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.

Mobile applications in radiation oncology-current choices and future potentials.

PURPOSE: To review existing scientific literature on mobile applications (apps) in the field of radiation oncology and to evaluate characteristics of commercially available apps across different platforms. METHODS: A systematic review of the literature for publications presenting apps in the field of radiation oncology was carried out using the PubMed database, Cochrane library, Google Scholar, and annual meetings of major radiation oncology societies. Additionally, the two major marketplaces for apps, App Store and Play Store, were searched for available radiation oncology apps for patients and health care professionals (HCP). RESULTS: A total of 38 original publications which met the inclusion criteria were identified. Within those publications, 32 apps were developed for patients and 6 for HCP. The vast majority of patient apps focused on documenting electronic patient-reported outcomes (ePROs). In the two major marketplaces, 26 apps were found, mainly supporting HCP with dose calculations. CONCLUSION: Apps used in (and for) scientific research in radiation oncology are rarely available for patients and HCP in common marketplaces.

Deep inspiration breath-hold radiation therapy in left-sided breast cancer patients: a single-institution retrospective dosimetric analysis of organs at risk doses.

BACKGROUND: Radiotherapy can induce cardiac injury in left-sided breast cancer cases. Cardiac-sparing irradiation using the deep inspiration breath-hold (DIBH) technique can achieve substantial dose reduction to vulnerable cardiac substructures compared with free breathing (FB). This study evaluated the dosimetric differences between both techniques at a single institution. METHODS: From 2017 to 2019, 130 patients with left-sided breast cancer underwent breast-conserving surgery (BCS; n = 121, 93.1%) or mastectomy (ME; n = 9, 6.9%) along with axillary lymph node staging (n = 105, 80.8%), followed by adjuvant irradiation in DIBH technique; adjuvant systemic therapy was included if applicable. 106 (81.5%) patients received conventional and 24 (18.5%) hypofractionated irradiation. Additionally, 12 patients received regional nodal irradiation. Computed tomography (CT) scans in FB and DIBH position were performed for all patients. Intrafractional 3D position monitoring of the patient surface in deep inspiration and breath gating was performed using Sentinel and Catalyst HD 3D surface scanning systems (C-RAD, Catalyst, C­RAD AB, Uppsala, Sweden). Individual coaching and determination of breathing amplitude during the radiation planning CT was performed. Three-dimensional treatment planning was performed using standard tangential treatment portals (6 or 18 MV). The delineation of cardiac structures and both lungs was done in both the FB and the DIBH scan. RESULTS: All dosimetric parameters for cardiac structures were significantly reduced (p < 0.01 for all). The mean heart dose (Dmean) in the DIBH group was 1.3 Gy (range 0.5-3.6) vs. 2.2 Gy (range 0.9-8.8) in the FB group (p < 0.001). The Dmean for the left ventricle (LV) in DIBH was 1.5 Gy (range 0.6-4.5), as compared to 2.8 Gy (1.1-9.5) with FB (p < 0.001). The parameters for LV (V10 Gy, V15 Gy, V20 Gy, V23 Gy, V25 Gy, V30 Gy) were reduced by about 100% (p < 0.001). The LAD Dmean in the DIBH group was 4.1 Gy (range 1.2-33.3) and 14.3 Gy (range 2.4-37.5) in the FB group (p < 0.001). The median values for LAD such as V15 Gy, V20 Gy, V25 Gy, V30 Gy, and V40 Gy decreased by roughly 100% (p < 0.001). An increasing volume of left lung in the DIBH position resulted in dose sparing of cardiac structures. CONCLUSION: For all ascertained dosimetric parameters, a significant dose reduction could be achieved in DIBH technique.

Satisfaction with radiotherapy care among cancer patients treated in Germany-secondary analysis of a large multicenter study.

