[en] Purpose: Increasing evidence suggests that signaling mediated by the epidermal growth factor receptor (EGFR) pathway contributes to radiation resistance. The anti-EGFR monoclonal antibody, C225, has been shown to enhance radiation response for several tumor types in preclinical models. Malignant gliomas are known to express, and quite frequently overexpress, EGFR. Our objectives in this study were to 1) Evaluate the efficacy of C225 as a radiation response modifier in EGFR-expressing glioma cell lines and to 2) Investigate the underlying molecular mechanisms mediating C225-induced enhancement of radiation response. Materials and Methods: Twelve EGFR-expressing glioma cells lines, established from patient tumors, were used for this study. Cells were incubated with C225, irradiated, and then evaluated for radiation response. Assays used to evaluate efficacy of C225-mediated radiosensitization included time-course apoptosis assays (Annexin V and TUNEL), viability assays (MTT), and clonogenic survival assays. The changes along MAPK (p44/p42)/JNK/p38-MAPK signal transduction pathways were then investigated using quantitative Western analysis with phospho-specific antibodies to determine the molecular mechanisms by which C225 mediates a given response. Results: C225 clearly enhanced radiation response for 7 of the 12 primary glioma cell lines studied. Enhancement of both immediate and delayed apoptotic responses was evident in these 7 responsive cell lines after C225 administration. The average apoptosis index at 6 hours post-RT+C225 for the 7 responsive lines was 9.5%, compared to 1.2% for the RT-only controls. A pattern of delayed apoptosis was evident in these 7 lines, with secondary apoptotic peaks (∼ 8.0%) occurring at 24 hours post-RT+C225. Time course viability measurements revealed a steady decrease in viable tumor cells in these responsive cell lines from 75% at 6 hours post-RT+C225 to 20% at 7 days. Clonogenic survival was also diminished in these 7 lines after C225 + RT compared to lines treated by RT alone (D0=2.0 vs. 2.8, respectively). The other 5 of 12 glioma cell lines demonstrated resistance to C225-mediated radiosensitization. Treatment of these 5 cell lines by combined RT + C225 failed to result in any enhancement of apoptosis or reduction in clonogenic survival compared to RT alone. C225 demonstrated distinct effects on the signaling pathways of responsive vs. resistant glioma cell lines. All 12 glioma cell lines demonstrated reduced levels of phospho-EGFR, demonstrating antagonism of EGFR by C225. JNK and p38 activation states, as measured by quantitative Western analysis using phospho-specific antibodies, were enhanced by 2.5-3.0 fold in the 7 responsive cell lines after RT + C225, compared to no measurable induction in the 5 resistant lines. The absence of JNK/p38 activation in the 5 resistant lines was reflected by a concomitant absence of phospho-MKK4 and MKK 3/6 induction after RT + C225, implying the presence of signaling deficits further upstream of JNK/p38 not directly regulated by EGFR activity. MAPK activity (p44/p42) was reduced 1.5-2.0 fold in the responsive lines compared to a more modest 0.5 fold in the resistant lines. Conclusion: C225 appears to enhance radiation response of a distinct subset of primary glioma cell lines through activation of JNK/p38 pathways and downregulation of signaling through MAPK. However, EGFR-expressing glioma cell lines resistant to C225-mediated enhancement of radiation-induced apoptosis demonstrated MAPK/JNK/p38 signaling that was not as directly impacted by inhibition of EGFR. It is critical to better understand the upstream signals mediating activation of these pathways to develop more effective strategies for enhancing radiation response

