Volumetric modulated arc therapy versus intensity-modulated proton therapy in the irradiation of infra diaphragmatic Hodgkin Lymphoma in female patients.

PURPOSE: To investigate the role of infra diaphragmatic intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for female Hodgkin Lymphoma (HL) patients and to estimate the risk of secondary cancer and ovarian failure. METHODS: A comparative treatment planning study was performed on 14 patients, and the results were compared according to conventional dose-volume metrics. In addition, estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the bowel, the bladder and the rectum. For the ovaries, the risk of ovarian failure was estimated. RESULTS: The dosimetric findings demonstrate the equivalence between VMAT and IMPT in terms of target coverage. A statistically significant reduction of the mean and near-to-maximum doses was proven for the organs at risk. The EAR ratio estimated for IMPT to VMAT was 0.51 ± 0.32, 0.32 ± 0.35 and 0.05 ± 0.11 for the bowel, bladder and rectum, respectively. Concerning the risk of ovarian failure for the chronologic age ranging from 18 to 46 years, the expected net loss in fertility years ranged from 4.8 to 3.0 years for protons and 12.0 to 5.7 years for photons. CONCLUSION: This in-silico study confirmed the beneficial role of IMPT from a dosimetric point of view. Mathematical models suggested that the use of protons might be further advantageous due to the expected reduction of the risk of secondary cancer induction and its milder impact on the reduction of fertility.

Involved Site Radiotherapy Extends Time to Premature Menopause in Infra-Diaphragmatic Female Hodgkin Lymphoma Patients - An Analysis of GHSG HD14- and HD17-Patients.

INTRODUCTION: Consolidation radiotherapy in intermediate stage Hodgkin´s lymphoma (HL) has been the standard of care for many years as involved field radiotherapy (IFRT) after chemotherapy. It included initially involved region(s). Based on randomized studies, radiation volumes could be reduced and involved site radiation therapy (ISRT) became the new standard. ISRT includes the initially affected lymph nodes. In young adults suffering from HL, infertility and hypogonadism are major concerns. With regard to these questions, we analyzed the influence of modern radiotherapy concepts such as consolidating ISRT in infradiaphragmatic involvement of HL after polychemotherapy. PATIENTS AND METHODS: Five hundred twelve patients treated within German Hodgkin Study Group (GHSG) HD14 and HD17 trials were evaluated. We analyzed log-adjusted follicle-stimulating-hormone (FSH)- and luteinizing-hormone (LH)-levels of HD14-patients with infradiaphragmatic radiotherapy (IDRT) in comparison with HD14-patients, who had a supradiaphragmatic radiotherapy (SDRT). In a second step, we compared IFRT with ISRT of female HD17 patients regarding the effects on ovarian function and premature menopause. RESULTS: We analyzed FSH- and LH-levels of 258 female and 241 male patients, all treated with IFRT. Of these 499 patients, 478 patients had SDRT and 21 patients had IDRT. In a multiple regression model, we could show that log-adjusted FSH (p=0.0006) and LH values (p=0.0127) were significantly higher after IDRT than after SDRT. The effect of IDRT on gonadal function was comparable to two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). We compared the effect of IFRT with ISRT in thirteen female HD17 patients with infradiaphragmatic (ID) involvement. The mean ovarian dose after ISRT was significantly lower than after IFRT. The calculated proportion of surviving non-growing follicles (NGFs) increased significantly from 11.87% to 24.48% in ISRT compared to IFRT, resulting in a significantly longer calculated time to menopause. The younger the age at therapy, the greater the absolute time gain until menopause. CONCLUSION: Infradiaphragmatic IFRT impairs gonadal function to a similar extent as two cycles of BEACOPPesc. In comparison, the use of ISRT target volume definition significantly reduced radiation dose to the ovaries and significantly extends the time interval from treatment to premature menopause.

CyberKnife radiation therapy as a platform for translational mouse studies.

PURPOSE: Radiation therapy (RT) is a common nonsurgical treatment in the management of patients with cancer. While genetically engineered mouse models (GEMM) recapitulate human disease, conventional linear particle accelerator systems are not suited for state-of-the-art, imageguided targeted RT (IGRT) of these murine tumors. We employed the CyberKnife (CK; Accuray) platform for IGRT of GEMM-derived non-small cell lung cancer (NSCLC) lesions. MATERIAL AND METHODS: GEMM-derived KrasLSL-G12D/+/Trp53fl/fl -driven NSCLC flank tumors were irradiated using the CK RT platform. We applied IGRT of 2, 4, 6, and 8 Gy using field sizes of 5-12.5 mm to average gross tumor volumes (GTV) of 0.9 cm3 using Xsight Spine Tracking (Accuray). RESULTS: We found that 0 mm planning target volume (PTV) margin is sufficient for IGRT of murine tumors using the CK. We observed that higher RT doses (6-8 Gy) decreased absolute cell numbers of tumor infiltrating leukocytes (TIL) by approximately half compared to low doses (2-4 Gy) within 1 h, but even with low dose RT (2 Gy) TIL were found to be reduced after 8-24 h. CONCLUSION: We here demonstrate that the CK RT system allows for targeted IGRT of murine tumors with high precision and constitutes a novel promising platform for translational mouse RT studies.

