline imaging assessment. The study is ongoing but not recruiting participants. This study is registered with ClinicalTrials.gov , number NCT01725165. Findings Between Nov 28, 2012, and Jan 19, 2016, 74 patients were enrolled either during or at the completion of first-line systemic therapy. The study was terminated early after randomisation of 49 patients (25 in the local consolidative therapy group and 24 in the maintenance treatment group) as part of the annual analyses done by the Data Safety Monitoring Committee of all randomised trials at MD Anderson Cancer Center, and before a planned interim analysis of 44 events. At a median follow-up time for all randomised patients of 12·39 months (IQR 5·52–20·30), the median progression-free survival in the local consolidative therapy group was 11·9 months (90% CI 5·7–20·9) versus 3·9 months (2·3–6·6) in the maintenance treatment group (hazard ratio 0·35 90% CI 0·18–0·66, log-rank p=0·0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Grade 3 adverse events in the maintenance therapy group were fatigue (n=1) and anaemia (n=1) and in the local consolidative therapy group were oesophagitis (n=2), anaemia (n=1), pneumothorax (n=1), and abdominal pain (n=1, unlikely related). Interpretation Local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone. These findings suggest that aggressive local therapy should be further explored in phase 3 trials as a standard treatment option in this clinical scenario. Funding MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core), National Cancer Institute, National Institutes of Health.
The incidence of early-stage non-small cell lung cancer (NSCLC) among older adults is expected to increase because of demographic trends and computed tomography-based screening; yet, optimal ...treatment in the elderly remains controversial. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort spanning 2001-2007, we compared survival outcomes associated with 5 strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic ablative radiation therapy (SABR), and observation.
Treatment strategy and covariates were determined in 10,923 patients aged ≥ 66 years with stage IA-IB NSCLC. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for the 5 strategies. In a second exploratory analysis, propensity-score matching was used for comparison of SABR with other options.
The median age was 75 years, and 29% had moderate to severe comorbidities. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SABR (1.1%). In Cox regression analysis with a median follow-up time of 3.2 years, SABR was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio HR 0.48; 95% confidence interval CI 0.38-0.63; referent is lobectomy). After 6 months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after SABR was similar to that after lobectomy (HR 0.71; 95% CI 0.45-1.12; referent is SABR). Conventional radiation and observation were associated with poor outcomes in all analyses.
In this population-based experience, lobectomy was associated with the best long-term outcomes in fit elderly patients with early-stage NSCLC. Exploratory analysis of SABR early adopters suggests efficacy comparable with that of surgery in select populations. Evaluation of these therapies in randomized trials is urgently needed.
In this study we sought to identify how contractility at adherens junctions influences apoptotic cell extrusion. We first found that the generation of effective contractility at steady-state ...junctions entails a process of architectural reorganization whereby filaments that are initially generated as poorly organized networks of short bundles are then converted into co-aligned perijunctional bundles. Reorganization requires coronin 1B, which is recruited to junctions by E-cadherin adhesion and is necessary to establish contractile tension at the zonula adherens. When cells undergo apoptosis within an epithelial monolayer, coronin 1B is also recruited to the junctional cortex at the apoptotic/neighbor cell interface in an E-cadherin-dependent fashion to support actin architectural reorganization, contractility, and extrusion. We propose that contractile stress transmitted from the apoptotic cell through E-cadherin adhesions elicits a mechanosensitive response in neighbor cells that is necessary for the morphogenetic event of apoptotic extrusion to occur.
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•Actomyosin network reorganization is necessary for effective junctional contractility•Coronin 1B recruits to E-cadherin contacts, where it regulates F-actin architecture•Actomyosin network reorganization supports apoptotic contractility•E-cadherin recruits coronin 1B for effective apoptotic contractility
Michael et al. show that coronin 1B regulates F-actin network architecture reorganization at cell-cell junctions. This not only maintains junctional tension in epithelia at steady state but is also required for apoptotic cell extrusion, suggesting that extrusion requires a mechanosensitive response in neighboring cells elicited by contractile stress in the apoptotic cell.
Our previously published findings reported that local consolidative therapy (LCT) with radiotherapy or surgery improved progression-free survival (PFS) and delayed new disease in patients with ...oligometastatic non-small-cell lung cancer (NSCLC) that did not progress after front-line systemic therapy. Herein, we present the longer-term overall survival (OS) results accompanied by additional secondary end points.
This multicenter, randomized, phase II trial enrolled patients with stage IV NSCLC, three or fewer metastases, and no progression at 3 or more months after front-line systemic therapy. Patients were randomly assigned (1:1) to maintenance therapy or observation (MT/O) or to LCT to all active disease sites. The primary end point was PFS; secondary end points were OS, toxicity, and the appearance of new lesions. All analyses were two sided, and
values less than .10 were deemed significant.
