Spatial Distribution of Recurrence and Long-Term Toxicity Following Dose Escalation to the Dominant Intra-Prostatic Nodule for Intermediate-High-Risk Prostate Cancer: Insights from a Phase I/II Study.

Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate-high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25-74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17-76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate-high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent.

Long-Term Results of Stereotactic Radiotherapy in Patients with at Least 10 Brain Metastases at Diagnosis.

PURPOSE: to evaluate an SRT approach in patients with at least 10 lesions at the time of BM initial diagnosis. METHODS: This is a monocentric prospective cohort of patients treated by SRT, followed by a brain MRI every two months. Subsequent SRT could be delivered in cases of new BMs during follow-up. The main endpoints were local control rate (LCR), overall survival (OS), and strategy success rate (SSR). Acute and late toxicity were evaluated. RESULTS: Seventy patients were included from October 2014 to January 2019, and the most frequent primary diagnosis was non-small-cell lung cancer (N = 36, 51.4%). A total of 1174 BMs were treated at first treatment, corresponding to a median number of 14 BMs per patient. Most of the patients (N = 51, 72.6%) received a single fraction of 20-24 Gy. At 1 year, OS was 62.3%, with a median OS of 19.2 months, and SSR was 77.8%. A cumulative number of 1537 BM were treated over time, corresponding to a median cumulative number of 16 BM per patient. At 1-year, the LCR was 97.3%, with a cumulative incidence of radio-necrosis of 2.1% per lesion. Three patients (4.3%) presented Grade 2 toxicity, and there was no Grade ≥ 3 toxicity. The number of treated BMs and the treatment volume did not influence OS or SSR (p > 0.05). CONCLUSIONS: SRT was highly efficient in controlling the BM, with minimal side effects. In this setting, an SRT treatment should be proposed even in patients with ≥10 BMs at diagnosis.

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy.

Stereotactic body radiation therapy (SBRT) has made the hypofractionation of high doses delivered in a few sessions more acceptable. While the benefits of hypofractionated SBRT have been attributed to additional vascular, immune effects, or specific cell deaths, a radiobiological and mechanistic model is still needed. By considering each session of SBRT, the dose is divided into hundreds of minibeams delivering some fractions of Gy. In such a dose range, the hypersensitivity to low dose (HRS) phenomenon can occur. HRS produces a biological effect equivalent to that produced by a dose 5-to-10 times higher. To examine whether HRS could contribute to enhancing radiation effects under SBRT conditions, we exposed tumor cells of different HRS statuses to SBRT. Four human HRS-positive and two HRS-negative tumor cell lines were exposed to different dose delivery modes: a single dose of 0.2 Gy, 2 Gy, 10 × 0.2 Gy, and a single dose of 2 Gy using a non-coplanar isocentric minibeams irradiation mode were delivered. Anti-γH2AX immunofluorescence, assessing DNA double-strand breaks (DSB), was applied. In the HRS-positive cells, the DSB produced by 10 × 0.2 Gy and 2 Gy, delivered by tens of minibeams, appeared to be more severe, and they provided more highly damaged cells than in the HRS-negative cells, suggesting that more severe DSB are induced in the "SBRT modes" conditions when HRS occurs in tumor. Each SBRT session can be viewed as hyperfractionated dose delivery by means of hundreds of low dose minibeams. Under current SBRT conditions (i.e., low dose per minibeam and not using ultra-high dose-rate), the response of HRS-positive tumors to SBRT may be enhanced significantly. Interestingly, similar conclusions were reached with HRS-positive and HRS-negative untransformed fibroblast cell lines, suggesting that the HRS phenomenon may also impact the risk of post-RT tissue overreactions.

3D-conformal very-high energy electron therapy as candidate modality for FLASH-RT: A treatment planning study for glioblastoma and lung cancer.

