Fertilité après cancer du testicule

Objectives

To study the fertility of patients treated for testicular cancer and to identify predictive factors of infertility after treatment.

Material and Methods

314 men with germ cell tumor, followed by the CECOS Midi-Pyrénées center between 1978 and 1998, were included in the study. They were evaluated retrospectively and interviewed by a mailed questionnaire concerning their reproductive history. If they failed to respond to the questionnaire, they were contacted twice by mail, and once by telephone. The response rate was 92%.

Results

The reproductive history of 277 men was known: 138 men had tried to have a child. 91 (66%) succeeded and 47 (34%) failed to achieve a “spontaneous” pregnancy. Age greater than 25 (p<0.004), a history of undescended testis, and a sperm count lower than 10 million per ml were inversely correlated with fertility (p<0.004, p<0.01, p<0.0001, respectively). However, no relationship was found between radiotherapy or chemotherapy and fertility after treatment.

Conclusion

Men treated for testicular cancer are at high risk of infertility. We identified various prognostic factors for fertility after treatment for testicular cancer: radiotherapy and chemotherapy had no significant effect on fertility.     

Paternité après traitement du cancer du testicule: enquête sur 136 patients

We sent a questionnaire to 136 patients, treated between 1981 and 1993, to try to evaluate, retrospectively, fertility amongst patients following treatment for testicular cancer. From the 76 complete questionnaires, 56% of patients had fathered at least one child. After treatment, approximately 35% of patients were steriles. Treatment, in wich ever form, does not seem to influence fertility. Only 3 couples resorted to infertility treatment. There were 46 pregnancies in total, one of wich resulted from IVF, on average 4 years after the end of treatment for testicular cancer. A prospective study carried out in conjonction with the centre for study and conservation of sperm would seem to be neceessary to consolidate these findings.     

Fertilité et cancer du testicule. Impact des traitements

Objectives

To study the fertility of patients with testicular cancer.

Population and Method

The fertility of a consecutive series of 489 men treated for germ cell tumour of the testis in the Midi-Pyrénées region, between 1978 and 1998, was investigated by means of a questionnaire sent by mail to the patients. A participation rate of 95% was obtained.

Results

Information concerning fertility was obtained for 446 men. 90.1% of patients who had tried to have children prior to their testicular cancer had succeeded, but only 61.8% of men were able to have a child after treatment of their cancer. Radiotherapy and surgery of residual masses appear to be more harmful to fertility than BOE chemotherapy.

Conclusion

The population of men treated for testicular cancer present a high risk of infertility, as the fertility of these men decreases by about 30% after treatment.     

La sélection des spermatozoïdes à fort grossissement permet-elle une diminution de la fréquence des aneuploïdies spermatiques?