PURPOSE: Patient satisfaction with healthcare has been linked to clinical outcomes and regulatory agencies demand its regular assessment. Therefore, we aimed to investigate patient satisfaction with radiotherapy care and its determinants. METHODS: This is a secondary analysis of a multicenter prospective cross-sectional study. Eligible cancer patients anonymously completed questionnaires at the end of a course of radiotherapy. The outcome variable was overall patient satisfaction with radiotherapy care measured with a 10-point Likert scaled single-item. Given patient satisfaction was defined for patients scoring ≥ 8 points. Determinants of given patient satisfaction were assessed by univariable and multivariable analyses. A p-value < 0.05 was considered statistically significant. RESULTS: Out of 2341 eligible patients, 1075 participated (participation rate 46%). Data on patient satisfaction was provided by 1054 patients. There was a right-skewed distribution towards more patient satisfaction (mean = 8.8; SD = 1.68). Given patient satisfaction was reported by 85% (899/1054) of the patients. Univariable analyses revealed significant associations of lower patient satisfaction with tumor entity (rectal cancer), concomitant chemotherapy, inpatient care, treating center, lower income, higher costs, and lower quality of life. Rectal cancer as tumor entity, treating center, and higher quality of life remained significant determinants of patient satisfaction in a multivariable logistic regression. CONCLUSION: Overall patient satisfaction with radiotherapy care was high across 11 centers in Germany. Determinants of patient satisfaction were tumor entity, treating center, and quality of life. Although these data are exploratory, they may inform other centers and future efforts to maintain high levels of patient satisfaction with radiotherapy care.

The influence of antibiotic administration on the outcomes of head-and-neck squamous cell carcinoma patients undergoing definitive (chemo)radiation.

PURPOSE: Effects of antibiotic administration on patients' microbiome may negatively influence cancer outcomes, and adverse prognoses after antibiotic application have been demonstrated for cancer patients receiving immune checkpoint inhibitors. While the microbiome may play an important role also in head-and-neck squamous cell carcinoma (HNSCC), the prognostic value of antibiotic treatment here is largely unknown. We therefore analyzed whether antibiotic prescription is associated with impaired oncological outcomes of HNSCC patients undergoing definitive (chemo)radiation. METHODS: A cohort of 220 HNSCC patients undergoing definitive (chemo)radiation between 2010 and 2019 was analyzed. The influence of antibiotic administration on locoregional control, progression-free survival (PFS) and overall survival (OS) was determined using Kaplan-Meier and Cox analyses. RESULTS: A total of 154 patients were treated with antibiotics within 30 days before (chemo)radiation (pretherapeutic) or during (chemo)radiation (peritherapeutic). While antibiotic prescription was not associated with age, ECOG, tumor localization or radiotherapy characteristics, patients treated with antibiotics had significantly higher tumor stages. Peritherapeutic antibiotic administration diminished PFS (HR = 1.397, p < 0.05, log-rank test) and OS (HR = 1.407, p < 0.05), whereas pretherapeutic administration did not. Antibiotic application was an independent prognosticator for OS (HR = 1.703, p < 0.05) and PFS (HR = 1.550, p < 0.05) in the multivariate Cox analysis within the subgroup of patients aged < 75 years. CONCLUSION: Peritherapeutic antibiotic usage was associated with impaired oncological outcomes in HNSCC patients undergoing (chemo)radiation. Further studies including microbiome analyses are required to elucidate underlying mechanisms.

Cost effectiveness and health-related quality of life of chemoradiotherapy versus radiation therapy alone in elderly head and neck cancer patients.

