Host conditioning and rejection monitoring in hepatocyte transplantation in humans.

BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

A non-human primate model of acute liver failure suitable for testing liver support systems.

Acute hepatic failure is associated with high morbidity and mortality for which the only definitive therapy is liver transplantation. Some fraction of those who undergo emergency transplantation have been shown to recover native liver function when transplanted with an auxiliary hepatic graft that leaves part of the native liver intact. Thus, transplantation could have been averted with the development and use of some form of hepatic support. The costs of developing and testing liver support systems could be dramatically reduced by the availability of a reliable large animal model of hepatic failure with a large therapeutic window that allows the assessment of efficacy and timing of intervention. Non-lethal forms of hepatic injury were examined in combination with liver-directed radiation in non-human primates (NHPs) to develop a model of acute hepatic failure that mimics the human condition. Porcine hepatocyte transplantation was then tested as a potential therapy for acute hepatic failure. After liver-directed radiation therapy, delivery of a non-lethal hepatic ischemia-reperfusion injury reliably and rapidly generated liver failure providing conditions that can enable pre-clinical testing of liver support or replacement therapies. Unfortunately, in preliminary studies, low hepatocyte engraftment and over-immune suppression interfered with the ability to assess the efficacy of transplanted porcine hepatocytes in the model. A model of acute liver failure in NHPs was created that recapitulates the pathophysiology and pathology of the clinical condition, does so with reasonably predictable kinetics, and results in 100% mortality. The model allowed preliminary testing of xenogeneic hepatocyte transplantation as a potential therapy.

Testicular recovery after irradiation differs in prepubertal and pubertal non-human primates, and can be enhanced by autologous germ cell transplantation.

BACKGROUND: Although infertility is a serious concern in survivors of pediatric cancers, little is known about the influence of the degree of sexual maturation at the time of irradiation on spermatogenic recovery after treatment. Thus, we address this question in a non-human primate model, the rhesus monkey (Macaca mulatta). METHODS: Two pubertal (testis size 3 and 6.5 ml, no sperm in ejaculate) and four prepubertal (testis size 1 ml, no sperm in ejaculate) macaques were submitted to a single fraction of testicular irradiation (10 Gy). Unilateral autologous transfer of cryopreserved testis cells was performed 2 months after irradiation. Testicular volume, histology and semen parameters were analyzed to assess irradiation effects and testicular recovery. RESULTS: Irradiation provoked acute testis involution only in the two pubertal monkeys. Subsequently, testis sizes recovered and sperm was present in the ejaculates. Longitudinal outgrowth of seminiferous tubules continued, and, in testes without autologous cell transfer, 4-22% of tubular cross sections showed spermatogenesis 2 years after irradiation. In contrast, the four prepubertal monkeys showed neither a detectable involution as direct response to irradiation, nor a detectable growth of seminiferous tubules later. However, two of these animals showed spermarche 2 years after irradiation, and 8-12% of tubules presented spermatogenesis. One prepubertally irradiated monkey presented fast growth of one testis after cell transfer, and showed spermarche 1 year after irradiation. The infused testis had spermatogenesis in 70% of the tubules. The contralateral testis remained smaller. CONCLUSION: We conclude that irradiation before puberty has a severe detrimental effect on outgrowth of seminiferous tubules. But, within the seminiferous epithelium, spermatogenetic recovery occurs at a low rate with no detectable relation to the maturity of the epithelium at irradiation. We also show that autologous testis cell transplantation can enhance spermatogenesis, but only in isolated cases.

Unintended attenuation in the Leksell Gamma Knife Perfexion calibration-phantom adaptor and its effect on dose calibration.

The calibration of Leksell Gamma Knife Perfexion (LGK PFX) is performed using a spherical polystyrene phantom 160 mm in diameter, which is provided by the manufacturer. This is the same phantom that has been used with LGK models U, B, C, and 4C. The polystyrene phantom is held in irradiation position by an aluminum adaptor, which has stainless steel side-fixation screws. The phantom adaptor partially attenuates the beams from sectors 3 and 7 by 3.2% and 4.6%, respectively. This unintended attenuation introduces a systematic error in dose calibration. The overall effect of phantom-adaptor attenuation on output calibration of the LGK PFX unit is to underestimate output by about 1.0%.

Measurement of relative output factors for the 8 and 4 mm collimators of Leksell Gamma Knife Perfexion by film dosimetry.

Three types of films, Kodak EDR2, Gafchromic EBT, and Gafchromic MD-V2-55, were used to measure relative output factors of 4 and 8 mm collimators of the Leksell Gamma Knife Perfexion. The optical density to dose calibration curve for each of the film types was obtained by exposing the films to a range of known doses. Ten data points were acquired for each of the calibration curves in the dose ranges from 0 to 4 Gy, 0 to 8 Gy, and 0 to 80 Gy for Kodak EDR2, Gafchromic EBT, and Gafchromic MD-V2-55 films, respectively. For the measurement of relative output factors, five films of each film type were exposed to a known dose. All films were scanned using EPSON EXPRESSION 10000 XL scanner with 200 dpi resolution in 16 bit gray scale for EDR2 film and 48 bit color scale for Gafchromic films. The scanned images were imported in the red channel for both Gafchromic films. The background corrections from an unexposed film were applied to all films. The output factors obtained from film measurements were in a close agreement both with the Monte Carlo calculated values of 0.924 and 0.805 for 8 and 4 mm collimators, respectively. These values are provided by the vendor and used as default values in the vendor's treatment planning system. The largest differences were noted for the Kodak EDR 2 films (-2.1% and -4.5% for 8 and 4 mm collimators, respectively). The best agreement observed was for EBT Gafchromic film (-0.8% and +0.6% differences for 8 and 4 mm collimators, respectively). Based on the present values, no changes in the default relative output factor values were made in the treatment planning system.

Dosimetric comparison of the Leksell Gamma Knife Perfexion and 4C.

OBJECT: The recently introduced Leksell Gamma Knife (LGK) Perfexion is an entirely new system with a different beam geometry compared with the LGK 4C. The new Perfexion system has 192 cobalt-60 sources that are fixed on 8 sectors (each sector has 24 sources). Each sector can be moved independently of the others and can be set to 1 of 5 different positions: 3 positions defining collimator sizes of 4, 8, and 16 mm; an off position (sources are blocked); and a home position. The purpose of this study is to compare the dosimetric characteristics of the GK 4C and the Perfexion models. This comparison is important especially for the treatment of functional disorders when only a single shot with the 4- or 8-mm collimator is used. METHODS: A 160-mm-diameter spherical polystyrene phantom was used for all measurements and calculations. The irradiation geometry consisted of the placement of a single shot at the center of this phantom. Comparisons were made among different dosimetric parameters obtained from calculations performed using Leksell GammaPlan v. 8.0 and measurements performed using film dosimetry. The dosimetric parameters investigated were dose profiles for all collimators in all 3 stereotactic planes (x, y, and z) including the full width at half maximum and the penumbra for each profile, cumulative dose-volume histograms, the volume encompassed by the 50% isodose surface, the mean doses delivered to a defined matrix volume, and relative output factors for all collimator sizes. RESULTS: There was excellent agreement between the dosimetric parameters of GK 4C and Perfexion for the 4- and 8-mm collimators. CONCLUSIONS: The results of this study suggest that consistent treatments of functional disorders will be delivered using either GK 4C or Perfexion.

Brachytherapy in the treatment of Stage IV carcinoma of the base of tongue.

PURPOSE: Survival in patients with Stage IV carcinoma of the base of tongue (BOT) treated by surgery and radiotherapy remains poor. External beam radiotherapy (EBRT) and brachytherapy (BT) have been used as an alternative treatment. METHODS AND MATERIALS: Eighteen patients with Stage IV carcinoma of the BOT were treated by EBRT and BT. RESULTS: Local control is 89%. The 5-year overall (OS) and disease specific survival (DSS) rates are 52% and 67%. No neck node positive patient implanted in the neck developed cervical metastases. Two patients (11%) developed complications. CONCLUSIONS: Local regional control, survival, and complications in patients with Stage IV carcinoma of the BOT treated by EBRT and BT have been satisfactory. The use of brachytherapy for nodal metastases has eliminated the need for neck dissection. We recommend this approach in the treatment of Stage IV carcinoma of the BOT.

Hematopoietic chimerism following allotransplantation of the spleen, splenocytes or kidney in pigs.

