Orchidectomy after primary chemotherapy for metastatic testicular cancer.

OBJECTIVE: To examine the outcome of orchidectomy following primary chemotherapy in patients with metastatic testicular cancer. PATIENTS AND METHODS: This was a retrospective analysis of patients who underwent primary chemotherapy without initial orchidectomy for testicular cancer between 1982 and 2006. The patients were identified from the regional oncology cancer database in our tertiary referral hospital. Their case notes were reviewed regarding initial presentation, chemotherapy, clinical progress and pathological outcomes following surgery. RESULTS: 21 evaluable patients were identified (14 non-seminomatous germ cell tumours, 7 seminomas). 16 patients underwent standard orchidectomy within 12 months of commencing chemotherapy and 5 patients underwent significantly delayed orchidectomy (19-68 months, mean 45.1 months). Orchidectomy in the standard group showed tumour necrosis or a scar in 13 patients (81%) and differentiated or mature teratoma in 3 patients associated with bulky poorly responsive retroperitoneal disease (19%). In the delayed orchidectomy group 3 out of 5 patients had viable seminoma, of which two were associated with carcinoma in situ. CONCLUSION: Our study raises concerns as regards a potentially high risk of late tumour development in testes which are preserved following apparent tumour resolution after chemotherapy.

Monoclonal antibodies against a specific nonhistone chromosomal protein of Drosophila associated with active genes.

Hybridomas secreting monoclonal antibodies have been produced by fusion of NS-1 mouse myeloma cells with the spleen cells of mice inoculated with a 60-65,000-mol wt fraction of proteins released from Drosophila embryo nuclei treated with DNase I. The antibodies secreted by the hybridomas were examined with polytene chromosomes of formaldehyde-fixed salivary gland squashes by an immunofluorescence assay. Most of the clonal antibodies obtained resulted in specific staining of the chromosomes relative to the cytoplasmic debris. In the case of clone 28, the antibodies showed a preferential association with sites of gene activity, both puffs and loci identified as puffing at some time during the third instar and prepupal period. In larvae that were heat shocked (exposed to 35 degrees C for 15 min before removal and fixation of the glands), the antibodies of clone 28 stained preferentially the induced heat-shock loci while continuing to stain most of the normal set of loci. The antigen for clone 28 was identified as a single protein of approximately 62,000 mol wt by using the antibodies followed by 125I-rabbit anti-mouse Ig to stain nitrocellulose replicas of SDS polyacrylamide gels of total chromosomal proteins. This study demonstrates that monoclonal antibodies can be used successfully in immunofluorescence staining of formaldehyde-fixed polytene chromosomes. The results verify the hypothesis that a specific nonhistone chromosomal protein is preferentially associated with the set of loci that includes both active sites and those scheduled to be active at some time in this developmental program. Such proteins may play a general role in the mechanisms of cell determination and gene activation.

Distribution studies on polytene chromosomes using antibodies directed against hnRNP.

The distribution of nuclear ribonucleoprotein (hnRNP) particles in Drosophila polytene chromosomes has been investigated using anti-B-36 serum as a probe. The use of polytene chromosomes allows resolution at the level of the chromomere, and provides the opportunity to look for both positive and negative correlations with transcriptional activity. The antiserum was obtained using the nuclear protein B-36 from Physarum polycephalum as the immunogen. It has been shown to precipitate hnRNP particles from HeLa cells through a cross-reaction with the major 32,000- and 34,000-dalton hnRNP particle proteins. The antiserum cross-reacts with a Drosophila nuclear protein of approximately 34,000 daltons. By indirect immunofluorescence, we observed that the antiserum reacts preferentially with transcriptionally active loci of the polytene chromosomes, whereas loci previously or subsequently active do not show significant fluorescence. The overall pattern of fluorescence is very similar to that generated with anti-RNA polymerase B serum. The correlation of fluorescence and transcriptional activity observed suggests that the anti-B-36 serum is recognizing hnRNP proteins which have combined with nascent RNA molecules at the sites of transcription.

Altered interaction of Cis-dichlorodiammineplatinum(II)--modified alpha 2-macroglobulin (alpha 2M) with the low density lipoprotein receptor-related protein/alpha 2M receptor but not the alpha 2M signaling receptor.

