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Abstract Background and purpose Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments. Materials and methods Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms. Results Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported. Conclusions The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity.

Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours ( n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK , Estrogen , EGFR , TGFbeta , WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD-L1 expression/PD-1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC.

Background: Definitive chemoradiotherapy (dCRT) is a standard treatment for patients with locally advanced head and neck cancer. There is a clinical need for a stratification of this prognostically heterogeneous group of tumors in order to optimize treatment of individual patients. We retrospectively reviewed all patients with head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx, treated with dCRT from 09/2008 until 03/2016 at the Department of Radiation Oncology, LMU Munich. Here we report the clinical results of the cohort which represent the basis for biomarker discovery and molecular genetic research within the framework of a clinical cooperation group., Methods: Patient data were collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors., Results: We identified 184 patients with a median follow-up of 65 months and a median age of 64 years. Patients received dCRT with a median dose of 70 Gy and simultaneous chemotherapy in 90.2% of cases, mostly mitomycin C / 5-FU in concordance with the ARO 95-06 trial. The actuarial 3-year overall survival (OS), local, locoregional and distant failure rates were 42.7, 29.8, 34.0 and 23.4%, respectively. Human papillomavirus-associated oropharynx cancer (HPVOPC) and smaller gross tumor volume were associated with significantly improved locoregional tumor control rate, disease-free survival (DFS) and OS in multivariate analysis. Additionally, lower hemoglobin levels were significantly associated with impaired DFS und OS in univariate analysis. The extent of lymph node involvement was associated with distant failure, DFS and OS. Moreover, 92 patients (50%) of our cohort have been treated in concordance with the ARO 95-06 study, corroborating the results of this study., Conclusion: Our cohort is a large unselected monocentric cohort of HNSCC patients treated with dCRT. Tumor control rates and survival rates compare favorably with the results of previously published reports. The clinical data, together with the available tumor samples from biopsies, will allow translational research based on molecular genetic analyses.

Purpose: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined., Experimental Design: We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed., Results: For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, P < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, P < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, P < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low ( n = 17), low-intermediate ( n = 80), high-intermediate ( n = 48), or high risk ( n = 17) for recurrence ( P < 0.001)., Conclusions: The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC. See related commentary by Clump et al., p. 1441 ., (©2018 American Association for Cancer Research.)

Previously, we have shown that copy number gain of the chromosomal band 16q24.3 is associated with impaired clinical outcome of radiotherapy-treated head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify a prognostic mRNA signature from genes located on 16q24.3 in radio(chemo)therapy-treated HNSCC patients of the TCGA (The Cancer Genome Atlas, n = 99) cohort. We applied stepwise forward selection using expression data of 41 16q24.3 genes. The resulting optimal Cox-proportional hazards regression model included the genes APRT, CENPBD1, CHMP1A, and GALNS. Afterward, the prognostic value of the classifier was confirmed in an independent cohort of HNSCC patients treated by adjuvant radio(chemo)therapy (LMU-KKG cohort). The signature significantly differentiated high- and low-risk patients with regard to overall survival (HR = 2.01, 95% CI 1.10-3.70; P = 0.02125), recurrence-free survival (HR = 1.84, 95% CI 1.01-3.34; P = 0.04206), and locoregional recurrence-free survival (HR = 1.87, 95% CI 1.03-3.40; P = 0.03641). The functional impact of the four signature genes was investigated after reconstruction of a gene association network from transcriptome data of the TCGA HNSCC cohort using a partial correlation approach. Subsequent pathway enrichment analysis of the network neighborhood (first and second) of the signature genes suggests involvement of HNSCC-associated signaling pathways such as apoptosis, cell cycle, cell adhesion, EGFR, JAK-STAT, and mTOR. Furthermore, a detailed analysis of the first neighborhood revealed a cluster of co-expressed genes located on chromosome 16q, substantiating the impact of 16q24.3 alterations in poor clinical outcome of HNSCC. The reported gene expression signature represents a prognostic marker in HNSCC patients following postoperative radio(chemo)therapy., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Postoperative (chemo) radiation improves tumor control and survival in high-risk patients with head and neck squamous cell carcinoma based on established risk factors. The clinical cooperation group "Personalized Radiotherapy in Head and Neck Cancer" focuses on the identification and validation of new biomarkers, which are aimed at eventually stratifying and personalizing the therapy concept. Hence, we reviewed all patients with head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, treated with postoperative (chemo) radiation from 06/2008 until 06/2015 at the Department of Radiation Oncology in the University Hospital, LMU Munich. Here we report the clinical results of the cohort, laying the foundation for further research within the framework of a clinical cooperation group., Methods: Patient data were retrospectively (until 2013) and prospectively (from 2013) collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors., Results: We identified 302 patients (median follow-up 45 months, average age 60.7 years), having received postoperative (chemo)radiation (median 64 Gy). Chemotherapy was added in 58% of cases, mostly Cisplatin/5- Fluorouracil in concordance with the ARO 96-3 study. The 3-year overall survival, local, locoregional and distant failure estimates were 70.5, 9.7, 12.2 and 13.5%, respectively. Human papillomavirus-associated oropharyngeal cancer was associated with a significant improved overall survival, locoregional, distant and overall tumor control rates in multivariate analysis. Additionally, in multivariate analysis, for local failure, resection status and perineural invasion, for locoregional and distant failure extracapsular extension and for overall survival the presence of nodal disease were significant adverse factors. Moreover, 138 patients have been treated in concordance with the ARO 96-3 protocol, corroborating the results of this study., Conclusions: Our cohort represents a large unselected cohort of patients with head and neck squamous cell carcinoma treated with postoperative (chemo)radiation. Tumor control rates and survival rates are consistent with the results of previously reported data.

