The HLA system in the families of patients with juvenile diabetes mellitus.

The HLA and Bf genotypes were determined in 10 families with one or more children with JDM. A statistically significant association was found between HLA-D-identity and the chance to present JDM within a sibship. No such association was detectable with the SD antigens. A highly significant increase in the frequency of intra-HLA recombination was also found in these families.

Modification of sister chromatid exchanges and radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids.

Modification of sister chromatid exchanges and radiation-induced transformation in mouse C3H/10T 1/2 and Syrian hamster embryo cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, the trimethylmethoxyphenyl analog of N-ethyl retinamide and beta-all-trans-retinoic acid, has been studied. 12-O-tetradecanoylphorbol-13-acetate alone enhances, and retinoids alone reduce radiation-induced transformation. When both compounds were present, the retinoids not only reduced the oncogenic effects of radiation but completely eliminated the promoting effects of 12-O-tetradecanoylphorbol-13-acetate. These results were not paralleled by changes in sister chromatid exchange frequencies, indicating that, while sister chromatid exchanges may be useful as indicators of primary carcinogen mutagens, they may have little utility when secondary agents after the response of cells to a primary initiator.

Transforming growth factor-beta improves healing of radiation-impaired wounds.

Exogenously applied TGF-beta 1 has been shown to increase wound strength in incisional wounds early in the healing process. An impaired wound healing model was first established in guinea pigs by isolating flaps of skin and irradiating the flaps to 15 Gray in one fraction using a 4-MeV linear accelerator. Incisions made 2 d after irradiation were excised 7 d later, and showed decreased linear wound bursting strength (WBS) as compared to non-irradiated control wounds on the contralateral side of each animal (p = 0.001). The effect of TGF-beta on healing of radiation-impaired wounds was studied using this model. Skin on both left and right sides of guinea pigs was irradiated as above. A linear incision was made in each side. Collagen with either 1, 5, or 20 micrograms of TGF-beta was applied to one side prior to closure with staples, whereas the contralateral side received saline in collagen. Wounds given either 1 or 5 micrograms of TGF-beta were found to be stronger than controls at 7 d (p less than 0.05), whereas those receiving the higher 20-micrograms dose were weaker than controls (p less than 0.05). Thus, TGF-beta in lower doses improved healing at 7 d but very large amounts of the growth factor actually impaired healing. In situ hybridization done on wound samples showed increased type I collagen gene expression by fibroblasts in wounds treated with 1 micrograms TGF-beta over control wounds. These results indicate that TGF-beta improved wound healing as demonstrated by increased WBS. This improvement is accompanied by an up-regulation of collagen gene expression by resident fibroblasts.

Dosimetric considerations in radiation therapy of coin lesions of the lung.

PURPOSE: The dose distribution in small lung lesions (coin lesions) is determined by the combined effects of reduced attenuation and electronic disequilibrium. The magnitude of the dose delivered also depends on the algorithm used to correct for reduced lung density. These effects are investigated experimentally and computationally for 10 MV photons. METHODS AND MATERIALS: Using a polystyrene miniphantom embedded in cork or cedar, thermoluminescent dosimetry and film dosimetry was performed to investigate interface effects and the central dose per monitor unit (MU). Three frequently applied calculation techniques--no density correction, ratio of tissue maximum ratios (TMRs), and the Batho correction--were also used to calculate the dose per MU. The measurements and calculations were compared with a one-dimensional phenomenological theory with parameters taken from the literature. RESULTS: The measurements at the entrance surface and center of the miniphantom agreed well with the predictions of the phenomenological theory. The interface regions are usually thin enough (2-3 mm) to be clinically unimportant for 10 MV. Depending on the algorithm used to correct for decreased lung density, the lesion dose may be larger or smaller than the prescribed dose by as much as 20% in extreme cases. A clinical example is presented. CONCLUSIONS: In comparing clinical results of treatments of small lung lesions, it is important to be aware of the density correction used.

CT-assisted assessment of bladder and rectum dose in gynecological implants.

Eight patients who received gynecological implants with Fletcher-Suit type applicators were involved in this study. An orthogonal pair of films and computed tomographic scans were obtained for each patient. In the CT study, judicious use of contrast materials and selective window and level settings permitted clear delineation of the bladder and the rectum boundaries relative to the implanted applicators. In comparison to reference organ doses derived from the orthogonal film pair method, the maximum organ doses estimated from the CT-assisted evaluation were considerably higher, by approximately twofold on the average. The differences between the values estimated from the two methods vary from patient to patient, being highly dependent on the individual anatomy and the geometry of the implanted sources. These preliminary results point to the inaccuracy of the conventional method of estimating organ doses. CT-assisted evaluation may be necessary to accurately calculate organ doses in gynecological applications.

