In vitro effects of OK-432 on irradiated mouse bone marrow cells.

PURPOSE: In vitro effects of OK-432 on irradiated mouse bone marrow cells are examined. METHODS AND MATERIALS: Bone marrow cells of BDF1 mouse (1 x 10(6) cells/ml) were incubated with alpha medium, 2% fetal calf serum and OK-432 in a CO2 incubator at 37 degrees C for 24, 48 and 72 h, respectively. After centrifugation, each supernatant was collected and used for conditioned medium in CFU-GM assay: Changes in CFU-GM as a function of incubation time and OK-432 dose was examined; changes of CFU-GM according to various doses of OK-432 were examined in two mouse strains, BDF1 and BALB/c mouse; changes in protective effect of OK-432 in terms of CFU-GM as a function of administration timing of OK-432 in relation to irradiation. As a radiation source, 137Cs at a dose rate of 500 cGy/min was used. RESULTS: The CFU-GM decreased with the incubation time when OK-432 was not administered, while it significantly increased with incubation time when OK-432 was added at 0.5 and 1.0 KE/ml at 48-72 h of incubation. The former showed marked increase at 48-72 h of incubation. CFU-GM of BDF1 mouse was always higher than that of BALB/c mouse for any dose of OK-432. CFU-GM per femur according to the timing of administration of OK-432 from 24 h before to 24 h after irradiation showed 10299 +/- 2300 (24 h before), 10783 +/- 2463 (3 h before), 10045 +/- 1501 (immediately after), 8504 +/- 1188 (3 h after), 4898 +/- 1212 (6 h after), 1214 +/- 736 (12 h after) and 181 +/- 113 (24 h after irradiation), respectively. CONCLUSION: OK-432 stimulates cultured mouse bone marrow cells to produce GM-CSF in vitro by direct contact action. This direct stimulating action of OK-432 on GM-CSF production of bone marrow cells can be kept from 24 h before to at least 3 h after irradiation.

Compensation techniques in NIRS proton beam radiotherapy.

Proton beam has the dose distribution advantage in radiation therapy, although it has little advantage in biological effects. One of the best advantages is its sharp fall off of dose after the peak. With proton beam, therefore, the dose can be given just to cover a target volume and potentially no dose is delivered thereafter in the beam direction. To utilize this advantage, bolus techniques in conjunction with CT scanning are employed in NIRS proton beam radiation therapy planning. A patient receives CT scanning first so that the target volume can be clearly marked and the radiation direction and fixation method can be determined. At the same time bolus dimensions are calculated. The bolus frames are made with dental paraffin sheets according to the dimensions. The paraffin frame is replaced with dental resin. Alginate (a dental impression material with favorable physical density and skin surface contact) is now employed for the bolus material. With fixation device and bolus on, which are constructed individually, the patient receives CT scanning again prior to a proton beam treatment in order to prove the devices are suitable. Alginate has to be poured into the frame right before each treatments. Further investigations are required to find better bolus materials and easier construction methods.

High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme.

BACKGROUND AND PURPOSE: Although glioblastoma multiforme is clearly radiation-resistant, there is evidence of a dose-dependent response relationship. The purpose of the study was to evaluate the impact of higher dose by rotational multileaf collimator (MLC) conformal radiation therapy. MATERIALS AND METHODS: From 1984 to 1995, 38 consecutive cases with intracranial glioblastoma multiforme were treated using the rotational MLC conformal therapy. There were 25 men and 13 women with a median age of 47 years (12-73 years, mean 46.5 years). Median Karnofsky performance score was 80 (30-100, mean 78.2). Median tumor volume was 64 cc (8-800 cc, mean 110.3 cc). All underwent surgical intervention (only biopsy in 1, partial resection in 13, subtotal resection in 21, and gross total resection in 3). Radiation dose to was 60 to 80 Gy (median 68.5 Gy, mean 68.3 Gy) in 21 patients treated before 1990 and 90 Gy in the 17 patients thereafter. Biweekly i.v. chemotherapy was also administered for both arms. RESULTS: The 1-year, 2-year, 5-year, and 10-year overall survival rates were 75%, 42%, 20%, and 15%, respectively. Univariate analysis showed the initial tumor volume, residual tumor volume, and Karnofsky performance score were statistically significant factors for survival. Only the residual tumor volume was statistically significant by multivariate analysis. The 5-year survival rate of patients with residual tumors of 5 cc or less in volume was as good as 37%. Survival of the 90-Gy Group appeared inferior to that of the Low-Dose Group, though no statistical difference was seen (the 3-year survival was 40% vs. 22%). Local failure was observed in 16 of the 19 recurrences in the Low-Dose Group, whereas it was observed in only 4 of the 13 recurrences in the 90-Gy Group. The difference in pattern of failure was statistically significant. Two patients of the High-Dose Group developed radiation necrosis and one died of it. CONCLUSIONS: The high-dose conformal radiotherapy did not improve survival in the disease, but did change the pattern of failure.

