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Goal: To longitudinally investigate sexual functioning in testicular cancer patients during the first year, and examine the effect of relationship status (with a partner or single) and depressive symptoms on sexual functioning.Patients and methods: 93 testicular cancer patients (39% single) treated in two large referral centers for testicular cancer filled in the International Index of Erectile Function (IIEF) and CES-D after orchiectomy (T1) and 3 (T2) and 12 (T3) months later.Results: Orgasmic functioning, overall satisfaction and total sexual functioning decreased between T1 and T2 and increased to an above T1 level at T3. Levels of erectile functioning and intercourse satisfaction were higher at T3 than at T1 and T2. Desire remained stable. Type of treatment did not affect sexual functioning. Singles reported worse sexual functioning at all measurement times than committed patients, and comparable desire. One year after surgery, singles also reported worse sexual functioning on three domains when compared with norms. Depressive symptoms were highest and significantly but weakly related to one domain of sexual functioning at T1, to three domains at T2, and to none at T3. Early depressive symptoms had small to moderate predictive power on sexual functioning at T2, but not at T3.Conclusion: Sexual functioning, but not desire, fluctuates during the first year after testicular cancer. Type of treatment and depressive symptoms were no risk factors for sexual dysfunction in the longer term. Singles reported more sexual problems than patients in a relationship and norms, they may need more information and guidance concerning their sexuality. Copyright (C) 2009 John Wiley & Sons, Ltd.

Extrapulmonary small cell carcinoma (EPSCC) is usually treated similarly to small cell lung cancer. Differences in aetiology, clinical course, frequency of brain metastases, and survival, however, warrant a differential therapeutic approach. In this review, we focus on the treatment of the most predominant sites of origin of EPSCC; the gastrointestinal tract, the genitourinary tract, the head and neck region, and small cell carcinoma of unknown primary. Furthermore we review the available data concerning the controversial issue of prophylactic cranial irradiation (PCI) after optimal treatment of EPSCC. We found in the literature a significant lower incidence of brain metastases in EPSCC as compared to pulmonary small cell carcinoma when PCI is omitted and therefore we do not recommend PCI. An exception is EPSCC originating from the head and neck region which is associated with a higher incidence of brain metastasis, justifying addition of PCI. (C) 2008 Elsevier Ltd. All rights reserved.

We studied relatives of adult patients with acquired aplastic anaemia. Eight patients were found to have 11 family members with peripheral blood pancytopenia. Six of the 11 affected relatives had diminished and four normal cellularity and one had hypercellularity of the bone marrow. Thus, 19 persons in these eight families were affected. In two families, father and son were affected, in four families brother and/or sister, in one family a brother and an aunt and in one a nephew of the index patient. None of the patients or family members had congenital defects. All patients were diagnosed at an adult age and, furthermore, also the mode of inheritance in some of the families seems to exclude Fanconi's syndrome. It is concluded that relatives of patients with aplastic anaemia should be screened for manifestations of this syndrome of familial acquired blood pancytopenias.

Purpose Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival. Patients and Methods Data were collected on survival and BLMH genotype of 304 patients with TC treated with bleomycin-containing chemotherapy at the University Medical Center Groningen, the Netherlands, between 1977 and 2003. Survival according to genotype was analyzed using Kaplan-Meier curves with log-rank testing and Cox regression analysis with adjustment for confounders. Results BLMH gene SNP A1450G has a significant effect on TC-related survival (log-rank P = .001). The homozygous variant (G/G) genotype (n = 31) is associated with decreased TC related survival compared with the heterozygous variant (A/G; n = 133) and the wild-type (A/A; n = 140). With Cox regression the G/G genotype proves to be an unfavorable prognostic factor, in addition to the commonly used International Germ Cell Consensus Classification prognosis group, with a hazard ratio of 4.97 (95% CI, 2.17 to 11.39) for TC-related death. Furthermore, the G/G genotype shows a higher prevalence of early relapses. Conclusion The homozygous variant G/G of BLMH gene SNP A1450G is associated with reduced survival and higher prevalence of early relapses in TC patients treated with bleomycin-containing chemotherapy. This association is hypothesis generating and may eventually be of value for risk classification and selection for alternative treatment strategies in patients with disseminated TC.

In this paper we review clinical and genetic aspects of testicular germ cell tumours (TGCTs). TGCT is the most common type of malignant disorder in men aged 15-40 years. Its incidence has increased sharply in recent years. Fortunately, survival of patients with TGCT has improved enormously, which can chiefly be attributed to the cisplatin-based polychemotherapy that was introduced in the nineteen eighties to treat patients with metastasized TGCT. In addition, new strategies have been developed in the surgical approach to metastasized/non-metastasized TGCT and alterations have been made to the radiotherapy technique and radiation dose for seminoma. Family history of TGCT is among the strongest risk factors for this tumour type. Although this fact and others suggest the existence of genetic predisposition to develop TGCT, no germline mutations conferring high risk of developing TGCT have been identified so far. A small deletion, referred to as gr/gr, identified on the Y chromosome is probably associated with only a modest increase in TGCT risk, and linkage of familial TGCT to the Xq27 region has not been confirmed yet. Whether highly penetrant TGCT-predisposing mutations truly exist or familial clustering of TGCT can be explained by combinations of weak predispositions, shared in utero or postnatal risks factors and coincidental somatic mutations is an intriguing puzzle, still waiting to be solved.

The monoclonal antibody against HER2, trastuzumab (Herceptin), has become an important player in the treatment of patients with HER2-positive breast cancer. Both in the metastatic and adjuvant setting, the addition of trastuzumab to other systemic treatments has led to a striking increase in tumor response and survival. The downside with the use of this agent, however, is its inherent cardiotoxicity, which is particularly common when anthracyclines are used concurrently. This review will focus on all aspects of the cardiac side-effects of trastuzumab, ranging from epidemiology and pathophysiology to cardiac monitoring, and treatment and prevention.

