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Purpose: Extensive-stage small cell lung cancer (ES-SCLC) carries a dismal prognosis. The benefit of consolidative thoracic radiotherapy (TR) after first-line chemoimmunotherapy with PD-L1 inhibitors in this setting remains unclear. As TR can improve overall survival (OS) after conventional chemotherapy, we retrospectively analyzed OS of an inhouse cohort treated either with TR or with chemoimmunotherapy alone., Methods: A total of 41 patients treated with chemoimmunotherapy with PD-L1 inhibitors (atezolizumab or durvalumab) for ES-SCLC at our hospital since 2019 were analyzed. TR was administered in 10 fractions of 3 Gy. Patient characteristics, number of immunotherapy cycles received, brain irradiation, and presence of hepatic and cerebral metastasis at diagnosis were assessed. Primary endpoint was OS after first diagnosis., Results: Consolidative TR was associated with a significantly longer OS than systemic therapy alone (1-year OS 78.6% and 2‑year OS 37.1% vs. 1‑year OS 39.7% and 2 years not reached, p = 0.019). With regard to radiotherapy indication, survival at 1 year was 88.9% (log-rank p = 0.016) for patients receiving consolidative TR. For patients receiving TR in case of progression, 1‑year survival was 66.7%. Hepatic and cerebral metastasis at first diagnosis had no significant effect on OS., Conclusion: TR was significantly associated with longer OS. The survival benefit of TR was most pronounced for consolidative radiotherapy after initial chemoimmunotherapy compared to TR in case of progression. Although retrospective findings need to be interpreted with caution, in the absence of prospective data, our findings provide a basis for offering consolidative TR in the era of chemoimmunotherapy., (© 2023. The Author(s).)

Background: Patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC., Methods: Thirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival., Discussion: PUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques., Trial Registration: ClinicalTrials.gov: NCT05237453 ., (© 2023. The Author(s).)

