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The optimal treatment strategy for low-grade glioma (LGG) is still a matter of controversy. Considering that the prognosis is typically favorable, the prevention of late sequelae is of particular importance. Proton beam therapy (PRT) has the potential to further reduce the burden of treatment related side effects. We set out to evaluate the clinical outcome of proton irradiation with a particular focus on morphologic features on magnetic resonance imaging (MRI).We assessed prospectively 110 patients who received radiotherapy with protons for histologically proven LGG. Clinical and radiological information were analyzed resulting in more than 1200 available MRI examinations with a median follow-up of 39 months. Newly diagnosed contrast-enhancing lesions on MRI were delineated and correlated with parameters of the corresponding treatment plan. A voxel-based dose-matched paired analysis of the linear energy transfer (LET) inside vs outside lesions was performed.Proton beam irradiation of patients with low-grade glioma results in overall survival (OS) of 90% after seven years. Median progression free survival had not yet been reached with surviving fraction of 54% after seven years. The incidence of temporary or clinically silent radiation induced contrast enhancement was significantly higher than previously assumed, however, symptomatic radiation necrosis was only detected in one patient. These radiation-induced contrast-enhancing lesions were almost exclusively seen at the distal beam end of the proton beam. In 22 out of 23 patients, the average LET of voxels inside contrast-enhancing lesions was significantly increased, compared to dose-matched voxels outside the lesions.Symptomatic radiation necrosis following PRT was as rare as conventional photon-based treatment series suggest. However, the increased incidence of asymptomatic radiation-induced brain injuries with an increased average LET observed in this cohort provides strong clinical evidence to support the hypothesis that the relative biological effectiveness of protons is variable and different to the fixed factor of 1.1 currently used worldwide.

Purpose: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. Methods: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45–60 Gy (RBE) (1.5–2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan–Meier method. Results: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1–2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. Conclusions: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed.

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to −48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another −39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose–response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.

Background: To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). Methods: Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45–50 Gy with a simultaneous integrated boost of 50–56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. Results: The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p = 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). Conclusions: The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

Background Following surgery for soft tissue sarcoma of the retroperitoneum, the predominant pattern of failure is local recurrence, which remains the main cause of death. Radiotherapy is utilized to reduce recurrence rates but the efficacy of this strategy has not been definitely established. As treatment tolerability is more favorable with preoperative radiotherapy, normofractionated neoadjuvant treatment is the current approach. The final results of the prospective, randomized STRASS (EORTC 62092) trial, which compared the efficacy of this combined treatment to that of surgery alone, are still awaited; preliminary results presented at the 2019 ASCO Annual Meeting indicated that combined treatment is associated with better local control in patients with liposarcoma (74.5% of the cohort, 11% benefit in abdominal progression free survival after 3 years, p = 0.049). Particles allow better sparing of surrounding tissues at risk, e.g., bowel epithelium, and carbon ions additionally offer biologic advantages and are preferred in slow growing tumors. Furthermore, hypofractionation allows for a significantly shorter treatment interval with a lower risk of progression during radiotherapy. Methods and design We present a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the retroperitoneum will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5–6 fractions per week] in each arm). The primary objective is the safety and feasibility based on the proportion of grade 3–5 toxicity (CTCAE, version 5.0) in the first 12 months after surgery or discontinuation of treatment for any reason related to the treatment. Local control, local progression-free survival, disease-free survival, overall survival, and quality of life are the secondary endpoints of the study. Discussion The aim of this study is to confirm that hypofractionated, accelerated preoperative radiotherapy is safe and feasible. The rationale for the use of particle therapy is the potential for reduced toxicity. The data will lay the groundwork for a randomized phase III trial comparing hypofractionated proton and carbon ion irradiation with regard to local control. Trial registration ClinicalTrials.gov NCT04219202. Retrospectively registered on January 6, 2020

