Articles Routine molecular pro? ling of patients with advanced
non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic
Intergroup (IFCT)
Fabrice Barlesi, Julien Mazieres, Jean-Philippe Merlio, Didier Debieuvre, Jean Mosser, Hervé Lena, L’Houcine Oua? k, Benjamin Besse,
Isabelle Rouquette, Virginie Westeel, Fabienne Escande, Isabelle Monnet, Antoinette Lemoine, Rémi Veillon, Hélène Blons, Clarisse Audigier-Valette,
Pierre-Paul Bringuier, Régine Lamy, Michèle Beau-Faller, Jean-Louis Pujol, Jean-Christophe Sabourin, Frédérique Penault-Llorca, Marc G Denis,
Sylvie Lantuejoul, Franck Morin, Quan Tran, Pascale Missy, Alexandra Langlais, Bernard Milleron, Jacques Cadranel, Jean-Charles Soria,
Gérard Zalcman, for the Biomarkers France contributors*
Summary
Background The molecular pro?ling of patients with advanced non-small-cell lung cancer (NS CLC) for known
oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and e? ects on outcomes
of this policy are unknown. We aimed to assess the characteristics, molecular pro? les, and clinical outcomes of
patients who were screened during a 1-year period by a nationwide programme funded by the French National
Cancer Institute.
Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certi? ed regional genetics
centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013.
We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in
obtaining molecular results, and patients’ clinical outcomes. This study is registered with https://www.doczj.com/doc/d06879190.html,,
number NCT01700582.
Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median
age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma).
The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16).
A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of
17 706 analyses for which data were available,HER2mutations in 98 (1%) of 11 723,KRAS mutations in 4894 (29%)
of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements
were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months
(95% CI 24·8–25·0). The presence of a genetic alteration a? ected ? rst-line treatment for 4176 (51%) of 8147 patients
and was associated with a signi? cant improvement in the proportion of patients achieving an overall response in
? rst-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a
genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001).Presence of a
genetic alteration was also associated with improved ?rst-line progression-free survival (10·0 months [95% CI 9·2–10·7]
vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5];
p<0·0001) compared with absence of a genetic alteration.
Interpretation Routine nationwide molecular pro? ling of patients with advanced NSCLC is feasible. The frequency of
genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by
detection of a genetic alteration suggest that this policy provides a clinical bene? t.
Funding French National Cancer Institute (INCa).
Introduction
Lung cancer is one of the most frequent types of cancer in developed countries and is the leading cause of cancer deaths, with more than 1 million deaths expected per year.1 H owever, understanding of the molecular hallmarks of this cancer has developed only recently.2 The treatment of lung cancer has entered a new era because of the discovery of epidermal growth factor receptor (EGFR)-activating mutations and anaplastic
lymphoma kinase (ALK) gene rearrangements, which
lead to changes in outcomes in some patients with lung
cancer.3,4 Moreover, compared with other cancers, lung
cancer has one of the highest rates of genetic
alterations,5 some of which are actionable via the
administration of drugs that have already been
approved, are available o?-label for other indications
Published Online
January 14, 2016
https://www.doczj.com/doc/d06879190.html,/10.1016/
S0140-6736(16)00004-0
See Online/Comment
https://www.doczj.com/doc/d06879190.html,/10.1016/
S0140-6736(15)01125-3
*Members listed at end of paper
Assistance Publique H?pitaux
de Marseille, Multidisciplinary
Oncology and Therapeutic
Innovations Department, Aix
Marseille University, Centre
d’Investigation Clinique,
Marseille, France
(Prof F Barlesi MD); H?pital
