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Background: The Surgery in Early Metastatic Seminoma (SEMS) trial examined retroperitoneal lymph node dissection as first-line treatment for patients with isolated 1-3 cm retroperitoneal lymphadenopathy. To date, the standard of care for these patients has been either chemotherapy or radiotherapy. Herein, we evaluated the relative cost-effectiveness of these management strategies., Methods: A microsimulation model assessed the cost-effectiveness of retroperitoneal lymph node dissection, chemotherapy, and radiotherapy for stage IIA seminoma. Sensitivity analyses were performed to evaluate model robustness. Retroperitoneal lymph node dissection recurrence probabilities were obtained from the SEMS trial. All other probability and utility values were obtained from published literature. Primary outcomes included costs from a commercial insurer's perspective, effectiveness (quality adjusted life-years [QALYs]), and incremental cost-effectiveness ratios using a willingness-to-pay threshold of $100 000/QALY., Results: At a lifetime horizon, the mean costs per patient for retroperitoneal lymph node dissection, radiotherapy, and chemotherapy were $58 469, $98 783, and $104 096, and the mean QALYs were 40.61, 40.70, and 39.15, respectively. Retroperitoneal lymph node dissection was found to be the most cost-effective approach because of high costs and accrued disutility of chronic toxicities associated with radiotherapy (cost-effectiveness ratios = $433 845/QALY) and chemotherapy (dominated). On 1-way sensitivity analyses, retroperitoneal lymph node dissection was no longer cost-effective if the probabilities of infertility and cardiovascular toxicity after radiotherapy were less than 13% and 16%, respectively, or if the 2-year probability of progression after retroperitoneal lymph node dissection was more than 26%., Conclusions: Retroperitoneal lymph node dissection was the most cost-effective treatment approach for stage IIA seminoma. These findings support clinical guideline consideration of including retroperitoneal lymph node dissection as a treatment option for well-selected patients with stage IIA seminoma., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Testicular germ cell cancer (TC) incidence peaks during reproductive age, but knowledge on fertility after treatment is insufficient. The aim was to evaluate paternity after today's TC treatment., Methods: Clinical data were extracted from the Danish Testicular Cancer database, and patients were divided into 4 groups: 1) surveillance; 2) bleomycin, etoposide, and cisplatin (BEP); 3) BEP + postchemotherapy retroperitoneal surgery (BEP + surgery); and 4) abdominal radiotherapy. For each patient, 10 men matched on date of birth were randomly sampled from the normal population. Paternity was defined as date of birth of first child after TC treatment with or without the use of assisted reproductive technology and was assessed by linkage to the Danish Medical Birth Register and the Danish in vitro fertilization register., Results: We included 4846 unilateral TC patients and 48 456 men from the normal population. The 20-year predicted chance of obtaining fatherhood for a 30-year-old man was 39.7% in TC patients compared with 42.5% in the normal population. The chance of obtaining fatherhood was statistically significantly decreased after BEP (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.78 to 0.97) and BEP + surgery (HR = 0.74, 95% CI = 0.63 to 0.87), but not after radiotherapy (HR = 0.89, 95% CI = 0.75 to 1.06) or surveillance (HR = 0.95, 95% CI = 0.89 to 1.02). The risk of needing assisted reproductive technology to obtain fatherhood was increased after all treatment modalities., Conclusions: The chance of obtaining fatherhood after TC treatment was substantially higher than previously reported. Patients followed on a surveillance program had a similar chance of obtaining fatherhood as noncancerous men., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Orchiectomy followed by infradiaphragmatic radiotherapy is a common treatment for stage I-II testicular seminoma. Long-term effects of orchiectomy and radiotherapy for testicular seminomas on body image and sexual function have been reported; however, few data are available on short-term effects. Patients are usually of reproductive age and sexually active; therefore, short-term effects on body image and sexual function should also be studied., Aims: To prospectively evaluate short-term effects of orchiectomy and radiotherapy on body image and sexual function in testicular seminoma patients., Methods: Questionnaires on body image and sexual function were prospectively distributed to all testicular seminoma patients treated between 1999 and 2013. The questionnaire distributed prior to radiotherapy was returned by 161 patients; 133 (82%) returned the second after 3 months, and 120 (75%) completed the questionnaire after 6 months., Main Outcome Measures: Body image and sexual function as assessed by a Dutch questionnaire on body image and sexuality after radiotherapy and orchiectomy., Results: Median age was 36 years (range 18-70). After orchiectomy, 48% expressed fertility concerns, and 61% reported their body had changed. Six months after treatment, erectile rigidity was significantly decreased compared with prior to radiotherapy (P = 0.016), and 23% reported decreased sexual interest, activity, and pleasure. Changes in body image were significantly associated with decreased sexual interest, pleasure, and erectile function. Even though 45% reported that treatment negatively affected their sexual life, the number of sexually active patients remained stable at 91%. [Correction added on 12 November 2014, after first online publication: 'prior radiotherapy' was corrected to 'prior to radiotherapy'.], Conclusions: Short-term effects of treatment included fertility concerns and changes in body image. Reported erectile rigidity was significantly decreased after 6 months, as were sexual interest, activity, and pleasure. Disease and treatment had negative effects on sexual life, and changes in body image were associated with sexual dysfunction. Therefore, body image and sexual functioning should be addressed at an early stage in order to offer adequate treatment and counseling., (© 2014 International Society for Sexual Medicine.)

