Androgen deprivation and cognition in prostate cancer.

Androgen deprivation (AD) is commonly used in neoadjuvant and adjuvant setting with prostate cancer (PC) radiotherapy. This prospective study assessed whether cognitive functioning is impaired during 12 months of AD therapy. Longitudinal testing of 25 patients treated with AD and curative radiotherapy was undertaken at baseline, and at 6 and 12 months. CogniSpeed software was used for measuring attentional performances. Other cognitive performances were evaluated using verbal, visuomotor and memory tests. The Beck depression inventory was employed to evaluate depressive mood and EORTC QLQ-C30 for quality of life (QoL). During longitudinal testing of the AD group, no impairment in cognitive performances was found. Instead, improvement was observed in object recall (immediate, P=0.035; delayed, P<0.001), and in semantic memory (P=0.037). In QoL, impairment in physical function was observed. Androgen deprivation of 12 months appears to be associated with preserved cognitive functioning, although physical impairment occurs. These results have implications for counseling and psychosocial support of patients in the context of treatment options in PC.

Bleomycin, vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma.

This EORTC multicentre study analysed the efficacy and tolerability in patients with metastatic uveal melanoma of BOLD chemotherapy in combination with recombinant interferon alpha-2b. The dose of bleomycin was 15 mg on days 2 and 5, of vincristine 1 mg/m(2) on days 1 and 4, of lomustine 80 mg on day 1, and of dacarbazine (DTIC) 200 mg/m(2) on days 1-5, given every 4 weeks for a minimum of two cycles. Subcutaneous (s.c.) interferon alpha-2b at a dose of 3 x 10(6) IU was initiated on day 8 of the first cycle, and continued at a dose of 6 x 10(6) IU three times per week after 6 weeks. A median of two cycles were administered to 24 patients (median age 60.5 years). None achieved an objective response (0%; 95% Confidence Interval (CI): 0-14), 2 (8.3%) remained stable, 20 showed progression, and 2 (8.3%) were invaluable. The median progression-free survival was 1.9 months (95% CI: 1.8-3.4) and overall survival 10.6 months (95% CI: 6.9-16.4). Overall survival improved with increasingly favourable pretreatment characteristics (median, 14.7 versus 6.9 versus 6.0 months for Helsinki University Central Hospital (HUCH) Working Formulation stages IVBa, IVBb and IVBc, respectively; P=0.018). Grade 3 alopecia and neurotoxicity occurred in 13% of the patients. This multicentre study did not confirm earlier reports that BOLD with human leucocyte or recombinant interferon would induce at least 15% objective responses in metastatic uveal melanoma.

Serum adhesion molecules and interleukin-2 receptor as markers of tumour load and prognosis in advanced cutaneous melanoma.

Cell adhesion molecules are cell surface glycoproteins that may act as mediators in the metastatic process. Soluble interleukin-2 receptor (sIL-2R) is an immunological marker that may also serve as an indicator of tumour progression. Normal and neoplastic cells are capable of releasing these molecules into circulation. We evaluated the association between pretreatment serum levels of soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1) and sIL-2R and metastases and survival in 50 patients with advanced melanoma. The patients with liver and/or bone metastases had significantly higher sICAM-1 levels than those with soft tissue and/or lung involvement (P=0.002). In addition, there was a trend towards higher sIL-2R levels in patients with more metastatic sites (P=0.07). In univariate analysis, the number of metastatic sites (P=0.0001, odds ratio (OR) 3.0, 95% confidence interval (CI): 1.7-5.3), the metastatic site (P=0.01, OR 2.3, 95% CI: 1.2-4.4) and the levels of sICAM-1 (P=0.011, OR 2.5, 95% CI: 1.2-5.0), sVCAM-1 (P=0.036, OR 2.1, 95% CI: 1.0-4.3) and sIL-2R (P=0.0016, OR 3.0, 95% CI: 1.5-6.0) were found to be statistically significant prognostic factors for survival. In multivariate analysis, the number of metastatic sites was the dominant prognostic indicator. After it was excluded from the analysis, the sIL-2R level and the metastatic site were found to be significant. It can be concluded, that high sICAM-1 levels suggest liver metastases and sIL-2R seems to serve as a marker of tumour load in metastatic melanoma. Furthermore, the sIL-2R level appears to add to clinical data predicting the patient's outcome.