Radiation therapy in early glottic carcinoma: uni- and multivariate analysis of prognostic factors affecting local control.

PURPOSE: The purpose of this report is to clarify prognostic factors affecting local control of T1 and T2 glottic tumors and to define an optimal regimen for radiation therapy. METHODS AND MATERIALS: Two hundred and ten patients (199 males, 11 females, age range 30 to 86 years with an average of 62 years) with previously untreated invasive squamous cell carcinoma of the glottis were treated with radiation therapy at the University of Tokyo between January 1972 and December 1989. Endoscopic microsurgery was introduced as an integral part of treatment in 1974. From 1974 to 1979 the radiation dose was gradually reduced, reaching a mean of 20 Gy in 2 weeks in 1979. From 1980 to 1983, the total dose increased to 50.4 Gy, with a fraction size of 1.8 Gy, over a mean of 5.6 weeks. From 1984 onward, the mean total radiation dose increased to 60 Gy with a fraction of 2 Gy. RESULTS: Recurrence-free 5 year survival rates for T1a, T1b, and T2 were 79%, 73%, and 67%, respectively. When the relationship between radiation dose and local control rates was analyzed for each year from 1974 to 1989, total doses were strongly associated with local control for patients with T1a disease. Age, sex, daily dose, total dose, radiation machine (Co-60 or 10 MV Lineac), treatment technique (anterior wedged pair or parallel opposed fields), treatment volume, use of endoscopic microsurgery, and involvement of the anterior commissure were examined for effects upon relapse-free survival in T1a disease by uni- and multivariate analysis. Total dose was the only significant factor for T1a disease (p < 0.02). The effect of these variables upon relapse-free survival in T2 disease as well as the effect of cord mobility, and number of involved sites was examined by multivariate analysis. Total dose (p < 0.03), cord mobility (p < 0.05), and number of involved sites (p < 0.04) significantly affected relapse-free survival in T2 disease. CONCLUSION: At least 50 Gy is required for treatment of T1 disease when 2 Gy is used as a daily dose, even if endoscopic microsurgery is performed. Better local control of T2 disease in patients with impaired cord mobility or more than three involved sites leads to an improved prognosis; we recommend doses of at least 70 Gy or use of hyperfractionation in such patients with these factors. Although the daily dose did not significantly affect prognosis in multivariate analyses, 1.8 Gy is not recommended for treatment of T2 tumors instead of 2 Gy.

Thermoradiotherapy in the treatment of locally advanced nonsmall cell lung cancer.

PURPOSE: To improve the treatment results of locally advanced non-small cell lung cancer (NSCLC), we have been conducting a clinical trial using regional hyperthermia combined with radiotherapy. METHODS AND MATERIALS: Between 1985 and 1990, 19 patients were treated. All cases except one were regarded as initially unresectable. There were 10 Stage IIIA cases and nine Stage IIIB cases. In 10 cases thermoradiotherapy was used definitively, and in the other nine cases preoperatively. Radiotherapy was administered with conventional fractionation. Total dose ranged from 42 to 80 Gy (mean 62.9 Gy) for definitive treatment cases, and 38 to 47 Gy (mean 40.6 Gy) for preoperative cases. Radiofrequency (RF) capacitive hyperthermia was administered twice weekly, immediately after radiotherapy. Total sessions of hyperthermia ranged from 5 to 16 times (mean 9.0) for definitive treatment cases and 3 to 8 times (mean 6.7) for preoperative cases. RESULTS: The results of thermoradiotherapy group (HTRT group) were compared with our historical control group (RT group); initially unresectable Stage III NSCLC irradiated definitively with 50 Gy or more (26 cases), or became resectable after radiotherapy and operated (4 cases). As for initial response, there were 5 complete responses (CRs), 13 partial responses (PRs), and 1 no change (NC) (CR rate 26%, response rate 95%) in the HTRT group, whereas there were no CR, 21 PRs, and 9 NCs in the RT group (CR rate 0%, p < 0.005, response rate 70%, p < 0.05). Overall 3-year local relapse-free survival and survival rate for the HTRT group was 73% and 37%, respectively, and 20% and 6.7%, respectively, for the RT group (p < 0.01, p < 0.01). The rate of death from uncontrolled primary disease for the HTRT group was significantly lower than for the RT group (21% vs. 53%, p < 0.03). CONCLUSION: Although the number of cases is rather small, thermoradiotherapy in the treatment of locally advanced NSCLC is promising in raising resectability, local control, and, thus, long-term survival.