Objective: To elucidate the patterns and risk factors for loss to follow-up during active surveillance for Stage I seminoma., Methods: A total of 425 cases with Stage I seminoma underwent radical orchiectomy from 1985 to 2006 at 25 Japanese institutions, including 22 community hospitals and 3 university hospitals. The post-orchiectomy management selected was active surveillance for 186 patients, adjuvant radiotherapy for 182 patients and chemotherapy for 57 patients. The Kaplan-Meier method was used to estimate the recurrence-free survival and loss to follow-up rate. The risk factors for loss to follow-up were examined using Cox's proportional hazards model with multiple variables., Results: The 2-, 5- and 10-year loss to follow-up rates in the active surveillance group were 14.2, 37.8 and 71.3%, respectively, which were not significantly different in comparison with those in the active surveillance and adjuvant radiotherapy or chemotherapy groups. With regard to the active surveillance group, the multivariate analysis demonstrated that patients younger than 36 years at diagnosis, patients diagnosed since 2000 and patients treated at hospitals that enrolled more than 10 cases had a significant risk for loss to follow-up. No significant correlation between the loss to follow-up rate and pathological risk factors such as tumor size (≤4 versus >4 cm) and rete testis invasion (presence versus absence) was shown., Conclusions: The loss to follow-up rates beyond 5 years were unsatisfactorily high during active surveillance. Further approaches to improve the quality of active surveillance are needed, especially for high-risk patients such as those of younger age.

We report the case of a 41-year-old man with a late recurrence of nonseminomatous germ cell tumor, which was successfully treated with intensity-modulated radiation therapy. For the residual retrocrural tumor invading the 11th and 12th thoracic vertebrae with an abnormal level of tumor marker (α-fetoprotein: 23.2 ng/ml) after salvage chemotherapy, chemotherapy could not be continued due to its neurotoxicity, and surgery could not be performed due to the location. In this situation, intensity-modulated radiation therapy achieved a complete response of tumor marker. The patient remained in complete clinical remission after 3 years. The efficacy of radiotherapy, especially intensity-modulated radiation therapy, for a nonseminomatous germ cell tumor is discussed.

