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Abstract Background While surgical resection remains the primary treatment approach for symptomatic or growing meningiomas, radiotherapy represents an auspicious alternative in patients with meningiomas not safely amenable to surgery. Biopsies are often omitted in light of potential postoperative neurological deficits, resulting in a lack of histological grading and (molecular) risk stratification. In this prospective explorative biomarker study, extracellular vesicles in the bloodstream will be investigated in patients with macroscopic meningiomas to identify a biomarker for molecular risk stratification and disease monitoring. Methods In total, 60 patients with meningiomas and an indication of radiotherapy (RT) and macroscopic tumor on the planning MRI will be enrolled. Blood samples will be obtained before the start, during, and after radiotherapy, as well as during clinical follow-up every 6 months. Extracellular vesicles will be isolated from the blood samples, quantified and correlated with the clinical treatment response or progression. Further, nanopore sequencing-based DNA methylation profiles of plasma EV-DNA will be generated for methylation-based meningioma classification. Discussion This study will explore the dynamic of plasma EVs in meningioma patients under/after radiotherapy, with the objective of identifying potential biomarkers of (early) tumor progression. DNA methylation profiling of plasma EVs in meningioma patients may enable molecular risk stratification, facilitating a molecularly-guided target volume delineation and adjusted dose prescription during RT treatment planning.

Introduction Postoperative radiotherapy can improve locoregional control (LC) in oral cavity squamous cell carcinoma (OCSCC) patients with positive resection margins. The present study aimed to evaluate the impact of surgical margin size on LC in this patient population. Methods This retrospective study involved 162 patients with OCSCC who underwent postoperative radiotherapy between 2000 and 2020 at the Department of Radiation Oncology, University Hospital Heidelberg and the German Cancer Research Center. The study aimed to determine the impact of different resection margins on LC, as well as overall survival (OS), progression-free survival (PFS), and treatment-related toxicity (CTCAE 4.03). Results Seventy-seven patients (47.5%) had involved (5 mm) margins. A surgical margin ≤ 5 mm was a significant predictor for worse LC (HR 2.6, 95% CI 1.2, 6.1), but not for OS (HR 1.2, CI 0.7, 1.9) or PFS (HR 1.2, 0.7, 2.0). Conclusion Patients who have narrow resection margins (1-5 mm) experience poor local control and should receive postoperative radiotherapy. It is necessary to conduct further prospective studies to determine whether a narrower margin window could be achieved to better determine the appropriate indication for adjuvant radiotherapy.

Abstract Introduction Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation. Patients & methods We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2). Results Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04). Conclusion OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy.

Abstract Background Due to the increasing expertise in transoral laser surgery and image-guided radiation therapy, treatment outcomes have recently improved in patients with early-stage glottic cancer. The objective of the current study was to evaluate intensity-modulated proton therapy (IMPT) as novel treatment option. Methods A total of 15 patients with T1-2N0 glottic squamous cell carcinoma, treated between 2017 and 2020, were evaluated. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Results The majority were T1a/b tumors (66.7%) and no patient had lymph node or distant metastases. The median total dose was 70 Gy relative biological effectiveness (RBE) (range 66–70 Gy RBE). The one- and two-year OS and metastases-free survival were 100%. One patient developed local failure and received salvage laryngectomy. No higher-grade acute or late toxicity was reported. The mean number of CTCAE grade I and II overall toxicity events per patient was 4.1 (95%-[confidence interval] CI 3.1–5.3) and 1.0 (95%-CI 0.5–1.5). Conclusion High-precision proton therapy of T1-2N0 glottic cancer resulted in exceptional treatment tolerability with high rates of laryngeal function preservation and promising oncological outcome. IMPT has the potential to become a standard treatment option for patients with early-stage laryngeal cancer.

