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Background: Glioblastoma is the most common malignant brain tumor in adults. Even after maximal safe resection and adjuvant chemoradiotherapy, patients normally relapse after a few years or even months. Standard treatment for recurrent glioblastoma is not yet defined, with re-resection, re-irradiation, and systemic therapy playing key roles. Usually, re-irradiation is combined with concurrent chemotherapy, harnessing the radiosensitizing effects of alkylating agents., Methods: A retrospective analysis of 101 patients with recurrent glioblastoma treated with re-irradiation was conducted, evaluating the survival impact of concurrent chemotherapy regimens, as well as prior resection. Patients were subcategorized according to concurrent chemotherapy (temozolomide vs. CCNU vs. combination of both vs. none) and details are given regarding treatment toxicity and patterns of relapse after first- and second-line treatment., Results: Patients were treated with normo-fractionated re-irradiation (with prescription dose of ~40 Gy to the PTV), resulting in a moderate cumulative EQD2 (~100 Gy). The mean overall survival was 11.3 months (33.5 months from initial diagnosis) and mean progression free survival was 9.5 months. Prior resection resulted in increased survival ( p < 0.001), especially when gross total resection was achieved. Patients who received concurrent chemotherapy had significantly longer survival vs. no chemotherapy ( p < 0.01), with the combination of CCNU and TMZ achieving the best results. Overall survival was significantly better in patients who received the CCNU + TMZ combination at any time during treatment (first or second line) vs. monotherapy only. The treatment of larger volumes (mean PTV size = 112.7 cm 3 ) was safe and did not result in worse prognosis or increased demand for corticosteroids. Overall, the incidence of high-grade toxicity or sequential radionecrosis (5%) was reasonably low and treatment was tolerated well. While second-line chemotherapy did not seem to influence patterns of relapse, patients who received TMZ + CCNU as first-line treatment had a tendency towards better local control with more out-field recurrence., Conclusions: Normo-fractionated re-irradiation appears to be safe and is accompanied by good survival outcomes, even when applied to larger treatment volumes. Patients amenable to undergo re-resection and achieving concurrent systemic therapy with alkylating agents had better OS, especially when gross total resection was possible. Based on existing data and experiences reflected in this analysis, we advocate for a multimodal approach to recurrent glioblastoma with maximal safe re-resection and adjuvant second chemoradiation. The combination of TMZ and CCNU for patients with methylated MGMT promoter yielded the best results in the primary and recurrent situation (together with re-RT). Normo-fractionated RT enables the use of more generous margins and is tolerated well.

Background: This study aims to evaluate patients with locally advanced cervical cancer who underwent definitive radiochemotherapy, including brachytherapy, at the University Hospital of Muenster (UKM), focusing on target volume coverage, oncologic outcome parameters, and organs at risk (OAR) toxicities. Results are compared with the Gyn GEC-ESTRO (GGE) recommendations., Methods: Of a cohort of 48 patients, treated between 2013 and 2023, the physical radiation treatment planning with application of CT and MRI and oncologic follow-up data was analyzed. Target volume structures, comprising the high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume (IR-CTV), Point A, and corresponding EQD2 (α/β=10) doses were determined. Endpoints included local tumor control, overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). Total OAR (D2cc) EQD2 (α/β=3) doses were correlated with adverse events defined by CTCAE v5.0 and LENT-SOMA criteria., Results: Median follow-up was 58.0 months (95% CI [27.6, 88.4]). FIGO stage I was present in 7 (15%) patients, II in 13 (27%), and III in 28 (58%) patients. A total of 38 (79%) patients showed a complete remission 3 months after treatment. The 5-year event-free rate was 67.4% (95% CI [49.3, 80.3]) for OS, 77.0% (95% CI [56.7, 88.6]) for RFS and 68.1% (95% CI [49.7, 80.9]) for PFS. Incomplete radiation treatment and advanced tumor stages led to worse outcomes. Meeting Point A GGE recommendations increased chances for complete remission and could decrease chances of an event occurring for OS, PFS, and RFS. Compliance with GGE recommendations lowered the chances of OAR toxicity occurring., Conclusions: MRI-based target volume definition for brachytherapy in cervical cancer may improve patients' OS, PFS, and RFS. Time-to-event endpoints are consistent with comparable studies, and adherence to current ESGO/ESTRO/ESP guidelines is endorsed.

In our study, the post-radiotherapy quality of life of prostate cancer patients who previously underwent transurethral resection of the prostate (TURP) is compared to those who had thulium laser enucleation of the prostate (ThuLEP) and those who had no prior surgery. It also aims to identify and assess risk factors affecting therapy tolerance in this patient group. We analyzed 132 patients with localized prostate cancer treated with definitive radiotherapy (RT), including 23 who had prior TURP and 19 who previously underwent ThuLEP. A total of 62% of patients underwent irradiation within 12 months after surgery. We included only patients treated with radiotherapy using the IMRT technique. Changes in patient-reported urinary toxicity were evaluated using the International Prostate Syndrome Score (IPSS) and the quality of life index of the World Health Organization (QoL/WHO-PSS) over a three-year post-radiotherapy period. Patients with prior TURP experienced significant deterioration in QoL and IPSS immediately after irradiation ( p < 0.001), whereas those without previous surgery showed both less significant differences in IPSS and QoL scores. In conclusion, patients with previous TURP/ThuLEP differ from those without previous surgery in urinary quality of life and acute and chronic urinary symptom profiles after RT. The surgical technique (ThuLEP vs. TURP) and the time interval to irradiation are crucial factors affecting RT tolerance in acute and late settings. The previously operated patient group reported a significantly longer period of increased symptom burden.

Reducing side effects in non-cancerous tissue is a key aim of modern radiotherapy. Here, we assessed whether the use of the antioxidants hydroxytyrosol (HT) and thioredoxin-mimetic peptide CB3 (TMP) attenuated radiation-induced normal tissue toxicity in vitro. We used primary human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (HaCaT) as normal tissue models. Cells were treated with HT and TMP 24 h or immediately prior to irradiation. Reactive oxygen species (ROS) were assessed via luminescent- and fluorescence-based assays, migration was investigated using digital holographic microscopy, and clonogenic survival was quantified by colony formation assays. Angiogenesis and wound healing were evaluated via time-dependent microscopy. Secreted cytokines were validated in quantitative polymerase chain reaction (qPCR) studies. Treatment with HT or TMP was well tolerated by cells. The application of either antioxidant before irradiation resulted in reduced ROS formation and a distinct decrease in cytokines compared to similarly irradiated, but otherwise untreated, controls. Antioxidant treatment also increased post-radiogenic migration and angiogenesis while accelerating wound healing. HT or TMP treatment immediately before radiotherapy increased clonogenic survival after radiotherapy, while treatment 24 h before radiotherapy enhanced baseline proliferation. Both antioxidants may decrease radiation-induced normal tissue toxicity and deserve further pre-clinical investigation.

Competing Interests: None disclosed.