Computed tomography (CT) imaging contributes to a major part of medical radiation exposure. With regard to patients safety, frequent CT examinations (CTEs) performed on the same patient are of particular concern. Tools for tracking the individual patient radiation exposure history and cumulative dose assessment may become important. Here, the applicability of the NRPB-SR250 software was assessed in a retrospective analysis of radiation doses from CTE made consecutively in male patients. Most of the examinations focused on the abdomen or the whole body. The mean number of CTs per patient was 6.8. Significant cumulative effective doses were observed: 76 (66 %) patients received an effective dose higher than 50 mSv, while the maximum was ∼280 mSv. A more than 3-fold effective dose difference was observed between scanners, depending on the scanning protocols. The NRPB-SR250 software proved to be a robust tool for the assessment of organ doses and the effective radiation dose from CT, while challenges were encountered in finding the precise imaging data in retrospective protocols.

Background: From July 1, 1989, through March 31, 2001, 2466 patients with stage I seminoma were evaluated in three randomized noninferiority trials: the TE10, TE18, and TE19 trials. We analyzed mature results of these studies., Methods: The TE10 trial randomly assigned 478 patients to para-aortic and ipsilateral iliac lymph node (dogleg field) or para-aortic only radiation therapy (total dose = 30 Gy). The TE18 trial randomly assigned 1094 patients to a total dose of 30 or 20 Gy of radiation therapy, predominantly to a para-aortic field. The TE19 trial randomly assigned 1477 patients to radiation therapy or a single injection of carboplatin at a dose of seven times the area under the curve. Time to relapse was determined from Kaplan-Meier curves, and such data were compared by use of Cox regression models. Noninferiority in TE18 and TE19 required the upper limit of the 90% confidence intervals (CIs) (reflecting the one-sided test for noninferiority at a 5% statistical significance level) to exclude a hazard ratio (HR) of greater than 2.0 and a doubling of the 5-year relapse rates observed in the control arm. The TE10 trial was not powered to exclude clinically relevant differences in overall relapse rates but was assessed against the same criteria., Results: Median follow-up times were 6.4-12 years in the three trials. We identified the noninferiority of the following treatments: 20 Gy of radiation therapy in the TE18 trial (HR of relapse = 0.63, 90% CI = 0.38 to 1.04) and carboplatin in the TE19 trial (HR of relapse = 1.25, 90% CI = 0.83 to 1.89). Para-aortic radiation therapy in the TE10 trial was associated with a hazard ratio of relapse of 1.15 (90% CI = 0.54 to 2.44). Relapse occurred after 3 years in only four (0.2%) of all 2466 patients. Computed tomography scans had little impact on the detection of relapse after radiation therapy; seven of the 904 patients allocated radiation therapy in TE19 had a relapse detected by this method., Conclusion: This large and mature dataset from three randomized trials has provided support for the use of either radiation therapy or carboplatin therapy as adjuvant treatment for stage I seminoma.

Background: We assessed sperm DNA fragmentation index (DFI) in cancer patients before and after treatment to evaluate if sperm DNA integrity is compromised by cancer itself or its treatment., Methods: In a prospective study, DFI was assessed in 127 patients diagnosed with testicular germ cell tumours (TGCT), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL) and various malignancies. The severity of cancer and tumour markers at diagnosis was recorded. Follow-up DFI after treatment was available in 52 patients who were mostly less severely affected., Results: In patients diagnosed with TGCT, HL and various malignancies, pretreatment DFI levels were not significantly different from that of proven fertile controls, but in patients with NHL an increased DFI was found. An overall significant decrease in post-treatment DFI (13.2% range 5.0-70.5) compared with pretreatment values (17.1% range 5.1-66.6) was found (P = 0.040). In TGCT patients, post-treatment DFI was significantly higher in patients who were treated with radiotherapy (16.9% range 11.5-39.9) compared with that in patients treated with chemotherapy (CT) alone (10.9% range 5.5-39.9) (P = 0.037). In HL patients, the type of treatment or number of CT cycles was not associated with DFI. Overall, post-treatment DFI in cancer patients was not significantly different from that of proven fertile controls., Conclusions: In this study, the presence of cancer does not seem to negatively affect the sperm DNA integrity in TGCT and HL patients; only NHL patients showed increased DFI at the time of diagnosis compared with healthy controls. Our results confirm previous reports that DFI decreases significantly following various anti-cancer treatments. In contrast, radiotherapy in TGCT patients is associated with an increase in DFI compared with CT treatment alone.