The Data Safety and Monitoring Board recommended early trial closure after 49 patients were randomly assigned because of a significant PFS benefit in the LCT arm. With an updated median follow-up time of 38.8 months (range, 28.3 to 61.4 months), the PFS benefit was durable (median, 14.2 months 95% CI, 7.4 to 23.1 months with LCT
4.4 months 95% CI, 2.2 to 8.3 months with MT/O;
= .022). We also found an OS benefit in the LCT arm (median, 41.2 months 95% CI, 18.9 months to not reached with LCT
17.0 months 95% CI, 10.1 to 39.8 months with MT/O;
= .017). No additional grade 3 or greater toxicities were observed. Survival after progression was longer in the LCT group (37.6 months with LCT
9.4 months with MT/O;
= .034). Of the 20 patients who experienced progression in the MT/O arm, nine received LCT to all lesions after progression, and the median OS was 17 months (95% CI, 7.8 months to not reached).
In patients with oligometastatic NSCLC that did not progress after front-line systemic therapy, LCT prolonged PFS and OS relative to MT/O.
With the release of Gaia DR2, it is now possible to measure the proper motions (PMs) of the lowest-mass, ultrafaint satellite galaxies in the Milky Way's (MW) halo for the first time. Many of these ...faint satellites are posited to have been accreted as satellites of the Magellanic Clouds (MCs). Using their six-dimensional phase-space information, we calculate the orbital histories of 13 ultrafaint satellites and five classical dwarf spheroidals in a combined MW+LMC+SMC potential to determine which galaxies are dynamically associated with the MCs. These 18 galaxies are separated into four classes: (i) long-term Magellanic satellites that have been bound to the MCs for at least the last two consecutive orbits around the MCs (Carina 2, Carina 3, Horologium 1, Hydrus 1); (ii) Magellanic satellites that were recently captured by the MCs < 1 Gyr ago (Reticulum 2, Phoenix 2); (iii) MW satellites that have interacted with the MCs (Sculptor 1, Tucana 3, Segue 1); and (iv) MW satellites (Aquarius 2, Canes Venatici 2, Crater 2, Draco 1, Draco 2, Hydra 2, Carina, Fornax, Ursa Minor). Results are reported for a range of MW and LMC masses. Contrary to previous work, we find no dynamical association between Carina, Fornax, and the MCs. Finally, we determine that the addition of the SMC's gravitational potential affects the longevity of satellites as members of the Magellanic system (long-term versus recently captured), but it does not change the total number of Magellanic satellites.
Findings from Radiation Therapy Oncology Group (RTOG) 0617 suggested that collateral radiation to the heart may contribute to early death in patients receiving chemoradiation therapy for non-small ...cell lung cancer (NSCLC); however, reports of cardiac toxicity after thoracic radiation therapy (RT) remain limited. Because pericardial disease is the most common cardiac complication of thoracic RT, we investigated the incidence of and risk factors for pericardial effusion (PCE) in patients enrolled in a phase 2 prospective randomized study of intensity modulated RT versus proton therapy for locally advanced NSCLC.
From July 2009 through April 2014, 201 patients were prospectively treated with proton beam therapy or intensity modulated RT to 60 to 74 Gy with concurrent chemotherapy. The primary endpoint (grade ≥2 PCE) was diagnosed on review of follow-up images. Clinical characteristics and cardiac dose-volume parameters associated with PCE were identified via Cox proportional hazards modeling and recursive partitioning analysis of null Martingale residuals. Reproducibility was evaluated in a separate retrospective cohort of 301 patients.
The cumulative incidence rates of PCE among patients in the trial were 31.4% at 1 year and 45.4% at 2 years, with a median time to PCE of 8.9 months. Several cardiac dose-volume parameters (eg, V20 volume receiving ≥20 Gy to V65 volume receiving ≥65 Gy) predicted PCE, but heart volume receiving ≥35 Gy (HV35) was the most strongly associated, with a cutoff volume of 10%. On multivariate analysis, HV35 >10% independently predicted PCE (hazard ratio HR, 2.14; P=.002), a finding that maintained reproducibility in the retrospective validation cohort. Other factors associated with PCE included receipt of adjuvant chemotherapy (HR, 2.82; P<.001) and prior cardiac disease (HR, 1.68; P=.020).
PCE was common after RT for NSCLC, occurring in nearly half of patients even after moderate radiation doses to the heart. Adjuvant chemotherapy may increase the risk of PCE, and HV35 >10% may identify patients at risk of development of this cardiac toxicity.
Intensity modulated proton therapy (IMPT) can improve dose conformality and better spare normal tissue over passive scattering techniques, but range uncertainties complicate its use, particularly for ...moving targets. We report our early experience with IMPT for thoracic malignancies in terms of motion analysis and management, plan optimization and robustness, and quality assurance.
Thirty-four consecutive patients with lung/mediastinal cancers received IMPT to a median 66 Gy(relative biological equivalence RBE). All patients were able to undergo definitive radiation therapy. IMPT was used when the treating physician judged that IMPT conferred a dosimetric advantage; all patients had minimal tumor motion (<5 mm) and underwent individualized tumor-motion dose-uncertainty analysis and 4-dimensional (4D) computed tomographic (CT)-based treatment simulation and motion analysis. Plan robustness was optimized by using a worst-case scenario method. All patients had 4D CT repeated simulation during treatment.