Real-time beam monitoring in dynamic conformation therapy.

PURPOSE: Although portal imaging is a promising method of verification during static multiport irradiation, it cannot be applied directly to dynamic irradiation such as rotational conformation with multileaf collimator movement. A real-time beam monitoring system based on megavoltage computed tomography scanning has been developed to establish a verification method for the rotational conformation technique. METHODS AND MATERIALS: Exit beam through the patient is extracted by the same detector unit as used for megavoltage scanning during the actual treatment. Beam edge is defined as the 50% level of the maximum dose of the detector array. Megavoltage computed tomography is done after patient setup and just prior to the actual irradiation. Detected beam pathways are overlaid on this image approximately every 1 s. Therapists can monitor correlation between the target and actual beam pathways on a real-time computer display. RESULTS: The accuracy of field edge detection has been proven to be less than 2 mm from various measurements. Real-time monitoring is more useful in rotational conformation than in static multiport irradiation due to dynamic movement of the collimator. Field errors were identified in two of 54 sessions using this method. CONCLUSIONS: Although several limitations remain to be solved, the method presented is a useful tool for treatment verification of high accuracy radiation therapy, particularly rotational conformation irradiation.

Radiosensitivity of CD45RO+ memory and CD45RO- naive T cells in culture.

Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4+ helper and CD8+ killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO+ memory and CD45RO- naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO+ cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity.

Factors possibly influencing the prognosis of oligodendroglioma.

Fifty-seven cases of oligodendroglioma (including eight cases of malignant oligodendroglioma) treated at the University of Tokyo Hospital between 1961 and 1985 were analyzed for factors influencing the survival rate. Factors related to a poor outcome were findings of malignancy and symptoms of dementia. Survival rate and postoperative survival period were not influenced significantly by radiation therapy, extent of resection, tumor characteristics, or ABO blood groups.

Postradiation astrocytoma. Report of two cases.

The authors describe two cases of malignant astrocytomas associated with previous radiation therapy in childhood for intracranial germinoma and craniopharyngioma. In both patients, there was no recurrence at the primary tumor site. Because of a geometric coincidence between the tumor location and the radiation field, radiotherapy was strongly implicated as a cause of these two astrocytomas.

Clinical method to estimate time of origin and maximum volume of malignant tumors.

The purpose of this study is to investigate a method to obtain the magnitude of growth parameters in the Gompertzian function growth model and to extrapolate this function forwards and backwards by applying the parameters. Non exponential linearity of malignant tumors has been reported and experimental and clinical evidence of growth limitation even in malignant tissues has also been detected. In clinical practices the conventional exponential growth model is often insufficient. So we applied the Gompertzian function to infer growth patterns using the parameters obtained from breast carcinoma skin metastases and from leiomyosarcoma lung metastases. We found that breast carcinoma grows faster but its growth rate retards more quickly, whereas the leiomyosarcoma grows slowly but its growth rate hardly regresses. Interesting results are obtained extrapolating this function forwards and backwards using the parameters. As a consequence the retardation factor becomes more important than the growth rate.

An effective dose computation model for fractionated radiation dose.

A mathematical model of sensitivity change and cell proliferation for fractionated radiation effect is presented here in which cell proliferation is regarded as part of the virtual recovery of radiated tissues. The obtained values of parameters in this model were applied to reported fractionated radiation data. The values in normal and malignant tissues were not identical. The difference of the values accounts for the increased therapeutic ratio in fractionated radiation. A procedure to optimize fractionated radiation schemes is also presented.

