Two colonisation stages generate two different patterns of genetic diversity within native and invasive ranges of Ulex europaeus.

Genetic diversity and the way a species is introduced influence the capacity of populations of invasive species to persist in, and adapt to, their new environment. The diversity of introduced populations affects their evolutionary potential, which is particularly important for species that have invaded a wide range of habitats and climates, such as European gorse, Ulex europaeus. This species originated in the Iberian peninsula and colonised Europe in the Neolithic; over the course of the past two centuries it was introduced to, and has become invasive in, other continents. We characterised neutral genetic diversity and its structure in the native range and in invaded regions. By coupling these results with historical data, we have identified the way in which gorse populations were introduced and the consequences of introduction history on genetic diversity. Our study is based on the genotyping of individuals from 18 populations at six microsatellite loci. As U. europaeus is an allohexaploid species, we used recently developed tools that take into account genotypic ambiguity. Our results show that genetic diversity in gorse is very high and mainly contained within populations. We confirm that colonisation occurred in two stages. During the first stage, gorse spread out naturally from Spain towards northern Europe, losing some genetic diversity. During the second stage, gorse was introduced by humans into different regions of the world, from northern Europe. These introductions resulted in the loss of rare alleles but did not significantly reduce genetic diversity and thus the evolutionary potential of this invasive species.

Genetic variation in flowering phenology and avoidance of seed predation in native populations of Ulex europaeus.

The genetic variation in flowering phenology may be an important component of a species' capacity to colonize new environments. In native populations of the invasive species Ulex europaeus, flowering phenology has been shown to be bimodal and related to seed predation. The aim of the present study was to determine if this bimodality has a genetic basis, and to investigate whether the polymorphism in flowering phenology is genetically linked to seed predation, pod production and growth patterns. We set up an experiment raising maternal families in a common garden. Based on mixed analyses of variance and correlations among maternal family means, we found genetic differences between the two main flowering types and confirmed that they reduced seed predation in two different ways: escape in time or predator satiation. We suggest that this polymorphism in strategy may facilitate maintain high genetic diversity for flowering phenology and related life-history traits in native populations of this species, hence providing high evolutionary potential for these traits in invaded areas.

[Modalities of radiotherapy in small cell lung cancer: thoracic radiotherapy and prophylactic cerebral irradiation]. / Modalités de la radiothérapie dans les carcinomes bronchiques à petites cellules: radiothérapie thoracique et irradiation prophylactique cérébrale.

Small cell lung cancers (SCC) represent 20% of all lung cancers. After the initial control of the extension, only one third of the patients with SCC will finally have limited disease. The treatment of limited SCC currently relies on chemo-radiotherapeutic combinations that have improved overall survival and survival without metastases over the last few years. Nevertheless, even in limited forms, survival at 5 years varies from 10 to 15% and rarely exceeds 25% in the best series. The risk of relapse is high: although around 70% of patients with a limited form will have complete response, only 15 to 20% of them will exhibit prolonged survival. Indeed, most patients relapse, and the risk of cerebral dissemination for example is particularly high, reaching 50% at 2 years even in complete responders. After the results of a meta-analysis evaluating prophylactic cranial irradiation (PCI) among SCC complete responders, demonstrating 5% enhancement of survival at 3 years, PCI is part of the standard management of SCC in complete response. Despite the improvement in overall survival with the combined treatments, the mediocre results observed in terms of long-term survival warrant further clinical trials in order to define the optimal polychemotherapeutic and radiotherapeutic modalities, the best means of combining these two therapies and the place for new therapies.

Patterns of failure after prophylactic cranial irradiation in small-cell lung cancer: analysis of 505 randomized patients.

BACKGROUND: Prophylactic cranial irradiation (PCI) has a beneficial effect on overall survival in patients with small-cell lung cancer (SCLC) in complete remission as shown in a worldwide meta-analysis. The current analysis aimed to evaluate PCI effects on patterns of failure in this patient category. PATIENTS AND METHODS: The Institut Gustave-Roussy coordinated two parallel randomized studies including a total of 511 patients with SCLC. Patients were randomly assigned to either PCI (24 Gy in eight fractions and 12 days) or no PCI. Patterns of failure were analyzed according to (i) total event rates and (ii) isolated first site of relapse using a competing risk approach. RESULTS: Five hundred and five patients were analyzed. The 5-year cumulative rate of brain metastasis as an isolated first site of relapse was 37% in the control group and 20% in the PCI group (P < 0.001). The overall 5-year rates of brain metastasis were 59% and 43%, respectively [relative risk (RR) 0.50; P < 0.001]. The 5-year overall survival rates were 15% in the control group and 18% in the PCI group (RR 0.84; P = 0.06). CONCLUSIONS: PCI decreased significantly the risk of brain metastasis. Other events were not influenced. The relative death risk reduction was of borderline significance. Results reported as isolated first cause of failure and subsequent competing events may explain why a major treatment effect on brain metastases rate has a rather moderate effect on survival.

