Normative data for interpreting the SNOT-22.

Objectives: The Sino-Nasal Outcome Test 22 (SNOT-22) is a validated patient-reported outcome instrument to evaluate the health-related quality of life (HRQoL) in patients with chronic rhinosinusitis (CRS). There are no published normative SNOT-22 scores, limiting its interpretation. Methods: Symptom scores from 1,000 SNOT-22 questionnaires were analysed by principal component analysis (PCA) and exploratory factor analyses. Data were derived from a survey with 1,000 healthy Europeans (reference cohort) who were recruited using the Respondi panel for market and social science research. This subsample was quoted to the population distribution of the German Microcensus and selected from a non-probability panel. Results: The overall normative SNOT-22 score can be detected to be 20.2 ± 19.44. Male (18.49 ± 19.15) and older (> 50 years old; 18.3 ± 17.49) participants had overall lower SNOT-22 mean results than females (21.8 ± 19.6) and younger (21.4 ± 20.55) participants, indicating higher levels of satisfaction. PCA proposed two SNOT-22 domains ("physiological well-being" and "psychological well-being"), which explained 65% of the variance. Conclusions: These are the first published (German) normative scores for the SNOT-22 and provide a clinical reference point for the interpretation of data.

[Validity of the German Menière's Disease Patient-Oriented Symptom Severity Index]. / Validierung des deutschsprachigen Menière's Disease Patient-Oriented Symptom Severity Index.

BACKGROUND: The MD POSI is a disease-specific questionnaire to determine the health-related quality of life (HRQoL) of patients with Menière's disease (MD). OBJECTIVES: Validity and reliability of the German translation of the MD POSI. MATERIAL AND METHODS: Prospective data analysis of a patient group with vertigo (n = 162), which was treated in the otorhinolaryngology of a University Hospital from 2005-2019. A clinical selection was made according to the new Bárány classification in a "definite" and "probable" Menière's disease. HRQoL was assessed using the German translation of the MD POSI, the Vertigo Symptom Score (VSS) and the Short Form (SF-36). Reliability was measured by Cronbach's α and test-retesting after 12 months and again 2 weeks later. Content and agreement validity were examined. RESULTS: Cronbach α values greater than 0.9 indicated good internal consistency. There was no statistically significant difference from baseline to 12 months, except for the subscore "during the attack". There were significant positive correlations between the VSS overall/VER/AA and the overall index of the MD POSI and negative significant correlations with the SF-36 domains physical functioning, physical role functioning, social functioning, emotional role functioning, mental well-being. There were low SRM (standardized response mean) values below 0.5. CONCLUSIONS: The German translation of the MD POSI is a valid and reliable instrument to evaluate the impact of MD on patients' disease-specific quality of life.

Long-term analysis of prognostic risk factors impacting surgical outcomes in patients with external auditory canal carcinoma.

BACKGROUND: Malignant neoplasms of the external auditory canal (EAC) are rare. No consensus on management has emerged. OBJECTIVE: To determine possible risk factors influencing tumorgenesis and prognosis of EAC carcinoma. MATERIALS AND METHODS: 108 patients (87 men/21 women) with an average age of 74 ± 13.8 years were recruited from 2005 to 2019 at Department of Otorhinolaryngology, Head and Neck Surgery Heidelberg. The follow-up interval was 43.62 ± 55.39 months. Partial and (sub)total ablative otis, supplementary surgery (petrosectomy, parotidectomy, neck dissection, mastoidectomy) and adjuvant radio(chemo)therapy belonged to treatment options. TNM status was determined at time of diagnosis using the AJCC staging system. RESULTS: 63.9% of patients underwent a total ablative otis. Tumor recurrence was seen in 24.1%. The 1-year survival rate was 87%, the 5-year survival rate was 52%, the mean overall survival (OS) was 3.82 ± 4.6 years. Male EAC carcinoma patients had a better OS (p < 0.001), PFS (p < 0.001) and DSS (p = 0.02) than females. T1 patients had a better OS (p = 0.01), PFS (p = 0.01) and DSS (p < 0.001) than T4 patients. Lymph node but not distant metastasis, tumor grading, perineural, venous and lymphatic invasion, histology, age and tumor localization influenced the OS in EAC carcinoma patients (p = 0.04). The more radical the ablative otis, the worse the OS (p = 0.002), PFS (p = 0.02) and DSS (p < 0.001). Radio(chemo)therapy did not improve the OS. CONCLUSIONS: EAC carcinoma are difficult to treat and benefit from early diagnosis so that a radical combined treatment approach does not need to be used.