BACKGROUND: Pre-clinical ultra-high dose rate (UHDR) electron irradiations on time scales of 100 ms have demonstrated a remarkable sparing of brain and lung tissues while retaining tumor efficacy when compared to conventional dose rate irradiations. While clinically-used gantries and intensity modulation techniques are too slow to match such time scales, novel very-high energy electron (VHEE, 50-250 MeV) radiotherapy (RT) devices using 3D-conformed broad VHEE beams are designed to deliver UHDR treatments that fulfill these timing requirements. PURPOSE: To assess the dosimetric plan quality obtained using VHEE-based 3D-conformal RT (3D-CRT) for treatments of glioblastoma and lung cancer patients and compare the resulting treatment plans to those delivered by standard-of-care intensity modulated photon RT (IMRT) techniques. METHODS: Seven glioblastoma patients and seven lung cancer patients were planned with VHEE-based 3D-CRT using 3 to 16 coplanar beams with equidistant angular spacing and energies of 100 and 200 MeV using a forward planning approach. Dose distributions, dose-volume histograms, coverage (V95% ) and homogeneity (HI98% ) for the planning target volume (PTV), as well as near-maximum doses (D2% ) and mean doses (Dmean ) for organs-at-risk (OAR) were evaluated and compared to clinical IMRT plans. RESULTS: Mean differences of V95% and HI98% of all VHEE plans were within 2% or better of the IMRT reference plans. Glioblastoma plan dose metrics obtained with VHEE configurations of 200 MeV and 3-16 beams were either not significantly different or were significantly improved compared to the clinical IMRT reference plans. All OAR plan dose metrics evaluated for VHEE plans created using 5 beams of 100 MeV were either not significantly different or within 3% on average, except for Dmean for the body, Dmean for the brain, D2% for the brain stem, and D2% for the chiasm, which were significantly increased by 1, 2, 6, and 8 Gy, respectively (however below clinical constraints). Similarly, the dose metrics for lung cancer patients were also either not significantly different or were significantly improved compared to the reference plans for VHEE configurations with 200 MeV and 5 to 16 beams with the exception of D2% and Dmean to the spinal canal (however below clinical constraints). For the lung cancer cases, the VHEE configurations using 100 MeV or only 3 beams resulted in significantly worse dose metrics for some OAR. Differences in dose metrics were, however, strongly patient-specific and similar for some patient cases. CONCLUSIONS: VHEE-based 3D-CRT may deliver conformal treatments to simple, mostly convex target shapes in the brain and the thorax with a limited number of critical adjacent OAR using a limited number of beams (as low as 3 to 7). Using such treatment techniques, a dosimetric plan quality comparable to that of standard-of-care IMRT can be achieved. Hence, from a treatment planning perspective, 3D-conformal UHDR VHEE treatments delivered on time scales of 100 ms represent a promising candidate technique for the clinical transfer of the FLASH effect.

Toxicity, quality of life, and PSA control after 50 Gy stereotactic body radiation therapy to the dominant intraprostatic nodule with the use of a rectal spacer: results of a phase I/II study.

OBJECTIVES: We conducted a phase I/II prospective trial to determine whether stereotactic dose escalation to the dominant intra-prostatic nodule (DIN) up to 50 Gy incorporating a rectal balloon spacer is safe, does not affect patient quality of life, and preserves local control in patients with intermediate-high risk PCa. METHODS: Eligible patients included males with stage ≤T3b localized disease, a prostate-specific antigen (PSA) level ≤50 , International Prostate Symptom Score (IPSS) ≤14, and a gland volume ≤70 cm3. Patients underwent perirectal spacer placement, followed by a planning MRI and were subsequently treated with SBRT doses of 36.25 Gy in five fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image visible DIN up to 50 Gy. Primary endpoint: safety. Secondary endpoints: biochemical control, quality of life (QofL), and dosimetry outcome. RESULTS: Nine patients were treated in the Phase I part of the study. Dose limiting toxicities (DLTs) were not observed. Further characterization of tolerability and efficacy was conducted in the subsequent 24 patients irradiated at the recommended Phase II dose (50 Gy, RP2D). At a median follow-up of 61 months, biochemical control is 69%. Grade 1 and 2 acute GU and GI toxicity was 57.5 and 15%, and 24.2 and 6.1%, respectively. Grade 1 and 2 late GU and GI toxicity was 66.6 and 12.1%, and 15.1 and 3%, respectively. No Grade 3 or higher toxicity was reported. QofL data confirmed physician's reported side effects. Dosimetry analysis showed adherence to the doses prescribed in the protocol. CONCLUSIONS: SBRT of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN, when combined with a peri-rectal balloon spacer, was tolerable and established the RP2D. QofL analysis showed minimal negative impact in GU, GI, and sexual domains. ADVANCES IN KNOWLEDGE: Extreme hypofractionated prostate radiation therapy with focal dose escalation to the DIN is well tolerated with efficacy comparable to normal fractionated radiation therapy.

Commissioning and validation of RayStation treatment planning system for CyberKnife M6.

