Patterns of recurrence and survival after surgery or stereotactic radiotherapy for early stage NSCLC

IntroductionSurgery is the standard treatment for early stage non–small-cell lung cancer (NSCLC). For medically inoperable patients, stereotactic ablative radiotherapy (SABR) has emerged as widely used standard treatment. The aim of this study was to analyze survival and patterns of tumor recurrence in patients with clinical stage I NSCLC treated with surgery or SABR.MethodsClinical data from all subsequent fluoro-deoxyglucose positron emission tomography/computed tomography-based stage I NSCLC patients (cT1-T2aN0M0) treated with surgery or SABR at our center between 2007 and 2010 were collected. Primary endpoints were overall survival and tumor recurrences/new primary lung tumors. Treatment groups were compared using multivariable Cox regression and competing risk analyses.ResultsThree hundred-forty patients treated with surgery (n = 143) or SABR (n = 197) were included. Surgical patients were younger, had a better WHO performance status and less comorbidities. After adjustment for prognostic covariables, treatment did not influence overall survival (adjusted hazard ratio [HR], SABR versus surgery 1.07; 95% confidence interval [CI]: 0.74–1.54; p = 0.73). Local control and distant recurrence were equal, whereas locoregional recurrences were significantly more frequent after SABR compared with surgery (adjusted sub-HR 2.51; 95% CI: 1.10–5.70; p = 0.028). Nodal failure (HR: 2.16; 95% CI: 1.34–3.48) and distant metastases (HR: 2.12; 95% CI: 1.52–2.97), but not local failure (HR: 1.00; 95% CI: 0.53–1.89) predicted overall survival.ConclusionsIn patients with fluoro-deoxyglucose positron emission tomography/computed tomography-based stage I NSCLC, SABR confers worse locoregional tumor control because of more nodal failures compared with surgery, stressing the need to improve mediastinal and hilar staging

A new CT-based method to quantify radiation-induced lung damage in patients

SummaryA new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT

A taste of the deep-sea: The roles of gustatory and tactile searching behaviour in the grenadier fish <i>Coryphaenoides armatus</i>

The deep-sea grenadier fishes (Coryphaenoides spp.) are among the dominant predators and scavengers in the ocean basins that cover much of Earth's surface. Baited camera experiments were used to study the behaviour of these fishes. Despite the apparent advantages of rapidly consuming food, grenadiers attracted to bait spend a large proportion of their time in prolonged periods of non-feeding activity. Video analysis revealed that fish often adopted a head-down swimming attitude (mean of 21.3 degrees between the fish and seafloor), with swimming velocity negatively related to attitude. The fish also swam around and along vertical and horizontal structures of the lander with their head immediately adjacent to the structure. We initially hypothesised that this behaviour was associated with the use of the short chin barbel in foraging. Barbel histology showed numerous taste buds in the skin, and a barbel nerve with about 20,000 axons in adult fish. A tracing experiment in one undamaged animal revealed the termination fields of the barbel neurons in the trigeminal and rhombencephalic regions, indicating both a mechanoreceptory and a gustatory role for the barbel. Our conclusion was that olfactory foraging becomes ineffective at close ranges and is followed by a search phase using tactile and gustatory sensing by the barbel. The development of this sensory method probably co-evolved alongside behavioural changes in swimming mechanics to allow postural stability at low swimming speeds

The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray.

BACKGROUND: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). METHODS: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. RESULTS: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. CONCLUSION: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential

Micro- and Nanoplastics Breach the Blood–Brain Barrier (BBB): Biomolecular Corona’s Role Revealed

Humans are continuously exposed to polymeric materials such as in textiles, car tires and packaging. Unfortunately, their break down products pollute our environment, leading to widespread contamination with micro- and nanoplastics (MNPs). The blood–brain barrier (BBB) is an important biological barrier that protects the brain from harmful substances. In our study we performed short term uptake studies in mice with orally administered polystyrene micro-/nanoparticles (9.55 µm, 1.14 µm, 0.293 µm). We show that nanometer sized particles—but not bigger particles—reach the brain within only 2 h after gavage. To understand the transport mechanism, we performed coarse-grained molecular dynamics simulations on the interaction of DOPC bilayers with a polystyrene nanoparticle in the presence and absence of various coronae. We found that the composition of the biomolecular corona surrounding the plastic particles was critical for passage through the BBB. Cholesterol molecules enhanced the uptake of these contaminants into the membrane of the BBB, whereas the protein model inhibited it. These opposing effects could explain the passive transport of the particles into the brain

External validation of NTCP-models for radiation pneumonitis in lung cancer patients treated with chemoradiotherapy

PURPOSE: Normal tissue complication probability (NTCP) models can be used to estimate the risk of radiation pneumonitis (RP). The aim of this study was to externally validate the most frequently used prediction models for RP, i.e., the QUANTEC and APPELT models, in a large cohort of lung cancer patients treated with IMRT or VMAT. [1-2] METHODS AND MATERIALS: This prospective cohort study, included lung cancer patients treated between 2013 and 2018. A closed testing procedure was performed to test the need for model updating. To improve model performance, modification or removal of variables was considered. Performance measures included tests for goodness of fit, discrimination, and calibration.RESULTS: In this cohort of 612 patients, the incidence of RP ≥ grade 2 was 14.5%. For the QUANTEC-model, recalibration was recommended which resulted in a revised intercept and adjusted regression coefficient (from 0.126 to 0.224) of the mean lung dose (MLD),. The APPELT-model needed revision including model updating with modification and elimination of variables. After revision, the New RP-model included the following predictors (and regression coefficients): MLD (B = 0.250), age (B = 0.049, and smoking status (B = 0.902). The discrimination of the updated APPELT-model was higher compared to the recalibrated QUANTEC-model (AUC: 0.79 vs. 0.73).CONCLUSIONS: This study demonstrated that both the QUANTEC- and APPELT-model needed revision. Next to changes of the intercept and regression coefficients, the APPELT model improved further by model updating and performed better than the recalibrated QUANTEC model. This New RP-model is widely applicable containing non-tumour site specific variables, which can easily be collected.</p

18F-FDG PET during stereotactic body radiotherapy for stage I lung tumours cannot predict outcome: a pilot study

(18)F-Fluorodeoxyglucose positron emission tomography (FDG PET) has been used to assess metabolic response several months after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. However, whether a metabolic response can be observed already during treatment and thus can be used to predict treatment outcome is undetermined. Ten medically inoperable patients with FDG PET-positive lung tumours were included. SBRT consisted of three fractions of 20 Gy delivered at the 80% isodose at days 1, 6 and 11. FDG PET was performed before, on day 6 immediately prior to administration of the second fraction of SBRT and 12 weeks after completion of SBRT. Tumour metabolism was assessed semi-quantitatively using the maximum standardized uptake value (SUV(max)) and SUV(70%). After the first fraction, median SUV(max) increased from 6.7 to 8.1 (p = 0.07) and median SUV(70%) increased from 5.7 to 7.1 (p = 0.05). At 12 weeks, both median SUV(max) and median SUV(70%) decreased by 63% to 3.1 (p = 0.008) and to 2.5 (p = 0.008), respectively. SUV increased during treatment, possibly due to radiation-induced inflammation. Therefore, it is unlikely that (18)F-FDG PET during SBRT will predict treatment success

Current practice in proton therapy delivery in adult cancer patients across Europe

BACKGROUND AND PURPOSE Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. MATERIALS AND METHODS We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. RESULTS Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). CONCLUSION Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT

Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells

Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine’s bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH