[18F]Fluorodeoxyglucose-positron emission tomography/computed tomography response evaluation can predict histological response at surgery after induction chemotherapy for oligometastatic bladder cancer.

OBJECTIVE: Patients with limited metastatic and locally advanced bladder cancer have a poor prognosis, and no definite treatment recommendations exist. However, long-term survival is possible for selected patients if surgery is combined with multiple courses of chemotherapy (i.e. induction chemotherapy). Patients with tumours that are insensitive to chemotherapy probably have little to gain from subsequent extensive surgery. The aim of this study was to evaluate sequential FDG-PET/CT examinations as an indicator of chemotherapy response. MATERIALS AND METHODS: Between 2007 and 2015, 50 patients with oligometastatic invasive bladder cancer selected for induction chemotherapy underwent two FDG-PET/CT examinations: the first before the start of chemotherapy and the second after three courses of cisplatinum-based combination chemotherapy. Responders were given up to six courses of chemotherapy. FDG-PET/CT response was correlated with histological response in excised lymph-node metastases. RESULTS: Three patients showed progression to incurable disease during chemotherapy and another two patients did not undergo surgery, for medical reasons. Lymphadenectomy was performed in the remaining 45 patients, of whom 43 had lymph-node metastasis. FDG-PET/CT prediction of the histological nodal chemotherapy response was correct in 37 (86%) of those 43. The second FDG-PET/CT examination identified four out of nine non-responders. For response, the sensitivity, specificity, and positive and negative predictive values for FDG-PET/CT accuracy were 37 out of 37 (100%), one out of six (17%), 37 out of 42 (88%) and one out of one (100%), respectively. CONCLUSIONS: Repeated FDG-PET/CT seems to predict histological response. However, with the histological response criteria used in this study, five non-responders were not identified by the second FDG-PET/CT investigation.

Risk factors for post-treatment hypogonadism in testicular cancer patients.

OBJECTIVES: Testicular germ-cell cancer (TGCC) patients are at risk of developing hypogonadism but no risk factors have yet been defined. METHODS: Blood was collected from 143 TGCC patients (after orchidectomy, prior to further therapy (T0) and 6, 12, 24, 36 and 60 months (T6, T12, T24, T36 and T60) after therapy). Biological hypogonadism (BH) was defined as: serum testosterone below 10 nmol/l and/or LH >10 IU/l; odds ratios (ORs) for BH with BH at T0, age, stage of disease, testicular characteristics, and androgen receptor polymorphism as predictors were calculated as well as the OR for developing BH post-treatment (one to two cycles of adjuvant chemotherapy (ACT) versus three to four cycles of higher dose chemotherapy (HCT) versus adjuvant radiotherapy (RT)). RESULTS: HCT increased the OR for BH at T6 (OR 22, 95% confidence interval (CI) 4.4-118) and T12 (OR 5.8, 95% CI 1.5-22). RT increased the OR at T6 (OR 10, 95% CI 2.1-47) and at T12 (OR 3.9, 95% CI 1.1-14). Microlithiasis predicted BH at T0 (OR 11, 95% CI 1.2-112), T12 (OR 3.9, 95% CI 1.1-13), T24 (OR 3.0, 95% CI 1.0-8.8), T36 (OR 5.4, 95% CI 1.7-17) and T60 (OR 4.4, 95% CI 1.2-16). BH at T0 was a risk for BH at T6 (OR 53, 95% CI 19-145), T12 (OR 125, 95% CI 37-430), T24 (OR 88, 95% CI 26-300) and T36 (OR 121, 95% CI 32-460). CONCLUSIONS: It is clinically relevant that BH at T0 and testicular microlithiasis were predictive factors for post-treatment BH. HCT and RT gave temporary BH.

The RsaI polymorphism in the estrogen receptor-beta gene is associated with male infertility.

CONTEXT: Hypospadias, cryptorchidism, testicular cancer, and low semen quality have been proposed as being parts of the testicular dysgenesis syndrome (TDS) hypothetically due to changes in the androgen-estrogen balance in utero. Estrogens and estrogen receptors (ERs) play a role in regulating testicular function. ERbeta contains two silent polymorphisms, RsaI (G1082A) and AluI (G1730A). OBJECTIVE: We investigated the significance of these polymorphisms in the etiology of disorders being part of TDS. SETTING: The patients were recruited consecutively through university hospital clinics. PARTICIPANTS: Four groups of Caucasian patients were included: 106 men from infertile couples with a sperm concentration less than 5 x 10(6) spermatozoa/ml, 86 testicular cancer patients, 51 boys with hypospadias, and 23 cases with cryptorchidism. Military conscripts (n = 186) with sperm concentration higher than 5 x 10(6) spermatozoa/ml served as controls. MAIN OUTCOME MEASURES: ERbeta polymorphisms RsaI and AluI were determined by allele-specific PCR. In addition, reproductive hormone analyses were performed in controls and infertile men. RESULTS: Compared with the controls, the frequency of the heterozygous RsaI AG-genotype was three times higher in infertile men (13.2 vs. 4.3%; P = 0.01). The heterozygous RsaI AG genotype was associated with an approximately 20% reduction in LH concentration, compared with the wild-type RsaI GG genotype in both controls and infertile men. Subjects with testicular cancer, hypospadias, or cryptorchidism did not differ from controls regarding the frequency of any of the polymorphisms. CONCLUSIONS: Polymorphisms in ERbeta may have modulating effects on human spermatogenesis. The phenotype of TDS seems to be, at least partly, determined by the genotype.

Linkage between androgen receptor gene CAG trinucleotide repeat length and testicular germ cell cancer histological type and clinical stage.

Sex hormones and/or gonadotropins may play a crucial role in the development of testicular germ cell cancer (TGCC). A direct link between this malignancy and endocrine factors has not been confirmed. We tested whether CAG and GGN repeats of the androgen receptor gene (AR) play a role in the aetiology or pathogenesis of TGCC. Eighty-three TGCC patients and 220 controls were included. Mean CAG or GGN lengths did not differ between the TGCC cases and controls. The proportion of males with CAG lengths above 25, indicative of reduced androgen sensitivity, was significantly lower among patients with pure seminomas and in the combined group of seminomas and mixed tumours compared with non-seminomas and controls. The median CAG length was higher if the tumour was metastasing at diagnosis. This is the first study showing an association between the AR polymorphism and histological type as well as the progression rate of TGCC.

The impact of testicular carcinoma and its treatment on sperm DNA integrity.

BACKGROUND: In patients with testicular germ cell carcinoma (TGCC), spermatogenesis and fertility are impaired. Intracytoplasmic sperm injection has improved their possibility of fatherhood, but might also impose a risk of transmitting DNA defects to the offspring. The aim of the current study was to evaluate the impact of chemotherapy and irradiation on sperm DNA integrity. METHODS: The study included 74 patients with TGCC. Semen samples were collected before and at specific time points after patients received therapy. Sperm DNA integrity was assessed by the sperm chromatin structure assay. Controls comprised 278 military conscripts. RESULTS: There was no significant difference in the fraction of sperm with fragmented DNA (DNA fragmentation index [DFI]) between controls and patients with TGCC before postoperative cancer treatment (11% vs. 13%). Men treated with adjuvant radiotherapy had a transiently (up to 2 years) higher DFI than nontreated patients (18% vs. 13%; P = 0.03). Patients who received 1-2 cycles of adjuvant chemotherapy had a significantly lower DFI 6 months after treatment than after 1-2 years (9.1% vs. 13%; P = 0.004). Higher doses of chemotherapy among patients resulted in a significantly lower DFI compared with controls (7.3% vs. 11%; P = 0.028), which persisted throughout the 5 years of follow-up. CONCLUSIONS: Postorchiectomy, the DFI in sperm samples from patients with testicular carcinoma was at the level of controls. Radiotherapy caused a transient increase in the proportion of DFI, whereas this value decreased after chemotherapy. The biologic implications of such changes in sperm DNA after cancer therapy need to be elucidated.

Effects of probucol on endothelial damage by 5-fluorouracil.

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.

Endothelial damage after treatment with low-molecular weight heparins--a morphological study.

OBJECTIVE: Recent studies failed to show long-term benefit with low-molecular weight heparins (LMWH) in unstable coronary heart disease. A previous study of vascular effects of the cytostatic agent 5-fluorouracil (5-FU) showed that dalteparin prevented thrombosis induced by 5-FU but endothelial damage was not ameliorated and was present also in animals treated with dalteparin only. This study investigates the influence of LMWH currently in clinical use on arterial endothelium in vivo. DESIGN: Eighty rabbits in four groups were treated with dalteparin, enoxaparin, tinzaparin and saline, respectively. Arterial endothelium was examined after 3, 14, 30 and 60 days with scanning electron microscopy. RESULTS: All three groups treated with LMWH showed moderate damage to the endothelium, with contracted vessel wall and endothelial cells, cell membrane damage, denudation of subendothelium and adhering platelets. Contrarily, the control group exhibited a normal endothelium. CONCLUSION: Morphologic examination of arterial endothelium shows that all investigated LMWH exert a moderate toxic effect on endothelial cells. The clinical impact of these observations, e.g. concerning effect of long-term LMWH treatment, needs to be further elucidated.