Background Desmoid-type fibromatosis is a rare, potentially locally aggressive disease. Herein we present our experience in the treatment with radiotherapy. Methods and materials In total 40 patients who received 44 treatments from 2009 to 2018 at the Heidelberg University Hospital with photons (N = 28) as well as protons (N = 15) and carbon ions (N = 1) were investigated. The median age at radiotherapy was 41 years [range 8–78]. Familial adenomatous polyposis (FAP) was confirmed for nine patients and 30 had a unifocal desmoid tumor. The localizations were abdominal wall, abdominopelvic cavity, thoracic wall, extremity, head and neck and trunk. The median prescribed dose was 54 Gy/ Gy (RBE) [range 39.6–66, IQR 50–60]. Eleven treatments were performed at the time of first diagnosis; 33 at the time of progression or recurrence. Post-operative radiotherapy was performed in 17 cases. The median planning target volume was 967 ml [84–4364 ml, IQR 447–1988]. Survival analysis was performed by the Kaplan-Meier Method. Results The median follow-up time was 32 months [1–153]. At the end of the follow-up interval all patients but one were alive. The estimated local progression free survival of the treated lesion in 3 and 5 years was 76.4% and 63,8%, respectively. The progression-free survival in 3 and 5 years was 72.3 and 58.4% and the overall survival was 97.4 and 97.4%, respectively. In case of macroscopic tumor (N = 31) before radiotherapy a partial remission was observed in 12 cases (38.7%) and a complete remission in 4 cases (12.9%). Progression was observed in 13 (29.5%) cases, predominantly at the margin of the planning target volume (PTV, N = 5, 38,4%) followed by progression within the PTV (N = 4, 30.8%). In univariate analysis multifocal localization was associated with impaired progression-free survival (p = 0.013). One patient developed a grade V gastrointestinal bleeding, otherwise no acute toxicity >°III was observed. Late toxicity was depending on the localization of the desmoid tumor and was especially severe in patients with FAP and abdominopelvine desmoids including gastrointesinal fistula, perforation and abscess. Conclusion Radiotherapy in the treatment of desmoids can lead to long term control. Treatment of patients with abdominopelvine desmoids should be avoided, as the risk of higher-grade complications is substantial.

Background This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. Methods A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan–Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. Results During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8–53.8; reverse Kaplan–Meier median follow-up time 56.3 months, 95% CI: 51.9–60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1‑year, 3‑year, and 5‑year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. Conclusion Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

In cases of simultaneous chemoradiotherapy (CRT), early recognition of toxic side effects is important, as drug discontinuation may prevent further injury. It appears favorable to undertake further steps to investigate whether patient subgroups behave differently depending on their toxicity profile. We retrospectively analyzed 125 consecutive patients with non-metastasized carcinoma of the head and neck who were treated with CRT (cisplatin 40 mg/m2 weekly) in 2013/2014. Patients were planned to receive six cycles of cisplatin. Statistical analyses were performed using the chi2 test, t-test, Kaplan–Meier method, and the log-rank test, as appropriate. Eighty-six patients did not reach the intended sixth cycle (68.8%; 60.0% of whom were ≥60 years, p

Ventricular arrhythmia storm is a potentially life-threatening clinical event that requires immediate intervention.1, 2, 3 Therapeutic strategies include antiarrhythmic drug therapy, deep sedation, cardiac pacing, catheter ablation, and the use of cardiac assist systems.1, 4 Only recently, a novel innovative therapeutic approach has been successfully established in patients with refractory ventricular tachycardia (VT). Cuculich and colleagues5 presented a series of 5 patients with recurrent VT episodes that could be successfully treated with noninvasive cardiac radiation using a single fraction of 25 Gy targeting the suspected VT exit site and the associated ventricular scar. These first promising results were further validated by a recent prospective study published by the same group that included 17 patients with refractory VT episodes and 2 patients with cardiomyopathy related to premature ventricular contractions.6 However, none of the patients published so far was treated with stereotactic radiotherapy for ventricular fibrillation (VF) storm.

