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A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents., ((c) 2007 Wiley-Liss, Inc.)

Objectives: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands., Methods: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update., Results: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma., Conclusions: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Background: The purpose of this study was to validate a prognostic index [surgical complete response 1 (sCR1)] in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT)., Patients and Methods: Data and specimens from 61 patients with normalized tumor markers and postchemotherapy viable nonteratomatous NSGCT treated in 13 institutions were collected., Results: With a median follow-up of 5.4 years, the 5-year progression-free survival (PFS) rate was 65%; the 5-year overall survival (OS) rate was 72%. Favorable PFS was predicted by a complete resection, <10% of viable malignant cells, and a good International Germ Cell Consensus Classification group at presentation. Patients were assigned to one of three risk groups defined in sCR1: no risk factor (good risk), one risk factor (intermediate risk) and two to three risk factors (poor risk group). The 5-year PFS rate was 92%, 78%, and 42%, respectively (P = 0.002) (as compared with 90%, 76%, and 41% in the original sCR1 study). The 5-year OS rate was 90%, 86%, and 52%, respectively (P = 0.009) (as compared with 100%, 83%, and 51% in the original sCR1 study). Postoperative chemotherapy did not appear to improve OS compared with surveillance and treatment only at relapse., Conclusion: In patients with postchemotherapy viable NSGCT, a complete resection of residual masses should be rigorously pursued. These data validate the sCR1 prognostic index. Given their excellent outcome, patients in the favorable group may not require postoperative chemotherapy.

Background: Small-cell lung cancer (SCLC) accounts for 15%-20% of all lung cancer cases. Accurate and fast staging is mandatory when choosing treatment, but current staging procedures are time consuming and lack sensitivity., Patients and Methods: A prospective study was designed to examine the role of combined positron emission tomography/computed tomography (PET/CT) compared with standard staging (CT, bone scintigraphy and immunocytochemical assessment of bone marrow biopsy) of patients with SCLC. Thirty-four consecutive patients were included. Twenty-nine patients received initial PET/CT., Results: PET/CT caused change of stage in 5/29 (17%). Excluding patients with unconfirmed findings or pleural effusion, the sensitivity for accurate staging of patients with extensive disease was the following: for standard staging 79%, PET 93% and PET/CT 93%. Specificity was 100%, 83% and 100%, respectively., Conclusion: The results from this first study on PET/CT in SCLC indicates that PET/CT can simplify and perhaps even improve the accuracy of the current staging procedure in SCLC. A larger clinical trial, preferably with consequent histological confirmation in case of discordance, however, is warranted.

Unlabelled: There is an increasing amount of evidence on the usability of PET in response evaluation of non-small cell lung cancer. However, data on SCLC is scarce and mainly retrospective. This prospective study assesses the use of PET (positron emission tomography) and PET/CT in response evaluation of patients with small cell lung cancer (SCLC)., Methods: Assignment of early and final response was compared between PET, PET/CT, and CT in 20 patients with SCLC. Final response as assigned by CT (RECIST) served as reference., Results: At response evaluation after one cycle of chemotherapy major disagreement (responder versus non-responder) between PET and CT in predicting final response was seen in 1 of 12 patients. At final response evaluation major disagreement between PET, PET/CT and CT was seen in 2 of 19 patients (11%). All measurements of FDG-uptake were significantly correlated to size and changes in size as measured by CT. A significant difference in relative change in tumour FDG-uptake and volume was found between responding and non-responding patients. No significant difference was found between a visual and semi-quantitative analysis of PET., Conclusion: Response evaluation of SCLC by PET/CT is feasible, but it is uncertain whether it adds further information to evaluation by RECIST, thus further studies and standardization of methods are needed.

E-cadherin (CDH1) is a transmembrane glycoprotein involved in cellular adhesion. In our recent microarray studies of testicular germ cell tumours (TGCTs) and the common precursor carcinoma in situ (CIS), CDH1 mRNA was highly expressed in CIS and embryonal carcinoma. It has previously been reported that the CDH1 protein is not expressed in CIS. To resolve the discrepancy, we performed a detailed analysis of the expression of CDH1 mRNA and protein in a series of normal and neoplastic testes. High expression of CDH1 mRNA in CIS was confirmed by real-time PCR and in situ hybridisation. At the protein level, however, CDH1 was only detected with one of three tested antibodies, but Western blotting analysis with this antibody showed additional bands, suggesting unspecific staining. The levels of a CDH1 protein fragment in serum samples from 58 patients with TGCTs were analysed by ELISA; we found significantly higher levels in patients with advanced disease (stage II/III) when compared to healthy individuals and patients with stage I TGCT. In conclusion, despite high mRNA levels, the CDH1 protein is not expressed in CIS, suggesting translational suppression of CDH1 protein expression. CDH1 serum levels may be a serological marker for staging of TGCT patients.

