Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings.

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).

Combined proton-photon treatment for breast cancer.

Objective.Proton therapy remains a limited resource due to gantry size and its cost. Recently, a new design without a gantry has been suggested. It may enable combined proton-photon therapy (CPPT) in conventional bunkers and allow the widespread use of protons. In this work, we explore this concept for breast cancer.Methods.The treatment room consists of a LINAC for intensity modulated radiation therapy (IMRT), a fixed proton beamline (FBL) with beam scanning and a motorized couch for treatments in lying positions with accurate patient setup. Thereby, proton and photon beams are delivered in the same fraction. Treatment planning is performed by simultaneously optimizing IMRT and IMPT plans based on the cumulative dose. The concept is investigated for three breast cancers where the goal is to minimize mean dose to the heart and lung while delivering 40.05 Gy in 15 fractions to the PTV with a SIB of 48 Gy to the tumor bed. The probabilistic approach is applied to mitigate the sensitivity to range uncertainties.Results. CPPT is particularly advantageous for irradiating concave target volumes that wrap around a curved chest wall. There, protons may deliver dose to the peripheral and medial parts of the target volume including lymph nodes. Thereby, the mean dose in normal tissues is reduced compared to single-modality IMRT. However, tangential photon beams may treat parts of the target volume near the interface to the lung. To ensure target coverage for range undershoot in an IMPT plan, proton beams have to deliberately overshoot into the lung tissue-a problem that can be mitigated via the photon component which ensures plan conformity and robustness.Conclusion.CPPT using an FBL may represent a realistic approach to make protons available to more patients. In addition, CPPT may generally improve treatment quality compared to both single-modality proton and photon treatments.

Operating procedures, risk management and challenges during implementation of adaptive and non-adaptive MR-guided radiotherapy: 1-year single-center experience.

BACKGROUND: Main purpose was to describe procedures and identify challenges in the implementation process of adaptive and non-adaptive MR-guided radiotherapy (MRgRT), especially new risks in workflow due to the new technique. We herein report the single center experience for the implementation of (MRgRT) and present an overview on our treatment practice. METHODS: Descriptive statistics were used to summarize clinical and technical characteristics of treatment and patient characteristics including sites treated between April 2019 and end of March 2020 after ethical approval. A risk analysis was performed to identify risks of the online adaptive workflow. RESULTS: A summary of the processes on the MR-Linac including workflows, quality assurance and possible pitfalls is presented. 111 patients with 124 courses were treated during the first year of MR-guided radiotherapy. The most commonly treated site was the abdomen (42% of all treatment courses). 73% of the courses were daily online adapted and a high number of treatment courses (75%) were treated with stereotactic body irradiation. Only 4/382 fractions could not be treated due to a failing online adaptive quality assurance. In the risk analysis for errors, the two risks with the highest risk priority number were both in the contouring category, making it the most critical step in the workflow. CONCLUSION: Although challenging, establishment of MRgRT as a routinely used technique at our department was successful for all sites and daily o-ART was feasible from the first day on. However, ongoing research and reports will have to inform us on the optimal indications for MRgRT because careful patient selection is necessary as it continues to be a time-consuming treatment technique with restricted availability. After risk analysis, the most critical workflow category was the contouring process, which resembles the need of experienced staff and safety check paths.

Hypofractionated Radiotherapy for Breast Cancer Including Risk-adapted Boost: Update on Tolerance and Efficacy of an Accelerated START A Regime.

AIM: To present an update of a prospective study evaluating an accelerated hypofractionated whole breast irradiation (WBI) schedule of the START A trial plus hypofractionated boost in breast cancer patients. PATIENTS AND METHODS: One hundred and forty consecutive patients ≥55 years were included in this study. Patients received postoperative WBI with 13×3.2 Gy to 41.6 Gy plus a boost of 3.0 Gy/fraction to 9-12 Gy applied in <3.5 weeks, depending on the resection margin. Prospectively planned follow-up (FU) visits, including objective and subjective assessment of treatment tolerance, were performed at 0 and 8 weeks, as well as one, two, four or more years following radiotherapy (RT). RESULTS: The 3-year rates of local control, nodal control, disease-free and overall survival were 99%, 100%, 96% and 91%, respectively. Cosmetic outcome was very good with 99% (n=110/111), 98% (n=99/101) and 100% (n=59/59) of the patients being satisfied or very satisfied one, two and four years after RT, respectively. CONCLUSION: Acceleration of the START A regime with 41.6 Gy WBI plus additional boost of 9-12 Gy remained effective and well-tolerated.