[en] A primary tumor arising in the hand or foot represents an uncommon presentation for patients with Ewing's sarcoma (ES) or soft tissue sarcoma (STS). While there exists considerable literature on the treatment of extremity sarcomas, very little deals specifically with lesions of the hand or foot. It remains controversial whether these lesions can be successfully treated with combined modality therapy which preserves the extremity and maintains function. From 1972 to 1979, 10 patients with sarcomas arising in the hand or foot were treated with combined modality therapy at the National Cancer Institute. Seven patients with ES of bone received local irradiation to 5000 rad and combination chemotherapy following an incisional biopsy. Three patients with STS received a gross tumor excision and local irradiation to 6000 rad. Local control was achieved in nine patients (90%) with a follow-up of 30 to 119 months (median 56 months). These patients have complete or almost complete function of the treated extremity. Nine patients are alive with five patients remaining disease-free following the initial combined modality treatment. We conclude that for selected patients with sarcomas arising in the hand or foot, combined modality therapy which leaves the extremity intact results in excellent local tumor control and preserves function. Careful treatment planning is an essential aspect of successful radiation therapy of a hand or foot primary. Our treatment recommendations are outlined. This approach is a viable alternative to amputation in these patients

[en] With the availability of gamma knife units and the development of modified linear accelerators, there is new interest in radiosurgery, especially as it applies to intracranial tumors. Among its advantages are the ability to precisely localize tumor and through small beam sizes deliver steep dose gradients at the field edges. This sharp dose gradient allows for the prescribed dose of radiation to be given to a tumor while avoiding vital structures only millimeters away. Radiosurgery has produced good results in the treatment of inoperable arteriovenous malformations and can be used as the sole curative therapy for small, radiographically distinct, benign noninvasive tumors. It is also used as salvage therapy in recurrent benign or malignant tumors that have previously been irradiated

[en] Radiation-related thyroid dysfunction is a common occurrence in patients with Hodgkin's disease treated with mantle field radiation. Although chemical and clinical hypothyroidism are most commonly seen, Graves' disease has also been described. We have examined the records of 437 surgically staged patients who received mantle field irradiation between April 1969 and December 1980 to ascertain the frequency of manifestations of Graves' disease. Within this group, seven patients developed hyperthyroidism accompanied by ophthalmic findings typical of those seen in Graves' disease. The actuarial risk of developing Graves' disease at 10 years following mantle irradiation for Hodgkin's disease was 3.3% in female patients and 1% in male patients in this study. The observed/expected ratios were 5.9 and 5.1 for female and male patients, respectively. This observed risk significantly exceeded that seen in the general population

[en] From 1986 to 1988, 44 patients have been treated for tumors or vascular lesions with stereotactic radiosurgery using a modified standard linear accelerator. In seven patients, nausea and vomiting occurred within 6 hours after the completion of radiosurgery. One of these patients with nausea and occasional vomiting pretreatment had exacerbation several hours after treatment, in spite of droperidol and prochlorperazine prophylaxis. Nausea and vomiting in the other six patients was self-limited and was completely resolved by 12 hours from onset. None of these six patients suffered from nausea and vomiting before treatment. This was directly correlated with the total dose to the vomiting center in the floor of the fourth ventricle (area postrema). The median dose to the vomiting center in the seven patients was 618 cGy (range 275-1257). The final patient in the series received 1088 cGy to the area postrema after droperidol and dexamethasone prophylaxis without developing nausea or vomiting. In the remaining 36 patients who received from less than 5 to 184 cGy to area postrema, nausea and vomiting did not occur. We recommend that patients treated with large fractions of radiation by radiosurgery in this area be premedicated appropriately