BACKGROUND: Mixed chimerism is associated with donor-specific tolerance. Spleen or splenocyte allotransplantation (Tx) is recognized as potentially tolerogenic. There is no definitive report comparing chimerism levels following spleen and splenocyte Tx in a large animal model. We have compared chimerism after spleen, splenocyte, or kidney Tx in pigs. METHODS: Outbred (n = 5) and MHC-defined miniature (n = 1) pigs underwent orthotopic spleen Tx. Outbred pigs received splenocytes through a systemic vein (n = 1) or the portal vein (n = 3). Kidney Tx (n = 2) or concomitant Tx of spleen+kidney (n = 2) was carried out. All except one recipient pigs were irradiated (700 cGy thymic and 100-125 cGy whole body) on day-2. Cyclosporine or tacrolimus was administered for 42 days. All donors were males and all recipients were females; chimerism in the blood was determined by Quantification-PCR for the donor Y chromosome. Mixed lymphocyte reaction (MLR) was performed before and after Tx. RESULTS: One week after spleen Tx in outbred and MHC-defined pigs, chimerism ranged between 0.8 and 22.5%, and 5.4-20.1%, respectively, and remained between 17.7 and 67.4%, and 2.2-7.4%, respectively, until day 28. One week after splenocyte Tx, chimerism ranged between 0.1 and 8.5%, and decreased to 0.1-0.8% at 3-4 weeks. There was no detectable chimerism 14 days after kidney Tx. The response on MLR of all recipient pigs to donor cells was decreased after Tx, except in one case of splenocyte Tx, indicating that this pig might have become sensitized. After discontinuation of immunosuppression, most isolated spleen or kidney grafts were not rejected, but the kidney was rejected after concomitant spleen+kidney Tx. CONCLUSIONS: There was a significantly higher level of blood chimerism following spleen Tx compared to splenocyte or kidney Tx. However, concomitant Tx of spleen+kidney may be associated with accelerated kidney graft rejection.

A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury.

BACKGROUND: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. METHODS AND MATERIALS: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. RESULTS: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. CONCLUSIONS: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

A multi-national report on methods for institutional credentialing for spine radiosurgery.

BACKGROUND: Stereotactic body radiotherapy and radiosurgery are rapidly emerging treatment options for both malignant and benign spine tumors. Proper institutional credentialing by physicians and medical physicists as well as other personnel is important for the safe and effective adoption of spine radiosurgery. This article describes the methods for institutional credentialing for spine radiosurgery at seven highly experienced international institutions. METHODS: All institutions (n = 7) are members of the Elekta Spine Radiosurgery Research Consortium and have a dedicated research and clinical focus on image-guided spine radiosurgery. A questionnaire consisting of 24 items covering various aspects of institutional credentialing for spine radiosurgery was completed by all seven institutions. RESULTS: Close agreement was observed in most aspects of spine radiosurgery credentialing at each institution. A formal credentialing process was believed to be important for the implementation of a new spine radiosurgery program, for patient safety and clinical outcomes. One institution has a written policy specific for spine radiosurgery credentialing, but all have an undocumented credentialing system in place. All institutions rely upon an in-house proctoring system for the training of both physicians and medical physicists. Four institutions require physicians and medical physicists to attend corporate sponsored training. Two of these 4 institutions also require attendance at a non-corporate sponsored academic society radiosurgery course. Corporate as well as non-corporate sponsored training were believed to be complimentary and both important for training. In 5 centers, all cases must be reviewed at a multidisciplinary conference prior to radiosurgery treatment. At 3 centers, neurosurgeons are not required to be involved in all cases if there is no evidence for instability or spinal cord compression. Backup physicians and physicists are required at only 1 institution, but all institutions have more than one specialist trained to perform spine radiosurgery. All centers believed that credentialing should also be device specific, and all believed that professional societies should formulate guidelines for institutions on the requirements for spine radiosurgery credentialing. Finally, in 4 institutions radiation therapists were required to attend corporate-sponsored device specific training for credentialing, and in only 1 institution were radiation therapists required to also attend academic society training for credentialing. CONCLUSIONS: This study represents the first multi-national report of the current practice of institutional credentialing for spine radiosurgery. Key methodologies for safe implementation and credentialing of spine radiosurgery have been identified. There is strong agreement among experienced centers that credentialing is an important component of the safe and effective implementation of a spine radiosurgery program.

Radiosurgery for benign tumors of the spine: clinical experience and current trends.