Severe male infertility concerns two categories of men. Men with abnormal karyotype, who represent 2 to 14% of infertile men and who can produce sperm cells carrying unbalanced chromosomes related to the patients initial chromosomal reorganization inducing a variable risk of transmission of the abnormality to their conceptus. The second category is men with a normal karyotype but an increased rate of spermatic aneuploidy in a context of severe oligo- and/or asthenozoospermia and men from couples in implantation failure. ICSI is the standard Assisted Medical Reproductive technique for most of these 2 categories despite the obvious increased chromosomal risk. This raises the question of how to morphologically identify sperm cells with abnormal chromosome content during ICSI ? Unfortunately, no relationship has yet been found between sperm morphology in the ICSI sperm fraction (×200) and their chromosome content. Nevertheless, since the end of the 1990s, Bartoov’s team has developed MSOME (Motile Sperm Organelle Morphology Examination) consisting of high-power examination of sperm cells up to × 12,250. This technique was indicated for cases of repeated ICSI failures and appeared to increase pregnancy rates. But was this improvement due to better selection of the chromosomal content of sperm cells to be injected? The present study addressed this question by estimating the value of MSOME in the selection of euploid sperm cells in 2 groups of patients known to have an increased rate of sperm aneuploidy. Group 1 was composed of 2 patients with normal karyotype who presented a macrocephalic sperm syndrome with more than 99% of aneuploid sperm. Group 2 was composed of 11 patients with abnormal karyotype: 6 patients with reciprocal translocation and 5 patients with Robertsonian translocation. The purpose of this study was to compare spermatozoa aneuploidy rates in fresh semen, to those obtained after ICSI selection (×200) and MSOME selection (×6000). Three specific steps of the protocol were (1) all sperm cells selected in MSOME were “top sperm cells“ (2) fixation of selected sperm cell (average loss of 15% during FISH washes) (3) FISH results were validated by two different examiners. FISH analysis of X, Y and 18 chromosomes showed that MSOME eliminates polyploid and diploid sperm cells in patients with macrocephalic sperm syndrome, but the 6 sperm cells selected were all haploid and aneuploid. FISH analysis of X, Y and 18 chromosomes of all other patients did not show any influence of the selection method on the aneuploidy rate. For the 5 subjects with a Robertsonian translocation, the global results of FISH analysis paradoxically showed a significant decrease of the euploidy rate in MSOME selection. The global results of FISH analysis for the 6 patients with mutual reciprocal translocations, showed that the various mutual translocations were not modified between whole sperm and the 2 selection methods. On the other hand, a significant decrease of adjacent 1 and 2 segregation frequency was observed between whole sperm and MSOME selection, associated with a significant increase of 3:1 segregation frequency suggesting that the segregations which modify the structure of chromosomes, for example adjacent 1 and 2 segregations, would induce visible morphological modifications selected by MSOME. We hypothesized that the efficacy of spermatic apoptosis could be modulated by morphology but also by the chromosome contents of the sperm cell. In conclusion, MSOME does not provide any guarantee of the normal chromosome contents of the TOP selected sperm cell. However, these results obtained in a small series of patients suggest that MSOME can eliminate some chromosome abnormalities (adj1 and 2) which would alter sperm nuclear structures.     

Troubles sexuels après curiethérapie par implants permanents d’I-125 dans le cancer localisé de prostate

Brachytherapy by permanent implants is an alternative to radical prostatectomy or external beam radiotherapy for good prognosis localized prostate cancer. The advantages of this treatment are effective and precise irradiation, limited to the prostate gland with moderate and transient morbidity. Erectile dysfunction, frequent erection after surgery and external beam radiotherapy, is observed in 6% to 61% of cases in the literature after brachytherapy. This wide range is related to differences in terms of follow-up, definition of sexual disorders, and the measuring instruments used. These erectile disorders occur between 9 and 17 months after treatment and appear to be related to vascular radiation lesions of the erectile bodies close to the prostatic apex (urethral bulb and base of the corpora cavernosa). However, the majority of erectile disorders respond favourably to oral treatments such as yohimbine or sildenafil. Among the various curative treatment options for localized prostate cancer, permanent implant brachytherapy is the treatment ensuring the best preservation of erectile function.     

Génotoxicité des chimiothérapies et radiothérapies: Quelles sont les conséquences pour le spermatozoïde humain?

The prognosis of cancer in young men of childbearing potential has been considerably improved over recent decades as a result of therapeutic progress. Chemotherapy and radiotherapy have well known effects on spermatogenesis. Apart from quantitative and qualitative impairment of spermatogenesis, animal studies have also demonstrated nuclear lesions (aneuploidy, presence of adducts, DNA fragmentation, etc.) and sometimes lesions affecting the F1 and F2 generations. Chromosomal studies of human spermatozoa after radiotherapy have demonstrated an increased frequency of chromosomal anomalies. The first studies concerning the effects of chemotherapy used the heterospecific fertilization technique to demonstrate spermatozoal chromosomal anomalies. More recently, thefluorescence in situ hybridization (FISH) technique has been used to study several chromosomes on a large number of spermatozoa. The results of various studies based on small sample sizes vary as a function of the therapeutic protocol administered and the time of sperm collection in relation to the end of treatment. We studied 5 patients who provided a semen sample 6 to 17 months after completing the BOE chemotherapy protocol (Bleomycin, Etoposide, Cisplatin). We demonstrated an increased rate of aneuploid and diploid spermatozoa. The results of our study and those reported by R. Martin et al. [45, 47] suggest the possibility of a transient effect of chemotherapy on gamete chromosomes. Other studies, conducted in the context of Hodgkin’s disease, have demonstrated the transient nature of the aneuploidy effect. Apart from the harmful action on chromosomes, treatments could also damage spermatozoal DNA. Studies conducted on larger sample sizes and using other methods of analysis therefore appear to be essential. In the meantime, it appears preferable to systematically propose semen cryopreservation before treatment and to provide very cautious advice to patients desiring a pregnancy soon after completion of treatment.     

