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Background: Hormone therapy, which is widely prescribed for prostate cancer, might induce cognitive impairment and affect the autonomy of elderly patients. However, previous studies provided conflicting results. The aim of this systematic review and meta-analysis was to synthesize the longitudinal impact of hormone therapy on objective (cognitive tests) and subjective (questionnaires) cognition., Methods: A search was performed of the PubMed, Web of Science, and PsycINFO databases. Studies that longitudinally assessed cognition in patients undergoing androgen-deprivation therapy and new-generation hormone therapy were considered. To perform a meta-analysis, available scores were aggregated and classified into six objective domains and one subjective domain. Weighted mean effect sizes were computed using a random effect model., Results: Twenty studies were included in the systematic review (1440 patients), and 15 could be included in the meta-analysis (1093 patients). In the systematic review, 20%-50% of patients had objective cognitive impairment before treatment initiation. The meta-analysis revealed a decline in subjective cognition (g = -0.44; p = .03) with androgen-deprivation therapy and new-generation hormone therapy. All other effect sizes were small (from g = -0.02 to g = 0.18), and none of them indicated a significant decline in objective cognition. Significant heterogeneity was observed in all domains of objective cognition., Conclusions: This synthesis presents the first meta-analytic evidence of the negative impact of androgen-deprivation therapy and new-generation hormone therapy on subjective cognition. In contrast, there was no conclusive evidence of a decline in objective cognition. The high heterogeneity underscores the need for homogeneous cognitive research on prostate cancer., Plain Language Summary: There is no consensus on the cognitive impairment induced by hormone therapy for prostate cancer, despite the implications for patients' care and daily life. This synthesis of published studies demonstrated an increase in perceived cognitive difficulties but did not prove a decline in cognitive performance during treatment., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Elderly cancer patients often experience cognitive difficulties that can affect their quality of life and autonomy. However, they are rarely included in clinical trials, and only one study has explored the feasibility of cognitive training in this population. While digital cognitive training has been successful in improving cognition in younger patients, its feasibility in elderly patients requires evaluation., Objectives: This feasibility study primarily focused on evaluating patients' ability to use digital cognitive stimulation (usability). Secondary objectives were to evaluate acceptability, adherence, and satisfaction with regard to digital cognitive stimulation in elderly breast cancer patients., Methods: Elderly breast cancer patients at least 70 years old who were receiving cancer treatment (chemotherapy, targeted therapy, and/or radiotherapy) were recruited. Cognitive complaints were evaluated at baseline using the Functional Assessment of Cancer Therapy-Cognitive Function scale (FACT-Cog). Participants were invited to attend three 20-minute sessions of digital cognitive stimulation using HappyNeuron PRESCO software App on tablets, with the first session being supervised by a neuropsychologist and the two others being performed independently either at home or at the cancer center. We hypothesized that participants would spend 10 of the 20 min of the given time with the tablet completing exercises (training time). Thus, the usability of digital cognitive stimulation was defined as completing at least three exercises during the training time (10 min) of one of the two training sessions in autonomy. The proportion of patients who agreed to participate (acceptability) and completion of planned sessions (adherence) were also estimated. Satisfaction was evaluated post-intervention through a self-report questionnaire., Results: 240 patients were initially screened, 60% (n = 145) were eligible and 38% agreed to participate in the study. Included patients (n = 55) had a mean age of 73 ± 3 years, 96% an ECOG score of 0-1 and were undergoing radiotherapy (64%), and/or chemotherapy (47%) and/or targeted therapy (36%) for stage I-II breast cancer (79%). Most patients reported significant cognitive complaints (82%) and 55% had previous experience with digital tools (n = 30). The usability rate was 92%, with 46 out of 50 evaluable participants completing at least three exercises during the training time. The adherence rate was 88%, with 43/50 participants completing all planned sessions. Participants were largely satisfied with the cognitive intervention format (87%). They preferred to complete sessions at the cancer center under the supervision of the neuropsychologist than alone at home (90%)., Conclusions: The high level of usability, adherence and satisfaction in this study shows for the first time the feasibility of digital cognitive stimulation in cancer patients older than 70 years. However, the intervention should be proposed only to patients reporting cognitive complaints and should be structured and supervised to improve acceptability and adherence., Trial Registration: ClinicalTrials identifier: NCT04261153, registered on 07/02/2020., (© 2024. The Author(s).)