Larrey, Centre Hospitalier
Universitaire, Université Paul
Sabatier, Toulouse, France
(Prof J Mazieres MD); Centre
Hospitalier Universitaire de
Bordeaux, P?le Biologie et
Anatomie Pathologique,
Pessac, France
(Prof J-P Merlio MD); Université
de Bordeaux, Histologie et
Pathologie Moléculaires des
Tumeurs, Bordeaux, France
(Prof J-P Merlio); H?pital Emile
Muller, Service de
Pneumologie, Mulhouse,
France (D Debieuvre MD);
Centre Hospitalier Universitaire
de Rennes, Département de
Génomique et Génétique
Moléculaire, Plateforme INCA,
Rennes, France
(Prof J Mosser MD); H?pital
Pontchaillou, Service de
Pneumologie, Centre
Hospitalier Universitaire,
Rennes, France (H Lena MD);
Assistance Publique H?pitaux
de Marseille, Service de
Transfert d’Oncologie
Biologique, Aix Marseille
University, Marseille, France
(Prof L’H Ouafik MD); Gustave
Roussy, Cancer Campus,
Villejuif, France (B Besse MD,
Prof J-C Soria MD); University
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Paris-Sud, Chatenay-Malabry, France (B Besse, Prof J-C Soria); Institut Universitaire du Cancer de Toulouse, Oncop?le, Service d’Anatomie Pathologique,
Toulouse, France (I Rouquette MD); Université de
Franche-Comté, EA3181, Centre Hospitalier Universitaire
Jean Minjoz, Service de
Pneumologie, Besan?on,
France (Prof V Westeel MD); Centre Hospitalier Universitaire de Lille, Département de
Biochimie et Biologie Moléculaire, Centre de Biologie Pathologie, Lille, France
(F Escande MD); Centre Hospitalier Intercommunal de Créteil, Service de Pneumologie
et de Pathologie Professionnelle, Créteil, France
(I Monnet MD); Assistance
Publique-H?pitaux de Paris,
Groupe Hospitalier des
H?pitaux Universitaires
Paris-Sud, Service
d’Oncogénétique– Oncomolpath, Université
Paris 11, Villejuif, France (Prof A Lemoine MD); Centre
Hospitalier Universitaire de Bordeaux, Service des Maladies Respiratoires, Pessac, France
(R Veillon MD); UMR-S1147,
INSERM, Université Paris Descartes, Assistance Publique H?pitaux de Paris Département de Biologie, H?pital Européen Georges Pompidou, Paris,
France (H Blons PharmD);
Centre Hospitalier Sainte
Musse, Service de Pneumologie, Toulon, France (C Audigier-Valette MD); H?pital
Edouard Herriot, Service d’Anatomie et de Cytologie Pathologique, Hospices Civils de Lyon, Université Claude
Bernard Lyon 1, Lyon Cancer
Research Center, UMR 1057
INSERM, Lyon, France (Prof P-P Bringuier DVM); Centre Hospitalier de Bretagne Sud, Service d’Oncologie Médicale, Lorient, France (R Lamy MD); Centre Hospitalier Universitaire de Hautepierre, Laboratoire de Biochimie et de Biologie Moléculaire & Plate-forme de Génomique des Cancers,
Strasbourg, France (M Beau-Faller MD); Centre
Hospitalier Universitaire de Montpellier, Unité d’Oncologie
Thoracique, P?le C?ur Poumon, H?pital Arnaud de Villeneuve, Montpellier, France (Prof J-L Pujol MD); Centre
Hospitalier Universitaire de
Rouen, Département (eg, dabrafenib or vemurafenib for BRAF mutations,6
trastuzumab or afatinib for HER2 [also known as
ERBB2] mutations,7 and crizotinib for ROS1
rearrangements8), or are under investigation in clinical
trials. Therefore, high expectations are placed on
personalised (also referred to as strati? ed or precision)
medicine in this setting.
In this context, many medical centres have been
organised to provide patients with lung cancer with routine
assessments of EGFR mutations and ALK rearrange m ents.
In some of these centres, additional molecular alterations
are tested, typically by research programmes.9–12 The
preliminary data obtained from such programmes suggest
that molecular pro?ling helps to orient patients towards
targeted therapies and dedicated trials. However, the actual
e?ects of broad molecular screening and subsequent
personalised medicine have yet to be addressed in a
prospective randomised trial.10 Additionally, the character-
istics and e? cacy results reported by these programmes
are based on a limited series of selected patients. Therefore,
a wide overview is needed in an unselected, all-comer
population to increase understanding of the epidemiology
of lung cancer biomarkers and their potential e? ect on
therapeutic strategies.