Background: Testicular cancer survivors, many of whom have undergone radiotherapy, are at substantial risk of second cancers. Treatment for testicular cancer may limit treatment options for second cancers, thereby adversely affecting survival after the second cancer. However, no data on outcomes of testicular cancer survivors with second cancers compared to patients with comparable first cancers exist., Methods: Among 29356 white testicular cancer patients reported to the Surveillance, Epidemiology, and End Results (SEER) program (1973-2002), 621 developed a second cancer with known stage and were matched to a random sample of 12420 white male first cancer patients in the SEER program by cancer site, stage, diagnosis year, and age at diagnosis. Mortality was ascertained through 2002. Cancer-specific and all-cause mortality following second cancers were compared with those of matched first cancers, and rate ratios (RRs) were estimated using proportional hazards analysis. Survival functions were calculated using product-limit estimates., Results: During the study period, 284 testicular cancer survivors with second cancers died, 191 from their second cancer; 5443 matched first cancer patients died, 3929 from their first cancer. Rate ratios for cancer-specific and all-cause mortality for second cancers compared with matched first cancers were 1.05 (95% confidence interval [CI] = 0.90 to 1.23) and 1.09 (95% CI = 0.96 to 1.23), respectively. However, among testicular cancer patients who were diagnosed during 1973-1979, an era in which radiation therapy was given at high doses and to the chest area, all-cause mortality following second cancers at sites below the diaphragm (79 deaths) and second lung cancers (29 deaths) was statistically significantly higher than that from matched first cancers (RR = 1.44, 95% CI = 1.13 to 1.83, and RR = 1.65, 95% CI = 1.12 to 2.42, respectively)., Conclusions: Mortality from second cancers following testicular cancer was similar to matched first cancers, except for selected tumors in the radiotherapy field among testicular cancer patients who were diagnosed during 1973-1979, a time when radiotherapy doses for treatment of testicular cancer were high and chest irradiation was an option in standard practice.

Background: Although modern treatments for testicular cancer are associated with increased survival, the long-term health effects of these treatments are unclear. We conducted a population-based study to quantify the long-term risks of mortality from noncancer causes among men with testicular cancer., Methods: We identified 38,907 one-year survivors of testicular cancer within 14 population-based cancer registries in North America and Europe (from 1943 through 2002). We used data from these registries to calculate standardized mortality ratios (SMRs) for noncancer deaths and to evaluate associations between histology, age at testicular cancer diagnosis, calendar year of diagnosis, and initial treatment and the risk of noncancer mortality. All statistical tests were two-sided., Results: A total of 2942 deaths from all noncancer causes were reported after a median follow-up of 10 years, exceeding the expected number of deaths from all noncancer causes in the general population by 6% (SMR = 1.06, 95% confidence interval [CI] = 1.02 to 1.10); the noncancer standardized mortality ratios did not differ statistically significantly between patients diagnosed before and after 1975, when cisplatin-based chemotherapy came into widespread use. Compared with the general population, testicular cancer survivors had higher mortality from infections (SMR = 1.28, 95% CI = 1.12 to 1.47) and from digestive diseases (SMR = 1.44, 95% CI = 1.26 to 1.64). Mortality from all circulatory diseases was statistically significantly elevated in men diagnosed with testicular cancer before age 35 years (1.23, 95% CI = 1.09 to 1.39) but not in men diagnosed at older ages (SMR = 0.94; 95% CI = 0.89 to 1.00). Men treated with chemotherapy (with or without radiotherapy) in 1975 or later had higher mortality from all noncancer causes (SMR = 1.34, 95% CI = 1.15 to 1.55), all circulatory diseases (SMR = 1.58, 95% CI = 1.25 to 2.01), all infections (SMR = 2.48, 95% CI = 1.70 to 3.50), and all respiratory diseases (SMR = 2.53, 95% CI = 1.26 to 4.53). Testicular cancer patients who were younger than 35 years at diagnosis and were treated with radiotherapy alone in 1975 or later had higher mortality from all circulatory diseases (SMR = 1.70, 95% CI = 1.21 to 2.31) compared with the general population., Conclusion: Men who have survived for at least 1 year after being diagnosed with testicular cancer have a slightly higher risk of dying from noncancer causes, including infections, digestive diseases, and circulatory diseases, than the general population. Men treated with chemotherapy in 1975 or later may be at particularly high risk.

