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A method is described for a titre-tray based two-site lectinoenzymatic assay of glycoproteins. WGA lectin, reacting with the core-part of glycans, was combined with lectins PNA and DBA, the latter two reacting with terminal parts of glycans. A standard curve was obtained with bovine submaxillary gland asialomucin, and measurements of human rectal secretion were calibrated against this curve. The assay showed an intra-assay reproducibility of 2.4-7.5%, and inter-assay reproducibility of 3.9-20.8%. Recovery tests showed a linearity close to predicted values. The selected standard was ideal as inhibition of lectin binding by monosaccharides showed similar inhibition profiles for human rectal secretion and for asialomucin standard. Neuraminidase treatment dramatically increased the PNA binding to human rectal secretion immobilized on WGA. Western blotting of human rectal secretion demonstrated a large range of lectin-reactive glycoproteins, the main fraction reacting with all lectins being approximately 250 kDa. The assay described is well suited for studies of the glycan part of tumour marker glycoproteins, and changes occurring in these. It has a high sensitivity by ignoring that the glycans may be present on different molecules. Examination of rectal secretions from various cancer patients showed significantly increased PNA binding, as well as an increased PNA/DBA binding ratio, in patients with colorectal cancer (p<3x10(-3)) and, unexpectedly, in patients with other cancers (p<5x10(-3)).

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The testes of CDF1 mice were irradiated with single doses of X-rays ranging from 2-16 Gy. The number of haploid cells in the testis at different times after irradiation (42-350 days) was determined by one-parameter flow cytometry both for irradiated animals and for age-matched controls. Based on literature data on the kinetics of the spermatogenesis in mice, a mathematical model of the (hierarchical) germ tissue was developed. Using this model, the processes of radiation-induced cell loss and subsequent recovery were simulated and free parameters of the model were estimated by fitting the model prediction to the experimental data. One of the aims of the study was to investigate the kinetic behaviour of spermatogonial stem cells and the corresponding control mechanisms. In order to fit the data, the model has to include the following features: (i) A preferential self-repopulation of spermatogonial stem cells following tissue injury. The model-estimated probability of a self-renewing division rises from 50% (the steady-state value) to 95% if the stem-cell population is reduced to 10% of its normal size. (ii) A relatively low, almost constant turnover rate of the stem-cell compartment. It is suggested by the analysis that less than 10% of the spermatogonial stem cells present in the testis divide per day, regardless of the degree of cellular depletion. (iii) A mechanism responsible for incomplete recovery. The observed incomplete recovery of spermatogenesis after single doses exceeding 10 Gy can be described quantitatively assuming that the stem cells are organized into discrete proliferative structures, the number of cells per structure being about 60.

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Exocrine and endocrine gonadal function is abnormal in some of the testicular cancer patients who have been treated with orchidectomy alone and receive no cytotoxic treatment. A review of the literature reveals that cisplatin-based chemotherapy seems to induce additional long-term damage to spermatogenesis and Leydig cell function. Most patients regain active spermatogenesis after chemotherapy, whereas subclinical Leydig cell dysfunction persists. In order to elucidate whether the cisplatin-induced gonadal toxicity has clinical implications, observation periods exceeding those previously reported are required.

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The effect of single doses of vincristine (VCR) or bleomycin (BLM) on mice spermatogonia was investigated, and the influence of either of these drugs on the radiation response of murine spermatogonial stem cells was examined. When assessed by flow cytometry, VCR (1.0 mg/kg) or BLM (100 mg/kg) reduced the survival in the differentiated spermatogonia to 4% and 37% of controls, respectively (p less than 0.05). VCR reduced the stem cells to 79% of controls (p less than 0.05), whereas BLM had no apparent effect on the stem cells (p greater than 0.05). Drugs were administered intraperitoneally up to 28 days before or after local irradiation with 9 Gy. VCR produced significant enhancement of radiation-induced damage to spermatogonial stem cells, which was most prominent when administered 6 or 12 hr after irradiation. BLM administered before irradiation or 1 hr after radiotherapy produced significant enhancement.

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Paternity before and after treatment was investigated in 177 patients with unilateral germ cell tumours of the testis. Before the cancer was diagnosed, 51% had fathered at least 1 child, 9% had a history of infertility and 40% had not wanted to have children. It was estimated that 72% of the patients would have fathered at least 1 child at the age of 40 years. After treatment 41 patients had wished to have children. Infertility was still a problem 5 years after the end of treatment in 53% of these men. No significant differences was observed between patients treated with orchiectomy alone and patients treated with cisplatin-based chemotherapy or subdiaphragmatic irradiation. In 8 patients, infertility was present in spite of an evident recovery of spermatogenesis. Congenital malformations were recorded in 3.8% of the live-born children conceived before the orchiectomy. This incidence did not exceed the Danish national rate, the relative risk being 2.5 (95% confidence limits, 0.9-5.5). No malformations were observed in the 22 children conceived after ending treatment.