[en] This work assesses the relative field shaping advantages of dynamic field shaping devices for stereotactic radiosurgery using a linear accelerator. The authors modeled five field shaping devices, each including a fixed auxilliary circular collimator: (a) fixed circular collimator alone; (b) two independent parallel jaws; (c) four independent rectangular jaws; (d) four independent rotable jaws; and (e) ideal multileaf collimator. They adjusted the model parameters until the minimum target isodose was 80% of the dose delivered to isocenter. They defined the treatment volume ratio as the target volume divided by the treatment volume (volume receiving at least the minimum target dose). They used the treatment volume ratio to compare the five models and the actual patient treatments. For 34 tumors originally treated with one isocenter, the median Treatment Volume Ratio was higher for all of the device models except the fixed circular collimator compared to the actual patient treatments. For the nine tumors originally treated with multiple isocenters, the median Treatment Volume Ratio for the actual multiple isocenter treatments was similar to that for two parallel jaws, four rectangular jaws and four rotatable jaws. Only the median ideal collimator treatment volume ratio was higher for these nine tumors. Simple field shaping devices have approximately 50% of the conformal advantage of an open-quotes idealclose quotes multileaf collimator. Approximately 50% of typical radiosurgical tumors between 2 and 4 cm have field shaping advantages which exceed the geometrical uncertainties inherent in linear accelerator radiosurgery treatments. The three models, two parallel, four rectangular, or four rotatable independent jaws would improve current linear accelerator technology by providing homogeneous doses with equivalent field shaping for most tumors originally treated with inhomogeneous multiple isocenter plans (6/9 tumors in the current series). 26 refs., 5 figs., 3 tabs

[en] Primary lymphomas of the CNS are rare tumors accounting for less than 2% of all extranodal non-Hodgkin's lymphomas. The treatment for this disease has been disappointing. Radiation therapy and surgery have produced consistently poor control of this disease, with a median survival of 15 months. A review of ten cases of primary lymphoma of the CNS treated at the Joint Center for Radiation Therapy or Dana-Farber Cancer Institute (Boston) from 1968 to 1981 is presented. All patients had biopsy- proven CNS lymphomas without systemic disease at presentation. In this series, control of CNS lymphoma was seen only in patients receiving craniospinal radiation or CNS-penetrating chemotherapy

[en] Sequential thallium-201-chloride and technetium-99m-hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) images were obtained in a patient with extracranial metastatic glioblastoma multiforme. Thallium-201 uptake was high (three times the scalp background) in all pathologically confirmed extracranial metastases and moderate (1.6 times scalp background) intracranially, where most biopsy specimens showed gliosis with scattered atypical astrocytes. Technetium-99m-HMPAO uptake was decreased intracranially in the right frontal and parietal lobes which had been irradiated. It was also decreased in one well-encapsulated scalp lesion and high in another scalp mass with less defined borders. Possible mechanisms of tumor uptake of these agents are reviewed

[en] A method for registering three-dimensional CT, MR, and PET data sets that require no special patient immobilization or other precise positioning measures was adapted to high-resolution SPECT and MRI and was applied in 14 subjects [five normal volunteers, four patients with dementia (Alzheimer's disease), two patients with recurrent glioblastoma, and three patients with focal lesions (stroke, arachnoid cyst and head trauma)]. T2-weighted axial magnetic resonance images and transaxial 99mTc-HMPAO and 201Tl images acquired with an annular gamma camera were merged using an objective registration (translation, rotation and rescaling) program. In the normal subjects and patients with dementia and focal lesions, focal areas of high uptake corresponded to gray matter structures. Focal lesions observed on MRI corresponded to perfusion defects on SPECT. In the patients who had undergone surgical resection of glioblastoma followed by interstitial brachytherapy, increased 201Tl corresponding to recurrent tumor could be localized from the superimposed images. The method was evaluated by measuring the residuals in all subjects and translational errors due to superimposition of deep structures in the 12 subjects with normal thalamic anatomy and 99mTc-HMPAO uptake. This method for superimposing magnetic resonance and high-resolution SPECT images of the brain is a useful technique for correlating regional function with brain anatomy

[en] Between May 1986 and August 1989, we treated 18 patients with 21 recurrent or persistent brain metastases with stereotactic radiosurgery using a modified linear accelerator. To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. The most common histology of the metastatic lesion was carcinoma of the lung (seven patients), followed by carcinoma of the breast (four patients), and melanoma (four patients). With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy