Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome.

OBJECTIVES: To investigate the prepubertal prevalence of intratubular germ cell neoplasia of the unclassified type (ITGCNU) and its significance as a predictor of testicular cancer and to evaluate the effect of early orchiopexy (at younger than 2 years of age) on subsequent fertility of patients with bilateral cryptorchidism. METHODS: Testicular biopsies (n = 660) from 440 prepubertal patients with cryptorchidism who underwent orchiopexy between January 1, 1970 and December 31, 1979 were evaluated for ITGCNU using placental-like alkaline phosphatase (PLAP) antibody. The clinical outcome in 15 patients with PLAP-positive germ cells was evaluated in 1997. In addition, the effect of age at surgery on the fertility of patients with bilateral cryptorchidism was assessed by clinical follow-up until 1997 and was correlated with the histologic data at orchiopexy. RESULTS: PLAP-positive germ cells morphologically identical with adult ITGCNU were found in the biopsies of 22 patients (5%). After more than two decades, none of the 15 patients with successful follow-up developed testicular cancer. The fertility outcome in the patients with bilateral cryptorchidism correlated with the number of spermatogonia at orchiopexy (P = 0.018), but correlated inversely with age at orchiopexy (P = 0.021). CONCLUSIONS: PLAP-positive germ cells in prepubertal testicular biopsy specimens are not necessarily precursors of testicular cancer after orchiopexy. In addition, our data support the idea that early orchiopexy may be beneficial in preventing infertility.

Malignant glioma: should chemotherapy be overthrown by experimental treatments?

Despite more than two decades of clinical research with chemotherapy, the outcome of malignant gliomas remains poor. Recent years have seen major advances in elucidation of the biology of these tumors, which in turn have led to the current development of innovative therapeutic strategies. The question confronting us at the end of the 1990s is whether we should continue to use and investigate chemotherapy or whether the time has come for experimental treatments. As a contribution to this debate, we reviewed the abundant literature on chemotherapy of malignant glioma, paying special attention to methodological features. The new treatment approaches based on current knowledge about glioma biology are then briefly summarized. Assessment of more than 20 years of chemotherapy trials is discouraging despite a few areas of modest success. Only patients with specific histology (oligodendroglioma, anaplastic astrocytoma) and good prognostic factors (young age, good performance status) may benefit from chemotherapy, with a possible reversal of neurological dysfunction. However, the real impact on survival is small (anaplastic astrocytoma) or undefined (oligodendroglioma). Furthermore, it is unfortunately obvious that the outcome of glioblastoma patients is not significantly modified by chemotherapy. We believe the time has come to explore the potential of novel biological therapies in glioblastoma patients. This could also be proposed for anaplastic astrocytoma and oligodendroglioma patients after failure of chemotherapy.

Effect of low-dose chest irradiation before chemotherapy on the rate of local failure in small-cell lung cancer.

PURPOSE: To evaluate the rate of tumor recurrence within the irradiated volume after initial low-dose irradiation of limited-stage small-cell lung cancer (SCLC), to assess the tolerance of a sequential combination of low-dose chest irradiation followed by chemotherapy, and to confirm the responsiveness of limited-stage SCLC to low-dose irradiation. METHODS AND MATERIALS: In this pilot study, 26 patients with limited-stage SCLC were treated by first-line 20-Gy thoracic irradiation followed 3 weeks later by chemotherapy (cisplatin, doxorubicin, and etoposide for six cycles). RESULTS: We present our final results with a median follow-up of surviving patients of 7 years. The response rate to this low-dose irradiation was 83%, with an overall response rate to radiochemotherapy of 96% and a median survival of 21 months. No unexpected early or late toxicity was observed. The rate of initial isolated local failure was 8%, which compares favorably with other published series using higher doses of radiochemotherapy. CONCLUSION: An initial chest irradiation of 20 Gy before chemotherapy could be sufficient to reduce the risk of local failure during the time of survival of patients with limited-stage SCLC. Potential advantages of this treatment may be the prevention of resistance mechanisms to radiotherapy induced by preliminary chemotherapy and a reduced radiation-induced toxicity.

[Traumatic loosening of apophyses in the pelvic area and the proximal femur]. / Traumatische Apophysenlösungen im Bereich des Beckens und des koxalen Femurendes.