IMPT produced lower mean lung dose (MLD), lung V5 and V20, heart V40, and esophageal V60 than did IMRT (P<.05) and lower MLD, lung V20, and esophageal V60 than did passive scattering proton therapy (PSPT) (P<.05). D5 to the gross tumor volume and clinical target volume was higher with IMPT than with intensity modulated radiation therapy or PSPT (P<.05). All cases were analyzed for beam-angle-specific motion, water-equivalent thickness, and robustness. Beam angles were chosen to minimize the effect of respiratory motion and avoid previously treated regions, and the maximum deviation from the nominal dose-volume histogram values was kept at <5% for the target dose and met the normal tissue constraints under a worst-case scenario. Patient-specific quality assurance measurements showed that a median 99% (range, 95% to 100%) of the pixels met the 3% dose/3 mm distance criteria for the γ index. Adaptive replanning was used for 9 patients (26.5%).
IMPT using 4D CT-based planning, motion management, and optimization was implemented successfully and met our quality assurance parameters for treating challenging thoracic cancers.
Many amphibian species exploit temporary or even ephemeral aquatic habitats for reproduction by maximising larval growth under benign conditions but accelerating development to rapidly undergo ...metamorphosis when at risk of desiccation from pond drying. Here we determine mechanisms enabling developmental acceleration in response to decreased water levels in western spadefoot toad tadpoles (Pelobates cultripes), a species with long larval periods and large size at metamorphosis but with a high degree of developmental plasticity. We found that P. cultripes tadpoles can shorten their larval period by an average of 30% in response to reduced water levels. We show that such developmental acceleration was achieved via increased endogenous levels of corticosterone and thyroid hormone, which act synergistically to achieve metamorphosis, and also by increased expression of the thyroid hormone receptor TRΒ, which increases tissue sensitivity and responsivity to thyroid hormone. However, developmental acceleration had morphological and physiological consequences. In addition to resulting in smaller juveniles with proportionately shorter limbs, tadpoles exposed to decreased water levels incurred oxidative stress, indicated by increased activity of the antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase. Such increases were apparently sufficient to neutralise the oxidative damage caused by presumed increased metabolic activity. Thus, developmental acceleration allows spadefoot toad tadpoles to evade drying ponds, but it comes at the expense of reduced size at metamorphosis and increased oxidative stress.
PDL1 Regulation by p53 via miR-34 Cortez, Maria Angelica; Ivan, Cristina; Valdecanas, David ...
JNCI : Journal of the National Cancer Institute,
01/2016, Letnik:
108, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), the regulation of PDL1 expression is poorly understood. Here, we show that PDL1 is ...regulated by p53 via miR-34.
p53 wild-type and p53-deficient cell lines (p53(-/-) and p53(+/+) HCT116, p53-inducible H1299, and p53-knockdown H460) were used to determine if p53 regulates PDL1 via miR-34. PDL1 and miR-34a expression were analyzed in samples from patients with NSCLC and mutated p53 vs wild-type p53 tumors from The Cancer Genome Atlas for Lung Adenocarcinoma (TCGA LUAD). We confirmed that PDL1 is a direct target of miR-34 with western blotting and luciferase assays and used a p53(R172HΔ)g/+K-ras(LA1/+) syngeneic mouse model (n = 12) to deliver miR-34a-loaded liposomes (MRX34) plus radiotherapy (XRT) and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs). A two-sided t test was applied to compare the mean between different treatments.
We found that p53 regulates PDL1 via miR-34, which directly binds to the PDL1 3' untranslated region in models of NSCLC (fold-change luciferase activity to control group, mean for miR-34a = 0.50, SD = 0.2, P < .001; mean for miR-34b = 0.52, SD = 0.2, P = .006; and mean for miR-34c = 0.59, SD = 0.14, and P = .006). Therapeutic delivery of MRX34, currently the subject of a phase I clinical trial, promoted TILs (mean of CD8 expression percentage of control group = 22.5%, SD = 1.9%; mean of CD8 expression percentage of MRX34 = 30.1%, SD = 3.7%, P = .016, n = 4) and reduced CD8(+)PD1(+) cells in vivo (mean of CD8/PD1 expression percentage of control group = 40.2%, SD = 6.2%; mean of CD8/PD1 expression percentage of MRX34 = 20.3%, SD = 5.1%, P = .001, n = 4). Further, MRX34 plus XRT increased CD8(+) cell numbers more than either therapy alone (mean of CD8 expression percentage of MRX34 plus XRT to control group = 44.2%, SD = 8.7%, P = .004, n = 4). Finally, miR-34a delivery reduced the numbers of radiation-induced macrophages (mean of F4-80 expression percentage of control group = 52.4%, SD = 1.7%; mean of F4-80 expression percentage of MRX34 = 40.1%, SD = 3.5%, P = .008, n = 4) and T-regulatory cells.
We identified a novel mechanism by which tumor immune evasion is regulated by p53/miR-34/PDL1 axis. Our results suggest that delivery of miRNAs with standard therapies, such as XRT, may represent a novel therapeutic approach for lung cancer.
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