Abstract Background Carbon ion radiotherapy (CIRT) yields biophysical advantages compared to photons but randomized studies for the reirradiation setting are pending. The aim of the current project was to evaluate potential clinical benefits and drawbacks of CIRT compared to volumetric modulated arc therapy (VMAT) in recurrent head and neck cancer. Methods Dose-volume parameters and local failure patterns of CIRT compared to VMAT were evaluate in 16 patients from the randomized CARE trial on head and neck cancer reirradiation. Results Despite an increased target dose, CIRT resulted in significantly reduced organ at risk (OAR) dose across all patients (− 8.7% Dmean). The dose-volume benefits were most pronounced in the brainstem (− 20.7% Dmax) and the optic chiasma (− 13.0% Dmax). The most frequent local failure was type E (extraneous; 50%), followed type B (peripheral; 33%) and type A (central; 17%). In one patient with type A biological and/or dosimetric failure after CIRT, mMKM dose recalculation revealed reduced target coverage. Conclusions CIRT resulted in highly improved critical OAR sparing compared to VMAT across all head and neck cancer reirradiation scenarios despite an increased prescription dose. Local failure pattern analysis revealed further potential CIRT specific clinical benefits and potential pitfalls with regard to image-guidance and biological dose-optimization.

Abstract Objectives Osteoradionecrosis (ORN) of the lower jaw is a serious late complication after radiotherapy in patients with oral cavity cancer. The aim of this study is to generate more insight into which patient- and treatment-related factors are associated with the development of ORN in oral cavity cancer patients undergoing postoperative radiotherapy. Material and methods Retrospective evaluation and comparison of 44 patients with ORN (event group 1) matched according to 45 patients without ORN (control group 2) who received postoperative radiotherapy of oral cavity squamous cell carcinoma at our institution between 2012 and 2020. Dosimetric factors that favor the occurrence of ORN should be detected. The cumulative occurrence rate of ORN was calculated according to the Kaplan–Meier method and analyzed by Cox regression and log-rank test. Results The median time to develop ORN was 18 months (3–93 months) after radiotherapy. Dental status before radiotherapy (RT) treatment (HR 4.5; 1.8–11.5) and dosimetric parameters including Dmean > 45 Gy (HR 2.4; 1.0–5.7), Dmax > 60 Gy (HR 1.3; 1.1–2.8) and planning target volume (PTV) proportion > 40% intersection with the lower jaw (HR 1.1; 1.0–1.1) were significantly associated with ORN. Conclusion The results of this retrospective study reveal that oral cavity cancer patients who underwent pre-RT dental surgery as well as dosimetric parameters using Dmax > 60 Gy, higher mean doses > 45 Gy and more than 40% PTV intersection with the lower jaw bone are independent risk factors for ORN. These findings can assist in the management of patients undergoing RT for head and neck cancer regarding ORN prevention. Clinical relevance Poor oral hygiene and desolate dental status as well as high radiation doses to the mandibular bone significantly increase the risk of developing osteoradionecrosis. Before irradiating a patient with oral cavity cancer, an appointment with the dentist should be made and teeth sanitized if necessary. Likewise, maximum radiation doses to the lower jaw should be minimized.

Abstract Background Adenoid cystic carcinoma is a rare form of head and neck cancer with a slow, but aggressive growth pattern which remains a challenge for local tumor control. Based on phase II data, radiation treatment using partially high LET radiation results in a prolonged PFS and OS. There is a paucity of randomized clinical data examining the role of the use of high LET radiation only. Therefore, the purpose of this prospective clinical trial is to analyze local control rates in patients with node negative ACC treated with carbon ion radiotherapy alone compared to a combined modality approach. Methods This trial is conducted as a prospective, open-label, phase II, two-armed, investigator-initiated study comparing the local control rates in node negative ACCs of the head and neck treated either with sole carbon ion radiotherapy or a combination of carbon ions and photons. Secondary outcomes investigated are progression-free survival, overall survival, acute and late toxicity, and quality of life. A total of 314 patients will be randomly assigned to C12 treatment alone or bimodal treatment: Patients in the experimental group will receive a dose of 51 Gy (RBE) in 17 fractions and a boost of 15 Gy (RBE) in 5 fractions. Patients in the control group will receive 25 fractions photon IMRT 50Gy and a boost using 8 × 3 Gy (RBE) carbon ions. Local control will be assessed in regular follow up examinations until 5 years after the completion of treatment. Discussion The present trial aims to evaluate local control rates to compare sole carbon ion radiotherapy to bimodal radiotherapy with carbon ions and photons in patients with node negative ACCs of the head and neck region. Local control is selected as the primary endpoint due to its major clinical relevance because of slow but aggressive growth patterns. Trial registration The study was prospectively registered on 2nd January 2020: ClinicalTrials.gov, NCT04214366 . “Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation (ACCO)”. Study status Under recruitment, participant recruitment is not completed. Start of recruitment was January 2020. There are no results been published or submitted to any journal.

Abstract 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 .

