Influence of beam efficiency through the patient-specific collimator on secondary neutron dose equivalent in double scattering and uniform scanning modes of proton therapy.

PURPOSE: Conventional proton therapy facilities use double scattering nozzles, which are optimized for delivery of a few fixed field sizes. Similarly, uniform scanning nozzles are commissioned for a limited number of field sizes. However, cases invariably occur where the treatment field is significantly different from these fixed field sizes. The purpose of this work was to determine the impact of the radiation field conformity to the patient-specific collimator on the secondary neutron dose equivalent. METHODS: Using a WENDI-II neutron detector, the authors experimentally investigated how the neutron dose equivalent at a particular point of interest varied with different collimator sizes, while the beam spreading was kept constant. The measurements were performed for different modes of dose delivery in proton therapy, all of which are available at the Midwest Proton Radiotherapy Institute (MPRI): Double scattering, uniform scanning delivering rectangular fields, and uniform scanning delivering circular fields. The authors also studied how the neutron dose equivalent changes when one changes the amplitudes of the scanned field for a fixed collimator size. RESULTS: The secondary neutron dose equivalent was found to decrease linearly with the collimator area for all methods of dose delivery. The relative values of the neutron dose equivalent for a collimator with a 5 cm diameter opening using 88 MeV protons were 1.0 for the double scattering field, 0.76 for rectangular uniform field, and 0.6 for the circular uniform field. Furthermore, when a single circle wobbling was optimized for delivery of a uniform field 5 cm in diameter, the secondary neutron dose equivalent was reduced by a factor of 6 compared to the double scattering nozzle. Additionally, when the collimator size was kept constant, the neutron dose equivalent at the given point of interest increased linearly with the area of the scanned proton beam. CONCLUSIONS: The results of these experiments suggest that the patient-specific collimator is a significant contributor to the secondary neutron dose equivalent to a distant organ at risk. Improving conformity of the radiation field to the patient-specific collimator can significantly reduce secondary neutron dose equivalent to the patient. Therefore, it is important to increase the number of available generic field sizes in double scattering systems as well as in uniform scanning nozzles.

Multi-modality imaging of uveal melanomas using combined PET/CT, high-resolution PET and MR imaging.

UNLABELLED: We investigated the efficacy of combined FDG-PET/CT imaging for the diagnosis of small-size uveal melanomas and the feasibility of combining separate, high-resolution (HR) FDG-PET with MRI for its improved localization and detection. PATIENTS, METHODS: 3 patients with small-size uveal melanomas (0.2-1.5 ml) were imaged on a combined whole-body PET/CT, a HR brain-PET, and a 1.5 T MRI. Static, contrast-enhanced FDG-PET/CT imaging was performed of head and torso with CT contrast enhancement. HR PET imaging was performed in dynamic mode 0-180 min post-injection of FDG. MRI imaging was performed using a high-resolution small-loop-coil placed over the eye in question with T2-3D-TSE and T1-3D-SE with 18 ml Gd-contrast. Patients had their eyes shaded during the scans. Lesion visibility on high-resolution FDG-PET images was graded for confidence: 1: none, 2: suggestive, 3: clear. Mean tumour activity was calculated for summed image frames that resulted in confidence grades 2 and 3. Whole-body FDG-PET/CT images were reviewed for lesions. PET-MRI and PET/CT-MRI images of the head were co-registered for potentially improved lesion delineation. RESULTS: Whole-body FDG-PET/CT images of 3/3 patients were positive for uveal melanomas and negative for disseminated disease. HR FDG-PET was positive already in the early time frames. One patient exhibited rising tumour activity with increasing uptake time on FDG-PET. MRI images of the eye were co-registered successfully to FDG-PET/CT using a manual alignment approach. CONCLUSIONS: Small-size uveal melanomas can be detected with whole-body FDG-PET/CT. This feasibility study suggests the exploration of HR FDG-PET in order to provide additional diagnostic information on patients with uveal melanomas. First results support extended uptake times and high-sensitivity PET for improved tumour visibility. MRI/PET co-registration is feasible and provides correlated functional and anatomical information that may support alternative therapy regimens.

Vectors for efficient expression in mammalian fibroblastoid, myeloid and lymphoid cells via transfection or infection.

We have constructed two related types of multi-cloning mammalian expression vectors. The first, pMPSVEH/HE, carries the promoter of the myeloproliferative sarcoma virus (MPSV). This promoter was found to be stronger than both the SV40 early and the trans-activated human immunodeficiency virus promoters in many cell lines including human and rodent fibroblastoid, lymphoid or myeloid cells. The other, pBEH/HE, carries the simian virus 40 (SV40) early promoter and origin of replication. This offers the possibility of encapsidation in SV40 pseudovirions and subsequent gene transfer into, e.g., hemopoietic cells, via infection. The usefulness of the expression systems was tested with a number of genes and cell lines.