Benefit of surgery after chemoradiotherapy in stage IIIB (T4 and/or N3) non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to evaluate postchemoradiotherapy surgery in stage IIIB non-small cell lung cancer. METHODS: Forty patients with stage IIIB non-small cell lung cancer were included in this phase II study. A preoperative diagnosis of stage IIIB cancer was based on mediastinoscopy or a thoracotomy in all patients. Induction treatment included two cycles of cisplatin (100 mg/m(2), day 1), 5-fluorouracil (1 g/m(2), days 1-3), and vinblastine (4 mg/m(2), day 1) combined with 42 Gy of hyperfractionated radiotherapy delivering 21 Gy in two sessions. Patients with a clinical response were offered surgery. RESULTS: The minimum follow-up for survivors was 48 months. Thirty patients had a T4 lesion and 18 had N3 disease. Twenty-nine patients (73%) had a clinical objective tumor response after induction treatment. These 29 patients underwent thoracotomy, and a complete resection was performed in 23 (58%). Two postoperative deaths occurred (7%). Four patients had a pathologic complete response at the time of surgery (10%). The 5-year survival is 19% for the overall population. When only patients who had persistent viable tumor cells at surgery are considered (n = 25), the 5-year survival is 28%. The 5-year survival is 42% for patients having no mediastinal lymph node involvement at the time of surgery and being treated with complete resection. CONCLUSION: This study shows that surgery, when feasible, is associated with a 28% long-term survival for patients in whom chemoradiotherapy alone fails to control disease.

Exploring the genetic basis and proximate causes of female fertility advantage in gynodioecious Thymus vulgaris.

In many gynodioecous species, females produce more viable seeds than hermaphrodites. Knowledge of the relative contribution of inbreeding depression in hermaphrodites and maternal sex effects to the female fertility advantage and the genetic basis of variation in female fertility advantage is central to our understanding of the evolution of gender specialization. In this study we examine the relative contribution of inbreeding and maternal sex to the female fertility advantage in gynodioecious Thymus vulgaris and quantify whether there is genetically based variation in female fertility advantage for plants from four populations. Following controlled self and outcross (sib, within-population, and between-population) pollination, females had a more than twofold fertility advantage (based on the number of germinating seeds per fruit), regardless of the population of origin and the type of pollination. Inbreeding depression on viable seed production by hermaphrodites occurred in two populations, where inbreeding had been previously detected. Biparental inbreeding depression on viable seed production occurred in three of four populations for females, but in only one population for hermaphrodites. Whereas the maternal sex effect may consistently enhance female fertility advantage, inbreeding effects may be limited to particular population contexts where inbreeding may occur. A significant family x maternal sex interaction effect on viable seed production was observed, illustrating that the extent of female fertility advantage varies significantly among families. This result is due to greater variation in hermaphrodite (relative to female) seed fertility between families. Despite this genetic variation in female fertility advantage and the highly female biased sex ratios in populations of T. vulgaris, gynodioecy is a stable polymorphism, suggesting that strong genetic and/or ecological constraints influence the stability of this polymorphism.

Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.

We conducted a randomised clinical trial on 211 patients with small-cell lung cancer in complete remission (CR). The aim of this trial was to evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival. Eligible patients were randomly assigned to receive either PCI (100 patients) or no PCI (111 patients). Each centre was allowed to use its own PCI protocol as long as the total dose was within the range of 24-30 Gy and delivered in less than 3 weeks with fractions of 3 Gy or less. The mean follow-up is 5 years. The survival curves do not differ significantly (P = 0.25) between the two groups. The 4-year overall survival rate (95% confidence interval) is 22% [15-32%] in the PCI group versus 16% [10-25%] in the control group. The relative risk of death in the PCI group compared to the control group is 0.84 (95% CI = [0.62-1.13]). The incidence of brain metastasis is lower in the PCI group, but the difference is not statistically significant (P = 0.14). The 4-year cumulative rate of brain metastasis is 44% [32-57%] in the PCI group compared to 51% [38-63%] in the control group. In conclusion, in this study, which had to be closed prematurely, no significant difference was found in terms of the incidence of brain metastases nor in survival.

Alternating radiotherapy and chemotherapy in limited disease small cell lung cancer.