BACKGROUND: RaySearch (AB, Stockholm) has released a module for CyberKnife (CK) planning within its RayStation (RS) treatment planning system (TPS). PURPOSE: To create and validate beam models of fixed, Iris, and multileaf collimators (MLC) of the CK M6 for Monte Carlo (MC) and collapsed cone (CC) algorithms in the RS TPS. METHODS: Measurements needed for the creation of the beam models were performed in a water tank with a stereotactic PTW 60018 diode. Both CC and MC models were optimized in RS by minimizing the differences between the measured and computed profiles and percentage depth doses. The models were then validated by comparing dose from the plans created in RS with both single and multiple beams in different phantom conditions with the corresponding measured dose. Irregular field shapes and off-axis beams were also tested for the MLC. Validation measurements were performed using an A1SL ionization chamber, EBT3 Gafchromic films, and a PTW 1000 SRS detector. Finally, patient-specific QAs with gamma criteria of 3%/1 mm were performed for each model. RESULTS: The models were created in a straightforward manner with efficient tools available in RS. The differences between computed and measured doses were within ±1% for most of the configurations tested and reached a maximum of 3.2% for measurements at a depth of 19.5-cm. With respect to all collimators and algorithms, the maximum averaged dose difference was 0.8% when considering absolute dose measurements on the central axis. The patient-specific QAs led to a mean result of 98% of points fulfilling gamma criteria. CONCLUSIONS: We created both CC and MC models for fixed, Iris, and MLC collimators in RS. The dose differences for all collimators and algorithms were within ±1%, except for depths larger than 9 cm. This allowed us to validate both models for clinical use.

A new method to visualize and to spare the ureters during SBRT for oligo metastatic patients.

This article describes a ureter-sparing procedure used to treat lymph node metastases with SBRT. We delivered 35 Gy in 5 fractions of 7 Gy to patients with lesions located less than 7 mm from the ureters using a urography CT scan for planification. Two dosimetry plans were created, one using a CT scan urography-based contour and the other using the native phase. PTV coverage were not statistically different but this technique was able to significantly reduce median delivered Dmax to the ureters. These preliminary results demonstrate the feasibility of locating the ureters in a planning CT scan to protect them.

Stereotactic lung reirradiation for local relapse: A case series.

INTRODUCTION: Local recurrence after lung SBRT for early stage NSCLC is rare but its treatment remains a challenge due to limited surgical options. We report a case series of 5 patients treated by stereotactic lung salvage reirradiation for local relapse after a previous lung SBRT. MATERIAL AND METHODS: Included patients presented an isolated primary lung relapse within at least the 50% isodose of the previous SBRT treatment. Typical reirradiation schedule was 60 Gy in 8 fractions at isodose 80% and was delivered by Cyberknife® using Synchrony® fiducial tracking system. Dose summations were performed to evaluate the safety of the reirradiation. RESULTS: We identified 5 patients presenting peripheral lesions. All reirradiated lesions were locally controlled after a median follow-up of 11.1 months (6,7-12,2), while PFS at 6 months was 60% (n = 3). We did not notice any Grade 3 or more acute or late adverse event. CONCLUSION: We observed encouraging short-term outcome of lung SBRT reirradiation in patients presenting isolated local relapse of an early-stage NSCLC. Further studies are necessary to confirm the safety and efficiency of this salvage treatment approach.

Stereotactic Radiotherapy for the Management of Refractory Ventricular Tachycardia: Promise and Future Directions.

Ventricular tachycardia (VT) caused by myocardial scaring bears a significant risk of mortality and morbidity. Antiarrhythmic drug therapy (AAD) and catheter ablation remain the cornerstone of VT management, but both treatments have limited efficacy and potential adverse effects. Stereotactic body radiotherapy (SBRT) is routinely used in oncology to treat non-invasively solid tumors with high precision and efficacy. Recently, this technology has been evaluated for the treatment of VT. This review presents the basic underlying principles, proof of concept, and main results of trials and case series that used SBRT for the treatment of VT refractory to AAD and catheter ablation.

Percussion assisted radiation therapy in Hodgkin lymphoma allows a marked reduction in heart dose.