Background: Heart valve clinics (HVC) have been introduced to manage patients with valvular heart disease within a multidisciplinary team., Objective: To determine the outcome benefit of HVC approach compared with standard of care (SOC) for patients with moderate and asymptomatic severe aortic stenosis (mAS and asAS)., Methods: Single-centre, observational registry of patients with mAS and asAS with at least one cardiac ambulatory consultation at our Cardiovascular Centre. Based on the outpatient strategy, patients were divided into HVC group, if receiving at least one visit at HVC, and SOC group, if followed by routine cardiac consultations., Results: 2129 patients with mAS and asAS were divided into those followed in HVC (n=251) versus SOC group (n=1878). The mean age was 76.5±12.4 years; 919 (43.2%) had asAS. During a follow-up of 4.8±1.8 years, 822 patients (38.6%) died, 307 (14.4%) were hospitalised for heart failure and 596 (28%) underwent aortic valve replacement (AVR). After propensity score matching, the number of consultations per year, exercise stress tests, brain natriuretic peptide (BNP) determinations and CTs were higher in the HVC cohort (p<0.05 for all). A shorter time between indication of AVR and less advanced New York Heart Association class was reported in the HVC cohort (p<0.001 and p=0.032). Compared with SOC, the HVC approach was associated with reduced all-cause mortality (HR=0.63, 95% CI 0.40 to 0.98, p=0.038) and cardiovascular death (p=0.030). At multivariable analysis, the HVC remained an independent predictor of all-cause mortality (HR=0.54, 95% CI 0.34 to 0.85, p=0.007)., Conclusions: In patients with mAS and asAS, the HVC approach was associated with more efficient management and outcome benefit compared with SOC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Research in the field of local and locoregional breast cancer radiotherapy aims to maintain excellent oncological outcomes while reducing treatment-related toxicity. Adaptive radiotherapy (ART) considers variations in target and organs at risk (OARs) anatomy occurring during the treatment course and integrates these in re-optimized treatment plans. Exploiting ART routinely in clinic may result in smaller target volumes and better OAR sparing, which may lead to reduction of acute as well as late toxicities. In this review MR-guided and CT-guided ART for breast cancer patients according to different clinical scenarios (neoadjuvant and adjuvant partial breast irradiation, whole breast, chest wall and regional nodal irradiation) are reviewed and their advantages as well as challenging aspects discussed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The MR-Linac research program is funded by the German Research Council (to D.T. and D.Z., ZI 736/2-1). Radiation Oncology Tübingen receives financial and technical support from Elekta AB, Kaiku Health and TheraPanacea under a research agreement. C.D.C. is supported by the Medical Faculty Tübingen (TüFF). Odense University Hospital has research agreements with Elekta and Philips., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Development of left ventricle (LV) hypertrophy in aortic stenosis (AS) is accompanied by adaptive coronary flow regulation. We aimed to assess absolute coronary flow, microvascular resistance, coronary flow reverse (CFR) and microvascular resistance reserve (MRR) in patients with and without AS., Methods: Absolute coronary flow and microvascular resistance were measured by continuous thermodilution in 29 patients with AS and 29 controls, without AS, matched for age, gender, diabetes and functional severity of epicardial coronary lesions. Myocardial work, total myocardial mass and left anterior descending artery (LAD)-specific mass were quantified by echocardiography and cardiac-CT., Results: Patients with AS presented a significantly positive LV remodelling with lower global longitudinal strain and global work efficacy compared with controls. Total LV myocardial mass and LAD-specific myocardial mass were significantly higher in patients with AS (p=0.001). Compared with matched controls, absolute resting flow in the LAD was significantly higher in the AS cohort (p=0.009), resulting into lower CFR and MRR in the AS cohort compared with controls (p < 0.005 for both). No differences were found in hyperaemic flow and resting and hyperaemic resistances. Hyperaemic myocardial perfusion (calculated as the ratio between the absolute coronary flow subtended to the LAD, expressed in mL/min/g), but not resting, was significantly lower in the AS group (p=0.035)., Conclusions: In patients with severe AS and non-obstructive coronary artery disease, with the progression of LV hypertrophy, the compensatory mechanism of increased resting flow maintains adequate perfusion at rest, but not during hyperaemia. As a consequence, both CFR and MRR are significantly impaired., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Funding Support and Author Disclosures Drs Paolisso, Bertolone, and Leone are supported by a research grant from the CardioPaTh PhD Program. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Use of the current echocardiography-based indications for aortic regurgitation (AR) surgery might result in late valve replacement at the stage of irreversible myocardial damage. Therefore, we aimed to identify simple models combining multiple echocardiography or magnetic resonance imaging (MRI)-derived indices and natriuretic peptides (BNP [brain natriuretic peptide] or NT-proBNP [N-terminnal pro-B type natriuretic peptide]) to predict early disease decompensation in asymptomatic severe AR., Methods: This prospective and multicenter study included asymptomatic patients with severe AR, preserved left ventricular ejection fraction (>50%), and sinus rhythm. The echocardiography and MRI images were analyzed centrally in the CoreLab. The study end point was the onset of indication for aortic valve surgery as per current guidelines., Results: The derivative cohort consisted of 127 asymptomatic patients (age 45±14 years, 84% males) with 41 (32%) end points during a median follow-up of 1375 (interquartile range, 1041-1783) days. In multivariable Cox regression analysis, age, BNP, 3-dimensional vena contracta area, MRI left ventricular end-diastolic volume index, regurgitant volume, and a fraction were identified as independent predictors of end point (all P <0.05). However, a combined model including one parameter of AR assessment (MRI regurgitant volume or regurgitant fraction or 3-dimensional vena contracta area), 1 parameter of left ventricular remodeling (MRI left ventricular end-diastolic volume index or echocardiography 2-dimensional global longitudinal strain or E wave), and BNP showed significantly higher predictive accuracy (area under the curve, 0.74-0.81) than any parameter alone (area under the curve, 0.61-0.72). These findings were confirmed in the validation cohort (n=100 patients, 38 end points)., Conclusions: In asymptomatic severe AR, multimodality and multiparametric model combining 2 imaging indices with natriuretic peptides, showed high accuracy to identify early disease decompensation. Further prospective studies are warranted to explore the clinical benefit of implementing these models to guide patient management., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02910349.

Coronary artery disease (CAD) continues to be the leading cause of mortality and morbidity in developed countries. Assessment of pre-test probability (PTP) based on patient's characteristics, gender and symptoms, help to identify more accurate patient's clinical likelihood of coronary artery disease. Consequently, non-invasive imaging tests are performed more appropriately to rule in or rule out CAD rather than invasive coronary angiography (ICA). Coronary computed tomography angiography (CCTA) is the first-line non-invasive imaging technique in patients with suspected CAD and could be used to plan and guide coronary intervention. Invasive coronary angiography remains the gold-standard method for the identification and characterization of coronary artery stenosis. However, it is recommended in patients where the imaging tests are non-conclusive, and the clinical likelihood is very high, remembering that in clinical practice, approximately 30 to 70% of patients with symptoms and/or signs of ischemia, referred to coronary angiography, have non obstructive coronary artery disease (INOCA). In this contest, physiology and imaging-guided revascularization represent the cornerstone of contemporary management of chronic coronary syndromes (CCS) patients allowing us to focus specifically on ischemia-inducing stenoses. Finally, we also discuss contemporary medical therapeutic approach for secondary prevention. The aim of this review is to provide an updated diagnostic and therapeutic approach for the management of patients with stable coronary artery disease., (© 2022. The Author(s).)