The French National Cancer Institute (INCa) funded a
nationwide programme for the systematic routine
analysis of EGFR mutations and ALK rearrangements as
well as HER2, KRAS, BRAF, and PIK3CA mutations in
patients with advanced stage, non-squamous, non-small-
cell lung cancer (NSCLC) in 28 certi? ed molecular
genetics centres covering the whole of France, including
overseas entities.13–15 The Biomarkers France study
assessed the characteristics, molecular pro? les, and
clinical outcomes of patients who were screened by this
programme during a 1-year period.
Methods
Participants
All consecutive patients with NSCLC who were routinely
screened for molecular alterations during a 1-year period at
one of the 28 certi? ed molecular genetics centres in France
were eligible for inclusion in this study. The prescription
of this routine molecular screening, mandatory for
advanced non-squamous NSCLC, was solely the
responsibility of the treating physician. Notably, national
recommendations for screening for EGFR mutations
(both activating and Thr790Met), ALK rearrangements,
and four emerging biomarkers (KRAS, BRAF, HER2, and
PIK3CA mutations) have been available since 2010.16
Additionally, patients with a less advanced stage of NSCLC
or patients carrying other tumour types (eg, mixed
histology, never smokers) could have been screened upon
approval by their local multidisciplinary tumour board.
This study was approved by a national ethics committee
for observational studies (Comité d’Evaluation des
Protocoles de Recherche Observationnelle), by the
French Advisory Committee on Information Processing
in Material Research in the Field of H ealth (Comité
Consultatif sur le Traitement de l’Information en Matière
de Recherche dans le Domaine de la Santé), and by the
National Commission of Informatics and Liberty (CNIL),
according to French laws.
Each clinician identi?ed as the prescriber of a
molecular analysis between April, 2012, and April, 2013,
received written information describing the study
protocol and the process for accessing the database as
well as a con?dential password to connect to the
Biomarkers France secured online case report form.
All patients with NSCLC included in this programme
received information from their institution or referring
clinician, as recommended by competent authorities, Research in context
Evidence before this study
We did a systematic review of the scienti? c literature to identify
studies assessing nationwide routine molecular pro? ling of
patients with advanced non-small-cell lung cancer (NSCLC) for
one or more genetic alterations known (or supposed) to be
oncogenic drivers. We searched PubMed for English language
reports published up to Dec 3, 2010, with the terms “non small
cell lung cancer”, “advanced” or “metastatic”, and “EGFR” or
“ALK” or “BRAF” or “HER2” or “PIK3CA” or “KRAS” or “multiplex”
or “sequencing” and “nationwide”, or names of various
countries around the world. We also searched abstracts from
ASCO and ESMO meetings (2007–10). We did not identify any
published data.
Added value of this study
Our study shows that routine nationwide molecular pro? ling of
patients with advanced NSCLC is feasible with an acceptable
turnaround time in obtaining the results. Even with assessment
of a limited number of genetic alterations (ie, currently
six genes), the frequency of these genetic alterations might
allow the consideration of targeted therapy for treating these
patients (either commercially available for EGFR and ALK, or
within a clinical trial for the other alterations). Finally, when a
genetic alteration was detected, the outcome was a longer
median overall survival, suggesting a possible prognostic
advantage or a major change in the management of these
patients with advanced NSCLC, or both.
Implications of all the available evidence
The Lung Cancer Mutation Consortium (LCMC) initiative
(the largest multi-institutional study in developed countries)
suggested that molecular pro? ling helps to orient patients
towards targeted therapies and dedicated trials, and individuals
with drivers receiving a matched targeted agent lived longer
than patients who did not receive genotype-directed therapy.
Our study extends the LCMC study to a nationwide scale, and
suggests that routine nationwide molecular pro? ling provides a
clinical bene? t to patients with advanced NSCLC.