Purpose: Hodgkin lymphoma is a hematologic malignancy with excellent outcomes even in advanced stages. Consequently, the importance of treatment-associated toxicity increases. However, the exact estimation of individualized rates is difficult due to different disease extents, treatment strategies and techniques. The following analysis aims at a pre-treatment estimation of relevant mediastinal toxicities., Methods: Normal tissue complication probability calculations were used to evaluate the toxicity rates for the heart, lungs and female breast of patients undergoing radiotherapy for early-stage Hodgkin lymphoma. Overall, 45 Patients of the HD16 and HD17 trials by the German Hodgkin study group were included and risks were calculated using the Lyman-Kutcher-Burman model., Results: The median values for pericarditis, pneumonitis and fibrosis of the left or right breast were 0.0%, 0.0%, 0.7% and 0.6% in the HD16 cohort, and 0.0%, 0.1%, 1.1% and 1.0% in the HD17 cohort, respectively. Correspondingly, none of the included patients displayed any of the evaluated toxicities during clinical follow-up. The use of higher doses (30 Gy) in the HD17 cohort led to an increase in toxicity compared to the HD16 cohort (20 Gy). No significant influence of the planning target volume size or the radiation technique could be found in this study., Conclusion: Both the clinically observed and calculated toxicity rates corroborate the overall low-risk profile of radiotherapy for Hodgkin lymphoma. Further treatment individualization will be attempted in the future.

Background: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W)., Patients and Methods: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables., Results: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL., Conclusions: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite improvements in surgical as well as adjuvant therapies over the last decades, the prognosis for patients with glioblastoma remains poor. Five-Aminolevulinic acid (5-ALA) induced porphyrins are already used for fluorescence-guided resection and as photosensitizer for photodynamic therapy. New findings reveal their potential use as sensitizing agents in combination with ionizing radiation., Methods: We initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). This prospective single-center study based in the University Hospital Münster aims to recruit 30 patients over 18 years of age with histologically verified recurrence of supratentorial glioblastoma in good performance status (KPS ≥ 60). Following a 3 + 3 dose-escalation design, patients having undergone re-resection will receive a 36 Gy RT including radiodynamic therapy fractions (RDT). RDT constitutes of oral administration of 5-ALA before the irradiation session. Two cohorts will additionally receive two fractions of neoadjuvant treatment three and two days before surgery. To determine the maximum tolerated dose of repeated 5-ALA-administration, the number of RDT-fractions will increase, starting with one to a maximum of eight fractions, while closely monitoring for safety and toxicity. Follow-up will be performed at two and five months after treatment. Primary endpoint will be the maximum tolerated dose (MTD) of repeated ALA-administration, secondary endpoints are event-free-, progression-free-, and overall-survival. Additionally, 5-ALA metabolites and radiobiological markers will be analysed throughout the course of therapy and tissue effects after neoadjuvant treatment will be determined in resected tissue. This protocol is in accordance with the SPIRIT guidelines for clinical trial protocols., Discussion: This is the protocol of the ALA-RDT in GBM-study, the first-in-man evaluation of repeated administration of 5-ALA as a radiosensitizer for treatment of recurrent glioblastoma., Trial Registration: This study was approved by the local ethics committee of the Medical Association of Westphalia-Lippe and the University of Münster on 12.10.2022, the German federal institute for Drugs and medical devices on 13.10.2022 and the federal office for radiation protection on 29.08.2022. This trial was registered on the public European EudraCT database (EudraCT-No.: 2021-004631-92) and is registered under www.cliniclatrials.gov (Identifier: NCT05590689)., (© 2024. The Author(s).)

This biophysical study aimed to determine fitting parameters for the Lyman-Kutcher-Burman (LKB) dose-response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24-54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5-45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose-response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL.

Background: Primary lymphoma of the central nervous system (PCNSL) encompasses a variety of lymphoma subtypes, with the majority being diffuse large B-cell lymphomas, which require aggressive systemic treatment. In contrast, low-grade lymphomas are reported infrequently and are mostly limited to dural manifestations. Very rarely, parenchymal low-grade PCNSL is diagnosed, and the cases documented in the literature show a wide variety of treatment approaches., Methods: We screened all cases of PCNSL treated at our department (a tertiary hematooncology and neurooncology center) in the last 15 years and conducted a comprehensive literature research in the PubMed database., Results: Overall, two cases of low-grade primary parenchymal PCNSL treated with irradiation were identified. The dose prescriptions ranged from 30.6 to 36 Gy for the involved site, with sparing of the hippocampal structures. Both patients had an excellent response to the treatment with a mean follow-up of 20 months. No clinical or radiological signs of treatment toxicity were detected., Conclusions: Our analysis corroborates the results from the literature and demonstrates that parenchymal low-grade PCNSL shows a good response to localized radiation treatment, enabling a favorable outcome while avoiding long-term treatment toxicity.

RNA-binding proteins have increasingly been identified as important regulators of gene expression given their ability to bind distinct RNA sequences and regulate their fate. Mounting evidence suggests that RNA-binding proteins are involved in the onset and progression of multiple malignancies, prompting increasing interest in their potential for therapeutic intervention.The Musashi RNA binding proteins Musashi-1 and Musashi-2 were initially identified as developmental factors of the nervous system but have more recently been found to be ubiquitously expressed in physiological tissues and may be involved in pathological cell behavior. Both proteins are increasingly investigated in cancers given dysregulation in multiple tumor entities, including in female malignancies. Recent data suggest that the Musashi proteins serve as cancer stem cell markers as they contribute to cancer cell proliferation and therapy resistance, prompting efforts to identify mechanisms to target them. However, as the picture remains incomplete, continuous efforts to elucidate their role in different signaling pathways remain ongoing.In this review, we focus on the roles of Musashi proteins in tumors of the female - breast, endometrial, ovarian and cervical cancer - as we aim to summarize current knowledge and discuss future perspectives., (© 2023. Yumed Inc. and BioMed Central Ltd., part of Springer Nature.)

The optimal first-line treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) diagnosed in early stages is largely undefined. We, therefore, analyzed 100 NLPHL patients treated in the randomized HD16 (early-stage favorable; n = 85) and HD17 (early-stage unfavorable; n = 15) studies. These studies investigated the omission of consolidation radiotherapy (RT) in patients with a negative interim positron emission tomography (iPET) (ie, Deauville score <3) after chemotherapy (HD16: 2× doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; HD17: 2× escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP] plus 2× ABVD). Patients with NLPHL treated in the HD16 and HD17 studies had 5-year progression-free survival (PFS) rates of 90.3% and 92.9%, respectively. Thus, the 5-year PFS did not differ significantly from that of patients with classical Hodgkin lymphoma treated within the same studies (HD16: P = .88; HD17: P = .50). Patients with early-stage favorable NLPHL who had a negative iPET after 2× ABVD and did not undergo consolidation RT tended to have a worse 5-year PFS than patients with a negative iPET who received consolidation RT (83% vs 100%; P = .05). There were 10 cases of NLPHL recurrence. However, no NLPHL patient died during follow-up. Hence, the 5-year overall survival rate was 100%. Taken together, contemporary Hodgkin lymphoma-directed treatment approaches result in excellent outcomes for patients with newly diagnosed early-stage NLPHL and, thus, represent valid treatment options. In early-stage favorable NLPHL, consolidation RT appears necessary after 2× ABVD to achieve the optimal disease control irrespective of the iPET result., (© 2023 by The American Society of Hematology.)