The value of serum S-100beta and interleukins as tumour markers in advanced melanoma.

Recently serum S-100beta has shown promise as a tumour marker in melanoma; however, its use as a prognostic marker in the advanced stage needs to be confirmed. Interleukins (ILs) may mediate regression or progression of cancer. In order to study their relation to the metastatic profile and survival, we evaluated the association between pretreatment serum levels of S-100beta, IL-6, IL-10 and IL-12 and metastatic site and survival in 50 patients with advanced melanoma who were to receive chemoimmunotherapy. Patients with liver and/or bone metastases had significantly higher median concentrations of S-100beta, IL-6 and IL-10 than those with only skin, nodal and/or lung involvement. The differences in IL-12 levels were unremarkable. Using univariate analysis, the S-100beta level and metastatic profile were found to be statistically significant prognostic factors for survival. Using multivariate analysis the S-100beta level was the most powerful prognostic indicator, while the metastatic profile was found to be significant after exclusion of S-100beta. The findings suggest that elevated serum levels of S-100beta, IL-6 and IL-10 reflect concurrent liver or bone metastases in melanoma. S-100beta is also an independent prognostic marker. Pretreatment IL levels were not associated with outcome.

Serum matrix metalloproteinase-2 as a prognostic marker in advanced cutaneous melanoma.

The association was studied between serum concentration of matrix metalloproteinase-2 (MMP-2) and metastatic site, survival and disease progression in patients with advanced cutaneous melanoma. The patient population consisted of 50 patients who were treated with chemoimmunotherapy. The median baseline serum concentration of MMP-2 was 724 ng/ml (range 500-2,297 ng/ml). There were no significant differences in MMP-2 levels according to metastatic site. Baseline MMP-2 concentration did not have a prognostic value. The patients with levels below 800 ng/ml survived for 8.8 months and those with higher levels for 9.7 months. On serial measurements, median serum MMP-2 concentration at disease progression in 25 patients was significantly higher than before treatment. Only five samples at response were available, and the levels were not significantly different from baseline levels. In conclusion, serum MMP-2 is not a prognostic marker in advanced melanoma. It also appears to be of limited clinical value in monitoring.

A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844.

PURPOSE: Cerebral low-grade gliomas (LGG) in adults are mostly composed of astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. There is at present no consensus in the policy of treatment of these tumors. We sought to determine the efficacy of radiotherapy and the presence of a dose-response relationship for these tumors in two multicentric randomized trials conducted by the European Organization for Research and Treatment of Cancer (EORTC). The dose-response study is the subject of this article. METHODS AND MATERIALS: For the dose-response trial, 379 adult patients with cerebral LGGs were randomized centrally at the EORTC Data Center to receive irradiation postoperatively (or postbiopsy) with either 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks with quality-controlled radiation therapy. All known parameters with possible influences on prognosis were prospectively recorded. Conventional treatment techniques were recommended. RESULTS: With 343 (91%) eligible and evaluable patients followed up for at least 50 months with a median of 74 months, there is no significant difference in terms of survival (58% for the low-dose arm and 59% for the high-dose arm) or the progression free survival (47% and 50%) between the two arms of the trial. However, this prospective trial has revealed some important facets about the prognostic parameters: The T of the TNM classifications as proposed in the protocol appears to be one of the most important prognostic factors (p < 0.0001) on multivariate analysis. Other prognostic factors, most of which are known, have now been quantified and confirmed in this prospective study. CONCLUSION: The EORTC trial 22844 has not revealed the presence of radiotherapeutic dose-response for patients with LGG for the two dose levels investigated with this conventional setup, but objective prognostic parameters are recognized. The tumor size or T parameter as used in this study appears to be a very important factor.