Avulsion fractures of the pelvis and the proximal femur are relatively rare injuries in the adolescent age group of 11 to 17 years. The overall prognosis for spontaneous healing is good. The injury most frequently involves the apophysis of the anterior inferior iliac spine and of the lesser trochanter, followed by anterior superior iliac spine. In our experience the avulsion fractures involving the ischial tuberosity and the greater trochanter are extremely rare. The latter can have dire consequences.

[Cement-free hip endoprosthesis: PCA shaft prosthesis, 5-7-year results]. / Zementfreie Hüftendoprothetik: PCA-Schaftprothesen, 5-7 Jahresresultate.

73 patients (out of a total of 79) with altogether 87 PCA-stems were followed up 5 to 7 years after total hip arthroplasty. The cups combined in these operations were not part of this study. In 11% the PCA-stem had to be removed respectively changed because of loosening. 50% of all patients suffered from thigh pain during the first 6 months postoperatively. Generally this pain disappeared within the first year after operation. Nevertheless 40% reported periods of transient thigh pain after the first postoperative year. Only when this pain was increasing and persisting over months, a correlation to loosening of the stem was found. Subsidence of more than 4 mm after the first postoperative year proved to be the only confident radiological sign of loosening. A strong correlation however was also found between appearance of a continuous radiolucent line through the zones 3-5 (according to Gruen) and loosening. We conclude that PCA-stems to our experience are not satisfactory because of the relatively high rate of loosening as well as the frequent occurring of transient thigh pain, even if this has not to be regarded as a sign of loosening.

[Early treatment of varicocele in children and adolescents]. / Zur Frühbehandlung der Varikozele bei Kindern und Jugendlichen.

Since 1970 we perform the prophylactic operation of grade II and III varicocele during childhood and puberty, even if there were overtreatment. Varicocele may very early interfere with testicular development and already causes histological changes in boys at the beginning of puberty. We have made a follow-up study of 25 adult men, who have been operated by high resection of spermatic vessels during childhood (mean age 13 years). Results are very good: no testicular atrophy and in nearly all cases a normal sperm count or only slight OAT-syndrome. Compared with a group of non-treated men of the same age sperm counts are better and the number of fertile sperms higher. For that reason we recommend treatment as early as possible in childhood and puberty.

[Varicocele--results following early treatment of children and adolescents]. / Varikozele--Resultate nach Frühbehandlung bei Kindern und Jugend-lichen.

Between 1970 and 1987, 50 children and adolescents aged between 9 and 17 were operated for left grade II and III varicocele. All cases involved high resection of the spermatic vessels according to the methods of Palomo and Bernardi. Out of this group, 21 adult men aged between 20 and 29 were rechecked later on. The following were found: 1 left-hand recurrence, twice one right-hand varicocele, three times one hydrocele testis due to a lesion of lymphatic vessels. The anatomical result was very good in 95% of cases, with full regression of the venous convolution. The spermiograms of the patients who had an early operation were compared with those of a control group of untreated varicocele patients of the same age group. In the patients who had had the operation, the volumes of the left testicles are larger than, or identical to, those of the right testicles. Due to the change in testicular blood flow brought about by the operation, testicular atrophy is stopped during puberty. The quality of the spermiograms of the patients who had early surgery was better and the percentage of normal sperms is higher than in the control group. We advocate this operation for children and adolescents.

Determination and characterization of immunoreactive trypsin in amniotic fluid from normal and cystic fibrosis fetuses.

High concentrations of immunoreactive trypsin (IRT) in the blood, and low concentrations of trypsin activity in fecal specimens have been found in newborn infants with cystic fibrosis (CF). The amniotic fluid concentrations of IRT and of IRT in complex with alpha 1-antitrypsin (alpha 1AT) were studied in 39 samples taken in about the 17th gestational week, and in 7 samples taken because the mothers had previously given birth to children with CF. The midtrimester samples contained trypsin in complex with alpha 1AT in a concentration of 30-200 micrograms/liter, and small amounts of trypsinogen, 0-50 micrograms/liter. Three of four amniotic fluid samples from CF fetuses had very low concentrations of trypsin in complex with alpha 1AT (less than 10 micrograms/liter), and only small amounts of trypsinogen (less than 10 micrograms/liter). Further prospective studies are needed to ascertain whether the determination of IRT in amniotic fluid may be of use in prenatal diagnosis of CF.

