Protective effect of hypoxia in the ram testis during single and split-dose X-irradiation.

Spermatogonial stem-cell survival in the ram was studied after single (6 Gy) and split-dose (2 x 3 Gy, interval 21-24 h) X-irradiation both under normal and hypoxic conditions. Hypoxia was induced by inflation of an occluder implanted around the testicular artery. The occluders were inflated about 10 min before irradiation and deflated immediately after. Stem-cell survival was measured at 5 or 7 weeks after irradiation by determination of the Repopulation Index (RI) in histological testis sections. The RI-values after fractionated irradiation were only half those after single dose irradiation. Hypoxia had a protective effect on the stem-cell survival. After split-dose irradiation under hypoxic conditions two times more stem cells survived than under normal oxic conditions; the RI-values increased from 34% (oxic) to 68% (hypoxic). This effect of hypoxia was also found after single dose irradiation where the RI-values increased from 68% (oxic) to 84% (hypoxic). The development of the epithelium in repopulated tubules was also studied. Under hypoxia, a significantly higher fraction of tubules with complete epithelium was found after single (38 vs. 4%) as well as after split-dose irradiation (12 vs. 0%).

Major complications and causes of death in patients treated for Hodgkin's disease.

A total of 340 patients with Hodgkin's disease were evaluated for the occurrence of intercurrent fatalities after treatment with radiotherapy, chemotherapy, combined modality therapy, and salvage chemotherapy. Mean follow-up time was 76.6 months. Causes of death were compared with the expected risk, calculated from mortality statistics of the Netherlands' population. Sixty-seven patients died of progressive Hodgkin's disease, whereas 37 patients died of causes unrelated to advanced disease. Patients showed an increased risk of dying of leukemia and solid tumors (P less than .001), whereas the risk of dying of cardiovascular complications was not increased. The 10-year actuarial risk of dying of leukemia varied between 0% for patients treated with radiotherapy only and 5.7% for those needing salvage chemotherapy. The 10-year risk of dying of solid tumors was 0% for patients treated with chemotherapy and 6.5% for those receiving radiotherapy. Treatment-related fatalities were highest after combined modality therapy (P less than .025); the corresponding 10-year risk was 6.1%. Compared with younger ones, patients greater than or equal to 40 years had an increased risk of dying of causes unrelated to progressive Hodgkin's diseases. The actuarial risk of developing intercurrent fatalities at 10 years was 4.9% in patients less than 40 years, and 34.7% in those greater than or equal to 40 years (P less than .001). Compared with population based statistics, patients successfully treated for Hodgkin's disease still showed an increased risk of dying (P less than .001). Treatment modality, stage, and histologic subtype were not predictors of intercurrent death.

DNA-flow cytometry of squamous cell carcinomas from the human uterine cervix: the identification of prognostically different subgroups.

The relevance of DNA-index, alone and in combination with other parameters, was assessed for patients with squamous cell carcinomas of the uterine cervix by using the method of flow cytometry (FCM). Tumours with a diploid or a tetraploid DNA-content appeared to be associated with a less favourable prognosis than was observed in the group with non-diploid/non-tetraploid tumours. DNA-index in combination with either the age of patients or the histological grade of tumours, enabled the separation of prognostically different subgroups. Particularly, the combination of an age under 51 years with a DNA-index of 1 or 2 appeared to define a group with a low survival rate. Furthermore, within the group of well and moderately differentiated tumours, it was possible to identify prognostically different subgroups by combining this parameter with DNA-index, i.e. a non-diploid/non-tetraploid DNA-content of these tumours was associated with a more favourable prognosis. From this study it is concluded that FCM clearly contributes to the recognition of subgroups of patients with different prognosis.

Kinetic aspects of misonidazole and its major metabolite in radiotherapy.

Oral doses of misonidazole between 0.75 and 1.3 g/m2 were administered during 3-5 days per week to 21 patients with various malignancies. Mean plasma levels of misonidazole and desmethylmisonidazole at the times of radiotherapy were in the range 20-50 and 2-12 mg/l respectively. Slight accumulation of misonidazole and desmethylmisonidazole in plasma was observed with a dosage interval of 24 h. In patients with anticonvulsant comedication plasma elimination half-lives of misonidazole of 4.1-8.9 h were found. Observed side-effects were nausea and vomiting (9%), exanthema or rashes (14%) and mild peripheral neuropathy (9%).

Intensive cytotoxic therapy followed by autologous bone marrow transplantation for non-Hodgkin's lymphoma of high-grade malignancy.

Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.

Treatment of retinoblastoma and choroidal melanoma. A multidisciplinary approach.