Every year, thousands of seabirds are cast ashore and are found dead along the coasts of North America and Western Europe. These massive mortality events called 'winter wrecks' have generally been attributed to harsh climatic conditions and prolonged storms which affect bird energy balance and impact their body condition. Nevertheless, additional stress factors, such as contaminant body burden, could potentially cumulate to energy constraints and actively contribute to winter wrecks. However, the role played by these additional factors in seabird massive winter mortality has received little attention to date. In February/March 2014, an unprecedented seabird wreck occurred along the Atlantic French coasts during which > 43,000 seabirds were found dead. By analyzing mercury (Hg) concentrations in various tissues collected on stranded birds, we tested the hypothesis that Hg played a significant role in this mortality. More specifically, we aimed to (1) describe Hg contamination in wintering seabirds found along the French coasts in 2014, and (2) determine if Hg concentrations measured in some vital organs such as kidney and brain reached toxicity thresholds that could have led to deleterious effects and to an enhanced mortality. We found some of the highest Hg levels ever reported in Atlantic puffins, common guillemots, razorbills and kittiwakes. Measured concentrations ranged from 0.8 to 3.6 μg · g(-1) of dry weight in brain, 1.3 to 7.2 μg · g(-1) in muscle, 2.5 to 13.5 μg · g(-1) in kidney, 2.9 to 18.6 μg · g(-1) in blood and from 3.1 to 19.5 μg · g(-1) in liver. Hg concentrations in liver and brain were generally below the estimated acute toxicity levels. However, kidney concentrations were not different than those measured in the liver, and above levels associated to renal sub-lethal effects, suggesting a potential Hg poisoning. We concluded that although Hg was not directly responsible for the high observed mortality, it has been a major aggravating stress factor for emaciated birds already on the edge. Importantly, this study also demonstrated that total blood, which can be non-lethally collected in seabirds, can be used as a predictor of Hg contamination in other tissues., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: A few models for pneumonectomy in rats have been described, and in most of these, anesthesia includes orotracheal intubation, which increases morbidity and mortality and also adds technical complexity. Models without tracheal intubation but with injectable anesthesia are difficult to reproduce, however, and lead to a lengthy postoperative-recovery period with high morbidity and mortality rates., Objective: The objective of this study was to describe a simple, safe, and effective experimental model for pneumonectomy in rats without tracheal intubation., Materials and Methods: A left-sided pneumonectomy was performed on 26 Sprague-Dawley rats anesthetized by isoflurane applied via a mask without tracheal intubation. To avoid dangerous traction movements, the lung pedicle was ligated en bloc using clips., Results and Discussion: No rat demonstrated cardiorespiratory depression. Of the 26 rats, 1 was dehydrated and had lost more than 10% of its body weight, resulting in death on the third day after surgery. Total mortality was therefore 3.8%. Mean (standard deviation [SD]) anesthesia duration was 9.8 (1.0) minutes, surgery time was 3.0 (0.6) minutes, and open pneumothorax time was 1.2 (0.3) minutes. Mean (SD) weight loss during the early postoperative period was 4.5% (3.5%). These results were more satisfactory than results obtained using ketamine mixtures as anesthetic agents (ketamine plus xylacine, and ketamine plus diazepam)., Conclusion: Our model for left-sided pneumonectomy in isoflurane-anesthetized rats does not require endotracheal intubation and is effective, safe, quick, and easily reproducible., (Georg Thieme Verlag KG Stuttgart · New York.)

The protection of key areas for biodiversity at sea is not as widespread as on land and research investment is necessary to identify biodiversity hotspots in the open ocean. Spatially explicit conservation measures such as the creation of representative networks of marine protected areas (MPAs) is a critical step towards the conservation and management of marine ecosystems, as well as to improve public awareness. Conservation efforts in ecologically rich and threatened ecosystems are specially needed. This is particularly urgent for the Mediterranean marine biodiversity, which includes highly mobile marine vertebrates. Here, we studied the at sea distribution of one of the most endangered Mediterranean seabird, the critically endangered Balearic shearwater Puffinus mauretanicus. Present knowledge, from vessel-based surveys, suggests that this species has a coastal distribution over the productive Iberian shelf in relation to the distribution of their main prey, small pelagic fish. We used miniaturised satellite transmitters to determine the key marine areas of the southern population of Balearic shearwaters breeding on Eivissa and spot the spatial connections between breeding and key marine areas. Our tracking study indicates that Balearic shearwaters do not only forage along the Iberian continental shelf but also in more distant marine areas along the North African coast, in particular W of Algeria, but also NE coast of Morocco. Birds recurrently visit these shelf areas at the end of the breeding season. Species distribution modelling identified chlorophyll a as the most important environmental variable in defining those oceanographic features characterizing their key habitats in the western Mediterranean. We identified persistent oceanographic features across time series available in the study area and discuss our results within the current conservation scenario in relation to the ecology of the species.

In mammals with precocial neonates, exclusive maternal care and investment depend on mutual mother-young recognition. In sheep, this is ensured by rapid olfactory recognition of the neonate by its mother. However, recent studies suggest that other processes may participate in preferential maternal care. We investigated the possibility that acoustic communication promotes preferential nursing of the lamb. In the first of two studies, we examined the association between nursing and vocal activity in ewes and their lambs during the first 2 weeks of lactation. As early as 3 and 6 h postpartum, vocal activity was preferentially concentrated before nursing and by day 15 all vocal activity occurred within 2.5 min before nursing. In the second study, we tested the responses of ewes and lambs at 15 days postpartum to the playback of recorded bleats of their partner or from unrelated ewes and lambs. When playback was performed 30 min after a nursing episode, both ewes and lambs responded to bleats of their partner but not to bleats from alien subjects. When playback was performed 5 min after nursing, ewes did not respond to any lamb's bleats, while lambs continued responding to the bleats of their mothers, but significantly less than 30 min after nursing. Nursing therefore appears to play an important role in structuring very early vocal communication between the mother and her neonate. In turn, if the motivational state of the members of the mother-young dyad is adequate, this ensures the display of mutual acoustic recognition and prepares them for preferential nursing before maternal olfactory recognition of the lamb comes into play.

Drugs used in oncology represent more than half of the innovative and costly drugs which are not covered by a Group Homogène de Soins (DRG type classification) within the context of the case-mix based payment system (termed T2A). For these drugs, good practice reference guidelines have been drawn up by scientific societies and registration agencies. Recognised indications, relevant indications and situations where the treatment should not be prescribed are defined by the National Institute of Cancer. The reference guidelines should lead towards the good use of these drugs and allow the sick funds to control prescriptions. They should evolve with time, which means that bibliographic monitoring and independent expert opinion is necessary to update them as science provides new data. Manufacturers are involved in this process which in no case should undermine developmental efforts leading to registration. The objective of this protocolisation is to allow all patients early and legitimate access to drugs representing real therapeutic progress. These reference guidelines should be integrated into the life-cycle of a drug and should give rise to new developments allowing the good use of cancer products in situations which have been properly validated.