Activité des pyrophosphatases inorganiques acide et alcaline après traitement avec divers herbicides

Various herbicides are applied on seventeen-day-old cucumber seedlings growing in a nutrient solution. After 1 and 3 days, acid and alkaline pyrophosphatase activities are measured in the leaves and the roots of seedlings treated with lethale dosis of atrazine, chlortoluron, ioxynil, MCPA, dicamba, alachlor. The same enzymes are determined after 5 h in seedlings on which previously paraquat and DNOC were pulverised. In the leaves, acid pyrophosphatase activity is stimulated by almost all the herbicides, especially by ioxynil, paraquat and DNOC while alkaline pyrophosphatase remains similar to the controls. The alkaline and acid pyrophosphatase activity in the roots is either unchanged or stimulated or inhibited without any correlation with the various modes of action of the herbicides.     

Étude de la cytodifférenciation du rein de l'Epinoche femelle après traitement par la méthyltestostérone

Résumé Au microscope électronique, l'action de la méthyltestostérone sur les cellules rénales de l'Epinoche femelle se traduit par une cytodifférenciation conduisant à la formation de cellules glandulaires muqueuses. Elle a lieu simultanément à deux niveaux distincts:Au niveau du tubule proximal, le premier signe visible de cytodifférenciation est une activation du nucléole, accompagnée par une augmentation de taille des cellules. Puis on assiste à un développement de l'ergastoplasme et de l'appareil de Golgi et à l'élaboration de deux types de sécrétions: d'abord des granules de 2000–2500 Å, ensuite des grains de mucigène typiques, qui subissent rapidement une transformation muqueuse.Une cytodifférenciation régressive intervient en même temps. Elle concerne la pinocytose apicale qui disparaît.Au niveau des tubules collecteurs, la cytodifférenciation se traduit par la formation d'un mucus hyalin d'origine golgienne. Elle s'accompagne également d'une disparition de la pinocytose.La méthyltestostérone est capable de provoquer, chez la femelle, une cytodifférenciation rénale identique à celle que l'on observe chez le mâle pendant la période de reproduction. La transformation muqueuse des cellules rénales est donc sous le contrôle de la seule testostérone, qui déclenche au niveau cellulaire un ensemble de processus conduisant à la formation de mucus.Au microscope électronique, on constate que l'élaboration de mucus prêt à l'excrétion est achevée au bout de trois jours dans les tubules proximaux alors que dans les tubules collecteurs elle ne demande que 24 heures.

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Action of methyl testosterone on the cytodifferentiation of the kidney of the female three-spined Stickleback

Summary At the microscopic level, the action of methyl testosterone on the cells of the kidney of the female three-spined Stickleback gives raise to a cytodifferentiation which leads to the formation of mucous glandular cells. This action is evident at two different levels:At the level of the proximal tubule, the first visible sign of cytodifferentiation is an activation of the nucleolus, accompanied by a growth of the cell size. Then a rapid development of the ergastoplasm and the Golgi apparatus takes place, which leads to the elaboration of two types of secretory particles: granules of 2000–2500 Å in diameter appear first, then typical mucigen granules become visible. These latter undergo a rapid mucous transformation.A regressive cytodifferentiation occurs at the same time. It concerns the apical pinocytosis which disappears in the cells undergoing the glandular differentiation.At the level of the collecting tubules, the cytodifferentiation is characterized by the elaboration of a clear mucus which originates in the Golgi apparatus and migrates to the apex of the cells. A disappearance of the pinocytosis is also noticeable.In the kidney of the female, methyl testosterone induces a cytodifferentiation which is identical to that occuring in the male during the breeding period. So the mucous transformation of renal cells is under the control of a single hormone: the testosterone, which is able to give raise to a succession of phenomena leading to the formation of a mucous secretion.With the electron microscope, it is possible to demonstrate that three days are necessary for the elaboration of the mucus ready to be discharged in the lumen of the renal proximal tubules. In the collecting tubules, the reaction occurs more quickly, after only two days of treatment.