PURPOSE: Radiotherapy (RT) constitutes a mainstay in the treatment of elderly patients with head and neck cancer (HNC), but use of simultaneous chemoradiotherapy (CRT) remains controversial. We have conducted a prospective analysis based on real-world patient data to examine the health-related quality of life (HRQoL) and cost effectiveness (CE) of CRT vs. RT in elderly HNC patients. METHODS: Eligible participants ≥ 65 years treated in a large tertiary cancer center between July 2019 and February 2020 who completed the validated EQ-5D-5L questionnaire (health state index [HI] and visual analog scale [VAS]) before and after RT were included. CE referred to direct medical costs, including diagnosis-related group (DRG)-based billings for inpatients and uniform assessment standard (EBM)-based costs for outpatients. The primary endpoint was cost (euros [€]) per quality-adjusted life year (QALY). The incremental cost-effectiveness ratios (ICERs) were calculated. Costs and QALYs were not discounted for short overall survival (OS). RESULTS: Baseline HRQoL was 0.878 (±0.11) in the CRT group and 0.857 (±0.17) in the RT group. Upon completion of therapy, HRQoL amounted to 0.849 (±0.14) in the CRT and 0.850 (±0.13) in the RT group. The mean treatment-related cost in the CRT cohort was €22,180.17 (±8325.26) vs. €18,027.87 (±26,022.48) in the RT group. The corresponding QALYs amounted to 2.62 in the CRT and 1.91 in the RT groups. The ICER was €5848.31. CONCLUSION: This is the first analysis from the German health care system demonstrating that the addition of chemotherapy to RT for selected elderly HNC patients is cost effective and not associated with a significant HRQoL decline.

Financial toxicity in cancer patients treated with radiotherapy in Germany-a cross-sectional study.

PURPOSE: Financial toxicity arises in cancer patients from subjective financial distress due to objective financial burden from the disease or treatment. Financial toxicity associates with worse outcomes. It has not been described in cancer patients undergoing radiotherapy in Germany and its publicly funded health system. In this context, we therefore investigated the prevalence of financial toxicity, associated risk factors, and patient preferences on communication of financial burden. METHODS: We conducted a preregistered ( https://doi.org/10.17605/OSF.IO/KH6VX ) cross-sectional study surveying patients at the end of their course of radiotherapy in two institutions. Objective financial burden was assessed by direct costs and loss of income. Financial toxicity was measured by subjective financial distress per EORTC QLQ-C30. We used Spearman's correlation and Fisher's exact test for univariate analysis, an ordinal regression for multivariate analysis. A p-value < 0.05 was considered statistically significant. RESULTS: Of the 100 patients participating in the study, 68% reported direct costs, 25% loss of income, and 31% subjective financial distress. Per univariate analysis, higher subjective financial distress was significantly associated with active employment, lower quality of life, lower household income, higher direct costs, and higher loss of income. The latter three factors remained statistically significant in the multivariate analysis. A relative majority of the patients welcomed communication regarding financial burden with their radiation oncologist. CONCLUSION: Financial toxicity is prevalent in cancer patients treated with radiotherapy in Germany. The reported risk factors may help to identify patients at risk. Future studies should validate these results and investigate interventions for financial toxicity to potentially improve outcomes.

Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation-results from a prospective pilot trial.

PURPOSE: Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [18F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [18F]FMISO PET/CT as reference. METHODS: Within a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [18F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson's correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses. RESULTS: Mean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013). CONCLUSION: Plasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts. TRIAL REGISTRATION: The prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015.

Incidental irradiation of the regional lymph nodes during deep inspiration breath-hold radiation therapy in left-sided breast cancer patients: a dosimetric analysis.