Objectives: Surgical resection of postchemotherapy retroperitoneal lymph nodes is often performed in patients with advanced nonseminomatous testicular germ cell cancer. We previously developed a model to predict the probability that the lymph nodes contain only necrotic or fibrotic (benign) tissue versus mature teratoma and viable cancer (tumour) to identify patients who actually need resection. The present study used an updated model with new patient data and studied the validity of the updated model across various settings.Methods: We combined data of 544 patients from the original model with data of 550 new patients and performed a new logistic regression analysis, which included the same six predictors: histology of the primary tumour, prechemotherapy serum levels of alpha-fetoprotein, human chorionic gonadotropin, lactate dehydrogenase, residual mass size measured on computed tomography, and change in mass size. The validity of the updated model was studied in individual centres. Calibration of the predicted probabilities was assessed graphically and with the Hosmer-Lemeshow test. Discrimination was studied with the concordance (c)-statistic.Results: The updated model had slightly different, although more precise, regression coefficients. Statistically nonsignificant Hosmer-Lemeshow tests confirmed good calibration in most centres. The c-statistic for all centres except one exceeded 0.80. The updated model was valid over the complete range of predicted probabilities across a broad spectrum of centres.Conclusions: This finding gives confidence in the applicability of the model to select patients for resection, particularly patients with small residual masses and low predicted probabilities of benign tissue (i.e., substantial predicted risks of residual tumour). (c) 2006 European Association of Urology.

We report a patient with a nonresectable histologically benign solitary fibrous tumor who suffered from paraneoplastic non-islet cell tumor hypoglycemia (NICTH). Diagnostic workup revealed malignant characteristics in which the tumor showed up as, presumably, false-negative on fluorodeoxyglucose-positron emission tomography (FDG-PET), while being positive on tyrosine-PET. Neoadjuvant treatment, which consisted of combined chemo-radiation and consecutive selective embolization of the tumor feeding vessels, caused such a therapeutic effect, on both NICTH and reduction in tumor volume, that a secondary resection, with the patient in a normoglycemic status, was possible. Our report highlights several important issues in the management of the patient with a nonresectable solitary fibrous tumor with severe episodes of hypoglycemia due to NICTH.

Objective: (1) To investigate cancer-related stress symptoms among testicular cancer survivors (TCSs), (2) to gain insight into the relationship Of sociodemographic and cancer-related variables with cancer-related stress symptoms and (3) to assess whether objective and subjective aspects of cancer diagnosis and treatment can be associated with ongoing distress after cancer.Methods: Three hundred and fifty-four TCSs were enrolled in this study and completed the Impact of Events Scale (IES). Thirty TCSs were also selected for interviews: 15 with no and 15 with high levels of cancer-related stress symptoms.Results: Thirteen percent of the TCSs reported experiencing cancer-related stress symptoms. Single TCSs, those with less education, and those who were not employed for wages reported higher levels of stress. Cancer-related variables appeared to play almost no role. Information obtained through interviews suggested that subjective perceptions were more strongly associated with cancer-related stress symptoms than were actual medical histories. Perceptions about the impact of the illness on current life and fear of the future were particularly decisive factors in the presence or absence of cancer-related stress symptoms.Conclusions: It would be beneficial to ask TCSs during follow-up about their thoughts concerning the threats posed by testicular cancer and its effects for their current and future lives, as such perceptions do not necessarily coincide with actual medical histories or current state of health.Practice implications: TCSs who feel that their lives continue to be threatened by their experiences with testicular cancer should be referred for psychosocial intervention. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Stressful life events, such as cancer, may threaten the belief that life is meaningful and this may have a negative effect on well-being. This study aimed at: (1) examining meaning in testicular cancer survivors (TCSs); (2) changes in outlook on life after testicular cancer (TC); (3) the contribution of meaning in the prediction of psychosocial well-being and cancer-related distress. A total of 354 TCSs completed relevant questionnaires. Results showed that: (1) TCSs experience their lives as meaningful; (2) most TCSs (60%) report a more positive outlook on life since TC; (3) meaning is the most important predictor for psychosocial well-being, but its relationship with cancer-related distress is weak. These results indicate that the cancer experience did not (permanently) disrupt the sense of meaning in TCSs. Furthermore, results confirm the idea that a sense of meaning has a positive effect on psychosocial well-being. Meaning appeared to have little effect on cancer-related distress. However, previous research has shown that this relationship may be too complex to unravel with a cross-sectional design. Therefore, it is suggested to further investigate the underlying interacting mechanisms between meaning and cancer-related distress.

Goals of Work: The aim of this study was to (1) assess the quality of life (QoL) of testicular cancer survivors (TCSs) by comparing them to a reference group; (2) investigate the relationship between the QoL of TCSs and sociodemographics, cancer-related variables, and life events; and (3) identify TCSs at risk for an impaired QoL. Patients and methods: Of the TCSs approached, 50% (n=354) participated and completed a generic QoL questionnaire (RAND-36) once. Time since completion of treatment varied from 3 months to 24 years. Main results: (1) TCSs had significantly higher mean scores on the subscales physical functioning (p=0.02) and pain (p=0.001), but lower mean scores on mental health (p=0.04) and vitality (p

Testicular cancer is the most frequent malignancy to men between 20 and 40 years of age. This is a period in life in which important life events take place, such as starting a career and establishing a relationship. The goal of the study was to explore self-esteem. social support. and mental health in 3 groups of survivors of testicular cancer: singles. those with the same partner as at diagnosis (relationship during testicular cancer). and those with a partner they met after completion of treatment (relationship after testicular cancer). A total of 129 survivors completed the Social Support List. the Rosenberg self-esteem scale. and the subscale mental health of the RAND-36. Mean time since diagnosis for single survivors was 8.3 years (range 1-23). for survivors with a relationship during testicular cancer 9.3 years (range 1-24), and for survivors with a relationship after testicular cancer 13.6 years (range 1-24). Levels of social support were equal ill groups. but satisfaction with support was not. Survivors with a relationship during testicular cancer were most satisfied with support, and had the highest self-esteem and mental health. Survivors with a relationship after testicular cancer reported the next best levels of functioning but had the same mental health as singles. Singles and survivors with a relationship established after testicular cancer had a lower mental health than a reference group of men. The difference in self-esteem between singles and survivors of testicular cancer with a relationship during testicular cancer appeared most distinct and was clinically relevant. Mental health was predicted by different factors for the 3 groups. Being single at diagnosis seems to cause a vulnerability that remains when survivors do develop a relationship after treatment is completed because these groups are at risk for a lower mental health. (C) 2006 Elsevier Inc. All rights reserved.