In a pilot study of 29 patients treated for localized small cell lung cancer, three new approaches were introduced, i.e. an increased initial drug dose, an early alternation of chemotherapy and thoracic radiotherapy and initial accelerated and hyperfractionated irradiation. The results were interesting. However, a high rate of fatal toxicity (21%) was observed.

The spatial genetic structure of cytoplasmic (cpDNA) and nuclear (allozyme) markers within and among populations of the gynodioecious Thymus vulgaris (Labiatae) in southern France.

Recent advances in molecular biology have allowed the development of techniques to contrast spatial differentiation in nuclear and cytoplasmic genes and thus provide important data on relative levels of gene flow by pollen and seed in higher plants. In this paper, we compare the spatial structure of nuclear (allozymes) and cytoplasmic (cpDNA) genes among populations of the gynodioecious Thymus vulgaris in southern France. Based on a combination of three restriction enzymes (CfoI, EcoRV, and PstI), eight chlorotypes (combination of three restriction enzyme patterns revealed by Southern hybridization of Beta vulgaris cpDNA) were identified in the 13 studied populations. One chlorotype was particularly abundant and was detected in nearly all populations. Only one chlorotype was specific to a single population. Up to four different chlorotypes were observed in some populations. An FST of 0.238 (P < 0.002) for cpDNA haplotypes indicates spatial structure of cytoplasmic genes among the studied populations. Similar patterns were found within a single young population (CAB) structured in patches and surrounded by a continuous cover of T. vulgaris where the FST is 0.546 (P < 0.002). No significant correlation between sex and chlorotype nor between cpDNA diversity and female frequency was detected. Allozyme markers showed markedly less spatial structure (FST = 0.021 among populations and 0.019 in the CAB population, P < 0.001). This difference between cpDNA and nuclear allozyme markers suggests that pollen dispersal is more important than seed dispersal both among and within populations.

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.

BACKGROUND: Prophylactic cranial irradiation in patients with small-cell lung cancer decreases the overall rate of brain metastases without an effect on overall survival. It has been suggested that this treatment may increase neuropsychological syndromes and brain abnormalities indicated by computed tomography scans. However, other retrospective data suggested a beneficial effect on overall survival for patients in complete remission. PURPOSE: Our purpose was to evaluate the effects of prophylactic cranial irradiation on brain metastasis, overall survival, and late-occurring toxic effects in patients with small-cell lung cancer in complete remission. METHODS: We conducted a prospective study of 300 patients who had small-cell lung cancer that was in complete remission. The patients were randomly assigned to receive either prophylactic cranial irradiation delivering 24 Gy in eight fractions during 12 days (treatment group) or no prophylactic cranial irradiation (control group). A neuropsychological examination and a computed tomography scan of the brain were performed at the time of random assignment and repeatedly assessed at 6, 18, 30, and 48 months. Patterns of failure were analyzed according to total event rates and also according to an isolated first site of relapse, using a competing-risk approach. RESULTS: Two hundred ninety-four patients who did not have brain metastases at the time of random assignment were analyzed. The 2-year cumulative rate of brain metastasis as an isolated first site of relapse was 45% in the control group and 19% in the treatment group (P < 10(-6)). The total 2-year rate of brain metastasis was 67% and 40%, respectively (relative risk = 0.35; P < 10(-13)). The 2-year overall survival rate was 21.5% in the control group and 29% in the treatment group (relative risk = 0.83; P = .14). There were no significant differences between the two groups in terms of neuropsychological function or abnormalities indicated by computed tomography brain scans. CONCLUSIONS: Prophylactic cranial irradiation given to patients with small-cell lung cancer in complete remission decreases the risk of brain metastasis threefold without a significant increase in complications. A possible beneficial effect on overall survival should be tested with a higher statistical power. IMPLICATIONS: The results of the trial favor, at present, the indication of prophylactic cranial irradiation for patients who are in complete remission. A longer follow-up and confirmatory trials are needed to fully assess late-occurring toxic effects. The possible effect on overall survival needs to be evaluated with a larger number of patients in complete remission, and a meta-analysis of similar trials is recommended.

Triangular test and randomized trials: practical problems in a small cell lung cancer trial.

The triangular test has been used to monitor survival data from a randomized trial in patients with small cell lung cancer. The results of consecutive interim analyses and the problems met by the data monitoring committee and the co-ordinators are described. The methods as well as the consequences of the early stopping on the analysis and the results of this trial are discussed. From this experience, we believe that statistical stopping rules--only one of the factors to be taken into account when deciding to stop a trial--should be used with caution. Independent data monitoring committees may be useful in helping to review the ongoing results and advise the participants in the trial.

Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma.

