Association of PAI-1 gene polymorphism with survival and chemotherapy-related vascular toxicity in testicular cancer.

BACKGROUND: High Plasminogen-Activator Inhibitor 1 (PAI-1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI-1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the PAI-1 promoter (rs1799889), which may influence PAI-1 expression, is associated with survival and chemotherapy-related vascular toxicity in testicular cancer (TC). METHODS: Data were collected on PAI-1 4G/5G polymorphism, survival, venous thromboembolism (VTE), and coronary heart disease (CHD) for 324 non-seminomatous TC patients treated with platinum-based chemotherapy. Genotypes were compared regarding survival and disease outcome. VTE and CHD incidence were compared with adjustment for cardiovascular risk factors and prothrombotic gene polymorphisms of coagulation factors II/prothrombin (G20210A) and V (G1691A). RESULTS: The 4G/4G variant of PAI-1 4G/5G polymorphism shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared with 4G/5G and 5G/5G (24% vs 8% and 15%; chi-square P = .003). In addition, the 4G/4G variant shows reduced TC-related survival with a hazard ratio of 2.69 (95% CI, 1.26-5.73; P = .010) for TC-related death (adjusted for IGCCC). This is related to an increased risk for refractory disease and early relapses (odds ratio, 3.35; 95% CI, 1.48-7.59; P = .004). PAI-1 4G/5G polymorphism is not associated with VTE and CHD risk. CONCLUSIONS: The 4G/4G variant of PAI-1 4G/5G polymorphism may be an unfavorable prognostic as well as predictive factor for response to chemotherapy in TC patients. If confirmed, it may contribute to the identification of patients with increased risk for refractory disease.

The metabolic syndrome in cancer survivors.

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.

Sexual function, depressive symptoms and marital status in nonseminoma testicular cancer patients: a longitudinal study.

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.

Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer.

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.

Testicular cancer: a longitudinal pilot study on stress response symptoms and quality of life in couples before and after chemotherapy.

GOALS OF WORK: The current study was designed to longitudinally examine stress response symptoms (SRS) and quality of life (QoL) in couples confronted with disseminated testicular cancer. The objectives were to examine couples' patterns of adjustment over time and possible differences in adjustment between the patient and his partner. MATERIALS AND METHODS: Couples completed the Impact of Event Scale and the QoL subscales physical functioning, social functioning, and mental health of the RAND-36 before chemotherapy (T1), after completion of chemotherapy (T2), and 1 year later (T3). RESULTS: Before chemotherapy 26% of the patients and 50% of partners reported clinically elevated levels of SRS. Patients reported lower physical and social functioning at T2 compared to T1 and T3. Partners reported an improvement in social functioning over the year and no changes in physical functioning or mental health. No relationships between patients and partners' functioning were found. One year after diagnosis, QoL of patients and partners was similar to that of reference groups, and patients even reported better physical functioning than the reference group. SRS of patients and partners were negatively related at T1, and patients and partners' social functioning were positively related at T2. CONCLUSIONS: According to stress response levels, the period before the start of chemotherapy was most stressful for couples. Adjustment patterns differ between testicular cancer patients and their partners with patients reporting lowered QoL after completion of chemotherapy. QoL of couples returned to normal levels 1 year after diagnosis. The effect of disseminated testicular cancer on the QoL of patients and their partners seems to be temporary. A minority may need clinical attention for severe SRS.

Self-esteem, social support, and mental health in survivors of testicular cancer: a comparison based on relationship status.

Testicular cancer is the most frequent malignancy in 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 in 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.

Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer.

PURPOSE: After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. PATIENTS AND METHODS: In 65 testicular cancer patients (median age, 27 years; range, 18 to 48 years), we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy: platelet numbers, plasma levels of hemostatic and fibrinolytic factors, 24-hour ambulatory blood pressure, baroreflex sensitivity, intima-media thickness of the common carotid artery, and flow-mediated vasodilation of the brachial artery. RESULTS: Compared with prechemotherapy values, the intima-media thickness of the carotid artery and plasma von Willebrand factor levels increased significantly after treatment. Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly. Blood pressure decreased significantly, but flow-mediated vasodilation and baroreflex sensitivity did not change. CONCLUSION: In testicular cancer patients treated with cisplatin-based chemotherapy, we found an increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term.