Drugs used in oncology represent more than half of the innovative and costly drugs which are not covered by a Group Homogène de Soins (DRG type classification) within the context of the case-mix based payment system (termed T2A). For these drugs, good practice reference guidelines have been drawn up by scientific societies and registration agencies. Recognised indications, relevant indications and situations where the treatment should not be prescribed are defined by the National Institute of Cancer. The reference guidelines should lead towards the good use of these drugs and allow the sick funds to control prescriptions. They should evolve with time, which means that bibliographic monitoring and independent expert opinion is necessary to update them as science provides new data. Manufacturers are involved in this process which in no case should undermine developmental efforts leading to registration. The objective of this protocolisation is to allow all patients early and legitimate access to drugs representing real therapeutic progress. These reference guidelines should be integrated into the life-cycle of a drug and should give rise to new developments allowing the good use of cancer products in situations which have been properly validated., (Copyright © 2006 Société Française de Pharmacologie et de Thérapeutique. Publié par Elsevier Masson SAS.)

Post-transplant lymphoproliferative disorder (PTLD) after haemopoietic stem cell transplantation is a serious complication that occurs in 8-22% of patients with high-risk factors. We retrospectively investigated tolerance and efficacy of humanized anti-CD20 monoclonal antibody (rituximab) as first-line treatment in 12 children with B-cell PTLD. At diagnosis, eight patients had tumoral involvement. The other four patients had fever, associated with raised Epstein-Barr virus (EBV) viral load and monoclonal gammopathy. Rituximab was given at the dose of 375 mg/m2 once a week by intravenous infusion (1-9 infusions). Only 1/48 infusions was associated with a grade 2 clinical adverse event. Eight out of 12 (66%) patients responded to the treatment and were in complete remission. All patients without tumoral involvement responded to the treatment. A rapid decrease in fever within 1 week was observed in all responders. Non-responders did not show any clinical response during the first week. Tumoral involvement and immunodepression seemed to be more marked in non-responders. Rituximab was an effective and well-tolerated treatment of B-cell PTLD. Early treatment before tumoral involvement seemed to be the most effective approach. Lack of rapid response should lead to intensification of PTLD treatment. Pre-emptive treatment should be considered and evaluated in further longitudinal multicentre studies.

The clinical activity of rituximab, a chimeric monoclonal antibody which binds to the CD20 antigen, was evaluated as a single first-line therapy for patients with follicular non-Hodgkin lymphoma (NHL). Fifty patients with follicular CD20(+) NHL and a low tumor burden were analyzed for clinical and molecular responses. They received 4 weekly infusions of rituximab at a dose of 375 mg/m(2). The response rate a month after treatment (day 50) was 36 of 49 (73%), with 10 patients in complete remission, 3 patients in complete remission/unconfirmed, and 23 patients in partial remission. Ten patients had stable disease, and the disease progressed in 3 patients. One of 13 (8%) patients in complete remission, 9 of 23 (39%) patients in partial remission, and 5 of 10 (50%) patients with stable disease exhibited disease progression during the first year. Within the study population, 32 patients were initially informative for polymerase chain reaction (PCR) data on bcl-2-J(H) rearrangement. On day 50, 17 of 30 patients (57%) were negative for bcl-2-J(H) rearrangement in peripheral blood, and 9 of 29 (31%) were negative in bone marrow; a significant association was observed between molecular and clinical responses (P <.0001). At month 12, 16 of 26 patients (62%) were PCR negative in peripheral blood. These results indicate that early molecular responses can be sustained for up to 12 months and that this response is highly correlated with progression-free survival. Rituximab has a high clinical activity and a low toxicity and induces a high complete molecular response rate in patients with follicular lymphoma and a low tumor burden.

Purpose: To determine the efficacy and tolerability of irinotecan (CPT-11) in advanced or recurrent cervical carcinoma., Patients and Methods: Eligible patients had histologically confirmed, inoperable, progressive, metastatic or recurrent squamous cell cervical carcinoma and had received no radiotherapy in the preceding 3 months and had never received chemotherapy. The initial irinotecan dosage of 350 mg/m(2) every 3 weeks was modifiable according to toxicity. Treatment continued for six cycles after complete response, or until disease progression or excessive toxicity after partial response, or for three additional cycles in the case of stable disease. Patients were stratified into group A (>/= one measurable lesion in a previously unirradiated area, with or without progressive disease in irradiated fields) or group B (measurable new lesion[s] in an irradiated field)., Results: Fifty-one of 55 enrolled patients were eligible for inclusion (median age, 47 years; range, 30 to 71 years). The response rate was 15.7% (95% confidence interval [CI], 7.0% to 28.6%) overall, 23.5% (95% CI, 10.7% to 41.2%) for group A (complete response, 2.9%), and zero for group B. The median time to progression and median survival were 4.0 and 8.2 months for group A and 2.5 and 4.2 months for group B, respectively. The major grade 3/4 toxicities for groups A and B were diarrhea (24.3% and 55.5%, respectively) and neutropenia (24.3% and 33.3%, respectively). There were four toxicity-related deaths, three in group B. Patients with no prior external pelvic irradiation experienced fewer grade 3 and 4 adverse events., Conclusion: Irinotecan is effective in treating cervical squamous cell carcinoma if disease is located in an unirradiated area. Because of toxicity, a reduced dose is advised for patients previously treated with external pelvic irradiation.