BACKGROUND: Radiotherapy using the deep inspiration breath-hold (DIBH) technique compared with free breathing (FB) can achieve substantial reduction of heart and lung doses in left-sided breast cancer cases. The anatomical organ movement in deep inspiration also cause unintended exposure of locoregional lymph nodes to the irradiation field. METHODS: From 2017-2020, 148 patients with left-sided breast cancer underwent breast conserving surgery (BCS) or mastectomy (ME) with axillary lymph node staging, followed by adjuvant irradiation in DIBH technique. Neoadjuvant or adjuvant systemic therapy was administered depending on hormone receptor and HER2-status. CT scans in FB and DIBH position with individual coaching and determination of the breathing amplitude during the radiation planning CT were performed for all patients. Intrafractional 3D position monitoring of the patient surface in deep inspiration and gating was performed using Sentinel and Catalyst HD 3D surface scanning systems (C-RAD, Catalyst, C-RAD AB, Uppsala, Sweden). Three-dimensional treatment planning was performed using standard tangential treatment portals (6 or 18 MV). The delineation of ipsilateral locoregional lymph nodes was done on the FB and the DIBH CT-scan according to the RTOG recommendations. RESULTS: The mean doses (Dmean) in axillary lymph node (AL) level I, II and III in DIBH were 32.28 Gy (range 2.87-51.7), 20.1 Gy (range 0.44-53.84) and 3.84 Gy (range 0.25-39.23) vs. 34.93 Gy (range 10.52-50.40), 16.40 Gy (range 0.38-52.40) and 3.06 Gy (range 0.21-40.48) in FB (p < 0.0001). Accordingly, in DIBH the Dmean for AL level I were reduced by 7.59%, whereas for AL level II and III increased by 22.56% and 25.49%, respectively. The Dmean for the supraclavicular lymph nodes (SC) in DIBH was 0.82 Gy (range 0.23-4.11), as compared to 0.84 Gy (range 0.22-10.80) with FB (p = 0.002). This results in a mean dose reduction of 2.38% in DIBH. The Dmean for internal mammary lymph nodes (IM) was 12.77 Gy (range 1.45-39.09) in DIBH vs. 11.17 Gy (range 1.34-44.24) in FB (p = 0.005). This yields a mean dose increase of 14.32% in DIBH. CONCLUSIONS: The DIBH technique may result in changes in the incidental dose exposure of regional lymph node areas.

Improved Oxygenation of Human Skin, Subcutis and Superficial Cancers Upon Mild Hyperthermia Delivered by WIRA-Irradiation.

Clinical trials have shown that mild hyperthermia (HT) serves as an adjunct to cancer treatments such as chemo- and radiotherapy. Recently, a high efficacy of mild HT immediately followed by hypofractionated radiotherapy (RT) in treatment of recurrent breast cancer has been documented if temperatures of 39-43 °C are achieved for 40-60 min. In the present study, temperature and oxygenation profiles were measured in superficial tissues of healthy volunteers exposed to water-filtered infrared-A- (wIRA)- irradiation, to verify that adequate thermal doses together with the improved tumor oxygenation necessary for radiosensitisation are obtained. Experiments were performed using a wIRA-system equipped with two wIRA-radiators, each with a thermography camera for real-time monitoring of the skin surface temperature. Temperatures within the abdominal wall were measured with fibre optic sensors at defined tissue depths (subepidermal, and 1-20 mm inside the tissue). The corresponding tissue pO2 values were assessed with fluorometric microsensors. In selected situations, hyperspectral tissue imaging was used to visualise the oxygenation status of normal skin and superficial tumours in patients. Pre-treatment skin surface temperature was 34.6 °C. Upon wIRA exposure, average skin surface temperatures reached 41.6 °C within 5-12 min. Maximum tissue temperatures of 41.8 °C were found at a tissue depth of 1 mm, with a steady decline in deeper tissue layers (41.6 °C @ 5 mm, 40.8 °C @ 10 mm, 40.6 °C @ 15 mm, and 40.1 °C @ 20 mm). Effective HT levels ≥39 °C were established in tissue depths up to 25 mm. Tissue heating was accompanied by a significant increase in tissue pO2 values [e.g., at a tissue depth of 13 mm mean pO2 rose from 46 mmHg to 81 mmHg (@ T = 40.5 °C). In the post-heating phase (+ 5 min), pO2 was 79 mmHg (@ T = 38 °C) and 15 min post-heat pO2 was 72 mmHg (@ T = 36.8 °C)]. pO2 values remained elevated for 30-60 min post-heat. Non-invasive monitoring of normal skin and of recurrent breast cancers confirmed the improved O2 status by wIRA-HT. In conclusion, wIRA-irradiation enables effective tissue heating (T = 39-43 °C) associated with distinct increases in blood flow and pO2. These adjustments unequivocally meet the requirement for effective radiosensitisation.

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.

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.