Objective: Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP).Methods: From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype.Results: BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes.Conclusions The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.

Purpose The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men. Patients and Methods We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine. Results Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n = 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI. Conclusion We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.

In recent years, apoptosis has increasingly drawn the attention of both oncologists and cardiologists alike. Anticancer treatment is possible by induction of apoptosis in cancer cells, and targeted anticancer drugs are being developed to promote this. However, since these drugs usually are not selective for malignant cells, side effects on non-cancerous tissue, such as the myocardium must be anticipated. Since apoptosis is a pathophysiological mechanism in cardiac diseases leading to heart failure, cardiologists in contrast to oncologists, aim at preventing apoptosis in the heart. The purpose of this review is to describe new insights in mechanisms of cardiomyocyte apoptosis. In addition to the mitochondrial and death receptor apoptotic pathways, apoptosis through lack or inhibition of growth factor receptor-mediated signalling is discussed. Exploration of the apoptotic pathways in the heart can contribute to the safer use of new anticancer drugs and to the development of new therapies for heart failure. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

The drug-efflux pumps P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are present in the blood-testis barrier (BTB) and may hamper the delivery of cytotoxic drugs to the testis. The precise localisation of P-gp and MRP1 in testicular tissue and the presence of the efflux pumps MRP2 and breast cancer resistance protein (BCRP) in the BTB are unknown. We therefore studied the localisation of these pumps in the BTB in normal testis (n=12), in non-seminoma (n=10) seminoma (n=10), and testicular lymphoma (n=9). Slides were scored semi-quantitatively for P-gp, MRP1, MRP2 and BCRP and blood vessels with factor VIII antibody. In normal testis, P-gp and BCRP were strongly expressed by myoid cells and luminal capillary endothelial wall and P-gp also by Leydig cells. MRP1 was observed at the basal side of Sertoli cells and on Leydig cells. MRP2 was only weakly expressed by myoid cells. Seminomas and non-seminomas expressed P-gp and/or BCRP and/or MRP1, lymphomas strongly expressed P-gp, weakly expressed BCRP and did not or showed weak expression of MRP1. There was very little staining for MRP2 in the tumours. Newly formed vessels in all tumours only expressed P-gp and BCRP. P-gp, BCRP and MRP1 are present in different cell layers of the normal testis, suggesting the optimal protection of spermatogenesis. In germ cell tumours, this expression pattern may explain the chemoresistance observed to P-gp, BCRP and MRP1 substrates. In germ cell tumours and testicular lymphomas, P-gp and BCRP expression by tumour cells and by newly formed vessels may also contribute to chemoresistance. These findings underscore the importance of removing the affected testis in cases of primary germ cell tumours and testicular lymphomas, irrespective of whether the patient has already undergone chemotherapy. (C) 2004 Elsevier Ltd. All rights reserved.

Testicular germ-cell tumours (TGCT) are the most common neoplasm in young men. Various studies have suggested the existence of an inherited predisposition to development of these tumours. Genome-wide screens subsequently provided evidence of a TGCT susceptibility gene on chromosome Xq27 (TGCT1) that might also predispose to cryptorchism. However, this putative gene has yet to be identified, and other TGCT susceptibility genes probably exist. Completion of the human gene map and advances in genetic research will facilitate further investigation of genetic predisposition to TGCT. Insight into inheritance of TGCT might lead to the identification of individuals at increased risk of developing the disorder, increase our understanding of the mutation pathways that lead to sporadic cases, and contribute to improvement in diagnosis and treatment. Clinicians should record the family history of cancer and urogenital differentiation defects in patients with TGCT.

Testicular cancer (TC) as well as malignant lymphoma (NIL), both have nowadays an excellent prognosis. However, both types of cancer may be diagnosed at young adulthood and patients may experience sexual concerns. In this article the need for information and support concerning sexuality will be explored, and the traumatic impact of cancer diagnosis with respect to this will be considered. A total of 264 patients with testicular cancer, median age 36 (S.D. 9.7) years, and 50 patients with malignant lymphoma, median age 42 (S.D. 11.7) years returned a questionnaire concerning sexual functioning; four items assessed the need for information or support concerning sexuality, at diagnosis and at follow-up. It appeared that more than half of the patients with testicular cancer reported a lack of information and support concerning sexuality during treatment; 67% of them still had a need for information at follow-up. These rates were significantly lower for patients with malignant lymphoma. Especially patients with testicular cancer who suffered sexual dysfunction reported extremely high needs for information and support. According to these findings it can be concluded that more attention should be paid to the doctor-patient communication with respect to sexual concerns in general, and especially where it concerns patients with testicular cancer. (C) 2003 Published by Elsevier Science Ireland Ltd

BACKGROUND The association with histocompatibility antigens (HLA), in particular Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic factors involved in testicular germ cell tumor (TGCT) development. The current study, which uses genotyping of microsatellite markers, was designed to replicate previous associations. METHODS In 151 patients, along with controls comprising parents or spouses, the HLA region (particularly Class II) on chromosome 6p21 was genotyped for a set of 15 closely linked microsatellite markers. RESULTS In both patients and controls, strong linkage disequilibrium was observed in the genotyped region, indicating that similar haplotypes are likely to be identical by descent. However, association analysis and the transmission disequilibrium test did not show significant results. Haplotype sharing statistics, a haplotype method that derives extra information from phase and single marker tests, did not show differences in haplotype sharing between patients and controls. CONCLUSION The current genotyping study did not confirm the previously reported association between HLA Class II genes and TGCT. As the HLA alleles for which associations were reported are also prevalent in the Dutch populations, these associations are likely to be nonexistent or much weaker than previously reported. Cancer 2002;95:1857–63. © 2002 American Cancer Society. DOI 10.1002/cncr.10903