L'auteur tient à remercier Monsieur le Professeur E. Follénius pour ses conseils et son aide précieuse au cours de la réalisation de ce travail.     

Altérations de la spermiogenèse de Locusta migratoria migratorioïdes après implantation de corps allates et après irradiation

Résumé Une faible dose de rayonnement gamma appliquée à des larves de Locusta migratoria provoque des altérations de la spermiogenèse et entraine la stérilité des mâles. Ces résultats sont comparables à ceux obtenus après implantation des corps allates.Au niveau des organites cellulaires, les altérations morphologiques des spermatides sont semblables dans les deux cas: vacuolisation des mitochondries et transformation du Nebenkern, pycnoses nucléaires, multiplication centriolaire, invagination de la membrane plasmique. Certaines de ces altérations se manifestent tardivement, au moment de la fixation des spermatides sur les cellules pariétales. Celles-ci n'élaborent pas les matériaux de la coiffe des spermatodesmes: leur fonction physiologique est donc également perturbée.Le rapport entre cette altération physiologique et l'évolution anormale des spermatides est envisagé. Le mode d'action de l'hormone juvénile sur la gonade est également discuté.

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Alterations in spermiogenesis of Locusta migratoria migratorioïdes after corpora allata implantation and after irradiation

Summary Low doses of gamma-rays, given to larvae of Locusta migratoria, lead to alteration of spermiogenesis and male sterility. These results are similar to those which follow corpora allata implantation.At cellular level, morphological alterations in spermatids are the same in both treatments: mitochondrial vacuolization, nuclear pycnosis, centriole multiplication, plasmic membrane invagination. Some of these alterations reveal themselves late, at the time the spermatids fix on the parietal cells. These don't elaborate the substances of the spermatodesm's cap: their physiological functions are therefore also disturbed.The relationship beetween this physiological disturbance and abnormal evolution of spermatid are considered and the way in which juvenile hormone acts upon gonads is discussed.

     

Ultrasons focalisés de forte intensité pour la thérapie transcrânienne du cerveau

A novel MR-guided brain therapy device operating at 1 MHz has been designed and constructed. The system has been installed and tested in a clinical 1.5 T Philips Achieva MRI. Skull bone distortions induced on the ultrasonic beam are corrected using the concept of time reversal focusing. Prior to the treatment, a 3D CT scan of the patient head is performed and used as entry parameters for three-dimensional finite differences simulations that compute the propagation of the wave field through the human skull. The simulated phase distortions are then used as inputs for transcranial corrections. Temperature elevations during the treatment are imaged using MRI thermometry thus ensuring the control and safety of this therapeutic approach. First experiments are performed on four human cadavers and the promising results allow us to envision a first clinical investigation of this therapeutic approach in a near future. First targeted applications correspond to the non-invasive treatment of brain metastases and neurologic disorders such as the essential tremor.     

Traitement par ultrasons focalisés du cancer localisé de la prostate: Résultats carcinologiques et pronostic sexuel

Introduction

Since 1999, a therapeutic device using High Intensity Focused Ultrasound (HIFU) technology has been marketed in Europe for the treatment of localized prostate cancer. Clinical and technical development was designed to provide a minimally invasive alternative for these patients. The purpose of this study was to evaluate the efficacy of HIFU therapy for localized prostate cancer and its impact on sexual function.