Purpose: To develop prognostic biomarker signatures for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on previously published molecular analyses of the retrospective biomarker study of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG)., Material and Methods: In previous studies on the retrospective DKTK-ROG HNSCC cohort treated with primary RCTx, the following clinical parameters and biomarkers were evaluated and found to be significantly associated with loco-regional tumour control (LRC) or overall survival (OS): tumour volume, p16 status, expression of cancer stem cell markers CD44 and SLC3A2, expressions of hypoxia-associated gene signatures, tumour mutational burden (TMB), single nucleotide polymorphisms (SNPs) in the ERCC2 gene (rs1799793, rs13181) and ERCC5 gene (rs17655) as well as the expression of CXCR4, SDF-1 and CD8. These biomarkers were combined in multivariable modelling using Cox-regression with backward variable selection., Results: A baseline signature containing the widely accepted parameters tumour volume, p16 status, cancer stem cell marker expression (CD44), and hypoxia-associated gene expression has been defined, representing the main hypothesis of the study. Furthermore, the baseline signature was extended by additional prognostic biomarkers and a data-driven signature without any pre-hypothesis was generated for both endpoints. In these signatures, the SNPs rs1799793 and rs17655 as well as CXCR4, SDF-1 and SLC3A2 expression were additionally included. The signatures showed significant patient stratifications for LRC and OS., Conclusion: Three biomarker signatures were defined for patients with locally advanced HNSCC treated with primary RCTx for the endpoints LRC and OS. These signatures will be validated in the prospective HNprädBio study of the DKTK-ROG that recently completed recruitment, before potential application in an interventional trial., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first-pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin-monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP., (© 2021 Neurogastrx Inc. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Aims: Non-invasive myocardial work (MW) is a validated index of left ventricular (LV) systolic performance, incorporating afterload and myocardial metabolism. The role of MW in predicting the first hospitalization for de novo heart failure with preserved ejection fraction (HFpEF) is still unknown. We aim to investigate the diagnostic performance of MW to predict the first de novo HFpEF hospitalization in ambulatory individuals with preserved LV ejection fraction., Methods and Results: Twenty-nine patients with transthoracic echocardiography performed at least 6 months before the first HFpEF hospitalization were compared with 29 matched controls. MW was derived as the area of pressure-strain loop using speckle-tracking and brachial artery blood pressure. Global work index, global constructive work, global wasted work (GWW), and global work efficiency (GWE) were collected. First HFpEF hospitalization and its combination with cardiovascular death [major adverse cardiovascular events (MACE)] and all-cause of death [major adverse events (MAE)] were assessed. At baseline, future HFpEF patients showed lower global work index, global constructive work, GWE, and higher GWW than controls (all P < 0.05). At admission vs. baseline, GWE significantly decreased, and GWW increased in the HFpEF group (P < 0.05), whereas no significant difference was observed in the controls over time. GWW, with a cut-off of 170 mmHg%, showed the largest area under the curve (AUC) to predict first HFpEF hospitalization [AUC = 0.80, 95% confidence interval (CI) 0.69-0.91, P < 0.001], MACE (AUC = 0.80, 95% CI 0.66-0.90, P < 0.001), and MAE (AUC = 0.79, 95% CI 0.62-0.88, P = 0.001). GWW > 170 mmHg% was associated with a 4-fold increase of MACE (HR = 4.5, 95% CI 1.59-13.12, P = 0.005) and a 3-fold higher risk of MAE (HR = 2.9, 95% CI 1.24-6.6, P = 0.014)., Conclusions: In ambulatory patients with preserved LV ejection fraction and risk factors, GWW showed high accuracy to predict the first HFpEF hospitalization and its combination with mortality. The GWW routine assessment may be clinically helpful in patients with dyspnoea., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: To evaluate the long-term efficacy of combined radiotherapy (RT) and hyperthermia (HT) in a large mono-institutional cohort of breast cancer (BC) patients affected by recurrent, newly diagnosed non-resectable or high risk resected tumor., Materials and Methods: Records of BC patients treated with RT + HT between 1995 and 2018 were retrospectively analyzed. RT doses of 50-70 Gy concurrent to a twice per week superficial HT were applied. For HT, a temperature between 41 and 42 °C was applied for approximately 1 h. Primary endpoint was local control (LC), secondary endpoints comprised toxicity, overall survival (OS), and progression-free survival (PFS)., Results: A total of 191 patients and 196 RT + HT treatments were analyzed. In 154 cases (78.6%) RT + HT was performed for patients with recurrent BC. Among these, 93 (47.4% of the entire cohort) had received RT prior to RT + HT. Median follow up was 12.7 years. LC at 2, 5, and 10 years was 76.4, 72.8, and 69.5%, respectively. OS at 2, 5, and 10 years was 73.5, 52.3, and 35.5%, respectively. PFS at 2, 5, and 10 years was 55.6, 41, and 33.6%, respectively. Predictive factors for LC were tumor stage, distant metastases, estrogen/progesterone receptor expression, resection status and number of HT fractions. At multivariate analysis tumor stage and receptor expression were significant. No acute or late toxicities higher than grade 3 were observed., Conclusion: Combined RT + HT offers long-term high LC rates with acceptable toxicity for patients with recurrent, newly diagnosed non-resectable or resected BC at high risk of relapse.