An integrated radiotherapy treatment system and its clinical application.

A new total system for radiation therapy installed in our department consists of a linear accelerator unit with microcomputer-controlled multileaf collimators, along with a CT scanner installed in the same treatment room. Also included are a digitally controlled communal couch, a minicomputer, and a system of treatment planning devices. We have developed various kinds of external radiation treatment planning techniques (including dynamic ones) with this system on the basis of the concept of dose corresponding technique. A reference point setup method is needed to maintain a unified coordinate system through each step of the treatment procedure, and, as developed by us, permits a volume-oriented setup. This system has been evaluated for accuracy in a variety of clinical setups. A true three-dimensional dose calculation algorithm is required for treatment planning associated with multileaf collimator treatments in order to realize the potential accuracy of such a system.

Radiation therapy for primary non-Hodgkin's lymphoma of the head and neck in stages I and II.

From January 1975 through December 1986, 58 previously untreated patients with primary non-Hodgkin's lymphoma of the head and neck in stages I and II were treated at our department. Thirty-seven patients were classified as stage I and 21 as stage II. Complete local remission was obtained in all cases. The 5-year survival rates were 68% and 79% in stages I and II, respectively. The 5-year survival rates according to site of origin were as follows: Waldeyer's ring 77% and neck lymph node 63%. The 5-year survival rates according to the histological classification of the Working Formulation were 73% intermediate grade malignancy and 63% for high grade malignancy. Chemotherapy combined with radiotherapy was essential, especially for cases in stage II. The 5-year survival rate was 100% for patients with chemotherapy and 71% without chemotherapy. The relapse-free 5-year survival rate was 67% with chemotherapy and 36% without chemotherapy. Most first failures were due to the development of generalized disease and the 5-year survival rate after salvage was 44%.

Carcinoma of the maxillary sinus: the role of radiotherapy.

From 1975 to 1986, 75 M0 patients with squamous cell carcinoma of the maxillary sinus were treated at the Department of Radiology, Tokyo University Hospital. The overall 5-year survival rate calculated with the Kaplan-Meier method was 24%. During the period of the study, the method of treatment used in our hospital changed. From 1975 to 1979 (the first period), the treatment of choice was low-dose irradiation and frequent necrotomy. From 1980 to 1982 (the second period), more extensive surgery was performed and 50 to 60 Gy of irradiation was given. The 5-year survival in the first period was 20%, that in the second 14%. From 1983 to 1986 (the third period), trimodal therapy (surgery + radiation + intra-arterial infusion) was introduced and 5-year survival was improved to 50%. Intra-arterial cisplatinum infusion and treatment planning using CT scans were especially useful in improving survival.

Radiation therapy of carcinoma of the oropharynx.

Forty consecutive cases of carcinoma of the oropharynx were treated by irradiation from 1973 through 1987. The overall five-year survival rate calculated by the Kaplan-Meier method was 21%. Data were also analyzed retrospectively to investigate the factors associated with prognosis. The following results were obtained. (1) The results of re-irradiation as salvage treatment were poor. (2) Irradiation to neck lymph node metastases was not particularly effective, especially under 50 Gy. (3) Stage T2(-4) primary tumors were difficult to control with irradiation of 50 Gy.

A dose distribution evaluation utilizing megavoltage CT imaging system.

An isodose distribution (collision kinetic energy distribution) was acquired using a megavoltage CT imaging system. Direct comparison of dose distributions has become important for verification in innovative treatment techniques. Three-dimensional implementation of this system is considered highly feasible.

Radiation therapy of intracranial germ cell tumors with radiosensitivity assessment.

Fifty patients with pineal and/or suprasellar tumors were treated in the Department of Radiology, University of Tokyo, from 1975 to 1988. Histological diagnosis was obtained in 28 cases, whereas 22 patients were irradiated without pathological verification. Of the 28 patients with histological diagnosis, 11 had germinomas, 13 non-germinoma germ cell tumors, including nine teratomas, two choriocarcinomas and two embryonal carcinomas, two pineocytomas and two pineoblastomas. The treatment protocol since 1981 has been that, after 20 Gy is given with a local irradiation field, if tumor regression is marked and germinoma is highly suspected, whole brain or whole CNS irradiation is performed subsequently; otherwise, surgical intervention is performed followed by systemic chemotherapy plus radiation therapy. The five-year survival rates of histologically proven germinomas, histologically proven non-germinoma germ cell tumors, and clinically suspected germinomas by means of the above-mentioned method as well as tumor marker status were 73%, 28%, and 83%, respectively. The overall five-year survival rate was 61.3%. A statistically significant difference was found between the survival rates for the 11 cases with histologically proven germinoma and the 13 cases with non-germinoma germ cell tumors, although there was no significant difference between the survival rates for the histologically proven germinomas and the clinically suspected germinomas. Therefore radiation therapy is an effective treatment method for the management of intracranial germ cell tumors.