We report the results observed in a large randomized study comparing radiotherapy alone to combined radiotherapy and chemotherapy in unresectable squamous cell and large cell lung carcinoma. Radiation dose was 65 Gy in both groups and chemotherapy included vindesine, cyclophosphamide, cisplatin and lomustine. One hundred seventy-seven patients received radiotherapy alone, and 176 received the combined treatment. The 2-year survival rate was 14% for patients receiving radiotherapy vs. 21% for patients receiving the combined treatment (P = 0.02). The distant metastasis rate was significantly lower in the group receiving the combined treatment (P < 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively) and remains a major problem in locally advanced non-small cell lung cancer.

A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial.

PURPOSE: We report a prospective randomized study comparing the relative efficacy of alternating chemotherapy mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) with the standard MOPP chemotherapy in patients with stage IIIB and IV Hodgkin's disease (HD). The purpose is to study the influence of time of remission on clinical outcome. PATIENTS AND METHODS: After two courses of MOPP, patients were randomized to receive six further courses of MOPP, or two courses of ABVD followed by two courses of MOPP and two courses of ABVD. Radiotherapy was given to areas presenting with masses > or = 5 cm and to residual masses after course no. 4. Evaluation of response (complete remission [CR]) took place after two courses (CR2), after four courses (CR4), at the end of chemotherapy (CR8), and after additional radiotherapy (CR(CT + RT)). Logistic regression analysis was used to study prognostic factors for response at the end of chemotherapy. Cox analysis was used to study prognostic factors for survival. Two hundred seven patients were registered, 192 (93%) of whom were randomized. RESULTS: The CR rate at the end of chemotherapy (CR8) was similar in both arms (57% v 59%). However, there were more progressions in the MOPP arm compared with the MOPP/ABVD arm (23% v 8%, P = .014). A significantly higher failure-free survival (FFS) rate was found in the MOPP/ABVD arm (60% v 43% at 6 years, P = .025). There was no difference in the relapse-free survival (RFS) or survival rate. Of patients not in CR4, only 28% still reached a CR8. RFS at 6 years of patients with CR4 (69%) was not different from that of patients with CR8 (68%); patients with a CR(CT + RT)) had a lower RFS rate (48%). CR4 (P < .001) predicted strongly for final remission at the end of chemotherapy. Cox analysis showed that age more than 50 years, six or more involved lymph node areas, no CR by the fourth cycle, chemotherapy with MOPP alone, and no radiotherapy were unfavorable factors for survival. CONCLUSION: MOPP/ABVD chemotherapy significantly improved response and FFS rates, but had no influence on RFS and survival rates. Early CR (CR4) is an important factor for final remission and might be used to select a group of patients with a good prognosis.

Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer.

BACKGROUND: Moderate increases in the initial doses of certain chemotherapeutic drugs, such as cisplatin and cyclophosphamide, may prolong overall survival in patients with limited small-cell lung cancer. METHODS: We conducted a prospective study of 105 patients with limited small-cell lung cancer. The patients were randomly assigned to receive higher or lower initial doses of cisplatin (100 or 80 mg per square meter of body-surface area) and cyclophosphamide (300 or 225 mg per square meter daily for four days); all patients received the same doses of doxorubicin and etoposide. The first course of chemotherapy was followed by five additional courses and by three courses of radiotherapy. All patients received the lower doses of cisplatin and cyclophosphamide and the same doses of doxorubicin and etoposide from the second through the sixth cycle of chemotherapy. RESULTS: The median follow-up was 33 months. The two-year survival rate for the 55 patients who received the higher doses of chemotherapy was 43 percent, as compared with 26 percent for the 50 patients who received the lower doses (P = 0.02). The rates of complete response at six months were 67 percent in the higher-dose group and 54 percent in the lower-dose group (P = 0.16). Disease-free survival at two years was 28 percent in the higher-dose group, as compared with 8 percent in the lower-dose group (P = 0.02). Side effects from treatment were not increased in the higher-dose group. CONCLUSIONS: Higher initial doses of cyclophosphamide and cisplatin improve disease-free and overall survival in patients with limited small-cell lung cancer.

[Combination of chemotherapy (vindesine, lomustine, cisplatin, cyclophosphamide) and thoracic radiotherapy in nonresectable non-small cell bronchial carcinoma: final results of a phase II clinical trial]. / Association chimiothérapie (vindésine, lomustine, cisplatine, cyclophosphamide)--radiothérapie thoracique dans les carcinomes bronchiques non à petites cellules inopérables: résultats définitifs d'un essai phase II.