Retinoblastoma and choroidal melanoma are two malignant ocular tumours that still give rise to discussions about diagnosis, natural history with respect to metastasis an choice of treatment. The therapeutic problems are best solved within a multidisciplinary oncology team in which the ophthalmologist, ophthalmopathologist and the general pathologist play an important role. In most institutes for ophthalmology a patient with a tumour in or in the region of the eye, is first seen by a specialist for eye diseases, who is also a surgeon in this field. In general the ophthalmologist decides on the diagnosis, the treatment and the follow-up without consulting other specialists in oncology. This solely ophthalmological approach can harbour a potential danger for the patient. Decisions on treatment made in a multidisciplinary team of specialists trained in oncological principles are responsible for the best results. Surgery combined with radiotherapy and chemotherapy can be a better choice than surgery alone, but even when surgery alone seems the best treatment, the discussion with the members of an oncological team can be of importance for the surgeon. The natural history of the tumour which includes the growth patterns, the growth rate and the tendency to metastasize may influence the choice of the surgical procedure; surgical intervention might be more or less extensive than previously foreseen. Dr. W.A. Manschot, professor in ophthalmic pathology, rightly advocates the contribution of the ophthalmopathologist to such an oncological team, because such a person has acquired knowledge in histopathology of the ocular tumours and experience in evaluating international literature in this field, the results of the treatment of groups of patients with the same tumour and publishing the statistically verified conclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of retinoblastoma by precision megavoltage radiation therapy.

The principal treatment concept in the Utrecht Retinoblastoma Centre is megavoltage irradiation, followed by light coagulation and/or cryotherapy if there is any doubt as to whether the residual tumour is still active. Radiation therapy is administered by means of a simple but highly accurate temporal beam technique. A standardized dose of 45 Gy is given in 15 fractions of 3 Gy at 3 fractions per week. From 1971 to 1982, 39 children with retinoblastoma have been irradiated in at least one eye. Of the 73 affected eyes, 18 were primarily enucleated, one received light coagulation only, and 54 received radiation therapy. Of the 54 irradiated eyes, 32 were additionally treated by light coagulation and/or cryotherapy for suspicious residual tumour (in 29 eyes), recurrent tumour (in 1 eye), and/or new tumour (in 3 eyes) and 10 were ultimately enucleated. Two eyes also received hyperthermia. The percentages of cure of the irradiated eyes with a minimum follow-up of 2 years were 100% (14/14), 100% (9/9), 83% (10/12), 79% (11/14) and 0% (0/5) in the Reese-Ellsworth groups I to V-A, respectively. Of the saved eyes 95% achieved useful vision. Eighteen eyes developed a clinically detectable radiation cataract; in five of these the lens was aspirated. Cataracts developed exclusively in those lenses of which a posterior portion of more than 1 mm had to be included in the treatment field. The likelihood and the degree of cataract formation was found to be directly related to the dose of radiation to the germinative zone of the lens epithelium. The minimum cataractogenic dose found in this series was 8 Gy.

Sequential non-cross-resistant chemotherapy regimens (MOPP and CAVmP) in Hodgkin's disease stage IIIB and IV.

Fifty consecutive patients with advanced Hodgkin's disease were treated in a multicentre study with 6 cycles of an alternating scheme of MOPP and CAVmP followed by irradiation to a dose of 20 Gy. The objective was to increase complete remission (CR) and cure rates by alternating two effective noncross-resistant regimens with subsequent consolidation of the remission by irradiating bulky nodes. A total of 47 patients completed the treatment and are evaluable. In the first 13 patients the irradiation fields amounted to a total or subtotal nodal irradiation with inclusion of the spleen. In case of organ involvement the affected organ was also included in the irradiation field. The irradiation protocol was later changed to an irradiation of the initially involved sites because of severe leucopenia and thrombopenia. After completion of the chemotherapy 32 (68%) patients (for Stage IIIB and IV patients: 63% and 71%, respectively) achieved a CR, after ending the radiotherapy the percentage of CR increased to 87% (for stage IIIB and IV patients: 90% and 86%, respectively). Five of the patients relapsed in an irradiated and nonirradiated area, three patients in a nonirradiated field. The actuarial 3-year survival rate for the entire group was 86% and for patients in CR 94%. The relapse-free survival was 73%. It is concluded that this alternating chemotherapy scheme followed by irradiation is at least equally effective as MOPP treatment in achieving a CR, and is probably superior in terms of survival.

Choroidal melanoma. Enucleation or observation? A new approach.

Application of the knowledge of growth rate of malignant neoplasms on choroidal melanomas shows that (1) fatalities within two years after enucleation only exceptionally can be due to dissemination of tumor cells during enucleation because the growth rate of uveal melanomas generally is far too low; (2) the apparent relationship between enucleation and death by metastasis actually is a relationship in time between diagnosis of the primary tumor and death by metastasis; (3) simultaneous diagnosis of the primary tumor and its metastases rarely is possible; (4) long intervals between enucleation and death by metastasis are explained by a low growth rate of metastases. Early enucleation, especially of small melanomas, is obligatory, because it prevents (further) dissemination of tumor cells. Preoperative local radiotherapy of two doses of 400 rads each will devitalize about 90% of the primary cells and largely will prevent possible iatrogenic dissemination.