Classification and occurrence of clinically significant drug interactions with irinotecan and oxaliplatin in patients with metastatic colorectal cancer.

BACKGROUND: Pharmacokinetic and pharmacodynamic drug interactions with cytotoxic drugs may significantly influence the efficacy and toxicity of chemotherapy. OBJECTIVE: The purpose of this study was to identify drug interactions with irinotecan and oxaliplatin reported in the literature, to assess their clinical significance, and to examine the occurrence of these interactions in patients with metastatic colorectal cancer treated with either irinotecan or oxaliplatin or both. METHODS: To obtain data on drug-drug interactions with irinotecan and oxaliplatin, a literature search of PubMed and EMBASE was conducted using the search terms irinotecan, oxaliplatin, and interactions (English-language studies only published between 1980 and August 2004). The interactions found were subsequently classified for documentation evidence and severity of clinical effect, according to a 5-level classification system of a standard reference text, by a study panel of medical oncologists and clinical pharmacists. Comedication of patients who were treated with irinotecan or oxaliplatin, or both, was then examined to determine the occurrence of clinically significant interactions. RESULTS: Ninety-eight patients (50 women, 48 men;mean age, 60 years) were included in the study. Seventeen interactions with irinotecan were found in the literature, and 11 were classified as clinically significant. Only 1 nonspecific, clinically significant interaction was identified for oxaliplatin. Irinotecan-treated patients received a mean of 8 different comedications and oxaliplatin-treated patients received a mean of 6. Apart from antiemetic and antidiarrheal drugs that were prescribed for treatment-related toxicities, only 1 patient appeared to be exposed to a possible clinically significant interaction (between irinotecan and phenytoin). CONCLUSIONS: Eleven of the 17 interactions with irinotecan that were found in the literature were classified as clinically significant versus 1 clinically significant interaction with oxaliplatin. The occurrence of these interactions in the study patients with metastatic colorectal cancer was low. For medication surveillance purposes, however, the significant interactions should be considered in clinical practice.

Educational needs of general practitioners in palliative care: outcome of a focus group study.

BACKGROUND: The objective of this study was to identify the general practitioner's perception of educational needs in palliative care. METHOD: A qualitative study with focus groups was performed. RESULTS: General practitioners estimate palliative care as an important and valuable part of primary care. Nevertheless, they consider their coordinating role as a course with increasing obstacles. Pain, nausea, dysphagia, delirium, insomnia, anxiety, and depression were mentioned frequently as symptoms difficult to deal with in palliative care. Also, psychosocial issues such as communication, bereavement, and defense mechanisms were subject to discussion in the focus groups. Ethical issues such as euthanasia were mentioned as the most complex subject in palliative care. CONCLUSIONS: General practitioners experience difficulties with their coordinating role in palliative care. With more basic knowledge and skills in communication, but also with consultation, their roles as coordinators of palliative care in primary care will improve. Reflection and deepening of ethical values are necessary conditions for an optimal functioning.

The dilemma of the strive for apoptosis in oncology: mind the heart.

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.

Marital and sexual satisfaction in testicular cancer survivors and their spouses.

GOAL: To compare marital and sexual satisfaction of men who survived testicular cancer (TC) and their spouses to a reference group, and to compare marital and sexual satisfaction of couples who had a relationship at time of diagnosis (couples during TC) to couples who developed a relationship after completion of treatment (couples after TC). PATIENTS AND METHODS: Two hundred and nineteen couples during TC and 40 couples after TC completed the Maudsley Marital Questionnaire, a validated instrument to measure marital and sexual satisfaction. RESULTS: Survivors and spouses of both couple groups reported similar marital satisfaction as men and women of the reference group. Survivors (t=2.9, p<0.01) and spouses (t=2.9, p<0.01) of couples during TC and survivors of couples after TC (t=1.9, p=0.05) reported less sexual satisfaction than the reference groups. Survivors of couples after TC reported less sexual satisfaction than survivors of couples during TC (F=4.0, p<0.05). Correlations between sexual satisfaction of survivors and spouses in couples during TC (r=0.76, p<0.001) and couples after TC (r=0.77, p<0.001) were high. CONCLUSION: Testicular cancer did not appear to have a negative effect on marital satisfaction in couples during TC, although TC survivors and their spouses reported less sexual satisfaction than men and women of the reference group. Survivors who developed a relationship after completion of treatment seemed to form a vulnerable group: their sexual satisfaction was lower than that of men in the reference group and of TC survivors with a longer relationship. Besides that, they more often reported marital problems than their spouses did.