Adenosine phosphorylase activity as a technique for detection of mycoplasmas in biological media.

The importance of cell culture contamination by mycoplasmas is well recognized, but the means used to detect such contamination still need improvement. Most mycoplasmas possess an enzyme, adenosine phosphorylase, which is not found in cell lines. We used the ultramicromethod of Uitendaal et al. to detect the presence of mycoplasmas in sera and in tissue culture medium. The absence of adenosine phosphorylase activity seems to be the best guarantee that a serum is not contaminated by mycoplasmas. This test is also most efficient for the detection of mycoplasmas in tissue or cell cultures in vitro.

Diagnosis of cystic fibrosis homozygotes and heterozygotes from plasma and fibroblast cultures. A three-generation family study.

The diagnosis of cystic fibrosis (CF) homozygotes and heterozygotes and of individuals without the CF gene, based on differences in the thermal stability of acid phosphatase and alpha-mannosidase, is reported. The residual activities at 36.5 degrees C and 41.3 degrees C were below 10% of the activity in unheated samples for homozygotes, 40-50% for heterozygotes and above 90% for normals. The intracellular alkaline phosphatase and extracellular beta-hexosaminidase activities after treatment with heparin and gammaglobulin were 500% and 200%, respectively, of the activities without this treatment in CF homozygotes, whereas for heterozygotes and normals the values were the same after treatment as before. Pedigrees of four CF families, covering 2-3 generations, are presented. The possible use of these tests as diagnostic tools is further discussed.

Uptake and killing of Leishmania mexicana amazonensis amastigotes by human skin fibroblasts.

This paper describes the in vitro infection of human established fibroblast lines by Leishmania mexicana amazonensis amastigotes. Intracellular parasites were located within vacuoles. The proportion of infected cells reached a peak of about 50% on Days 2 or 3, and decreased to almost 0 on Days 6 or 8. Transmission electron microscopy was used to document different stages of the degeneration of L. m. amazonensis amastigotes on Days 4 and 5. The proportion of infected fibroblasts decreased in both the control and the irradiated cells, indicating that dilution of the parasites by cell multiplication was not the main factor in the observed decrease of the infection with time. This conclusion was also supported by studies with fibroblasts prelabelled with 3H thymidine. In these studies, total cell associated radioactivity as well as the total and TCA precipitable radioactivity of the culture medium were similar for infected and non-infected fibroblasts during the course of infection. The abortive infection of fibroblasts by L. m. amazonensis provides a potentially useful model for the study of the relationship between host cells and intracellular parasites.

Enzyme activity profiles in mouse teratocarcinomas. A quantitative ultramicroscale analysis.

Nine tumour lines with different developmental capacities were derived from spontaneous as well as from one induced teratocarcinoma: three teratocarcinoma-derived rhabdomyosarcomas TDR 602, TDR 694, and TDR 114; two teratocarcinoma-derived neuroblastomas TDN 2151 and TDN 2283; two teratocarcinoma-derived endodermal tumours TDE 274 and TDE 113; one multipotential teratocarcinoma OTT 2289, and one undifferentiated teratocarcinoma OTT 2158. Quantitative analyses of ten catabolic enzymes, i.e. alkaline and acid phosphatase, alpha- and beta-galactosidase, alpha- and beta-glucosidase, alpha-mannosidase, alpha-fucosidase, beta-glucuronidase, and hexosaminidase were carried out at the 20-cell level, and specific enzyme activity profiles were established for each of the tumour lines studied. These profiles may be used for the biochemical identification of a tumour type at the single cell level in addition to morphological and biological criteria.

Alkaline phosphatase and acid lysosomal hydrolases in pancreatic juice and fibroblast cell cultures of patients with chronic calcifying pancreatitis.

Nine lysosomal enzymes and alkaline phosphatase have been assayed in human pancreatic juice from controls and patients with chronic calcifying pancreatitis. Specific activities were evaluated by a nonparametric test (Wilcoxon) with a probability of 2 P less than or equal to 0.5. The values of acid phosphatase, alpha-glucosidase, beta-glucosidase and alpha-galactosidase are significantly higher in pathological juices; the values of alpha-mannosidase and beta-glucuronidase are also increased in the same patients but at the limit of significance. Alkaline phosphatase, beta-hexosaminidase and alpha-fucosidase follows the same trend but the values are not statistically significant between the two groups of patients. Studies on skin cultures of four patients with chronic calcifying pancreatitis demonstrate that the increased specific activities of lysosomal enzymes in the pathological juices do not correspond to a leakage of these enzymes into the extracellular space as described for cystic fibrosis.

