Effects of tumor treating fields (TTFields) on human mesenchymal stromal cells.

PURPOSE: Mesenchymal stromal cells (MSCs) within the glioblastoma microenvironment have been shown to promote tumor progression. Tumor Treating Fields (TTFields) are alternating electric fields with low intensity and intermediate frequency that exhibit anti-tumorigenic effects. While the effects of TTFields on glioblastoma cells have been studied previously, nothing is known about the influence of TTFields on MSCs. METHODS: Single-cell RNA sequencing and immunofluorescence staining were employed to identify glioblastoma-associated MSCs in patient samples. Proliferation and clonogenic survival of human bone marrow-derived MSCs were assessed after TTFields in vitro. MSC' characteristic surface marker expression was determined using flow cytometry, while multi-lineage differentiation potential was examined with immunohistochemistry. Apoptosis was quantified based on caspase-3 and annexin-V/7-AAD levels in flow cytometry, and senescence was assessed with ß-galactosidase staining. MSCs' migratory potential was evaluated with Boyden chamber assays. RESULTS: Single-cell RNA sequencing and immunofluorescence showed the presence of glioblastoma-associated MSCs in patient samples. TTFields significantly reduced proliferation and clonogenic survival of human bone marrow-derived MSCs by up to 60% and 90%, respectively. While the characteristic surface marker expression and differentiation capacity were intact after TTFields, treatment resulted in increased apoptosis and senescence. Furthermore, TTFields significantly reduced MSCs' migratory capacity. CONCLUSION: We could demonstrate the presence of tumor-associated MSCs in glioblastoma patients, providing a rationale to study the impact of TTFields on MSCs. TTFields considerably increase apoptosis and senescence in MSCs, resulting in impaired survival and migration. The results provide a basis for further analyses on the role of MSCs in glioblastoma patients receiving TTFields.

Clinical Workflow of Cone Beam Computer Tomography-Based Daily Online Adaptive Radiotherapy with Offline Magnetic Resonance Guidance: The Modular Adaptive Radiotherapy System (MARS).

PURPOSE: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. METHODS: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. RESULTS: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5-63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7-39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6-32.2), 0.4 min (IQR 0.3-1,0) and 5.3 min (IQR 4.5-6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. CONCLUSION: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

Primary and adjuvant intensity-modulated radiotherapy in oropharyngeal carcinoma patients from a single institution.

BACKGROUND: To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with intensity-modulated radiotherapy (IMRT). METHODS: Ninety-eight OPC patients were treated between 2000 and 2015. Thirty-three patients received definitive and 65 adjuvant radiotherapy. Seventy-one percent had simultaneous chemotherapy. Patients were systematically followed up (mean 114 months, range 19-197 months). Statistical analysis used Kaplan-Meier method, Cox regression analysis, and log-rank test. Adverse events were classified according to common toxicity criteria version (CTCAE) 4.03. RESULTS: The 1-, 5-, and 10-year overall survival rates in the adjuvant vs. definitive cohort were 90.8% vs. 66.7%, 67.4% vs. 33.1%, and 57.7% vs. 16.5%. Survival in the adjuvant cohort was significantly longer than in the definitive cohort (P < 0.00005). Patients <65 years had a significantly longer survival than older patients. Locoregional tumor control rates after 1-, 5-, and 10 years in the adjuvant vs. definitive cohort were 90.2% vs. 66.7%, 82.2% vs 45.4%, and 72.1% vs. 30.3%. Locoregional tumor control in the adjuvant cohort was significantly longer than in the definite cohort (P < 0.005). Distant metastases were diagnosed in 20.4% of all patients. Most patients had mild CTCAE grade 1 and 2 adverse events and mild late adverse events including xerostomia, dysphagia, and lymphedema. CONCLUSION: Intensity-modulated radiotherapy for OPC is an important part of the treatment algorithm alone and in particular after surgery while the additional benefits of chemotherapy might be age dependent. Despite advanced tumor stages, nearly half of our patients were alive in the long term. The majority of patients had relatively mild chronic adverse events.