In distinction to the development of the clinical indications for intracranial radiosurgery, spine radiosurgery's initial primary focus was and still remains the treatment of malignant disease. The role of stereotactic radiosurgery for the treatment of intracranial benign tumors has been well established. However, there is much less experience and much more controversy regarding the use of radiosurgery for the treatment of benign tumors of the spine. This study presents the clinical experience and current trends of radiosurgery in the treatment paradigm of benign tumors of the spine as part of a dedicated spine radiosurgery program. Forty consecutive benign spine tumors were treated using cone beam computed tomography (CBCT) image guidance technology for target localization. Lesion location included 13 cervical, 9 thoracic, 11 lumbar, and 7 sacral tumors. Thirty-four cases (85%) were intradural. The most common tumor histologies were schwannoma (15 cases), neurofibroma (7 cases), and meningioma (8 cases). Eighteen cases (45%) had previously undergone open surgical resection, and 4 lesions (10%) had previously been treated with conventional fractionated external beam irradiation techniques. This cohort was compared to a prior institutional experience of 73 consecutive benign spine tumors treated with radiosurgery. No subacute or long term spinal cord or cauda equina toxicity occurred during the follow-up period (median 26 months). Radiosurgery was used as the primary treatment modality in 22 cases (55%) and for recurrence after prior open surgical resection in 18 cases (45%). The mean prescribed dose to the gross tumor volume (GTV) was 14 Gy (range 11 to 17) delivered in a single fraction in 35 cases. In 5 cases in which the tumor was found to be intimately associated with the spinal cord with distortion of the spinal cord itself, the prescribed dose to the GTV was 18 to 21 Gy delivered in 3 fractions. The GTV ranged from 0.37 to 94.5 cm(3) (mean 13.2 cm(3), median 5.1 cm(3)). No evidence of tumor growth was seen on serial imaging in any case. Compared to the prior cohort, there was a trend towards increased patient age, GTV, and use of radiosurgery in the post-surgical setting, as well as a simultaneous decrease in the prescription dose. Radiosurgery is a safe and clinically effective treatment alternative for benign spinal neoplasms. While surgical extirpation is currently felt to be the best initial treatment option for most benign spinal tumors, spine radiosurgery has been demonstrated to have long-term clinical and radiographic benefit for the treatment of such lesions. In a similar manner in which spine radiosurgery has become a primary treatment option for a variety of intracranial benign tumors, radiosurgery may become the most favorable treatment alternative for similar histologies when found in the spine. The application of radiosurgery for non-neoplastic spine disease deserves future investigation.

Radiosurgery for benign tumors of the spine using the Synergy S with cone-beam computed tomography image guidance.

OBJECT: There is a growing body of evidence to support the safe and effective use of spine radiosurgery. However, there is much less experience regarding the use of radiosurgery for the treatment of benign as opposed to malignant spine tumors. This study represents an evaluation of, and reporting on, the technical aspects of using a dedicated radiosurgery system for the treatment of benign spine tumors. METHODS: Forty-five consecutive benign spine tumors were treated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and cone-beam computed tomography (CBCT) image guidance technology for target localization. The study cohort included 16 men and 29 women, ranging in age from 23 to 88 years (mean age 52 years). There were 14 cervical, 12 thoracic, 14 lumbar, and 5 sacral tumors. Forty-one lesions (91%) were intradural. The most common histological types of tumor were schwannoma, neurofibroma, and meningioma. Indications for radiosurgery included primary treatment in 24 cases (53%) and treatment of recurrent or residual tumor after open resection in 21 cases (47%). RESULTS: No subacute or long-term spinal cord or cauda equina toxicity occurred during the follow-up period (median 32 months). The mean maximum dose received by the gross tumor volume (GTV) was 16 Gy (range 12-24 Gy) delivered in a single fraction in 39 cases. The mean lowest dose received to the GTV was 12 Gy (range 8-16 Gy). The GTV ranged from 0.37 to 94.5 cm(3) (mean 13.7 cm(3), median 5.9 cm(3)). In the majority of cases, a planning target volume expansion of 2 mm was employed (38 cases; 84%). The mean maximum point dose delivered to the spinal cord was 8.7 Gy (range 4-11.5 Gy); the mean volume of the spinal cord that received greater than 8 Gy was 0.9 cm(3) (range 0.0-5.1 cm(3)); and the mean dose delivered to 0.1 cm(3) of the spinal cord was 7.5 Gy (range 3-10.5 Gy). The mean maximum point dose delivered to the cauda equina was 10 Gy (range 0-13 Gy); the mean volume of the cauda equina that received greater than 8 Gy was 1.45 cm(3) (range 0.0-10.6 cm(3)); and the mean dose delivered to 0.1 cm(3) of the cauda equina was 8 Gy (range 0.5-11 Gy). CONCLUSIONS: In this study the authors describe the contouring and prescribed dose techniques used in the treatment planning and delivery of radiosurgery for benign neoplasms of the spine using CBCT image guidance. This technique may serve as an important reference for the performance of radiosurgery when one believes it is clinically indicated as a treatment modality for a benign spine tumor that is associated with both a high safety profile and a strong positive clinical outcome.