Ovarian cancer has a poor prognosis due to the frequent appearance of a drug-resistant state. An alternative therapeutic approach may lie in combinations of conventional chemotherapeutic agents with new classes of drug, such as interferons (IFN) and differentiation-inducing agents. There is clinical evidence that both IFN-alpha2a-all-trans retinoic acid (ATRA) and IFN-alpha2a-cisplatin have significant activities on growth of malignant cells, cell differentiation or programmed cell death in solid tumors. In order to throw more light on the cellular basis of these findings and to optimize a schedule of such drug combinations, we examined the cytotoxic effects of various combinations on five human ovarian carcinoma cell lines. The experiments were based on a clonogenic assay on plastic. The different cell lines exhibited different sensitivities to the three drugs tested. Using the cell line most sensitive to these drugs, we then examined the effect of different sequences of two drug combinations. We observed a potentiation after pretreatment with ATRA followed by IFN-alpha2a and ATRA or after pretreatment with IFN-alpha2a followed by IFN-alpha2a and cisplatin. Using this schedule of administration, cytotoxic interactions between the two drugs were investigated by median effect analysis. Synergism or antagonism were observed depending on the intrinsic sensitivity of the cell line to the first drug and the concentrations used. The magnitude of these interactions was found to be influenced by the cellular sensitivity to the second drug. These results show that schedules of drug combinations are not easy to design and may help account for the various failures and the discrepant effects observed in clinical trials.

In the practice of medically assisted conception it is important to avoid harming both the mother and the future child. A rigorous and permanent evaluation of the techniques and their consequences afford the basis of a detailed and complete information of the couples before obtaining written consent. Medical records must include the state of the newborn. Records can be consulted later on according to confidentiality, administrative rules and avoiding any action which can determine anxiety.

Background: We conducted a phase I and pharmacokinetic study to determine the maximum tolerable dose (MTD), toxicities, pharmacokinetic profile, and antitumor activity of Irinotecan (CPT-11) in patients with refractory solid malignancies., Patients and Methods: Forty-six patients were entered in this phase I study. CPT-11 was administered intravenously over 30 minutes for 3 consecutive days every 3 weeks. Dose levels ranged from 33 mg/m2/day to 115 mg/m2/day on days 1 through 3. The pharmacokinetics of total CPT-11 and its active metabolite SN-38 were assayed by HPLC., Results: The combination of leukopenia and diarrhea was dose-limiting toxicity at 115 mg/m2/day dose level, since 50% of the patients (5/10) experienced either grade 3-4 leukopenia, or diarrhea, or both. Leukopenia appeared to be a cumulative toxicity, with a global increase in its incidence and severity upon repeated administration of CPT-11. Other toxicities included nausea, vomiting, fatigue and alopecia. CPT-11 and active metabolite SN-38 pharmacokinetics were determined in 21 patients (29 courses). Both CPT-11 and SN-38 pharmacokinetics presented a high interpatient variability. CPT-11 mean maximum plasma concentrations reached 2034 ng/ml at the MTD (115 mg/m2). The terminal-phase half-life was 8.3 h and the mean residence time 10.2 h. The mean volume of distribution at steady state was 141 l/m2/h. CPT-11 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Total body clearance did not vary with increased dosage (mean = 14.3 l/h/m2), indicating linear pharmacokinetics within the dose range administered in this trial. The total area under the plasma concentration versus time curve (AUC) increased proportionally to the CPT-11 dose. Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD. A significant correlation was observed between CPT-11 area under the curve (AUC) and its corresponding metabolite SN-38 AUC (r = 0.52, p < 0.05). SN-38 rebound concentrations were observed in many courses at about 0.5 to 1 hour following the end of the i.v. infusion, which is suggestive of enterohepatic recycling. Mean 24-h urinary excretion of CPT-11 accounted for 10% of the administered dose by the third day, whereas SN-38 urinary excretion accounted for 0.18% of the CPT-11 dose. In this phase I trial, the hematological toxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrhea grade correlated significantly with CPT-11 AUC. Two partial (breast adenocarcinoma and carcinoma of unknown primary) and 2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responses were observed., Conclusion: The MTD for CPT-11 administered in a 3 consecutive-days-every-3 weeks schedule in this patient population is 115 mg/m2/day. The recommended dose for phase II studies is 100 mg/m2/day.

Background: CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecin and exerts its activity by inhibiting DNA topoisomerase I. A phase II study of this drug was performed in patients with pancreatic cancer., Patients and Methods: Eligibility criteria included advanced non-chemotherapy-pretreated pancreatic cancer. CPT-11 was administered as a 30-minute i.v. infusion at a dose of 350 mg/m2 diluted in 250 ml normal saline every 3 weeks., Results: Thirty-four eligible patients were enrolled in the study, thirty-two of them were evaluated, and three achieved partial responses (9%; 95% C.I. = 3%-25%). The duration of response was 7.2, 7.5 and 7.8 months, respectively. Thirteen patients had no change, fourteen patients had progressive disease and two had early progressive disease. The median duration of survival for all patients treated was 5.2 months. The main toxicities (CTC grade > or = 3) were diarrhea, leukocytopenia, asthenia, nausea and vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses. These toxicities were reversible and manageable with anti-emetics and prophylactic or curative antidiarrheal agents., Conclusion: CPT-11 is an interesting moderately effective drug in pancreatic cancer.