Material and Methods

HIFU technology is based on a convergent beam of high intensity ultrasound that creates a sudden and sharp increase in temperature (85°C to 100°C) in the tissues at the focal point. This leads to a precise lesion in the tissue, adjustable from 19 to 24 mm in height and 2 mm in diameter. Successive displacements of the focal point are computer-driven, allowing treatment of a defined volume. All patients were treated with the ABLATHERM® device (EDAP SA, France); they were treated using the device prototypes between 1993 to 1999 and then with the marketed machine. The treatment procedure was improved from 2000 onwards with the combination of transurethral resection of the prostate (TURP) in order to reduce post-treatment catheter time. A nerve-sparing procedure was also tested in 2002. The selected population included 120 patients considered to be potentially curable with clinical stage T1–T2 prostate cancer and an initial PSA < 10 ng/ml (group 1). A larger group of 167 patients with an initial PSA < 30 ng/ml was also considered (group 2). All patients were not candidates for surgery due to their age or comorbidities. In the two groups, clinical failure was defined by the need for administration of an adjuvant prostate cancer treatment (hormone deprivation or external radiation). Disease progression, or biochemical failure, was strictly defined as any evidence of residual cancer on follow-up biopsies (regardless of the PSA level), or 3 successive increases of the PSA level (with negative follow-up biopsies), with a velocity > 0.75 ng/ml/year. Disease-free survival rates were calculated using the Kaplan-Meier method. Survival rates were compared using the log-rank test. The impact of HIFU treatment on sexual function was assessed by a questionnaire in 70 patients who underwent standard HIFU treatment and in 28 patients in whom a nerve-sparing procedure was performed.

Results

Patient baseline characteristics (± SD) were, in group 1 and group 2 respectively: mean age: 71.2 (± 5.34) years and 71.8 (± 5.11) years; clinical stage: T1 for 61 patients and T2 for 59 patients in group 1, and T1 for 77 patients, T2 for 85 patients and T3 for 5 patients in group 2; mean initial PSA level: 5.67 (± 2.47) ng/ml and 9.30 (± 6.01) ng/ml; Gleason score: 2–6 for 77 patients and 7–10 for 43 patients in group 1, and 2–6 for 98 patients, 7 for 44 patients, and 8–10 for 25 patients in group 2; mean prostate volume: 33.6 (± 16.5) ml and 34.4 (± 16.7) ml, respectively. Mean follow-up was 27 months (range: 3–96 months) in group 1, and 23 months (range: 3–90 months) in group 2. In group 1, a residual cancer was diagnosed in 17 patients, but only 6 patients needed adjuvant treatment due to a significant rise of the PSA level (hormone deprivation: n=2, external radiation: n=4), leading to a clinical success rate of 95%. Similarly, in group 2, 36 patients presented with positive follow-up biopsies, and 21 of them required adjuvant treatment (hormone deprivation: n=10, external radiation: n=11), leading to a clinical success rate of 87.5%. The disease-free survival rates (previously defined on the combined biopsy and PSA criteria) were 76.9% and 66% in group 1 and 2, respectively. In addition, the disease-free survival rate in group 2 was stratified according to the initial prognosis risk level: 85% in low-risk patients (i.e. patients with clinical stage T1–T2a and PSA < 10 ng/ml and Gleason score < 7), 67.5% in intermediate-risk patients (i.e. clinical stage T2b or PSA 10–20 ng/ml or Gleason score = 7), and 42% in high-risk patients (i.e. clinical stage T2c or PSA > 20 ng/ml or Gleason score > 7). In the overall population, 70 patients had normal sexual function prior to HIFU treatment; 25 patients (36%) still had erections allowing sexual intercourse with penetration after treatment. A nerve-sparing procedure was also performed in 28 potent patients: 43% of these patients had persistent erections allowing sexual intercourse with penetration after treatment, indicating that this nerve-sparing procedure still needs to be improved.

Conclusion

The efficacy results observed after HIFU treatment are similar to those observed after other non-surgical treatments for prostate cancer. After complete HIFU treatment of the gland, more than 1/3 of patients still reported erections allowing sexual intercourse with penetration; these results must be interpreted for an elderly population (mean age: 72 years). A nerve-sparing procedure is currently being perfected and tested.     