The zebrafish--Danio rerio--is a useful model for measuring the effects of small-molecule mitigators of late effects of ionizing irradiation.

BACKGROUND/AIM: Use of zebrafish models may decrease the cost of screening new irradiation protectors and mitigators. MATERIALS AND METHODS: Zebrafish (Danio rerio) models were tested for screening water-soluble radiation protectors and mitigators. Irradiation of embryos and monitoring survival, and measuring fibrosis of the caudal musculature of adults allowed for testing of acute and late effects, respectively. RESULTS: Incubation of zebrafish embryos either before or after irradiation in ethyl pyruvate (1 mM) increased survival. Irradiation of adults to 15 to 75 Gy, delivered in single-fraction at 13 Gy/min, showed dose-dependent fibrosis at 30 days, quantitated as physiological decrease in swimming tail movement, and histopathological detection of collagen deposition in the dorsal musculature. Continuous administration of small-molecule radioprotector drugs in the water after irradiation reduced both acute and chronic injuries. CONCLUSION: The zebrafish is cost-effective for screening new radiation countermeasures.

International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery.

PURPOSE: Spinal stereotactic radiosurgery (SRS) is increasingly used to manage spinal metastases. However, target volume definition varies considerably and no consensus target volume guidelines exist. This study proposes consensus target volume definitions using common scenarios in metastatic spine radiosurgery. METHODS AND MATERIALS: Seven radiation oncologists and 3 neurological surgeons with spinal radiosurgery expertise independently contoured target and critical normal structures for 10 cases representing common scenarios in metastatic spine radiosurgery. Each set of volumes was imported into the Computational Environment for Radiotherapy Research. Quantitative analysis was performed using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) with kappa statistics calculating agreement between physicians. Optimized confidence level consensus contours were identified using histogram agreement analysis and characterized to create target volume definition guidelines. RESULTS: Mean STAPLE agreement sensitivity and specificity was 0.76 (range, 0.67-0.84) and 0.97 (range, 0.94-0.99), respectively, for gross tumor volume (GTV) and 0.79 (range, 0.66-0.91) and 0.96 (range, 0.92-0.98), respectively, for clinical target volume (CTV). Mean kappa agreement was 0.65 (range, 0.54-0.79) for GTV and 0.64 (range, 0.54-0.82) for CTV (P<.01 for GTV and CTV in all cases). STAPLE histogram agreement analysis identified optimal consensus contours (80% confidence limit). Consensus recommendations include that the CTV should include abnormal marrow signal suspicious for microscopic invasion and an adjacent normal bony expansion to account for subclinical tumor spread in the marrow space. No epidural CTV expansion is recommended without epidural disease, and circumferential CTVs encircling the cord should be used only when the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or there is extensive metastatic disease along the circumference of the epidural space. CONCLUSIONS: This report provides consensus guidelines for target volume definition for spinal metastases receiving upfront SRS in common clinical situations.

Prospective evaluation of spinal cord and cauda equina dose constraints using cone beam computed tomography (CBCT) image guidance for spine radiosurgery.