Does a closed reduction improve aesthetical and functional outcome after nasal fracture?

BACKGROUND AND PURPOSES: How closed reduction (CR) to repair a nasal fracture affects the patient's quality of life (QoL) has not been investigated. Here, we assessed QoL before and after CR using disease-specific questionnaires and compared the QoL scores of patients with nasal fractures with normative scores from a reference cohort. METHODS: This was a prospective study of 96 patients with nasal fractures undergoing CR. Patients were interviewed about aesthetic, functional, and QoL issues before and after surgery using the Functional Rhinoplasty Outcome Inventory (FROI-17) and the Rhinoplasty Outcome Evaluation (ROE). Photographs of the nasal area were taken before and after surgery and reviewed. Data were compared with those from a reference cohort (n = 1000). RESULTS: Most fractures were type I (80.6%) and most were caused by sport-related accidents (36.5%). The ROE scores increased from 67.3 preoperatively to 73.4 postoperatively (p = 0.001). The FROI-17 also improved, indicating the overall effect of the nose on QoL (p = 0.002). Compared with the reference cohort, patients felt more affected by nasal symptoms before surgery (- 9.37, p = 0.02) than by more general aspects. ROE scores returned to normative values after surgery (p < 0.001). The postoperative cohort had lower scores for the FROI-17 item overall effects of the nose on QoL than the reference cohort did, although the nasal symptom score remained higher in patients than in reference controls. CONCLUSIONS: This study showed that CR can improve the aesthetical but not the functional outcome of the nose.

Long-term outcomes and quality of life following parotidectomy for benign disease.

Objective: Parotidectomy worsens quality of life (QoL) in the short-term, but the long-term impact is unknown. In this study, we analysed the long-term effects of parotidectomy on QoL. Methods: In this prospective long-term follow-up study, participants were divided into three groups: short-term (ST) follow-up of six weeks, long-term (LT) follow-up of 13 years and short- and long-term (SLT) follow-up. QoL was assessed using the Parotidectomy Outcome Inventory (POI-8). Parotidectomies were classified based on whether the great auricular nerve (GAN) had been preserved or sacrificed. Results: In total, 164 observations were analysed, 74 in the LT group, 57 in the ST group and 33 in the SLT group. Hypoaesthesia was a major problem and facial palsy was a minor problem. Pain (p < 0.01) and hypoaesthesia (p < 0.001) were significantly lower after 13 years compared with after six weeks, and QoL was higher after 13 years compared with after six weeks (p = 0.04). The disease-specific impairment rate decreased from 70% at short-term follow-up to 30% at long-term follow-up. Removal of the GAN was associated with hypoaesthesia in the ST group (p = 0.028). Conclusions: Hypoaesthesia has a long-term impact on the QoL, and this should be emphasised during preoperative discussions.

Mitochondrial RNA modifications shape metabolic plasticity in metastasis.

Aggressive and metastatic cancers show enhanced metabolic plasticity1, but the precise underlying mechanisms of this remain unclear. Here we show how two NOP2/Sun RNA methyltransferase 3 (NSUN3)-dependent RNA modifications-5-methylcytosine (m5C) and its derivative 5-formylcytosine (f5C) (refs.2-4)-drive the translation of mitochondrial mRNA to power metastasis. Translation of mitochondrially encoded subunits of the oxidative phosphorylation complex depends on the formation of m5C at position 34 in mitochondrial tRNAMet. m5C-deficient human oral cancer cells exhibit increased levels of glycolysis and changes in their mitochondrial function that do not affect cell viability or primary tumour growth in vivo; however, metabolic plasticity is severely impaired as mitochondrial m5C-deficient tumours do not metastasize efficiently. We discovered that CD36-dependent non-dividing, metastasis-initiating tumour cells require mitochondrial m5C to activate invasion and dissemination. Moreover, a mitochondria-driven gene signature in patients with head and neck cancer is predictive for metastasis and disease progression. Finally, we confirm that this metabolic switch that allows the metastasis of tumour cells can be pharmacologically targeted through the inhibition of mitochondrial mRNA translation in vivo. Together, our results reveal that site-specific mitochondrial RNA modifications could be therapeutic targets to combat metastasis.

