The Role of Folate Deficiency as a Potential Risk Factor for Nontraumatic Anterior Spinal Artery Syndrome in an Adolescent Girl.

Nontraumatic anterior spinal artery syndrome (ASAS) is an extremely rare clinical condition in pediatric populations with a mostly unknown underlying etiology. Here we discuss the case of a previously healthy 14-year-old girl presenting with sudden onset acute flaccid paralysis to the emergency department. A spinal STIR/DWI MRI revealed hyperintensities extending from cervical vertebrae C3-6, consistent with the diagnosis of ASAS. In order to determine any precipitating causes of ASAS, we also extensively investigated established potential risk factors for ASAS in our patient and noticed that she had a marked folate deficiency requiring folic acid supplementation to prevent future episodes of ASAS as well as to repair the patient's injured spinal cord. Interestingly, the patient did not display elevated levels of homocysteine nor did she possess the three pathogenic MTHFR mutations characteristic of ASAS. Although her folate deficiency did not cause responsive hyperhomocysteinemia, and she did not have pathogenic MTHFR mutations that impair the function of methylenetetrahydrofolate reductase in folate cycle, we suggest that isolated folate deficiency may play a role in adolescent cases of ASAS that, once identified, would require prompt identification and early intervention to improve the prognosis of these patients.

TU-E-BRB-07: An EPID Based Dosimetric Verification Tool for SBRT with High Dose Rate FFF Beams.

PURPOSE: The increasing use of unflattened high dose rate and/or small sized fields in stereotactic body radiosurgery (SBRT) presents a significant challenge and calls for new tools for dosimetric measurements and quality assurance (QA). The purpose of this work is to investigate a high spatial resolution (0.2mm) and high frame rate (50Hz) amorphous silicon flat-panel electronic portal imaging device (EPID) from Perkin Elmer for SBRT. METHODS: A Monte Carlo N-Particle eXtended (MCNPX) simulation and convolution based calibration procedure has been developed to derive a voxel-based response function specific to the EPID construct and beam characteristics. Both standard photon beams and flattening filter free (FFF) beams of all energies from Varian TrueBeam STX were studied and the linearity and dose rate dependence were tested. EPID with detailed materials composition was simulated using the MCNPX to generate a scatter kernel composed of dose deposition in the EPID phosphor, and optical photon spreading and to deconvolve the EPID images to high spatial resolution photon fluence map. The fluence map was convolved with MCNPX generated kernels to the 3D dose distribution in the phantom and compared with pinpoint ion chamber and film measurements. RESULTS: EPID response showed excellent linearity (R2>0.9998) and dose rate dependence less than 1.8% for up to 2400MU/min. Output factors for field sizes ranging from 1×1 to 20×20cm2 were measured and used to fit the optical photon glare kernel. Fluence profiles deconvolved using MCNPX scattering kernel agrees with the measurements to within 2%. Results of typical pre-treatment QA test exhibit excellent spatial resolution required for SBRT. CONCLUSIONS: The high spatial resolution and high frame rate EPID proved to be an accurate and efficient tool for SBRT QA. Through convolution with MCNPX scattering core and comprehensive EPID calibration, accurate 3D dose maps can be generated for independent dosimetric verification of SBRT treatments.

Gamma knife radiosurgery for metastatic melanoma: an analysis of survival, outcome, and complications.