Delayed diagnosis and large size of breast cancer after a false negative mammogram.

The aim of this prospective, multicentre study was to investigate the effects of a false negative mammogram on treatment delay and tumour size. Among 306 consecutive women with histologically diagnosed, invasive breast cancer, the frequency of a false negative mammogram was small (13%) among women aged over 50 years, but 35% among those aged 50 or younger (P < 0.0001). Forty-five per cent of the women with a false negative mammogram had a longer than 2-month and 29% a longer than 6-month interval from mammography to surgery as compared with only 2 and 0% of women, respectively, who had a true positive mammogram (P < 0.0001 for both). Women with a false negative mammogram and a longer than 2-month interval to surgery had larger primary tumour size (60 versus 26% pT2-4, P = 0.005) and more often positive axillary nodes (60% versus 32% pN+, P = 0.03) at the time of surgery than those with a shorter delay. We conclude that a false negative mammogram is common in women younger than 50, and may lead to treatment delay and advanced clinical stage.

Combined bleomycin treatment and radiation therapy in squamous cell carcinoma of the head and neck region.

Forty-six patients with squamous cell carcinoma of the head and neck region were randomized to either irradiation or irradiation plus bleomycin. If possible, the patients later underwent radical surgery. In the bleomycin group, significantly fewer patients had remaining tumour cells in the tissue removed at operation, and a longer time elapsed before recurrences occurred. However, bleomycin had no significant effect on the 3-and 5-year survival rates, and it did not significantly reduce the incidence of local recurrences.

Prospidin combined to preoperative irradiation in head and neck cancer.

Twenty-seven patients with operable squamous cell cancer of head and neck were randomized into the study. Twelve patients received Prospidin combined to preoperative radiotherapy and fourteen patients were treated with preoperative radiotherapy alone. The daily dose of the drug was from 0.70 mg/kg to 2 mg/kg and the total dose during preoperative radiotherapy was between 1800 mg and 2250 mg with a mean of 2073 mg. The recurrence rate was in patients receiving Prospidin three out of twelve and in patients treated with irradiation alone four out of fourteen during the observation time of 33 months. In the present study Prospidin combined with preoperative radiotherapy had no advantage as compared to irradiation alone.

Chemotherapy in advanced breast carcinoma. Comparison between doxorubicin-cyclophosphamide and cyclophosphamide-methotrexate-5-fluorouracil-vincristine-prednisone.

Two chemotherapeutic regimens were compared in 102 patients with metastatic breast carcinoma, randomized to either doxorubicin-cyclophosphamide (DC) or cyclophosphamide-methotrexate-5-fluorouracil-vincristine-prednisone (CMFVP). The objective response rates were 32 per cent in the former and 35 per cent in the latter group, the complete response rates 6.4 and 21.8 per cent, and mean duration of the remission 7.7 and 11.2 months, respectively. Most responders had multiple metastases and had received previous hormonal treatment. The DC regimen was found to be slightly more toxic than CMFVP.

Toxic and mutagenic influences on spermatogenesis.

Cells at various stages of spermatogenesis show remarkable differences in their sensitivities to toxic and mutagenic agents. For accurate analyses of toxicity and mutagenicity, the most sensitive cell types should be obtained for studies soon after treatment before development of disturbing secondary alterations. The transillumination phase contrast microscopic technique has proved to be useful for this purpose. It allows recognition of rat and mouse seminiferous tubules in living unstained conditions for accurate selection of the desired stages of the cycle of the seminiferous epithelium for morphological and biochemical studies. Specific cell damage can be frequently recognized by transillumination only, whereas in most cases phase contrast microscopy is useful in screening the early stage-specific toxic alterations. A summary is presented of the results obtained by treatment with heat and with anticancer drugs. A meiotic micronucleus method has been developed for direct estimation of the severity of mutagenic insult on rat spermatogenesis. The segment that contains the second meiotic division and the early postmeiotic cells (stages XIV and I) is selected for study. Chromosome damage induced by mutagens may result in the formation of acentric fragments that after meiotic divisions are seen in early spermatids as separate micronuclei. They can be quantitated in squash preparations; the sensitivity of this method is comparable with that of the meiotic metaphase scoring. Recently, an in vitro technique has been developed for stage and cell specific measurements of replicative and repair syntheses of DNA during rat spermatogenesis after mutagen treatments.

