Stereotactic body radiotherapy for recurrent hemoptysis due to chronic pulmonary aspergillosis: a case report and systematic review of the literature.

PURPOSE Chronic pulmonary aspergillosis (CPA) can manifest as fungus balls in preexisting cavities of lung parenchyma and recurrent hemoptysis is among the most frequent complications. Radiotherapy can be considered for treatment-refractory aspergilloma and severe hemoptysis. To the best of our knowledge, we present the first application of stereotactic body radiotherapy (SBRT) for a pulmonary aspergilloma in a patient with limited functional lung capacity. The topic was further expanded on with a systematic review of the literature addressing the implementation of radiotherapy in CPA patients. CASE REPORT A 52-year-old man presented with recurring and treatment-refractory hemoptysis caused by chronic cavitary aspergillosis localized in the left lower lobe. We applied SBRT on two consecutive days with a total dose of 16 Gy. Hemoptysis frequency decreased to a clinically insignificant level. SYSTEMATIC REVIEW We performed a systematic search of the literature in line with the PRISMA statement. The initial PubMed search resulted in 230 articles, of which 9 were included. RESULTS The available literature contained 35 patients with CPA who received radiotherapy. Dose fractionation usually ranged from 2 to 4 Gy per fraction, applied almost exclusively in conventional two-dimensional (2D) techniques. There is no report of SBRT usage in such a scenario. Most cases report a positive treatment response after irradiation. CONCLUSION The presented case demonstrates long-term clinical stability after SBRT for recurrent hemoptysis due to pulmonary aspergilloma. The systematic literature search revealed that concept definition is still uncertain, and further work is necessary to establish radiotherapy in clinical practice

Correction: An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies.

ISSN:1420-682XISSN:1420-907

Efficiency enhancements of a Monte Carlo beamlet based treatment planning process: implementation and parameter study.

OBJECTIVE The computational effort to perform beamlet calculation, plan optimization and final dose calculation of a treatment planning process (TPP) generating intensity modulated treatment plans is enormous, especially if Monte Carlo (MC) simulations are used for dose calculation. The goal of this work is to improve the computational efficiency of a fully MC based TPP for static and dynamic photon, electron and mixed photon-electron treatment techniques by implementing multiple methods and studying the influence of their parameters. APPROACH A framework is implemented calculating MC beamlets efficiently in parallel on each available CPU core. The user can specify the desired statistical uncertainty of the beamlets, a fractional sparse dose threshold to save beamlets in a sparse format and minimal distances to the PTV surface from which 2x2x2=8 (medium) or even 4x4x4=64 (large) voxels are merged. The compromise between final plan quality and computational efficiency of beamlet calculation and optimization is studied for several parameter values to find a reasonable trade-off. For this purpose, four clinical and one academic case are considered with different treatment techniques. MAIN RESULTS Setting the statistical uncertainty to 5% (photon beamlets) and 15% (electron beamlets), the fractional sparse dose threshold relative to the maximal beamlet dose to 0.1% and minimal distances for medium and large voxels to the PTV to 1 cm and 2 cm, respectively, does not lead to substantial degradation in final plan quality. Only OAR sparing is slightly degraded. Furthermore, computation times are reduced by about 58% (photon beamlets), 88% (electron beamlets) and 96% (optimization) compared to using 2.5% (photon beamlets) and 5% (electron beamlets) statistical uncertainty and no sparse format nor voxel merging. SIGNIFICANCE Several methods are implemented improving computational efficiency of beamlet calculation and plan optimization of a fully MC based TPP without substantial degradation in final plan quality

An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies.

PURPOSE Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells. EXPERIMENTAL DESIGN: We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment. RESULTS We identified an 'oncogene addiction phosphorylation signature' (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments. CONCLUSIONS We propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene

DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions.