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Gonadal function was evaluated before irradiation and by serial analyses after treatment in 27 patients with seminomas and 24 patients with nonseminomatous germ cell tumors of the testis. During subdiaphragmatic irradiation, a median testicular dose of 1.7 Gy (range, 1.2 to 4.8 Gy) reached the remaining testis. Twenty nonseminoma patients were treated with adjuvant chemotherapy using vincristine and bleomycin (OB) or cisplatin/dactinomycin, vinblastine, and bleomycin (P/DVB). After orchiectomy, 94% had spermatozoa in semen, 49% had a total sperm count exceeding the reference value (80 x 10(6], and in 67% serum follicle-stimulating hormone levels were normal. The corresponding estimated values 5 and 9 years after treatment were 61%, 13%, 14%, and 84%, 35%, 32%, respectively. A Cox regression analysis of recovery, with azoospermia used as an endpoint, showed that (1) recovery depended on the radiation dose, (2) adjuvant chemotherapy prolonged the recovery period, (3) recovery was decreased in patients with low pretreatment total sperm counts and in patients older than 25 years. A prognostic index was derived from the regression model and radiation dose-response curves were calculated (+/- chemotherapy). We conclude that a profound, dose-dependent impairment of spermatogenesis is caused by radiation scatter reaching the testis during subdiaphragmal irradiation. An effective gonadal shield should reduce the gonadal dose to a level low enough to preserve spermatogenesis in most patients.

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Gonadal function was evaluated in 25 patients with metastatic testicular cancer who were treated with orchiectomy plus chemotherapy with cisplatin, vinblastine, and bleomycin (PVB) and in 21 patients with clinical stage I disease who were treated only with orchiectomy and then kept under surveillance. Four years after PVB treatment, none of the patients were azoospermic; after 5 years, the total sperm counts in 46% of the patients had reached their pretreatment levels. In the group under surveillance, sperm counts below the reference level persisted or developed in 55% of the patients. Sperm production was similar in the two groups of patients 1.5 years after treatment and beyond. We conclude that spermatogenesis is not restored in all patients treated with PVB because of both preexisting germ cell defects and treatment toxicity.

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Sperm counts, serum gonadotropins, and androgen levels were investigated in 39 seminoma patients and 58 patients with a nonseminomatous germ cell tumor of the testis after unilateral orchiectomy. In 58% of the patients, the total sperm count was below the lower reference value (80 million). A multiregression analysis demonstrated a correlation between a decreased total sperm count and the following three explanatory variables: (1) an elevated serum alpha-fetoprotein (AFP), (2) a history of chryptorchidism, or (3) a seminomatous tumor. In 42% of the patients, the sperm concentration and the sperm motility met criteria considered sufficient for cryopreservation. Serum follicle-stimulating hormone (FSH) was elevated in 33% of the patients. Androgens (serum testosterone [T] or urine 17-oxy-steroids [17-OS]) were subnormal in 5% of the patients, whereas serum luteinizing hormone (LH) was elevated in 14% of the patients without human chorionic gonadotropin beta-subunit (beta-HCG) in serum.

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Nicotinamide induced radiosensitization of tumors has been suggested to be a consequence of a reduction in tumor hypoxia. We have investigated the possibility that nicotinamide may produce significant radiosensitization in a normal tissue in which the radiation response is also influenced by hypoxia. The normal tissue studied was testis and radiation damage was assessed by measuring survival of spermatogonial stem cells. The radiosensitizing action of nicotinamide in testis was compared to that observed in a C3H mammary carcinoma when assayed by both regrowth delay and local tumor control. Our results show that nicotinamide (1000 mg/kg; i.p.) enhanced radiation damage in both tissue types when the radiation was given up to at least 3 hr after drug injection. Enhancement ratios obtained when the drug and radiation were separated by a 1 hr time interval were between 1.1 to 1.2 for the testis and 1.0 to 1.5 for the tumor. The results suggest that nicotinamide will produce radiosensitization in testis, but the effect is small and less than that observed in tumors.