Intraoperative radiotherapy boost as part of breast-conservation therapy for breast cancer: a single-institution retrospective analysis.

BACKGROUND: There are currently no data from randomized controlled trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost as part of a breast-conservation approach for breast cancer. This study retrospectively reviewed the safety and efficacy of IORT as a boost treatment at a tertiary cancer center. METHODS: From 2015 to 2019, patients underwent breast-conserving surgery with axillary lymph node staging and a single dose of 20 Gy IORT with 50-kV photons, followed by whole-breast irradiation (WBI) and adjuvant systemic therapy (if applicable). Patients were followed for assessment of acute and late toxicities (using the Common Terminology Criteria for Adverse Events version 5.0) at 3-6-month intervals. Outcomes included ipsilateral (IBTR) and contralateral breast progression-free survival (CBE), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: Median follow-up for the 214 patients was 28 (range 2-59) months. Most patients had T1 disease (n = 124) and were clinically node negative. Only few patients had high-grade and/or triple-negative disease. The vast majority of patients underwent sentinel node biopsy, and 32 (15%) required re-resection for initially positive margins. Finally, all tumor bed margins were clear. Nine (4.2%) and 48 (22.4%) patients underwent neoadjuvant and adjuvant chemotherapy, respectively. WBI was predominantly performed as conventionally fractionated WBI (n = 187, 87.4%), and the median time from BCS to WBI was 54.5 days. IORT was delivered with a single dose of 20 Gy. The median WBI dose was 50 Gy (range 29.4-50.4 Gy). No patients experienced grade 4 events; acute grade 3 toxicities were limited to 17 (8%) cases of radiation dermatitis. Postoperative toxicities were mild. After WBI only one case of late grade ≥ 2 events was reported. There were two recurrences in the tumor bed and one contralateral breast event. CONCLUSION: This investigation provides additional preliminary data supporting the using of IORT in the boost setting and corroborates the existing literature. These encouraging results should be prospectively validated by the eventual publication of randomized studies such as TARGIT­B.

Value of PET imaging for radiation therapy.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.

Radiation-induced toxicities and outcomes after radiotherapy are independent of patient age in elderly salivary gland cancer patients: results from a matched-pair analysis of a rare disease.

PURPOSE: This study analyzed survival and toxicity after (chemo)radiotherapy for primary salivary gland cancer patients aged ≥ 65 years and compared these results with younger patients using a matched-pair analysis. METHODS: Twenty-nine elderly patients with primary salivary gland carcinomas treated with (chemo)radiotherapy from 2008 to 2020 at University of Freiburg Medical Center were analyzed for oncological outcomes and therapy-associated toxicities. Local/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the influence of clinical parameters on patient outcomes was assessed. A matched-pair analysis was performed after matching with patients < 65 years. RESULTS: Nine patients (31.0%) received definitive (chemo)radiotherapy, and 20 patients (69.0%) were treated in the adjuvant setting. 2-year LRC, PFS and OS ranged at 82.4%, 53.7% and 71.8%, respectively. Smoking (HR 3.980, p = 0.020), reduced performance status (HR 3.735, p = 0.016) and higher comorbidity burden (HR 4.601, p = 0.005) correlated with inferior OS. Using a matched-pair analysis with younger patients, elderly patients exhibited a trend towards reduced OS (HR 3.015, p = 0.065), but not PFS (HR 1.474, p = 0.371) or LRC (HR 1.324, p = 0.633). Acute and chronic grade 3 toxicities occurred in 31.0% and 12.5% of elderly patients, respectively, and the matched-pair analysis revealed no significant differences between age groups regarding treatment-related toxicities. CONCLUSION: Treatment-related toxicities as well as LRC and PFS were comparable for salivary gland cancer patients undergoing radiotherapy. Therefore, concerns for more pronounced toxicities or reduced local/locoregional response rates should not guide treatment decisions in affected elderly patients.

Oncology Informatics: Status Quo and Outlook.