Background: We evaluated the impact of testicular germ cell cancer (TGCC), its treatment and length of follow-up on sperm DNA integrity., Methods: In 96 TGCC patients, semen was collected at specific intervals until 5 years after treatment. Sperm DNA integrity was assessed by the sperm chromatin structure assay (SCSA, n = 193) and by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL, n = 159) assay. Results were expressed as DNA fragmentation index (DFI). Controls comprised of 278 military conscripts., Results: Post-surgery testicular cancer (TC) patients did not differ from controls. Compared with pretreatment values, radiotherapy induced a transient increase in SCSA(DFI) (medians: 12 versus 19%; P = 0.03), normalizing after 3-5 years. One year or more after therapy, 5/13 (38%) of normozoospermic, irradiated patients had SCSA(DFI) >27% compared with 7% of normozoospermic controls (P = 0.002). More than two cycles of chemotherapy decreased DFI 3-5 years post-therapy (median SCSA(DFI): 12 versus 9.1%, P = 0.02; median TUNEL(DFI): 11 versus 7.5%, P = 0.03)., Conclusion: Irradiation increases sperm DNA damage 1-2 years after treatment, and 38% of irradiated patients with normozoospermia had high (>27%) DNA damage, which may affect the sperm-fertilizing ability. TC per se is not associated with an increase of DFI, and DFI is reduced by three or more cycles of chemotherapy.

Background: The aims of our study were to investigate the short- and long-term effects of chemo- or radiotherapy on spermatogenesis in patients with testicular cancer and to establish any correlation between pre-therapy sperm parameters, histotype and treatment type/intensity and the progress of spermatogenesis during the post-therapy period., Methods: We evaluated 166 patients affected by testicular cancer, who cryobanked about 1 month after the removal of the cancerous testis and before beginning chemo- (CH group; n = 71) or radiotherapy (RT group; n = 95)., Results: For the CH group, there was a statistically significant decrease in sperm parameters, which was most significant 3 months after the end of chemotherapy. For the RT group, this decrease was most relevant 6 months after the end of radiotherapy. Two years after therapy, 3% of the CH group and 6% of the RT group remained azoospermic. To evaluate whether spermatogenesis recovery is a function of baseline semen quality, we divided each group into two subgroups by pre-therapy total sperm count (A, <40 x 10(6)/ejaculate; B, >or=40 x 10(6)/ejaculate). At t(24), subgroup A of both the CH and RT groups showed improved sperm parameters over the baseline, whereas subgroup B for both CH and RT groups showed a return of sperm parameters to those of baseline values., Conclusions: In conclusion, the recovery of spermatogenesis after chemo- or radiotherapy in our group of testicular cancer patients was not a function of pre-therapy sperm parameter quality. Cryopreservation of sperm before performing such therapy is therefore imperative.