The DNA-PK holoenzyme is a fundamental element of the DNA damage response machinery (DDR), which is responsible for cellular genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant DNA-PK status and activity with cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT), hypoxia, metabolism, nuclear receptors signaling and inflammatory responses. In particular tumor entities as prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by DNA-PK that control metastasis and tumor progression. Correspondingly, DNA-PK emerges as an obvious therapeutic target in cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with DNA-damaging agents (DDAs) that act by inflicting DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of DNA-PK and its role in cancer. In the current article we are aiming to systematically describe the main findings on DNA-PK signaling in major cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the DNA-PK inhibitors repertoire

Postoperative Radiotherapy of Prostate Cancer: Adjuvant versus Early Salvage.

Results of three randomized clinical trials (RCTs) comparing adjuvant radiotherapy (ART) and early salvage radiotherapy (eSRT) of prostate carcinoma and a subsequent meta-analysis of the individual patient data from these RCTs were recently published. The results suggest that early eSRT is as effective and potentially less toxic than ART. Therefore, eSRT should be considered the standard of care. However, due to limitations in the RCTs, ART remains a valid treatment option in patients with the combination of high-risk features such as Gleason Score (GS) 8-10, positive surgical margins (R1) and pathological T-stage 3 or 4 (pT3/4). This article provides a critical appraisal of the RCTs and the rationale for recommendations adopted in the current national guidelines regarding patients with high-risk features after radical prostatectomy (RP): ART should be offered in case of pT3/pT4 and R1 and Gleason Score 8-10; ART can be offered in case of pT3/pT4 and R0 and Gleason Score 8-10 as well as in case of multifocal R1 (including pT2) and Gleason Score 8-10. In any case, the alternative treatment option of eSRT in case of rising PSA should be discussed with the patient

The predictive value of segmentation metrics on dosimetry in organs at risk of the brain.

BACKGROUND Fully automatic medical image segmentation has been a long pursuit in radiotherapy (RT). Recent developments involving deep learning show promising results yielding consistent and time efficient contours. In order to train and validate these systems, several geometric based metrics, such as Dice Similarity Coefficient (DSC), Hausdorff, and other related metrics are currently the standard in automated medical image segmentation challenges. However, the relevance of these metrics in RT is questionable. The quality of automated segmentation results needs to reflect clinical relevant treatment outcomes, such as dosimetry and related tumor control and toxicity. In this study, we present results investigating the correlation between popular geometric segmentation metrics and dose parameters for Organs-At-Risk (OAR) in brain tumor patients, and investigate properties that might be predictive for dose changes in brain radiotherapy. METHODS A retrospective database of glioblastoma multiforme patients was stratified for planning difficulty, from which 12 cases were selected and reference sets of OARs and radiation targets were defined. In order to assess the relation between segmentation quality -as measured by standard segmentation assessment metrics- and quality of RT plans, clinically realistic, yet alternative contours for each OAR of the selected cases were obtained through three methods: (i) Manual contours by two additional human raters. (ii) Realistic manual manipulations of reference contours. (iii) Through deep learning based segmentation results. On the reference structure set a reference plan was generated that was re-optimized for each corresponding alternative contour set. The correlation between segmentation metrics, and dosimetric changes was obtained and analyzed for each OAR, by means of the mean dose and maximum dose to 1% of the volume (Dmax 1%). Furthermore, we conducted specific experiments to investigate the dosimetric effect of alternative OAR contours with respect to the proximity to the target, size, particular shape and relative location to the target. RESULTS We found a low correlation between the DSC, reflecting the alternative OAR contours, and dosimetric changes. The Pearson correlation coefficient between the mean OAR dose effect and the Dice was -0.11. For Dmax 1%, we found a correlation of -0.13. Similar low correlations were found for 22 other segmentation metrics. The organ based analysis showed that there is a better correlation for the larger OARs (i.e. brainstem and eyes) as for the smaller OARs (i.e. optic nerves and chiasm). Furthermore, we found that proximity to the target does not make contour variations more susceptible to the dose effect. However, the direction of the contour variation with respect to the relative location of the target seems to have a strong correlation with the dose effect. CONCLUSIONS This study shows a low correlation between segmentation metrics and dosimetric changes for OARs in brain tumor patients. Results suggest that the current metrics for image segmentation in RT, as well as deep learning systems employing such metrics, need to be revisited towards clinically oriented metrics that better reflect how segmentation quality affects dose distribution and related tumor control and toxicity

Superior loco-regional control after primary surgery compared to chemo-radiotherapy for advanced stage laryngeal cancer.