Oncology has undergone rapid progress, with emerging developments in areas including cancer stem cells, molecularly targeted therapies, genomic analyses, and individually tailored immunotherapy. These advances have expanded the tools available in the fight against cancer. Some of these have seen broad media coverage resulting in justified public attention. However, these achievements have only been possible due to rapid developments in the expanding field of biomedical informatics and information technology (IT). Artificial intelligence, radiomics, electronic health records, and electronic patient-reported outcome measures (ePROMS) are only a few of the developments enabling further progress in oncology. The promising impact of IT in oncology will only become reality through a multidisciplinary approach to the complex challenges ahead.

Digital Follow-Up and the Perspective of Patient-Centered Care in Oncology: What's the PROblem?

There is accumulating evidence from randomized trials suggesting that digital patient-centered care allows a more reliable detection of tumour-related symptoms and adverse events - with a direct impact on overall survival. Consequently, a variety of unsynchronized approaches were kicked off to (electronically) measure patient-reported outcomes (PROs). Despite increasing evidence that PRO data are highly relevant for patient care, the data generated in these initial projects lack standardized processing pathways in order to impact clinical routine; therefore, potential future routine PRO assessments require adequate analysis, storage and processing to allow a robust, reproducible and reliable incorporation into routine clinical decision-making. Here, we discuss relevant challenges of digital follow-up that need to be tackled to render PRO data as relevant to physicians as laboratory or biomarker data.

Correlative analyses between tissue-based hypoxia biomarkers and hypoxia PET imaging in head and neck cancer patients during radiochemotherapy-results from a prospective trial.

PURPOSE: Tumor hypoxia impairs the response of head-and-neck cancer (HNSCC) patients to radiotherapy and can be detected both by tissue biomarkers and PET imaging. However, the value of hypoxia biomarkers and imaging for predicting HNSCC patient outcomes are incompletely understood, and potential correlations between tissue and PET data remain to be elucidated. Here, we performed exploratory analyses of potential correlations between tissue-based hypoxia biomarkers and longitudinal hypoxia imaging in a prospective trial of HNSCC patients. METHODS: Forty-nine patients undergoing chemoradiation for locally advanced HNSCCs were enrolled in this prospective trial. They underwent baseline biopsies and [18F]FDG PET imaging and [18F]FMISO PET at weeks 0, 2, and 5 during treatment. Immunohistochemical analyses for p16, Ki67, CD34, HIF1α, CAIX, Ku80, and CD44 were performed, and HPV status was assessed. Biomarker expression was correlated with biological imaging information and patient outcome data. RESULTS: High HIF1α tumor levels significantly correlated with increased tumor hypoxia at week 2 as assessed by the difference in the [18F]FMISO tumor-to-background ratios, and high HIF1α and CAIX expressions were both associated with a deferred decrease in hypoxia between weeks 2 and 5. Loco-regional recurrence rates after radiotherapy were significantly higher in patients with high CAIX expression and also increased for high levels of the DNA repair factor Ku80. HPV status did not correlate with any of the tested hypoxia biomarkers, and HPV-positive patients showed higher loco-regional control rates and progression-free survival independent of their hypoxia dynamics. CONCLUSION: In this exploratory trial, high expression of the tissue-based hypoxia biomarkers HIF1α and CAIX correlated with adverse hypoxia dynamics in HNSCCs during chemoradiation as assessed by PET imaging, and high CAIX levels were associated with increased loco-regional recurrence rates. Hence, hypoxia biomarkers warrant further investigations as potential predictors of hypoxia dynamics and hypoxia-associated radiation resistance.

Intraindividual comparison between 68Ga-PSMA-PET/CT and mpMRI for intraprostatic tumor delineation in patients with primary prostate cancer: a retrospective analysis in 101 patients.