Background: Studies of fertility in men treated for testicular cancer have mainly addressed serum follicle-stimulating hormone levels and sperm parameters. We assessed post-treatment paternity among long-term survivors of testicular cancer., Methods: Men (n = 1814) who had been treated for unilateral testicular cancer in Norway during 1980 through 1994 were invited to participate in a national multi-center follow-up survey in 1998 through 2002. The participants were allocated to five groups according to the treatment received after orchiectomy, including treatment at relapse (surveillance, retroperitoneal lymph node dissection, radiotherapy, low-dose chemotherapy [i.e., < or = 850 mg cisplatin], and high-dose chemotherapy [i.e., > 850 mg cisplatin]). Cox proportional hazards analysis was used to assess predictive factors for post-treatment paternity. Statistical tests were two-sided., Results: A total of 1433 men were assessable, of whom 827 were fathers at diagnosis. Post-treatment conception was attempted by 554 men, among whom the overall 15-year actuarial post-treatment paternity rate was 71% (95% confidence interval [CI] = 66% to 75%) without the use of cryopreserved semen. This rate ranged from 48% (95% CI = 30% to 69%) in the high-dose chemotherapy group to 92% (95% CI = 78% to 98%) in the surveillance group (P < .001). The median actuarial time from diagnosis to the birth of the first child after treatment was 6.6 years overall but varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for post-treatment fatherhood, with dry ejaculation as the most important negative factor., Conclusions: Although the overall paternity rate after treatment for testicular cancer was high, the ability to conceive and the time to conception reflected the intensity of treatment. These data may help inform patients about their future ability to father biological children.

Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantified risks among long-term survivors., Methods: Within 14 population-based tumor registries in Europe and North America (1943-2001), we identified 40,576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided., Results: A total of 2,285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis (P < .001); the EAR increased with attained age (P < .001) but the excess RR decreased. Among 10-year survivors diagnosed with testicular cancer at age 35 years, the risk of developing a second solid tumor was increased (RR = 1.9, 95% confidence interval [CI] = 1.8 to 2.1). Risk remained statistically significantly elevated for 35 years (RR = 1.7, 95% CI = 1.5 to 2.0; P < .001). We observed statistically significantly elevated risks, for the first time, for cancers of the pleura (malignant mesothelioma; RR = 3.4, 95% CI = 1.7 to 5.9) and esophagus (RR = 1.7, 95% CI = 1.0 to 2.6). Cancers of the lung (RR = 1.5, 95% CI = 1.2 to 1.7), colon (RR = 2.0, 95% CI = 1.7 to 2.5), bladder (RR = 2.7, 95% CI = 2.2 to 3.1), pancreas (RR = 3.6, 95% CI = 2.8 to 4.6), and stomach (RR = 4.0, 95% CI = 3.2 to 4.8) accounted for almost 60% of the total excess. Overall patterns were similar for seminoma and nonseminoma patients, with lower risks observed for nonseminoma patients treated after 1975. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2). For patients diagnosed with seminomas or nonseminomatous tumors at age 35 years, cumulative risks of solid cancer 40 years later (i.e., to age 75 years) were 36% and 31%, respectively, compared with 23% for the general population., Conclusions: Testicular cancer survivors are at statistically significantly increased risk of solid tumors for at least 35 years after treatment. Young patients may experience high levels of risk as they reach older ages. The statistically significantly increased risk of malignant mesothelioma in testicular cancer survivors has, to our knowledge, not been observed previously in a cohort of patients treated with radiotherapy.