Abstract Background Intensity-modulated re-radiotherapy (reIMRT) has been established as a standard local treatment option in patients with non-resectable, recurrent head and neck cancer (rHNC). However, the clinical outcome is unfavorable and severe toxicities (≥grade III) occurred in 30–40% of patients. The primary aim of the current trial is to investigate carbon ion reirradiation (reCIRT) compared to reIMRT in patients with rHNC regarding safety/toxicity as well as local control, overall survival (OS), and quality of life (QoL). Methods The present trial will be performed as a single center, two-armed, prospective phase II study. A maximum of 72 patients will be treated with either reIMRT or reCIRT to evaluate severe (≥grade III) treatment-related toxicities (randomization ratio 1:1). The primary target value is to generate less than 35% acute/subacute severe toxicity (≥grade III), according to the Common Terminology Criteria for Adverse Events v5.0, within 6 months after study treatment. The total dose of reirradiation will range between 51 and 60 Gy or Gy (RBE), depending primarily on the radiotherapy interval and the cumulative dose to organs at risk. Individual dose prescription will be at the discretion of the treating radiation oncologist. The local and distant progression-free survival 12 months after reirradiation, the OS, and the QoL are the secondary endpoints of the trial. Explorative trial objectives are the longitudinal investigation of clinical patient-related parameters, tumor parameters on radiological imaging, and blood-based tumor analytics. Discussion Recent retrospective studies suggested that reCIRT could represent a feasible and effective treatment modality for rHNC. This current randomized prospective trial is the first to investigate the toxicity and clinical outcome of reCIRT compared to reIMRT in patients with rHNC. Trial registration ClinicalTrials.gov ; NCT04185974 ; December 4th 2019.

Abstract Chromate, Cr(VI), contamination in soil and groundwater poses serious threat to living organisms and environmental health worldwide. Sulphate green rust (GRSO4), a naturally occurring mixed-valent iron layered double hydroxide has shown to be highly effective in the reduction of Cr(VI) to poorly soluble Cr(III), giving promise for its use as reactant for in situ remedial applications. However, little is known about its immobilization efficiency inside porous geological media, such as soils and sediments, where this reactant would ultimately be applied. In this study, we tested the removal of Cr(VI) by GRSO4 in quartz sand fixed-bed column systems (diameter × length = 1.4 cm × 11 cm), under anoxic conditions. Cr(VI) removal efficiency (relative to the available reducing equivalents in the added GRSO4) was determined by evaluating breakthrough curves performed at different inlet Cr(VI) concentrations (0.125–1 mM) which are representative of Cr(VI) concentrations found at contaminated sites, different flow rates (0.25–3 ml/min) and solution pH (4.5, 7 and 9.5). Results showed that (i) increasing Cr(VI) inlet concentration substantially decreased Cr(VI) removal efficiency of GRSO4, (ii) flow rates had a lower impact on removal efficiencies, although values tended to be lower at higher flow rates, and (iii) Cr(VI) removal was enhanced at acidic pH conditions compared to neutral and alkaline conditions. For comparison, Cr(VI) removal by sulphidized nanoscale zerovalent iron (S-nZVI) in identical column experiments was substantially lower, indicating that S-nZVI reactivity with Cr(VI) is much slower compared to GRSO4. Overall, GRSO4 performed reasonably well, even at the highest tested flow rate, showing its versatility and suitability for Cr(VI) remediation applications in high flow environments.