Prospective study on health-related quality of life in patients before and after cochlear implantation.

PURPOSE: Assessing cochlear implant (CI)-associated patient outcomes is a focus of implant research. Most studies have analyzed outcomes retrospectively with low patient numbers and few measurement time points. In addition, standardized CI-specific health-related quality of life (HRQoL) instruments have not been used. To address this, we prospectively assessed HRQoL in patients before and after implantation. METHODS: We assessed HRQoL using the Nijmegen Cochlear Implant Questionnaire (NCIQ), Abbreviated Profile of Hearing Aid Benefit (APHAB), Hearing Participation Scale (HPS), and the Visual Analogue Scale (VAS) in 100 deaf or severely hearing-impaired patients (57 unilaterally deaf and 43 bilaterally deaf) before and 3, 6, and 12 months after cochlear implantation. We compared the results of unilaterally and bilaterally hearing-impaired patients and patients with or without a hearing aid. Principal component (PCA) and exploratory factor analyses (EFA) were also conducted. RESULTS: The NCIQ measured improvements in all 6 domains after CI and correlated well with other QoL instruments. The PCA revealed that the NCIQ can be better explained by physical, physical advanced, and socio-psychological components. The APHAB score ameliorated over time, except for the background noise domain. The overall HPS score improved over time, but the hearing handicap subscore significantly decreased. Sociodemographic influences on the questionnaire scores were relatively weak. CONCLUSION: Assessing HRQoL is essential for quantifying the patient outcome after CI. NCIQ scores in our patient cohort showed improved HRQoL in all domains and we recommend that the NCIQ be used as a first-line questionnaire for assessing QoL in hearing-impaired patients after CI.

Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy.

Biomarkers with relevance for loco-regional therapy are needed in human papillomavirus negative aka HPV(-) head and neck squamous cell carcinoma (HNSCC). Based on the premise that DNA methylation pattern is highly conserved, we sought to develop a reliable and robust methylome-based classifier identifying HPV(-) HNSCC patients at risk for loco-regional recurrence (LR) and all-event progression after postoperative radiochemotherapy (PORT-C). The training cohort consisted of HPV-DNA negative HNSCC patients (n = 128) homogeneously treated with PORT-C in frame of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA Methylation analysis was performed using Illumina 450 K and 850 K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in the training set namely hypoxia-, 5-microRNA (5-miR), stem-cell gene-expression signatures and immunohistochemistry (IHC)-based immunological characterization of tumors (CD3/CD8/PD-L1/PD1). Validation occurred in an independent cohort of HPV(-) HNSCC patients, pooled from two German centers (n = 125). We identified a 38-methylation probe-based HPV(-) Independent Classifier of disease Recurrence (HICR) with high prognostic value for LR, distant metastasis and overall survival (P < 10-9 ). HICR remained significant after multivariate analysis adjusting for anatomical site, lymph node extracapsular extension (ECE) and size (T-stage). HICR high-risk tumors were enriched for younger patients with hypoxic tumors (15-gene signature) and elevated 5-miR score. After adjustment for hypoxia and 5-miR covariates, HICR maintained predicting all endpoints. HICR provides a novel mean for assessing the risk of LR in HPV(-) HNSCC patients treated with PORT-C and opens a new opportunity for biomarker-assisted stratification and therapy adaptation in these patients.

[Validity and reliability of the Nijmegen Cochlear Implant Questionnaire in German]. / Validierung und Reliabilitätsprüfung des Nijmegen Cochlear Implant Questionnaire in deutscher Sprache.