Daily AI-Based Treatment Adaptation under Weekly Offline MR Guidance in Chemoradiotherapy for Cervical Cancer 1: The AIM-C1 Trial.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

In Vitro Carbon Ion Beam and Gemcitabine Chemoradiation in a Mucoepidermoid Carcinoma Cell Line.

BACKGROUND/AIM: To determine the interaction of gemcitabine in chemoradiotherapy with heavy carbon ions in vitro in a mucoepidermoid carcinoma (MEC) cell line. MATERIALS AND METHODS: The human lymphatic MEC metastasis cell line NCI-H292 was used. The cells were treated with photons, carbon ions, and gemcitabine. Survival fractions (SF), apoptosis, and cell cycle progression were analyzed. A paired two-sided t-test was used. Significance was defined as p<0.05. RESULTS: Cell proliferation assays showed a significant reduction in SF for combined photon chemoradiation versus photons only. The linear-quadratic fits of combined therapy with carbon ion dose of 0 to 2.5 Gy led to reductions of mean 15% in SF. The LD50 (lethal radiation dose required to reduce cell survival by 50%) for carbon ions only was 0.7 Gy and for carbon ions with gemcitabine 0.6 Gy. The LD50 for photons (with gemcitabine) was 2.8 Gy (2.0 Gy) and for carbon ions (with gemcitabine) 0.7 Gy (0.6 Gy), resulting in a relative biological effectiveness at 10% cell survival (RBE10) of 3.0 (2.7). Carbon ions and photons reduced S phase and increased G2/M phase cell distribution. Isolated treatment with gemcitabine as well as combination with photons led to prolonged S phase transit, whereas combined treatment with carbon ions led to early accumulation in G2/M phase. A significant increase in the sub-G1 population as a hint of relevant number of apoptotic cells was not observed. CONCLUSION: Gemcitabine showed radiosensitizing effects in combination with photons. The combination of gemcitabine and carbon ions had independent additive effects. Carbon ions only had a RBE10 of 3.0, compared to photons only. The combination of gemcitabine, photon, and carbon ions in patients with MEC seems promising and warrants further investigation.

Helical Tomotherapy of Lymph Node-negative Early-stage Breast Cancer After Breast-conserving Surgery: Long-term Results.

BACKGROUND/AIM: Adjuvant radiotherapy is an integral part of the interdisciplinary curative treatment of breast cancer. We aimed to examine the long-term clinical results of helical tomotherapy in female patients with local restricted, lymph node negative breast cancer after breast-conserving surgery. PATIENTS AND METHODS: In this single-centre analysis, 219 female patients with early-stage breast cancer (T1/2) and no lymph node metastasis (N0) following breast-conserving surgery and sentinel-node biopsy were treated with adjuvant fractionated whole breast radiation therapy using helical tomotherapy. When boost irradiation was indicated, it was administered sequentially or using the simultaneous-integrated boost technique. Local control (LC), metastasis and survival rates, acute toxicity, late toxicity, and secondary malignancy rates were analysed retrospectively. RESULTS: The mean follow-up time was 71 months. The 5- and 8-year overall survival (OS) rates were 97.7% and 92.1%, respectively. The 5- and 8-year LC rates were 99.5% and 98.2%, while the 5- and 8-year metastasis-free survival (MFS) rates of 97.4% and 94.3%, respectively. Patients with G3 grading or negative hormone receptor status did not show significantly different results. Acute erythema occurred in 79% (grade 0-2) and 21% (grade 3) of the patients. Lymphedema of the ipsilateral arm and pneumonitis occurred in 6.4% and 1.8% of the treated patients. None of the patients developed >grade 3 toxicities during follow-up, while 1.8% developed a secondary malignancy during follow-up. CONCLUSION: Helical tomotherapy showed excellent long-term results and low toxicity rates. The incidence rates of secondary malignancy were relatively low and correlated with pre-existing data on radiotherapy, suggesting wider implementation of helical tomotherapy in adjuvant radiotherapy for breast cancer patients.

Tumor treating fields as novel combination partner in the multimodal treatment of head and neck cancer.