Two patients were treated with CPT-11 for colorectal cancer and had a percutaneous biliary catheter for extrahepatic biliary obstruction. The first patient was treated with CPT-11 according to the 100-mg/m2 weekly therapeutic schedule, and the second patient was treated every 3 weeks, with a dose of 350 mg/m2 being given at the first course, after which it was decreased to 300 mg/m2 for the following courses. In plasma, the active identified metabolite of CPT-11, SN-38, occurred mainly in the form of a glucuronide conjugate. CPT-11 was mainly excreted in bile and urine as CPT-11. The cumulative biliary and urinary excretion of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide conjugate) over a period of up to 48 h ranged from 25% (100 mg/m2 weekly) to 50% (300 mg/m2 every 3 weeks). This means that CPT-11 can be excreted under other, not yet identified metabolite forms.

The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.

Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m2 (30-90 min i.v. infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and appeared to be dose related, reversible and noncumulative. However, interpatient variability of toxic effects was substantial. Prolongation of the infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and anemia. CPT-11 plasma disposition was bi- or triphasic with a terminal half-life of 9.3 h. CPT-11 area under the plasma concentration versus time curves increased linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the plasma concentration versus time curve correlated significantly with that of CPT-11, but not with that of CPT-11 dose. Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m2. Using this weekly schedule, recommended doses for phase II studies are 100 mg/m2 in high risk patients and 115 mg/m2 in others.

In Down syndrome screening by maternal serum human chorionic gonadotropin (hCG) determination at 15, 16, 17, and 18 weeks of gestation, we prospectively examined 23,369 sera from white (21,549), North African (970), black African (525), and Asian (325) patients. When expressed as multiples of the median (MOM), no difference was observed between white, North African, and black African patients. However, higher serum hCG concentrations were noted in Asians, for whom we therefore recommend correction of hCG values before calculation of the risk of Down syndrome.

The median maternal serum free beta human chorionic gonadotropin (hCG) multiple of the median (MOM) of 480 Down syndrome cases in the second trimester was 2.64, significantly greater than the reported median MOM of intact hCG (p < 0.0001). In 234 of these cases from retrospective and prospective studies, the effectiveness of maternal serum free beta hCG was evaluated in combination with alpha-fetoprotein (AFP) and maternal age in second-trimester Down syndrome screening. Down syndrome detection in the gestational age range of 14-16 weeks was 82 per cent. In all gestational weeks (14-22), a 77.7 per cent Down syndrome detection rate was achieved. In prospective screening of 44,272 patients under the age of 35 years, 69 per cent of Down syndrome cases were detected (73 per cent in gestational weeks 14-16). The false-positive rate for the prospective study was 3.8 per cent. The use of free beta hCG combined with maternal serum AFP and maternal age-related risk for Down syndrome in a screening population (i.e., women under 35 years) yields an improved detection efficiency over other protocols.

The phenotypically normal sister of a patient affected by fragile X syndrome was referred for genetic counselling and was found to carry a mosaic karyotype 46,X,r(X)/45,X. Because the probability of the simultaneous chance occurrence of fragile X syndrome and a ring chromosome X in the same family is very low, we postulated that the breakpoint of the ring chromosome X originated in the cytogenetic break in Xq27.3 responsible for fragile X syndrome. In order to determine the relative positions of the breakpoint on the ring chromosome X and the (CGG)n unstable sequence responsible for the fragile X mutation, we used molecular markers to analyse the telomeric regions of chromosome X in this family. The results showed that the ring chromosome X was the maternal fragile X chromosome and that the telomeric deletion on the long arm encompassed the (CGG)n sequence. This suggests that the cytogenetic break in Xq27.3 is distinct from the unstable (CGG)n sequence, or that the break followed by the end-to-end fusion creating the ring chromosome was not completely conservative. Analysis of DNA markers on the short arm of chromosome X evidenced a deletion of a large part of the pseudoautosomal region, allowing us to position the genes involved in stature and in some syndromes associated with telomeric deletions of Xp on the proximal side of the pseudoautosomal region.

The efficacy of the topoisomerase I inhibitor CPT-11 [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxycamptothec in] has been evaluated against a panel of human tumor xenografts derived from adult and pediatric malignancies. Tumors included eight colon adenocarcinomas representing intrinsically chemorefractory malignancies, six lines derived from childhood rhabdomyosarcoma (three embryonal and three alveolar) representing a chemoresponsive histiotype, and sublines of rhabdomyosarcomas selected in vivo for resistance to vincristine, melphalan, and the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan). CPT-11 was given by i.v. administration daily for 5 days each week for 2 weeks (one cycle of therapy) or on the same schedule with cycles repeated every 21 days. The maximum tolerated dose for a single cycle of treatment was 40 mg/kg/dose, and for 3 cycles the maximum tolerated dose was 10 mg/kg/dose. Treatment was started against advanced tumors. Against colon adenocarcinomas CPT-11 administered for one cycle at the maximum tolerated dose caused complete or partial regression (> or = 50% reduction in tumor volume) in 5 of 8 lines. One cycle of CPT-11 therapy caused significant inhibition of tumor growth, without 50% regression, in 2 of 3 other colon adenocarcinomas. Rhabdomyosarcoma xenografts derived from untreated patients were highly responsive to CPT-11, which caused complete regression in 5 of 6 lines even at 20 or 10 mg/kg/dose. CPT-11 retained complete activity against rhabdomyosarcomas selected for resistance to vincristine and caused complete regressions in a line selected for resistance to melphalan that was also completely cross-resistant to topotecan. Of note was the observation that CPT-11 was as active against two xenografts selected for primary resistance to topotecan as it was against the respective parental tumors. Preliminary data indicate that CPT-11, like the topoisomerase I inhibitor topotecan, may have increased therapeutic efficacy when administered at a low dose for protracted periods (3 cycles). A comparison of the efficacy of CPT-11 with topotecan is presented.