Quality of life and stress response symptoms in long-term and recent spouses of testicular cancer survivors.

The aim of this study was to gain insight into the quality of life (QoL) and stress response of female spouses of men cured of testicular cancer in the long-term. Time since treatment completion varied from 0.5 to 23.8 years. Two hundred and fifty nine testicular cancer survivors and their spouses completed the Dutch version of the MOS Short Form (SF)-36 and the Impact of Event Scale. QoL data from a reference group of women were used for comparison. Spouses who had relationship with the testicular cancer survivor before the diagnosis (spouses during testicular cancer) had better functioning scores than the reference group, especially with respect to the physical QoL domains. Spouses who had started a relationship after treatment (spouses after testicular cancer) experienced more problems with psychological QoL domains than spouses during testicular cancer and than the reference group. The stress response of spouses during testicular cancer was related to that of the testicular cancer survivors and to the extent of treatment they had received. Although stress response levels were low, spouses during testicular cancer reported more stress response than the testicular cancer survivors. Time since completion of treatment did not affect QoL or stress response. This study showed that spouses during testicular cancer had a good QoL and little stress response. Functioning of spouses after testicular cancer was poorer with respect to various QoL domains, particularly the psychological measures.

Male sexuality after cancer treatment--needs for information and support: testicular cancer compared to malignant lymphoma.

Testicular cancer (TC) as well as malignant lymphoma (ML), 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.

Non-germ cell malignancy in residual or recurrent mass after chemotherapy for nonseminomatous testicular germ cell tumor.

BACKGROUND: After chemotherapy for nonseminomatous testicular germ cell tumor (NSTGCT), residual masses or recurrent disease may contain a non-germ cell malignancy (NGCM). METHODS: Over 20 years, 369 patients with disseminated NSTGCT were treated with cisplatin-based polychemotherapy at the University Medical Center Groningen. Residual tumor masses were resected in 244 patients and recurrent tumor masses in 37 patients. Histology was reviewed, focusing on the presence of NGCM. RESULTS: Nine patients developed an NGCM. Four patients had an NGCM in the resected residual tumor mass after chemotherapy: three patients had a sarcoma, and one patient had both a sarcoma and an adenocarcinoma. Five patients developed a late recurrence with an NGCM after 39, 40, 72, 72, and 84 months. One patient had a primitive neuroectodermal tumor, one had a sarcoma, and three had an adenocarcinoma in the resected recurrent tumor mass. A complete surgical resection was achieved in five (56%) of the nine patients. After a median follow-up of 48 months (range, 3-271 months), five patients had no evidence of disease (56%), three patients were dead of disease (33%), and one patient was alive with disease (11%). CONCLUSIONS: Sarcoma, adenocarcinoma, or both in residual or recurrent tumor masses after combined-modality NSTGCT treatment are rare. Complete surgical resection of the tumor mass is the only curative treatment option.

Testicular carcinoma and HLA Class II genes.

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.

The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures.

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.

The educational yield of the international summer school "Oncology for Medical Students".

BACKGROUND: The international summer school "Oncology for Medical Students" (ISOMS) is a two-week summer program for medical students aiming to increase knowledge of cancer care in general health practice, to reduce fear related to contacts with patients with malignant disease, and to expose them to cancer-related problems in other countries. This study was undertaken to evaluate the impact of the program on cancer-related knowledge and attitudes of the participants. METHOD: The 39 students enrolled in the fifth ISOMS in July 2000 were assessed using precourse and postcourse tests. The students and tests were both split in two groups with crossover to improve the validity of the test results. The attitude-related questions were the same in the precourse and postcourse tests. RESULTS: Increases in knowledge were significant (p = 0.001), and there was a slight change in attitudes towards cancer-related problems. Evaluation by the students revealed that the course had mainly improved their overview of the field of oncology, awareness of the psychosocial aspects of cancer care, and approach to cancer patients, which they appreciated more than the knowledge gain. CONCLUSION: The ISOMS has a significant impact on knowledge as well as on attitudes towards cancer patients.

The availability of diseases for medical students in a university hospital.

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. At 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.