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d’Anatomie et de Cytologie Pathologiques, Rouen, France
(Prof J-C Sabourin MD); Centre
Jean Perrin, Département d’Anatomie et de Cytologie Pathologique, Clermont-Ferrand, France
(Prof F Penault-Llorca MD);
Centre Hospitalier Universitaire de Nantes, Laboratoire de Biochimie, Nantes, France
(Prof M G Denis MD); Centre Hospitalier Universitaire A Michallon, Département d’Anatomie et Cytologie Pathologiques DACP, Institut de Biologie et de Pathologie, Université
Joseph Fourier-INSERM U 823, Institut Albert Bonniot, Grenoble, France
(Prof S Lantuejoul MD); Clinical Research Unit (F Morin MSc, Q Tran MSc, P Missy PhD) and Biostatistics Unit
(A Langlais MSc), French Cooperative Thoracic
Intergroup (IFCT), Paris, France; Assistance Publique H?pitaux de Paris, H?pital Tenon, Service de Pneumologie, Sorbonne Universités, UPMC Université Paris 06, Paris, France (B Milleron MD,
Prof J Cadranel MD); and Centre Hospitalier Universitaire de Caen, Service de Pneumologie et Oncologie Thoracique, Centre de Recherche Clinique, Université de Caen-Basse Normandie, Caen, France (Prof G Zalcman MD)
Correspondence to:
Dr Fabrice Barlesi, Assistance Publique H?pitaux de Marseille, Aix Marseille University, Marseille Cedex 20, France fabrice.barlesi@ap-hm.fr which speci? ed, according to French laws, that they were allowed to ask for complete access to and removal of their own collected data. Patients were not required to provide written informed consent to be included in the study.
The feasibility and potential technical issues of this project were initially investigated by analysing patients screened at three certi? ed molecular genetics centres during a 3-month period (November, 2011, to January, 2012); this analysis served as a test for the subsequent nationwide study. Because no major di? culties were noted in this initial analysis of 346 patients, the steering committee decided to open the 1-year national recruitment period in April, 2012. The 28 molecular genetics centres had to send their results to the French Cooperative Thoracic Intergroup (IFCT) using a speci? c data sheet for each patient. Then, the data were recorded and monitored by the IFCT . The investigators had full access to the de-identi? ed data and analyses for the current report.
Molecular analyses
The molecular analyses of EGFR
HER2 (NG_007503.1), KRAS (NG_007524.1), BRAF (NG_007873.3), and PIK3CA (NG_012113.2) mutations and ALK (NG_009445.1) rearrangements were done on a routine basis at the molecular genetics centres (appendix p 13). The methods used in these analyses 16 and the results of the prospective cross-validation quality assessment studies have been reported elsewhere.17–19 Brie? y, each molecular
genetics centre used either the Sanger sequencing method or a more sensitive validated allele-speci? c technique (generally to be con? rmed by Sanger sequencing) to assess EGFR (exons 18–21),17,18 HER2 (exon 20), BRAF (exon 15), KRAS (exon 2),17–19 and PIK3CA (exons 9 and 20) mutations (appendix pp 1–2). A certi? ed break-apart ? uorescence in-situ hybridisation assay was used to assess ALK rearrangements.20 Additionally, each regional genetics centre either did a concurrent analysis of all recommended See Online for appendix
Figure 1: Study ? ow chart
NSCLC=non-small-cell lung cancer. *Data availability subject to sequential strategies at regional genetics centres. ?Data availability (see table 1) subject to the completion of the database by treating physicians.
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molecular alterations in the six genes or used a sequential approach in which the EGFR and ALK assessments were done ? rst, and then each of the other molecular alterations were assessed until a mutation was found.Data collection
The molecular genetics centres provided IFCT with the results of molecular assessments of the six genes under investigation, histological typing and the percentage of
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tumour cells measured by the referring pathologist, and the turnaround time before obtaining the analysis results (from the date of tumour receipt to the date of submission of the written molecular report to the clinician). Simultaneously, the treating physician (n=3831) of each patient was provided with secure access to his or her own patient’s data.
The following data were obtained: sex; ethnic origin (Asian vs non-Asian); smoking history (never, former, or current smoker); past familial medical history of cancer;
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Eastern Cooperative Oncology Group performance status (0–1 vs ≥2); TNM stage, as de? ned by the seventh edition of the American Joint Committee on Cancer;21 patho l ogical diagnosis, as de?ned by the 2011 International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society classi ? cation;22 and the method of sample collection (bronchoscopy, transthoracic biopsy, thoracic surgery, or other). The following information was obtained and reported per investigator review: the type of treatment (standard chemotherapy, type of chemotherapy or targeted therapy, or, if applicable, the clinical trial along with the type of treatment); the e?ect of the molecular results on the treatment decision; and outcomes (overall response assessed by treating physician, usually according to Response Evaluation Criteria in Solid Tumors [RECIST], which de? ne a response by a decrease in target lesions by at least 30% and disease progression by an increase of target lesions by at least 20%; ? rst-line treatment and, when applicable, second-line treatment and date[s] of disease progression; and survival status).