BACKGROUND AND PURPOSE: Early-stage Hodgkin lymphoma (HL) is a highly curable disease but the treatment can induce late complications many years later. Irradiation of the healthy heart is inevitable during radiation treatment of mediastinal sites. We developed a novel method to induce a prolonged apnea-like state that can help decrease the dose to organs at risk during radiation therapy. We present the results of the first 8 HL patients treated routinely with percussion assisted radiation therapy (PART) in our clinic. MATERIAL AND METHODS: We used a newly developed high-frequency non-invasive ventilation system to suppress respiratory motion for prolonged periods and push the heart away from the treated volume. RESULTS: All 8 patients were able to rapidly learn the technique and had an advantage to be treated by PART. We lowered the mean heart dose by an average of 3 Gy with similar target coverage compared to a classical free breathing treatment plan. They were all treated for 15 radiotherapy sessions by PART without any notable side effects. CONCLUSIONS: Percussion assisted radiation therapy can be used routinely to reduce the dose to the heart in Hodgkin lymphoma.

Curative management of a cardiac metastasis from lung cancer revealed by an electrical storm.

Although cardiac metastases (CM) are more common than primary cardiac malignant tumors, they remain a rare localization of metastatic cancer. Until recently, CM were surgically treated as a palliative approach because of a lack of ablative solutions even for oligometastatic patients. Technological advances in radiation therapy (RT) in thoracic oncology have led to high precision delivery that enlarged the indications for stereotactic body radiotherapy (SBRT). To date, there are limited reports of cardiac SBRT for CM. Herein, we report a cardiac SBRT performed in curative intent for a lung cancer patient metastatic to the heart.

[Management of refractory ventricular tachycardia using stereotactic body radiotherapy]. / Prise en charge des tachycardies ventriculaires réfractaires par radiothérapie stéréotaxique.

Stereotactic body radiotherapy (SBRT) is routinely used in oncology to treat non-invasively solid tumors with high precision and efficacy. Recently, this technology has been evaluated in the treatment of ventricular tachycardia (VT). This article presents the basic underlying principles, proofs of concept and main results of clinical studies that used SBRT for the treatment of VT.

La radiothérapie stéréotaxique (SBRT) est une technologie couramment utilisée en oncologie pour traiter de façon non invasive les tumeurs solides avec précision et efficacité. Récemment, cette technologie a été évaluée dans le traitement des tachycardies ventriculaires (TV). Cet article présente les principes de base sous-jacents, le concept ainsi que les résultats des premières études cliniques ayant traité avec succès des patients souffrant de TV avec la SBRT.

Lausanne checklist for safe stereotactic radiosurgery.

INTRODUCTION: Stereotactic radiosurgery (SRS) is increasingly used as a minimally invasive alternative in many neurosurgical conditions, including benign and malignant tumors, vascular malformations, and functional procedures. As for any surgical procedure, strict safety guidelines and checklists are necessary to avoid errors and the inherent unnecessary complications. With regard to the former, other groups have already reported human and/or technical errors. We describe our safety checklist for Gamma Knife radiosurgical procedures. METHODS: We describe our checklist protocol after an experience gained over 1500 radiosurgical procedures, using Gamma Knife radiosurgery, performed over a period of 8 years, while employing the same list of items. Minor implementation has been performed over time to address some safety issues that could be improved. RESULTS: Two types of checklist are displayed. One is related to the indications when a specific tissue volume is irradiated, including tumors or vascular disorders. The second corresponds to functional disorders, such as when the dose is prescribed to one specific point. Using these checklists, no human error had been reported during the past 8 years of practice in our institution. CONCLUSION: The use of a safety checklist for SRS procedures promotes a zero-tolerance attitude for errors. This can lower the complications and is of major help in promoting multidisciplinary cooperation. We highly recommend the use of such tool, especially in the context of the increased use of SRS in the neurosurgical field.

50-Gy Stereotactic Body Radiation Therapy to the Dominant Intraprostatic Nodule: Results From a Phase 1a/b Trial.