Radiotherapy (RT) is an established treatment modality in the management of patients with multiple myeloma (MM), aiming at analgesia and stabilization of osteolytic lesions. As a multifocal disease, the combined use of RT, systemic chemotherapy, and targeted therapy (ST) is pivotal to achieve better disease control. However, adding RT to ST may lead to increased toxicity. The aim of this study was to evaluate the tolerability of ST given concurrently with RT. Overall, 82 patients treated at our hematological center with a median follow-up of 60 months from initial diagnosis and 46.5 months from the start of RT were evaluated retrospectively. Toxicities were recorded from 30 days before RT up to 90 days after RT. 54 patients (65.9%) developed at least one non-hematological toxicity, with 50 patients (61.0%) showing low-grade (grade I or II) and 14 patients (17.1%) revealing high-grade (grade III and IV) toxicities. Hematological toxicities were documented in 50 patients (61.0%) before RT, 60 patients (73.2%) during RT, and 67 patients (81.7%) following RT. After RT, patients who had received ST during RT showed a significant increase in high-grade hematological toxicities ( p = 0.018). In summary, RT can be safely implemented into modern treatment regimens for MM, but stringent monitoring of potential toxicities even after completion of RT has to be ensured.

Introduction: The German Hodgkin Study Group (GHSG) HD17 trial established the omission of radiotherapy (RT) for patients with early-stage unfavorable Hodgkin lymphoma being PET-negative after 2 cycles of BEACOPP escalated plus 2 cycles of ABVD. This patient group reveals heterogeneity in characteristics and disease extent which prompted us to perform a decisive dosimetric analysis according to GHSG risk factors. This may help to tailor RT individually balancing risks and benefits., Methods: For quality assurance, RT-plans were requested from the treating facilities (n= 141) and analyzed centrally. Dose-volume histograms were scanned either paper-based or digitally to obtain doses to mediastinal organs. These were registered and compared according to GHSG risk factors., Results: Overall, RT plans of 176 patients were requested, 139 of which had dosimetric information on target volumes within the mediastinum. Most of these patients were stage II (92.8%), had no B-symptoms (79.1%) and were aged < 50 years (89.9%). Risk factors were present in 8.6% (extranodal involvement), 31.7% (bulky disease), 46.0% (elevated erythrocyte sedimentation rate) and 64.0% (three involved areas), respectively. The presence of bulky disease significantly affected the mean RT doses to the heart (p=0.005) and to the left lung (median: 11.3 Gy vs. 9.9 Gy; p=0.042) as well as V5 of the right and left lung, respectively (median right lung: 67.4% vs. 51.0%; p=0.011; median left lung: 65.9% vs. 54.2%; p=0.008). Significant differences in similar organs at risk parameters could be found between the sub-cohorts with the presence or absence of extranodal involvement, respectively. In contrast, an elevated erythrocyte sedimentation rate did not deteriorate dosimetry significantly. No association of any risk factor with radiation doses to the female breast was found., Conclusion: Pre-chemotherapy risk factors may help to predict potential RT exposure to normal organs and to critically review treatment indication. Individualized risk-benefit evaluations for patients with HL in early-stage unfavorable disease are mandatory., Competing Interests: Authors HE and MO report support of the present work from the German Cancer Aid. Author KH reports grants or contracts from Roche Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oertel, Hering, Baues, Kittel, Fuchs, Kriz, Kröger, Vordermark, Herfarth, Engenhart-Cabillic, Lukas, Haverkamp, Borchmann and Eich.)

Background and Purpose: Glioblastoma (GBM) patients face a strongly unfavorable prognosis despite multimodal therapy regimens. However, individualized mortality prediction remains imprecise. Harnessing routine radiation planning cranial computed tomography (CT) scans, we assessed cervical body composition measures as novel biomarkers for overall survival (OS) in GBM patients., Materials and Methods: We performed threshold-based semi-automated quantification of muscle and subcutaneous fat cross-sectional area (CSA) at the levels of the first and second cervical vertebral body. First, we tested this method's validity by correlating cervical measures to established abdominal body composition in an open-source whole-body CT cohort. We then identified consecutive patients undergoing radiation planning for recent GBM diagnosis at our institution from 2010 to 2020 and quantified cervical body composition on radiation planning CT scans. Finally, we performed univariable and multivariable time-to-event analyses, adjusting for age, sex, body mass index, comorbidities, performance status, extent of surgical resection, extent of tumor at diagnosis, and MGMT methylation., Results: Cervical body composition measurements were well-correlated with established abdominal markers (Spearman's rho greater than 0.68 in all cases). Subsequently, we included 324 GBM patients in our study cohort (median age 63 years, 60.8% male). 293 (90.4%) patients died during follow-up. Median survival time was 13 months. Patients with below-average muscle CSA or above-average fat CSA demonstrated shorter survival. In multivariable analyses, continuous cervical muscle measurements remained independently associated with OS., Conclusion: This exploratory study establishes novel cervical body composition measures routinely available on cranial radiation planning CT scans and confirms their association with OS in patients diagnosed with GBM., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Introduction: In patients with mantle cell lymphoma (MCL), long-term remissions can be achieved by stem cell transplantation (SCT). Different conditioning treatment protocols exist with or without total body irradiation (TBI). There are few data published on the role of TBI before autologous stem cell transplantation (autoSCT) or allogenic stem cell transplantation (alloSCT). We report on the long-term survival data of patients treated by TBI prior to autologous or allogenic SCT at our center., Patients: In a retrospective analysis, the data of patients treated at the University Hospital of Muenster from May 2004 to February 2015 were collected and evaluated. For the analysis, all data of patients who were histopathologically diagnosed with MCL and underwent TBI prior to stem cell transplantation (SCT) were evaluated., Results: A total of 22 patients (19 men and 3 women) were treated with a TBI-based conditioning prior to SCT. The median age at initial diagnosis was 57.5 years (38-65 years). Seventeen patients had Ann Arbor stage IV, two patients had Ann Arbor stage III, and three patients Ann Arbor stage II disease. AutoSCT was performed in 19 patients and alloSCT was performed in 3 patients. In 18 patients, autoSCT was applied as part of first-line therapy, and in one patient after relapse. Two patients received alloSCT after relapse of MCL, and one patient received alloSCT during first-line therapy after an inadequate treatment response. TBI was performed in 12 patients with 10 Gy and in 6 patients with 12 Gy, these patients subsequently received autoSCT. In the group of four patients who received TBI with four Gy, four patients subsequently received alloSCT and one patient received autoSCT. Median overall survival after autoSCT and previous TBI was 11.4 years (142 months). In total, 11 out of 19 patients treated with autoSCT lived longer than 6.8 years (82-202 months). After alloSCT and previous TBI, the median overall survival was 3.25 years (14-59 months)., Conclusions: A large proportion of patients with advanced MCL survived remarkably longer than 11.4 years after high-dose chemotherapy, TBI, and SCT. The present results of multimodal treatment support the published reports that TBI-based high-dose therapy followed by autoSCT is highly effective in this prognostically unfavorable disease situation.