Objective: To evaluate the incidence of inguinal metastases in patients with testicular cancer and relapse after initial stage I disease., Patients and Methods: Of 695 patients, 14 (2%) with stage I testicular cancer developed inguinal metastases during the follow-up on a surveillance programme. At orchidectomy, one patient had involvement of the tunica albuginea and one a history of cryptorchidism and development of testicular cancer on the contralateral side. The remaining patients had no history of previous surgery in the inguinal region or in the scrotal area, or any other known risk factors for developing inguinal-node metastases. Two patients had a seminoma (0.5%) and 12 (4%) a nonseminoma. The histopathological examination showed that the metastases were in lymph nodes in four patients, the remainder having a more diffuse involvement of the tissue in the inguinal region. At relapse, patients were treated by three or four cycles of bleomycin, etoposide and cisplatin, except those with low-stage seminomas (stage IIa and IIb), who were treated by radiation therapy., Results: All patients had a complete remission after treatment with chemotherapy or radiotherapy. No patients died or developed a recurrence during the median follow-up of 72 months., Conclusion: Metastases to the inguinal region are found in approximately 2% of patients with testicular cancer; about a quarter have lymph-node metastases, the rest probably having metastases to the spermatic cord with direct invasion into the surrounding tissue. High ligation of the spermatic cord is therefore important. Chemotherapy for patients with nonseminoma and radiotherapy for patients with seminoma gives excellent results.

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease.

Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the "gr/gr" deletion--has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3-3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5-6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.

Testicular germ cell tumours (TGCT), including seminomas, embryonal carcinomas, teratomas and yolk sac tumours, have a common precursor, the carcinoma in situ (CIS) cell. Recent gene expression studies displaying close similarity of CIS cells to embryonic stem cells support the longstanding theory that CIS most likely originates in utero from fetal gonocytes. The clinical association between the testicular dysgenesis syndrome components (TGCT, cryptorchidism, genital malformations, some forms of decreased spermatogenesis) also implies a prenatal origin. Despite high cure rates of TGCT, efforts should be made to obtain diagnosis at the CIS stage, as intervention is possible before an invasive tumour develops, thus reducing the necessity for intensive therapy. CIS may be suspected in patients with an assumed extragonadal GCT or cryptorchidism, and in intersex patients and selected cases with infertility (presenting with atrophic testes and ultrasonic microlithiasis). Surgical testicular biopsy seems the only reliable diagnostic method. The management of choice of unilateral CIS is orchidectomy, or localised irradiation in bilateral cases. At least 5% of TGCT patients present with contralateral CIS; therefore, contralateral biopsy is recommended at the time of orchidectomy. Further research is warranted to identify causal factors explaining the increasing incidence of TGCT and to obtain a method of non-invasive CIS detection.

Background: The use of anthracyclines in treatment of cancer is limited by cardiotoxicity of these compounds and may lead to heart failure. Therefore monitoring of cardiac function is necessary during therapy., Aim: We evaluated the value of natriuretic peptides (N-terminal pro-atrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP)) for monitoring and predicting anthracycline induced cardiotoxicity using radionuclide left ventricular ejection fraction (EF) measurements as reference., Methods and Results: A total of 107 consecutive patients receiving anthracycline as part of their chemotherapy for malignant disease were studied. Plasma concentrations of the peptides were measured by radioimmunoassay and EF by radionuclide cardiography. For reduced EF values, i.e. below 0.50 a fairly strong correlation was found between N-ANP or BNP and EF. Of 48 patients with serial EF and peptide measurements, 19% showed a significant EF decrease (>0.10) and ended with a final EF value below 0.50. Baseline EF was no predictor of a change in EF during treatment. Neither baseline levels of N-ANP or BNP nor a change in the same variables during therapy were predictive of a change in EF., Conclusions: In spite of correlations between peptide concentrations and reduced EF values neither baseline values nor serial measurements can safely substitute EF monitoring in patients undergoing anthracycline therapy.

Germ cell tumour is the most frequent malignant tumour type in young men with a 100% rise in the incidence every 20 years. Despite this, the high sensitivity of germ cell tumours to platinum-based chemotherapy, together with radiation and surgical measures, leads to the high cure rate of > or = 99% in early stages and 90%, 75-80% and 50% in advanced disease with 'good', 'intermediate' and 'poor' prognostic criteria (IGCCCG classification), respectively. The high cure rate in patients with limited metastatic disease allows the reduction of overall treatment load, and therefore less acute and long-term toxicity, e.g. organ sparing surgery for specific cases, reduced dose and treatment volume of irradiation or substitution of node dissection by surveillance or adjuvant chemotherapy according to the presence or absence of vascular invasion. Thus, different treatment options according to prognostic factors including histology, stage and patient factors and possibilities of the treating centre as well may be used to define the treatment strategy which is definitively chosen for an individual patient. However, this strategy of reduction of treatment load as well as the treatment itself require very high expertise of the treating physician with careful management and follow-up and thorough cooperation by the patient as well to maintain the high rate for cure. Treatment decisions must be based on the available evidence which has been the basis for this consensus guideline delivering a clear proposal for diagnostic and treatment measures in each stage of gonadal and extragonadal germ cell tumour and individual clinical situations. Since this guideline is based on the highest evidence level available today, a deviation from these proposals should be a rare and justified exception.

Cancer of unknown origin (CUO) is defined by the absence of any primary tumour in biopsy-proved metastatic cancer. CUO accounts for a 5-10% of all malignancies. These tumors have a specific biology with clinical characteristics of rapid progression and atypical metastases. Diagnostic evaluation is directed at the identification of treatable subset. Accurate diagnostic workup is crucial because both prognosis and survival rates depend mainly on detection of the primary tumor site. Although these patients undergo extensive imaging procedures, nuclear medicine techniques are under-utilized despite their ability of providing molecular information. Positron emission tomography has an emerging role in this clinical challenge along with other nuclear medicine methods including, bone scan, thyroid scintigraphy.