BACKGROUND: The Nijmegen Cochlear Implant Questionnaire (NCIQ) is a disease-specific questionnaire to determine the health-related quality of life (HRQoL) of patients before and after cochlear implantation. OBJECTIVE: This study aimed to assess the validity and reliability of the German translation of the NCIQ. MATERIALS AND METHODS: A prospective study was performed in 100 postlingually deaf or severely hearing-impaired patients. HRQoL was assessed using the NCIQ, the Abbreviated Profile of Hearing Aid Benefit (APHAB), and the Hearing Participation Scale (HPS) before as well as 3 and 6 months after cochlear implantation. An untreated group of postlingually deaf or severely hearing-impaired patients (n = 54) served as a control. Cronbach's α and test-retest reliability were measured. The content, discrimination, and agreement validity were tested. The evaluation of construct validity was based on recently published data. Sensitivity and receiver operating curve (ROC) analysis, including consideration of the area under the curve (AUC), were used as quality criteria. RESULTS: The test-retest analysis showed stable NCIQ values 3 and 6 months postoperatively. The Cronbach's α values indicated good internal consistency. The NCIQ validly discriminated between treated and untreated patient groups. There were statistically significant albeit weak correlations between the NCIQ and the APHAB (r = -0.22; p = 0.04) and the HPS (r = 0.30; p = 0.01). Sensitivity and ROC analyses showed good measurement quality of the German-speaking NCIQ. CONCLUSION: The German translation of the NCIQ reliably and validly measures HRQoL before and after cochlear implantation and can be used for clinical monitoring after treatment with cochlear implants.

Definitive radiotherapy for squamous cell carcinoma of the oral cavity: a single-institution experience.

BACKGROUND: Surgery is standard of care for oral cavity cancer (OCC). We provide a single-institution experience using definitive radiotherapy (RT) with or without concurrent systemic therapy for primary unresectable OCC. PATIENTS AND METHODS: We retrospectively examined 49 patients with non-metastatic primary unresectable OCC treated with definitive RT between 2000 and 2019. The majority of patients (63.3%) were treated with definitive chemoradiotherapy while 26.5% were given single-agent cetuximab weekly simultaneous to definitive RT. Five patients were treated with definitive RT alone because of limited disease and no nodal involvement. RESULTS: Median follow-up was 73 months (range, 6-236 months), median progression free survival (PFS) was 42 months (range, 2-157 months), median local disease-free survival (LDFS) was 44 months (range, 2-157 months) and median overall survival (OS) from the time of RT initiation was 52 months (range, 5-236 months). There were 65.3% locoregional failures, 84.4% local and 15.6% distant metastasis. The majority of patients with local failure presented with American Joint Committee on Cancer (AJCC) Stage III-IV disease (59.2%). The 5-year Kaplan-Meier estimates for OS (III-IV vs. I-II) was 22.8% vs. 54.2 % (p = 0.03, HR 2.090, 1.1-4.2). Patients who were treated with systemic therapy had a significant better 5-year overall survival compared to those with RT alone (43.9% vs. 23.1%, p = 0.05, 1.0-4.1). RT with doses less than 70 Gy (p = 0.046, HR 2.1 (1.0-4.5) was associated with worse overall survival. Mucositis was the most common ≥ grade 3 acute toxicity and occurred in 19 patients (39%). Incidences of chronic toxicities were loss of taste, trismus, osteoradionecrosis and xerostomia. CONCLUSIONS: Definitive RT with or without concurrent systemic agents in patients with unresectable OCC resulted in an eloquent rate of locoregional control and good overall survival rates and is currently the best available treatment option in this patient collective.

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity.

Squamous cell carcinoma (SCC) is the most prevalent histological type of human cancer, including head and neck squamous cell carcinoma (HNSCC). However, reliable prognostic gene signatures for SCC and underlying genetic and/or epigenetic principles are still unclear. We identified 37 prognostic candidate genes by best cutoff computation based on survival in a pan-SCC cohort (n = 1334) of The Cancer Genome Atlas (TCGA), whose expression stratified not only the pan-SCC cohort but also independent HNSCC validation cohorts into three distinct prognostic subgroups. The most relevant prognostic genes were prioritized by a Least Absolute Shrinkage and Selection Operator Cox regression model and were used to identify subgroups with high or low risks for unfavorable survival. An integrative analysis of multi-omics data identified FN1, SEMA3A, CDH2, FBN1, COL5A1, and ADAM12 as key nodes in a regulatory network related to the prognostic phenotype. An in-silico drug screen predicted two MEK inhibitors (Trametinib and Selumetinib) as effective compounds for high-risk SCC based on the Cancer Cell Line Encyclopedia, which is supported by a higher p-MEK1/2 immunohistochemical staining of high-risk HNSCC. In conclusion, our data identified a molecular classifier for high-risk HNSCC as well as other SCC patients, who might benefit from treatment with MEK inhibitors.