With increasing numbers of cancer survivors, attention has been drawn to long-term complications of curative cancer treatment, including a range of metabolic disorders. These metabolic disorders often resemble the components of the so-called metabolic syndrome, or syndrome X, which is an important risk factor for the development of cardiovascular disease. The mechanisms behind the development of metabolic disorders in cancer survivors have not been fully elucidated. However, association studies in the general population have demonstrated correlations between the components of the metabolic syndrome on the one hand and hormonal deficiencies, hypomagnesaemia, and endothelial dysfunction on the other. These latter disorders are regularly reported following curative cancer treatment and could, therefore, be important aetiologic factors in the development of the metabolic syndrome in cancer survivors. This review discusses data on the associations between the metabolic syndrome and treatment-related complications in cancer survivors and possibilities for preventive measures.

Because medical students in The Netherlands should achieve common national objectives, it is important to know whether clinical experiences in different hospitals are comparable. The research questions were: (1) Do students achieve learning experiences of the required diseases during the internship in Internal Medicine and to what extent do they achieve these experiences? (2) Are there differences between the diseases experienced at a university hospital and at community hospitals? Completed logbooks of students were analysed; the percentage of students that achieved the required diseases and the mean number of experiences of diseases were calculated. A t-test was done to test for differences. Medical students in the university and in community hospitals get broad experience (76-131%) of the required diseases. In both hospitals there are many students who are not achieving the requirements, but the mean number of experiences of students at the community hospitals is higher than those at the university hospital. To eliminate the differences between students from the university hospital and the community hospitals, the educational programmes within both hospitals should be adjusted.

The Dutch national objectives for the education of medical doctors (in terms of diseases), expressed in the form of a student compiled logbook, must be attained at the time of graduation. The diseases that are required are divided into the categories 'essential' and 'compulsory choice: The aim of this study is to investigate whether the inpatient department of internal nedicine offers medical students sufficient diseases during two four-week periods in the clerkship, such that the required diseases related to Internal Medicine as described in our logbook can be met. Ar five subdivisions, medical doctors recorded the diseases available for students. Of the 37 'essential' diseases students may be expected to encounter during one four-week stay in the department: 57% in internal medicine-I; 55% in internal medicine-ii; 47% in nephrology; 41% in respiratory medicine; 13% in oncology. Of the 65 'compulsory choice' diseases the number of diseases encountered is respectively: 78%; 57%; 41%; 34%; 33%. We conclude that a considerable number of the diseases required by the Blueprint and therefore by the government is available in two four-week periods in the inpatient clerkship, when this comprises a stay at a general subdivision and a specialist-oriented subdivision. To be more precise about the fulfilment of the logbook requirements, further research is necessary.

Patients cured of metastatic testicular cancer with cisplatin chemotherapy may suffer late adverse effects even after 20 years. The cause of these late adverse effects has not been elucidated yet. One cause might be prolonged tissue retention of platinum in these patients. Therefore, an extremely sensitive method for measuring platinum in plasma was used to investigate whether platinum is still detectable in plasma 10 to 20 years after cisplatin chemotherapy. High-pressure decomposition of plasma is followed by adsorptive voltametric determination of platinum, with a limit of quantification of 6 pg/g plasma. This procedure appeared suitable for the measurement of platinum in 44 former patients with platinum levels ranging from 22 to 140 pg/g plasma. This method is approximately 6000 times more sensitive than the standard flameless atomic absorption spectrophotometry (AAS) method. The platinum levels of these 44 patients were significantly elevated when compared with 20 control patients who were cured of testicular cancer but did not receive cisplatin chemotherapy (p < 0.001). There was a significant correlation between plasma platinum concentrations and follow-up time after cisplatin administration (r = -0.658, p < 0.001). This study shows that patients with testicular cancer who were treated with cisplatin can retain platinum in their body for at least 20 years. More data are needed to investigate whether there is a relation between the prolonged retention of platinum and long-term toxicity.

Literature concerning sexual functioning after treatment for testicular cancer from 1975-2000 is reviewed. After a literature search in Medline and Psylit was conducted, as well as a search for cross-references made, a meta-analysis was performed. To describe sexual functioning, several aspects of the sexual response cycle were used: sexual desire, sexual arousal, erection, and orgasm; ejaculatory function, sexual activity, and sexual satisfaction were used as well. The number of patients included in the studies as well as treatment modalities were taken into account. A total of 36 relevant studies was screened (28 retrospective and 7 prospective studies), concerning 2,786 cases of testicular cancer. Meta-analysis revealed that ejaculatory dysfunction was reported most frequently and was related to surgery in the retroperitoneal area. Erectile dysfunction was related to irradiation, but was reported least frequently. Other sexual functions were not related to treatment modality. Meta-analysis revealed no deterioration of sexual functioning in the course of time, except a decrease in sexual desire and an increase in sexual satisfaction. Retrospective studies reported more sexual dysfunction than did prospective studies. Detailed analysis of separate studies, however, revealed a wide variation in reported sexual morbidity, as well as in assessment methods. Somatic consequences of disease and treatment may reduce ejaculation; however, other aspects of sexual functioning are not clearly related to disease- or treatment-related factors and may instead refer to a psychological vulnerability caused by one's confrontation with a life-threatening, genito-urinary disease, such as testicular cancer.