Purpose: Radiation therapy (RT) is an integral part of treatment concepts for early-stage Hodgkin lymphoma. This analysis reports on RT quality in the recent HD16 and 17 trials of the German Hodgkin Study Group (GHSG)., Methods and Materials: All RT plans of involved-node radiation therapy (INRT) in HD 17 were requested for analysis, along with 100 and 50 involved-field radiation therapy (IFRT) plans in HD 16 and 17, respectively. A structured assessment regarding field design and protocol adherence was performed by the reference radiation oncology panel of the GHSG., Results: Overall, 100 (HD 16) and 176 (HD 17) patients were eligible for analysis. In HD 16, 84% of RT series were evaluated as correct, with significant improvement compared with the predecessor studies ( P < .001). In HD 17, 76.1% of INRT cases revealed a correct RT design compared with 69.0% of IFRT-cases, which was superior to previous studies ( P < .001). Comparing INRT and IFRT, we found no significant differences in the percentage of any deviation ( P  = .418) or major deviations ( P  = .466). Regarding dosimetry, INRT was accompanied by an improvement in thyroid doses. Comparing different RT techniques, we found that intensity-modulated RT showed a reduction of high doses in the lung at the expense of an increased low-dose exposure in HD 17., Conclusions: The latest study generation of the GHSG demonstrates an improved quality in RT. A modern INRT design could be established without deterioration in quality. On a conceptual level, an individual consideration of the appropriate RT technique has to be performed., (© 2022 The Author(s).)

The aim of this retrospective study is to compare the two boost subgroups, IORT or IMRT, in terms of overall survival (OS), progression-free survival (PFS), cosmesis, and acute and late toxicity. It shall be shown whether and which of the boost techniques offers better results with respect to the facial points, since there are already many studies on applying boost to the tumor bed after/during breast conserving surgery, and there are few which compare the different techniques. For this comparison, two subgroups of 76 patients each (n = 152), treated between 2002 and 2015, were enrolled in the study. In one subgroup, the 9 Gy boost was intraoperatively administered after complete removal of the primary tumor, while the other subgroup received the boost of 8.4 Gy percutaneously and simultaneously integrated into the tumor bed after breast conserving surgery. Both subgroups have subsequently undergone whole breast irradiation (WBI) of 50.4/50 Gy in 1.8−2 Gy per fraction. OS and the incidence of late toxicity did not differ between the two subgroups and no risk factor was found regarding PFS. Acute toxicities initially occurred significantly less (p < 0.001) in the IORT subgroup; however, after WBI took place, this difference vanished. Therefore, boost application by means of IORT or IMRT can be considered equivalent.

Background and Purpose: Malignant melanoma constitutes an aggressive tumor of the skin, the pathogenesis of which is influenced by immunological processes. In this context, the influence of radiotherapy (RT) on inflammatory markers has not been studied in detail, yet., Materials and Methods: In this prospective analysis, 28 patients were recruited, 24 of these could be included for further analysis. According to protocol, patients underwent three blood-draws: before, after half of RT-fractions and after completion of RT. Serum levels of programmed death-ligand (PD-L) 1 and 2, interleukin 6 and cytotoxic t-lymphocyte-associated protein 4 were assessed via enzyme-linked immunosorbent assay and compared to healthy volunteers. Correlation with clinical data was attempted., Results: Comparing patients with healthy volunteers, a significant difference in the mean baseline serum-level of PD-L1 (90.1 pg/ml vs. 76.7 pg/ml for patients vs. control, respectively; p = 0.024) and PD-L2 (4.4 ng/ml vs. 8.7 ng/ml; p = 0.04) could be found. Increased levels of PD-L1 were only found in patients with prior immunotherapy. There was a tendency for higher interleukin 6 levels in the patients (8.5 pg/ml vs. 0.6 pg/ml; p = 0.052). No significant differences in serum levels could be found between the three time points., Conclusion: The present study reveals a characteristic immunological pattern for melanoma patients in comparison to healthy controls. Future studies will have to focus on a putative correlation between immunological markers and clinical outcome parameters., (© 2022. The Author(s).)

Background: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. Patients and Methods: This retrospective study investigates the inner ear toxicity of 46 patients who received radio(chemo-)therapy for nasopharyngeal carcinoma at our institution from 2004 to 2021 according to CTCAE 5.0 criteria. For each inner ear, the mean (Dmean) and maximum (Dmax) dose in Gray (Gy) was evaluated and correlated with clinical toxicity data. Based on the data, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. Results: In 11 patients (23.9%) hearing impairment and/or tinnitus was observed as a possible therapy-associated toxicity. Dmean was between 15−60 Gy, whereas Dmax was between 30−75 Gy. There was a dose-dependent, sigmoidal relation between inner ear dose and toxicity. A Dmean of 44 Gy and 65 Gy was associated with inner ear damage in 25% and 50% of patients, respectively. The maximum curve slope (m) was found at 50% and is m=0.013. The Dmax values showed a 25% and 50% complication probability at 58 Gy and 69 Gy, respectively, and a maximum slope of the sigmoid curve at 50% with m=0.025. Conclusion: There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of <44 Gy (Dmean) or <58 Gy (Dmax) are suggested to limit the probability of inner ear toxicity <25%.

Background: Endometrial carcinoma is the most common gynecological cancer in Europe. Musashi-1 is known to be a key regulator of endometrial cancer stem cells and a negative prognostic marker. In the present study, we aimed to understand growth and gene expression patterns in endometrial carcinoma after Musashi-1 knockdown in vitro and in vivo. Changes in therapeutic resistance were also assessed., Methods: First, we performed analyses to understand Musashi-1 expression patterns using The Cancer Genome Atlas database. We then proceeded to assess effects of small interfering RNA-based Musashi-1 targeting in two endometrial carcinoma cell lines, Ishikawa and KLE. After quantifying baseline changes in cell metabolism, we used MTT tests to assess chemotherapy effects and colony formation assays to understand changes in radioresistance. For mechanistic study, we used quantitative polymerase chain reaction (qPCR) and western blotting of key Musashi-1 target genes and compared results to primary tissue database studies. Finally, xenograft experiments in a mouse model helped understand in vivo effects of Musashi-1 knockdown., Results: Musashi-1 is aberrantly expressed in primary tumor tissues. In vitro, silencing of Musashi-1 resulted in a strong decline in cell proliferation and radioresistance, while chemoresistance remained unchanged. Loss of Musashi-1 led to downregulation of telomerase, DNA-dependent protein kinase, the Notch pathway and overexpression of cyclin-dependent kinase inhibitor p21, the latter of which we identified as a key mediator of Msi-1 knockdown-related anti-proliferative signaling. In vivo, the anti-proliferative effect was confirmed, with Msi-1 knockdown tumors being about 40% reduced in size., Conclusions: Musashi-1 knockdown resulted in a strong decrease in endometrial cancer proliferation and a loss of radioresistance, suggesting therapeutic potential., (© 2022. The Author(s).)

Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group., Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance., Results and Conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic., Competing Interests: DIsclosure CB reports honoraria from Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, Regeneron; he reports consulting or advisory role: Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, Novartis; he reports speaker’s engagement: Roche, Janssen, BeiGene, Celltrion, AbbVie, Pfizer, Gilead Sciences; he reports research funding: Roche/Genentech, Janssen, Celltrion, Merck Sharp & Dohme (MSD), Pfizer, Amgen. MD reports honoraria as Advisory Board Member of AstraZeneca, Bayer, BeiGene, Celgene, Genmab, Gilead, Incyte, Janssen, Lilly, MorphoSys, Novartis, Roche; he reports honoraria for speaker’s engagement from Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, Novartis, Roche; he reports institutional research grants from AbbVie, Bayer, Gilead, Celgene, Janssen, Roche. AA-L has declared no conflicts of interest. JA reports personal financial interests as advisory board and invited speaker from Incyte, advisory board from Mallinckrodt, advisory board and invited speaker from Novartis, advisory board and invited speaker from Pfizer; she reports non-financial interests as principal investigator from Incyte, principal investigator from Novartis. LA received advisory honoraria from Roche, Celgene, Janssen-Cilag, Verastem, Eusa Pharma, Incyte, ADC Therapeutics and Gilead; research support from Gilead, and travel expenses from Roche, Celgene, Janssen-Cilag, and Eusa Pharma; speakers bureau from Novartis. CB has declared no conflicts of interest. LB reports Advisory Committee activities for AbbVie, Amgen, Astellas, Bristol Myers Squibb (BMS), Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics and has research support from Bayer and Jazz Pharmaceuticals. PC has declared no conflicts of interest. MGDP has declared no conflicts of interest. MD reports personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, personal fees from BeiGene, personal fees from BMS, outside the submitted work. SD reports personal financial interests as advisory board, invited speaker, fellow funding, and coordinating PI from BeiGene, writing engagement from Karger, advisory board and coordinating PI from Sanofi, funding, and other from Janssen; she reports non-financial interests as advisory role at British Society for Haematology Lymphoma Special Interest Group, advisory role at Lymphoma Action, member of board of directors at WMUK Charity. HTE has declared no conflicts of interest. RF reports honoraria for advisory boards and/or speaker bureau from Janssen, Gilead, AbbVie, Amgen, Novartis, Roche, Incyte, Pfizer, all outside the submitted work. PG reports grants and personal fees from AbbVie, grants and personal fees from Acerta/AstraZeneca, personal fees from BeiGene, personal fees from Celgene/Juno/BMS, grants and personal fees from Janssen, personal fees from Lilly/Loxo, personal fees from MEI, personal fees from Roche, personal fees from Sanofi, personal fees from ArQule/MSD, outside the submitted work; MGdS reports grants, personal fees, non-financial support and other from Gilead Sciences, grants from AstraZeneca, personal fees, non-financial support, and other from Janssen Cilag, personal fees and non-financial support from Roche, non-financial support from AbbVie, personal fees and non-financial support from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from Takeda, personal fees from Novartis, personal fees from ADC Therapeutics, outside the submitted work. JG reports personal fees from AbbVie, grants and personal fees from AstraZeneca, grants and personal fees from BMS/Celgene, grants and personal fees from Janssen, personal fees from Kite/Gilead, personal fees from MorphoSys, personal fees from Novartis, personal fees from TG Therapeutics, outside the submitted work. RH has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. CH reports grants and personal fees from Novartis, grants and personal fees from BMS, personal fees from Sierra Oncology, personal fees from CTI pharmaceuticals, personal fees from Jannsen, personal fees from Geron, grants and personal fees from AOP Orphan Pharma, personal fees from Galecto, grants, personal fees and other from Constellation, outside the submitted work. MH reports personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from AbbVie, personal fees from Daiichi Sankyo, personal fees from Bayer Pharma AG, personal fees from Jazz Pharmaceuticals, personal fees from BMS, personal fees from Tolremo, outside the submitted work. BK has received honoraria for lectures from Ipsen, Novartis and MSD (all outside of the submitted work). J-JK reports consulting fees and honoraria from Novartis, consulting fees from AbbVie, honoraria from AOP Orphan Pharma, participation on a monitoring board or advisory board from BMS/Celgene, participation on a monitoring board or advisory board from Incyte. NK reports grants and honoraria from Neovii, honoraria from Sanofi, grants and honoraria from Jazz, grants and honoraria from Celgene, grants and honoraria from Riemser, honoraria from Gilead/Kite, honorarium from AOP Oprhan Pharma, grants and honorarium from Novartis, honorarium from Amgen. PM reports personal fees from Celgene, Amgen, Janssen, AbbVie, Sanofi, outside the submitted work. JP has declared no conflicts of interest. FP has declared no conflicts of interest. DR received honoraria from Incyte, Novartis Pharma, Pfizer; clinical trial steering committee membership: Novartis; membership on advisory boards: Incyte, Novartis Pharma, Pfizer. J-MR reports grants and honoraria from Novartis, Amgen, Pfizer, Takeda, Incyte, and Servier. TR has declared no conflicts of interest. JF-M reports consulting and advisory boards honoraria (received by CUN ) from AbbVie, Amgen, BMS, Celgene, Janssen, GlaxoSmithKline, Karyopharm, MSD, Novartis, Takeda, Sanofi, SecuraBio, Regeneron, Roche, outside the submitted work. VS has declared no conflicts of interest. GFS reports personal fees and other from AbbVie, other from Amgen, other from Astellas, other from Boehringer-Ingelheim, grants, personal fees and other from Celgene, other from Helsinn Healthcare, grants, personal fees, and other from Janssen-Cilag, grants and other from Novartis, other from Onconova, grants, personal fees and other from Roche, and other from Takeda, outside the submitted work. PS reports honoraria from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda, and research support from Celgene, Janssen, Amgen, Takeda, BMS, SkylineDx, Karyopharm, all outside the submitted work. MvL-T has received travel grants and honoraria from Celgene, Gilead, Chugai, Janssen, Novartis, Amgen, Takeda, BMS, Medac, Oncopeptides, Merck, CDDF, Pfizer, Medac, Thermo Fisher, AstraZeneca; is a consultant for Celgene, Gilead, Oncopeptides, MSD, 4D Pharma, Janssen, Shionogi and received research funding from BMBF, Deutsche Jose Carreras Leukämie-Stiftung, IZKF Jena, Novartis, Gilead, Deutsche Krebshilfe, Celgene, Oncopeptides, Deutsche Forschungsgemeinschaft (DFG). CW has declared no conflicts of interest. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, grants and personal fees from BMS, grants from Lilly, grants and personal fees from MSD, grants and personal fees from Novartis, outside the submitted work. FP reports grants from Novartis, Celgene, BMS, Abbvie, Karyopharma, Janssen., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The role of cranio-spinal irradiation (CSI) for primary extraosseous intraspinal Ewing sarcoma (EwS) remains unclear. Here, we evaluate clinical and survival outcomes in patients with primary intraspinal EwS treated with CSI as part of multimodal primary therapy regimens. We abstracted patient information, including details on treatment application, efficacy, and tolerance from the literature and our hospital database for a cohort of 24 primary intraspinal EwS patients treated with CSI. Median age was 25.5 years, median CSI dose was 36 Gy and mean boost dose was 12.8 Gy. Sixteen patients (66.7%) achieved complete radiological remission, another 5 patients demonstrated partial response and 1 patient showed no response to treatment. Compared to a cohort of patients treated with focal radiotherapy, CSI patients were more likely to have multifocal disease at time of diagnosis (p = 0.001) and intradural tumor location (p < 0.001). Despite over-representation of these unfavorable characteristics, there was no survival difference between groups (p = 0.58). While CSI shows promising results in the treatment of primary intraspinal EwS, treatment should be considered individually based on tumor and patient characteristics in the absence of prospective trials.