Locally challenging osteo- and chondrogenic tumors of the axial skeleton: results of combined proton and photon radiation therapy using three-dimensional treatment planning.

PURPOSE: Tumors of the axial skeleton are at high risk for local failure. Total surgical resection is rarely possible. Critical normal tissues limit the efficacy of conventional photon therapy. This study reviews our experience of using combined high dose proton and photon radiation therapy following three-dimensional (3D) treatment planning. METHODS AND MATERIALS: Between December 1980 and September 1992, 47 patients were treated at the Massachusetts General Hospital and Harvard Cyclotron Laboratory for primary or recurrent chordomas and chondrosarcomas (group 1, 20 patients), osteogenic sarcomas (group 2, 15 patients) and giant cell tumors, osteo-or chondroblastomas (group 3, 12 patients). Radiation treatment was given postoperatively in 23 patients, pre- and postoperatively in 17 patients, and 7 patients received radiation therapy as definitive treatment modality following biopsy only. The proton radiation component was delivered using a 160 MeV proton beam and the photon component using megavoltage photons up to 23 MV energy with 1.8-2.0 Cobalt Gray Equivalent (CGE) per fraction, once a day. Total external beam target dose ranged from 55.3 CGE to 82.0 CGE with mean target doses of 73.9 CGE (group 1), 69.8 CGE (group 2), and 61.8 CGE (group 3). RESULTS: Group 1 (chordoma and chondrosarcoma): Five of 14 patients (36%) with chordoma recurred locally, and 2 out of 5 patients developed distant metastasis, resulting in 1 death from disease. A trend for improved local control was noted for primary vs. recurrent tumors, target doses > 77 CGE and gross total resection. All patients with chondrosarcoma achieved and maintained local control and disease-free status. Five-year actuarial local control and overall survival rates were 53% and 50% for chordomas and 100% and 100% for chondrosarcomas, respectively. Group 2 (osteogenic sarcoma): Three of 15 patients (20%) never achieved local control and died within 6 months of completion of radiation treatment. Only 1 out of 12 patients who were controlled for more than 6 months failed locally, yielding a 5-year local control rate of 59% for 15 patients. Overall, 4 patients (27%) developed distant metastasis (two in patients with uncontrolled primary); 4 patients succumbed to their disease, 3 patients died of intercurrent disease, resulting in overall survival of 44% at 5 years. Group 3 (giant cell tumors, osteo- and chondroblastoma): One of 8 patients with giant cell tumor failed locally, 1 patient distantly, and all patients are alive. Three of 4 patients with osteo- or chondroblastoma are alive and well. One patient suffered local recurrence and died of disease. Local control rate and overall survival for this group of 12 patients was 76% and 87% and local control for patients with giant cell tumors 83% at 5 years. In the majority of cases radiotherapy was well tolerated. However, one patient with a large base of skull tumor developed retinopathy, one patient required enucleation of a previously blind eye, and another patient with sacral tumor developed chronic diarrhea. CONCLUSION: Combined proton and photon radiation therapy optimized by 3D treatment planning, allows the delivery of higher radiation doses to tumors of the axial skeleton, while respecting normal tissue constraints. High radiation doses can result in improved long-term local control.

Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: a novel technique.

PURPOSE: Most children with orbital rhabdomyosarcoma will survive their disease. However, conventional photon-radiation treatment, as part of multimodality therapy, results in varying degrees of long-term functional and cosmetic side effects. This report introduces external beam proton radiation therapy (PRT) as a conformal, three-dimensional planned radiation technique for this disease, analyzes normal tissue dosimetry, and describes the technique's application in the first 2 patients. MATERIAL AND METHODS: Between January 1995 and February 1996, 2 patients underwent PRT following biopsy and chemotherapy for orbital rhabdomyosarcoma. Fifty and 55 Cobalt Gray Equivalent (CGE) were delivered to the gross tumor volume and 40 CGE to clinical target volumes in both patients. A relative biologic effectiveness (RBE) of 1.1 was utilized to correlate proton dose calculations with CGE. To achieve dose conformity, a "patch technique" was utilized, where target regions were divided into segments, each treated by a separate proton field. Dose-volume histograms were obtained for target and nontarget regions, including lens, bony orbit, pituitary gland, optic chiasm, optic nerves, lacrimal gland, and ipsilateral frontal and temporal lobes. RESULTS: At 3.4 and 2.5 years after PRT, both patients are clinically and radiographically free of disease. Visual acuity remains excellent, without signs of cataract formation; pituitary function is normal; cosmetically, only mild enophthalmos is noticeable. Doses to 90%, 50%, and 5% of lens volume were kept at less than 1%, less than 2%, and less than 8%, respectively. Fifty percent of lacrimal gland volume received less than 36% of the prescribed dose and 50% of the volume of the optic chiasm, pituitary gland, and hypothalamus were restricted to less than 2%. Proton conformity to orbital contents resulted in between 9% and 36% of the prescribed dose reaching the ipsilateral temporal and frontal lobes immediately adjacent to bony orbit (5% volume). CONCLUSION: PRT can offer excellent sparing of lens and selected intraorbital and ocular normal structures, while maintaining conformal target-dose coverage. The steep dose gradient beyond the orbit minimizes irradiation of normal brain parenchyma, with almost complete sparing of the pituitary gland. Reduction of integral irradiation exposure of the periorbital region will, hopefully, reduce the risk of second malignancy later in life. Reduced radiation dose to specific organs in close proximity to, but not part of the target region promises improved functional outcome and better cosmesis for childhood cancer survivors.