PurposeTo explore the benefit of adaptive magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) for treatment of lung tumors in different locations with a focus on ultracentral lung tumors (ULT).Patients & MethodsA prospective cohort of 21 patients with 23 primary and secondary lung tumors was analyzed. Tumors were located peripherally (N = 10), centrally (N = 2) and ultracentrally (N = 11, planning target volume (PTV) overlap with proximal bronchi, esophagus and/or pulmonary artery). All patients received MRgSBRT with gated dose delivery and risk-adapted fractionation. Before each fraction, the baseline plan was recalculated on the anatomy of the day (predicted plan). Plan adaptation was performed in 154/165 fractions (93.3%). Comparison of dose characteristics between predicted and adapted plans employed descriptive statistics and Bayesian linear multilevel models. The posterior distributions resulting from the Bayesian models are presented by the mean together with the corresponding 95% compatibility interval (CI).ResultsPlan adaptation decreased the proportion of fractions with violated planning objectives from 94% (predicted plans) to 17% (adapted plans). In most cases, inadequate PTV coverage was remedied (predicted: 86%, adapted: 13%), corresponding to a moderate increase of PTV coverage (mean +6.3%, 95% CI: [5.3–7.4%]) and biologically effective PTV doses (BED10) (BEDmin: +9.0 Gy [6.7–11.3 Gy], BEDmean: +1.4 Gy [0.8–2.1 Gy]). This benefit was smaller in larger tumors (−0.1%/10 cm³ PTV [−0.2 to −0.02%/10 cm³ PTV]) and ULT (−2.0% [−3.1 to −0.9%]). Occurrence of exceeded maximum doses inside the PTV (predicted: 21%, adapted: 4%) and violations of OAR constraints (predicted: 12%, adapted: 1%, OR: 0.14 [0.04–0.44]) was effectively reduced. OAR constraint violations almost exclusively occurred if the PTV had touched the corresponding OAR in the baseline plan (18/19, 95%).ConclusionAdaptive MRgSBRT is highly recommendable for ablative treatment of lung tumors whose PTV initially contacts a sensitive OAR, such as ULT. Here, plan adaptation protects the OAR while maintaining best-possible PTV coverage.

Surgical therapy of osteoradionecrosis of the jaw (ORN) is challenging and requires treatment of the affected hard and soft tissue. To understand how tissue injury after irradiation influences surgical outcomes, the objective of this study was to find out whether (a) bone-related, (b) soft tissue-related, and (c) treatment-related parameters influence the surgical success of patients with ORN. A total of 175 patients (324 lesions) were included in this retrospective, single-center study. All patients were diagnosed with ORN and underwent surgical therapy. The primary outcome was complete soft tissue recovery (mucosa/skin) and the absence of symptoms 3 months after surgery. At the time of follow-up, 58% of patients (189 of 324 lesions) had intact intraoral or extraoral soft tissue. The extent of bone destruction had no effect on treatment success, whereas soft tissue injury due to fibrosis (OR: 0.344; CI 0.142–0.834; p = 0.01818) and xerostomia (OR: 0.163; CI 0.064–0.419; p = 0.00016) increased the probability of treatment failure. Soft tissue reconstruction with a microvascular graft improved therapeutic success compared to local wound closure (OR: 2.998; CI 1.371–6.555; p = 0.006). Thus, for the treatment of ORN, it is extremely important to pay attention not only to the extent of bone destruction but especially to soft tissue defects. Because the extent of soft tissue injury is a predictor for therapeutic success, it should influence the choice of surgical treatment.

This single-center, single-arm trial investigates the feasibility of a psycho-oncological care program, which aims to reduce psychological distress and improve compliance with radiotherapy with mask fixation in patients with head and neck cancer or brain malignancies. The care program comprised (1) a screening/needs assessment and (2) the provision of a psycho-oncological intervention using imaginative stabilization techniques for distressed patients (distress due to anxiety ≥5) or in a case of subjective interest in the psycho-oncological intervention. Another allocation path to the intervention was directly through the radiation oncologist in charge who classified the patient as: in need of support to tolerate the immobilization device. Of a total of 1,020 screened patients, 257 (25.2%) patients indicated a distress ≥5 and 141 (13.8%) patients reported panic attacks. 25% of the patients reported a subjective interest in psycho-oncological support. A total of 35 patients received the psycho-oncological intervention, of which 74% were assigned by radiation oncologists. In this small patient cohort, no significant pre-post effects in terms of depression, anxiety, distress, and quality of life (mental and physical component scores) could be detected. Our results indicate a good feasibility (interdisciplinary workflow and cooperation, allocation by physicians in charge) of the psycho-oncological care program for this cohort of patients before radiotherapy with mask fixation. The screening results underline the high psychological distress and demand for psycho-oncological support. However, since the utilization of our intervention was low, future studies should reduce the barriers and improve compliance to psycho-oncological services by these patients.Clinical Trial Registration: https://www.drks.de/drks_web/setLocale_EN.do #DRKS00013493

