Effect of hyperthermia on murine myeloid precursors.

Murine bone marrow was exposed to hyperthermia temperatures of 41.5 to 45.5 degrees C. The proliferation capacity of myeloid progenitor and committed precursors was assayed in vivo utilizing spleen colony formation and diffusion chamber (DC) techniques. The survival of both pluripotential (CFU-S) and committed myeloid (CFU-DG) stem cells decreased exponentially with an increase in the heating period. Progression from CFU-S to CFU-DG significantly altered thermal sensitivity in the temperature range examined. Proliferation of mature granulocyte-monocytes (G-M) in DC is more thermostable than their stem cell precursors. Heat inactivation energies (enthalpies) of CFU-S and CFU-DG were derived from the slope of the heating time survival curves. Enthalpy of CFU-S is 300 kcal/mole below 43 degrees and 105 kcal/mole above 43 degrees. The enthalpy of CFU-DG is 250 and 145 kcal/mole below and above 43 degrees, respectively.

The effect of ultrasound-induced hyperthermia and X irradiation on skin.

Local hyperthermia for up to 60 min at 42.5-43.0 degrees C was induced in the skin of the mouse leg using ultrasound (780 kHz, 0.5-2.0 W/cm2). X radiation at doses of 10 to 30 Gy was delivered either before, during, or after the hyperthermia and the skin reactions were followed for 50 days. The thermal enhancement factor (TEF) was estimated using three criteria: (1) the maximum skin reaction; (2) the skin reaction integrated over the 50-day experimental period; (3) the skin reaction integrated over Days 8 to 32, which have a larger estimate. The TEF was independent of the sequence of heat and X radiation for intervals up to 1 hr. For 1 hr of hyperthermia, the TEF as measured by the maximum skin reaction did not change with radiation doses of 10 to 20 Gy. When the skin reaction integrated over 50 days or Days 8 to 32 was used as the criterion of response, the TEF varied with radiation dose from 4.7 at 10 Gy to 1.6 at 20 Gy. For a fixed radiation dose of 20 Gy, the TEF was not increased significantly by extending the duration of the hyperthermia from 30 to 60 min. The TEF for a radiation dose of 20 Gy delivered in three fractions over 5 days was smaller than that for a single 10-Gy fraction.

The response of kidney to ionizing radiation combined with hyperthermia induced by ultrasound.

Mouse kidneys were made hyperthermic (42.5 degrees C for 30 min) one hour before, during, or one hour after local irradiation to determine the effect of hyperthermia on radiation damage. An ultrasound beam was used to induce hyperthermia. The urinary concentrations of total protein and albumin were used as criteria of kidney injury. Hyperthermia alone did not induce proteinuria. Radiation alone produced proteinuria that was not correlated with dose. Hyperthermia induced during or after irradiation resulted in a thermal enhancement factor of 1.29 +/- .33. Hyperthermia induced one hour before irradiation resulted in a thermal enhancement factor of 0.88 +/- .05, indicating a radioprotective effect. To the authors' knowledge, this is the first time such an effect has been shown.

The influence of warfarin of levamisole on the incidence of metastases following local irradiation of a solid tumor.

KHT sarcomas were implanted in the right rear legs of C3H mice. An x-ray dose of 6000 rad, delivered in ten equal fractions over 12 days, resulted in 60% local tumor control, but 83% of these mice developed metastases. Three strategies to use the tumoricidal effect of x-radiation and reduce the incidence of metastases were compared. A modification of the fractionation scheme to deliver an initial large fraction of 1800 rad followed by seven 600-rad fractions resulted in a decreased incidence of metastases compared with the same dose delivered in ten equal fractions. The use of warfarin anticoagulation during the ten-fraction course of radiation resulted in a small decrease in the incidence of metastases. Immune stimulation with levamisole, injected subcutaneously every second day during the irradiation, also resulted in a decrease in the incidence of metastases. However, when warfarin or levamisole were combined with the eight-fraction radiation scheme there were fewer metastases than following the ten-fraction scheme. The combination of the eight-fraction radiation course with levamisole also produced a significant increase in primary tumor control. In this treatment regimen, therefore, levamisole appears to act as a radiation sensitizer. An hypothesis to explain this action is proposed.