How to predict the outcome of septorhinoplasty? A normative study of ROE and FROI-17 scores.

OBJECTIVE: Normative values of patient-reported outcome instruments are needed to identify good candidates for rhinoplasty. Rhinoplasty Outcome Evaluation (ROE) and Functional Rhinoplasty Outcome Inventory-17 (FROI-17) are disease-specific questionnaires that evaluate quality of life in patients undergoing rhinoplasty. METHODS: The reference cohort contained 1,000 participants, selected from a non-probability panel. Normative ROE and FROI-17 scores from this reference cohort were compared with ROE and FROI-17 scores from a patient cohort before (n = 104) and 6 (n = 55) and 12 months (n = 32) after septorhinoplasty. RESULTS: Mean FROI-17 scores (± SD) were: overall score, 20.8 ± 17; nasal symptoms, 16.8 ± 7; general symptoms, 24.8 ± 22; and self-confidence, 16.4 ± 21. The ROE total score was 73.1 ± 16. Normative values differed significantly from the preoperative ROE and FROI-17 scores of septorhinoplasty patients (p < 0.01). Except for the FROI-17 general score at 12 months postoperatively (p = 0.004), there were no significant differences between normative ROE/FROI-17 and septorhinoplasty scores postoperatively, indicating that they returned to normalcy. CONCLUSIONS: Normative scores for ROE and FROI-17 provide a reference point from which to identify patients who are most likely to benefit from rhinoplasty.

Digital Pathology Scoring of Immunohistochemical Staining Reliably Identifies Prognostic Markers and Anatomical Associations in a Large Cohort of Oral Cancers.

Utilizing digital pathology algorithms for the objective quantification of immunohistochemical staining, this study aimed to identify robust prognostic biomarkers for oral cancer. Tissue microarrays with specimens of a large cohort of oral squamous cell carcinoma (n=222) were immunohistochemically stained to determine the expression of PD-L1, EGFR, and COX-2 and the amount of infiltrating NK cells and CD8-positive T cells. Immunoreactivity scores were assessed using both a classical manual scoring procedure and a digital semi-automatic approach using QuPath. Digital scoring was successful in quantifying the expression levels of different prognostic biomarkers (CD8: p<0.001; NK cells: p=0.002, PD-L1: p=0.026) and high levels of concordance with manual scoring results were observed. A combined score integrating EGFR expression, neck node status and immune cell signatures with a significant impact on overall and progression-free survival was identified (p<0.001). These data may contribute to the ongoing research on the identification of reliable and clinically relevant biomarkers for the individualization of primary and adjuvant treatment in oral cancer.

[Oral and pharyngeal cancer: incidence, mortality, and survival in Germany]. / Mundhöhlen- und Pharynxkarzinome: Inzidenz, Mortalität und Überleben in Deutschland.

BACKGROUND: Lip, oral cavity, and pharynx cancers (ICD-10: C00-C14) describe a heterogeneous group of tumors with strong variations in incidence, mortality, and survival by entity. OBJECTIVES: This work provides a detailed overview of epidemiologic measures for these tumor entities, taking into account heterogeneity in age, sex, location, and stage. MATERIAL AND METHODS: Incidence and mortality data for Germany for the years 1999-2016 were extracted from the interactive database of the Center for Cancer Registry Data (ZfKD). Age and stage distributions and five-year relative survival were calculated on the pooled ZfKD data set (diagnosis years 1999-2017). RESULTS: In 2016, overall incidence and mortality for all entities were 17.6 and 7.0 per 100,000 men and 6.5 and 1.8 per 100,000 women, respectively. The five-year relative survival in 2015-2017 was 53 and 63%, respectively. There were marked differences in survival as well as age and stage distributions between entities. Trend analyses showed an increase in age at diagnosis, particularly in male patients, and no change in stage distributions. However, five-year relative survival increased from 45% (men) and 59% (women) in 1999-2002 to 52% and 63% in 2013-2017. CONCLUSION: The marked heterogeneity of the studied tumors highlights the need to differentiate the analysis by sex and entity for meaningful interpretation of epidemiologic metrics. With the expansion of clinical cancer registration in Germany, additional analyses including other important clinical factors will be possible in the future.