PurposeIn this benign tumor entity, preservation of cranial nerve function is of special importance. Due to its advantageous physical properties, proton beam radiotherapy (PRT) is a promising approach that spares healthy tissue. Could PRT go along with satisfactory preservation rates for cranial nerve function without compromising tumor control in patients with cranial nerve schwannoma unsuitable for stereotactic radiosurgery?MethodsWe analyzed 45 patients with cranial nerve schwannomas who underwent PRT between 2012 and 2020 at our institution. Response assessment was performed by MRI according to RECIST 1.1, and toxicity was graded following CTCAE 5.0.ResultsThe most common schwannoma origin was the vestibulocochlear nerve with 82.2%, followed by the trigeminal nerve with 8.9% and the glossopharyngeal nerve as well as the vagal nerve, both with each 4.4%. At radiotherapy start, 58% of cranial nerve schwannomas were progressive and 95.6% were symptomatic. Patients were treated with a median total dose of 54 Gy RBE in 1.8 Gy RBE per fraction. MRI during the median follow-up period of 42 months (IQR 26–61) revealed stable disease in 93.3% of the patients and partial regression in 6.7%. There was no case of progressive disease. New or worsening cranial nerve dysfunction was found in 20.0% of all patients, but always graded as CTCAE °I-II. In seven cases (16%), radiation-induced contrast enhancements (RICE) were detected after a median time of 14 months (range 2–26 months). RICE were asymptomatic (71%) or transient symptomatic (CTCAE °II; 29%). No CTCAE °III/IV toxicities were observed. Lesions regressed during the follow-up period in three of the seven cases, and no lesion progressed during the follow-up period.ConclusionThese data demonstrate excellent effectiveness with 100% local control in a median follow-up period of 3.6 years with a promising cranial nerve functional protection rate of 80%. RICE occurred in 16% of the patients after PRT and were not or only mildly symptomatic.

Abstract Background The objective of this investigation is to evaluate the outcomes and toxicity of carbon-ion re-irradiation (CIR) in patients with rare head and neck cancers (HNC). There is a paucity of data regarding treatment approaches in this patient cohort, which we aim to address in this work. Methods Thirty-two (n = 32) consecutive patients with uncommon HNC treated between 2010 and 2017 were retrospectively analyzed in terms of clinical outcomes, patterns of failure, and toxicity. Results Mucoepidermoid carcinoma (MEC) was the most common histology (22%). Patients received a median cumulative dose equivalent in 2 Gy fractions (EQD2) after CIR of 128.6 Gy (range, 105.8–146.5 Gy). The local and distant control rates 1 year after CIR were 66 and 72%. No serious acute or late toxicity (≥ grade 3) after CIR was observed. Conclusions CIR may represent an effective and safe treatment alternative to palliative systemic therapies in these rare indications.

Abstract Purpose Salvage surgery of recurrent hypopharyngeal and laryngeal squamous cell carcinoma (SCC) results in limited local control and survival rates. As a result of recent technological progress, radiotherapy (RT) has become a valuable, potentially curative therapeutic option. Thus, we aimed to determine prognostic factors for survival outcome in order to optimize patient selection for salvage radiotherapy after failure of first-line treatment with surgery alone in this special patient cohort. Methods Seventy-five patients (85% male, median age of 64 years) underwent salvage RT in a secondary setting for recurrent hypopharyngeal or laryngeal SCC after prior surgery alone between 2007 and 2017. On average, patients were treated with one prior surgery (range 1–4 surgeries). Median time between surgery and salvage RT was 7 months (range 1–47 months) for initially advanced tumors (T3/4, N+, extracapsular spread) and 18 months (range 5–333 months) for initially early stage tumors. The majority of patients received concomitant chemotherapy (n = 48; 64%) or other kind of systemic treatment concurrent to radiotherapy (n = 10; 13%). Results Median follow-up was 41 months (range 3–120 months). Overall, fifteen patients were diagnosed with local failure (all were in-field) at last follow-up (20%). Median time to recurrence was 35 months (range 3–120 months) and 3-year local progression-free survival (LPFS) was 75%, respectively. Dose-escalated RT with 70.4 Gy applied in 2.1 Gy or 2.2 Gy fractions corresponding an EQD2 > 70 Gy (p = 0.032) and the use of concomitant cisplatin weekly chemotherapy (p = 0.006) had a significant positive impact on LPFS. 3-year OS and DPFS were 76 and 85%, respectively. No toxicity-related deaths occurred. Reported grade > 3 side effects were rare (n = 4/70, 6%). Conclusion Salvage radiotherapy resulted in excellent local control rates while radiation dose and the use of cisplatin weekly chemotherapy were identified as prognostic factors for LPFS. Nevertheless, patient selection for curative salvage treatment remains challenging.