The sizes of the fragile X mutation in 33 sib pairs affected with fragile X syndrome were determined by Southern blot analysis. An age-dependent decrease in the size of the mutation was found, suggesting positive selection of blood cells carrying small mutations during life or maternal imprinting.

In order to investigate the origin of mutations responsible for the fragile X syndrome, two polymorphic CA repeats, one at 10 kb (FRAXAC2) and the other at 150 kb (DXS548) from the mutation target, were analyzed in normal and fragile X chromosomes. Contrary to observations made in myotonic dystrophy, fragile X mutations were not strongly associated with a single allele at the marker loci. However, significant differences in allelic and haplotypic distributions were observed between normal and fragile X chromosomes, indicating that a limited number of primary events may have been at the origin of most present-day fragile X chromosomes in Caucasian populations. We propose a putative scheme with six founder chromosomes from which most of the observed fragile X-linked haplotypes can be derived directly or by a single event at one of the marker loci, either a change of one repeat unit or a recombination between DXS548 and the mutation target. Such founder chromosomes may have carried a number of CGG repeats in an upper-normal range, from which recurrent multistep expansion mutations have arisen.

Some 250 different mutations have so far been screened in the cystic fibrosis (CF) gene. The 50 nonsense, 33 splicing and 60 frameshift mutations are randomly distributed within the gene, unlike the 107 missense mutations or amino acid deletions. A large excess of missense mutations affects the exons encoding the first transmembrane (MS1) and first ATP-binding fold (NBF1) domains. Sixty-four of the 107 missense mutations may be classified as private, demic, local and general mutations on the basis of their geographic distribution in Europe. Private and demic mutations are randomly distributed within the gene; local and general mutations are not. It is well known that some RFLP markers are in linkage disequilibrium with some mutations. Private, demic and local mutations are randomly associated with each class of RFLP haplotypes. In contrast, general mutations, frequent and infrequent, are not randomly associated with RFLP markers. General mutations usually affect a specific part of the gene and are more likely to be associated with a specific RFLP marker. This suggests the existence of selective factors favoring these mutations, a hypothesis formerly postulated as a possible cause of the high frequency of the disease.

Introduction of maternal serum markers for prenatal screening of Down's syndrome implies a redefinition of the criteria used for identifying at risk women for screening by amniocentesis, which are currently based on maternal age. On the basis of the first French prospective study of human chorionic gonadotropin measurement in maternal serum as a predictor of Down's syndrome, this paper shows that a screening policy combining maternal age with hCG measurement was more cost-effective than one relying on maternal age alone. A cost-benefit analysis (using the "avoided" lifelong costs of care for a trisomic 21 child that are allowed by prenatal screening) would justify lower hCG cut-off values and an higher detection rate of Down's syndrome (74.5%) than other decision rules based on alternative principles such as: equalization to 1% of fetal risk of Down's syndrome for access to amniocentesis at all maternal ages or equalization to 1/1000 of fetal risk of Down's syndrome among women not undergoing amniocentesis. However, results of the cost-benefit analysis are very sensitive to other factors such as the cost associated with loss of a normal fetus due to iatrogenic risk of amniocentesis (false positives of hCG). Ethical and value-laden issues that necessarily underlie economic evaluation of screening programmes, as well as other decision rules based on equalization of acceptable risk for each maternal age, are discussed.

Eleven complete Spanish pedigrees with fragile X syndrome were analysed by Southern blotting with the DNA probe StB12.3 previously isolated and described by Oberlé et al. [1991]. This probe allowed the direct detection of affected males and carrier females and was able to distinguish between normal males and normal transmitting males (NTMs). One hundred and twenty three individuals were analyzed, 115 from the pedigrees and 8 from the general population. Five mosaic cases were found (4 males and one female) showing both the premutation and the full mutation. One half of the females with the full mutation were mentally retarded but no female with mental retardation carried the premutated pattern, suggesting that the absence of the full mutation in females is a very good criterion for pre-or postnatal diagnosis of normal mental status.

CPT-11 (I; 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin) is a new anticancer agent currently under clinical development. A sensitive high-performance liquid chromatographic assay suitable for the simultaneous determination of I and its active metabolite SN-38 (II) in human plasma, and their preliminary clinical pharmacokinetics, are described. Plasma samples were processed using a solid-phase (C18) extraction step allowing mean recoveries of I, II and the internal standard camptothecin (III) of 84, 99 and 72%, respectively. The extracts were chromatographed on a C18 reversed-phase column with a mobile phase composed of acetonitrile, phosphate buffer and heptanesulphonic acid, with fluorescence detection. The calibration graphs were linear over a wide range of concentrations (1 ng/ml-10 micrograms/ml), and the lower limit of determination was 1 ng/ml for both I and II. The method showed good precision: the within-day relative standard deviation (R.S.D.) (5-1000 ng/ml) was 13.0% (range 4.9-19.4%) for I and 12.8% (6.7-19.1%) for II; the between-day R.S.D. (5-10,000 ng/ml was 7.9% (5.4-17.5%) for I and 9.7% (3.5-15.1%) for II. Using this assay, plasma pharmacokinetics of both I and II were simultaneously determined in three patients receiving 100 mg/m2 I as a 30-min intravenous infusion. The mean peak plasma concentration of I at the end of the intravenous infusion was 2400 +/- 285 ng/ml (mean +/- standard error of the mean). Plasma decay was triphasic with half-lives alpha, beta and gamma of 5.4 +/- 1.8 min, 2.5 +/- 0.5 h and 20.2 +/- 4.6 h, respectively. The volume of distribution at steady state was 105 +/- 15 l/m2, and the total body clearance was 12.5 +/- 1.9 l/h.m2. The maximum concentrations of the active metabolite II reached 36 +/- 11 ng/ml.