In a prospective observational pilot study on patients undergoing elective cardiac surgery with cardiopulmonary bypass, we evaluated label-free quantitative phase imaging (QPI) with digital holographic microscopy (DHM) to describe perioperative inflammation by changes in biophysical cell properties of lymphocytes and monocytes. Blood samples from 25 patients were investigated prior to cardiac surgery and postoperatively at day 1, 3 and 6. Biophysical and morphological cell parameters accessible with DHM, such as cell volume, refractive index, dry mass, and cell shape related form factor, were acquired and compared to common flow cytometric blood cell markers of inflammation and selected routine laboratory parameters. In all examined patients, cardiac surgery induced an acute inflammatory response as indicated by changes in routine laboratory parameters and flow cytometric cell markers. DHM results were associated with routine laboratory and flow cytometric data and correlated with complications in the postoperative course. In a subgroup analysis, patients were classified according to the inflammation related C-reactive protein (CRP) level, treatment with epinephrine and the occurrence of postoperative complications. Patients with regular courses, without epinephrine treatment and with low CRP values showed a postoperative lymphocyte volume increase. In contrast, the group of patients with increased CRP levels indicated an even further enlarged lymphocyte volume, while for the groups of epinephrine treated patients and patients with complicative courses, no postoperative lymphocyte volume changes were detected. In summary, the study demonstrates the capability of DHM to describe biophysical cell parameters of perioperative lymphocytes and monocytes changes in cardiac surgery patients. The pattern of correlations between biophysical DHM data and laboratory parameters, flow cytometric cell markers, and the postoperative course exemplify DHM as a promising diagnostic tool for a characterization of inflammatory processes and course of disease.

Gastric marginal zone lymphoma (gMZL) of mucosa-associated lymphoid tissue (MALT) may persist even after H. pylori eradication, or it can be primarily Helicobacter pylori ( H. pylori ) independent. For patients without the successful eradication of lymphoma, or with progressive disease, treatment options have historically included partial or total gastrectomy. Presently, in these instances, curative radiation therapy (RT) is the current standard of care. This review emphasizes the historically changing role of radiation therapy in gMZL, progressing from large-volume RT without surgery, to localized RT, on its own, as a curative organ-preserving treatment. This overview shows the substantial progress in radiation therapy during the recent two to three decades, from high-dose, large-field techniques to low-dose, localized target volumes based on advanced imaging, three-dimensional treatment planning, and advanced treatment delivery techniques. RT has evolved from very large extended field techniques (EF) with prophylactic treatment of the whole abdomen and the supradiaphragmatic lymph nodes, applying doses between 30 and 50 Gy, to involved-field RT (IF), to the current internationally recommended involved site radiation therapy (ISRT) with a radiation dose of 24-30 Gy in gMZL. Stage-adapted RT is a highly effective and safe treatment with excellent overall survival rates and very rare acute or late treatment-related toxicities, as shown not only in retrospective studies, but also in large prospective multicenter studies, such as those conducted by the German Study Group on Gastrointestinal Lymphoma (DSGL). Further de-escalation of the radiation treatments with low-dose 20 Gy, as well as ultra-low-dose 4 Gy radiation therapy, is under investigation within ongoing prospective clinical trials of the International Lymphoma Radiation Oncology Group (ILROG) and of the German Lymphoma Alliance (GLA).

Total body irradiation is an effective conditioning modality before autologous or allogeneic stem cell transplantation. With the whole body being the radiation target volume, a diverse spectrum of toxicities has been reported. This fact prompted us to investigate the long-term sequelae of this treatment concept in a large patient cohort. Overall, 322 patients with acute leukemia or myelodysplastic syndrome with a minimum follow-up of one year were included (the median follow-up in this study was 68 months). Pulmonary, cardiac, ocular, neurological and renal toxicities were observed in 23.9%, 14.0%, 23.6%, 23.9% and 20.2% of all patients, respectively. The majority of these side effects were grades 1 and 2 (64.9-89.2% of all toxicities in the respective categories). The use of 12 Gray total body irradiation resulted in a significant increase in ocular toxicities ( p = 0.013) and severe mucositis ( p < 0.001). Renal toxicities were influenced by the age at transplantation (relative risk: 1.06, p < 0.001) and disease entity. In summary, total body irradiation triggers a multifaceted, but manageable, toxicity profile. Except for ocular toxicities and mucositis, a 12 Gray regimen did not lead to an increase in long-term side effects.

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.

Background/aim: Image-guided intensity-modulated radiotherapy (IG-IMRT) is increasingly being used to treat patients with head and neck malignancies. This analysis compared conventional radiotherapy (CRT) and IMRT outcomes for head and neck aggressive extranodal non-Hodgkin lymphomas (EN-NHL)., Patients and Methods: Forty-eight patients who underwent irradiation between 2005 and 2019 were identified., Results: The median follow-up was 42 months. Patients treated with IMRT experienced higher overall responde rate than patients who received 3DCRT (85% vs. 73%, p=0.4). There was non-significant longer survival following IMRT compared with 3DCRT in terms of 5-year OS (p=0.16). Complete responders after primary treatments had a significantly higher 5-year progression-free (p<0.001) and overall survival (p=0.003) in comparison with those without a complete response. Regarding toxicities, IMRT was associated with less acute and chronic adverse events., Conclusion: IG-IMRT following systemic therapy seems to be associated with a favorable survival and toxicity profile in patients with EN-NHL., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Central neurocytoma (CN) is a rare tumor accounting for <0.5% of all intracranial tumors. Surgery ± radiotherapy is the mainstay treatment. This international multicentric study aims to evaluate the outcomes of CNs patients after multimodal therapies and identify predictive factors., Patients and Methods: We retrospectively identified 33 patients with CN treated between 2005 and 2019. Treatment characteristics and outcomes were assessed., Results: All patients with CN underwent surgical resection. Radiotherapy was delivered in 19 patients. The median radiation dose was 54 Gy (range, 50-60 Gy). The median follow-up time was 56 months. The 5-year OS and 5-year PFS were 90% and 76%, respectively. Patients who received radiotherapy had a significantly longer PFS than patients without RT ( p = 0.004) and a trend towards longer OS. In addition, complete response after treatments was associated with longer PFS ( p = 0.07)., Conclusions: Using RT seems to be associated with longer survival rates with an acceptable toxicity profile.