Dose-escalation with proton/photon irradiation for Daumas-Duport lower-grade glioma: results of an institutional phase I/II trial.

PURPOSE: The role of dose escalation with proton/photon radiotherapy in lower-grade gliomas was assessed in a prospective Phase I/II trial. We report the results in terms of local control, toxicity, and survival. MATERIALS AND METHODS: Twenty patients with Grade 2/4 (n = 7) and Grade 3/4 (n = 13) gliomas according to the Daumas-Duport classification were treated on a prospective institutional protocol at Massachusetts General Hospital/Harvard Cyclotron Laboratory between 1993 and 1996. Doses prescribed to the target volumes were 68.2 cobalt Gray equivalent (CGE, 1 proton Gray = 1.1 CGE) to gross tumor in Grade 2 lesions and 79.7 CGE in Grade 3 lesions. Fractionation was conventional, with 1.8 to 1.92 CGE once per day. Eligibility criteria included age between 18 and 70 years, biopsy-proven Daumas-Duport Grade 2/4 or 3/4 malignant glioma, Karnofsky performance score of 70 or greater, and supratentorial tumor. Median age of the patient population at diagnosis was 35.9 years (range 19-49). Ten tumors were mixed gliomas, one an oligodendroglioma. RESULTS: Five patients underwent biopsy, 12 a subtotal resection, and 3 a gross total resection. Median interval from surgery to first radiation treatment was 2.9 months. Actuarial 5-year survival rate for Grade 2 lesions was 71% as calculated from diagnosis (median survival not yet reached); actuarial 5-year survival for Grade 3 lesions was 23% (median 29 months). Median follow-up is 61 months and 55 months for 4 patients alive with Grade 2 and 3 patients alive with Grade 3 lesions, respectively. Three patients with Grade 2 lesions died from tumor recurrence, whereas 2 of the 4 survivors have evidence of radiation necrosis. Eight of 10 patients who have died with Grade 3 lesions died from tumor recurrence, 1 from pulmonary embolus, and 1 most likely from radiation necrosis. One of 3 survivors in this group has evidence of radiation necrosis. CONCLUSION: Tumor recurrence was neither prevented nor noticeably delayed in our patients relative to published series on photon irradiation. Dose escalation using this fractionation scheme and total dose delivered failed to improve outcome for patients with Grade 2 and 3 gliomas.

Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma.

Conventional chondrosarcoma (CSA) of the skull base is an uncommon neoplasm that can resemble chordoma, and indeed it is misdiagnosed frequently as such. This has important clinical implications, because when treated with similar aggressive treatment strategies, CSA has a much better prognosis than chordoma. In an effort to identify those morphologic and immunohistochemical features that help to identify conventional skull base CSA correctly and to understand its prognosis better, particularly compared with chordoma, when treated with surgery and proton beam irradiation, the authors performed a clinicopathologic analysis of 200 CSAs. The patients ranged in age from 10 to 79 years (mean, 39 years), 87 patients were male and 113 patients were female, and most presented with symptoms related to the central nervous system. Approximately 6% of the tumors arose in the sphenoethmoid complex, 28% originated in the clivus, and 66% developed in the temperooccipital junction. Histologically, 15 tumors (7.5%) were classified as hyaline CSA, 59 (29.5%) as myxoid CSA, and 126 (63%) as mixed hyaline and myxoid CSA. A total of 101 (50.5%) tumors were grade 1, 57 (28.5%) had areas of grades 1 and 2, and 42 (21%) were pure grade 2 neoplasms. The vast majority of patients originated from referring hospitals, and the diagnosis was changed prospectively at our institution to CSA from chordoma in 74 patients (37%). Of the tumors studied immunohistochemically, 96 of 97 (98.9%) stained for S-100 protein, 0 of 97 (0%) stained for keratin, and faint staining for epithelial membrane antigen was seen in 7 of 88 tumors (7.95%). All patients underwent high-dose postoperative fractionated precision conformal radiation therapy with a dose that ranged from 64.2 to 79.6 Cobalt-Gray-equivalents (median, 72.1 Cobalt-Gray-equivalents, given in 38 fractions. The 200 patients had a median follow-up of 63 months (range, 2.1 mos - 18.5 yrs). Tumor control was defined as lack of progression by clinical and radiographic assessment. Based on this definition, there were three local recurrences, and two of these patients died of tumor-related complications. The 5- and 10-year local control rates were 99% and 98% respectively, and the 5- and 10-year disease-specific survival rates were both 99%. In contrast to CSA, the 5- and 10-year survival rates of chordoma have been reported to be approximately 51 % and 35% respectively, and in our institution intensive treatment has resulted in 5- and 10-year progression-free survival rates of 70% and 45% respectively. CSA of the skull base can be distinguished reliably from chordoma, and this distinction is important because skull base CSA has an excellent prognosis when treated with surgery and proton beam irradiation, whereas chordomas have a substantially poorer clinical course despite similar aggressive management.