Background: Testicular cancer (TC) patients have a high survival rate, and the question of post-therapy recovery of sperm production and its dependence on genetic predisposition is of major interest., Methods: Ejaculates were obtained from 112 TC patients at one or more of the following time points: post-orchidectomy, or 6, 12, 24, 36 and 60 months post-therapy. The lengths of the androgen receptor (AR) function modulating CAG and GGN repeats in leukocyte DNA were also analysed., Results: No significant decrease in sperm concentration was seen in men who received 1-2 cycles of adjuvant chemotherapy (ACT). Radiotherapy (RT) or more than two cycles of chemotherapy (HCT) caused an initial decline in sperm concentration, which returned to pre-treatment levels 2-5 years after therapy. In the HCT group, sperm concentration 12-24 months post-treatment (T(12-24)) was inversely correlated with CAG length (rho = -0.72, P = 0.03). The type of treatment, but not the concentration at T(0), was an independent predictor of sperm concentration at T(6) (P < 0.0005) and T(12-24) (P = 0.004)., Conclusion: ACT did not induce a significant decline in sperm concentration. After HCT and RT, a significant reduction of sperm concentration was observed, recovering to pre-treatment levels 2-5 years post-treatment. In HCT-treated patients, the AR CAG length influenced the recovery of spermatogenesis.

Advances in cancer treatment have led to significant improvements in the likelihood of reaching remission and long-term survival for men. Chemo- and radiotherapy-induced infertility are significant treatment side effects. Cryopreservation before the start of treatment enables sperm to be stored, thereby preserving the man's potential fertility. Here, we describe the successful use (with ICSI) of sperm cryopreserved prior to cancer treatment, for a total of 21 years. We believe this to be the longest period of sperm cryopreservation, resulting in a live birth, so far reported in the literature.

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.

Germ cell transplantation was developed in strains of mice. The infusion of germ cell preparations into the seminiferous tubules of infertile hosts led to repopulation of the testis with donor germ cells and restored fertility. Meanwhile, this technique has become a powerful tool to study the expansion of the testicular stem cell population and the kinetics of spermatogonial proliferation and re-induction of spermatogenesis. Further approaches, such as the transfer of rat/hamster/rabbit germ cells into mouse testes or cryopreservation or culture of spermatogonia, have widened the spectrum of applications associated with germ cell transplantation. Since the devastating effects of chemo- or radiotherapy on spermatogonia are the cause of infertility in oncological patients, germ cell transplantation might become an alternative approach for gonadal protection in prepubertal and postpubertal male tumour patients. This review focusses on recent developments with respect to germ cell transplantation and highlights the problems and perspectives of future clinical applications.

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

Azoospermia frequently represents the end-point of different pathological conditions that cause important quantitative and qualitative alterations of both spermatogenesis and testicular structure, including intratesticular blood vessels. In this study we performed colour Doppler ultrasound of the testis in 12 azoospermic subjects affected by primary testicular pathology (four bilateral post-orchitis, four postradiotheraphy for cancer, four post-traumatic) aged 28.2+/-3.3 (mean+/-SD) years, in six subjects affected by obstructive azoospermia aged 29.7+/-2.4 years and in 20 age-matched fertile subjects (aged 28.6+/-2.5 years). The analysis of intratesticular vessels per organ was quantified using a semiquantitative score: category 0, no vessels visible; category 1, between one and three intratesticular vessels visible; and category 2, more than three vessels visible. In obstructive azoospermic patients and in fertile subjects there were always more than three intratesticular vessels. No intratesticular vessels were detected in eight testes (33.3%) and fewer than three vessels in 16 testes (66.6%) in subjects affected by primary testicular pathology. In azoospermic subjects the testicular structure of the testis was evaluated by diagnostic fine needle aspiration cytology (FNAC) performed in the middle portion of the testis. In non-obstructive azoospermic patients this procedure showed the presence of only Sertoli cells in all cases. When detectable vessels were present, a new aspiration was performed in these areas. In 12 out of 16 cases, spermatogenetic cells including mature spermatozoa, were found when the FNAC was performed in testicular regions showing the presence of blood vessels. These results indicate that colour Doppler sonography of the testis may be useful in the differential diagnosis of azoospermia and suggest the evaluation of the intratesticular blood vessel distribution before performing any method to retrieve intratesticular spermatozoa for intracytoplasmic sperm injection.