BackgroundRadiotherapy 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.MethodsA 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.Results3D-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.ConclusionsThe 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.

Background: To assess outcomes and treatment related toxicity following intensity-modulated radiotherapy (IMRT) and a Carbon Ion Radiotherapy (CIRT) boost for salivary duct carcinoma (SDC).Methods: Twenty-eight consecutive patients with SDC who underwent a postoperative (82%) or definitive (18%) radiation therapy between 2010 and 2017 were assessed in this retrospective single-center analysis. CIRT boost was delivered with median 18 Gy(RBE) in 6 daily fractions, followed by an TomoTherapy®-based IMRT (median 54 Gy in 27 daily fractions). Treatment-related acute toxicity was assessed according to CTCAE Version 4.Results: Tumors were most commonly located in the major salivary glands (n = 25; 89%); 23 patients (82%) received previous surgery (R0: 30%; R1: 57%; R2: 4%; RX: 19%). Median follow-up was 30 months. Four patients (14%) experienced a local relapse and 3 (11%) developed locoregional recurrence. The two-year local control (LC) and locoregional control (LRC) was 96 and 93%, respectively. Median disease-free survival (DFS) was 27 months, metastasis-free survival (MFS) was 69 months, and overall survival (OS) was 93 months. Acute grade 3 toxicity occurred in 11 patients (mucositis, dermatitis, xerostomia; n = 2 each (7%) were the most common) and 2 osteonecroses of the mandibular (grade 3) occurred. No patients experienced grade ≥4 toxicities.Conclusions: Multimodal therapy approaches with surgery followed by IMRT and CIRT boost for SDC leads to good local and locoregional disease control. However, the frequent occurrence of distant metastases limits the prognosis and requires optimization of adjuvant systemic therapies.

Introduction: Data regarding treatment and survival outcome of patients with adenocarcinoma of the head and neck are limited to case reports and case series. As a consequence of lacking evidence, treatment guidelines do not exist. We aimed to analyze the effect of a bimodal irradiation regime with intensity modulated radiotherapy (IMRT) and carbon ion boost on local control (LC) and survival in adenocarcinoma patients for a large patient collective.Materials and Methods: Patient records of eighty consecutive patients treated between 2009 and 2018 were analyzed retrospectively and Kaplan-Meier estimates for LC, overall survival (OS) and progression-free survival (PFS) were compared among patients with salivary gland adenocarcinoma (SGAC), salivary duct adenocarcinoma (SDAC), and intestinal-type adenocarcinoma (ITAC) according to the World Health Organization (WHO). Prognostic factors were identified using the log-rank test and cox-regression modeling. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE).Results: Median follow-up was 41 months. The 3-year and estimated 5-year Kaplan-Meier rates for all patients were 83 and 75% for LC, 74 and 50% for OS and 60 and 53% for PFS, respectively. While bimodal RT for ITAC resulted in a significantly decreased 3-year LC rate of 50 vs. 93% for each SGAC and SDAC (p < 0.01), no statistical significant survival differences could be identified across the three groups regarding OS (p = 0.08) and PFS (p = 0.063). 3-year OS was 88% for SGAC, 78% for SDAC and 67% for ITAC and 3-year PFS was 72% for SGAC, 53% for SDAC and 44% for ITAC, respectively. Nevertheless, in subgroup analysis, OS for ITAC was significantly worse compared to SGAC (p = 0.024). In multivariate analysis, bilateral tumor side (vs. unilateral) solely could be identified as independent negative prognostic factor for LC (p < 0.01). Treatment was well-tolerated with 21% acute (n = 17) and 25% (n = 20) late grade ≥3 toxicities.Conclusion: Radiotherapy including active raster-scanning carbon ion boost for relatively radio resistant adenocarcinomas of the head and neck resulted in favorable survival outcome for salivary gland and salivary duct adenocarcinomas with moderate toxicity. However, local control and prognosis for bilateral intestinal-type adenocarcinomas (ITAC) seem to remain low even after dose-escalation.

Abstract Background According to current guidelines, acute pericarditis is an inflammatory pericardial syndrome with or without pericardial effusion. Case Description We report on a patient who was treated for purulent pericarditis and developed a fistula from the ascending aorta to the right ventricle (RV), leading to cardiac decompensation. Operative closure of the aortic and RV perforation solved the problem. Conclusion Bacterial pericarditis may lead to life-threatening complications. Early diagnosis and immediate therapy are essential for a successful outcome.