Background: The authors determined the incidence of acute and delayed chemotherapy-induced nausea and emesis (vomiting) (CINV) among patients receiving highly (HEC) or moderately (MEC) emetogenic chemotherapy. They also assessed whether physicians and nurses accurately recognized the incidence of acute and delayed CINV in their own practices., Methods: A prospective, observational study of adult patients receiving HEC or MEC for the first time was performed. Before patient enrollment, medical oncologists and oncology nurses estimated the incidence of acute (Day 1) and delayed (Days 2-5) CINV after first administration of HEC and MEC in their own practices. Eligible patients from their practices then completed a 6-day diary including emetic episodes, nausea assessment, and antiemetic medication use. Observed incidence rates of acute and delayed CINV were compared with physician/nurse predictions., Results: Twenty-four physicians and nurses and 298 eligible patients (67 receiving HEC and 231 receiving MEC) were recruited from 14 oncology practices in 6 countries. Greater than 35% of patients overall experienced acute nausea, whereas 13% experienced acute emesis. Delayed nausea and emesis were observed in 60% and 50% of HEC patients, respectively, and in 52% and 28% of MEC patients, respectively. Delayed symptoms appeared without acute symptoms after HEC (emesis, 38%; nausea, 33%) and MEC (emesis, 19%; nausea, 21%). Physicians and nurses accurately predicted the incidence of acute CINV but underestimated the incidence of delayed nausea and emesis after HEC by 21 and 28 percentage points, respectively, and delayed nausea after MEC by 28 percentage points. Greater than 75% of physicians and nurses underestimated the incidence of delayed CINV after both HEC and MEC., Conclusions: Physicians and nurses markedly underestimated the incidence of delayed nausea and emesis after both HEC and MEC. Delayed nausea and emesis, which may appear even in the absence of acute nausea and emesis, remain important targets for improved therapeutic intervention., (Copyright 2004 American Cancer Society.)

Testicular germ cell cancer is aetiologically linked to genital malformations and male infertility and is most probably caused by a disruption of embryonic programming and gonadal development during fetal life. In some cases, germ cell neoplasia is associated with a relative reduction of Y chromosomal material (e.g. 45,X/46,XY) or other abnormalities of the Y chromosome. The euchromatic long arm of the human Y chromosome (Yq11) contains three azoospermia factors (AZFa, AZFb, AZFc) functionally important in human spermatogenesis. Microdeletions encompassing one of these three AZF loci result in the deletion of multiple genes normally expressed in testis tissue and are associated with spermatogenic failure. The aim of our study was to investigate whether AZF microdeletions, in addition to causing infertility, predispose also to germ cell neoplasia, since subjects with poor spermatogenesis have an increased risk of testicular cancer. We screened for putative deletions of AZF loci on the Y chromosome in DNA isolated from white blood cells of 160 Danish patients with testicular germ cell neoplasia. Interestingly, although AZF microdeletions are found frequently in patients with idiopathic infertility, in all cases studied of testicular germ cell cancer the Yq region was found to be intact. We conclude that the molecular aetiology of testicular germ cell neoplasia of the young adult type most likely does not involve the same pathways as male infertility caused by AZF deletions. Malignant transformation of germ cells is thus caused by the dysfunction of some other genes that still need to be identified.

Background: The aim of this study was to determine the prevalence of testicular carcinoma in situ (CIS) in patients with a malignant extragonadal germ-cell tumour (EGGCT) and the incidence of metachronous invasive testicular cancer (TC) in relation to the pretreatment demonstration of CIS., Patients and Methods: Sixty-eight patients with EGGCT (53 retroperitoneal, 15 mediastinal) had pre-chemotherapy histological assessment of one (13) or both (55) testicle(s). A total of 123 testicles were examined for the presence of CIS., Results: Testicular CIS was found in 21 patients (31%) (18 retroperitoneal EGGCT, three mediastinal EGGCT). Two patients had bilateral CIS. Five patients, four of them with proven pretreatment CIS, developed a metachronous TC. The 10-year invasive-free TC survival rate for all 68 patients was 88%, but only 65% for those with proven pretreatment CIS. The overall 10-year survival rate for all patients was 82%. CIS was demonstrated in seven of 48 trans-scrotal core biopsies, in 10 of 56 trans-scrotal surgical biopsies and in five of 11 orchiectomy specimens., Conclusions: Approximately one-third of patients with EGGCT present with testicular CIS, predominantly those with a retroperitoneal tumour. These patients have a considerable risk of metachronous TC development in spite of chemotherapy. The pretreatment demonstration of testicular CIS in patients with EGGCT gives the possibility of individualised counselling and safe follow-up, and is therefore highly recommended. The data are in agreement with a multi-site development of malignant germ-cell tumours, but do not exclude the possibility that the retroperitoneal EGGCTs in particular represent metastases from a burned-out TC.