OBJECTIVE The optimal strategy to treat loco-regionally advanced squamous cell carcinoma of the larynx (LSCC) remains to be defined. The goal of this single institution retrospective study was to report on oncologic outcome of advanced LSCC treated with curative intent. METHODS Patients diagnosed and treated for stage T3-T4a LSCC between 2001 and 2014 were retrospectively analyzed. Time-to-event endpoints were calculated beginning from the date of histologic diagnosis, which were analyzed with log-rank test and Cox proportional hazard models. RESULTS The cohort was divided into two subgroups: primary radiotherapy with concomitant cisplatin (CRT) (n=30, 38%) and primary surgery (n=48, 62%). Median follow-up was 56 months. Locoregional control (LRC) for the primary surgery and CRT were 95% and 50% in 5 years, respectively (p<0.01). Progression free survival (PFS) for the primary surgery and CRT were 61% and 38% in 5 years, respectively (p=0.23). The overall survival (OS) after primary surgery and CRT in 5 years were 63% vs. 65%, respectively (p=0.93). The 5-years LRC was significantly superior after surgery compared to RT for cT3 primaries (100% vs 50%, p= 0.0022). No significant differences were observed in the remaining subgroups regarding cT stage and PFS or OS. CONCLUSION Our series demonstrated superior LRC after primary surgery followed by risk-adapted adjuvant (C)RT compared to primary CRT in cT3 LSCC, but no significant difference in PFS or OS in locally-advanced LSCC. The optimal patient selection criteria for the ideal treatment for loco-regionally advanced LSCC still needs to be defined

Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control

Delivery time reduction for mixed photon-electron radiotherapy by using photon MLC collimated electron arcs.

Electron arcs in mixed-beam radiotherapy (Arc-MBRT) consisting of intensity-modulated electron arcs with dynamic gantry rotation potentially reduce the delivery time compared to mixed-beam radiotherapy containing electron beams with static gantry angle (Static-MBRT). This study aims to develop and investigate a treatment planning process (TPP) for photon multileaf collimator (pMLC) based Arc-MBRT.&#xD;&#xD;Approach: An existing TPP for Static-MBRT plans is extended to integrate electron arcs with a dynamic gantry rotation and intensity modulation using a sliding window technique. The TPP consists of a manual setup of electron arcs, and either static photon beams or photon arcs, shortening of the source-to-surface distance for the electron arcs, initial intensity modulation optimization, selection of a user-defined number of electron beam energies based on dose contribution to the target volume and finally, simultaneous photon and electron intensity modulation optimization followed by full Monte Carlo dose calculation. Arc-MBRT plans, Static-MBRT plans, and photon-only plans were created and compared for four breast cases. Dosimetric validation of two Arc-MBRT plans was performed using film measurements.&#xD;&#xD;Main results: The generated Arc-MBRT plans are dosimetrically similar to the Static-MBRT plans while outperforming the photon-only plans. The mean heart dose is reduced by 32% on average in the MBRT plans compared to the photon-only plans. The estimated delivery times of the Arc-MBRT plans are similar to the photon-only plans but less than half the time of the Static-MBRT plans. Measured and calculated dose distributions agree with a gamma passing rate of over 98% (3% global, 2 mm) for both delivered Arc-MBRT plans. &#xD;&#xD;Significance: A TPP for Arc-MBRT is successfully developed and Arc-MBRT plans showed the potential to improve the dosimetric plan quality similar as Static-MBRT while maintaining short delivery times of photon-only treatments. This further facilitates integration of pMLC-based MBRT into clinical practice