PURPOSE: Although localized prostate cancer (PCa) is multifocal, the dominant intraprostatic nodule (DIN) is responsible for disease progression after radiation therapy. PCa expresses antigens that could be recognized by the immune system. We therefore hypothesized that stereotactic dose escalation to the DIN is safe, may increase local control, and may initiate tumor-specific immune responses. PATIENTS AND METHODS: Patients with localized PCa were treated with stereotactic extreme hypofractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image-visible DIN (45 Gy, 47.5 Gy, and 50 Gy in 5 fractions). The phase 1a part was designed to determine the recommended phase 1b dose in a "3 + 3" cohort-based, dose-escalation design. The primary endpoint was dose-limiting toxicities defined as ≥grade 3 gastrointestinal (GI) or genitourinary (GU) toxicity (or both) by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) up to 90 days after the first radiation fraction. The secondary endpoints were prostate-specific antigen kinetics, quality of life (QoL), and blood immunologic responses. RESULTS: Nine patients were treated in phase 1a. No dose-limiting toxicities were observed at either level, and therefore the maximum tolerated dose was not reached. Further characterization of tolerability, efficacy, and immunologic outcomes was conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase 1b expansion cohort. Toxicity was 45% and 25% for grades 1 and 2 GU, and 20% and 5% for grades 1 and 2 GI, respectively. No grade 3 or worse toxicity was reported. The average (±standard error of the mean) of the QoL assessments at baseline and at 3-month posttreatment were 0.8 (±0.8) and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% confidence interval, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for the International Prostate Symptom Score (mean difference, 0.87; 95% confidence interval, 0.3-1.9), respectively. A subset of patients developed antigen-specific immune responses against prostate-specific membrane antigen (n = 2), prostatic acid phosphatase (n = 1), prostate stem cell antigen (n = 4), and prostate-specific antigen (n = 2). CONCLUSIONS: Irradiation of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN was tolerable and determined as the recommended phase 1b dose. This treatment has promising antitumor activity, which will be confirmed by the ongoing phase 2 part. Preliminary QoL analysis showed minimal impact in GU, GI, and sexual domains. Stereotactic irradiation induced antigen-specific immune responses in a subset of patients.

Rescue procedure for an electrical storm using robotic non-invasive cardiac radio-ablation.

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive treatment in the management of ventricular tachycardia (VT). We report here an intensive care patient suffering from an electrical storm due to incessant VT, unresponsive to catheter ablation and anti-arrhythmic drugs, showing an immediate and durable response to electrophysiology-guided cardiac SBRT.

Dosimetric evaluation of modern radiation therapy techniques for left breast in deep-inspiration breath-hold.

PURPOSE: The dosimetric differences between four radiation therapy techniques for left sided whole breast irradiation were evaluated side by side in the same patient population. METHODS: Radiotherapy treatment plans were retrospectively created with Accuray TomoDirect (TD), Elekta Volumetric Modulated Arc Therapy (E-VMAT), Varian RapidArc (RA) and Field-in-field (FinF) technique for 20 patients, who had received left breast irradiation during deep-inspiration breath-hold. Dose characteristics of planning target volume and organs at risk were compared. RESULTS: The E-VMAT, TD and RA treatment plans had higher target coverage (V95%) than FinF plans (97.7-98.3% vs. 96.6%). The low-dose spillage to contralateral breast and lung was smaller with FinF and TD (mean 0.1 and 0.3 Gy) compared to E-VMAT and RA (mean 0.6 and 0.9 Gy). E-VMAT, RA and TD techniques were more effective than FinF in sparing left anterior descending artery (mean 4.0, 4.2 and 4.7 Gy vs. 6.1 Gy, respectively). CONCLUSIONS: In whole breast irradiation TD, E-VMAT and RA plans generated in this study achieved higher dose coverage and sparing of organs from the high dose in the vicinity of the PTV. The advantage of calculated FinF plans is the lowest dose on contralateral organs. The choice of the technique used should be weighted by each institution taking into account the dose characteristics of each technique and its fit with patient anatomy bearing in mind the increased workload of using modulated techniques and the increased beam on time.

Efficacy and safety of helical tomotherapy with daily image guidance in anal canal cancer patients.

Background and purpose Intensity-modulated radiotherapy (IMRT), also using volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) techniques, has been only recently introduced for treating anal cancer patients. We report efficacy and safety HT, and daily image-guided RT (IGRT) for anal cancer. Materials and methods We retrospectively analyzed efficacy and toxicity of HT with or without chemotherapy for anal cancer patients. Local control (LC) and grade 3 or more toxicity rate (CTC-AE v.4.0) were the primary endpoints. Overall (OS), disease-free (DFS), and colostomy-free survival (CFS) are also reported. Results Between October 2007 and May 2014, 78 patients were treated. Fifty patients presented a stage II or stage IIIA (UICC 2002), and 33 presented a N1-3 disease. Radiotherapy consisted of 36 Gy (1.8 Gy/fraction) delivered on the pelvis and on the anal canal, with a sequential boost up to 59.4 Gy (1.8 Gy/fraction) delivered to the anal and to nodal gross tumor volumes. Concomitant chemotherapy was delivered in 73 patients, mainly using mitomycin C and 5-fluorouracil (n = 30) or mitomycin C and capecitabine combination (n = 37). After a median follow-up period of 47 months (range 3-75), the five-year LC rate was 83.8% (95% CI 76.2-91.4%). Seven patients underwent a colostomy because of local recurrence (n = 5) or pretreatment dysfunction (n = 2). Overall incidence of grade 3 acute toxicity was 24%, mainly as erythema (n = 15/19) or diarrhea (n = 7/19). Two patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Conclusions HT with daily IGRT is efficacious and safe in the treatment of anal canal cancer patients, and is considered in our department standard of care in this clinical setting.

