Estimation of secondary cancer projected risk after partial breast irradiation at the 1.5 T MR-linac.

PURPOSE: For patients treated with partial breast irradiation (PBI), potential long-term treatment-related toxicities are important. The 1.5 T magnetic resonance guided linear accelerator (MRL) offers excellent tumor bed visualization and a daily treatment plan adaption possibility, but MRL-specific electron stream and return effects may cause increased dose deposition at air-tissue interfaces. In this study, we aimed to investigate the projected risk of radiation-induced secondary malignancies (RISM) in patients treated with PBI at the 1.5 T MRL. METHODS: Projected excess absolute risk values (EARs) for the contralateral breast, lungs, thyroid and esophagus were estimated for 11 patients treated with PBI at the MRL and compared to 11 patients treated with PBI and 11 patients treated with whole breast irradiation (WBI) at the conventional linac (CTL). All patients received 40.05 Gy in 15 fractions. For patients treated at the CTL, additional dose due to daily cone beam computed tomography (CBCT) was simulated. The t­test with Bonferroni correction was used for comparison. RESULTS: The highest projected risk for a radiation-induced secondary cancer was found for the ipsilateral lung, without significant differences between the groups. A lower contralateral breast EAR was found for MRL-PBI (EAR = 0.89) compared to CTL-PBI (EAR = 1.41, p = 0.01), whereas a lower thyroid EAR for CTL-PBI (EAR = 0.17) compared to MRL-PBI (EAR = 0.33, p = 0.03) and CTL-WBI (EAR = 0.46, p = 0.002) was observed. Nevertheless, when adding the CBCT dose no difference between thyroid EAR for CTL-PBI compared to MRL-PBI was detected. CONCLUSION: Better breast tissue visualization and the possibility for daily plan adaption make PBI at the 1.5 T MRL particularly attractive. Our simulations suggest that this treatment can be performed without additional projected risk of RISM.

Marker-less online MR-guided stereotactic body radiotherapy of liver metastases at a 1.5 T MR-Linac - Feasibility, workflow data and patient acceptance.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is an established ablative treatment for liver tumors with excellent local control rates. Magnetic resonance imaging guided radiotherapy (MRgRT) provides superior soft tissue contrast and may therefore facilitate a marker-less liver SBRT workflow. The goal of the present study was to investigate feasibility, workflow parameters, toxicity and patient acceptance of MRgSBRT on a 1.5 T MR-Linac. METHODS: Ten consecutive patients with liver metastases treated on a 1.5 T MR-Linac were included in this prospective trial. Tumor delineation was performed on four-dimensional computed tomography scans and both exhale triggered and free-breathing T2 MRI scans from the MR-Linac. An internal target volume based approach was applied. Organ at risk constraints were based on the UKSABR guidelines (Version 6.1). Patient acceptance regarding device specific aspects was assessed and toxicity was scored according to the common toxicity criteria of adverse events, version 5. RESULTS: Nine of ten tumors were clearly visible on the 1.5 T MR-Linac. No patient had fiducial markers placed for treatment. All patients were treated with three or five fractions. Median dose to 98% of the gross tumor volume was 38.5 Gy. The median time from "patient identity check" until "beam-off" was 31 min. Median beam on time was 9.6 min. Online MRgRT was well accepted in general and no treatment had to be interrupted on patient request. No event of symptomatic radiation induced liver disease was observed after a median follow-up of ten month (range 3-17 months). CONCLUSION: Our early experience suggests that online 1.5 T MRgSBRT of liver metastases represents a promising new non-invasive marker-free treatment modality based on high image quality, clinically reasonable in-room times and high patient acceptance. Further studies are necessary to assess clinical outcome, to validate advanced motion management and to explore the benefit of online response adaptive liver SBRT.

Development and validation of a 1.5 T MR-Linac full accelerator head and cryostat model for Monte Carlo dose simulations.