The anticancer agents fluorouracil, raltitrexed, irinotecan and oxaliplatin show limited efficacy in the treatment of colorectal cancer and may be associated with substantial toxicity. Therefore, the prevention and reduction of chemotherapy-induced adverse effects is of major significance, in accordance with the increasing concern for the quality of life of patients with cancer. Therapeutic drug monitoring of fluorouracil and chronomodulation of fluorouracil and oxaliplatin. have been effective in reducing the incidence and gravity of adverse effects in several clinical trials. However, these concepts have not been implemented in clinical practice yet. At the present time, dose adaptation and supportive measures are the main tools for toxicity control in the treatment of colorectal cancer. In this review, supportive measures for alleviation of the adverse effects of fluorouracil. raltitrexed. irinotecan and oxaliplatin, respectively, are described, based on study results. The main adverse effects of these agents are myelosuppression, oral mucositis, diarrhoea, acute cholinergic syndrome, nausea and emesis, neurotoxicity, hand-foot syndrome and other cutaneous adverse effects, ocular toxicity, cardiotoxicity, small bowel toxicity, asthenia. elevated liver transaminase levels and alopecia. The incidence and gravity of these adverse effects are more or less related to the agent and administration schedule involved. The supportive measures and recommendations include the use of specific drugs, alterations of administration schedule and several nonpharmacological methods. In addition, guidelines for dosage adjustments when toxicity occurs are presented. For optimal management of adverse effects. patients should be considered individually, while patients, nurses and physicians should cooperate to identify and treat adverse effects in an early stage of their development.

BAGKGROUND. The current study reviews chronologic changes in the long term outcome of patients with metastatic nonseminomatous testicular germ cell tumors (NSTGCT) who were treated at a single institution during the past two decades. The 10-year survival of prognostic subgroups according to the classification of the International Germ Cell Consensus Classification Group (IGCCCG) and various other prognostic classifications is examined in time to evaluate whether cumulative experience has led to an improved outcome of patients with metastatic NSTGCT and to explore differences in outcome of prognostic subgroups. METHODS. Two hundred ninety-nine patients with metastatic NSTGCT who were treated with cisplatin-based polychemotherapy during the period from 1977 to 1996 were staged retrospectively according to the Royal Marsden (RM) classification and the following prognostic classifications: IGCCCG, Indiana, Medical Research Council (MRC), and European Organization for Research and Treatment of Cancer (EORTC). The numbers of patients who were treated during the periods 1977-1986 and 1987-1996 were 146 and 153, respectively. Survival curves were constructed using the Kaplan-Meier method, and disease specific 10-year survival rates of prognostic subgroups treated during the two consecutive 10-year periods were compared using the log rank test. RESULTS. The median follow-up of surviving patients during the periods 1977-1986 and 1987-1996 was 14.7 years (range, 0.2-20.6 years) and 7.0 years (range, 0.4-11.4 years), respectively. The actuarial disease specific 10-year survival rate of patients with metastatic NSTGCT increased from 76% during the period 1977-1986 to 88% during the period 1987-1996 (relative risk [RR], 0.51; 95% confidence interval [95% CI], 0.29-0.89; P

Background: Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer. Methods: Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken, Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided. Results: Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend = .02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend = .001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks. Conclusions: Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.

Antitumour therapy in advanced colorectal cancer has limited efficacy. For decades, fluorouracil has been the main anticancer drug for the treatment of colorectal cancer. Recently, however, new agents have been introduced: raltitrexed, irinotecan and oxaliplatin. Currently, the dosage for an individual patient is calculated from the estimated body surface area of the patient. Toxicity, however, frequently necessitates decreasing the dosage, extending the dose interval or even discontinuing treatment. Risk factors with predictive value for toxicity have been identified in several studies, These risk factors are often determined by the pharmacokinetic and pharmacodynamic properties of the drug. In this review, the risk factors for toxicity of the cytotoxic agents used in the treatment of advanced colorectal cancer are con; sidered. For fluorouracil, age, gender, performance status, genetic polymorphism of dihydropyridine dehydrogenase, drug administration schedule, circadian rhythm of plasma concentrations, history of previous chemotherapy-related diarrhoea, xerostomia, low neutrophil levels, and drug-drug interactions have been identified as affecting chemotherapeutic toxicity. For raltitrexed, gender and renal and hepatic impairment, and for oxaliplatin, renal impairment and circadian rhythm of plasma concentrations, respectively, can be considered as risk factors for toxicity. In addition, age, performance status, bilirubinaemia, genetic polymorphism of uridine 5'-diphosphate-glucuronyltransferase-1A1 and drug administration schedule have been shown to be related to irinotecan toxicity. The available literature suggests that dose adjustment based on these risk factors can be used to individualise the dose in order to decrease toxicity and to improve the therapeutic index. This also applies to therapeutic drug monitoring, which has been shown to be effective controlling the toxicity of fluorouracil in some studies. Future research is warranted to assess the potential advantage of dose individualisation of chemotherapy founded on risk factors, over direct dose calculation from the estimated body surface area, with regard to toxicity, therapeutic index, and quality of life, in patients with advanced colorectal cancer.

Today, the standard treatment for patients with clinical Stage I non-seminomatous testicular germ cell tumors (NSTGCT) following orchidectomy is either primary retroperitoneal lymph node dissection (RPLND) or close surveillance with cisplatin-based polychemotherapy in case of a relapse. Both treatment modalities provide excellent overall survival rates up to 100%. Consequently, selection of the most appropriate management option is not primarily guided by survival considerations. The choice between the available options, each having its merits and its drawbacks, should be made based on a number of factors including treatment-related morbidity, views and expertise of the physician, patient preferences, the expected degree of patient compliance, and prognostic factor analysis. To date, the role of adjuvant chemotherapy as an alternative management option for patients with clinical Stage I NSTGCT at high risk of occult metastases is limited. This systemic treatment modality would be a realistic alternative if the reliability of prognostic factors to identify high-risk Stage I patients could be improved. This review addresses relevant issues in the management of patients with clinical Stage I NSTGCT to provide information that will allow a rational selection of the most appropriate management option. Semin. Surg. Oncol. 17:230-239, 1999. (C) 1999 Wiley-Liss, Inc.