BACKGROUND: We aimed to demonstrate the effects of tumor treating fields (TTFields) in head and neck squamous cell carcinoma (HNSCC) cells when combined with radiotherapy (RT) and chemotherapy. METHODS: Two human HNSCC cell lines (Cal27, FaDu) received five different treatments: TTFields, RT +/- TTFields and RT + simultaneous cisplatin +/- TTFields. Effects were quantified using clonogenic assays and flow cytometric analyses of DAPI, caspase-3 activation and γH2AX foci. RESULTS: Treatment with RT + TTFields decreased the clonogenic survival as strong as treatment with RT + simultaneous cisplatin. The triple combination of RT + simultaneous cisplatin + TTFields even further decreased the clonogenic survival. Accordingly, combination of TTFields with RT or RT + simultaneous cisplatin increased cellular apoptosis and DNA double-strand breaks. CONCLUSION: TTFields therapy seems a promising combination partner in the multimodal treatment of locally advanced HNSCC. It could be used to intensify chemoradiotherapy or as alternative to chemotherapy.

Multimodal therapy of epithelioid pleural mesothelioma: improved survival by changing the surgical treatment approach.

Background: The exact role and type of surgery for malignant pleural mesothelioma (MPM) remains controversial. This study aimed at analyzing a 20-year single center perioperative experience in MPM surgery at our high-volume thoracic surgery center and comparing the overall survival after trimodal extrapleural pneumonectomy (EPP) and extended pleurectomy and decortication combined with hyperthermic intrathoracic chemoperfusion (EPD/HITOC) and adjuvant chemotherapy with that after chemotherapy (CTx) alone. Methods: Patients with epithelioid MPM treated with neoadjuvant chemotherapy, EPP and adjuvant radiotherapy within a trimodal concept or EPD/HITOC in combination with adjuvant chemotherapy between 2001 and 2018 were included in this retrospective analysis. Surgical cohorts were compared to patients treated with standard chemotherapy. Results: Overall, 182 patients (69 EPP, 57 EPD/HITOC, 56 CTx) were analyzed. Due to occupational exposure to asbestos for most of the patients, 154 patients (84.6%) were male. The patients in the surgical cohorts were significantly younger than those in the CTx cohort. There was no significant difference between the proportion of patient age and side. The median overall survival of the EPD/HITOC cohort with 38.1 months was significantly longer than that of the EPP and CTx cohorts (24.0 and 15.8 months). Better survival was significantly associated with an ECOG 0 performance status, age below 70 years, and negative lymph node status. In the multivariate analysis, EPD/HITOC was significantly associated with improved overall survival. Perioperative morbidity was lower in the EPD/HITOC group than in the EPP cohort. Conclusions: EPD/HITOC is feasible and safe for localized epithelioid pleural mesothelioma. Changing the surgical approach to a less radical lung-sparing technique may improve overall survival compared to trimodal EPP.

Subclass Analysis of Malignant, Inflammatory and Degenerative Pathologies Based on Multiple Timepoint FAPI-PET Acquisitions Using FAPI-02, FAPI-46 and FAPI-74.

PURPOSE: FAPI-PET is a promising imaging technique for various malignant as well as non-malignant pathologies. In a recent retrospective analysis, we evaluated the diagnostic value of repetitive early FAPI-PET-imaging with FAPI-02, FAPI-46 and FAPI-74 for malignant, inflammatory/reactive and degenerative pathologies. Here, we apply a subgroup analysis to that dataset and describe the tracer-wise uptake kinetic behavior of multiple types of FAPI-positive lesions, which are encountered frequently during clinical routine. METHODS: A total of 24 cancer patients underwent whole-body FAPI-PET scans, and images were acquired at 10, 22, 34, 46 and 58 min after the administration of 150-250 MBq of 68Ga-FAPI tracer molecules (eight patients each regarding FAPI-02, FAPI-46 and FAPI-74). Standardized uptake values (SUVmax and SUVmean) of healthy tissues, cancer manifestations and non-malignant lesions were measured and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition timepoints. RESULTS: Differential uptake behavior over time was observed in several subclasses of malignant lesions, inflammatory/reactive lesions and degenerative lesions. These differences over time were particularly manifested in the direct comparison between the uptakes associated with pancreatic carcinoma (stable or increasing over time) and inflammatory lesions of the pancreas (markedly decreasing over time). Furthermore, marked differences were found between the three tracer variants regarding their time-dependent uptake and TBRs within different subclasses of malignant, inflammatory/reactive and degenerative pathologies. CONCLUSION: Multiple timepoint FAPI-PET/CT is a promising innovative imaging technique that provides additional imaging information compared to single timepoint imaging. Differences in the kinetic behavior of malignant and benign pathologies can facilitate the interpretation of FAPI-positive lesions.