Patients were treated on a routine basis after review by a local multidisciplinary tumour board and in accordance with national and international guidelines.23–25 At the time the study was done, erlotinib and ge? tinib were approved for the treatment of patients with EGFR mutations (including ?rst-line treatment), whereas crizotinib was available only for the second-line treatment
of patients with ALK rearrangements. KRAS, BRAF, HER2, and PIK3CA mutations were targetable by drugs available through clinical trials. Connection to and completion of the database was done voluntarily by the treating physicians.
Outcomes
The primary objective of this study was to describe the frequency of the molecular alterations in six genes that were routinely screened via a nationwide approach in consecutive patients with NSCLC. The secondary objectives were to combine the clinical and biological databases, document the turnaround time in obtaining molecular results, assess the ability of the treating physician to use these data to select an ad-hoc therapy (on a standard basis or via inclusion in a clinical trial), and measure patients’ outcomes (progression-free survival and overall survival).
Statistical analysis
Descriptive statistics, including median and range or quartiles for continuous variables or frequencies, and percentages for categorical variables, were used. Median duration of follow-up was de? ned as the time from date
of molecular analysis assessment to the closing date of the analysis. Median time until results were obtained was expressed to ?rst and third quartiles (IQR) to avoid excessive data dispersion. First-line progression-free survival was de?ned as the time from the date of molecular analysis assessment to the date of the ? rst progression or death from any cause. Second-line progression-free survival was de? ned as the time from initiation of second-line treatment to the date of the second progression or death from any cause. Overall survival was de? ned as the date of the molecular analysis assessment to the date of death or ? nal follow-up. Survival curves were estimated for the total population and for groups of interest by the Kaplan-Meier method. We compared the groups of interest by use of the two-sided log-rank test. Patient characteristics (with or without gene alteration of each biomarker) were compared with the χ2 test for qualitative variables or with
a non-parametric test for quantitative variables. Univariate Cox models were applied to select the most promising prognostic variables (threshold p=0·20). A multivariate Cox model was then applied to adjust for potential confounders (clinical or molecular characteristics associated with progression-free survival or overall survival). Adjusted hazard ratios (H Rs) with 95% CIs were calculated. All statistical tests were two-sided, and a p value of less than 0·05 was deemed statistically signi? cant. All analyses were done with SAS software, version 9.3 (SAS Institute).
Figure 2: Frequency of genetic alterations
Frequency of molecular alterations in six genes from 18 679 analysed samples (expressed as the percentage of positive samples for each molecular alteration relative to the number of available analyses, with unknown representing the cases with at least one unknown result after assessment of the six genes). Full WT=patients with an established molecular pro? le without an EGFR, KRAS, BRAF, HER2 (ERBB2), or PIK3CA mutation or ALK rearrangement. (A) Overall population, (B) adenocarcinoma only, (C) women only, and (D) never smokers only.
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This study is registered with https://www.doczj.com/doc/d06879190.html,, number NCT01700582.
Role of the funding source
The funding source had no role in study design, data collection, data analysis, data interpretation, or prep-aration of the report. The study’s steering committee included representatives of the certi? ed molecular genetics centres, INCa, and the IFCT. All authors had full access to all the data in the study and had ? nal responsibility for the decision to submit for publication.Results
The study recruitment period was from April, 2012, to April, 2013, and the database was locked for the current analysis on July 23, 2014. Overall, 19 386 results of routine molecular analyses were recorded in the database. After review, 707 (4%) analyses were excluded (? gure 1). The ?nal analysis consisted of 18 679 results, representing 17 664 patients with NSCLC.
Table 1 shows the primary characteristics of the 17 664 patients. The number of samples analysed per patient was typically one (16 696 [95%] patients), but two or
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more samples were analysed in 927 (5%) patients and 41 (<1%) patients, respectively. The median interval between tissue specimen collection and the initiation of molecular analysis was 8 days (IQR 4–16), and the median interval from the initiation of molecular analysis to the ? nal written report of the analysis (the results for EGFR mutation if the analyses were done sequentially) was 11 days (7–16).