OBJECTIVE: Although the mainstays for treatment of metastatic brain disease have been surgery and/or external beam radiation therapy, an increasing number of patients are being referred for stereotactic radiosurgery as the primary intervention for their intracranial pathological abnormalities. The lack of efficacy and cognitive and behavioral consequences of whole brain irradiation have prompted clinicians to select patients for alternative therapies. This study analyzes the effectiveness of Leksell gamma unit therapy for metastatic melanoma to the brain. METHODS: We present our experience with 59 Leksell gamma unit treatment sessions in 45 consecutive patients who presented with metastatic melanoma to the brain. Five of these procedures were performed as salvage therapy for patients who needed second radiosurgical treatment for new lesions that were remote from the previous targets and were not included in the overall analyses. RESULTS: The population included 78% male patients. The mean patient age was 53 years (age range, 24-80 yr). The mean time from diagnosis of primary melanoma to discovery of brain metastasis was 43 months (median, 27.5 mo; range, 1-180 mo). At the time of diagnosis of brain disease, 35.5% of the patients (16 of 45 patients) had neurological symptoms, 77.7% (35 of 45 patients) had known visceral metastases, and 11.1% (5 of 45 patients) had seizure disorders. Eighty-six percent of the lesions (80 of 93 lesions) were cortical, 12% (11 of 93 lesions) were cerebellar, 1% (1 of 93 lesions) were pontine, and 1% (1 of 93 lesions) were thalamic. Fifty-seven percent of the sessions (31 of 54 sessions) were performed for a single lesion, 24.1% (13 of 54 sessions) for two lesions, 9.2% (5 of 54 sessions) for three lesions, 7.4% (4 of 54 sessions) for four lesions, and 1.8% (1 of 54 sessions) for five lesions. The mean treatment volume was 5.6 cc, with a mean prescription of 21.6 Gy to the 56.0% mean isodose line. The median survival time of the patients in our population, using Kaplan-Meier curves, was 43 months from the time of diagnosis of primary melanoma (range, 3-180 mo) and 8 months (range, 1-20 mo) from the time of gamma knife treatment. Complications included seizures within 24 hours of the procedure in four patients, with transient nausea and vomiting in three patients, transient worsening of preprocedure paresis responsive to steroids in three patients, and increased confusion in one patient. All 45 patients were located for follow-up (mean follow-up duration, 1 yr). After gamma knife treatment, 78% of the patients (35 of 45 patients) experienced either improved or stable neurological symptomatology before death or at the time of the latest follow-up examination. There were 26 deaths (58%). The cause of death was determined to be neurological in only 2 of 45 patients (7.7%). Follow-up magnetic resonance images revealed a 97% local tumor control rate of gamma knife-treated lesions, with 28% radiographic disappearance (9 of 32 cases). Six patients developed new lesions remote from radiosurgical targets and underwent second procedures. CONCLUSION: Although metastatic melanoma to the brain continues to have a foreboding prognosis for long-term survival, gamma knife radiosurgery seems to be a relatively safe, noninvasive, palliative therapy, halting or reversing neurological progression in 77.8% of treated patients (35 of 45 patients). The survival rate matches or exceeds those previously reported for surgery and other forms of radiotherapy. Only 7.7% of the patients in our study population who died as a result of metastatic melanoma (2 of 26 patients) died as a result of neurological disease. The routine use of therapeutic level antiseizure medication is emphasized, considering the findings of our review.

Episcleral plaque thermoradiotherapy of posterior uveal melanomas.

Episcleral plaque radiotherapy is a widely applied treatment for selected patients with uveal melanomas. This treatment is well tolerated but may produce severe late radiation complications resulting in decreased visual acuity that reduces the attractiveness of conservative therapy. The purpose of this study was to access if the addition of episcleral hyperthermia decreases late radiation complications through radiation dose reduction while maintaining high incidence of local tumor control. In a 3-year period, episcleral plaque thermoradiotherapy was given to 25 patients with uveal melanoma in a Phase I study. The mean tumor height was 6.2 mm and the mean tumor basal area was 173 mm(2). The mean radiation dose given to the tumor apex was 72.2 Gy and the mean hyperthermia temperature, given once for 45 min, was 43.5 degrees C. Of the 25 patients treated, 22 (88%) showed tumor height reduction, 2 (8%) showed no change, and 1 (4%) had an increase in tumor height. At the last follow-up (range, 20-68 months; mean, 31.2 months), a 43% mean tumor height reduction was recorded (p = 0.0002). Of the 22 patients initially showing tumor regression, 2 (9%) had subsequent tumor progression. At least ambulatory vision (>5/200) was maintained by 20 (80%) patients. Severe complications, including hemorrhagic retinal detachment and a large vitreous hemorrhage, were seen in 2 (8%) patients early in this Phase I study. The treatment program was well tolerated by the study patients. Severe late treatment toxicity was sharply reduced by limiting the mean scleral temperature to < or equal to 44 degrees C. This study employing 30% lower radiation doses, showed tumor regression in the majority of patients. Longer follow-up is needed to assess long-term treatment efficacy and late treatment complications.