Factors affecting the pulmonary toxicity of bleomycin.

Bleomycin induced lung toxicity was retrospectively analyzed in 39 patients with vulval malignancy (group A) and in 23 patients with head and neck carcinoma (group B). Group A consisted of non-smokers, mean age 69.8 years, who received the drug as intravenous injections. Group B contained mainly heavy smokers, mean age 60.6 years, treated with intramuscular injections of bleomycin. In group A, 6 patients (15.4%) and in group B only one patient (4.3%) developed typical pulmonary fibrosis. Advanced age, a high total dose of bleomycin, and intravenous bolus injections of the drug seemed to be major factors responsible for the development of lung fibrosis, whereas smoking had no obvious effect.

Primary non-Hodgkin's lymphoma ('reticulum cell sarcoma') of bone in adults.

Thirty-one adult patients with a primary non-Hodgkin's lymphoma ('reticulum cell sarcoma') in the bone were analyzed. Twenty-one patients had stage I disease, one stage II disease and 9 stage IV disease. The relapse-free 5-year survival rate for these patients was 42 per cent. The authors regard radiation therapy as the treatment of choice in localized tumors. Chemotherapy did not seem to affect the long-term survival in this small series. However, clear responses to multidrug chemotherapy were observed in some patients with recurrent or disseminated disease.

Active movements of the chromatoid body. A possible transport mechanism for haploid gene products.

Recent data indicate that the chromatoid body typical of rat spermatogenesis may contain RNA synthesized in early spermatids by the haploid genome. Analyses of living step-1 and step-3 spermatids by time-lapse cinephotomicrography have shown that the chromatoid body moves in relation to the nuclear envelope in two different ways. Predominantly in step 1, the chromatoid body moves along the nuclear envelope on a wide area surrounding the Golgi complex and has frequent transient contacts with the latter organelle. In step 3, the chromatoid body was shown to move perpendicular to the nuclear envelope. It was seen located very transiently at the top of prominent outpocketings of the nuclear envelope with apparent material continuities through nuclear pore complexes to intranuclear particles. The rapid movements of the chromatoid body are suggested to play a role in the transport of haploid gene products in the early spermatids, including probably nucleocytoplasmic RNA transport.

Early effects of vinblastine and vincristine on the rat spermatogenesis: analyses by a new transillumination-phase contrast microscopic method.

Male sterility belongs to the recently recognized complications of cancer chemotherapy and has an increasing importance. Therefore, more information about the mode of action of anticancer drugs on mammalian spermatogenesis is needed. We have developed a technique based on transillumination of living, freshly isolated unstained rat seminiferous tubules, where the cells specifically killed by the drugs are recognized as dull zones. Early stages of cell degeneration can be rapidly analyzed by phase contrast microscopy of living cells. Because the transillumination technique, in addition, permits an accurate recognition of the segments of the seminiferous epithelial wave, the cells representing various stages of the mitotic and meiotic cell cycles during spermatogenesis can be isolated in living state for morphological analysis. Vinblastine and vincristine cause an arrest of mitotic and meiotic divisions to metaphase followed by cell death, which was more rapid after vincristine administration. Both alkaloids had a slight damaging effect on the pachytene spermatocytes. Large doses of both drugs primarily affected the Sertoli cells by destroying their microtubules and mitochondria. Vincristine specifically damaged the acrosomic system and the cytoplasmic bridges of the young spermatids.