Lung ultrasonography (LUS) has become in the last 10 years a technique that has reduced the need of second level diagnostic methods such as chest X-ray (CXR) and computerize tomography (CT) for the diagnostic imaging of lung and pleural space, throughout its diagnostic accuracy, radiation free, low cost, real time and bedside approach. The common use of LUS has been recently extend to cardiac and pulmonary disease even in context of Cardiac Rehabilitation Unit and it could be an additional tool for physiotherapist for the management of patients during Rehabilitation course. The authors performed a literature review in PubMed and suggested a new standardize protocol for LUS, based on guidelines and expert consensus document, for patients admitted to Cardiac Rehabilitation Unit. In this protocol, LUS should be performed in six scan each hemithorax, covering twelve imagine regions. For each scan will be noted a specific physiologic or pathological patterns. Furthermore, we suggest for each patient, the use of the Lung Ultrasound Score (LUS score) to obtain a global view of lung aeration and to monitor any changes during the hospitalization. An increase in score range indicates a more severe condition. This Lung Ultrasonography Protocol should be performed in all patients at the time of admission to Cardiac Rehabilitation Unit to monitoring the aeration of the lungs and the possible lung and/or pleura complications after a cardiac disease avoiding the use of second level surveys.

Aim: To assess radiation response using γH2AX assay in surgical specimens from glioblastoma (GB) patients and their corresponding primary gliosphere culture. To test the hypothesis that gliospheres (stem cell enriched) are more resistant than specimens (bulky cell dominated) but that the interpatient heterogeneity is similar., Material and Methods: Ten pairs of specimens and corresponding gliospheres derived from patients with IDH-wildtype GB were studied. Specimens and gliospheres were irradiated with graded doses and after 24 h the number of residual γH2AX foci was counted., Results: Gliospheres showed a higher Nestin expression than specimens and exhibited two different phenotypes: free floating (n = 7) and attached (n = 3). Slope analysis revealed an interpatient heterogeneity with values between 0.15 and 1.30 residual γH2AX foci/Gy. Free-floating spheres were more resistant than their parental specimens (median slope 0.13 foci/Gy versus 0.53) as well as than the attached spheres (2.14). The slopes of free floating spheres did not correlate with their corresponding specimens while a trend for a positive correlation was found for the attached spheres and the respective specimens. Association with MGMT did not reach statistical significance., Conclusion: Consistent with the clinical phenotype and our previous experiments, GB specimens show low radiation sensitivity. Stem-cell enriched free-floating gliospheres were more resistant than specimens supporting the concept of radioresistance in stem cell-like cells. The lack of correlation between specimens and their respective gliosphere cultures needs validation and may have a profound impact on future translational studies using γH2AX as a potential biomarker for personalized radiation therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Cancer-related fatigue (CRF) is a common side effect of cancer treatment, particularly in breast cancer patients. Over the past decade, the multimodal management of breast cancer has undergone several changes, such as the establishment of postoperative hypofractionated radiotherapy (RT) as a new standard protocol and the reduced use of chemotherapy. The aim of the current study was to investigate the impact of these changes on quality of life (QoL) and CRF., Methods: A total of 66 patients was assessed for QoL and CRF using the FACIT‑F questionnaire. Patients were asked to complete the paper-based questionnaire before (TP1) and at the end of radiotherapy (TP2) as well as at follow-up (TP3). Subgroups were compared based on fractionation and previous application of chemotherapy., Results: For the entire cohort, no significant changes in the severity of fatigue were seen. A mild decrease of physical wellbeing (PWB) from TP1 to TP2 was observed (22.2 vs. 20.7, p = 0.007). Fatigue at TP1 was more severe in patients receiving chemotherapy before RT (37.9 vs. 30.5, p = 0.041). Only patients without preceding chemotherapy showed a significant worsening of fatigue from TP1 to TP2 (37.9 vs 34.8, p = 0.005). The same is true for physical wellbeing (PWB), with a decrease from TP1 to TP2 in chemotherapy-naïve patients only (23.5 vs. 21.4, p = 0.002). Fractionation did not impact any of the investigated endpoints., Conclusion: Patients undergoing postoperative RT for breast cancer constitute a heterogeneous patient population with varying risks of developing CRF influenced by previous treatments. Therefore, patient selection seems to be critical when interventional studies addressing CRF during radiotherapy are designed.