IMRT credentialing for prospective trials using institutional virtual phantoms: results of a joint European Organization for the Research and Treatment of Cancer and Radiological Physics Center project.

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPC(PH)). Institutions were retrospectively requested to irradiate their institutional phantom (INST(PH)) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing. MATERIALS AND METHODS: CT data set of the institutional phantom and measured 2D dose matrices were requested from centers and sent to a dedicated secure EORTC uploader. Data from the RPC(PH) and INST(PH) were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA). RESULTS: Eighteen institutions participated to the VPP. The measurements of 6 (33%) institutions could not be analyzed centrally. All other centers passed both the VPP and the RPC ±7%/4 mm credentialing criteria. At the 5%/5 mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPC(PH) and INST(PH) (p = 0.29), respectively. The corresponding pass rate for the 3%/3 mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; p = 0.01), respectively. CONCLUSIONS: IMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INST(PH) measurements showed agreement at the gamma index criteria of ±5%/5 mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPC(PH) and INST(PH) comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Human tonsil implants xenotransplanted in SCID mice display broad lymphocytic diversity and cellular activation profile similar to those in the original lymphoid organ.

BACKGROUND: Models consisting of human immune cells in suspension transferred to severe combined immune deficient (SCID) mice have been invaluable for studying immune response, autoimmunity, and lymphomagenesis. The dissemination of human cells within the mouse body hampers immune functionality with time and favorites the development of human graft vs. mouse host (GvH) disease. To circumvent these limitations we surgically implanted tonsil pieces subcutaneously in SCID animals (hu-ton-SCID mice). Recall humoral responses was elicited and animals did not suffer from signs of GvH disease. A detailed cell subset and cell activation analysis of implants has not yet been reported. METHODS: Implants from 86 hu-ton-SCID mice were evaluated by immunohistochemistry and flow cytometry analyses to assess human lymphoid cell subpopulation surviving with time after implantation, and to evaluate status of human cell activation. RESULTS: B cells persist over 3 months in implants. The proportion of class and type-specific Ig+ cells varied between implants, but as a whole IgG+ cells were more abundant than IgA+, and IgM+ cells, and kappa+ cells predominated over lambda+ cells. The mean proportions of these cells resemble those in the original tonsil. Fine analysis of CD19+ B cells demonstrated no expansion of activated (CD5+, CD23+, CD69+) B cells in implants compared with tonsils, and a decrease of CD19+CD77+ B cells corresponding to a centroblastic phenotype, which is consistent with the disappearance of follicular structure in implants. Double positive CD20+CD27+ memory B cells were detected in implants by immunohistochemistry. T cell CD4+CD8-/CD4-CD8+ ratios were about 4 in implants, that is similar to those in tonsils, and there was no expansion of CD3+CD4+CD8+ and of CD3+CD4-CD8- T-cell subpopulations. T cells activation markers (CD25, CD69) were similarly expressed in implants and tonsils, and implants contained cells with a memory T cell phenotype (CD45RO). Finally cells within implants depicted a low rate of proliferation when assessed by Ki-67 expression levels. CONCLUSIONS: Compared with original tonsils, tonsil implants in hu-ton-SCID mice lose the germinal center architecture, which is correlated with the decrease of CD77+ B cells, but conserve T and B cell subpopulation diversity, notably memory cells. In addition, implant T and B cells are not differently activated when compared with those in original tonsils and do not proliferate extensively. These observations indicate indirectly absence of GvH reaction at the cellular level in this model. Collectively, the detailed implant cellular characterization in the hu-ton-SCID model provides a strong rationale for the use of this model in the study of human recall antibody response.