Avoidance of therapy-induced apoptosis is a hallmark of acquired resistance towards radiotherapy. Thus, breaking resistance still challenges modern cancer therapy. The Bcl-2 protein family is known for its regulatory role in apoptosis signaling, making Bcl-2, Mcl-1 and Bcl-xL promising targets. This study evaluates the effects of highly specific inhibitors for Bcl-xL (WEHI-539), Bcl-2 (ABT-199) and Mcl-1 (S63845) as radiosensitizers. Covering a broad spectrum of solid tumors, Non-Small-Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC) and synovial sarcoma cell lines were exposed to fractionated radiation as standard therapy with or without Bcl-2 protein inhibition. Protein expression was detected by Western blot and cell death was assessed by flow cytometry measuring apoptosis. In contrast to NSCLC, a high level of Bcl-xL and its upregulation during radiotherapy indicated radioresistance in HNSCC and synovial sarcoma. Radioresistant cell lines across all entities benefited synergistically from combined therapy with Bcl-xL inhibition and fractionated radiation. In NSCLC cell lines, Mcl-1 inhibition significantly augmented radiotherapy independent of the expression level. Our data suggest that among antiapoptotic Bcl-2 proteins, targeting Bcl-xL may break resistance to radiation in HNSCC, synovial sarcoma and NSCLC in vitro. In NSCLC, Mcl-1 might be a promising target that needs further investigation.

Background To investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. Methods Between August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. Results The median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. Conclusion CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.

During the last decades, radiation oncology has been subject to a number of technological innovations. Particle therapy has evolved in parallel to the modern high-precision photon radiotherapy techniques and offers a superior dose distribution with decreased integral dose to healthy tissues. With advancing precision of treatment, the necessity for accurate and confident target volume delineation is rising. When morphological imaging reaches its limitations, molecular imaging can provide valuable information.

During the last decades, radiation oncology has been subject to a number of technological innovations. Particle therapy has evolved in parallel to the modern high-precision photon radiotherapy techniques and offers a superior dose distribution with decreased integral dose to healthy tissues. With advancing precision of treatment, the necessity for accurate and confident target volume delineation is rising. When morphological imaging reaches its limitations, molecular imaging can provide valuable information.

ZusammenfassungAls Querschnittsdisziplin ist die Strahlentherapie in der Behandlung vieler onkologischer Krankheitsbilder vertreten, und deckt damit nahezu das gesamte Spektrum der Onkologie ab. Aufgrund der Komplexität der Krankheitsbilder, der Seltenheit der Erkrankungen und den speziellen Anforderungen multimodaler Therapieregime nimmt die pädiatrische Radioonkologie in diesem Spektrum eine Sonderstellung ein. Sowohl das besondere Nebenwirkungsprofil als auch der erhöhte logistische und technische Aufwand erfordern neben einer engen interdisziplinären Abstimmung insbesondere die Erfahrung eines auf die Behandlung pädiatrischer Patienten spezialisierten Teams. Dank ihrer besonderen physikalischen Eigenschaften mit einer sehr hohen Konformität verspricht die Protonentherapie bei gleicher Effektivität eine geringere Nebenwirkungsrate im Vergleich zur konventionellen Radiotherapie mittels Photonen. Der folgende Artikel bietet einen kurzen Überblick über die Besonderheiten der pädiatrischen Radioonkologie.

Background The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). Patients and methods This study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. Results Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets. Conclusions Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management., Highlights • Upfront LT delay intracranial progression, but do not prolong OS in oncogene-driven NSCLC. • Use of stereotactic versus whole-brain radiotherapy and primary tumor TP53 status do not significantly affect brain control. • Non-del19 EGFR mutations and ‘short’ EML4-ALK fusions are independent predictors of earlier intracranial failure.