A genetic alteration was recorded in about 50% of the analyses: EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses (table 2, table 3, and appendix pp 3–5). Figure 2 shows the frequencies of the molecular alterations in these six genes, overall and for three speci? c subgroups (ie, adenocarcinoma, women, and never smokers). The screen failure rates varied from 1% to 4%. 170 (1%) of 18 679 samples had two molecular alterations; three (<1%) samples had three or more molecular alterations (appendix p 6).
Of the 8448 patients with known data about their treatment and, speci? cally, the 8147 patients with known data about whether their molecular pro?le results were considered when deciding the treatment (yes vs no), results of the routine molecular pro? ling were considered when planning the ?rst-line therapeutic strategy for 4176 (51%) of 8147 patients. Conversely, for 836 (23%) of 3707 patients who had known data for the reason to plan the treatment strategy without consideration of these results, the too-long turnaround time motivated the local multidisciplinary tumour board’s decision to start before getting these results. The frequencies of genetic alterations in the patients who were managed without considering the results of the molecular analyses (data not shown) were similar to those in the total population of patients with known data about their treatment, apart from EGFR mutations (443 [11%] patients had EGFR mutations out of 3971 patients managed without considering the results of
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Outcomes of the
ed by molecular
le;
ed by
le. Unknown in
le EGFR, KRAS, BRAF, PIK3CA mutation or
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the molecular analyses vs 1128 [13%] with EGFR mutations out of 8448 patients in the total population, respectively; p=0·003). The types of ? rst-line and second-line treatments are shown in table 4. Because treatment-resistant EGFR Thr790Met mutations were syste m atically found concomitantly with an activating EGFR mutation, the frequencies of these two mutations are reported jointly. Radiotherapy was given to 796 (10%) of 7909 patients to improve local thoracic control and to 2030 (26%) of 7909 patients as a palliative treatment.The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). Table 5 shows the outcomes of patients for whom data were available (see appendix pp 7–8 for patients with advanced stage cancer only). The presence of a genetic alteration was associated with a signi? cantly higher proportion of patients achieving an overall response in ? rst-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001) compared with absence of a genetic alteration. The presence of a genetic alteration was also associated with signi? cantly longer ? rst-line progression-free survival and overall survival compared with the absence of a genetic alteration (? gure 3 and appendix p 14).When patients carrying an EGFR mutation were excluded from the analysis, the presence of a genetic alteration resulted in a non-signi? cant di? erence in the proportion of patients achieving an overall response in ? rst-line treatment (31% [95% CI 29·4–33·5] vs 33% [29·5–35·7]; p=0·54) or second-line treatment (11% [9·1–12·8] vs 9% [6·7–11·9]; p=0·34), and a non-signi? cant di? erence in overall survival (13·3 months [95% CI 12·1–14·3] vs 11·8 months [10·1–13·4]; p=0·37) compared with absence of a genetic alteration. Cox multivariate analysis con? rmed that ALK rearrangements (H R 0·70, 95% CI 0·5–0·9), EGFR mutations (H R 0·53, 0·4–0·6), and HER2 mutations (H R 0·60, 95% CI 0·4–1·0) had a favourable e? ect on prognosis (appendix pp 9–10).Discussion
One challenge of personalised medicine for patients with cancer is the provision of an assessment of molecular alterations that are related to the management of their disease. The results of our study show the success of a nationwide programme in this setting. The molecular screening done in the programme, which involved nearly 20 000 patients with advanced NSCLC per year, enabled the detection (with an acceptable turnaround time) of at least one potentially actionable molecular alteration in almost 50% of the analyses and a? ected the treatment decisions for 51% of patients. When a genetic alteration was detected, median overall survival was 4·7 months longer than when a genetic alteration was absent, suggesting a possible prognostic advantage or a major change in management for these patients, or both.