Background: The Dutch Blueprint 1994 (Raamplan 1994) describes the objectives of undergraduate medical education. The Blueprint, developed in order to improve medical education in the Netherlands, is accepted by all Dutch medical schools and has been legislated Aim: Translation of global objectives of the Blueprint into specific requirements of a Logbook (guideline and evaluation tool) far the internship Internal Medicine. Description: The Blueprint as such is impracticable as a guideline during the Internal Medicine internship. The content covers the objectives for the entire field of medicine, and the volume dedicated to Internal Medicine is too large to fit in with a twelve week internship. The practicability of the Blueprint leaves much to be desired because it is complex, and not easily accessible. So, the Blueprint was adapted on three points: (1) selecting those objectives out of the whole content, which are specifically relevant to Internal Medicine; (2) decreasing the volume Internal Medicine by clustering and defining the requirements; (3) making the Logbook usable as a guideline and evaluation instrument. Conclusion: The Logbook is a good starting-point to evaluate whether students meet the objectives of the Blueprint related to the discipline internal Medicine. (C) 1999 Elsevier Science B.V. All rights reserved.

The first published chromosomal pattern of the retroperitoneal lymph node metastasis of a malignant gonadal stroma cell tumor of the adult testis is presented. Karyotyping showed structural chromosomal abnormalities and loss of the Y-chromosome. This loss was confirmed in primary tumor and metastasis using fluorescence in situ hybridization (FISH). The characteristic chromosomal abnormality of adult testicular germ cell tumors, an i(12p), was not present. The results are compared with other data of testicular and ovarian sex cord stromal tumors. From the comparison of the male tumors, it is concluded that loss of the Y-chromosome might have a pathogenetic significance.

The present study was performed to gain insight into the decision-making process that patients go through when asked to participate in a cancer clinical trial. Fourteen cancer patients entered a pilot study concerning decision making. They were interviewed in a semistructured manner after consenting or refusing to participate in a randomized phase III clinical trial concerning chemotherapy or immunotherapy. Results from this study showed that patients, after receiving information from the medical oncologist, oncology nurse, or both, decide about participation instantaneously. This means that time for procedural soundness has not been used, which raises questions about the normative quality of the decision.

BACKGROUND This retrospective study evaluates changes in sexual functioning after treatment for testicular cancer and investigates whether there is a relationship with different treatment modalities. METHODS A self-reported questionnaire was sent to 337 men who had been treated for testicular cancer at the University Hospital Groningen between 1977 and 1994. Medical information was obtained from the patient records. RESULTS A response was received from 287 men (85%); 264 patients were included in this study (78%). The mean patient age at follow-up was 37.7 years (range, 17-71 years). The mean follow-up period was 6.7 years (range, 0.25-18 years). Decrease in sexual functions was reported by 40% of patients (decrease in libido: 19%; arousal: 12% erection: 12.5%; orgasm: 19%; and ejaculation: 26%). Moreover, 23.5% of patients responding reported decreased sexual activity and 12.5% were dissatisfied with their sexual functioning. Patients with Stage II-IV nonseminoma who had been treated with polychemotherapy (PCT) with or without resection of residual retroperitoneal tumor mass (RRRTM) (PCT ± RRRTM) reported a significantly sharper decrease in sexual functioning than patients who had been followed with a wait-and-see policy (W & S) (Stage I nonseminoma patients). It was noteworthy that patients treated by PCT alone reported more sharply decreased sexual functioning than patients treated by PCT + RRRTM. Patients treated by radiotherapy (Stage I-IIA seminoma) did not report findings significantly different from the W & S group. CONCLUSIONS Testicular cancer patients are at risk for reduced sexual functioning, especially when treated by chemotherapy, with or without resection of residual tumor. Although chemotherapy may influence somatic aspects of sexual functioning, it appears that psychologic factors arising from the confrontation with testicular cancer play a strongly mediating (if not determining) role. Cancer 1997; 80:454-64. © 1997 American Cancer Society.

Background: TRA 1-60 is a new tumor marker for embryonal carcinoma-positive nonseminomatous testicular germ cell tumors (NSTGCT). Upper normal reference value (RV) and serum half-life (t(1/2)) were determined. The value was determined in the follow-up of 154 patients with stage INSTGCT. Methods: TRA-1-60 was measured in normal controls (n = 100) to determine RV and in patients without recurrence for t(1/2). In all patients, TRA-1-60 was determined at the time of orchidectomy. In 42 patients with recurrence, values were also evaluated 1 month before and at the time of computed tomography-confirmed recurrence. Predictive values and survival probability were examined and compared with values for alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG). Results: RV was 230 U/ml and t(1/2) 9.5 days. Elevated TRA-1-60 at the time of orchidectomy was not associated with recurrence. One month before recurrence, 21 of 42 patients had elevated TRA-1-60 levels (50%); 10 were negative for both AFP and hCG. At the time of recurrence, 24 patients had elevated TRA-1-60 levels (57.1%); 9 were negative for AFP/hCG. Patients with TRA-1-60 levels of >500 U/ml had a poorer recurrence-free survival probability (p = 0.015). Conclusions: TRA-1-60 is useful in the follow-up of stage I NSTGCT. The combination of AFP, hCG, and TRA-1-60 may improve the early detection of recurrence.

In this update, the recent developments in the treatment of patients with advanced seminoma are reviewed. Also, the approach for patients with residual disease after chemotherapy is described. It is concluded that the combination of etoposide and cisplatin seems to be the standard treatment for patients with advanced seminoma, showing a durable response in about 90% of the patients. Although the combination of etoposide and carboplatin is less effective, newer carboplatin-based combinations seem to have a comparable efficacy. Residual disease after chemotherapy can be safely observed if the diameter is less than 3 cm; however, residuals larger than 3 cm frequently show a vital tumor and surgical evaluation should therefore be considered.

BACKGROUND: The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of gonadal function.METHODS: TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3-20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function.RESULTS: In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, [95% confidence interval (CI) 1.5-3.3] compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels CONCLUSIONS: The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.