Human Mesenchymal Stromal Cells Do Not Cause Radioprotection of Head-and-Neck Squamous Cell Carcinoma.

Radiotherapy of head-and-neck squamous cell carcinoma (HNSCC) can cause considerable normal tissue injuries, and mesenchymal stromal cells (MSCs) have been shown to aid regeneration of irradiation-damaged normal tissues. However, utilization of MSC-based treatments for HNSCC patients undergoing radiotherapy is hampered by concerns regarding potential radioprotective effects. We therefore investigated the influence of MSCs on the radiosensitivity of HNSCCs. Several human papillomavirus (HPV)-negative and HPV-positive HNSCCs were co-cultured with human bone marrow-derived MSCs using two-dimensional and three-dimensional assays. Clonogenic survival, proliferation, and viability of HNSCCs after radiotherapy were assessed depending on MSC co-culture. Flow cytometry analyses were conducted to examine the influence of MSCs on irradiation-induced cell cycle distribution and apoptosis induction in HNSCCs. Immunofluorescence stainings of γH2AX were conducted to determine the levels of residual irradiation-induced DNA double-strand breaks. Levels of connective tissue growth factor (CTGF), a multifunctional pro-tumorigenic cytokine, were analyzed using enzyme-linked immunosorbent assays. Neither direct MSC co-culture nor MSC-conditioned medium exerted radioprotective effects on HNSCCs as determined by clonogenic survival, proliferation, and viability assays. Consistently, three-dimensional microwell arrays revealed no radioprotective effects of MSCs. Irradiation resulted in a G2/M arrest of HNSCCs at 96 h independently of MSC co-culture. HNSCCs' apoptosis rates were increased by irradiation irrespective of MSCs. Numbers of residual γH2AX foci after irradiation with 2 or 8 Gy were comparable between mono- and co-cultures. MSC mono-cultures and HNSCC-MSC co-cultures exhibited comparable CTGF levels. We did not detect radioprotective effects of human MSCs on HNSCCs. Our results suggest that the usage of MSC-based therapies for radiotherapy-related toxicities in HNSCC patients may be safe in the context of absent radioprotection.

Repetitive Early 68Ga-FAPI PET Acquisition Comparing 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74: Methodologic and Diagnostic Implications for Malignant, Inflammatory/Reactive, and Degenerative Lesions.

68Ga-labeled fibroblast activation protein (FAP) inhibitor (68Ga-FAPI) PET targets 68Ga-FAPI-positive activated fibroblasts and is a promising imaging technique for various types of cancer and nonmalignant pathologies. However, discrimination between malignant and nonmalignant 68Ga-FAPI-positive lesions based on static PET with a single acquisition time point can be challenging. Additionally, the optimal imaging time point for 68Ga-FAPI PET has not been identified yet, and different 68Ga-FAPI tracer variants are currently used. In this retrospective analysis, we evaluate the diagnostic value of repetitive early 68Ga-FAPI PET with 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74 for malignant, inflammatory/reactive, and degenerative lesions and describe the implications for future 68Ga-FAPI imaging protocols. Methods: Whole-body PET scans of 24 cancer patients were acquired at 10, 22, 34, 46, and 58 min after the administration of 150-250 MBq of 68Ga-FAPI tracer molecules (8 patients each for 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74). Detection rates and SUVs (SUVmax and SUVmean) for healthy tissues, cancer manifestations, and nonmalignant lesions were measured, and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition time points. Results: For most healthy tissues except fat and spinal canal, biodistribution analysis showed decreasing uptake over time. We analyzed 134 malignant, inflammatory/reactive, and degenerative lesions. Detection rates were minimally reduced for the first 2 acquisition time points and remained at a constant high level from 34 to 58 min after injection. The uptake of all 3 variants was higher in malignant and inflammatory/reactive lesions than in degenerative lesions. 68Ga-FAPI-46 showed the highest uptake and TBRs in all pathologies. For all variants, TBRs versus blood constantly increased over time for all pathologies, and TBRs versus fat were constant or decreased slightly. Conclusion: 68Ga-FAPI PET/CT is a promising imaging modality for malignancies and benign lesions. Repetitive early PET acquisition added diagnostic value for the discrimination of malignant from nonmalignant 68Ga-FAPI-positive lesions. High detection rates and TBRs over time confirmed that PET acquisition earlier than 60 min after injection delivers high-contrast images. Additionally, considering clinical feasibility, acquisition at 30-40 min after injection might be a reasonable compromise. Different 68Ga-FAPI variants show significant differences in time-dependent biodistributional behavior and should be selected carefully depending on the clinical setting.

Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8.

Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56dim-like cytotoxic transcriptomic states. In experimental models, NF-κB and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56dim NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy.

Influence of photon, proton and carbon ion irradiation on differentiation, maturation and functionality of dendritic cells.

While the primary purpose of radiotherapy (RT) is the elimination of cancer cells by inducing DNA-damage, considerable evidence emerges that anti-neoplastic effects extend beyond mere tumor cell killing. These secondary effects are based on activation of dendritic cells (DCs) via induction of antitumoral immune reactions. However, there is an ongoing debate whether or not irradiation of the DCs themselves may negatively affect their maturation and functionality. Human monocytes were irradiated with different absorbed doses (1 × 15 Gy relative biological effectiveness (RBE), 5 × 2 Gy (RBE), 1 × 0.5 Gy (RBE)) with photons, protons and carbon ions. Differentiation and maturation of DCs were assessed by staining of corresponding cell surface molecules and functional analysis of irradiated DCs was based on in vitro analysis of phagocytosis, migration and IL-12 secretion. Irradiation of CD14-positive DCs did not alter surface phenotypes of immature DCs and mature DCs. Not only differentiation, but also functionality of immature DCs regarding phagocytosis, migration and IL-12 secretion capacity was not negatively influenced through RT with photons, protons or carbon ions as well as with different dose levels. After proton irradiation migratory capacity of immature DCs was increased. Our experiments reveal that phenotypic maturation of DCs remains unchanged after RT with different fractionations and after irradiation with particle therapy. Unaffected functionality (phagocytosis, migration and cytokine secretion) after RT of DCs indicated possible persistent potential for inducing adaptive immune response. Additional effects on the immunogenic potential of DCs will be investigated by further functional assays.

Fibroblast Activation Protein-Specific PET/CT Imaging in Fibrotic Interstitial Lung Diseases and Lung Cancer: A Translational Exploratory Study.