Purpose: Testicular germ cell tumors (GCT) occur at increased frequency in men with human immunodeficiency virus (HIV). This multicenter study addresses the characteristics of these tumors., Patients and Methods: Patients with HIV-related GCT were identified from six HIV treatment centers. The incidence was calculated from the center with the most complete linked oncology and HIV databases., Results: Thirty-five patients with HIV-related GCT were identified. The median age at GCT diagnosis was 34 years (range, 27 to 64 years). The median CD4 cell count was 315/mm3 (range, 90 to 960/mm3) at this time. The histologic classification was seminoma in 26 patients (74%) and nonseminomatous GCT in nine patients (26%). Twenty-one patients (60%) had stage I disease and 14 patients had metastatic disease. Overall six patients relapsed, three died from GCT, and seven died from HIV disease, resulting in a 2-year overall survival rate of 81%. HIV-related seminoma occurred more frequently than in the age- and sex-matched HIV-negative population, with a relative risk of 5.4 (95% confidence interval, 3.35 to 8.10); however, nonseminomatous GCT did not occur more frequently, and there was no change in the incidence of GCT since the introduction of highly active antiretroviral therapy., Conclusion: Testicular seminoma occurs significantly more frequently in HIV-positive men than in the matched control population. Patients with HIV-related GCTs present and should be treated in a similar manner to those in the HIV-negative population. After a median follow-up of 4.6 years, 9% of the patients died from GCT. Most of the mortality relates to HIV infection.

Relapse occurs in 30% of patients with stage I non-seminomatous germ cell tumours (NSGCT) within 1 year after orchiectomy. Whole-body positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) may detect small metastases when standard staging with computed tomography (CT) and tumour markers is negative. In this study, 46 patients underwent FDG-PET after staging with normal CT and tumour markers. To exclude diagnostic test bias and workup bias, all patients had routine follow-up with repeated CT and tumour marker evaluation, even though the initial FDG-PET was positive. Thirty-six patients have remained disease free with a median follow-up of 48 months (range 24-76). Ten patients (22%) suffered disease relapse after a median of 2 months (range 1-8), and of these, seven had a true positive initial PET with increased uptake of FDG indicating metastatic disease. There were three false negative and no false positive PET scans. The sensitivity, specificity and accuracy of PET were 70%, 100% and 93%, respectively. The sensitivity of detecting small retroperitoneal metastases was 88%. The negative and positive predictive values were 92% and 100%, respectively, whereas the negative predictive value of standard staging procedures was 78%. FDG-PET thus seems to be superior to conventional staging (P=0.06) in stage I NSGCT. This non-invasive method may improve the overall management of patients with NSGCT.

Treatment results on 695 stage I testicular cancer patients followed with surveillance are described. Seminoma (SGCT) was present in 394 patients and nonseminoma (NSGCT) in 301 patients. Relapses were detected in 155 patients (22%), in 69 patients with SGCT (17%) and 86 with NSGCT (29%). In patients with vascular invasion, relapse was detected in 54% of patients with NSGCT and 38% of patients with SGCT. Time to relapse was median 13 months (range 1 to 84 months) for SGCT and 5 months (range 1 to 171 months) for NSGCT. Forty-nine percent of relapses in SGCT patients were seen within the first year, 87% of the relapses were diagnosed within the first two years, and 98% of the relapses were detected within 5 years. The figures for NSGCT were 80%, 89% and 95%, respectively. Forty-five patients had carcinoma in situ in the contralateral testis, 62% had this together with a seminoma in the other testis. Ten patients died during the follow-up period. None of these deaths were caused by the germ cell tumour or the treatment. The overall survival for patients with stage I disease is 98.6%, and the cause specific survival 100%.

CIS is found in the contralateral testis in 5% of the patients with testicular germ cell cancer. The management of CIS in the contralateral testis is important because the majority - if not all - cases of CIS will progress to invasive disease without treatment. It is well documented that testicular irradiation with a total dose of 14-20 Gy (2 Gy x 7-10) is an effective and safe treatment for CIS in the contralateral testis in patients with unilateral testicular germ cell cancer. However few relapses of testicular cancer have been observed in testis treated with these regimens and the data on 14 Gy are sparse. One study has indicated that more radiotherapy with lower doses per fraction could be useful, but more data are needed to confirm this. Endocrine testicular function has been shown to be impaired already before treatment in patients with CIS and is further impaired after testicular irradiation with 14-20 Gy (2 Gy x 7-10) and only minor dose dependency is seen in the impairment of Leydig cell function. The optimal treatment of CIS in the contralateral testicle in patients orchidectomised for testicular cancer seems to be local radiotherapy of the testis with CIS in order to preserve at least a part of the Leydig cell function. However, the optimal dose level has to be defined.

Changes in the length of a polymorphic trinucleotide (CAG) repeat in the androgen receptor (AR) gene, which may lead to altered transactivation of the AR gene, have been implicated to play a role in the pathogenesis of several forms of endocrine cancer and certain reproductive disorders. Subjects with reproductive disorders that are associated with a relative deficiency of androgen function carry an increased risk for testicular cancer, therefore we have examined the (CAG)n in the AR gene in DNA isolated from peripheral blood cells of 102 patients diagnosed with testicular germ cell neoplasia and compared them with a control group of 110 healthy men with proven fertility. All patients and control subjects underwent comprehensive andrological examination that included reproductive hormone profiles and the analysis of the (CAG)n in the AR gene that was done by means of PCR and DNA sequencing. There was no difference in the distribution of (CAG)n between the subjects and controls, no association of (CAG)n and the tumor type and no association with severity of the disease. We conclude that the high risk of testicular germ cell cancer in the Danish population is not associated with the (CAG)n polymorphism in the AR gene., (Copyright 2002 Wiley-Liss, Inc.)