Background: Due to the complex surface of the human body, total or partial skin irradiation using large electron fields is challenging. The aim of the present study was to quantify the magnitude of dose optimization required after the application of standard fields., Methods: Total skin electron irradiation (TSEI) was applied using the Stanford technique with six dual-fields. Patients presenting with localized lesions were treated with partial skin electron irradiation (PSEI) using large electron fields, which were individually adapted. In order to verify and validate the dose distribution, in vivo dosimetry with thermoluminescent dosimeters (TLD) was performed during the first treatment fraction to detect potential dose heterogeneity and to allow for an individual dose optimization with adjustment of the monitor units (MU)., Results: Between 1984 and 2017, a total of 58 patients were treated: 31 patients received TSEI using 12 treatment fields, while 27 patients underwent PSEI and were treated with 4-8 treatment fields. After evaluation of the dosimetric results, an individual dose optimization was necessary in 21 patients. Of these, 7 patients received TSEI (7/31). Monitor units (MU) needed to be corrected by a mean value of 117 MU (±105, range 18-290) uniformly for all 12 treatment fields, corresponding to a mean relative change of 12% of the prescribed MU. In comparison, the other 14 patients received PSEI (14/27) and the mean adjustment of monitor units was 282 MU (±144, range 59-500) to single or multiple fields, corresponding to a mean relative change of 22% of the prescribed MU. A second dose optimization to obtain a satisfying dose at the prescription point was need in 5 patients., Conclusions: Thermoluminescent dosimetry allows an individual dose optimization in TSEI and PSEI to enable a reliable adjustment of the MUs to obtain the prescription dose. Especially in PSEI in vivo dosimetry is of fundamental importance.

In this case of suspected sphenoid wing meningioma, Ga-DOTATATE PET/CT showed a somatostatin receptor (SSR)-expressing tumor with extension to the nasopharynx and SSR-expressing cervical lymph nodes. Subsequent biopsy from the nasopharynx revealed an Epstein-Barr virus (EBV)-associated, undifferentiated World Health Organization type 3 nasopharyngeal carcinoma (NPC), a potential clinical pitfall due to the reported high SSR expression of this tumor subtype. In consideration of the high target-to-background contrast, SSR ligands might be superior to F-FDG for EBV-associated NPC PET imaging, particularly at the skull base. Somatostatin receptor ligands might furthermore offer interesting theranostic possibilities for patients with advanced/extensive EBV-associated NPC.

Background and Purpose: Our aim was to evaluate the feasibility and potential advantages of dose guided patient positioning based on dose recalculation on scatter corrected cone beam computed tomography (CBCT) image data., Material and Methods: A scatter correction approach has been employed to enable dose calculations on CBCT images. A recently proposed tool for interactive multicriterial dose-guided patient positioning which uses interpolation between pre-calculated sample doses has been utilized. The workflow was retrospectively evaluated for two head and neck patients with a total of 39 CBCTs. Dose-volume histogram (DVH) parameters were compared to rigid image registration based isocenter corrections (clinical scenario)., Results: The accuracy of the dose interpolation was found sufficient, facilitating the implementation of dose guided patient positioning. Compared to the clinical scenario, the mean dose to the parotid glands could be improved for 2 out of 5 fractions for the first patient while other parameters were preserved. For the second patient, the mean coverage over all fractions of the high dose PTV could be improved by 4%. For this patient, coverage improvements had to be traded against organ at risk (OAR) doses within their clinical tolerance limits., Conclusions: Dose guided patient positioning using in-room CBCT data is feasible and offers increased control over target coverage and doses to OARs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We report on the development and calibration of item banks for alcohol use, negative and positive consequences of alcohol use, and negative and positive expectancies regarding drinking as part of the Patient-Reported Outcomes Measurement Information System (PROMIS)., Methods: Comprehensive literature searches yielded an initial bank of more than 5000 items from over 200 instruments. After qualitative item analysis (including focus groups and cognitive interviewing), 141 items were included in field testing. Items for alcohol use and consequences were written in a first-person, past-tense format with a 30-day time frame and 5 response options reflecting frequency. Items for expectancies were written in a third-person, present-tense format with no time frame specified and 5 response options reflecting intensity. The calibration sample included 1407 respondents, 1000 from the general population (ascertained through an internet panel) and 407 from community treatment programs participating in the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN)., Results: Final banks of 37, 31, 20, 11, and 9 items (108 total items) were calibrated for alcohol use, negative consequences, positive consequences, negative expectancies, and positive expectancies, respectively, using item response theory (IRT). Seven-item static short forms were also developed from each item bank., Conclusions: Test information curves showed that the PROMIS item banks provided substantial information in a broad range of severity, making them suitable for treatment, observational, and epidemiological research., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.

Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.