A successful pregnancy was achieved by intracytoplasmic sperm injection (ICSI) using cryopreserved semen from a man with testicular cancer. He was a victim of right testicular seminoma, and was azoospermic after right orchidectomy and radiotherapy. The wife had had three successive failures of intrauterine insemination (IUI) using semen that was cryopreserved before radiotherapy. The couple then underwent in-vitro fertilization (IVF) treatment. ICSI was performed because the sperm motility was extremely poor after thawing. Eight of 12 injected oocytes had normal fertilization and embryo cleavage. After replacement of four embryos, a singleton pregnancy developed. She delivered a healthy male baby at 39 weeks gestation. In addition to IUI and IVF, ICSI further provides male patients with cancer an improved chance of fathering a child. Any men diagnosed with cancer who have not yet finished their families should have their spermatozoa frozen before treatment, regardless of its quality.

Twenty men (median age, 31 yr) previously treated for unilateral testicular cancer received localized irradiation in a dose of 20 Gray in 10 fractions for carcinoma in situ of the remaining testis. Follow-up testicular biopsies performed 3 (n = 19) and 24 (n = 14) months after the treatment showed in all cases a Sertoli cell-only pattern. Hormonal evaluation was performed before as well as 3, 12, 24, and 36 months after radiation treatment. Endocrine parameters were followed for a median of 30 months (3-36 months). Baseline serum testosterone values decreased during the follow-up period from 13.3 +/- 6.0 to 10.8 +/- 6.4 nmol/L (mean +/- SD), although the decrease was not statistically significant (P = 0.06). Serum LH values increased during the first 3 months of follow-up from 10.4 +/- 5.4 to 15.6 +/- 7.3 IU/L (P less than 0.0001) and then remained unchanged. Significant decreases in GnRH- and hCG-stimulated testosterone levels also indicated an impairment of Leydig cell function. FSH levels increased (P less than 0.0001) during the first 3 months of follow-up from 21.8 +/- 11.1 to 33.2 +/- 13.2 IU/L. We conclude that localized irradiation of 20 Gray eradicated carcinoma in situ germ cells. Development of a second testicular cancer has until now been prevented. Leydig cell function was partially impaired by the radiation dose given.

Two cases of tumours arising in or near the pancreatic head are reported in patients previously treated with abdominal irradiation for testicular tumours. These are only the third and fourth such cases to be reported and they suggest that second cancers may develop as a result of abdominal irradiation for malignant disease.

An alpha slow-moving high-density-lipoprotein (HDL) subfraction was seen in a patient presenting with radiation enteritis and peritoneal carcinosis, who was given long-term cyclic parenteral nutrition. This subfraction, observed in addition to normal HDL, was precipitated with low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) by sodium phosphotungstate-magnesium chloride. The patient's serum lipoproteins were analyzed after fractionation by density gradient ultracentrifugation. The alpha slow-moving HDL floated in the ultracentrifugation subfractions with densities ranging from 1.028 to 1.084 kg/L, and their main apolipoproteins included apolipoprotein E in addition to apolipoprotein A-I. These HDL were larger than HDL2. The pathogenesis of this unusual HDL subfraction is hypothesized.

Seminal analyses have been performed in 14 patients who have received radiation therapy following unilateral orchidectomy for testicular tumours. In patients receiving scrotal in addition to para-aortic and pelvic lymph node irradiation azoospermia occurred in 17 out 18 specimens examined, whereas in those patients not requiring scrotal irradiation, restoration of spermatogenesis occurred. The difference is a result of the increased dose of radiation received by the remaining testicle when the contralateral side of the scrotum is irradiated. Following scrotal aspiration, trans-scrotal biopsy or scrotal orchidectomy for testicular tumour, the scrotum becomes a possible site of recurrence and it should be electively irradiated. In order to give the patient the best chance of preserving fertility it is essential that scrotal interference in the management of testicular tumours must be avoided.