TRA-1-60 antigen has been related to the presence of embryonal germ cell carcinoma (EC) and carcinoma in situ. Our study further investigated the clinical efficacy of TRA-1-60 as a serum tumor marker for germ cell cancer in the testis. Three groups of patients with germ cell tumors were included: Group 1, 34 patients with disseminated disease (24 nonseminomatous germ cell tumors [NSGCT] and 10 seminomatous germ cell tumors [SGCT]); this group of patients were followed during the course of chemotherapy with measurements of TRA-1-60, HCG and AFP; Group 2, 28 patients with Stage I NSGCT (22 with embryonal carcinoma [EC]-component and 6 without EC-component, median follow-up 15 months); and Group 3, 40 patients with Stage I pure SGCT (median follow-up 15 months). Seventy-eight percent of patients with disseminated EC-positive NSGCT had increased levels of TRA-1-60 before chemotherapy. After chemotherapy, levels of TRA-1-60 had dropped significantly (p < 0.01). Levels of TRA-1-60 did not normalize in 15% of NSGCT and 30% of SGCT patients after chemotherapy. This was not associated with recurrent disease. Approximately one-third of patients with Stage I NSGCT had increased values of TRA-1-60 during follow-up without having a relapse. Contrary to earlier reports TRA-1-60 is not at present useful as a tumor marker in patients with germ cell tumors. Although detecting a few early relapses the rate of false positive elevations in the tumor marker makes it unreliable in the clinical setting. Our study did confirm that elevated levels of TRA-1-60 were present in approximately 80% of patients with disseminated EC-positive NSGCT before start of chemotherapy and chemotherapy induced a significant decrease in levels of TRA-1-60. Thus, the TRA-1-60 antigen might still prove clinically useful provided that the reliability of the assay can be increased., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function., Patients and Methods: Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients)., Results: All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels., Conclusion: Testicular irradiation is a safe treatment at dose level 20 Gy (10 x 2 Gy). Decrease of dose to 14 Gy (7 x 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.

Purpose: To elucidate the biologic association between germ cell neoplasia and testicular dysfunction, through investigation of Leydig cell function and semen quality in men with carcinoma-in-situ (CIS) of the testis., Patients and Methods: We examined two groups of men, unilaterally orchidectomized for testicular cancer. Biopsy of the contralateral testis had showed CIS in a group of 24 patients and no evidence of CIS in the other group of 30 patients. Semen quality and serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were compared in these two groups of men after orchidectomy but before further treatment for testicular cancer., Results: Significantly higher LH levels (median, 8.1 IU/L v 4.8 IU/L; P < .001) and generally lower testosterone levels (median, 12.5 nmol/L v 15.5 nmol/L; P = .13) were found in the CIS group. The proportion of patients with Leydig cell dysfunction was higher in the group of patients with CIS (11 of 24) than in the group of patients without (two of 30) (P = .01). Sperm concentration and total sperm count were significantly lower (P < .001) in patients with CIS (median, 0.03 x 10(6)/mL and 0.10 x 10(6), respectively) than in patients without (median, 9.1 x 10(6)/mL and 32 x 10(6), respectively), whereas the levels of FSH were significantly higher (P < .001) in the former group of men (median, 19.6 IU/L v 9.0 IU/L)., Conclusion: Not only spermatogenesis but also Leydig cell function is impaired in testes with CIS. This impairment could be due to common factors in the pathogenesis of germ cell neoplasm and testicular dysfunction. Alternatively, CIS cells may have a negative impact on Leydig cell function.

A group of men treated with testicular irradiation for carcinoma in situ in the remaining testis after orchidectomy for unilateral testicular germ cell cancer was used as a model to study of the effect of selective eradication of germ cells on the levels of serum inhibin B in the human male. Thirteen men with verified spermatogenesis and detectable preirradiation levels of serum inhibin B (median, 55; range, 23-193 pg/mL) were investigated before and after testicular irradiation (14-20 Gy). All patients had undetectable levels of inhibin B 2-12 months (median, 5 months) after radiotherapy (<20 pg/mL). Correspondingly, serum FSH increased in all men after radiotherapy [from a median of 9.6 (range, 3.0-24) IU/L to a median of 28 (range, 15-70) IU/L); P < 0.001]. Histological investigation showed a Sertoli cell-only pattern in all patients after radiotherapy. Neither LH nor testosterone showed a significant decrease after radiotherapy. Our data indicate that inhibin B production sufficient to maintain detectable serum levels in adults requires spermatogenic activity.

Brain metastases from small cell lung cancer respond to chemotherapy, but response duration is short and the intracerebral concentration of chemotherapy may be too low because of the characteristics of the blood-brain barrier. Positron emission tomography has been applied in a variety of tumors for studies of metabolic and hemodynamic features. This study was performed to determine regional cerebral metabolic rate of glucose (rCMRglu), regional cerebral blood flow (rCBF), and regional cerebral blood volume (rCBV) in brain metastases from small cell lung cancer and the surrounding brain. Tumor rCMRglu, rCBF, and rCBV exerted a broad variability, but were higher than the corresponding values in white matter and higher than or similar to those of gray matter. Tumor rCMRglu and rCBF were highly correlated (P < 0.01, r = 0.79). No correlation between survival and metabolic or hemodynamic parameters could be demonstrated. After radiotherapy, mean tumor rCMRglu decreased from 0.40 to 0.31 micromol/g/min (not significant), and rCBF and rCBV remained unchanged. However, cortical rCBF demonstrated a trend of increased values after radiotherapy from 0.37 to 0.49 ml/g/min (P = 0.13). No change in rCMRglu was observed in gray or white matter after radiotherapy. Global CBF seems to be reversibly depressed by the metastases, but local hemodynamic changes in the tumor could not be detected with positron emission tomography in this study. An association between high tumor rCMRglu and rCBF as an indicator of hypoxia was not observed. Other methods for noninvasive in vivo analysis of tumor hemodynamics are needed, especially for discrimination between tumor necrosis and hypoxia.