Receptor-recognized forms of alpha 2-macroglobulin (alpha 2M*) bind to two macrophage receptors: an endocytic receptor, the low density lipoprotein receptor-related protein/alpha 2M receptor (LRP/alpha 2MR), and a G protein-coupled receptor, the alpha 2M signaling receptor (alpha 2MSR). Binding of alpha 2M* to LRP/alpha 2MR but not alpha 2MSR is inhibited by receptor-associated protein. We now present binding characteristics of alpha 2MSR (kD approximately 50 pm; 1,530 sites/cell) using Scatchard analysis. We also demonstrate that chemical modification of alpha 2M* with cis-dichlorodiammineplatinum (cis-DDP) does not significantly alter binding to either receptor or signaling characteristics as compared with unmodified alpha 2M*. However, internalization by LRP/alpha 2MR is greatly affected. Cis-DDP-modified alpha 2M* (cis-DDP-alpha 2M*) and alpha 2M* show comparable internalization during a single round of endocytosis; however, cis-DDP modification of alpha 2M* results in a > or = 82% reduction in internalization involving receptor recycling and multiple rounds of endocytosis. Results from pH 5.0 dissociation and receptor recycling experiments suggest that the mechanism of decreased internalization of cis-DDP-alpha 2M* involves poor dissociation from the receptor in endosomes and a decrease in available surface receptors over the time of exposure to the ligand.

Identification of residues in alpha-macroglobulins involved in activation of the alpha 2-macroglobulin signaling receptor.

Site-directed mutagenesis of residues in the receptor binding fragment of rat alpha 1-macroglobulin identify residues 1377 and 1378 (human numbering) as crucial for interaction with the alpha 2M signaling receptor on murine macrophages. Secondary structure prediction and signaling studies with the mutant proteins suggest the alpha 2M signaling receptor binding site involves part of a loop-helix-loop motif comprised of residues 1372-1378.

Testicular sex cord-stromal tumours: the Edinburgh experience 1988-2002, and a review of the literature.

AIMS: Sex cord-stromal tumours of the testis are uncommon tumours, accounting for around 5% of testicular neoplasms. Treatment is primarily surgical, with no adjuvant therapy of proven benefit. We present a single-centre experience over a period of 15 years. MATERIALS AND METHODS: From 1988 to 2002, 18 patients with a diagnosis of sex cord-stromal tumour were referred to our centre. A retrospective analysis of their case notes was made and a pathological review undertaken. RESULTS: Sixteen were Leydig-cell tumours and two were Sertoli cell. For the Leydig-cell tumours, the median age at presentation was 42 years, 50% presented with a testicular mass and 31% with gynaecomastia. Two patients followed a malignant course: one revealing disease dissemination at initial staging, and a second 12 months after potentially curative orchidectomy. Salvage retroperitoneal lymphadenectomy in the latter patient proved unsuccessful. Clinical outcome correlated strongly with the presence of adverse pathological features described previously in the literature. After a median follow-up of 46 months, two patients have developed progressive disease, and two patients have died, one of metastatic Leydig-cell tumour. No patient defined as being of low malignant potential on pathological examination has relapsed outside our review period of 2 years. CONCLUSION: We confirm the overall excellent prognosis for most of the patients with sex cord-stromal tumours of the testis. Compared with most previous reports, pathological features seem to predict with reasonable accuracy the risk of malignant behaviour, and can adequately inform the subsequent review policy.

The management and outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre between 1988 and 2002.

AIMS: The aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts. MATERIALS AND METHODS: Patients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, were identified from the departmental database, and survival by stage and prognostic group was analysed. RESULTS AND CONCLUSIONS: The proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients with early stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend to improved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, but numbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ Cell Consensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-cell tumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator.

Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules.

AIMS: To determine whether palliation of chest symptoms from a 10 Gy single fraction (regimen 1) was equivalent to that from 30 Gy in 10 fractions (regimen 2). MATERIALS AND METHODS: Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0-3, were randomised to receive either 30 Gy in 10 fractions or a 10 Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer's quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS. RESULTS: We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3-28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P < 0.001), a difference in the proportion between the two regimens of 21% (95% CI 10-33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P = 0.197). CONCLUSIONS: Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen.

Sexual function following radical radiotherapy for bladder cancer.