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234-0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177-3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

Current research in radiotherapy (RT) for breast cancer is evaluating neoadjuvant as opposed to adjuvant partial breast irradiation (PBI) with the aim of reducing the volume of breast tissue irradiated and therefore the risk of late treatment-related toxicity. The development of magnetic resonance (MR)-guided RT, including dedicated MR-guided RT systems [hybrid machines combining an MR scanner with a linear accelerator (MR-linac) or 60 Co sources], could potentially reduce the irradiated volume even further by improving tumour visibility before and during each RT treatment. In this position paper, we discuss MR guidance in relation to each step of the breast RT planning and treatment pathway, focusing on the application of MR-guided RT to neoadjuvant PBI., (Copyright © 2020 Groot Koerkamp, Vasmel, Russell, Shaitelman, Anandadas, Currey, Vesprini, Keller, De-Colle, Han, Braunstein, Mahmood, Lorenzen, Philippens, Verkooijen, Lagendijk, Houweling, van den Bongard and Kirby.)

Introduction: External beam partial breast irradiation (PBI) provides equal oncological outcomes compared to whole breast irradiation when applied to patients with low risk tumours. Recently, linacs with an integrated magnetic resonance image-guidance system have become clinically available. Here we report the first-in-human PBI performed at the 1.5 T MR-Linac, with a focus on clinical feasibility and investigation of the air electron stream effect (ESE) and the electron return effect (ERE) in the presence of the 1.5 T magnetic field, which might influence the dose on the chin (out-of-field dose, due to the ESE), the skin and the lung/chest wall interface (in-field dose, ERE)., Methods: A 59 years old patient affected by a 15 mm unifocal grade 1 carcinoma not special type of the right breast staged pT1c pN0 cM0 was planned and treated at Unity 1.5 T MR-Linac. To investigate the ERE and the ESE, an MR-Linac treatment plan was simulated without considering the 1.5 T B field using a research version of Monaco (V. 5.19.03). In vivo dosimetry was performed using Gafchromic® EBT3 films placed on top and underneath a 1 cm bolus which was placed on the patient's chin. The plans with and without 1.5 T magnetic field were compared in terms of dose to the chin, to the skin and to the interface lung/chest wall. Finally, the dose on the chin measured with the in vivo dosimetry was compared with the dose calculated by Monaco., Results: PBI using the 1.5 T MR-Linac was successfully performed with a 7 MV photon 7-beams IMRT step-and-shoot plan. The treatment was well tolerated, the patient developed a slight acute toxicity, i.e. breast skin erythema and breast oedema CTC V.4 grade 1. The plan with 1.5 T magnetic field documented a fractional dose of 0.17 Gy in the chin area (2.6 Gy in 15 fractions), which was reduced to 0.05 Gy (0.75 in 15 fractions) by the presence of 1 cm bolus. The simulated plan without magnetic field showed a dose reduced by 2.3 Gy in the chin area. With the in vivo dosimetry a fractional dose of, respectively, 0.12 Gy and 0.034 Gy on top and underneath the bolus were measured (1.8 and 0.51 Gy in 15 fractions). The plan with 1.5 T magnetic field showed a skin D 2 of 40 Gy and a skin V 35 of 40.2%, which were reduced to, respectively, 39.7 Gy and 24.9% in the simulation without magnetic field. At the interface lung/chest there were no differences in DVH statistics., Conclusion: PBI with the 1.5 T MR-Linac was performed for the first time. ESE is accurately calculated by the treatment planning system, can be effectively reduced with a 1 cm bolus and is comparable to dose of cone beam-CT based position verification. The additional dose caused by ERE is not associated with an increased risk of acute toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Heterotopic ossification (HO) is abnormal formation of lamellar bone in soft tissue; the most frequent causes are total hip arthroplasty and trauma. Severe cases can lead to ankilosis with important impact on quality of life. Surgery is the elective treatment, but, especially in high-risk patients, it is important to prevent the re-formation of HO and, in these cases, radiotherapy (RT) can play an important role., Materials and Methods: we retrospectively analyzed a mono-institutional casistic of 30 patients (31 sites) at high risk for HO development, treated with surgery and pre- or postoperative RT. The majority of patients received a single RT fraction of 7 Gy, median age was 62, with a prevalence of male and hip as most frequently involved site. Radiological studies and clinical examination were performed in all patients during the follow-up period to evaluate both treatment efficacy and acute or late toxicity., Results: With a median follow up of 67 months, 23 patients had a complete response (CR) with excellent results in term of joint mobility. Two patients with CR showed a relapse of HO in the same site 19 and 12 months after treatment, respectively. Seven patients (22,6%) had a partial response (PR) to RT. One patient who reached CR had a history of previous irradiation in the same site 16 years before. No acute or late reactions have been reported., Conclusion: Our data confirm safety and efficacy of RT in preventing HO, especially in high-risk patients, preferring a single fraction of 7 Gy.