PURPOSE: Accurate delineation of intraprostatic gross tumor volume (GTV) is mandatory for successful fusion biopsy guidance and focal therapy planning of prostate cancer (PCa). Multiparametric magnetic resonance imaging (mpMRI) is the current gold standard for GTV delineation; however, prostate-specific membrane antigen positron emission tomography (PSMA-PET) is emerging as a promising alternative. This study compares GTV delineation between mpMRI and 68Ga-PSMA-PET in a large number of patients using validated contouring approaches. METHODS: One hundred one patients with biopsy-proven primary PCa who underwent mpMRI and 68Ga-PSMA-PET within 3 months before primary treatment were retrospectively enrolled. Clinical parameters (age, PSA, Gleason score in biopsy) were documented. GTV based on MRI and PET images were delineated; volumes measured and laterality determined. Additionally, biopsy data from 77 patients was analyzed. Univariate and multivariate binary logistic regression analyses were performed using concordance in laterality as the endpoint. RESULTS: In total mpMRI and 68Ga-PSMA-PET detected 151 and 159 lesions, respectively. Median GTV-MRI (2.8 ml, 95% CI 2.31-3.38 ml) was significantly (p < 0.0001) smaller than median GTV-PET (4.9 ml, 95% CI 3.9-6.6 ml). 68Ga-PSMA-PET detected significantly more bilateral lesions than mpMRI (71 vs 57, p = 0.03). Analysis of patients with bilateral lesions in biopsy showed a significant higher concordance of laterality in 68Ga-PSMA-PET (p = 0.03). In univariate analysis, PSA level and volume of GTV-MRI had an impact on concordance in laterality (p = 0.02 and p = 0.01), whereas in multivariate analysis, only GTV-MRI volume remained significant (p = 0.04). CONCLUSION: MpMRI and 68Ga-PSMA-PET detect a similar amount of PCa lesions. However, GTV-PET had approximately twice the volume (median 4.9 ml vs 2.8 ml) and detected significantly more bilateral lesions than mpMRI. Thus, 68Ga-PSMA-PET gives highly important complementary information. Since we could not find any strong evidence for parameters to guide when 68Ga-PSMA-PET is dispensable, it should be performed additionally to MRI in patients with intermediate and high-risk PCa according to D'Amico classification to improve GTV delineation.

Multipotent mesenchymal stromal cells are sensitive to thermic stress - potential implications for therapeutic hyperthermia.

Purpose: Hyperthermia demonstrated clinical efficacy in multimodal cancer treatment. Multipotent mesenchymal stromal cells (MSCs) as part of the tumor-supporting stroma modulate tumor response and tissue regeneration after hyperthermia. We aimed to investigate the effects of hyperthermia on the survival, stem cell characteristics and heat shock expression of human MSCs.Materials and methods: Human MSCs and normal human dermal fibroblasts (NHDFs) were exposed to temperatures between 37 °C and 44 °C for 60 min, and hyperthermic sensitivity was examined by clonogenicity, proliferation and viability assays. The influence of 42 °C hyperthermia on the MSCs' adhesion potential, migratory capacity, surface marker expression and multi-lineage differentiation capability was investigated. Cell cycle distribution, apoptosis and senescence after 42 °C hyperthermia were determined by flow cytometry and ß-galactosidase staining. Heat shock protein expression was determined by Western Blots.Results: MSCs exhibited decreased clonogenic survival after 40 °C and 42 °C hyperthermia compared to NHDFs, while proliferative activity and viability were comparable after hyperthermia up to 44 °C. MSC adhesion was reduced after 42 °C hyperthermia, while the characteristic surface marker expression and the migratory ability remained unaffected in 42 °C hyperthermia-exposed MSCs. 42 °C hyperthermia diminished the adipogenic differential potential of all tested MSC samples. A pronounced G2/M arrest was found after 42 °C hyperthermia and was associated with increased apoptosis and senescence levels in MSCs. MSCs exhibited slightly lower heat shock protein levels compared to NHDFs.Conclusion: Human MSCs exhibit a thermosensitive phenotype which reduced the multipotent cells' regenerative abilities, resulting in impaired tissue regeneration after hyperthermia treatment or thermal injuries. On the other hand, tumor-associated MSCs may be efficiently targeted by hyperthermia treatment.