Testicular tumors are bilateral in approximately 5% of the cases, although the incidence of bilaterality is affected by the treatment of the primary tumor. A biopsy of the contralateral testis of testicular tumor patients will show carcinoma in situ (CIS) in 5% to 6% of cases. Virtually all untreated cases of CIS will progress into invasive testicular germ cell tumors. In some countries, most testicular tumor patients have a contralateral biopsy at the time of the primary orchiectomy; but in many countries, urologists are not always aware of the advantages of simultaneous contralateral biopsy. The policy in the United States does not encourage surgeons to perform a contralateral biopsy at the initial orchidectomy or to offer a biopsy to patients after referral to a specialist center. The diagnosis of CIS is not of mere academic interest, but makes it possible to offer the patient optimal treatment.

Nine patients with stage III and stage IV thymoma were treated with cisplatin, vincristine, lomustine, cyclophosphamide and prednisolone. Two patients (22%) obtained remission, and four patients (44%) showed no change for 11 to 31 months. It was found that this five-drug regimen did not improve the results obtained by other chemotherapy modalities for thymoma.

Therapy-related acute myeloid leukemia (t-AML), often presenting as myelodysplasia (t-MDS), has become the most serious long-term complication of cancer therapy and offers a unique opportunity to study chemical leukemogenesis. Seven cohorts of patients treated for six different types of primary tumor have been followed closely for leukemic complications, and 115 consecutive patients with t-MDS or t-AML, including 45 cases from the cohorts, have been investigated cytogenetically at our institutions during the past 16 years. In patients primarily treated with alkylating agents, the risk of t-MDS and t-AML increased by approximately 1% per year from 2 to at least 8 years after start of treatment. In most cases, the disease presented as t-MDS with loss of a whole chromosome 5 or 7, or various parts of their long arms, and the leukemias were of FAB-subtypes M1, M2, or M4. In patients treated with drugs targeting at DNA-topoisomerase II, such as etoposide, doxorubicin, 4-epidoxorubicin, or mitoxantrone combined with drugs reacting directly with DNA, such as cisplatin or alkylating agents, the risk of leukemia increased much more steeply from only one year after start of therapy. These early onset cases often presented as overt leukemia of FAB-subtypes M4 or M5 with balanced translocations to chromosome bands 11q23 and 21q22, whereas later onset cases often shared characteristics with cases observed after therapy with alkylating agents alone. Both alkylation of DNA and poisoning of DNA-topoisomerase II may result in development of t-AML with different clinical and cytogenetic characteristics. There may be a synergistic leukemogenic effect between the two types of drug, and in patients with germ cell tumors treated with etoposide, cisplatin and bleomycin, reassessment suggested the risk of leukemia to increase exponentially with increasing doses of cisplatin and etoposide.

A total of 102 men treated for germ cell tumor with chemotherapy containing cisplatin was referred for a secondary operation with signs of tumor in the retroperitoneum or chest. Of the patients 85 underwent laparotomy, 14 underwent thoracotomy and 3 had both operations. Residual tumors were completely resected in 66 patients and incompletely resected in 30, while no tumor was found in 6. The resected specimen was malignant in 18 patients, of whom 11 had complete removal of all malignant tissue. All patients with malignancy in the resected specimen received further chemotherapy. Long-term disease-free status was obtained in 75% of those patients who had a complete resection, compared with 14% in the group with incomplete resection. There was no evidence of malignant disease at operation in 78 patients but 5 of them later died of the disease. Malignant tissue was present in the residual tumor in only 1 of 15 patients whose primary tumor was seminoma alone. Resection was attempted in 14 patients despite abnormal tumor markers preoperatively. Only 5 of these patients achieved a disease-free status and 2 of them died later of malignant disease. Over-all 79 of the 102 patients are without evidence of disease (medium postoperative observation 23 1/2 months). We conclude that a secondary operation constitutes an important part of the treatment of patients with germ cell cancer.

Cisplatin is currently one of the most used agents in the treatment of cancer and it is essential in the treatment of germ cell cancer. The use of the drug is hampered by side effects - especially renal toxicity which is dose limiting. The present work was undertaken to elucidate the pathophysiological mechanisms involved in cisplatin induced nephrotoxicity. Immediately after administration of cisplatin to dogs, renal blood flow (RBF) and glomerular filtration rate (GFR) remained unchanged, while proximal reabsorption rates decreased significantly. The cisplatin induced nephrotoxicity is thus initiated by an acute, mainly proximal tubular impairment, preceding alterations in renal hemodynamics. These data were confirmed in a micropuncture study in rats. At 48 to 72 hours after administration of cisplatin depressed renal function could be attributed to impairment of proximal as well as distal tubular reabsorptive capacities, now associated with increased renal vascular resistance. After administration of 4 cycles of 20 mg cisplatin/m2 d. for 5 days in humans, a small but significant decrease in 51Cr-EDTA clearance was observed. In the high-dose cisplatin group (40 mg/m2 d. for 5 days) a severe progressive decrease in GFR was observed during treatment and GFR remained decreased for up to 2 years after termination of treatment. The observation of an acute increase in N-acetyl-beta-D-glucosaminidase and beta-2-microglobulin indicates a primary tubular effect of cisplatin also in humans. A marked reduction of proximal tubular reabsorptive capacities of sodium and water was also observed in this group, together with a decrease in distal tubular function. These changes persist for at least 6 months after treatment. In the high-dose group proteinuria developed. This was mainly of tubular origin during cisplatin infusion and of glomerular origin between treatment cycles. Cisplatin remains one of the most potent antineoplastic agents ever developed. Further work should be performed to reduce its potential for renal toxicity.