Usual care regarding vasopressor initiation is ill-defined. We aimed to develop a quantitative “dynamic practice” model for usual care in the emergency department (ED) regarding the timing of vasopressor initiation in sepsis. In a retrospective study of 589 septic patients with hypotension in an urban tertiary care center ED, we developed a multi-variable model that distinguishes between patients who did and did not subsequently receive sustained (>24 h) vasopressor therapy. Candidate predictors were vital signs, intravenous fluid (IVF) volumes, laboratory measurements, and elapsed time from triage computed at timepoints leading up to the final decision timepoint of either vasopressor initiation or ED hypotension resolution without vasopressors. A model with six independently significant covariates (respiratory rate, Glasgow Coma Scale score, SBP, SpO2, administered IVF, and elapsed time) achieved a C-statistic of 0.78 in a held-out test set at the final decision timepoint, demonstrating the ability to reliably model usual care for vasopressor initiation for hypotensive septic patients. The included variables measured depth of hypotension, extent of disease severity and organ dysfunction. At an operating point of 90% specificity, the model identified a minority of patients (39%) more than an hour before actual vasopressor initiation, during which time a median of 2,250 (IQR 1,200–3,300) mL of IVF was administered. This single-center analysis shows the feasibility of a quantitative, objective tool for describing usual care. Dynamic practice models may help assess when management was atypical; such tools may also be useful for designing and interpreting clinical trials.

Objective: Novel applications of transcranial Doppler (TCD) ultrasonography, such as the assessment of cerebral vessel narrowing/occlusion or the non-invasive estimation of intracranial pressure (ICP), require high-quality maximal flow velocity waveforms. However, due to the low signal-to-noise ratio of TCD spectrograms, measuring the maximal flow velocity is challenging. In this work, we propose a calibration-free algorithm for estimating maximal flow velocities from TCD spectrograms and present a pertaining beat-by-beat signal quality index. Methods: Our algorithm performs multiple binary segmentations of the TCD spectrogram and then extracts the pertaining envelopes (maximal flow velocity waveforms) via an edge-following step that incorporates physiological constraints. The candidate maximal flow velocity waveform with the highest signal quality index is finally selected. Results: We evaluated the algorithm on 32 TCD recordings from the middle cerebral and internal carotid arteries in 6 healthy and 12 neurocritical care patients. Compared to manual spectrogram tracings, we obtained a relative error of -1.5%, when considering the whole waveform, and a relative error of -3.3% for the peak systolic velocity. Conclusion: The feedback loop between the signal quality assessment and the binary segmentation yields a robust algorithm for maximal flow velocity estimation. Clinical Impact: The algorithm has already been used in our ICP estimation pipeline. By making the code and the data publicly available, we hope that the algorithm will be a useful building block for the development of novel TCD applications that require high-quality flow velocity waveforms.

Artificial gravity (AG) has often been proposed as an integrated multi-system countermeasure to physiological deconditioning associated with extended exposure to reduced gravity levels, particularly if combined with exercise. Twelve subjects underwent short-radius centrifugation along with bicycle ergometry to quantify the short-term cardiovascular response to AG and exercise across three AG levels (0 G or no rotation, 1 G, and 1.4 G; referenced to the subject’s feet and measured in the centripetal direction) and three exercise intensities (25, 50, and 100 W). Continuous cardiovascular measurements were collected during the centrifugation sessions using a non-invasive monitoring system. The cardiovascular responses were more prominent at higher levels of AG and exercise intensity. In particular, cardiac output, stroke volume, pulse pressure, and heart rate significantly increased with both AG level (in most of exercise group combinations, showing averaged increments across exercise conditions of 1.4 L/min/g, 7.6 mL/g, 5.22 mmHg/g, and 2.0 bpm/g, respectively), and workload intensity (averaged increments across AG conditions of 0.09 L/min/W, 0.17 mL/W, 0.22 mmHg/W, and 0.74 bpm/W respectively). These results suggest that the addition of AG to exercise can provide a greater cardiovascular benefit than exercise alone. Hierarchical regression models were fitted to the experimental data to determine dose-response curves of all cardiovascular variables as a function of AG-level and exercise intensity during short-radius centrifugation. These results can inform future studies, decisions, and trade-offs toward potential implementation of AG as a space countermeasure.