Episcleral plaque thermoradiotherapy in patients with choroidal melanoma.

From 1988 to 1991, 21 patients with uveal melanoma were treated in a Phase I study with episcleral plaque radiotherapy (EPRT). This irradiation was combined with localized current field episcleral hyperthermia (LCFHT). Tumor stage was: T3 = 15 (71%) and T2 = 6 (29%). Follow-up ranged from 2 to 42 months (mean 9.2 months). EPRT was given using custom built I-125 gold plaques. Radiation doses to the tumor apex ranged from 13 to 123 Gy (mean dose 70.0 Gy) given at a mean dose rate of 55 cGy/hr. LCFHT was given with 500 KHz frequency for 45 min immediately before EPRT. The temperature was controlled on the scleral surface using four thermocouples. T mean ranged from 42.5 degrees C to 45 degrees C +/- 0.5 degrees C (mean 43.4 degrees C). The study patients showed rapid tumor necrosis. A 25% mean decrease of apical tumor dimension was noted, p = 0.0007. At least ambulatory vision (greater than 5/200) was maintained by 17/21 (81%) patients. Visual acuity was seen to improve greater than 6 months post-plaque therapy in 10 (48%) study patients. This was following an intermediate decrease in visual acuity. Severe complications, including large hemorrhagic retinal detachment and large vitreous hemorrhage, were seen in two (9.5%) of the early study patients. A mean scleral temperature reduction to less than or equal to 44 degrees C +/- 0.5 degrees C resulted in good treatment tolerance and a lack of serious complications in subsequently treated patients. A Phase II prospective randomized trial comparing LCFHT with 60 versus 80 Gy EPRT dose to the tumor apex is currently being activated for patients with choroidal melanoma.

Episcleral radioactive plaque therapy: initial clinical experience with 56 patients.

Between 1983 and 1987, 56 patients with choroidal melanoma were treated at the University of Southern California with episcleral plaque (RPT). There were 29 female and 27 male patients, with a mean age of 59 years. Tumor stage at diagnosis was T2 in 18 (32%) and T3 in 38 (68%) patients. The tumor height ranged from 2.9 to 15 mm (mean 6.8 mm). Radial dimensions ranged from 5 to 25 mm (mean 13.2 mm), and circumference ranged from 7 to 23 mm (mean 12.3 mm). Most (77%) patients had posteriorly located tumors, including 18% that were juxtapapillary. Custom-designed gold plaques were utilized in this study. Radioactive isotopes used were 125I for 26 procedures or 192Ir for 31 procedures. A total of 56 patients were treated, with one patient having two procedures. Radiation doses at the tumor apex ranged from 29.8 to 165.4 Gy (mean 94.5 Gy), with the dose at 5-mm depth ranging from 70.5 to 430 Gy (mean 161.5 Gy). Follow-up ranged from 29 to 57 months (mean 39 months). The overall 4-year survival was 96%, with a 91% incidence of free-of-disease progression at 4 years. The majority (84%) of patients experienced a decrease in tumor height, with 27 (48%) patients having greater than 50% decrease. Increase in tumor height was noted in 5 (9%) and no change in 4 (7%) patients. Useful vision (greater than 5/200) was observed in 59% of patients, including 21% who had improved vision. Metastatic tumor occurred in 5 (9%) patients, with a mean time to metastases of 14 months. There was a good correlation between radial tumor dimension and metastatic disease, p less than 0.001. Treatment complications were observed in 34 (61%) patients, with cataract and retinopathy being the most common. Enucleation was performed in 11 (20%) patients, with a mean time to enucleation of 14.5 months. Causative factors for enucleation were treatment complications in 6 and tumor progression in 5 patients. Enucleations were required primarily in patients with tumors greater than 8 mm in height (p = 0.009). Improved RPT techniques with three-dimensional dosimetry are needed to reduce the overall incidence of treatment complications. Adjuvant hyperthermia is being investigated in an attempt to improve tumor control in patients with larger tumors.