His+ reversions caused in Salmonella typhimurium by different types of ionizing radiation.

The yield of his+ reversions in the Ames Salmonella tester strain TA2638 has been determined for 60Co gamma rays, 140 kV X rays, 5.4 keV characteristic X rays, 2.2 MeV protons, 3.1 MeV alpha particles, and 18 MeV/U Fe ions. Inactivation studies were performed with the same radiations. For both mutation and inactivation, the maximum effectiveness per unit absorbed dose was obtained for the characteristic X rays, which have a dose averaged linear energy transfer (LET) of roughly 10 keV/micron. The ratio of the effectiveness of this radiation to gamma rays was 2 for inactivation and about 1.4 for the his+ reversion. For both end points the effectiveness decreases substantially at high LET, i.e., for the alpha particles and the Fe ions. The composition of the bottom and the top agar was the one recommended by Maron and Ames [Mutat. Res. 113, 173-215 (1983)] for application in chemical mutagenicity tests. The experiments with the less penetrating radiations differed from the usual protocol by utilization of a technique of plating the bacteria on the surface of the top agar. As in an earlier study [Roos et al., Radiat. Res. 104, 102-108 (1985)] greatly enhanced yields of mutations, relative to the spontaneous reversion rate, were obtained in these experiments by performing the irradiations 6 h after plating, which differs from the conventional procedure to irradiate the bacteria shortly after plating.

Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial.

OBJECT: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival. METHODS: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18%, respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p = 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume. CONCLUSIONS: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis.

Clonal heterogeneity in delayed decrease of plating efficiency of irradiated HeLa cells.

The clonogenic potential of progeny of irradiated HeLa cells was studied at different times after single doses of 4-12 Gy. The dose-dependent decrease in plating efficiency that was observed resembled the effect termed "delayed lethal mutation" by Seymour et al. (1986). The effect decreased with time after irradiation. Individual clones of irradiated and non-irradiated cells were isolated, expanded and replated 5 weeks after irradiation, i.e., after between 200,000 and 1,000,000 progeny had formed from the individual parent cell. The plating efficiency of progeny of unirradiated cells did not vary much, whereas clonal progeny of irradiated cells had plating efficiencies ranging from 3% to 76%. The plating efficiency was not related to the cell number in the original clone.

Serum markers for primary and recurrent breast cancer: BCM-EIA, CAM 26 and CAM 29.

Three sandwich enzyme immunoassays were used to evaluate serum from 93 women: 20 normal, 20 with benign breast disease, 22 with primary and 31 with recurrent breast cancer. Using the three assays, breast cancer mucin enzyme immunoassay (BCM-EIA) carcinoma-associated mucin antigen (CAM) 26 and CAM 29, both singly and in combination, we were unable to establish meaningful cut-offs to differentiate between patients with or without breast cancer. The sensitivity and specificity for BCM-EIA were 90% and 40%, for CAM 26, 89% and 42%, and for CAM 29, 91% and 66%, respectively. Serial serum specimens from 29 patients with recurrent breast cancer were assayed. At recurrence, an increase of 25% or more in marker level over the previous value was found in 24/29 (83%) BCM results, 14/29 (48%) CAM 26 results and 12/29 (41%) CAM 29 results. Prior to clinical detection of recurrence, stepwise increases in BCM and CAM 26 marker levels were seen up to 299 days prior to clinical detection of recurrence. We conclude that these markers may help in the early detection of recurrent breast cancer.