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Ninety-six patients with small cell anaplastic lung carcinoma were given monthly chemotherapy with vincristine-doxorubicin-cyclophosphamide alternating with CCNU-methotrexate-etoposide for 18 months or until evidence of progressive disease. Forty-four patients were randomized to chemotherapy alone and 52 patients to chemotherapy plus 600 cGy of both upper and lower half-body irradiation given day 60 and 100, respectively. In 78 evaluable patients surviving more than 100 days the overall response rate was identical in the two arms of the study, 68% vs. 66%. However, time to progression was significantly shorter in the irradiated patients (P = 0.05). Only 25% of the irradiated patients tolerated greater than or equal to 75% of the scheduled dose of chemotherapy, against 91% of the non-irradiated patients (P = 0.0001). Thus, half-body irradiation was associated with a shorter time to progression and a decreased ability to give maintenance chemotherapy at proposed doses.

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In a randomised trial patients with progressive metastatic breast cancer were allocated to one of three different treatments. A: Prednisone 10 mg X 3 daily. B: Medroxyprogesterone acetate (MPA) orally 500 mg daily. C: MPA i.m. 1000 mg daily for 3 weeks followed by 500 mg i.m. weekly. The study included 150 patients and was well-balanced with respect to different prognostic parameters. Most patients (83%) were postmenopausal, and 95% had previously received chemo- or hormonal therapy. In the MPA treated patients, analysis of serum MPA levels was performed once a month. The response rates were 4.6, 7.9 and 12.5% in treatments A, B and C, respectively. This difference was not statistically significant (P greater than 0.05). Furthermore, the follow-up of serum MPA levels revealed no significant difference between responders and non-responders. Analysis of time to progression did not indicate any advantage of MPA over prednisone, irrespective of MPA schedule. In accordance with these data, there was no difference as regards survival in the three groups. In conclusion, the study indicated that MPA is not superior to prednisone in this group of heavily pretreated patients with advanced breast cancer.

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The results of radiotherapy in 204 lesions of malignant melanoma in 114 patients were analysed with regard to radiobiological parameters such as total dose, dose per fraction, treatment time, tumour volume and also by various fractionation models. Ninety-seven of 204 lesions showed a complete response (CR) which was persistent in 80. Neither total dose, treatment time nor various modifications of the nominal standard dose (NSD) concept showed any well-defined correlation with response. There was, however, a significant relationship between dose per fraction and response so that high doses per fraction yielded a significantly better response (24% CR for doses less than 4 Gy vs. 57% CR for doses greater than or equal to 4 Gy, p less than 0.001). The lack of influence of treatment time influence allowed an analysis of the data according to the linear-quadratic model yielding an alpha/beta ratio of 2.5 Gy. Using this ratio, an iso-effect for different fractionation schedules could be estimated by the extrapolated total dose (ETD). This was further improved when corrected for the other important parameter which was tumour volume. Thus, an iso-effect formular for malignant melanomas could be calculated as ETDvol = D X ((d + 2.5)/2.5) X M-0.33 where d is total dose and dose per fraction in Gy, respectively and M is mean diameter (cm). The 50% response for ETDvol was found to be 86 Gy. This formular seems to be currently the best way to determine an optimal radiation schedule for effective radiation treatment of malignant melanoma. Treatment of 45 patients with only local or regional disease showed 26 patients who achieved local tumour control with a 56% 3-year survival compared to no survivors among 19 patients in whom the disease could not be controlled locally. This indicated that proper attention should be given to the local treatment of recurrent melanoma since this has important implications for survival. Successful treatment of malignant melanoma may be possible when the special radiobiological features of the disease are taken into account.

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Thirty-five patients with advanced metastatic breast cancer refractory to prior chemotherapy were treated with vindesine given at a fixed dose as a continuous 5-day infusion of 1.5 mg/day every 4 weeks. All patients were considered evaluable, and there were four patients with partial responses for more than 3 months (11%) and 13 patients with stable disease (37%). Two of the four responders had had disease progression on other vinca alkaloids. None of the responders had proven doxorubicin resistance. Side-effects included myelosuppression, neurotoxicity, nausea, stomatitis and fever, but these were seldom dose-limiting. The results--together with the results of other single-agent studies of vindesine summarized in the paper--indicate that the drug is an active agent in advanced breast cancer. However, the optimum way of administering vindesine and its inclusion in first-line therapy needs further study.

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Bone marrow necrosis (BMN) is a rare finding in specimens from living patients. It is most commonly found in patients with neoplastic disorders, severe infections and sickle cell disease. We present a patient with Hodgkin's disease who developed extensive BMN 11 months before death. A concise review of the literature is also presented.

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