Interstitial lung diseases (ILDs) comprise over 200 parenchymal lung disorders. Among them, fibrosing ILDs, especially idiopathic pulmonary fibrosis, are associated with a poor prognosis, whereas some other ILDs, such as sarcoidosis, have a much better prognosis. A high proportion manifests as fibrotic ILD (fILD). Lung cancer (LC) is a frequent complication of fILD. Activated fibroblasts are crucial for fibrotic processes in fILD. The aim of this exploratory study was to evaluate the imaging properties of static and dynamic fibroblast activation protein (FAP) inhibitor (FAPI) PET/CT in various types of fILD and to confirm FAP expression in fILD lesions by FAP immunohistochemistry of human fILD biopsy samples and of lung sections of genetically engineered (Nedd4-2-/- ) mice with an idiopathic pulmonary fibrosislike lung disease. Methods: PET scans of 15 patients with fILD and suspected LC were acquired 10, 60, and 180 min after the administration of 150-250 MBq of a 68Ga-labeled FAPI tracer (FAPI-46). In 3 patients, dynamic scans over 40 min were performed instead of imaging after 10 min. The SUVmax and SUVmean of fibrotic lesions and LC were measured and CT-density-corrected. Target-to-background ratios (TBRs) were calculated. PET imaging was correlated with CT-based fibrosis scores. Time-activity curves derived from dynamic imaging were analyzed. FAP immunohistochemistry of 4 human fILD biopsy samples and of fibrotic lungs of Nedd4-2-/- mice was performed. Results: fILD lesions as well as LC showed markedly elevated 68Ga-FAPI uptake (density-corrected SUVmax and SUVmean 60 min after injection: 11.12 ± 6.71 and 4.29 ± 1.61, respectively, for fILD lesions and 16.69 ± 9.35 and 6.44 ± 3.29, respectively, for LC) and high TBR (TBR of density-corrected SUVmax and SUVmean 60 min after injection: 2.30 ± 1.47 and 1.67 ± 0.79, respectively, for fILD and 3.90 ± 2.36 and 2.37 ± 1.14, respectively, for LC). SUVmax and SUVmean decreased over time, with a stable TBR for fILD and a trend toward an increasing TBR in LC. Dynamic imaging showed differing time-activity curves for fILD and LC. 68Ga-FAPI uptake showed a positive correlation with the CT-based fibrosis index. Immunohistochemistry of human biopsy samples and the lungs of Nedd4-2-/- mice showed a patchy expression of FAP in fibrotic lesions, preferentially in the transition zone to healthy lung parenchyma. Conclusion:68Ga-FAPI PET/CT imaging is a promising new imaging modality for fILD and LC. Its potential clinical value for monitoring and therapy evaluation of fILD should be investigated in future studies.

Human mesenchymal stromal cells maintain their stem cell traits after high-LET particle irradiation - Potential implications for particle radiotherapy and manned space missions.

The influence of high-linear energy transfer (LET) particle radiation on the functionalities of mesenchymal stromal cells (MSCs) is largely unknown. Here, we analyzed the effects of proton (1H), helium (4He), carbon (12C) and oxygen (16O) ions on human bone marrow-MSCs. Cell cycle distribution and apoptosis induction were examined by flow cytometry, and DNA damage was quantified using γH2AX immunofluorescence and Western blots. Relative biological effectiveness values of MSCs amounted to 1.0-1.1 for 1H, 1.7-2.3 for 4He, 2.9-3.4 for 12C and 2.6-3.3 for 16O. Particle radiation did not alter the MSCs' characteristic surface marker pattern, and MSCs maintained their multi-lineage differentiation capabilities. Apoptosis rates ranged low for all radiation modalities. At 24 h after irradiation, particle radiation-induced ATM and CHK2 phosphorylation as well as γH2AX foci numbers returned to baseline levels. The resistance of human MSCs to high-LET irradiation suggests that MSCs remain functional after exposure to moderate doses of particle radiation as seen in normal tissues after particle radiotherapy or during manned space flights. In the future, in vivo models focusing on long-term consequences of particle irradiation on the bone marrow niche and MSCs are needed.

COVID-19 and the ageing workforce: global perspectives on needs and solutions across 15 countries.

BACKGROUND: COVID-19 has a direct impact on the employment of older people. This adds to the challenge of ageism. The World Health Organization has started a worldwide campaign to combat ageism and has called for more research and evidence-based strategies that have the potential to be scaled up. This study specifically aims to identify solutions to combat the adverse effects of COVID-19 on the global ageing workforce. METHODS: We present 15 case studies from different countries and report on what those countries are doing or not doing to address the impact of COVID-19 on ageing workers. RESULTS: We provide examples of how COVID-19 influences older people's ability to work and stay healthy, and offer case studies of what governments, organizations or individuals can do to help ensure older people can obtain, maintain and, potentially, expand their current work. Case studies come from Australia, Austria, Canada, China, Germany, Israel, Japan, Nigeria, Romania, Singapore, Sweden, South Korea, Thailand, United Kingdom (UK), and the United States (US). Across the countries, the impact of COVID-19 on older workers is shown as widening inequalities. A particular challenge has arisen because of a large proportion of older people, often with limited education and working in the informal sector within rural areas, e.g. in Nigeria, Thailand and China. Remedies to the particular disadvantage experienced by older workers in the context of COVID are presented. These range from funding support to encouraging business continuity, innovative product and service developments, community action, new business models and localized, national and international actions. The case studies can be seen as frequently fitting within strategies that have been proven to work in reducing ageism within the workplace. They include policy and laws that have increased benefits to workers during lockdowns (most countries); educational activities such as coaching seniorpreneurship (e,g, Australia); intergenerational contact interventions such as younger Thai people who moved back to rural areas and sharing their digital knowledge with older people and where older people reciprocate by teaching the younger people farming knowledge. CONCLUSION: Global sharing of this knowledge among international, national and local governments and organizations, businesses, policy makers and health and human resources experts will further understanding of the issues that are faced by older workers. This will facilitate the replication or scalability of solutions as called for in the WHO call to combat ageism in 2021. We suggest that policy makers, business owners, researchers and international organisations build on the case studies by investing in evidence-based strategies to create inclusive workplaces. Such action will thus help to challenge ageism, reduce inequity, improve business continuity and add to the quality of life of older workers.