Effect of ultrasound-induced hyperthermia and cis-diamminedichloride platinum II on murine renal function.

Murine renal function was evaluated after ultrasound-induced kidney hyperthermia (42.5 degrees C and 46.5 degrees C for 35 minutes) and the administration of cis-diamminedichloride platinum II (8 mg/kg). A quantitative immunonephelometric technique was employed to determine urinary total protein (TP) and albumin (Alb) 1-180 days post-treatment. Hyperthermia of 46.5 degrees C elevated urinary TP excretion significantly more than that of 42.5 degrees C cis-diamminedichloride platinum (Cis DDP) administration greatly increase urine TP with a peak mean TP concentration of 488 microgram/ml, four days after Cis DDP (normal range was 26-48 microgram/ml). This returned to normal by day 14. The TP excretion after 42.5 degrees C hyperthermia with concurrent Cis DDP was similar to Cis DDP alone, implying there was no potentiation of early or late Cis-DDP-induced renal damage by hyperthermia. Late mouse mortality was greater (P = 0.08) after Cis DDP alone, than Cis DDP with 42.5 degrees C hyperthermia. There was a statistically significant increase (P less than 0.05) in the Alb/TP excretion ratio after the addition of 42.5 degrees C hyperthermia to Cis DDP, implying an alteration in the site or nature of the Cis DDP renal lesion by hyperthermia.

Dose local x-irradiation of a tumor increase the incidence of metastases?

KHT sarcomas were implanted into the right rear legs of C3H mice. Animals receiving no treatment died at 32 days with a 67% incidence of metastatic tumors. A dose of 6000 rads in ten fractions over 12 days, starting ten days after implant, delivered to the primary tumor (with the remainder of the body shielded) produced 55% local tumor control. However, 83% of the mice with local tumor control, subsequently developed metastatic lesions. Amputation of the tumor-bearing leg either prior to the start of radiation treatment, at the end of treatment or at intervals during treatment or sham treatment, indicated that 1) metastases occurred predominantly during the initial three radiation fractions and 2) the increased incidence of metastases following irradiation was a result of the manipulations associated with the irradiation and not the irradiation per se. Irradiation did not change the distribution of organ sites involved with metastatic tumors compared to untreated or sham-treated tumors.

The influence of ICRF-159 and levamisole on the incidence of metastases following local irradiation of a solid tumor.

Courses of irradiation consisting of 6000 rad in ten equal fractions over 12 days delivered to KHT sarcomas in mice controlled 55% of the local tumors but 83% of the mice died from metastases. Three strategies to reduce the risk of metastatic spread were tested. The fractionation scheme was changed to deliver the same total dose using a large initial fraction followed by seven equal portions with the same overall time. ICRF-159 was used with the intention of partially synchronizing the tumor growth fraction in a radiosensitive state of the growth cycle and of promoting normalization of the tumor vasculature. Levamisole was used to stimulate the immune system. The combination of ICRF-159 with the eight-fraction radiation course proved to be effective for both increasing local control and decreasing the incidence of metastases. The addition of levamisole did not improve the results obtained with a combination of ICRF-159 and irradiation.

CT scanning and interstitial therapy.

Computerized tomography is of considerable value in determining tumor volume at many anatomic sites that are otherwise difficult to visualize. The ability to define volume accurately by means of a CT scan can be employed in interstitial radiotherapy. First, CT scan information may be used to plan the implant volume by defining the tumor location and extent prior to implantation of radioactive materials. Second, radioactive sources and/or afterloading devices can be localized after implantation by means of a CT scan. Third, follow-up of tumors to assess both tumor regression and recurrence is facilitated.

Temperature-dependent inhibition of murine granulocyte-monocyte precursors.