PURPOSE: To develop, implement, and validate a full 1.5 T/7 MV magnetic resonance (MR)-Linac accelerator head and cryostat model in EGSnrc for high precision dose calculations accounting for magnetic field effects that are independent from the vendor treatment planning system. METHODS: Primary electron beam parameters for the implemented model were adapted to be in accordance with measured dose profiles of the Elekta Unity (Elekta AB, Stockholm, Sweden). Parameters to be investigated were the mean electron energy as well as the Gaussian radial intensity and energy distributions. Energy tuning was done comparing depth dose profiles simulated with monoenergetic beams of varying energies to measurements. The optimum radial intensity distribution was found by varying the radial full width at half maximum (FWHM) and comparing simulated and measured lateral profiles. The influence of the energy distribution was investigated by comparing simulated lateral and depth dose profiles with varying energy spreads to measured data. Comparison of simulations and measurements was performed by calculating average and maximum local dose deviations. The model was validated recalculating a clinical intensity-modulated radiation therapy plan for the MR-Linac and comparing the resulting dose distribution with simulations from the commercial treatment planning system Monaco using the gamma criterion. RESULTS: Comparison of simulated and measured data showed that the optimum initial electron beam for MR-Linac simulations was monoenergetic with an electron energy of (7.4 ± 0.2) MeV. The optimum Gaussian radial intensity distribution has a FWHM of (2.2 ± 0.3) mm. The average relative deviations were smaller than 1% for all simulated profiles with optimum electron parameters, whereas the largest maximum deviation of 2.07% was found for the 22 × 22 cm 2 cross-plane profile. Profiles were insensitive to energy spread variations. The IMRT plan recalculated with the final MR-Linac model with optimized initial electron beam parameters showed a gamma pass rate of 99.83 % using a gamma criterion of 3%/3 mm. CONCLUSIONS: The EGSnrc MR-Linac model developed in this study showed good accordance with measurements and was successfully used to recalculate a first full clinical IMRT treatment plan. Thus, it shows the general possibility for future secondary dose calculations of full IMRT plans with EGSnrc, which needs further detailed investigations before clinical use.

Correlation of FMISO simulations with pimonidazole-stained tumor xenografts: A question of O2 consumption?

PURPOSE: To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors. METHODS: Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis-Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M0 was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M0 was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity. RESULTS: After optimization, high pixel-based correlations up to R(2) = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p < 0.05), with R(2) ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M0 differed significantly (p < 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s. CONCLUSIONS: It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M0, whose optimum value differed significantly between tumor models.

Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.

BACKGROUND: Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment. PATIENTS AND METHODS: Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome. RESULTS: Mutational profiles and HPV status were successfully established for 179 cases. HPV- tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV- cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV- carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5-12.1, P=0.006) and death (HR 2.2, 95% CI 1.1-4.4, P=0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7-21.1, P=0.11). CONCLUSIONS: Distinct mutation profiles in HPV- and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.

Methodological aspects on hypoxia PET acquisition and image processing.

Tumor hypoxia is one of the main factors compromising the effectiveness of radiotherapy. As a consequence, non-invasive hypoxia imaging with positron emission tomography (PET) is very promising with regard to its potential to provide a functional basis for patient stratification or therapy modification. This review article aims at providing a comprehensive overview of different methodologies for hypoxia PET image acquisition protocols as well as data processing and analysis as used in recent studies and clinical trials. Furthermore, different physical and also technical aspects that may induce ambiguities and limitations into hypoxia PET image acquisition and interpretation are discussed in the context of this article. In the future, dedicated hypoxia PET image acquisition protocols and methodologies for processing, analysis and interpretation of hypoxia PET data are necessary to allow for comparison of hypoxia PET image data acquired in different study centers and enable for the definition of multicenter trials on hypoxia PET imaging and hypoxia-based treatment interventions.

[Pregnancies without complications of patients with jejuno-ileal bypass because of extreme obesity (author's transl)]. / Komplikationslos verlaufende Schwangerschaften bei bestehendem jejunoilealem Bypass wegen extremer Fettsucht.

Report about 3 pregnancies without complications of patients, who had been treated by jejuno-ileal bypass because of extreme obesity. There is no increased risk for the successful finishing of a pregnancy of these patients. A close cooperation between the treating doctors is necessary to cope with possible problems.