Establishment of a Plasticity-Associated Risk Model Based on a SOX2- and SOX9-Related Gene Set in Head and Neck Squamous Cell Carcinoma.

Recent studies highlighted SOX2 and SOX9 as key determinants for cancer-cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma (SCC) is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related genetic programs with risk factors and genetic or epigenetic alterations in primary head and neck SCC (HNSCC), and their prognostic value is largely unknown.Here, we identified differentially-expressed genes (DEG) related to SOX2 and SOX9 transcription in The Cancer Genome Atlas (TCGA)-HNSC, which enable clustering of patients into groups with distinct clinical features and survival. A prognostic risk model was established by LASSO Cox regression based on expression patterns of DEGs in TCGA-HNSC (training cohort), and was confirmed in independent HNSCC validation cohorts as well as other cancer cohorts from TCGA. Differences in the mutational landscape among risk groups of TCGA-HNSC demonstrated an enrichment of truncating NSD1 mutations for the low-risk group and elucidated DNA methylation as modulator of SOX2 expression. Gene set variation analysis (GSVA) revealed differences in several oncogenic pathways among risk groups, including upregulation of gene sets related to oncogenic KRAS signaling for the high-risk group. Finally, in silico drug screen analysis revealed numerous compounds targeting EGFR signaling with significantly lower efficacy for cancer cell lines with a higher risk phenotype, but also indicated potential vulnerabilities. IMPLICATIONS: The established risk model identifies patients with primary HNSCC, but also other cancers at a higher risk for treatment failure, who might benefit from a therapy targeting SOX2/SOX9-related gene regulatory and signaling networks.

EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers.

While genetic alterations in Epidermal growth factor receptor (EGFR) and PI3K are common in head and neck squamous cell carcinomas (HNSCC), their impact on oncogenic signaling and cancer drug sensitivities remains elusive. To determine their consequences on the transcriptional network, pathway activities of EGFR, PI3K, and 12 additional oncogenic pathways were inferred in 498 HNSCC samples of The Cancer Genome Atlas using PROGENy. More than half of HPV-negative HNSCC showed a pathway activation in EGFR or PI3K. An amplification in EGFR and a mutation in PI3KCA resulted in a significantly higher activity of the respective pathway (p = 0.017 and p = 0.007). Interestingly, both pathway activations could only be explained by genetic alterations in less than 25% of cases indicating additional molecular events involved in the downstream signaling. Suitable in vitro pathway models could be identified in a published drug screen of 45 HPV-negative HNSCC cell lines. An active EGFR pathway was predictive for the response to the PI3K inhibitor buparlisib (p = 6.36E-03) and an inactive EGFR and PI3K pathway was associated with efficacy of the B-cell lymphoma (BCL) inhibitor navitoclax (p = 9.26E-03). In addition, an inactive PI3K pathway correlated with a response to multiple Histone deacetylase inhibitor (HDAC) inhibitors. These findings require validation in preclinical models and clinical studies.

MicroRNA-sensitive oncolytic measles virus for chemovirotherapy of pancreatic cancer.

Advanced pancreatic cancer is characterized by few treatment options and poor outcomes. Oncolytic virotherapy and chemotherapy involve complementary pharmacodynamics and could synergize to improve therapeutic efficacy. Likewise, multimodality treatment may cause additional toxicity, and new agents have to be safe. Balancing both aims, we generated an oncolytic measles virus for 5-fluorouracil-based chemovirotherapy of pancreatic cancer with enhanced tumor specificity through microRNA-regulated vector tropism. The resulting vector encodes a bacterial prodrug convertase, cytosine deaminase-uracil phosphoribosyl transferase, and carries synthetic miR-148a target sites in the viral F gene. Combination of the armed and targeted virus with 5-fluorocytosine, a prodrug of 5-fluorouracil, resulted in cytotoxicity toward both infected and bystander pancreatic cancer cells. In pancreatic cancer xenografts, a single intratumoral injection of the virus induced robust in vivo expression of prodrug convertase. Based on intratumoral transgene expression kinetics, we devised a chemovirotherapy regimen to assess treatment efficacy. Concerted multimodality treatment with intratumoral virus and systemic prodrug administration delayed tumor growth and prolonged survival of xenograft-bearing mice. Our results demonstrate that 5-fluorouracil-based chemovirotherapy with microRNA-sensitive measles virus is an effective strategy against pancreatic cancer at a favorable therapeutic index that warrants future clinical translation.