Irradiation of bilateral orbital lymphoma: a non-coplanar technique with case reports.

Bilateral synchronous involvement of the orbits by lymphoma is an uncommon event. Therefore, the irradiation techniques for this disease are not well refined. Depending on the technique used, one has to decide between underdosing the anterior segment of the orbit and the frequently involved lacrimal glands or to tolerate shield related in homogeneities in the range of 40 to 50% as well as higher doses to the midline structures, e.g. the optic chiasma. To avoid the above shortcomings we developed a technique by which half the prescribed dose is delivered by pairs of beams angulated in the transverse plane and the other half by pairs of beams angulated in the sagittal plane. Film dosimetry in a phantom confirms that the entire orbit, including its anterior portion, is well covered, the lens is protected, and the dose to the mid-sagittal structures is not increased. The dose inhomogeneity is in the range of 20% which represents a substantial improvement over alternative methods. Two irradiated patients with bilateral orbital lymphoma are presented with local control and no ophthalmic or other side effects as of last follow-up.

Transverse axial film tomography with a therapy simulator.

A tomographic attachment was designed and developed that attaches to our existing simulator. The film tomograms obtained with the aid of this device exhibit very low geometrical distortion and good contrast and resolution for the objects used in this investigation. In addition, our results to date show that adjacent areas with densities differing by as little as 5% can be distinguished on film.

High-dose intra-arterial cisplatin therapy followed by radiation therapy for advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To assess the effectiveness of a protocol consisting of 4 cycles of high-dose intra-arterial cisplatin infusions followed by radiation therapy for improving chemotherapy response rates, organ preservation, and survival in patients with advanced-stage untreated and previously treated squamous cell carcinoma of the head and neck. DESIGN AND SETTING: A prospective study of sequentially enrolled patients treated in an academic medical center. The Kaplan-Meier method was used for survival analysis. PATIENTS: Fifty-eight nonpregnant adults, 18 years of age or older, with measurable untreated or recurrent advanced biopsy-proven squamous cell carcinoma of the head and neck. MAIN OUTCOME MEASURES: Response rate to targeted intra-arterial cisplatin infusions, organ preservation, and survival. RESULTS: Fifty-eight patients (44 men and 14 women) were followed up for at least 2 years (median duration of follow-up, 27 months). Twenty-nine (67%) of the 43 previously untreated patients had a complete response to intra-arterial cisplatin therapy. Of the untreated patients, 28 are alive and disease free after a median follow-up time of 30 months. Five of the patients with recurrent disease had a complete response to intra-arterial cisplatin therapy. There were 4 survivors after a median follow-up time of 17.5 months. Of note, there were no deaths or serious complications related to the treatment in either group. CONCLUSIONS: High-dose intra-arterial cisplatin therapy provides a high complete and partial response rate (91%). The combination of high-dose intra-arterial cisplatin and radiation therapy is effective in improving survival and organ preservation rates in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. This treatment protocol is much less effective for recurrent disease.

Oncogenic transformation and hyperthermia.

The potential of hyperthermia for producing oncogenic transformation in vitro was assessed using C3H/10T 1/2 mouse embryo cells. Temperatures in the range of 40 degrees to 45 degrees C caused no transformations, whether or not the heat treatment was associated with significant cell killing. In addition modest hyperthermia appreciably reduced the transformation frequencies associated with X-ray doses. The findings suggest an additional benefit in combining ionizing radiations with hyperthermia.

The role of radiation therapy in the management of metastatic renal cell carcinoma.

From 1965 to 1980, 35 patients were treated by radiation for palliation of symptoms related to metastatic renal cell carcinoma. The male:female ratio was 1.9:1. Eighty-six percent (30/35) of the patients were over 40 years of age at initial presentation. Sixty-three percent (22/35) of the patients showed symptoms of metastatic disease within three years of diagnosis of the primary malignancy. Sixty sites were irradiated in the 35 patients: 36 sites of metastatic bone pain, 14 obstructing and/or palpable masses, and ten sites treated for symptoms due to central nervous system (CNS) metastases. Efficacy of treatment was assessed at serial follow-up visits beginning one month after completion of radiotherapy. Bone pain responded at 77% of the treated sites. Mass effect responded in 64%. Disappointing results were obtained with CNS metastases. There was only a 30% response of brain and spinal cord lesions within the dose range that these patients were treated. No correlation between TDF equivalent dose of radiation administered and frequency of palliative response was found. In those sites where a response of bone pain to radiation was observed, 86% of the responses lasted the remainder of the patient's life. No correlation was found between TDF equivalent dose of radiation administered and duration of response. Radiation may be a useful palliative tool for bone pain and mass effect from metastatic renal cell carcinoma. Inordinately high doses need not be used to achieve the desired effect.