The response of nucleated bone marrow cells from C3H mice to hyperthermic temperatures of 41.5 to 49.5 degrees for a fixed heating period of 30 min has been determined. The threshold temperatures for cell lysis, loss of trypan blue exclusion, and histological evidence of cell injury were greater than 49.5 degrees, 45.5 degrees and 43.5 degrees, respectively. Growth of mature granulocyte-monocytes from precursors was evaluated in Millipore diffusion chamber culture. There was a biphasic decrease in granulocyte-monocyte growth after exposure to temperatures of 41.5 to 45.5 degrees. The ratio of granulocytes to monocytes in proliferated cultures was not altered after hyperthermia. Pluripotent and committed granuloid stem cells were assayed by the spleen colony and plasma clot diffusion chamber techniques. These also showed a biphasic decrease with increase in temperature, with committed stem cells having a greater thermal sensitivity at lower temperatures.

Cancer of the posterior hypopharyngeal wall.

Thirty-five patients with cancer of the posterior pharyngeal wall treated at the University of Virginia Hospital since 1956 have been reviewed. A minimum follow-up of five years was available in all patients. These have been analyzed by stage and treatment modality, and the crude and determinate three and five year survival figures presented. In contradistinction to results reported for other hypopharyngeal sites, radiotherapy alone has proved the most effective treatment in the posterior wall, particularly for T1 and T2, NO lesions, where the crude and determinate survival after 5 years were 45 and 50% respectively. For advanced lesions no treatment approach has approved efficacious, although 2 or 10 (20%) patients treated initally by radiotherapy alone survived disease free for 3 years with subsequent surgical removal of residual nodal disease.

Olfactory esthesioneuroblastoma--variables predictive of tumor control and recurrence.

This report surveys the world literature concerning prognostic variables for patients with esthesioneuroblastoma, an uncommon tumor arising from the olfactory epithelium. Specific sites of local and regional tumor extension, recurrence of disease after treatment, distant metastasis, and patient age were all found to be related to patient prognosis. There is a higher cure rate for patients treated after 1966, indicating an improvement in treatment methods. Also, the results indicate that in more recent years patients are being diagnosed and treated with less advanced disease. A statistical procedure, discriminant analysis, was employed, which permits the oncologist to predict patient outcome accurately. The discriminant function equation was 87% correct in identifying patients with tumor control (for a minimum period of 36 months) or recurrence and was 84% correct in classifying patients free of disease for at least 60 months or with recurrence. The statistical procedures employed in this report can be extended to other tumors and survival criteria.

Primary carcinoma of the female urethra.

A retrospective review of women with carcinoma of the urethra is reported. Twelve patients treated between 1947 and 1978 have been characterized as to presenting features, therapy, and prognosis. There average age of patients at diagnosis was 68 years; the most frequent presenting symptom was bleeding (92% of patients); average duration of symptoms before diagnosis was five months. Localized tumors of the distal urethra have been effectively controlled by using interstitial implantation of radioactive sources, five of five patients having no evidence of disease one to ten years after treatment. Our study agrees with reports in the literature on the results of interstitial implantation of radioactive sources. Patients with tumor involving the entire urethra have a poor prognosis, and four of five patients died within the first year after therapy.

Adenoid cystic carcinoma of the salivary gland.

We describe 15 patients with adenoid cystic carcinoma of the salivary glands treated by radiotherapy from 1960 to 1978. All patients were treated for localized disease either definitively or after surgical resection. The site of origin and local tumor extensions are reviewed and the results of treatment analyzed. Eighty-three percent of the tumors were controlled by combined treatment (surgery and postoperative radiotherapy) for one to ten years, 80% for more than five years. In the latter group, seven of ten patients had tumors with poor prognostic features. Eighteen patients treated by surgery alone have been reviewed for comparative five-year recurrence rates. This group and similar groups reported in the literature have higher recurrence rates at five years. Two patients treated definitively by radiotherapy have had tumor control for four years. This series and other reports demonstrate that adenoid cystic carcinoma is amenable to control by radiotherapy. Elective postoperative radiotherapy may assist in diminishing the high recurrence rates and improve survival.