Background. Hyperpentaploidy in testicular nonseminomatous germ cell tumors (TNSGCT) has been associated with progression of disease of patients who initially had TNSGCT in Stage 1. Methods. The authors used flow cytometry to investigate the relationship between ploidy and the clinical behavior in TNSGCT, focusing on hypertetraploid values (DNA index, > 2.00). Results. Patients with TNSGCT containing an aneuploid stemline with a hypertetraploid value more often had higher clinical stage of disease and a higher chance of relapse in advanced stages. The presence of multiple aneuploid stemlines in the tumors was found more frequently in patients who had higher clinical stage disease. Conclusions. The results suggest that the presence of highly aneuploid or multiple aneuploid stemlines in TNSGCT are associated with a clinically more malignant behavior.

Columnar-lined or Barrett's esophagus is a premalignant condition. It is almost unvariably due to chronic gastroesophageal reflux. Since there are some reports that Barrett's esophagus can be induced by chemotherapy, we investigated 20 male patients, treated with chemotherapy for testicular cancer, and 18 female patients, treated with high-dose chemotherapy for breast cancer. Only one patient in the testicular cancer group had Barrett's esophagus of the circumferential type, in addition to typical reflux esophagitis and a hiatal hernia four years after chemotherapy. In the breast cancer group one patient had an indeterminate junction. Our results do not support the hypothesis that chemotherapy poses a substantially increased risk for the development of Barrett's esophagus.

A phase I trial was conducted with lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) i.v. bolus daily for 5 days every 4 weeks. After entering five patients toxicity appeared to be related to renal function, therefore the individual dose (total dose 20-100 mg m-2 over 5 days) of lobaplatin was modified according to creatinine clearance (CRCL) and escalated in patients. Twenty-seven patients with refractory solid tumours received 72 courses. Thrombocytopenia was dose-limiting, its degree was related to dose and CRCL at time of drug administration. With a CRCL of 60-80 ml min-1 the maximum tolerated dose was 40 mg m-2, with a CRCL of 81-100 ml min-1 70 mg m-2, and with a CRCL > 100 ml min-1 it was 85 mg m-2. Platelet and leukocyte nadirs were observed around day 21. The percentual platelet nadir (percentage of day 1 platelet count) correlated with CRCL at different dose levels and could be described by 0.76 x CRCL (ml min-1) - (1.45 x dose (mg m-2) + 43.38. This equation tested in 20 patients (28 courses) produced a correlation between observed and predicted percentual platelet nadir (r = 0.82, P < 0.001). No renal function impairment occurred. Urinary excretion of platinum (by A.A.S) was estimated in six patients and revealed that 91.5% (s.e. +/- 7.9) of the platinum dose was excreted within 4 h. Responses (one PR, one CR) occurred in two patients with ovarian cancer (both pretreated with carboplatin and cisplatin). The recommended dose of lobaplatin i.v. bolus daily for 5 days for phase II studies depends on renal function, namely 30 mg m-2 at CRCL 60-80 ml min-1; 55 mg m-2 at CRCL 81-100 ml min-1; 70 mg m-2 at CRCL > 100 ml min-1.

In a phase I II study the safety, immunostimulatory and antitumour effects of a combined OKT3/interleukin 2 (IL-2) treatment was studied in 15 cancer patients who failed IL-2 treatment. OKT3 was given as a 2-h intravenous infusion. Doses of 50, 100, 200 and 400 μg OKT3 were studied. Within 24 h, subcutaneous IL-2 was started 5 days/week for 4 weeks, at a dose of 9–18 × 106 U daily. Maximum tolerated dose was 400 μg OKT3 with neurotoxicity as dose-limiting toxicity. Toxicity of subcutaneous IL-2 was acceptable. At the maximum tolerated dose, 9 patients with renal cell carcinoma with measurable disease were treated in a phase II testing. 8 patients were evaluable for response. 4 patients had stable disease and 4 had progressive disease. An increase of activated lymphocyte subpopulations could not be found, although OKT3 was detectable on lymphocytes in vivo. Only if laboratory studies shed light on methods of improving immunostimulating effects of OKT3 will further clinical studies be warranted.

5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhoea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.

The metabolic syndrome, as a cluster of cardiovascular risk factors, may represent an important connection between cancer treatment and its common late effect of cardiovascular disease. Insight into the aetiology of the metabolic syndrome after cancer treatment might help to identify and treat cancer survivors with increased cardiovascular risk. In this review, we summarise current knowledge on the prevalence and pathophysiology of the metabolic syndrome in cancer survivors, and discuss current intervention strategies with an emphasis on new developments.

To define the maximum tolerated dose and to study whether recombinant human interleukin-3 (rhIL-3) reduced chemotherapy-induced neutropenia and thrombocytopenia, 20 chemotherapy-naive patients with advanced ovarian cancer eligible for treatment with 6 cycles of carboplatin- cyclophosphamide every 4 weeks (day 1) were entered in a phase I/II open, single-center trial. Cohorts of five patients received during 7 days 1, 5, 10, or 15 micrograms/kg/d rhIL-3 (days 5 through 11) in cycles 1, 3, and 5 by continuous intravenous (IV) infusion or once daily subcutaneous (SC) administration. In control cycles 2, 4, and 6, no rhIL-3 was administered. rhIL-3 significantly increased the recovery of leukocyte, neutrophil, and platelet counts, especially at 5, 10, and 15 micrograms/kg rhIL-3. rhIL-3 also increased basophil, eosinophil, monocyte, and lymphocyte counts at this dose steps. Effects on reticulocytes were limited. No difference in efficacy between SC and IV rhIL-3 treatment was found. Chemotherapy postponement for insufficient bone marrow recovery was necessary in 22 of 45 control cycles versus 2 of 49 rhIL-3 cycles (P less than .001). Platelet transfusions were required in 7 of 45 control cycles versus 3 of 50 rhIL-3 cycles (P less than .5). rhIL-3 up to 10 micrograms/kg/d could be administered without severe side effects. At 15 micrograms/kg/d, rhIL-3 headache was dose- limiting. Other side effects were fever, flu-like symptoms, nausea, skin rash, flushing, facial erythema, and urticaria. Liver toxicity occurred in rhIL-3 and control cycles. rhIL-3 slightly increased tumor necrosis factor alpha, C-reactive protein, and serum amyloid A plasma levels, whereas no effect on IL-6 plasma levels was observed. rhIL-3 administered SC appears to be an interesting hematopoietic growth factor for reduction of chemotherapy-induced myelotoxicity.