Deep regional hyperthermia of the liver. A clinical study of 49 patients.

From 1981 to 1986, six medical centers participated in feasibility studies of radiofrequency deep regional hyperthermia (HT) in the treatment of hepatic metastases. A total of 49 patients, 32 men and 17 women, were treated with an annular phased array. Colon was the primary site in 74% of the patients, and adenocarcinoma was the diagnosis in 80%. More than one half of the patients had been treated previously. This included chemotherapy (CT) in 17 patients and radiotherapy (RT) in 10 patients, with a mean RT dose of 24 Gy. Upper abdominal pain was the dominant presenting symptom in 53% of patients. In the study, treatment was administered as follows: 14 (28%) patients received HT alone, 17 (35%) received HT + RT, 14 (28%) received HT + CT, and 4 (8%) received HT + RT + CT. A total of 157 HT treatments was administered at a mean frequency of 55 MHz and a mean power of 780 watts. The number of HT sessions ranged from 1 to 8, with a mean of 3.2 treatments per patient. Temperature was monitored continuously throughout each treatment session. The treatment aim was to reach and maintain a temperature of 42.5 degrees C for 30 min. In practice, owing to the difficulty in reaching this temperature, an equivalent (lower) temperature from 40 to 42 degrees C was used, extending the duration of treatment sessions to 45-60 min. Thermal dose was defined as the number of minutes at 42.5 degrees C or its equivalent. In 21 (43%) patients, a temperature less than 40 degrees C was obtained and thermal dose = 0. Thermal dose was less than or equal to 50 in 17 (35%) patients, greater than 50 less than or equal to 100 in 7 (14%), and greater than 100 in 4 (8%). RT was given at a daily dose of 1.8 Gy to a total of less than 20 Gy in 14 patients, greater than 20 less than or equal to 30 Gy in 6, and greater than 30 Gy in 1. CT consisted of 5-Fluorouracil by way of Hepatic Artery Infusion (HAI) in 9 patients, i.v. cisplatin in 5, and doxorubicin HAI in 3. Objective tumor regression (CR + PR) was seen in 6 (12%) patients. An additional 10 (20%) patients had less than 50% greater than 25% tumor regression, and 10 (20%) had complete or partial pain relief. The median duration of CR and PR was 26 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Interstitial thermoradiotherapy for recurrent head and neck cancer.

From 1985 to 1987, 22 head and neck sites in 20 patients with recurrent tumors were treated with interstitial thermoradiotherapy (ITRT). The sites treated were 15 neck (68%), four tongue (18%), two parotid (9%), and one buccal mucosa (4%). Squamous cell carcinoma was diagnosed in 21 sites and adenocarcinoma in the other. All patients had prior radiotherapy (RT), including 15 who underwent a combination of RT and surgery. Interstitial RT with iridium 192 (mean dose, 40 Gy) was combined with interstitial microwave hyperthermia (mean thermal dose, 90 units). Complete response (CR) was obtained in 15 (68%) sites and partial response (PR) in seven (32%) sites. There were no local recurrences in the 15 CR patients during a period of observation of up to 30 months. Of the seven PR patients, one had radical neck dissection and is free of tumor after 28 months. Tumor volume was an important factor influencing CR (P less than .001), whereas RT and thermal dose were not (P = .3). Of the 20 patients treated, 19 experienced major subjective benefit. Serious complications occurred in two patients: one had localized soft tissue necrosis, the other had aspiration pneumonia. ITRT was well-tolerated by patients despite prior aggressive therapy. High objective response rate and low toxicity demonstrate the value of this treatment combination in the management of patients with postradiation recurrence of head and neck tumors.