Introduction: Preclinical and clinical data suggest that the chemokine pathway governed by SDF-1 and CXCR4 contributes to a resistant phenotype. This retrospective biomarker study aims to explore the specific prognostic value of SDF-1 and CXCR4 expression in locally advanced head and neck squamous cell carcinomas (HNSCC) treated with primary radiochemotherapy (RT-CT)., Material and Methods: Biopsies from 141 HNSCC tumours of the oral cavity, oropharynx and hypopharynx were evaluated for SDF-1 and CXCR4 expression by immunofluorescence. SDF-1 and CXCR4 expression was correlated with clinico-pathological characteristics and outcome after RT-CT., Results: Patients with tumours exhibiting overexpression of intracellular SDF-1 and CXCR4 have a higher risk for loco-regional relapse and a worse overall survival after RT-CT (multivariate analysis, hazard ratio 2.33, CI [1.18-4.62], p = 0.02 and hazard ratio 2.02, CI [1.13-3.59], p = 0.02, respectively). Similar results were observed when only the subgroup of HPV DNA negative patients were analysed (hazard ratio 2.23 and 2.16, p = 0.02 and p = 0.01, respectively)., Conclusions: Our data support the importance of SDF-1 and CXCR4 expression for loco-regional control and overall survival in HNSCC after primary radiochemotherapy. Prospective multivariate validation and further studies into CXCR4 inhibition to overcome radiation resistance are warranted., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: The aim of the study is to assess inter-patient and intra-patient heterogeneity in tumour cell radiosensitivity using the ex vivo γH2AX assay in prostate cancer specimens., Methods: Excised specimens from untreated prostate cancer patients were cultivated 24h in media, irradiated ex vivo and fixed after 24h. Residual γH2AX foci were counted and the slope of the dose response was calculated. Intra-patient heterogeneity was studied from three to seven different biopsies., Results: In pathology-confirmed tumour samples from 21 patients the slope of residual γH2AX foci and radiation dose showed a substantial heterogeneity ranging from 0.82 to 3.17 foci/Gy. No correlation was observed between the slope values and the Gleason score (p=0.37), prostate specific antigen (p=0.48) and tumour stage (p=0.89). ANOVA indicated that only in 1 out of 9 patients, biopsies from different tumour locations yielded statistically significant differences. Variance component analysis indicated higher inter-patient than intra-patient variability. Bootstrap simulation study demonstrated that one biopsy is sufficient to estimate the mean value of residual γH2AX per dose level and account for intra-patient heterogeneity., Conclusions: In prostate cancer inter-patient heterogeneity in tumour cell radiation sensitivity is pronounced and higher than intra-patient heterogeneity supporting the further development of the γH2AX ex vivo assay as a biomarker for individualized treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)., Material and Methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data., Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found., Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.

The aim of this study was to evaluate local control, survival and toxicity profile of a consecutive cohort of early-stage breast cancer (EBC) patients treated with adjuvant hypofractionated radiotherapy (HF) with no boost delivered to the lumpectomy cavity, after breast-conserving surgery (BCS). Between 2005 and 2015, a total of 493 women affected with EBC were treated with HF (46 Gy/20 fractions or 40.05 Gy/15 fractions) to the whole breast without boost to tumor bed, because of age and/or favorable tumor characteristics. The primary endpoint was 5-year actuarial local control (LC); secondary endpoints included survival, toxicity profile and cosmesis. Median follow-up was 57 months (range 6-124). Actuarial 5-year overall, cancer-specific, disease-free survival and LC were 96.3, 98.9, 97.8 and 98.6 %, respectively. On multivariate analysis, tumor stage (T1 vs. T2) and hormonal status (positive vs. negative estrogen receptors) were significantly correlated with LC. Only 2 % of patients experienced ≥G3 acute skin toxicity. Late toxicity was mild with only 1 case of G3 fibrosis. Most of the patients (95 %) had good-excellent cosmetic results. HF to the whole breast with no boost delivered to the tumor bed is a safe and effective option for a population of low-risk breast cancer patients after BCS, with excellent 5-year LC, mild toxicity profile and promising cosmetic outcome. A subgroup of patients with larger tumors and/or with no estrogen receptor expression may potentially benefit from treatment intensification with a boost dose to the lumpectomy cavity.