We previously suggested that an activation defect of pancreatic proteolytic zymogens in newborns suffering from cystic fibrosis (CF) might contribute (by an adaptative-like process) to the significant increase of the serum trypsin level observed in the disease at birth. To give support to this hypothesis we studied two pancreatic enzymes: trypsin 1 (IRT) and chymotrypsin A (IRChT) by noncompetitive enzyme immunoassays in amniotic fluids taken at 17-18 weeks of pregnancy. In normal fluids (102), the levels of the two enzymes were widely dispersed between 5 and 100 micrograms/L. A similar pattern was observed for the fluids with a 1 in 4 risk of CF with a normal outcome (24). In contrast, the levels of pancreatic enzymes in the fluids with affected fetus (40) were always below 45 micrograms/L for IRT and 55 micrograms/L for IRChT and most of them were under 20 micrograms/L for both enzymes. The molecular forms of IRT and IRChT in amniotic fluids were studied by gel filtration. In amniotic fluids with affected fetus, a major form of IRT was eluted in a position consistent with the elution of proteins around 25 kDa and two peaks of IRChT were eluted at 75 kDa and 25 kDa. These patterns are similar to those observed in normal serum when zymogens are present and are quite different from the patterns obtained by gel filtration of amniotic fluids with normal outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to better characterize the chromosomic rearrangement of an unbalanced 45XX t(X;22) (q28;q11) DiGeorge patient, a somatic hybrid clone segregating the translocated chromosome was constructed and investigated using X and 22 linked markers. Our study demonstrated that this de novo translocation was from paternal origin. The breakpoint was assigned between DXS296 and IDS loci at Xq28 and between D22S9 and BCRL2 at 22q11. This observation and published data allow to locate a "critical region" for DiGeorge syndrome between these two last loci on 22q11. Our hybrid clone may be a useful tool for mapping new probes arising in this region.

A technique allowing the simultaneous screening of the four main CF mutations in the French population (delta F508, delta I507, G542X, S549N) has been developed by means of allele sequence-specific oligonucleotide (ASO) reverse dot blot. Using a strategy proposed by R. K. Saïki et al. (1989, Proc. Natl. Acad. Sci. USA 86: 6230-6234) for HLA-DQA, the seven ASOs for normal and mutant CF alleles were given a homopolymer T tail with terminal deoxyribonucleotidyltransferase and then immobilized on a nylon membrane. T-tail homopolymers were preferentially bound to the nylon, leaving the specific ASO sequences free to hybridize with amplified and radiolabeled exons 10 and 11 of a patient. These exons were simultaneously coamplified by a multiplex PCR and radiolabeled by random priming. ASO reverse dot blot currently appears to be the most efficient, rapid, and economic means of screening the population for CF mutations. This screening can detect nearly 80% of carriers and 64% of couples at risk and could prevent the birth of CF-affected infants in these families.

Thirteen mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been screened in a French sample of 185 cystic fibrosis (CF) patients, together with their respective associated RFLP haplotypes at the linked D7S23 locus (XV2C and KM19 markers). The respective frequencies of the mutations showed that 9 of them account for 80% of the CF chromosomes. Implications for prenatal diagnosis and heterozygote detection are defined and discussed. The well-known great excess of RFLP B marker within CF chromosomes is partially explained by two already characterized mutations highly associated with haplotype B: delta F508 and G542X. Similarly, the excess of haplotype D within CF chromosomes is partially explained by the association between delta I507 and this haplotype. These results may suggest the existence of two still untested or uncharacterized mutations, whose frequencies could be near 1%, one which would be associated with haplotype B and a second which would be associated with haplotype D. The possible cause of the specific association between most of the main different CF mutations and the RFLP haplotype B is discussed.

Three hundred and twenty-six French families with a cystic fibrosis-affected child who were referred for prenatal diagnosis were analysed by sibship size: 74.2 per cent of the couples had no further pregnancies to term after the affected child, who was deceased in 34.6 per cent of cases. These couples were followed prospectively after prenatal diagnosis and 77 had two or more consecutive pregnancies with prenatal diagnosis. The aim of these couples was to succeed in constituting a family with two normal children.

The main indications for cytogenetic prenatal diagnosis have been based on pregnancies with an increased risk of chromosomal anomaly. Advanced maternal age has been the most important criterion and presently 60% of women of 38 yr and over undergo prenatal diagnosis. Fetal malformations detected by ultrasound resulted in the selection of a group in which approximately 10% chromosomal anomalies were detected. An effort has been made to describe sonographic signs indicative of Down's syndrome. Maternal serum biochemical markers constitute another approach for screening. Human chorionic gonadotropin is the most discriminant test. Combining maternal and hCG cut-off levels, it is possible to detect approximately 70% of trisomy 21% in women aged between 30-38 yr.

