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.

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 use of strontium-90 in the treatment of carcinoma in situ of the conjunctiva.

Four patients with carcinoma in situ were treated with strontium-90 beta ray application. The dose used was 4,500 rads after surgical removal or with small recurrent tumor and 7,000 rads for primary treatment. All patients were disease-free at follow-up periods of 48 to 320 months after treatment. One patient required superficial x-ray treatment for recurrent disease. No serious complications developed with the treatment and no progressive cataracts have occurred.

Response of mouse kidney to hyperthermia: pathology and temperature--dependence of injury.

Hyperthermia either alone or in combination with radiotherapy and chemotherapy is being used increasingly in the treatment of malignant tumors. This study was designed to evaluate the response of the mouse kidney exposed to a range of hyperthermic temperatures (41 to 45 degrees C) used to induce regression of malignant tumors. Minimal histologic evidence of renal injury occurred in the proximal tubules of the subcapsular region. More extensive damage was characterized by necrosis of tubules and glomeruli in a sharply circumscribed area that involved the lateral subcapsular area where the temperature induced was highest. The tissue histologic reaction was maximal by 24 hours. At temperatures below 41 degrees C no necrosis occurred, whereas at temperatures between 42 and 45 degrees C there was an increasing incidence of necrosis. This increase in tissue reaction above 42 to 43 degrees C is consistent with reported observations from tissue culture and in vivo skin heating experiments, and indicates that normal tissue injury may occur in the same range of temperatures shown to cause regression in malignant tumors.

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.

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.

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.

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.

Radiation therapy in the treatment of malignant salivary gland tumors.

A retrospective analysis of 52 patients with malignant salivary gland tumors is reported. Seventeen patients received early postoperative radiation therapy and 16 (94%) were free of local or regional disease 2-14 years following initiation of therapy, although 14 were considered at high risk of developing local recurrence. Two subjects (12%) developed distant metastases and 14 (82%) were completely disease-free. Survival and disease-free status of patients treated for recurrent or inoperable disease were much worse with two of 13 disease-free at 45 and 168 months respectively. Various workers have reported recurrence rates after surgery along at 25-38% and over 50% for many histological types. On the basis of this report early postoperative radiation therapy is recommended to reduce the risk of postsurgical recurrence. Prognostic trends relating to both histological type and location of primary disease are discussed.

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.

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.

Esthesioneuroblastoma.

Esthesioneuroblastoma is an uncommon tumor of neural crest origin arising in the nasal cavity. Since 1966, 97 cases have been reported in the world literature. In this report an analysis is presented of the following aspects of these 97 patients: age and sex distribution, disease staging, treatment results, interval to recurrence, and survival. Staging was according to a system proposed by Kadish et al. There is a bimodal age distribution with peaks in age groups 11-20 years and 51-60 years. Prognosis is favorable in early stage disease (A and B) with 3-year crude survivals of 88.9% and 83.3%, respectively. Stage C patients have a poor prognosis, with 52.9% surviving 3 years. Treatment consisted of radiotherapy, surgery, or a combination of radiotherapy and surgery. In stage A, prognosis is favorable in all three treatment groups with one 1 of 24 patients dying of recurrent disease. In stage B, recurrence rates and 3-year survivals are also similar in the three treatment groups. Thus, single modality treatment is as effective as combined treatment for early stage disease. Local recurrence is the predominant site of failure occurring in 68% of recurrences. The overall crude survival for the 97 patients was 95.4%, while the determinate survival (corrected for intercurrent disease) was 70.8%.

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 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.