Low-dose radiotherapy for painful osteoarthritis of the elderly: A multicenter analysis of 970 patients with 1185 treated sites.

PURPOSE: Painful osteoarthritis is common in elderly patients, and low-dose radiotherapy has been demonstrated to provide effective symptomatic treatment. We examined the analgesic effects of low-dose radiotherapy for osteoarthritis in the elderly aiming to reveal potential differences in the response rates relating to increasing age. METHODS: A retrospective analysis was performed at two university hospitals including elderly patients (≥ 65 years) undergoing radiotherapy for osteoarthritis between 2008 and 2020. Pain intensity and response were quantified using the numerical rating scale (NRS) and the Pannewitz score. Age groups were defined for young old (65-74 years), older old (75-84 years), and oldest old patients (≥ 85 years). RESULTS: In all, 970 patients with 1185 treated sites and a median age of 76 years were analyzed. Mean NRS was 66 at baseline (t0), 53 after radiotherapy (t1), and 44 at first follow-up (t2) (p < 0.001 for t0-t1, t1-t2, and t0-t2). At t1, 1.5% exhibited a Pannewitz score of 0 (no pain), 58.5% of 1-2 (less pain), 36.1% of 3 (equal pain), and 3.9% of 4 (worse pain), while at t2, pain response shifted towards 6.9% (0), 58.6% (1-2), 28.1% (3), and 6.3% (4). Pain response did not differ between age groups at t1 (p = 0.172) or t2 (p = 0.684). In addition, pain response after re-irradiation (n = 384 sites) was 61.0% and was comparable between age groups (p = 0.535). CONCLUSION: Low-dose radiotherapy results in pain reduction in about two-thirds of treated sites with no difference relating to increasing age, showing that radiotherapy is an effective analgesic treatment for osteoarthritis even at advanced ages.

68Ga-FAPI-PET/CT improves diagnostic staging and radiotherapy planning of adenoid cystic carcinomas - Imaging analysis and histological validation.

BACKGROUND: Adenoid cystic carcinomas (ACCs) are rare epithelial tumors mostly situated in the head and neck region and characterized by infiltrative growth. The tumor stroma of ACCs includes cancer-associated fibroblasts (CAFs) expressing Fibroblast Activation Protein (FAP), a new target for positron emission tomography (PET) imaging. Here we describe the value of PET/ computed tomography (PET/CT) imaging using 68Ga-labelled FAP-Inhibitors (68Ga-FAPI-PET/CT) and their clinical potential for staging and radiotherapy planning in 12 ACC patients (7 primary, 5 recurrent). PATIENTS AND METHODS: Patients underwent contrast enhanced staging CT (ceCT) and magnetic resonance imaging (ceMRI) before 68Ga-FAPI - PET/CT. PET-scans were acquired 10, 60 and 180 minutes after administration of 150-250 MBq of 68Ga-labelled FAPI tracers. SUVmax and SUVmean values of ACCs and healthy organs were obtained using a 60% of maximum iso-contour. FAP and alpha smooth muscle actin (α-SMA) immunohistochemistry was performed in 13 cases (3 with and 10 without 68Ga FAPI-PET/CT). Staging and radiotherapy planning based on 68Ga-FAPI-PET/CT versus ceCT/MRI alone were compared. RESULTS: We observed elevated tracer uptake in all ACCs. Immunohistochemistry showed FAP-expressing CAFs in the tumor. Compared to conventional staging, 68Ga-FAPI-PET/CT led to upstaging in 2/12 patients and to detection of additional metastases in 3 patients, thus in total 42% of patients had their staging altered. Moreover, 68Ga-FAPI PET improved the accuracy of target volume delineation for radiotherapy, as compared to CT and MRI. CONCLUSION: 68Ga-FAPI-PET/CT is a promising imaging modality for ACC, increasing the accuracy of staging exams and radiotherapy planning volumes, as compared conventional to CT and MRI.

Hypofractionated Radiotherapy With Simultaneous-integrated Boost After Breast-conserving Surgery Compared to Standard Boost-applications Using Helical Tomotherapy With TomoEdge.

BACKGROUND/AIM: This comparative plan study examines a range of boost-radiation methods in adjuvant radiotherapy of breast cancer using helical intensity-modulated radiotherapy with TomoEdge-technique. Impact of hypofractionated radiation with simultaneous-integrated boost (SIB) and influence of differing assumed α/ß-values were examined. PATIENTS AND METHODS: For 10 patients with left-sided breast cancer each four helical IMRT-plans with TomoEdge-technique were created: hypofractionated+SIB (H-SIB) (42.4/54.4 Gy, 16 fractions), normofractionated+SIB (N-SIB) (50.4/64.4 Gy, 28 fractions), hypofractionated+sequential-boost (H-SB) (42.4 Gy/16 fractions+16 Gy/8 fractions), normofractionated+ sequential-boost (N-SB) (50.4 Gy/28 fractions+16 Gy/8 fractions). Equivalent doses (EQD2) to organs-at-risk (OAR) and irradiated mammary-gland were analysed for different assumed α/ß-values. RESULTS: The mean EQD2 to OAR was significantly lower using hypofractionated radiation-techniques. H-SIB and H-SB were not significantly different. H-SIB and N-SIB conformed significantly better to the breast planning-target volume (PTV) and boost-volume (BV) than H-SB and N-SB. Regarding BV, mean EQD2 was significantly higher for all α/ß-values investigated when using H-SIB and N-SIB. Regarding PTV, there were no clinically relevant differences. CONCLUSION: Relating to dosimetry, H-SIB is effective compared to standard-boost-techniques.

Biologically consistent dose accumulation using daily patient imaging.

BACKGROUND: This work addresses a basic inconsistency in the way dose is accumulated in radiotherapy when predicting the biological effect based on the linear quadratic model (LQM). To overcome this inconsistency, we introduce and evaluate the concept of the total biological dose, bEQDd. METHODS: Daily computed tomography imaging of nine patients treated for prostate carcinoma with intensity-modulated radiotherapy was used to compute the delivered deformed dose on the basis of deformable image registration (DIR). We compared conventional dose accumulation (DA) with the newly introduced bEQDd, a new method of accumulating biological dose that considers each fraction dose and tissue radiobiology. We investigated the impact of the applied fractionation scheme (conventional/hypofractionated), uncertainties induced by the DIR and by the assigned α/ß-value. RESULTS: bEQDd was systematically higher than the conventionally accumulated dose with difference hot spots of 3.3-4.9 Gy detected in six out of nine patients in regions of high dose gradient in the bladder and rectum. For hypofractionation, differences are up to 8.4 Gy. The difference amplitude was found to be in a similar range to worst-case uncertainties induced by DIR and was higher than that induced by α/ß. CONCLUSION: Using bEQDd for dose accumulation overcomes a potential systematic inaccuracy in biological effect prediction based on accumulated dose. Highest impact is found for serial-type late responding organs at risk in dose gradient regions and for hypofractionation. Although hot spot differences are in the order of several Gray, in dose-volume parameters there is little difference compared with using conventional or biological DA. However, when local dose information is used, e.g. dose surface maps, difference hot spots can potentially change outcomes of dose-response modelling and adaptive treatment strategies.