BACKGROUND AND PURPOSE: The effect of radical radiotherapy (RT) for bladder cancer on sexual function has not been previously investigated. The current study was designed as a pilot to assess sexual function in males pre- and post-radiotherapy. MATERIALS AND METHODS: An anonymous questionnaire was devised to examine the following sexual domains: libido, frequency of sexual function, erectile capacity, orgasm and ejaculation in the 6 months prior to radiotherapy and following treatment. Serum testosterone, FSH and LH were measured in 10 patients. RESULTS: Eighteen patients completed the questionnaire from 10 to 56 months following irradiation, 13 of whom were able to achieve an erection prior to RT. Over half of these patients noted a decline in the quality of erections after RT, with a similar proportion noting decreased libido and frequency of sexual activity. Three patients lost the ability to have any erections whatsoever. Of the 10 patients retaining erectile capacity, three noted reduced frequency of early morning erections suggesting a physical aetiology, five had decreased frequency of ejaculation and four had reduced intensity of orgasms. Seventy-one percent (12/17) felt their sex life was worse following RT but only 56% (9/16) were concerned about the deterioration. Testosterone levels were normal in all but one patient. CONCLUSIONS: Radical RT to the bladder can cause a decrease in sexual function in males.

Sexual morbidity following radiotherapy for germ cell tumours of the testis.

An anonymous questionnaire study was designed to assess sexual function after orchidectomy and radiotherapy for testicular cancer. Questionnaires were sent to: (1) 237 patients treated with orchidectomy and abdominal radiotherapy in Edinburgh from 1974 to 1988; (2) 32 patients under "surveillance" following orchidectomy alone; (3) 402 "normal" age-matched controls. All were asked questions concerning sexual function over the preceding 6 months. All the patients were also asked the same questions with reference to the first 6 months after completion of treatment. Completed questionnaires were returned from 137 (62%) radiotherapy patients, 18 (56%) surveillance patients and 121 (35%) controls. There was a significant difference between the radiotherapy patients and the controls in almost all the parameters looked at including erection, ejaculation and libido with the treated group performing less well. In addition, almost 24% of the radiotherapy patients felt disabled or disfigured by the treatment, most commonly because of the presence of only one testicle. A deterioration in sexual function was observed with increasing age. In the radiotherapy group of patients there was no difference in response between the two time periods or in any of the treatment variables. The clinical significance of these observations are unclear but together with the increasing information on other toxicities emerging following this therapy the role of radiation for early stage seminoma is being brought into question. This study also confirms the morbidity of orchidectomy. We suggest that testicular implants should be offered more widely.

Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules.

BACKGROUND: The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial. PURPOSE: To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases. MATERIALS AND METHODS: In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain. RESULTS: Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters. CONCLUSIONS: It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases.

Nipple aspirate fluid in relation to breast cancer.

Samples of breast ductal fluid can be obtained by nipple aspiration. Such samples may contain a variety of exfoliated or shed cells and display a distinctive biochemical profile reflecting the microenvironment of the ductal-alveolar system of the breast. Study of nipple aspirates may, therefore, shed light on the biology of breast cancer. This review summarizes the more important aspects of published data and explores potential avenues for future study with particular regard to molecular-biological approaches.

Metastatic oligodendroglioma presenting as a leukoerythroblastic anaemia.

The clinical course of a patient with oligodendroglioma, treated initially with surgery and radiotherapy, is described. The patient later presented with leukoerythroblastic anaemia due to metastasis to bone marrow. This behaviour had not been previously described in oligodendroglioma.

A clinical microwave hyperthermia system with multipoint real-time thermal dosimetry.

A clinical hyperthermia system using a 915 MHz microwave generator and incorporating multipoint thermocouple thermometry is described. Temperatures can be monitored simultaneously at 16 points and measurements displayed on a visual display unit and a plotter. The power output of the generator is adjusted under computer control to maintain a constant predetermined temperature in a chosen control channel. A clinically useful feature of the system is the ability to determine the effective cumulative thermal dose delivered to the tissue at points monitored in real time. The basis for the thermal dose calculation is discussed in detail. The calculated dose parameter is displayed for each of the 16 channels during the treatment and updated every 30 s. This real-time display of a thermal dose parameter has made possible a more homogeneous heating of tumours.

Radiotherapy for stages I and II testicular seminoma: results and morbidity in 238 patients.

