Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial.

OBJECTIVES: Chemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial. MATERIAL AND METHODS: NICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached. RESULTS AND CONCLUSION: As of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period. The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective.

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113-LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Intensity-modulated radiotherapy vs. parotid-sparing 3D conformal radiotherapy. Effect on outcome and toxicity in locally advanced head and neck cancer.

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) has rapidly become standard of care in the management of locally advanced head and neck squamous cell carcinoma (HNSCC). In this study, our aim was to retrospectively investigate the effect of the introducing IMRT on outcome and treatment-related toxicity compared to parotid-sparing 3D conformal radiotherapy (3DCRT). MATERIAL AND METHODS: A total of 245 patients with stage III and IV HNSCC treated with primary radiotherapy between January 2003 and December 2010 were included in this analysis: 135 patients were treated with 3DCRT, 110 patients with IMRT. Groups were compared for acute and late toxicity, locoregional control (LRC), and overall survival (OS). Oncologic outcomes were estimated using Kaplan-Meier analysis and compared using a log-rank test. Acute toxicity was analyzed according to the Common Terminology Criteria for Adverse Events v3.0 and late toxicity was scored using the RTOG/EORTC late toxicity scoring system. RESULTS: Median follow-up was 35 months in the IMRT group and 68 months in the 3DCRT group. No significant differences were found in 3-year LRC and OS rates between the IMRT group and 3DCRT group. Significantly less acute mucositis ≥ grade 3 was observed in the IMRT group (32% vs. 44%, p = 0.03). There was significantly less late xerostomia ≥ grade 2 in the IMRT group than in the 3DCRT group (23% vs. 68%, p < 0.001). After 24 months, there was less dysphagia ≥ grade 2 in the IMRT group although differences failed to reach statistical significance. CONCLUSION: The introduction of IMRT in the radiotherapeutic management of locally advanced head and neck cancer significantly improved late toxicity without compromising tumor control compared to a parotid-sparing 3D conformal radiotherapy technique.

WE-G-BRCD-01: A Procedure for Efficient Large-Scale Retrospective Clinical Studies for Online Adaptive Radiotherapy.

PURPOSE: Online adaptive radiotherapy (ART) is promising for handling inter-fraction variations of patient's geometry. Before a clinical implementation of this advanced technology, it is necessary to study its potential clinical gains and optimal frequencies to be used for various tumor sites. The goal of this work is to establish and examine a procedure for efficient large-scale retrospective clinical studies for online ART using a GPU-based re-planning platform. METHODS: The proposed procedure utilizes an in-house developed GPU-based replanning software called SCORE. SCORE starts by applying deformable registration from CT to CBCT and correcting CBCT artifacts and intensities. However, the CBCT image may not cover the whole treatment region due to the limited field of view. In that case, we use deformed CT for replanning and dose calculation. The final optimized fractional dose is calculated using the optimized fluence maps and a finite size pencil beam model. We also use the deformed CT to calculate the delivered fractional dose using the fluence maps from the original plan. The delivered fractional dose is compared to the optimized fractional dose to estimate the daily gain of replanning. To compare accumulated optimized dose and delivered dose, the delivered and optimized doses are mapped back to the original CT geometry using the deformation vector fields. RESULTS: We tested this procedure using prostate cancer IMRT cases and found that the re-optimized and delivered DVHs and dose distributions can be generated in a couple of minutes. CONCLUSIONS: We have developed a procedure using a GPU-based replanning software to retrospectively study the clinical gains of online ART in an efficient and large scale manner.

The cognitive model. Interventions for improved patient-provider communication.

1. Improving patient-provider interactions mandates an understanding on the part of health care providers of patients' situations, thoughts, feelings, and behaviors. 2. The cognitive model, a cornerstone of cognitive therapy, provides a framework to understand the patient's perspective of his or her situation or illness, which is a necessary component of effective patient-provider interactions. 3. Distance learning formats provide flexibility in meeting continuing education needs and allow learners and presenters to interact in a virtual mode.

Isolation and sequence analysis of the trpBA gene cluster, encoding tryptophan synthase, from Azospirillum brasilense.

The trpBA gene cluster of Azospirillum brasilense Sp7 was isolated by complementation of an Escherichia coli trpBA mutant. Both genes code for the two subunits of tryptophan synthase, which catalyzes the last step in tryptophan biosynthesis. No structural features indicating transcriptional regulation could be identified. Upstream of the trpBA cluster an open reading frame encoding a putative periplasmic binding protein, involved in amino acid transport, was identified. Analysis of the downstream region of the trpBA cluster revealed the presence of a putative open reading frame encoding a subunit of the acetyl-coenzyme A carboxylase carboxyl transferase complex.

Characterization of a sugar-binding protein from Azospirillum brasilense mediating chemotaxis to and uptake of sugars.

Our approach to the isolation of plant-inducible bacterial genes of Azospirillum brasilense, based on the analysis of protein patterns of bacteria grown in the presence and in the absence of plant root exudates, led to the identification of an acidic 40 kDa protein. Cloning and sequencing analysis of the corresponding coding DNA region revealed the presence of two open reading frames transcribed in the same orientation. The deduced ORF1 protein, which corresponds to the 40 kDa protein, is very similar to the periplasmic ChvE protein, identified in Agrobacterium tumefaciens and involved in enhanced virulence. The deduced ORF2 protein shows homology to members of the LysR family of transcriptional regulators. The function of the ChvE-like protein in A. brasilense was investigated further. The protein, designated as SbpA (sugar binding protein A), is involved in the uptake of D-galactose and functions in the chemotaxis of A. brasilense towards several sugars, including D-galactose, L-arabinose and D-fucose. Expression of the sbpA gene requires the presence of the same sugars in the growth medium and is enhanced further in combination with carbon starvation of A. brasilense cells.

Bi-functional gfp- and gusA-containing mini-Tn5 transposon derivatives for combined gene expression and bacterial localization studies.

The gfp gene, encoding the green fluorescent protein, was combined with the gusA gene, coding for the beta-glucuronidase enzyme, in mini-Tn5 transposon derivatives for use in Gram-negative bacteria. These mini-Tn5 elements allow simultaneously monitoring of gene expression and localization of the marked bacteria. Introduction of the resultant mini-Tn5 transposons into Rhizobium etli, Azospirillum brasilense and Pseudomonas stutzeri allowed us to visualise the interaction of these bacteria with their host plant. The dual-marker mini-Tn5 transposons constitute a powerful new tool for studying gene expression and ecology of bacteria in the environment and during the interaction with plants.

Auxins upregulate expression of the indole-3-pyruvate decarboxylase gene in Azospirillum brasilense.

Transcription of the Azospirillum brasilense ipdC gene, encoding an indole-3-pyruvate decarboxylase involved in the biosynthesis of indole-3-acetic acid (IAA), is induced by IAA as determined by ipdC-gusA expression studies and Northern analysis. Besides IAA, exogenously added synthetic auxins such as 1-naphthaleneacetic acid, 2,4-dichlorophenoxypropionic acid, and p-chlorophenoxyacetic acid were also found to upregulate ipdC expression. No upregulation was observed with tryptophan, acetic acid, or propionic acid or with the IAA conjugates IAA ethyl ester and IAA-L-phenylalanine, indicating structural specificity is required for ipdC induction. This is the first report describing the induction of a bacterial gene by auxin.