Apport de la TEP-FDG dans le staging initial des cancers du sein localement avancés traités par chimiothérapie néo-adjuvante

Axillary lymph node and distant metastases are unfavourable prognostic factors in breast cancer. The aim of our study was to evaluate the performance of PET-FDG in the staging of locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy (NAC) and surgery, and to compare the findings of pretherapeutic PET to those of axillary nodal status obtained by surgery after NAC (Sataloff classification). This retrospective study involved 89 patients with LABC explored at presentation by PET in addition to conventional clinical and imaging staging (CS). Breast cancer excision and axillary dissection were performed after NAC. PET and CS found an axillary involvement in 58 patients (65%) and 39 patients (44%), respectively. Compared to the histology of post-NAC axillary dissection, PET had sensitivity and specificity of 80% and 63%, respectively. PET revealed an extra-axillary lymph node involvement, not suspected by the CS, in 25 patients (28%). Bone and lung metastases, not suspected by the CS were found in two and one patients, respectively. A case of false-positive PET in the liver was observed (adenomatosis). This study confirms the value of PET in the initial staging of LABC, especially in assessing extra-axillary nodal status. In the determination of axillary status, PET has a high positive predictive value, cases of doubtful interpretation suggesting to perform ultrasound-guided fine needle aspiration in addition.     

Connaître les particularités du traitement par antivitamine K chez le patient âgé ou comment minimiser leur iatrogénie ?

Elderly patients are commonly frail, due to a lot of comorbid conditions and numerous medications. These patients are at high risk of bleeding when treated with vitamin K antagonist (VKA). Special considerations on the choice of VKA drug, dosing and monitoring have to be taken into account in the elderly in order to avoid over-anticoagulation and to minimize the haemorrhagic risk which consequences may be dramatic or fatal in this age group. In these patients, INR monitoring is crucial, especially at the start of treatment. The use of dosing algorithms specifically developed for elderly patients allows to decrease over-anticoagulation during the initiation period. INR has to be monitored more frequently in case of acute illness or in case of modification of the associated drugs. Patient education is of great importance, even in geriatric patients and has been shown to improve the quality of anticoagulation. New oral anticoagulants with a wider therapeutic index seem to be of great interest.     

Diagnostic et traitement du déficit en androgènes des patients infectés par le virus de l’immunodéficience humaine

Androgen deficiency is frequent among men infected by the human immune deficiency virus (HIV), with an estimated prevalence of between 35% and 50%. Primary testicular damage has been described, either due to the virus itself, opportunistic agents such as CMV,Toxoplasma gondii orMycobacterium avium intracellulare, or less frequently neoplastic invasion by lymphoma or in a context of Kaposi’s sarcoma. However, secondary hypogonadism remains a more frequent cause. Hypogonadotropic hypogonadism can be secondary to opportunistic infections, malnutrition, and sometimes even certain therapeutic agents. Since the introduction of highly active antiretroviral therapies, the prevalence of hypogonadism has substantially decreased. However, it remains a significant clinical problem, particularly among patients suffering from wasting, as androgen deficiency may aggravate the loss of lean body mass observed in the wasting syndrome of HIV patients. Screening for androgen deficiency is therefore indicated in HIV patients suffering from wasting, even in the absence of specific symptoms. Androgen replacement therapy is justified in symptomatic (loss of libido, impotence) and asymptomatic patients with documented hypogonadism. We recommend replacement therapy with testosterone by subcutaneous or intramuscular injection. In the absence of specific symptoms, it should be remembered that testosterone replacement therapy of HIV-infected hypogonadic patients is associated with improvements in body composition and muscle strength, bone densitometry, quality of life and mood. Similar improvements have also been demonstrated in hypogonadic patients with wasting syndrome. Synthetic testosterone analogues such as oxandrolone or nandrolone do not seem to be more powerful than testosterone at replacement doses, and may be associated with more side effects, particularly severe hepatic dysfunction. In contrast, there is no proven benefit of androgen treatment of eugonadic HIV-infected patients, and the treatment of such patients with androgens, even in the presence of wasting, cannot be recommended.