Background/aim: Heparanase (HPSE) is relevant to therapy resistance in many malignancies yet is largely unstudied in Hodgkin's lymphoma. Here, we investigated links between HPSE, cancer stem cell (CSC) features and radioresistance in KM-H2 and L428 Hodgkin's lymphoma cells., Materials and Methods: Firstly, HPSE expression in unsorted and sorted CSCs was assessed. Post-irradiation, HPSE and CSC-related gene expression changes were then quantified. Clonogenic ability was investigated with and without artificial changes in HPSE expression pre and post irradiation., Results: HPSE was highly expressed in L428 but barely present in KM-H2 cells. HPSE was overexpressed in sorted L428 CSCs. Irradiation induced HPSE and expression of CSC markers. High HPSE-expressing L428 cells showed higher clonogenic ability than low HPSE-expressing KM-H2 cells after irradiation. Down-regulation of HPSE in L428 cells reduced their clonogenic capability post-radiation, whilst overexpression of HPSE in KM-H2 cells increased colony formation., Conclusion: HPSE expression is associated with CSC features and contributes to radioresistance in Hodgkin's lymphoma cells., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Total body irradiation (TBI) is an essential part of various conditioning regimens prior to allogeneic stem cell transplantation, but is accompanied by relevant (long-term) toxicities. In the lungs, a complex mechanism induces initial inflammation (pneumonitis) followed by chronic fibrosis. The hereby presented analysis investigates the occurrence of pulmonary toxicity in a large patient collective and correlates it with data derived from normal tissue complication probability (NTCP) calculations. The clinical data of 335 hemato-oncological patients undergoing TBI were analyzed with a follow-up of 85 months. Overall, 24.8% of all patients displayed lung toxicities, predominantly pneumonia and pulmonary obstructions (13.4% and 6.0%, respectively). NTCP calculations estimated median risks to be 20.3%, 0.6% and 20.4% for overall pneumonitis (both radiological and clinical), symptomatic pneumonitis and lung fibrosis, respectively. These numbers are consistent with real-world data from the literature and further specify radiological and clinical apparent toxicity rates. Overall, the estimated risk for clinical apparent pneumonitis is very low, corresponding to the probability of non-infectious acute respiratory distress syndrome, although the underlying pathophysiology is not identical. Radiological pneumonitis and lung fibrosis are expected to be more common but require a more precise documentation by the transplantation team, radiologists and radiation oncologists.

This retrospective study examined the role of 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) in stage-related therapy of follicular lymphomas (FL). Twelve patients each in stages I and II, 13 in stage III and 11 in stage IV were treated in the Department of Radiation Oncology, University Hospital of Muenster, Germany from 2004 to 2016. Radiotherapy (RT), as well as additional chemoimmunotherapy were analyzed with a median follow-up of 87.6 months. Ultrasound (US), CT and 18 F-FDG-PET/CT were used to determine progression-free survival (PFS), overall survival (OS) and lymphoma-specific survival (LSS) over 5- and 10- years. 23 of 24 patients with stage I/II (95.8%) had complete remissions (CR) and 17 of 24 patients with stages III/IV FL showed CR (70.8%). 5- and 10-year PFS in stages I/II was 90.0%/78.1% vs. 44.3%/28.5% in stages III/IV. 5- and 10-year OS rates in stages I/II was 100%/93.3% vs. 53.7%/48.4% in stages III/IV. 5- and 10-year LSS of stages I/II was 100%/93.8% vs. 69.2%/62.3% in stages III/IV. FL of stages I/II, staged by 18 F-FDG-PET/CT, revealed better survival rates and lower risk of recurrence compared to studies without PET/CT-staging. Especially, patients with PET/CT proven stage I disease showed significantly better survival and lower relapses rates after RT.

Objective: The objective of this study was to assess the accuracy of 68 Ga-PSMA-11 PET/MRI, 18 F-PSMA-1007 PET/CT, 68 Ga-PSMA-11 PET/CT, and multiparametric (mp)MRI for the delineating of dominant intraprostatic lesions (IPL)., Materials and Methods: 35 patients with organ-confined prostate cancer who were assigned to definitive radiotherapy (RT) were divided into three groups based on imaging techniques: 68 Ga-PSMA-PET/MRI (n = 9), 18 F-PSMA-PET/CT (n = 16) and 68 Ga-PSMA-PET/CT (n = 10). All patients without PSMA-PET/MRI received an additional mpMRI. PSMA-PET-based automatic isocontours and manual contours of the dominant IPLs were generated for each modality. The biopsy results were then used to validate whether any of the prostate biopsies were positive in the marked lesion using Dice similarity coefficient (DSC), Youden index (YI), sensitivity and specificity. Factors that can predict the accuracy of IPLs contouring were analysed., Results: Diagnostic performance was significantly superior both for manual and automatic IPLs contouring using 68 Ga-PSMA-PET/MRI (DSC/YI SUV 70% -0.62/0.51), 18 F-PSMA-PET/CT (DSC/YI SUV 70% -0.67/0.53) or 68 Ga-PSMA-PET/CT (DSC/YI SUV 70% -0.63/0.51) compared to mpMRI (DSC/YI-0.47/0.41; p < 0.001). The accuracy for delineating IPLs was not improved by combination of PET/CT and mpMRI images compared to PET/CT alone. Significantly superior diagnostic accuracy was found for large prostate lesions (at least 15% from the prostate volume) and higher Gleason score (at least 7b) comparing to smaller lesions with lower GS., Conclusion: IPL localization was significantly improved when using PSMA-imaging procedures compared to mpMRI. No significant difference for delineating IPLs was found between hybrid method PSMA-PET/MRI and PSMA-PET/CT. PSMA-based imaging technique should be considered for the diagnostics of IPLs and focal treatment modality.

Radiation therapy (RT) for extremity soft tissue sarcoma is associated with lymphedema risk. In this study, we analyzed the influence of lymph-sparing volume on the lymphedema occurrence in patients who received adjuvant extremity RT. The lymph-sparing quotient (LSQ) was calculated by dividing the lymph-sparing volume by the total extremity volume with double weightingfor the narrowest lymph-sparing region. A total of 34 patients were enrolled in this analysis. The median applied total radiation dose was 66.3 Gy in 36 fractions. Acute lymphedema appeared in 12 patients (35%). Most of them ( n = 8) were lymphedema grade 1 and five patients had grade 2 to 3 lymphedema. Chronic lymphedema appeared in 22 patients (65%). 17 of these patients had at least a grade 2 lymphedema. In 13 of 14 patients with an LSQ ≤ 0.2 and 11 of 20 patients with an LSQ > 0.2, an acute or chronic lymphedema ≥ grade 2 was observed. A Kaplan-Meier Analysis of the two groups with the endpoint of a two-year lymph edema-free survival (=2-YLEFS) was estimated with an univariate, significant result (2-YLEFS LSQ ≤ 0.2 vs. LSQ > 0.2: 0% vs. 39%; p = 0.006; hazard ratio LSQ ≤ 0.2 vs. > 0.2 2-YLEFS 2.822 ( p = 0.013); 95% confidence interval (CI): 1.24-6.42). Maximizing the potential oncologically-justifiable lymph-sparing volume should be considered to reduce the risk of high-grade lymphedema when applying RT to extremities.