Patients with elevated human chorionic gonadotrophin (HCG) can have hyperthyroidism. We assessed the prevalence of hyperthyroidism in patients presenting with disseminated non-seminomatous germ-cell tumors (NSGCT).In all patients with metastatic NSGCT who started chemotherapy at our center from April 2001 to April 2007, thyroid function was analyzed. The association between thyroid function and HCG level was examined and the frequency of hyperthyroidism in patients with low (5000 IU/l), intermediate (or = 5000 but50 000 IU/l) and high (or = 50 000 IU/l) serum HCG was assessed.For 144 of 148 eligible patients, thyroid function tests were available. Five patients with hyperthyroidism (3.5%) were identified, who all had high-serum HCG (mean 1 325 147 IU/l). Fifty percent of the patients with high HCG levels had hyperthyroidism versus 0% of the patients with HCG50 000 IU/l (P0.001). Free thyroxin levels normalized within 26 days after starting chemotherapy in all patients.Hyperthyroidism frequently accompanies NSGCT with highly elevated HCG. Since its symptoms overlap with those of extensive metastatic disease, it may not be recognized. Thyroid function should be assessed in patients with high HCG levels and symptomatic hyperthyroidism should be treated temporarily with beta-blockade or antithyroidal medication.

We report on a malignant germ cell tumor located in the anterior mediastinum. After chemotherapy the tumor was classified as residual teratoma with sarcomatous components. There was extensive hematopoiesis in the tumor tissue. The tumor cells had a modal chromosome number of 76; the only structural abnormality was a deletion of the long arm of chromosome 9. An i(12p) chromosome was lacking in this tumor. Karyotyping of peripheral blood and bone marrow occasionally showed metaphases with numerical and structural abnormalities, probably related to chemotherapy. The patient died within two years after the initial diagnosis, of a poorly differentiated hematopoietic malignancy, probably of myelomonocytic origin, based on morphology and the fact that non-specific esterase activity was demonstrated in the tumor cells. The karyotype of this malignancy was highly abnormal, but unrelated to that of the mediastinal malignant GCT. In this case there is no proof that the secondary malignancy was derived from the primary mediastinal malignant GCT. In view of the multiple aneuploid stem lines in the primary tumor, this possibility cannot be dismissed either.

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 × 80 mg p.o. or MPA 2 × 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen. Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group ( 25% vs. 43% ), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different ( 20 vs. 16 months). Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20% , and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA. It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.

Serum levels of cortisol (C), androstenedione (A), dehydroepiandrosterone (D), estrone (E 1 ) and estradiol (E 2 ) were chosen as parameters to compare the bioavailability of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in postmenopausal patients with advanced breast cancer. In 36 patients randomized to MPA, the levels of A ( 13% vs. 19% ) and C ( 6% vs. 8% ) were slightly lower than in 36 patients on MA, but D-levels ( 68% vs. 59% ) and E 1 or E 2 , were similar. The correlation between baseline C and A disappeared during treatment. Treatment levels of E 1 and E 2 were correlated. There was no correlation between individual drug levels and any steroid, indicating a maximal suppression. After ingestion of a single dose of MA or MPA, peak levels were found after 2–3 h for MA and 3–4 h for MPA. Four hours after ingestion, the levels of A and C were similar, 40–60% of baseline values, while D levels remained unaltered. Doubling the dose of either drug did not enhance hormone suppression, indicating that the drug dosage is maximally suppressive. In conclusion, although the median serum MA levels are double those of MPA, suppression of A, C and D is usually similar, with corresponding estrogen levels, demonstrating a comparable and maximal bioavailability. Higher dosages of MA or MPA will not increase their pharmacological effects any further.

To establish whether alpha-fetoprotein (AFP) produced in the early post-treatment phase of a patient with a germ cell tumour of the testis or the ovary originates from the tumour or is due to an underlying disturbance in liver function, the binding of AFP to concanavalin A (Con A) was investigated as a discriminative variable. A two-step assay is described that can distinguish the type of AFP produced at levels as low as 10 ng/ml. A Con A-binding ratio of 12–43% was found in the patients with disseminated germ cell tumours and in patients with AFP-positive gastrointestinal carcinomas. AFP from the liver gives ratios below 10%.

Objective: To compare the semen quality and hormonal status between patients with testicular cancer and normal versus increased serum levels of beta-hCG.Design: Retrospective study.Setting: Academic research environment.Patient(s): All 203 patients with testicular cancer who required chemotherapy in the period 1995-2003 were included.Intervention(s): In 107 patients semen samples were stored by cryopreservation; 62 patients could be analyzed because both semen was stored and hormones were determined before starting chemotherapy (median age 25 years, range 17-49 years).Main Outcome Measure(s): Total motile sperm count, T, E(2), LH, FSH, and PRL.Result(s): Total motile sperm count was decreased in patients with increased beta-hCG (median 11.9 x 10(6)) compared with patients with normal beta-hCG (median 21.5 x 10(6)). Testosterone, E(2), and PRL were significantly higher in patients with increased beta-hCG levels, whereas LH and FSH were lower. Semen quality was significantly and negatively correlated with beta-hCG, E(2), and PRL.Conclusion(s): Patients with increased beta-hCG had an inferior spermatogenesis compared with patients with normal beta-hCG. Increased beta-hCG appears to be associated with impaired spermatogenesis and increased levels of E(2) and PRL. (Fertil Steril (R) 2009;91:2481-6. (c) 2009 by American Society for Reproductive Medicine.)