Purpose: To apply our previously published residual ex vivo γH2AX foci method to patient-derived tumour specimens covering a spectrum of tumour-types with known differences in radiation response. In addition, the data were used to simulate different experimental scenarios to simplify the method., Materials and Methods: Evaluation of residual γH2AX foci in well-oxygenated tumour areas of ex vivo irradiated patient-derived tumour specimens with graded single doses was performed. Immediately after surgical resection, the samples were cultivated for 24h in culture medium prior to irradiation and fixed 24h post-irradiation for γH2AX foci evaluation. Specimens from a total of 25 patients (including 7 previously published) with 10 different tumour types were included., Results: Linear dose response of residual γH2AX foci was observed in all specimens with highly variable slopes among different tumour types ranging from 0.69 (95% CI: 1.14-0.24) to 3.26 (95% CI: 4.13-2.62) for chondrosarcomas (radioresistant) and classical seminomas (radiosensitive) respectively. Simulations suggest that omitting dose levels might simplify the assay without compromising robustness., Conclusion: Here we confirm clinical feasibility of the assay. The slopes of the residual foci number are well in line with the expected differences in radio-responsiveness of different tumour types implying that intrinsic radiation sensitivity contributes to tumour radiation response. Thus, this assay has a promising potential for individualized radiation therapy and prospective validation is warranted., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The purpose of this study was to retrospectively report clinical outcomes on a consecutive series of older early breast cancer patients treated with once-weekly adjuvant whole-breast radiation therapy (WBRT) after breast-conserving surgery (BCS)., Patients and Methods: A total of 291 patients (298 breasts) were treated with WBRT between 2007 and 2013. Patients were given 6 to 6.5 Gy in 5 weekly fractions (total dose, 32.5-30 Gy) over 5 weeks. Clinical end points were local control (LC), disease-free (DFS), cancer-specific (CSS), and overall survival (OS), and acute and late toxicity and cosmesis. Prognostic clinical variables were assessed with respect to DFS., Results: Median follow-up was 46.5 months (range, 12-84 months). The 3- and 5-year LC rates were 99.5% (95% confidence interval [CI], 96.4-99.9) and 98% (95% CI, 91.1-99.6). The 3- and 5-year CSS and OS were 97.7% (95% CI, 94.5-99.1), 95.3% (95% CI, 90.5-97.7), 94.4% (95% CI, 90.4-96.7), and 83.6% (95% CI, 76.1-88.9), respectively. Maximum detected acute skin toxicity was Grade (G) 0 in 71.8% of patients, G1 in 22.6%, G2 in 4.8%, G3 in 1%, and G4 in 0.3%. Treatment interruption occurred in 2 patients because of severe skin reactions. Late skin toxicity consisted of G1 fibrosis in 31.5% of patients, G2 in 4.2%, and G3 in 3.5%. Grade 1 edema was observed in 7% of patients, G2 in 4.2%, and G3 in 1.4%. G1 telangiectasia occurred in 1.8% and G3 in 0.7%. G1 hyperpigmentation was found in 4.6% of patients, G2 in 2.4%, and G1 atrophy was detected in 2.1%. Pain was observed as G1 in 13%, G2 in 1.8%, and G3 in 0.4%. Cosmetic results were good to excellent in 86.4% and fair to poor in 13.6%., Conclusion: Once-weekly hypofractionated WBRT (30-32-5 Gy in 5 fractions), delivered with standard tangential fields with the patient in the supine position seems feasible and effective for a selected population of primarily old breast cancer patients with predominantly low-risk features. This schedule might allow fragile patients to receive adjuvant WBRT after BCS, increasing radiotherapy accessibility and utilization., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: A combined protocol of voxel-based morphometry (VBM) and diffusion-weighted imaging (DWI) was applied to investigate the neurodevelopment of gray and white matter in autism., Methods: Twenty children with autism (mean age= 7 ± 2.75 years old; age range: 4-14; 2 girls) and 22 matched normally developing children (mean age = 7.68 ± 2.03 years old; age range: 4-11; 2 girls) underwent magnetic resonance imaging (MRI). VBM was employed by applying the Template-o-Matic toolbox (TOM), a new approach which constructs the age-matched customized template for tissue segmentation. Also, the apparent diffusion coefficients (ADC) of water molecules were obtained from the analysis of DWI. Regions of interests (ROIs), standardized at 5 pixels, were placed in cortical lobes and corpus callosum on the non-diffusion weighted echo-planar images (b = 0) and were then automatically transferred to the corresponding maps to obtain the ADC values., Results: Compared to normal children, individuals with autism had significantly: (1) increased white matter volumes in the right inferior frontal gyrus, the right fusiform gyrus, the left precentral and supplementary motor area and the left hippocampus, (2) increased gray matter volumes in the inferior temporal gyri bilaterally, the right inferior parietal cortex, the right superior occipital lobe and the left superior parietal lobule, and (3) decreased gray matter volumes in the right inferior frontal gyrus and the left supplementary motor area. Abnormally increased ADC values in the bilateral frontal cortex and in the left side of the genu of the corpus callosum were also reported in autism. Finally, age correlated negatively with lobar and callosal ADC measurements in individuals with autism, but not in children with normal development., Conclusions: These findings suggest cerebral dysconnectivity in the early phases of autism coupled with an altered white matter maturation trajectory during childhood potentially taking place in the frontal and parietal lobes, which may represent a neurodevelopmental marker of the disorder, possibly accounting for the cognitive and social deficits., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Metabotropic glutamate receptors (mGluRs) belong to the family 3 of G-protein-coupled receptors. On these proteins, agonist binding on the extracellular domain leads to conformational changes in the 7-transmembrane domains required for G-protein activation. To elucidate the structural features that might be responsible for such an activation mechanism, we have generated models of the amino terminal domain (ATD) of type 4 mGluR (mGlu4R). The fold recognition search allowed the identification of three hits with a low sequence identity, but with high secondary structure conservation: leucine isoleucine valine-binding protein (LIVBP) and leucine-binding protein (LBP) as already known, and acetamide-binding protein (AmiC). These proteins are characterized by a bilobate structure in an open state for LIVBP/LBP and a closed state for AmiC, with ligand binding in the cleft. Models for both open and closed forms of mGlu4R ATD have been generated. ACPT-I (1-aminocyclopentane 1,3,4-tricarboxylic acid), a selective agonist, has been docked in the two models. In the open form, ACPT-I is only bound to lobe I through interactions with Lys74, Arg78, Ser159, and Thr182. In the closed form, ACPT-I is trapped between both lobes with additional binding to Tyr230, Asp312, Ser313, and Lys317 from lobe II. These results support the hypothesis that mGluR agonists bind a closed form of the ATDs, suggesting that such a conformation of the binding domain corresponds to the active conformation.