The accuracy of temperature measurement from within an interstitial microwave antenna.

Temperature measurement from within microwave interstitial antennas is a promising new development for hyperthermia. These antennas could enable the development of multipoint temperature regulation, leading to improved control of temperature distributions and therefore more effective hyperthermia treatments. In the complex environment of an antenna within a plastic catheter, measured temperatures were found to differ from the estimated local tissue temperature by up to 8 degrees C. In the design evaluated in this report the primary source of this error appears to be self-heating distal to the antenna junction, particularly in the outer copper conductor. The magnitude of self-heating is directly proportional to applied microwave power. Catheter wall thickness, tissue perfusion, and longitudinal temperature gradient also influence the measured temperature.

Interstitial thermoradiotherapy for recurrent or persistent tumours.

Between 1984 and 1986, 31 sites in 27 patients with biopsy proven tumours were treated with a combination of interstitial microwave hyperthermia (HT) and iridium 192 implants (RT). The 31 sites treated included fifteen (48 per cent) head and neck, six (20 per cent) breast, four (13 per cent) vagina and cervix, and six (20 per cent) others. All patients had prior surgery, RT, or chemotherapy. Of the 31 sites treated, 19 (61 per cent) had complete response (CR) with no recurrence in the volume treated. Additionally, eight patients remained free of tumour from 3 to 24 months. Partial response (PR) was seen in 11 (36 per cent) sites while one (3 per cent) had lesser degree tumour regression. Tumour control rate correlated well with the dose of radiation, p = 0.02, and tumour volume, p = 0.02, but not with thermal dose. Treatment complications of significance occurred in one (3 per cent) site, which developed soft tissue necrosis. This study again has demonstrated the effectiveness of RT-HT combination in treatment of recurrent tumours.

Interstitial radiotherapy combined with interstitial hyperthermia in the management of recurrent tumors.

During a 2-year period 31 sites in 27 patients with recurrent, previously treated tumors received a combination of interstitial 192Ir radiation (RT) with microwave hyperthermia (HT). Head and neck sites were treated most frequently (48%), with breast and vagina each representing about 20% of sites. Complete response (CR) with no local recurrence was obtained in 61%, partial response (PR) in 11 (36%), and one (3%) had less than 50% tumor regression. Of these patients, nine had no evidence of tumor following HT-RT therapy, 8/18 in the CR group and 1/11 in the PR group. Significant factors influencing CR were: radiation dose, tumor volume and duration of tumor control following the initial therapy (p less than 0.02). Treated site, histology and thermal dose were not significant factors influencing tumor regression. Complications of significance developed in one patient who had local skin necrosis. Interstitial HT-RT combination provides an effective palliative therapy for recurrent and/or persistent tumors. Randomized trials are necessary to assess the effectiveness of this combination as a component part of primary management of selected tumors.

A 500 KHz localized current field hyperthermia system for use with ophthalmic plaque radiotherapy.

Ophthalmic plaque radiotherapy has been demonstrated to be a useful alternative to enucleation in the treatment of small choroidal melanomas. The prognosis for tumours larger than 8 mm in height, however, continues to be poor. Treatment complications limit the radiation dose which may be delivered to these larger tumours. Hyperthermia has been shown to enhance the effectiveness of radiotherapy for many tumours, particularly malignant melanoma. The use of hyperthermia in conjunction with plaque radiotherapy may improve local tumour control for larger choroidal melanomas, allowing patients to maintain useful vision. We have developed an instrument which enables the combination of localized current field hyperthermia with radiotherapy using an episcleral plaque. The system is simple and inexpensive. We have measured temperature distributions in tissue-like phantoms, in excised bovine eyes, and in vivo in normal rabbits. In each of the cases studied, temperature varied by less than 1 degree C within 3 mm of, and across the concave surface of the plaque. At distances greater than 3 mm, the temperature gradient was approximately -0.3 degree C per millimetre.