Increased calcium content in cultured fibroblasts from trisomy patients: comparison with cystic fibrosis fibroblasts.

The elemental composition of cultured fibroblasts from trisomy patients, cystic fibrosis patients, and from healthy controls was compared by means of electron probe X-ray microanalysis. Significantly higher relative Ca concentrations (relative to phosphorus) and higher Ca/K ratios, were found in both trisomy and CF fibroblasts. Significantly lower relative Na concentrations and lower Na/K ratios were only found in CF fibroblasts; the Na content of trisomy fibroblasts was normal. Challenge with prostaglandin E2 did not cause any further rise in cell calcium in trisomy fibroblasts, nor did it cause elevated calcium levels in the control. If the mechanism causing elevated calcium levels in trisomy fibroblasts is similar to that causing abnormally high levels of calcium in CF fibroblasts, it might be located at the membrane level. The analytical results are discussed in the light of the observation that cyclic AMP levels are abnormally inducible in CF and trisomy fibroblasts.

[Polyenzymatic activation of cellular hydrolases induced by interferon; its role in cytolysis and other cellular manifestations induced by interferon]. / Activation polyenzymatique des hydrolases cellulaires induites par l'interféron; son rôle dans les processus de cytolyse et dans d'autres manifestations cellulaires provoquées par l'interféron.

Interferon (IFN) treatment of human effector T cells activates CMC directed against K562 targets. An increase of the activity of the different hydrolytic enzymes tested (hexosaminidase and acid-phosphatase) measured in the effector cell population parallels cytolysis activation. IFN and IFN inducers (PIC) treatment of cultured murine L-929 cells generate molecular mediated cytolysis. An increase of hydrolytic enzyme activity (hexosaminidase; B-glucuronidase, acid and alkalin phosphatases) precedes cell lysis. Thus, in both cytolytic systems, IFN induced a polyenzymatic activation of hydrolases. This activation is similar to coordinate enzyme induction discovered by Hosli [16] in pathological and experimental instances, when absorbed substrates cannot be hydrolyzed by lack of specific enzymes. Activation of hydrolytic enzymes induced by IFN which determines its enhancing effect on CMC and on fibroblast autolysis [17] could speculatively explain other effects of IFN such as antiviral action, diminution of cell protein synthesis, inhibition of cell division or molecular alterations of cell surface.

Polyenzymatic activation of cellular hydrolases induced by interferon; its role in cell lysis and other interferon--related phenomena.

Treatment of human cultured T cells by interferon (IFN), which enhances cell-mediated cytotoxicity directed against human K562 cell targets (NK-like activity) induces an activation of cell hydrolases. Treatment of mouse cultured L929 cells by IFN and double strand RNA enhancing cell autolysis induces first an activation of tested hydrolases (hexosaminidase, beta-glucuronidase, acid and alkaline phosphatases). Polyenzymatic activation of hydrolases induced by IFN is similar to coordinate enzymatic induction described by Hosli which occurs by lack of specific enzyme when non-digestible substrates are absorbed by cells. It is hypothesized that the polyenzymatic activation which accounts for cell lysis is a general defense mechanism which might also explain other actions related to IFN such as antiviral effect, inhibition of cell division, diminution of protein synthesis and cell surface alteration.

Heat inactivation of plasma hydrolases as a means of discriminating between the genotypes in cystic fibrosis: the experience in Israel.

The ability to discriminate between cystic fibrosis (CF) patients, carriers and control subjects, by determining the degree of hear inactivation of certain plasma enzymes has recently been reported. Material from Israel on 39 patients, 68 carriers and 65 control subjects, was tested under the originally described conditions with concordant results and distinct separation of the three genotypes. No carriers were detected in the 65 control subjects, perhaps because of the dilutional effect of those ethnic groups in Israel among whom the frequency of the CF gene is known to be rare. Biochemically, no evidence of heterogeneity of CF was found among the various ethnic groups.