Twenty-six patients, previously treated with cisplatin, vinblastine and bleomycin (pVB) had residual or recurrent germ cell tumors and were treated with cisplatin, etoposide and bleomycin (peB). Six patients obtained complete response and 11 patients partial response. Of the 11 patients with partial response 5 were disease free after post-chemotherapy surgery. Seven patients are still alive without evidence of disease with a median follow-up of 40 months (range 14+ - 57+ months). One patient died from acute non-lymphocytic leukemia without evidence of germ cell cancer. Toxicity was modest with only three patients having leukopenic fever. Retrospectively, the patients were analyzed in two groups according to their initial prognostic features. Thirteen patients were considered to have unfavourable prognostic factors and all had progress/relapse after treatment with peB. It is concluded that peB might be useful as first line therapy because of modest toxicity and considerable activity in pretreated patients and that more intensive therapy is necessary in patients with unfavourable prognostic features.

Forty-two patients with small cell carcinoma of the lung were treated with cycles given every 28 days consisting of a combination of vindesine (3 mg/m2 if on Days 1 and 15), cisplatin (75 mg/m2 iv on Day 1), and hexamethylmelamine (200 mg/m2 orally on Days 8-22). Thirty-four patients were evaluable for response. Partial remission (PR) or complete remission (CR) was noted in seven (three CRs and four PRs) of nine previously untreated patients (77%) and in eight (one CR and seven PRs) of 25 patients treated previously with intensive chemotherapy (32%). This drug combination deserves consideration for inclusion in sequential combination chemotherapy regimens.

Intensive combination chemotherapy consisting of cisplatin 40 mg/m2 daily X 5, VP-16 200 mg/m2 daily X 5 and bleomycin 15 mg/m2 every week was administered to 29 patients (22 previously untreated and seven previously treated) with poor prognosis germ cell tumors. Eighty-six per cent of the previously untreated patients obtained CR and 5% PR. Seventeen patients (77%) are alive without evidence of disease after a median observation time of 11 months (range 1+-19+ months) after treatment. Seventy-one per cent of the previously treated patients obtained CR and 14% PR. Six patients are still alive and four (57%) without evidence of disease after a median observation time of 9 months (range 3+-12+ months) after treatment. Toxicity was severe in both groups. In 73% of the cycles WBC was below 1.0 X 10(9)/1, and in 74% of the cycles thrombocytes was below 25 X 10(9)/1. Ninety-one per cent had at least one incidence with culture negative neutropenic fever, and in four patients bacteremia was documented. Kidney function decreased (median 33%) in previously untreated patients as measured by 51Cr-EDTA clearance. Ototoxicity was observed in around 60% of the patients (two patients has required the use of a hearing aid) and neurotoxicity in around 40%. Neurotoxicity was mild in most cases. The results of the present investigation are encouraging and justify an aggressive therapeutic approach to patients with poor prognosis germ cell tumors. The toxicity is substantial, but manageable, and only a prospective randomized study can substantiate whether this excess in toxicity can be translated into an improved survival and cure.

The effect of three cycles of high-dose cisplatin (40 mg/m2 day for 5 days) on renal tubular function was evaluated in 30 patients. A significant impairment of proximal tubular salt and water reabsorption rates was observed, but also distal tubular function seemed to be affected. These changes were also present 6 months after termination of treatment. Sodium and magnesium clearance increased significantly during treatment. Magnesium clearance normalized shortly after treatment but sodium clearance was significantly elevated 6 months after treatment. Proteinuria, albuminuria, and amino aciduria, together with an increase of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) excretion rates, were observed during each treatment cycle. A good correlation was registered between the increase in urinary excretion rates of protein, NAG, and magnesium and the decrease in proximal tubular salt and water reabsorption during cisplatin administration.

To investigate the effect of high-dose cisplatin (40 mg/m2 daily for 5 days), 51Cr-EDTA clearance was used as a measure of glomerular filtration rate (GFR). 51Cr-EDTA clearance decreased significantly from 109 +/- 3 ml/min * 1.73 m2 to 68 +/- 3 ml/min * 1.73 m2 after three cycles of cisplatin and remained at this decreased level during the observation period (24 months). To determine the reliability of creatinine as a measure of GFR, we compared the simultaneous clearance of creatinine to that of 51Cr-EDTA. A good correlation between 51Cr-EDTA clearance and creatinine clearance was observed before and 3 months after termination of treatment, but no correlation was found during treatment. S-creatinine decreased significantly during treatment, probably due to muscle wasting. We conclude that s-creatinine and creatinine clearance are unsuitable measures of glomerular function during high-dose cisplatin treatment. All patients developed proteinuria during treatment. The changes in clearance ratios of beta-2-microglobulin/albumin and IgG/albumin show that the proteinuria observed during cisplatin infusion is predominantly of tubular origin, whereas the proteinuria between the treatment periods is mainly of glomerular origin.