To characterize mutations in the CYP21B gene that are responsible for congenital adrenal hyperplasia (CAH), DNA samples from 91 French patients have been studied by allelic-specific oligonucleotide hybridization and Southern blot analysis. Seven sites mostly found in the CYP21A pseudogene and deletions of the functional CYP21B gene have been screened. Gene conversions involving small DNA segments accounted for 57% of the tested mutations and probably cause 74% of the mutations responsible for the disease. Complete deletion of the CYP21B gene accounted for 18% of the CAH mutations in the whole sample and for 21% in the classical form of the disease. Three mutations were found associated with specific clinical forms of the disease: a G-C substitution in the seventh exon was associated with the late-onset form of the disease, and both an 8-bp depletion in the third exon and complete deletion of CYP21B were associated with the salt-wasting form.

Spanish families (n = 75) with at least one affected cystic fibrosis (CF) child were typed for restriction fragment length polymorphisms (RFLPs) by the probes XV2c, KM19, and pMP6d-9. These families were also studied at the 508 mutation site by the polymerase chain reaction method. We have studied the linkage disequilibrium between these markers and the CF mutations, the probable number of independent secondary CFX (non-delta F508) mutations, and the genetic differences between Spain and Western Europe.

French families (n = 129) with at least one cystic fibrosis (CF) affected child and 44 unrelated subjects from the general population were tested for the presence of the delta F508 mutation by the polymerase chain reaction. The delta F508/CF mutation ratio (CF: uncharacterised CF mutations) was tested in the CF families with and without meconium ileus. The association between delta F508 and CF mutations and restriction fragment length polymorphism haplotypes (XV2c and KM19) has been estimated; these data suggest that the CF chromosomes include a panel of independent and probably different mutations.

A simple enzyme immunoassay measuring human chorionic gonadotropin in undiluted maternal serum has been developed in order to be used as a prenatal screening test for Down's syndrome. A retrospective study of maternal serum sampled during pregnancies associated with trisomy 21 shows that with a 5% amniocentesis rate determined on a single test, the detection rate of trisomy 21 would be around two-thirds of the affected pregnancies. A prospective study of 9040 pregnant women under 38 years has confirmed the usefulness of the assay.

The prenatal diagnosis of cystic fibrosis is now routinely performed by using two probes tightly linked to the CF locus (XV2C and KM19). These probes have been shown to exhibit a strong linkage disequilibrium with the CF locus. Our data (103 families) have been pooled with other French data (237 families). They are consistent with the hypothesis of a unique ancestral mutation initially associated with a B (D1E2) restriction fragment length polymorphism (RFLP) haplotype, subsequently reassociated by cross-over with A, C or D haplotypes. Assuming such an hypothesis, the mutation is supposed to be 3000-6000 years old, depending on generation length and the true recombination ratio between the KM19 and CF loci. Up-to-date Spanish, Danish and Greek data are reported together with other previously published population data in order to discuss the geographic origin and age of the mutation in Europe. The action of selection in terms of heterozygote advantage and distorsion of segregation is discussed.

With the currently available techniques, it is not possible to perform cytogenetic and enzymatic analyses on 1 or 2 cells collected from a human embryo prior to its reimplantation. The recent techniques of polymerase chain reaction may allow DNA analyses in some cases: sexing or diagnosis of monogenic diseases. The reliability of these techniques and the absence of adverse effects due to embryo micromanipulation have to be demonstrated. The practical medical application of preimplantation diagnosis requires in vitro fertilization in a fertile couple and its low rate of success has to be compared to the reliability of the early prenatal diagnosis on chorionic villus samples.

The evolution en enzymatic activity in the amniotic fluid follows the various stages of development of the gastrointestinal tract during pregnancy. Before 12 weeks of amenorrhea, no enzymatic activity can be detected, as this period corresponds to the persistence of the pharyngeal and anal membranes. At 13-14 weeks, a very high level of enzymatic activity is suddenly observed in the amniotic fluid, reaching its peak at 16-18 weeks. This phase corresponds to the opening of the pharyngeal membrane, the appearance of swallowing and the opening of the anal membrane. After 18 weeks, the digestive enzyme level progressively decreases until 22-24 weeks, after which date no gastrointestinal enzymatic activity can be evidenced in normal fetuses (probably because of functional anorectal obstruction). We have determined the enzymatic anomalies related to some gastrointestinal deformations (duodenal atresia, cystic fibrosis, atresia of the bile ducts, anorectal atresia).

Amniotic fluid porphyrins, biosynthesis of porphyrins by amniotic cells, and uroporphyrinogen III cosynthetase were studied after the 17th week of a pregnancy at risk for congenital erythropoietic porphyria (CEP). Only coproporphyrin was found in amniotic fluid. A diagnosis of CEP was ruled out by the demonstration of normal cosynthetase activity; biosynthesis of porphyrins was identical, not only in the porpositus and in control amniotic cells, but also in patients with CEP and in control skin fibroblasts.

Two hundred children and their mothers were examined when they were 10 months, 2 years and 4 years of age. Anti-cytomegalovirus, anti-Herpesvirus hominis and anti-rubella virus antibodies were titered. The evolution of antibody titers showed that primary infections with cytomegalovirus and Herpesvirus are especially frequent during the first months of life, and that mothers are the principal source of infection. In the group studied, it appeared that country of origin of the parents was the most important socio-economic factor influencing the frequency of infections in children, based upon the large variations of the serum positivity in mothers.