ZusammenfassungKaum eine andere Disziplin wird durch physikalische Erkenntnisse und technologischen Fortschritt beeinflusst wie die Radiotherapie. Die Einführung der Intensitätsmodulierten Radiotherapie (IMRT) ermöglichte eine höhere Präzision und bessere Risikoorganschonung. Der Einsatz von Protonen mit ihren speziellen Eigenschaften bietet insbesondere große Vorteile in der Therapie von pädiatrischen und jungen Patienten und ermöglicht die Therapie von Tumoren mit heikler anatomischer Lagebeziehung z. B. an der Schädelbasis. Zu den modernsten Errungenschaften gehört die Kohlenstoffionentherapie, sie steht gerade mal an 11 Standorten weltweit zur Verfügung. Durch die besonderen biophysikalischen Eigenschaften ist diese besonders für die Behandlung von strahlenresistenten Tumoren wie Chordomen, Chondrosarkomen und adenoidzystischen Karzinomen, in Angrenzung an strahlensensible Risikoorgane geeignet. Die Dosisverteilung der Partikeltherapie ist auch den modernsten Methoden der Photonentherapie weit überlegen. In besonderer Weise wird die Radiotherapie durch die Fortschritte in der Bildgebung, speziell MRT und PET, beeinflusst. Die Möglichkeiten der „image guidance“, der bildgebenden Betrachtung unter der laufenden Therapie zur Positionierungsgenauigkeit, gipfeln in der adaptiven Radiotherapie, der Anpassung an Veränderungen des Tumors in Größe und Lage sowie an Lageveränderungen von Risikoorganen. Für die weitere Erforschung dieser Möglichkeiten werden aktuell 2 Hybridgeräte aus MRT und Linearbeschleuniger in Heidelberg und Tübingen installiert. Mit Spannung gestaltet sich die Suche nach patientenspezifischen Biomarkern für Therapieansprechen sowie strahlensensibilisierenden Substanzen zur „Targeted Therapy“. Die große Herausforderung der modernen Strahlentherapie wird die Individualisierung der Therapie bezüglich der Dosis, Zielvolumendefinition und Therapiedauer darstellen.

Re-irradiation can offer a potentially curative solution in case of progression after initial therapy; however, a second course of radiotherapy can be associated with an increased risk of severe side-effects. Particle therapy with protons and especially carbon ions spares surrounding tissue better than most photon techniques, thus it is of high potential for re-irradiation. Irradiation of tumors of the brain, head and neck and skull base involves several delicate risk organs, e.g. optic system, brainstem, salivary gland or swallowing muscles. Adequate local control rates with tolerable side-effects have been described for several tumors of these locations as meningioma, adenoid cystic carcinoma, chordoma or chondrosarcoma and head and neck tumors. High life time doses nonetheless lead to a different scope of side-effects, e.g. an enhanced rate of carotid blow outs has been reported. This review summarizes the current data on particle irradiation of the aforementioned locations and malignancies.

Background An inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far. Methods Serial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model. Results Immunohistochemical analysis showed an improved prognosis of ALDH1A2high OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2highCRABP2high staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression. Conclusions This study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2low tumors might benefit from adjuvant treatment with retinoids. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0476-0) contains supplementary material, which is available to authorized users.

Purpose: To develop an automated method with which to distinguish metabolically different adipose tissues in a large number of subjects using whole-body magnetic resonance imaging (MRI) datasets for improving the understanding of chronic disease risk predictions associated with distinct adipose tissue compartments. Materials and Methods: In all, 314 participants were scanned using a 1.5T MRI-scanner with a 2-point Dixon whole-body sequence. Image segmentation was automated using standard image processing techniques and knowledge-based methods. Abdominal adipose tissue was separated into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) by statistical shape models. Bone marrow was removed to provide a more accurate measurement of adipose tissue. To assess segmentation accuracy, ground-truth segmentations in 52 images were performed manually by one operator. Due to the high effort of manual delineation, manual segmentation was limited to seven slices per volume. Results: Volumetric differences were 3.30 ± 2.97% and 6.22 ± 5.28% for SAT and VAT, respectively. The systematic error shows an overestimation of 4.22 ± 7.01% for VAT and 0.37 ± 4.45% for SAT. Coefficients-of-variation from repeated measurements were: 3.50 ± 2.93% for VAT and 0.35 ± 0.26% for SAT. The approach of removing bone marrow worked well in most body regions. Only occasionally the method failed for knees and/or shinbone, which resulted in an overestimation of SAT by 3.14 ± 1.45%. Conclusion: We developed a fully automatic process to assess SAT and VAT in whole-body MRI data. The method can support epidemiological studies investigating the relationship between excess body fat and chronic diseases. J. Magn. Reson. Imaging 2012; 36:1421–1434. © 2012 Wiley Periodicals, Inc.