In the brain, group-III metabotropic glutamate (mGlu) receptors mGlu(4), mGlu(7) and mGlu(8) receptors play a critical role in controlling the release process at many glutamatergic synapses. The pharmacological profile of mGlu(4) receptor has been studied extensively, allowing us to propose a pharmacophore model for this receptor subtype. Surprisingly, the activity of only a few compounds have been reported on mGlu(7) and mGlu(8) receptors. In order to identify new possibilities for the design of selective compounds able to discriminate between the members of the group-III mGlu receptors, we have undertaken a complete pharmacological characterization of mGlu(8) receptor and compared it with that of mGlu(4) receptor, using the same expression system, and the same read out. The activities of 32 different molecules revealed that these two mGlu receptors subtypes share a similar pharmacological profile. Only small differences were noticed in addition to that previously reported with S-carboxyglutamate (S-Gla) being a partial agonist at mGlu(4) receptor and a full antagonist at mGlu(8) receptor. These include: a slightly higher relative potency of the agonists 1S,3R and 1S,3S-aminocyclopentane-1,3-dicarboxylic acid (ACPD), S-4-carboxyphenylglycine (S-4CPG) and S-4-carboxy-3-hydroxyphenylglycine (S-4C3HPG), and a slightly higher potency of the antagonists 2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY354740) and RS-alpha-methyl-4-phosphonophenylglycine (MPPG) on mGlu(8) receptor. When superimposed on the mGlu(4) receptor pharmacophore model, these molecules revealed three regions that may be different between the ligand binding sites of mGlu(8) and mGlu(4) receptors.

The metabotropic glutamate receptors are GTP-binding-protein (G-protein) coupled receptors that play important roles in regulating the activity of many synapses in the central nervous system. As such, these receptors are involved in a wide number of physiological and pathological processes. Within the last few years, new potent and selective agonists and antagonists as well as radioligands acting on these receptors have been developed. Molecular modeling studies revealed the structural features of the glutamate binding site, and will be useful for the design of more selective and potent ligands. More interestingly, recent data revealed new regulatory sites on the receptor protein, able either to decrease or potentiate the action of the endogenous ligand. No doubt that in the near future a multitude of new tools to modulate the activity of these receptors will be discovered, enabling the identification of the possible therapeutic applications for these new neuroactive molecules.

In a previous study we reported that the addition of a carboxylic group to the mGlu receptor agonist aminocyclopentane-1,3-dicarboxylate (ACPD) changes its properties from agonist to antagonist at both mGlu1 and mGlu2 receptors, and resulted in an increase in affinity at mGlu4 receptors, with isomers being either agonists or antagonists. In the present study, the effect of gamma-carboxy-L-glutamic acid (Gla) and (2S,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), two carboxylic derivatives of non-selective agonists, were examined on all cloned mGlu receptors. We found that this additional carboxylic group on glutamate prevents its interaction with group-I mGlu receptors and generates a potent group-II antagonist (K(B) = 55 microM on mGlu2). At group-III mGlu receptors, Gla was found to be either an antagonist (mGlu7 and mGlu8 receptors) or a partial agonist (mGlu4 and mGlu6 receptors). We show here that L-CCG-I is a general mGlu receptor agonist activating all cloned receptors. We also confirm that DCG-IV, which corresponds to L-CCG-I with an additional carboxylic group, is a selective group-II agonist. However, this additional COOH group changes the properties of L-CCG-I from an agonist to an antagonist at all group-III receptors, making this compound one of the most potent group-III mGlu receptor antagonist known so far. These observations will be useful for the development of more potent and selective mGlu receptor agonists and antagonists.