Hyperthermia: biological studies at the cellular level.

Tissue culture techniques were used to study the effect of hyperthermia on several cell types, including normal liver and hepatoma cells, as well as cell lines that have been established in culture for many years. Short exposures (less than 30 min.) at 45 degrees C readily kill a large proportion of cells. The response to heat was strikingly similar in all cells tested, and no preferential killing of neoplastic cells could be demonstrated. By contrast, hypoxic cells were found to be dramatically more susceptible to killing by heat than aerated cells. This is the reverse of the situation for x irradiation. The effectiveness of x irradiation was potentiated by treating the irradiated cells for 20 min. at 43 degrees C, which did not kill a detectable number of cells.

Subclavian artery occlusion following radiotherapy for carcinoma of the breast.

Four cases of subclavian artery occlusion occurring 5-17 years after irradiation for breast carcinoma are presented. Although arterial insufficiency is a rarely reported sequel to radiotherapy, it may be the cause of pain and disability in the upper extremity in a postmastectomy patient. Particular attention should be paid to the presence of a bruit over the subclavian and axillary arteries. Arteriography will often reveal a short, segmental lesion of the subclavian artery that frequently can be repaired surgically.

Cerebellar hemangioblastomas.

Between 1950 and 1976, 24 patients with cerebellar hemangioblastomas received postoperative radiation therapy. In retrospect, the low-dose radiotherapy that was practiced in the 1950s and early 1960s has been associated with inferior survival rates. Since 1963 and with increased awareness of the effects of radiotherapy, patients receiving high-dose irradiation postoperatively have generally survived longer. Postoperative radiotherapy is used whenever the neoplasm has not been totally excised. This more likely to occur with solid hemangioblastoma and neoplasms arising in the brain stem. In addition, radiotherapy should be used when the tumor recurs after total excision. The recommended dose is in the range of 4500--5000 rads in 4 1/2--5 weeks.

Midline pineal tumors and suprasellar germinomas: highly curable by irradiation.

Sixty-one patients with midline pineal tumors and 16 patients with suprasellar germinomas were treated with surgical decompression and relatively high-dose radiotherapy of the primary site. Results were excellent, and there were no long-term complications. Ten per cent of midline pineal tumors and 37% of suprasellar germinomas metastasized to the cerebral or spinal subarachnoid space within 6 months to 5 years. Irradiation of the entire neural axis is recommended for locally extensive tumors, simultaneous pineal and hypothalamic lesions, and all biopsy-proved germinomas. The five-year survival rate was 79% for midline pineal tumors and 77% for suprasellar germinomas.

Thermal tolerance and repair of thermal damage by cultured cells.

Exposure of hamster cells to 42.5 degrees C for long periods leads to the development of thermal tolerance; the slope of the survival curve become shallower after about 3.5 to 4 hours. If two 4-hour exposures at 42.5 degrees C are separated by various periods of time, thermal tolerance is eliminated by 20 hours. Prolonged exposure at 42.5 degrees C offers considerable protection from subsequent treatments to acute hyperthermia at 45 degrees C indicate or in conditioned medium or balanced salt solution failed to reveal any evidence of repair of potentially lethal damage.

Lymphopenia caused by cranial irradiation in children receiving craniospinal radiotherapy.

The peripheral blood changes were studied in 67 children who received craniospinal irradiation for posterior fossa tumors. At the completion of a cranial dose of about 3500 rad to the whole brain port, the lymphocytes were reduced to 858/mm3 rom 3084/mm3 preoperatively. The counts of the remaining leukocytes stayed at a level somewhat higher than preoperatively; the eosinophils rose to 288/mm3 from 125/mm3. With the initiation of the spinal field irradiation, which included a large proportion of the total bone marrow, the numbers of all the leukocytes decreased rapidly; the observed leukopenia was mainly secondary to neutropenia. A mechanism that was operating to restore the number of leukocytes became manifest immediately after the completion of radiotherapy, though the number of lymphocytes had not been totally restored to the preoperative level 6 years later. Irradiation of the lymphocytes that circulate through the vascular bed can explain the lymphopenia observed during cranial radiotherapy. Mild leukopenia observed in patients receiving radiotherapy through a relatively small port may be secondary to lymphopenia, and this does not necessarily indicate impaired bone marrow reserves.