Implementation and validation of a new fixation system for stereotactic radiation therapy: An analysis of patient immobilization.

PURPOSE: Stereotactic radiation therapy is an established treatment technique for intracranial malignancies. We evaluated a new intracranial immobilization system with an emphasis on determining the intrafraction motion and the correlation of this motion with treatment time. METHODS AND MATERIALS: Patients were immobilized using the trUpoint ARCH fixation system (CIVCO Medical Solutions). We collected data from 85 lesions in 73 patients treated between November 2011 and December 2013. Sixty-nine of 73 patients (95%) used the complete mask system; for the remaining 4 patients, the system had to be adapted. Patients were treated using volumetric modulated arc therapy stereotactic radiation therapy on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA). Fraction doses of 2-8 Gy were applied in 4-30 fractions. Daily cone beam computed tomography imaging was performed before the treatment and was matched to the reference computed tomography using a 6-degrees-of-freedom automatching procedure. Additionally, posttreatment cone beam computed tomography scans were performed to assess intrafraction motion for 67 patients (375 fractions). RESULTS: The average 3-dimensional setup error was 2.1 ± 2.9 mm. The mean pitch and roll was -0.1 ± 0.7° and 0.2 ± 0.7°. A total of 98.0% of the pitch values and 98.9% of the roll values were <1.5°. Mean intrafractional motion was 0.51 mm (±0.27) and mean treatment time was 10.1 minutes (±1.4). The maximum intrafractional motion was 2.0 mm in the longitudinal direction; 95% of the total shifts were <1.4 mm. The linear regression showed a weak but significant influence (R(2) = 0.26, P = .01) of the treatment time on the total intrafractional shift. CONCLUSIONS: The new intracranial immobilization system appears to be robust in terms of setup accuracy, intrafraction motion, and repositioning of the mask system.

Safety of high-dose-rate stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: Flattening filter free (FFF) beams with high dose rate are increasingly used for stereotactic body radiotherapy (SBRT), because they substantially shorten beam-on time. The physical properties of these beams together with potentially unknown radiobiological effects might affect patient safety. Therefore here we analyzed the clinical outcome of our patients. MATERIAL AND METHODS: Between 3/2010 and 2/2014 84 patients with 100 lesions (lung 75, liver 10, adrenal 6, lymph nodes 5, others 4) were treated with SBRT using 6 MV FFF or 10 MV FFF beams at our institution. Clinical efficacy endpoints and toxicity were assessed by Kaplan-Meier analysis and CTCAE criteria version 4.0. RESULTS: Median follow-up was 11 months (range: 3-41). No severe acute toxicity was observed. There has been one case of severe late toxicity (1%), a grade 3 bile duct stricture that was possibly related to SBRT. For all patients, the 1-year local control rate, progression free survival and overall survival were 94%, 38% and 80% respectively, and for patients with lung lesions 94%, 48% and 83%, respectively. CONCLUSIONS: No unexpected toxicity occurred. Toxicity and treatment efficacy are perfectly in range with studies investigating SBRT with flattened beams. The use of FFF beams at maximum dose rate for SBRT is time efficient and appears to be safe.

Prevalence and predictors of fatigue in glioblastoma: a prospective study.

BACKGROUND: The main goal of this study was to assess frequency, clinical correlates, and independent predictors of fatigue in a homogeneous cohort of well-defined glioblastoma patients at baseline prior to combined radio-chemotherapy. METHODS: We prospectively included 65 glioblastoma patients at postsurgical baseline and assessed fatigue, sleepiness, mean bedtimes, mood disturbances, and clinical characteristics such as clinical performance status, presenting symptomatology, details on neurosurgical procedure, and tumor location and diameter as well as pharmacological treatment including antiepileptic drugs, antidepressants, and use of corticosteroids. Data on fatigue and sleepiness were measured with the Fatigue Severity Scale and the Epworth Sleepiness Scale, respectively, and compared with 130 age- and sex-matched healthy controls. RESULTS: We observed a significant correlation between fatigue and sleepiness scores in both patients (r = 0.26; P = .04) and controls (r = 0.36; P < .001). Only fatigue appeared to be more common in glioblastoma patients than in healthy controls (48% vs 11%; P < .001) but not the frequency of sleepiness (22% vs 19%; P = .43). Female sex was associated with increased fatigue frequency among glioblastoma patients but not among control participants. Multiple linear regression analyses identified depression, left-sided tumor location, and female sex as strongest associates of baseline fatigue severity. CONCLUSIONS: Our findings indicate that glioblastoma patients are frequently affected by fatigue at baseline, suggesting that factors other than those related to radio- or chemotherapy have significant impact, particularly depression and tumor localization.

Hypofractionated radiotherapy for breast cancer acceleration of the START A treatment regime: intermediate tolerance and efficacy.

PURPOSE: Prospective evaluation of accelerated hypofractionated radiotherapy (RT) in breast cancer patients treated with 41.6 Gy in 13 fractions plus boost delivered five times a week. PATIENTS AND METHODS: Between 03/2009 and 10/2012 98 consecutive patients aged >55 years presenting with breast cancer (invasive cancer: n = 95, ductal carcinoma in situ (DCIS): n = 3) after breast conserving surgery were treated in our institution with the following schedule: 41.6 Gy in 13 fractions 4 times a week and 9 or 12 Gy boost in 3 or 4 fractions (on day 5 each week), cumulative dose: 50.6 Gy in 3.2 weeks or 53.6 Gy in 3.4 weeks, respectively depending on resection status. 56 patients had a T1 tumor, 39 a T2 tumor. N-status was as follows: N0: n = 71, N1: n = 25, N2/3: n = 2. 23 patients (24%) received chemotherapy before RT. A prospectively planned follow-up (FU) visit with objective and subjective assessment of treatment tolerance (questionnaires) was performed 0 and 8 weeks after RT completion, and one, two and four years later, respectively. RESULTS: Mean/median follow-up was 32/28 months (range: 12-56). After 2 years local control, loco-regional control and disease-free survival was 100%, 100%, and 98%, respectively. Overall survival was 96% at 2 years. Cosmetic outcome was very good with patients being satisfied or very satisfied in 99% (n = 86/87), 97% (n = 55/57) and 100% (n = 25/25) after one, two and four years after RT, respectively. No grade ≥ 2 pain was described in the 25 patients with a FU of at least 4 years. Fibrosis, telangiectasia and edema were found in 7-15%, 0-22% and 0-11% at one, two, and four years, respectively, and are comparable to other trials. CONCLUSION: The applied hypofractionated RT regime with single doses of 3.2 Gy plus boost doses of 9-12 Gy in 3-4 fractions applied in 5 sessions a week was effective and well tolerated on intermediate term FU.

Late term tolerance in head neck cancer patients irradiated in the IMRT era.

BACKGROUND: The aim was to quantify severe transient and persisting late term effects in our single institution head neck cancer (HNC) cohort treated with curatively intended intensity modulated radiation therapy (IMRT). Hypothesis was if a 2-year follow up (FU) is sufficient to estimate the long term tolerance in HNC irradiated in the IMRT era. METHODS: Between 01/2002-8/2012, 707/1211 (58%) consecutively treated IMRT patients met the inclusion criteria of a FU time >12 months and loco-regional disease control (LRC). 45% presented with loco-regionally advanced disease; 55% were referred for curative definitive IMRT (66 Gy-72 Gy in 30-35 fractions), 45% underwent postoperative IMRT (60-66 Gy in 30-33 fractions). Systemic concomitant therapy was administered in 85%. Highly consistent treatment procedures were performed with respect to contouring processes, dose constraints, radiation schedules, and the use of systemic therapy. Grade 3/4 late term effects were prospectively assessed and analyzed with respect to subgroups at particular risk for specific late effects. RESULTS: Mean/median FU of the cohort was 41/35 months (15-124). 13% of the patients (92/707) experienced any grade 3/4 late effects (101 events in 92/707 patients), 81% in the first 12 months after radiation. 4% of all developed persisting late grade 3/4 effects (25 events in 25/707 patients). CONCLUSIONS: IMRT led to a high late term tolerance in loco-regionally disease free HNC patients. The onset of any G3/4 effects showed a plateau at 2 years. The question of the cervical vessel tolerance in disease free long time survivors is still open and currently under evaluation at our institution.

Clinical application of flattening filter free beams for extracranial stereotactic radiotherapy.

PURPOSE: To investigate the clinical application of flattening filter free (FFF) beams at maximum dose rate for stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Patients with tumors in the lung or abdomen were subjected to SBRT using 6 MV FFF or 10 MV FFF beams. For each patient, three plans were calculated using 6 MV flattened, 6 MV FFF, and 10 MV FFF beams. Treatment times were recorded and analyzed, and tumor displacements were assessed by pre- and post-treatment cone beam computed tomography (CBCT). RESULTS: Altogether, 26 patients (16 lung, 10 abdominal tumors) were treated. The average dose rate per patient ranged from 442 to 1860 MU/min. Beam-on time was on average 1.6 min (1SD=0.6 min), with the total treatment times recorded at 18.5 min (1SD=3.5 min). The time advantage of using FFF beams was dose-dependent and started at 4 Gy for 6 MV FFF and at 10 Gy for 10 MV FFF beams. The average of the tumor displacements during treatment was 2.0mm (1SD = 1.0mm). CONCLUSIONS: SBRT using FFF beams is time efficient and associated with excellent patient stability. According to Van Herk's formula, ITV-PTV margins of 6mm are sufficient in our patient cohort. Further studies are necessary to assess clinical outcome and toxicity.

Follow up after IMRT in oral cavity cancer: update.

PURPOSE: Except for early stages (T1/2 N0), the prognosis for patients with oral cavity cancer (OCC) is known to be worse than for those with pharyngeal carcinoma. While definitive intensity modulated radiation therapy (IMRT)-chemotherapy affords loco-regional control rates (LRC) of approximately 80% in advanced pharyngeal cancer, corresponding rates are reported to be much lower for OCC. The aim of this work was to evaluate loco-regional disease control and overall survival (OAS) in a relatively large OCC patient cohort treated in the IMRT era. METHODS AND MATERIALS: Between October 2002 and June 2011, 160 OCC patients were treated with curative intention IMRT at our department. 122 patients (76%) were referred with primary disease and 38 patients (24%) with a recurrent OCC at least 3 months after surgery alone. Definitive IMRT was performed in 44/160 patients (28%), whilst 116 patients underwent previous surgery. Simultaneous systemic therapy was administered in 72%. RESULTS: Patients with postoperative IMRT (+/-systemic therapy) with R0-1 status (n = 99) reached significantly higher LRC/OAS rates than patients following IMRT for macroscopic disease (n = 61), with 84%/80% versus 38%/33% at 3 years, respectively (p < 0.0001). This was found in patients treated for initial, as well as recurrent, disease. Less than 2% persisting grade 3/4 late effects were observed. CONCLUSIONS: IMRT for R0-1 situations translated into a highly significant superior LRC and OAS compared to the IMRT cohort treated for macroscopic disease. Treatment was well tolerated.

Total body irradiation (TBI) in pediatric patients. A single-center experience after 30 years of low-dose rate irradiation.

PURPOSE: To retrospectively analyze patient characteristics, treatment, and treatment outcome of pediatric patients with hematologic diseases treated with total body irradiation (TBI) between 1978 and 2006. PATIENTS AND METHODS: 32 pediatric patients were referred to the Department of Radiation-Oncology at the University of Zurich for TBI. Records of regular follow-up of 28 patients were available for review. Patient characteristics as well as treatment outcome regarding local control and overall survival were assessed. A total of 18 patients suffered from acute lymphoblastic leukemia (ALL), 5 from acute and 2 from chronic myelogenous leukemia, 1 from non-Hodgkin lymphoma, and 2 from anaplastic anemia. The cohort consisted of 15 patients referred after first remission and 13 patients with relapsed leukemia. Mean follow-up was 34 months (2-196 months) with 15 patients alive at the time of last follow-up. Eight patients died of recurrent disease, 1 of graft vs. host reaction, 2 of sepsis, and 2 patients died of a secondary malignancy. RESULTS: The 5-year overall survival rate (OS) was 60%. Overall survival was significantly inferior in patients treated after relapse compared to those treated for newly diagnosed leukemia (24% versus 74%; p=0.004). At the time of last follow-up, 11 patients survived for more than 36 months following TBI. Late effects (RTOG ≥ 3) were pneumonitis in 1 patient, chronic bronchitis in 1 patient, cardiomyopathy in 2 patients, severe cataractogenesis in 1 patient (48 months after TBI with 10 Gy in a single dose) and secondary malignancies in 2 patients (36 and 190 months after TBI). Growth disturbances were observed in all patients treated prepubertally. In 2 patients with identical twins treated at ages 2 and 7, a loss of 8% in final height of the treated twin was observed. CONCLUSION: As severe late sequelae after TBI, we observed 2 secondary malignancies in 11 patients who survived in excess of 36 months. However, long-term morbidity is moderate following treatment with the fractionated TBI at the low-dose rate that was generally used here. Conditioning for bone marrow transplantation without radiation is an attractive option, but is not sufficiently effective to completely replace TBI for the most common pediatric indications.

Surveillance of craniopharyngioma cyst growth in children treated with proton radiotherapy.

PURPOSE: Craniopharyngiomas are benign, slow-growing tumors that frequently contain a cystic component. Even with gross total resection, the cyst can reform and cause symptoms. Fluctuations in cyst volume during radiotherapy (RT) can affect treatment planning and delivery. The aim of this study was to report our experience with cyst enlargement during conformal proton RT for children with craniopharyngioma and to make recommendations regarding mid-treatment surveillance. METHODS AND MATERIALS: Between January 2001 and August 2007, 24 children (aged

A psychoeducational intervention reduces the need for anesthesia during radiotherapy for young childhood cancer patients.

BACKGROUND: Radiotherapy (RT) has become an important treatment modality in pediatric oncology, but its delivery to young children with cancer is challenging and general anesthesia is often needed. METHODS: To evaluate whether a psychoeducational intervention might reduce the need for anesthesia, 223 consecutive pediatric cancer patients receiving 4141 RT fractions during 244 RT courses between February 1989 and January 2006 were studied. Whereas in 154 RT courses corresponding with 2580 RT fractions patients received no psychoeducational intervention (group A), 90 RT courses respectively 1561 RT fractions were accomplished by using psychoeducational intervention (group B). This tailored psychoeducational intervention in group B included a play program and interactive support by a trained nurse according to age to get familiar with staff, equipment and procedure of radiotherapy. RESULTS: Group A did not differ significantly from group B in age at RT, gender, diagnosis, localization of RT and positioning during RT. Whereas 33 (21.4%) patients in group A got anesthesia, only 8 (8.9%) patients in group B needed anesthesia. The median age of cooperating patients without anesthesia decreased from 3.2 to 2.7 years. In both uni- and multivariate analyses the psychoeducational intervention significantly and independently reduced the need for anesthesia. CONCLUSION: We conclude that a specifically tailored psychoeducational intervention is able to reduce the need for anesthesia in children undergoing RT for cancer. This results in lower costs and increased cooperation during RT.

Distinct expression patterns of the immunogenic differentiation antigen NY-BR-1 in normal breast, testis and their malignant counterparts.

NY-BR-1 is a differentiation antigen and a potential target for cancer immunotherapy. Its mRNA expression is restricted to breast, testis, prostate and breast cancer by RT-PCR. In this study, we correlated NY-BR-1 protein and mRNA expression on tissue microarrays of mammary, prostatic and testicular malignancies using immunohistochemistry and in situ hybridization with probes for exon 4-7 and 30-33. NY-BR-1 mRNA was confined to primary spermatocytes, suggesting a role in spermatogenesis. Exon 4-7 and 30-33 were equally expressed this cell type. However, NY-BR-1 was absent in all germ cell tumours analyzed (n = 475) and present in one of 56 (2%) prostate carcinomas. In breast, NY-BR-1 mRNA expression was detected in 307 of 442 (70%) primary carcinomas, with strong correlation to its protein expression (p < 0.0001). mRNA expression was significantly stronger and more frequently detected by the exon 30-33 probe than by the exon 4-7 probe (70% vs. 35%, p < 0.0001), indicating the presence of alternative splice variants that lack 5-prime sequences. A similar restricted mRNA pattern was also observed in the normal breast epithelium. NY-BR-1 protein and mRNA correlated significantly with estrogen receptor alpha (ER alpha) protein expression (p < 0.0001), with stronger association to NY-BR-1 mRNA than protein (odds ratio 7.7 compared to 4.6). We identified 4 estrogen response elements (ERE)-like sequences nearby the promoter region, suggesting that NY-BR-1 transcription might be controlled by ER alpha. Accordingly, analysis of matching pairs of primary tumors with their recurrences showed a marked decrease of NY-BR-1 expression in recurrences after tamoxifen treatment (p < 0.0001).