[Synchronization chemoradiotherapy for malignant gliomas].

Cellular synchronization chemoradiotherapy was performed in 122 patients with glioblastoma and malignant astrocytoma (GrIII) registered between April 1977 and August 1982. The study was a non-randomized clinical phase II trial. The chemotherapeutic agents employed as synchronizers during the irradiation were VM26 (epipodophyllotoxin) and vincristine (VCR) as plant alkaloids and ACNU as a nitrosourea. Either VM26 or VCR was administered on D1, D2 and D3 at the dosage of 1 mg/kg (0.025 mg/kg-VCR) body weight. ACNU was administered on D2 and D3 at the dosage of 1 mg/kg body weight. The duration of the chemotherapy was eight to fourteen days at the initial induction stage and almost eight weeks at the maintenance stage. Thus, two synchronization arms of VM26 + ACNU and VCR + ACNU were employed. The regimen-VM 26 + ACNU + Radiation (Rad) could yield the initial induction of CR + PR-30%, NC-50%, and PG-15% in 58 cases. Long-term survival, calculated by the cumulative survival rate, was as follows: one year, 58%; two years, 42%; three years, 32%; four years, 30%, and five years, 25%. The regimen VCR + ACNU + Rad could yield the initial induction of CR + PR-28%, NC-49%, and PG-23% in 64 cases. The cumulative survival rate was calculated as follows: one year, 55%; two years, 42%; three years, 27%; four years, 22%, and five years, 22%. As a control, particularly for the survival rate, the data of the All-Japan Registry were revised to correspond to our study population. The survival rate of simple radiation cases thus revised was as follows: one year, 43%; two years, 23%; three years, 11%; four years, 7%, and five years, 5%. The comparison between VM 26 plus ACNU and VCR plus ACNU yielded a higher initial induction response of 35% for the former (vs. 28% for the latter), although it is difficult to make a judgement on the excellence of the regimen involving VM 26 plus ACNU, because this trial was clinical phase II. On the other hand, compared with the data from the All-Japan Registry, each regimen of cellular synchronization radiation therapy could achieve statistically more excellent responses both in the initial induction and the long-term survival (p less than 0.01). Thus, cellular synchronization radiation therapy is a hopeful therapeutic method for malignant glioma, with less side effects and statistically confirmed higher responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Conservative treatment of carcinoma of the anorectal region--the role of radiation therapy.

Radiation therapy has now an increasing role in the treatment of rectal cancer. Formerly it was used for the palliation of recurrent or residual tumors, but now it is more frequently used for preoperative purposes. Preoperative radiotherapy has the following advantages. It often makes unresectable tumors resectable, prevents tumor seeding during the operation, treats the lateral involvement by the tumor, and makes resectable tumors resected more conservatively. So far we've treated 22 patients with advanced stage rectal cancer by preoperative radiotherapy. Their 3 year local control rate and survival rate was 79% and 86%, respectively, with 9% complication rate. And as for the anal cancers preoperative irradiation and more conservatively, definitive irradiation with doses more than 60 Gy are quite worthwhile both in terms of local control and complication. Both for rectal and anal cancers radiotherapy seems quite promising modality in local tumor control and the patient's quality of life. Further clinical trials are necessary.

[A case of terminal cancer patient whom the home staying terminal cares were provided with ease supported by the regional core hospital].

A physician who practices generally at his private clinic will be sometimes referred to a cancer patient staying at home. This referral is hardly acceptable without helps from other medical and paramedical specialities. He needs a support organization in which a supporting hospital is the most important. A case of home staying terminal cancer patient is reported here whom a private practician provided terminal cares with great difficulties at the beginning and afterwards with no significant difficulties organizing a care team for the home staying patient and assisted by a supporting hospital.