Background: Approximately half of all patients with tumors need radiotherapy. Long-term survivors may suffer from late sequelae of the treatment. The existing radiotherapeutic techniques are being refined so that radiation can be applied more precisely, with the goal of limiting the radiation exposure of normal tissue and reducing late sequelae., Methods: This review is based on the findings of a selective search in PubMed for publications on late sequelae of conventional percutaneous radiotherapy, January 2000 to May 2020. Late sequelae affecting the central nervous system, lungs, and heart and the development of second tumors are presented, and radiobiological mechanisms and the relevant technical and conceptual considerations are discussed., Results: The current standard of treatment involves the use of linear accelerators, intensity-modulated radiotherapy (IMRT), image-guided and respiratory-gated radiotherapy, and the integration of positron emission tomography combined with computed tomography (PET-CT) in radiation treatment planning. Cardiotoxicity has been reduced with regard to the risk of coronary heart disease after radiotherapy for Hodgkin's lymphoma (hazard ratio [HR] 0.44 [0.23; 0.85]). It was also found that the rate of radiation- induced pneumonitis dropped from 7.9% with conformal treatment to 3.5% with IMRT in a phase III lung cancer trial. It is hoped that neurocognitive functional impairment will be reduced by hippocampal avoidance in modern treatment planning: an initial phase III trial yielded a hazard ratio of 0.74 [0.58; 0.94]. It is estimated that 8% of second solid tumors in adults are induced by radiotherapy (3 additional tumors per 1000 patients at 10 years)., Conclusion: Special challenges for research in this field arise from the long latency of radiation sequelae and the need for largescale, well-documented patient collectives in order to discern dose-effect relationships, and take account of cofactors, when the overall number of events is small. It is hoped that further technical and conceptual advances will be made in the areas of adaptive radiotherapy, proton and heavy-ion therapy, and personalized therapy.

Successful studies on radiation therapy for gastric lymphoma led to a decrease in planning target volume (PTV) and radiation dose with low toxicities, maintaining excellent survival rates. It remains unclear as to which effects are to be expected concerning dose burden on organs at risk (OAR) by decrease in PTV vs. dose and whether a direct impact on toxicity might be expected. We evaluated 72 radiation plans, generated prospectively for a cohort of 18 patients who were treated for indolent gastric lymphoma in our department. As a prospective work, four radiation plans with different radiation doses and target volumes (40 Gy-involved field, 40 Gy-involved site, 30 Gy-involved field, 30 Gy-involved site) were generated for each patient. Mean dose burden on adjacent organs was compared between the planning groups. Cohort toxicity data served to estimate parameters for the Lyman-Kutcher-Burman (LKB) model for normal tissue complication probability (NTCP). These were used to anticipate adverse events for OAR. Literature parameters were used to estimate high-grade toxicities of OAR. Decrease of dose and/or PTV led to median dose reductions between 0.13 and 5.2 Gy, with a significant dose reduction on neighboring organs. Estimated model parameters for liver, spleen, and bowel toxicity were feasible to predict cohort toxicities. NTCP for the endpoints elevated liver enzymes, low platelet count, and diarrhea ranged between 15.9 and 22.8%, 27.6 and 32.4%, and 21.8 and 26.4% for the respective four plan variations. Field and dose reduction highly impact dose burden and NTCP for OAR during stomach radiation. Our estimated LKB model parameters offer a good approximation for low-grade toxicities in abdominal organs with modern radiation techniques.

The COVID-19 pandemic is associated with significant morbidity, mortality, and restrictions on everyday life worldwide. This may be especially challenging for brain tumor patients given increased vulnerability due to their pre-existing condition. Here, we aimed to investigate the quality of life (QoL) in brain tumor patients and relatives in this setting. Over twelve weeks during the first wave of the pandemic (04-07/2020), brain tumor patients and their families from two large German tertiary care centers were asked to complete weekly questionnaires for anxiety, depression, distress, and well-being. Information regarding social support and living conditions was also collected. One hundred participants (63 patients, 37 relatives) completed 729 questionnaires over the course of the study. Compared to relatives, patients showed more depressive symptoms ( p < 0.001) and reduced well-being ( p = 0.013). While acceptance of lockdown measures decreased over time, QoL remained stable. QoL measures between patients and their families were weakly or moderately correlated. The number of social contacts was strongly associated with QoL. Age, living conditions, ongoing therapy, employment, and physical activity were other predictors. QoL is correlated between patients and their families and heavily depends on social support factors, indicating the need to focus on the entire family and their social situation for QoL interventions during the pandemic.

Background/aim: Modern intensity-modulated radiotherapy (IMRT) is frequently applied to treat patients with nasal cavity and paranasal sinus (NC/PNS) malignancies., Patients and Methods: One hundred and four patients who underwent radiotherapy (RT) between 1994 and 2020 were recognized. This analysis compared conventional-radiotherapy (CRT) and image-guided IMRT outcomes for NC/PNS malignancies., Results: The median follow-up was 69 months. Eighty-eight patients (85%) were managed with image-guided IMRT. The median initial radiation dose was 65 Gy, with 68 Gy applied for patients treated with primary RT versus 63 Gy applied for adjuvant therapy (p=0.1). The 5-year locoregional control (LRC) was 85%. The locoregional recurrence rate was 18% following IMRT versus 31% in the 2D/3D-conventional RT group (p=0.09). Moreover, IMRT was associated with a lower inner-ear toxicity rate (8% vs. 20%, respectively; p=0.045)., Conclusion: IMRT appears to be linked with higher LRC and lower inner-ear acute toxicities compared to conventional RT., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives : Recent trials with craniospinal irradiation (CSI) via helical Tomotherapy (HT) demonstrated encouraging medulloblastoma results. In this study, we assess the toxicity profile of different radiation techniques and estimate survival rates. Materials and Methods : We reviewed the records of 46 patients who underwent irradiation for medulloblastoma between 1999 and 2019 (27 conventional radiotherapy technique (CRT) and 19 HT). Patient, tumor, and treatment characteristics, as well as treatment outcomes-local control rate (LCR), event-free survival (EFS), and overall survival (OS)-were reviewed. Acute and late adverse events (AEs) were evaluated according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. Results : In total, 43 courses of CSI and three local RT were administered to the 46 patients: 30 were male, the median age was 7 years (range 1-56). A median total RT dose of 55 Gy (range 44-68) and a median CSI dose of 35 Gy (range, 23.4-40) was delivered. During follow-up (median, 99 months), six patients (13%) developed recurrence. The EFS rate after 5 years was 84%. The overall OS rates after 5 and 10 years were 95% and 88%, respectively. There were no treatment-related deaths. Following HT, a trend towards lower grade 2/3 acute upper gastrointestinal ( p = 0.07) and subacute CNS ( p = 0.05) toxicity rates was detected compared to CRT-group. The risk of late CNS toxicities, mainly grade 2/3, was significantly lower following HT technique ( p = 0.003). Conclusion : CSI via HT is an efficacious treatment modality in medulloblastoma patients. In all, we detected a reduced rate of several acute, subacute, and chronic toxicities following HT compared to CRT.