The present study was designed to investigate the early hemodynamic and tubular effects of cisplatin administration on dogs. To localize the nephrotoxic actions of cisplatin, we have taken advantage of the lithium clearance method. After infusion of 5 mg of cisplatin per kg, an immediate and significant increase in urinary flow rate (from 0.39 +/- 0.07 ml/min to 0.73 +/- 0.12 ml/min), sodium clearance (from 0.33 +/- 0.11 ml/min to 0.65 +/- 0.14 ml/min), potassium clearance (from 9.23 +/- 0.48 ml/min to 10.77 +/- 0.95 ml/min), lithium clearance (from 15.55 +/- 2.21 ml/min to 23.76 +/- 4.00 ml/min) and fractional lithium clearance (from 0.31 +/- 0.03 to 0.44 +/- 0.04) was seen. This occurred without measurable changes in glomerular filtration rate and renal blood flow. The calculated fractional as well as absolute rates of proximal reabsorption of sodium decreased significantly from 0.68 +/- 0.03 to 0.56 +/- 0.04 and from 4.76 +/- 0.32 mmol/min to 3.92 +/- 0.23 mmol/min, respectively. The results show that administration of cisplatin causes an acute, mainly proximal tubular impairment in dogs without alterations in renal hemodynamics.

After an observation period of about 10 years a follow-up examination was made of 22 Greeks earlier exposed to torture. All had physical symptoms and about 90% of the examinees had chronic psychological symptoms which had appeared after the torture experience, the most notable of which were emotional instability, depression, passivity, fatigue and disturbed sleep. Eight of the victims had a chronic organic psychosyndrome as defined by us. The clinical picture of the torture victims is very similar to other stress-conditioned syndromes, which underlines the significance of the psychological trauma for the pathogenesis. Certain physical symptoms can be related to specific forms of torture; in this series particularly, symptoms of the feet and lower extremities can be related to 'falanga' (repeated blows to the soles of the feet). The most noticeable objective finding was unilateral atrophy of testis in 2 of the examinees caused in all probability by genital torture. Treatment of the sequelae to torture should be initiated as early as possible in the course of the illness, and studies on the effect of this treatment should be carried out.

Testicular biopsies were done in 15 consecutive patients who were believed to have extragonadal germ-cell tumours. 8 patients (53%) had carcinoma-in-situ (CIS) in the gonads, although none had clinical signs of tumour. In addition, 3 of these patients had small areas of invasive tumour growth. Germ-cell tumours can only be diagnosed as being extragonadal in origin if testicular biopsy appearances are normal.

Sixteen patients with primary extragonadal germ-cell tumors were treated at the Department of Chemotherapy, Finsen Institute, Copenhagen from 1976 to 1982. Twelve patients received a combination of cis-diamminedichloroplatinum (cisplatin), vinblastine and bleomycin (PVB). Eight patients had a complete remission and 5 had a partial response. Eighty-six percent of the patients achieving complete remission remain free of disease after a median follow-up of 42 months. The best results with PVB were obtained in teratocarcinomas and embryonal carcinomas, while more effective chemotherapy regimens are needed for the treatment of choriocarcinomas and endodermal sinus tumours.

Forty patients with poor prognosis germ cell tumours were treated with a combination of cisplatin 40 mg/m2 and VP-16 200 mg/m2, both given days 1-5 every 3 weeks, and bleomycin 15 mg/m2 every week. Of thirty-three previously untreated patients twenty-eight (85%) patients obtained complete remission (CR) and four (12%) patients partial remission (PR). One patient was not evaluable for response. Twenty-four patients are alive 2-32 months after completion of therapy without evidence of disease (median observation 18.5 months). Of seven patients previously treated with cisplatin, five obtained CR (71%), one PR (14%) and one patient had progressive disease. Five patients are still alive, four without evidence of disease after a median follow-up of 22 months (range 16-25 months).

Administration of cisplatin (5 mg/kg) to dogs results in polyuric renal failure due initially to a proximal tubular functional impairment. 48-72 h after the cisplatin administration the depressed renal function can be attributed to impairment of proximal as well as distal tubular reabsorptive capacities associated with increased renal vascular resistance. The polyuria seems to be due to the impaired reabsorption rate in the distal nephron segments.

The immediate effect of cisplatin on rat proximal tubular function was investigated by two different methods, the lithium clearance method and the occlusion time-transit time method (TT-OT). Within minutes after administration of cisplatin a significant increase in lithium clearance, fractional lithium clearance (CLi/Cin) and e-TT/OT was observed (from 270 +/- 32 to 387 +/- 60 microliters/min/g kidney weight, 0.202 +/- 0.03 to 0.340 +/- 0.06 and 0.415 +/- 0.02 to 0.497 +/- 0.02, respectively). These increases indicate an increased fluid delivery from both the proximal straight segment and the late proximal convoluted tubule after cisplatin administration. Concomitantly absolute proximal reabsorption rate was significantly decreased. Intervention by saline loading (2% of body weight) did not prevent the increase in e-TT/OT, but the increase in CLi/Cin was significantly less than in the control group. This finding suggests that saline loading protects either the pars recta of the proximal tubule or the juxtamedullary nephrons. Thus, cisplatin-induced nephrotoxicity in the rat is initiated by an acute mainly proximal tubular impairment including both pars convoluta and pars recta of the proximal tubule.