Proton versus photon deep inspiration breath hold technique in patients with hodgkin lymphoma and mediastinal radiation : A PLANNING COMPARISON OF DEEP INSPIRATION BREATH HOLD INTENSITY MODULATION RADIOTHERAPY AND INTENSITY MODULATED PROTON THERAPY.

BACKGROUND: The benefits of proton therapy in the treatment of patients with Hodgkin lymphoma (HL) are controversially discussed. Therefore we compared intensitiy modulated proton therapy (IMPT) with intensity modulated radiotherapy (IMRT), in the form of volumetric modulated arc therapy (VMAT) in patients with Hodgkin lymphoma (HL), through a comparative treatment planning study. METHODS: Radiation plans for 21 patients with Hodgkin Lymphoma (HL) were computed for IMPT and deep inspiration breath hold (DIBH) VMAT. Plans were optimized and computed assuming deep inspiration breath holding conditions. Dosimetric comparison on standard metrics from dose volume histograms was performed to appraise the relative merits of the two techniques, while proton plan robustness was assessed by re-computing the dose distribution of each plan by varying the Hounsfield Units to stopping power calibration by applying a ± 3 and 4% error. RESULTS: DIBH-VMAT and IMPT both provided excellent coverage, conformity and heterogeneity of the clinical target volume (CTV) and planning target volume (PTV). IMPT reduced mean doses to the breasts, lungs, heart and normal tissue by 38-83%. IMPT significantly reduced mean doses to the heart to < 5 Gy despite bulky mediastinal disease and decreased breast doses in female patients to < 1 Gy. Despite the simulated 3 and 4% miscalibration errors, no remarkable or measurable impact was observed on the organs at risk (OARs). CONCLUSIONS: This is the first comparison between DIBH-VMAT and IMPT in HL treatment. We could demonstrate statistically significant decreases in all dose/volume metrics of the OARs. Regardless of the planning paradigm used, range uncertainties can substantially under dose the PTV, while perhaps not leading to clinically significant deterioration of CTV coverage. With the geometry applied no impact was observed for OARs, suggesting IMPT as a superior technique for potentially reducing future health risks for HL patients.

Toll-like receptor-4 signaling mediates pulmonary neutrophil sequestration in response to gram-positive bacterial enterotoxin.

BACKGROUND: Toll-like receptors (TLRs) serve as mediators of innate immune responses to pathogen-associated molecular patterns (PAMPs) which include lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB). TLR-4 is thought to act as the primary effector of LPS recognition and TLR-2 is thought to mediate responses to Gram-positive bacterial proteins. Chemokines such as macrophage inflammatory protein (MIP-2) are peptides that are responsible for lung neutrophil (PMN) sequestration following an infectious or inflammatory insult. Given the Gram-positive origin of SEB, we hypothesized that mice with altered TLR-4 signaling would exhibit no difference in lung PMN sequestration following SEB when compared to wild-type mice. METHODS: Wild-type and TLR-4 mutant mice were administered intratracheal saline, LPS (Escherichia coli 0.1 mg/kg), or SEB (1 mg/kg). After 24 h, lung PMN accumulation was determined by myeloperoxidase (MPO) assay and bronchoalveolar lavage fluid cell count (BALfcc). Total lung and BALf MIP-2 was measured by enzyme-linked immunosorbent assay. RESULTS: There was an increase in lung PMN accumulation (by both MPO and BALfcc) and MIP-2 following LPS and SEB in wild-type mice compared to saline-treated controls. In contrast, TLR-4 mice failed to exhibit an increase in lung MIP-2 or PMN accumulation following either LPS or SEB compared to wild-type mice. CONCLUSIONS: TLR-4 mutant mice are unresponsive to intratracheal LPS. SEB elicited an increase in lung MIP-2 and PMN accumulation in wild-type mice. However, TLR-4 mutant mice were protected from this process. This suggests that TLR-4 signaling may mediate the responses to other PAMPs in addition to LPS.