We have undertaken a retrospective analysis of 238 patients with Stages I and II seminoma of the testis treated with radiotherapy in Edinburgh between 1974 and 1989. There were five deaths from seminoma. Cause-specific survival for the whole group at 2 and 5 years was 99.2% and 98.1%, respectively. Cause-specific survival at 2 and 5 years by stage (Royal Marsden staging classification) was: Stage I, 99.5% and 98.7% and Stage II, 98.1% and 96.1%. Fourteen (5.9%) patients relapsed (one after treatment for his second testicular seminoma). Eight were given successful salvage treatment, five died of seminoma and one died of intercurrent disease. 13 (5.5%) patients developed World Health Organisation (WHO) grade 3 gastrointestinal or haematological toxicity and two developed grade 4 gastrointestinal toxicity as a result of abdominal radiotherapy. 22 patients (9.2%) developed problems ascribed to late morbidity of abdominal radiotherapy including 18 with peptic ulcer disease. Contralateral testicular tumours occurred in seven (2.9%) patients and five (2.1%) patients developed malignancies at other sites.

Regional hyperthermia for extensive pelvic tumours using an annular phased array applicator: a feasibility study.

Twenty patients with extensive pelvic tumours have been treated with radiotherapy and regional hyperthermia using an annular phased array applicator (APA). The majority of patients had bulky disease with a mean tumour volume of 206 cm3. In 63 of 67 attempted treatments heating was achieved, temperatures in excess of 42 degrees C being reached in the pelvis in 78%. Heat doses, however, were low, only 41% of treatments exceeding 5 min equivalent at 43 degrees C. Treatment was usually limited by acute toxicity and, although this was marked, it was of short duration and no long-term sequelae have been noted. With gain in operator experience, later treatments have achieved improved thermal doses. Response was difficult to assess but we have documented responses in six of 12 assessable patients. Palliation has been achieved in all patients with symptoms. Preliminary attempts to shift the region of maximum heating by phase variations in the APA output are promising, and this technique should improve the quality of treatments and reduce toxicity. The APA is thus capable of inducing pelvic regional hyperthermia, and a randomised controlled study is now planned to assess the value of pelvic hyperthermia as a treatment modality.

Fertility following cancer therapy.

This article reviews the literature relating to fertility following cancer therapy. Normal fertility clearly relies on normal gonadal and normal sexual function. Consideration is given here to the possible effects of surgery, radiotherapy and chemotherapy on fertility. Surgical techniques have now been described which in selected patients may allow normal erectile and ejaculatory function in the male, where previously impotence was inevitable. Maintaining radiation doses to the testes and ovaries to a minimum will reduce the incidence of radiation-induced sterility and may allow recovery of gonadal function. It is clear that cytotoxic chemotherapy does not inevitably result in permanent sterility. Some regimens are more toxic in this respect than others, and reducing the number of courses may improve the chances of retaining fertility. Hormonal manipulations designed to protect the gonad against cytotoxic damage have thus far been unsuccessful in the clinical situation.

Testicular seminoma in a patient with ataxia-telangiectasia.

The case history of a 27-year-old man with ataxia-telangiectasia (AT) and testicular seminoma is reported. This is the first documented description of such a malignancy in AT, a syndrome associated with a markedly increased risk of malignant disease. Furthermore, alpha-foetoprotein levels have limitations as a tumour marker in this situation because serum levels may be elevated as a biochemical manifestation of AT.

Split course radical radiotherapy for bladder cancer in the elderly: nonsense or commonsense? A report of 76 patients.

The role of split course radical radiotherapy in bladder cancer is controversial. We have pursued such a policy in elderly patients in view of the unpredictable toxicity of radical radiotherapy in this group. Between 1987 and 1992, 76 patients were treated in this way, with 2 weeks' treatment followed by a 3-week gap. Patients were then reassessed and, if considered fit enough, a further 2 weeks of treatment was given. Fifty-three patients (mean age 78.4 years) completed treatment and 23 (mean age 78 years) received phase 1 alone. Thirty-seven of 53 patients completing treatment has a follow-up cystoscopy at 6 months. Twenty-five percent of all patients, 36% of those completing treatment, and 51% of those undergoing cystoscopy, achieved a complete response. The reasons for not completing treatment and not being followed up cystoscopically are examined. We feel that this policy has a role in selected patients whose fitness to tolerate a conventional radical course of radiotherapy is in doubt.

Idiopathic epidural lipomatosis as a cause of pain and neurological symptoms attributed initially to radiation damage.

Epidural lipomatosis is a rare condition in which overgrowth of extradural fat can lead to back pain, spinal cord compression and radiculopathy. A 51-year-old man developed back pain and reduced mobility following a standard course of radiotherapy for a Stage I seminoma. His symptoms and radiological appearances were initially attributed to radiation fibrosis. Further investigations and operative intervention revealed epidural lipomatosis. The excess lipomatous tissue was removed with complete resolution of his symptoms.