Cone beam computed tomography (CBCT) image guidance has become more widely used for spine radiosurgery delivery.Our center began a dedicated spine radiosurgery program that utilizes CBCT image guidance technology for target localization. This study prospectively evaluated the spinal cord and cauda equina doses received during single fraction spine radiosurgery treatments in order to determine a safety profile for this technique. Two hundred consecutive spine and paraspinal lesions were treated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and CBCT image guidance combined with a HexaPOD couch that allows patient positioning correction in 3 translational and 3 rotational directions. Lesion location included 33 cervical, 84 thoracic, 60 lumbar, and 23 sacral tumors. Tumor histologies included 164 malignant and 36 benign. One hundred thirty-three lesions (66%) had received prior conventional fractionated radiotherapy. Thirty-three lesions (16%) were intradural. Radiosurgery was used as a primary treatment modality in 60 cases (30%), for radiographic progression after prior conventional radiotherapy in 96 cases (48%), and adjuvant post-surgery therapy in 44 cases (22%). For each case, the maximum point dose to the spinal cord and/or cauda equina as well as the volume of those organs at risk receiving greater than 8, 10, and 12 Gy were recorded. No subacute or long term spinal cord or cauda equina toxicity occurred during the follow-up period (median 21 months). For cases at the level of the spinal cord (117 cases) the mean prescribed dose to the gross tumor volume (GTV) was 14 Gy (range 11-18 Gy). The GTV ranged from 0.37 to 100.24 cm3 (mean 26.1 cm3). The mean maximum point dose to the spinal cord was 10 Gy (range 4-12 Gy), and the mean spinal cord volumes (cm3) receiving greater than 8, 10, and 12 Gy were 0.76 (0-3.45), 0.05 (0-.42), and 0.0, respectively. For cases at the level of the cauda equina (83 cases) the mean prescribed dose to the GTV was 15 Gy (range 10-20 Gy). The GTV ranged from 0.19 to 491.6 cm3 (mean 73.8 cm3). The mean maximum point dose to the cauda equina was 11 Gy (range 5-14 Gy), and the mean cauda equina volumes (cm3) receiving greater than 8, 10, and 12 Gy were 1.4 (0-6.68), 0.26 (0-2.99), and 0.02 (0-.39), respectively. This study demonstrates that limiting the spinal cord dose to 10 Gy and the cauda equina dose to 11 Gy can be achieved with therapeutic GTV prescription doses for single fraction spine radiosurgery using CBCT guidance. Such dose constraints are associated with a safe clinical outcome.

Attempted depletion of passenger leukocytes by irradiation in pigs.

Allograft/xenograft rejection is associated with "passenger leukocyte" migration from the organ into recipient lymph nodes. In Study 1, we attempted to deplete leukocytes from potential kidney "donor" pigs, using two regimens of total body irradiation. A dose of 700 cGy was administered, followed by either 800 cGy ("low-dose") or 1,300 cGy ("high dose") with the kidneys shielded. Neither regimen was entirely successful in depleting all leukocytes, although remaining T and 8 cell numbers were negligible. Study 2 was aimed at providing an indication of whether near-complete depletion of leukocytes had any major impact on kidney allograft survival. In non-immunosuppressed recipient pigs, survival of a kidney from a donor that received high-dose irradiation was compared with that of a kidney taken from a non-irradiated donor. Kidney graft survival was 9 and 7 days, respectively, suggesting that depletion had little impact on graft survival. The lack of effect may have been related to (i) inadequate depletion of passenger leukocytes, thus not preventing a direct T cell response, (ii) the presence of dead or dying leukocytes (antigens), thus not preventing an indirect T cell response, or (iii) constitutive expression of MHC class II and B7 molecules on the porcine vascular endothelium, activating recipient T cells.

Prospective evaluation of a dedicated spine radiosurgery program using the Elekta Synergy S system.