Individualized 3D-Printed Tissue Retraction Devices for Head and Neck Radiotherapy.

BACKGROUND: Radiotherapy for head and neck cancer may cause various oral sequelae, such as radiation-induced mucositis. To protect healthy tissue from irradiation, intraoral devices can be used. Current tissue retraction devices (TRDs) have to be either individually manufactured at considerable cost and time expenditure or they are limited in their variability. In this context, a 3D-printed, tooth-borne TRD might further facilitate clinical use. METHODS: A novel approach for the manufacturing of TRDs is described and its clinical application is analysed retrospectively. The devices were virtually designed for fabrication by 3D-printing technology, enabling-in only a single printing design-caudal or bi-lateral tongue displacement, as well as stabilization of a tongue-out position. For a total of 10 patients undergoing radiotherapy of head and neck tumors, the devices were individually adapted after pre-fabrication. Technical and clinical feasibility was assessed along with patient adherence. Tissue spacing was calculated by volumetric analysis of tongue retraction. In one exemplary case, radiotherapy treatment plans before and after tissue displacement were generated and compared. The reproducibility of maxillomandibular relation at device re-positioning was quantified by repeated intraoral optical scanning in a voluntary participant. RESULTS: 3D-printing was useful for the simplification of TRD manufacture, resulting in a total patient treatment time of less than 30 min. The devices were tolerated well by all tested patients over the entire radiation treatment period. No technical complications occurred with the devices. The TRDs caused an effective spacing of the healthy adjacent tissue, e.g., the tongue. Position changes of maxillomandibular relation were limited to a mean value of 98.1 µm ± 29.4 µm root mean square deviation between initial reference and follow-up positions. CONCLUSIONS: The presented method allows a resource-efficient fabrication of individualized, tooth-bourne TRDs. A high reproducibility of maxillomandibular relation was found and the first clinical experiences underline the high potential of such devices for radiotherapy in the head and neck area.

3D-printed individualized tooth-borne tissue retraction devices compared to conventional dental splints for head and neck cancer radiotherapy: a randomized controlled trial.

BACKGROUND: Despite modern treatment techniques, radiotherapy (RT) in patients with head and neck cancer (HNC) may be associated with high rates of acute and late treatment-related toxicity. The most effective approach to reduce sequelae after RT is to avoid as best as possible healthy tissues and organs at risk from the radiation target volume. Even small geometric changes can lead to a significant dose reduction in normal tissue and better treatment tolerability. The major objective of the current study is to investigate 3D printed, tooth-borne tissue retraction devices (TRDs) compared to conventional dental splints for head and neck RT. METHODS: In the current two-arm randomized controlled phase II trial, a maximum of 34 patients with HNC will be enrolled. Patients will receive either TRDs or conventional dental splints (randomization ratio 1:1) for the RT. The definition of the target volume, modality, total dose, fractionation, and imaging guidance is not study-specific. The primary endpoint of the study is the rate of acute radiation-induced oral mucositis after RT. The quality of life, local control and overall survival 12 months after RT are the secondary endpoints. Also, patient-reported outcomes and dental status, as well as RT plan comparisons and robustness analyzes, will be assessed as exploratory endpoints. Finally, mesenchymal stem cells, derived from the patients' gingiva, will be tested in vitro for regenerative and radioprotective properties. DISCUSSION: The preliminary clinical application of TRD showed a high potential for reducing acute and late toxicity of RT in patients with HNC. The current randomized study is the first to prospectively investigate the clinical tolerability and efficacy of TRDs for radiation treatment of head and neck tumors. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04454697; July 1st 2020; https://clinicaltrials.gov/ct2/show/record/NCT04454697 .