Seventy-five patients with locally advanced non small cell lung carcinoma were entered in a phase II study combining chemotherapy (vindesine, lomustine, cisplatin and cyclophosphamide) and radical thoracic radiotherapy delivering a total dose of 60-65 Gy. Patients were regularly assessed by radiological and fiberoptic bronchoscopy examinations in order to evaluate local control. An objective response was observed in 22 patients (29%) after initial chemotherapy (2 complete remissions and 20 partial responses). The complete response rate after the combined schedule was 30%. Toxicity of this combination was acceptable. Median survival was 13.5 months. Actuarial risk of developing distant metastases at 3 years was 60%. However, the main cause of failure was local with 80% of uncontrolled or recurrent thoracic tumor in the first 2 years of follow-up. The present study shows that local control remains a major problem in the management of patients with inoperable non metastatic non small cell lung cancer.

ASTRO (American Society for Therapeutic Radiology and Oncology) plenary: Effect of chemotherapy on locally advanced non-small cell lung carcinoma: a randomized study of 353 patients. GETCB (Groupe d'Etude et Traitement des Cancers Bronchiques), FNCLCC (Féderation Nationale des Centres de Lutte contre le Cancer) and the CEBI trialists.

Most patients with locally advanced non small cell lung carcinoma are treated with external thoracic radiotherapy. Because of the high incidence of distant metastasis the addition of chemotherapy has been proposed. The present randomized study was conducted from June 1983 to February 1989 and included 353 patients. The trial compared arm A, thoracic megavoltage radiotherapy alone at a total dose of 65 Gy in 26 fractions and 45 days, to arm B that comprised the same radiotherapy preceded and followed by 3 monthly cycles of VCPC (vindesine 1.5 mg/m2 d 1-2, cyclophosphamide 200 mg/m2 d 2-4, cisplatinum 100 mg/m2 d 2 and lomustine 75 mg/m2 d 3). Disease was deemed unresectable but non-metastatic after bronchoscopic, radiologic, CAT, and nuclear scans and physical examinations. Only patients in clinical, radiological, endoscopic, and histological complete remission were considered as locally controlled; these patients were monitored by fiberoptic bronchoscopy and systematic biopsies to the primary site. One hundred seventy-seven patients received thoracic radiotherapy alone and 176 received the combined modality. Twenty-seven percent of arm B patients had an objective response after 2 VCPC cycles. At the time of final assessment, performed 3 months after the end of thoracic radiotherapy in both arms, there were 20% of complete responders in arm A versus 16% in arm B. The two-year survival rate was 14% in arm A versus 21% in arm B (p = 0.08, logrank test). The distant metastasis rate was 67% in arm A versus 45% in arm B (p less than 0.001). Local control at 1 year was poor in both groups (17% and 15%, respectively). The striking effect of VCPC chemotherapy on the incidence of distant metastasis did not have a significant impact on overall survival. We conclude that thoracic tumor control remains a significant problem in unresectable non small cell lung cancer.

Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients.

We report the results observed in a large, randomized study that compared the effects of radiotherapy alone (the standard therapy) with those of a combination of radiotherapy and chemotherapy in nonresectable squamous cell and large-cell lung carcinoma. The radiation dose was 65 Gy in each group, and chemotherapy included vindesine, cyclophosphamide, cisplatin, and lomustine. In this study, 177 patients received radiotherapy alone (group A), and 176 patients received the combined treatment (group B). The 2-year survival rate was 14% in group A and 21% in group B (P = .08). The distant metastasis rate was significantly lower in group B (P less than .001). Local control was poor in both groups (17% and 15%, respectively) and remained the major problem.

Management of relapse and survival in advanced stage Hodgkin's disease: the EORTC experience.

The EORTC Lymphoma Cooperative Group and the Pierre and Marie Curie Group conducted a multicentre randomised trial on clinical stages IIIB-IV Hodgkin's disease from 1981-1986. Two hundred seven patients were registered and 192 randomised. Actuarial survival at five years for the whole group was 68%. Induction chemotherapy with eight cycles of MOPP resulted in more patients with progressive disease and fewer partial responders than a combination of MOPP and ABVD, for an equal complete remission rate. Half of the partial responders went into complete remission after radiotherapy. At five years there was no significant survival difference between the arms. Progression was recorded in 39 patients of whom only 4 survived. Relapses were most frequent in previously involved unirradiated areas. For 46 relapsed patients, including 21 early relapses within 18 months of start of treatment, the four-year survival rate was 53%. When complete remission was reached, whether early or late with combination chemotherapy or after additional radiotherapy, prognosis was independent of the way in which it was achieved. All efforts should be taken to reach a complete remission for initially progressing patients and for partial responders.