OBJECT: Cone beam CT (CBCT) image guidance has recently been adopted for the delivery of spine radiosurgery. In 2007, the authors' institution began a dedicated spine radiosurgery program using the Elekta Synergy S system, which incorporates CBCT technology. In this study, the authors prospectively evaluated the Synergy S platform as a dedicated spine radiosurgery delivery system, including an evaluation of the accuracy of patient positioning using this technology, as part of a quality assurance program. METHODS: One hundred sixty-six spine and paraspinal lesions were treated using the Elekta Synergy S 6-MV LINAC with a beam modulator and CBCT image guidance combined with a HexaPOD couch that allows correction of patient positioning in 3 translational and 3 rotational directions. Stratifying the lesion by location, there were 28 cervical, 69 thoracic, 48 lumbar, and 21 sacral lesions. The most common histological types for the metastatic lesions (136 cases total) were breast, lung, sarcomas, and renal cells. The most common benign tumors (30 cases total) included 10 schwannomas, 5 neurofibromas, and 5 meningiomas. Twenty-eight lesions (17%) were intradural. To measure intratreatment patient movement, 3 quality assurance CBCTs were performed and recorded at separate times: immediately before treatment started; at the first third of the procedure; and at the second third of the procedure. The positioning data and fused images of the planning CT and CBCT were analyzed to determine intrafraction patient movements. From each of 3 quality assurance CBCT images, 3 translational and 3 rotational coordinates were obtained. RESULTS: The prescribed dose to the gross tumor volume, delivered in a single fraction, ranged from 12 to 20 Gy (mean 16 Gy) in this cohort. This dose was delivered by between 7 and 14 coplanar intensity-modulated radiation therapy beams (mean 9 beams). The gross tumor volumes ranged from 1.2 to 491.7 cm(3) (mean 39.2 cm(3)). Mean treatment time including setup was 64 minutes. At the first third of the treatment, the magnitude of the 3D translational vector (X, Y, Z) was 1.1 ± 0.7 mm. Similarly, the 3D translational vector at the second third of the treatment was 1.0 ± 0.6 mm. The means ± SDs of the rotational angles were 0.2° ± 0.4°, 0.4° ± 0.5°, and 0.3° ± 0.5° along yaw, roll, and pitch, respectively, at the first third of the treatment, and 0.2° ± 0.3°, 0.4° ± 0.5°, and 0.4° ± 0.5°, respectively, at the second third of the treatment. CONCLUSIONS: Single-fraction spine radiosurgery performed using the Synergy S platform and incorporating CBCT image guidance was determined to be feasible, accurate, and safe. This technique provides an overall translational position accuracy of < 2.0 mm.

Setup accuracy of spine radiosurgery using cone beam computed tomography image guidance in patients with spinal implants.

OBJECT: Cone beam computed tomography (CBCT) image guidance technology has been adopted for use in spine radiosurgery. There is concern regarding the ability to safely and accurately perform spine radiosurgery without the use of implanted fiducials for image guidance in postsurgical cases in which titanium instrumentation and/or methylmethacrylate (MMA) has been implanted. In this study the authors prospectively evaluated the accuracy of the patient setup for spine radiosurgery by using CBCT image guidance in the context of orthopedic hardware at the site of disease. METHODS: The positioning deviations of 31 single-fraction spine radiosurgery treatments in patients with spinal implants were prospectively evaluated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and CBCT image guidance combined with a robotic couch that allows positioning correction in 3 translational and 3 rotational directions. To measure patient movement, 3 quality-assurance CBCT studies were performed and recorded: before, halfway through, and after radiosurgical treatment. The positioning data and fused images of planning CTs and CBCTs from the treatments were analyzed to determine intrafractional patient movements. From each of 3 CBCTs, 3 translational and 3 rotational coordinates were obtained. RESULTS: The prescribed dose to the gross tumor volume for the cohort was 12-18 Gy (mean 14 Gy) utilizing 9-14 coplanar intensity-modulated radiation therapy (IMRT) beams (mean 10 beams). At the halfway point of the radiosurgery, the translational variations and standard deviations were 0.6 +/- 0.6, 0.4 +/- 0.4, and 0.5 +/- 0.5 mm in the lateral (X), longitudinal (Y), and anteroposterior (Z) directions, respectively. The magnitude of the 3D vector (X,Y,Z) was 1.1 +/- 0.7 mm. Similarly, the variations immediately after treatment were 0.5 +/- 0.3, 0.4 +/- 0.4, and 0.5 +/- 0.6 mm along the X, Y, and Z directions, respectively. The 3D vector was 1.0 +/- 0.6 mm. The mean rotational angles were 0.3 +/- 0.4, 0.5 +/- 0.6, and 0.3 +/- 0.4 degrees along yaw, roll, and pitch, respectively, at the halfway point and 0.3 +/- 0.4, 0.6 +/- 0.6, and 0.4 +/- 0.5 degrees immediately after treatment. CONCLUSIONS: Cone beam CT image guidance used for patient setup for spine radiosurgery was highly accurate despite the presence of spinal instrumentation and/or MMA at the level of the target volume. The presence of such spinal implants does not preclude safe treatment via spine radiosurgery in these patients.