The successful implementation of molecular pro?
ling of patients with lung cancer at a single institution or in a
consortium of institutions has been reported pre
v iously.8–11 However, the number of examined patients was frequently small, with the largest multi-institutional study in developed countries—the Lung Cancer Mutation Consortium (LCMC) initiative—including 1007 patients. Our study follows LCMC but aims to broaden the number of centres able to provide molecular pro? ling, with a clear ambition of a nationwide approach. Because about 39 000 new cases of lung cancer (of any stage and histology) are reported every year in France,26 18 000 patients with advanced non-squamous NSCLC are expected to be screened for EGFR mutations and ALK rearrangements according to current guidelines.23–25 Our results not only involved the largest sample (17 664 patients), but were also unlikely to have been a? ected by patient selection at a speci? c institution or partici p ation in a given clinical trial
or research programme.
27
The frequency of some molecular alterations might seem to be lower than previously reported (eg, 11% of EGFR mutations compared with 17% for LCMC in the USA),9 but our results most likely re? ect the charac t eristics of an unselected population, particularly in developed countries. To the best of our knowledge, no other study at a nationwide level has been published. Therefore, our results provide solid evidence for clinical trials or routine programmes of molecular screening in patients with lung cancer, especially the HER2, BRAF , and PIK3CA data, because very rare genetic alterations at these three loci (0·8%, 1·9%, and 2·3%, respectively) could represent a large population in view of the high incidence of lung cancer worldwide.Our study attempted to collect data from a common cancer population from daily practice during a 1-year period. On the basis of this objective, a fairly simple case report form was selected and more than 3800 treating physicians were approached for the study. This design implied the acceptance of some degree of missing data, which was a drawback of the study. Another limitation of the study was related to the molecular alterations that
were screened. Several potential actionable targets for lung cancer have been described in recent years, and some of these targets were not included in the programme (including some of the known genetic alterations occurring at the time of disease progression). The molecular alterations screened in this programme were selected in 2009 and this strategy was largely a success, because the data for BRAF and HER2 targeting are now robust.6,7 However, other emerging biomarkers, such as KRAS mutations, remained uncertain.28 PIK3CA mutations are no longer routinely assessed, whereas ROS1 assessment is now part of routine molecular testing at certi? ed molecular genetics centres in France.29 More importantly, our results do not suggest an improvement in the inclusion rate of clinical trials. Only
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3% of the patients in the national database were enrolled in clinical trials while being assessed for molecular alterations that were actionable only with experimental compounds in clinical development; therefore, this objective of the national programme remains to be met.30 In conclusion, this national programme broadly (and exhaustively) screened patients with lung cancer for genetic alterations in six genes, including four emerging genetic alterations, to identify actionable targets that improved the survival of about 50% of patients, although at a non-negligible ? nancial cost.16 Therefore, our results should encourage all continuing worldwide initiatives to provide patients with cancer with access to personalised treatment, and provide robust information to inform these initiatives.
Contributors
FB, JMa, DD, FM, BM, QT, JC, J-CSo, and GZ designed the study; all authors participated in data acquisition; FB, JMa, FM, QT, PM, ALa, JC,
J-CSo, and GZ analysed and interpreted the data; FB, JMa, FM, QT, PM, ALa, JC, J-CSo, and GZ wrote the manuscript; all authors approved the
? nal version.
The Biomarkers France contributors
Listed here are the representatives of each regional molecular genetics centre and/or the pathologist who collaborated in this project and the treating physicians who provided data for 40 patients or more: F Al Freijat (Centre Hospitalier de Belfort-Montbéliard, Service de Pneumologie, Belfort), L Baala (UF Biologie Moléculaire, Structure de Génétique,
CHRO & UMR7355, INEM CNRS et Université Orléans, Orléans),
O Beaudoux (Laboratoire de Biologie Médicale, Institut Jean-Godinot, Reims), L Bigay-Game (H?pital Larrey, Centre Hospitalier Universitaire, Service de Pneumologie, Toulouse), P Bonnette (H?pital Foch, Service de Chirurgie Thoracique, Suresnes), J C Boyer (Plateforme de Génétique
Moléculaire des Cancers, Laboratoire de Biochimie, CHU N?mes, N?mes), T Chinet (H?pital Ambroise Paré, Assistance Publique H?pitaux de Paris, Service de Pneumologie, Boulogne-Billancourt), B Coudert (Centre Georges Fran?ois Leclerc, Service d’Oncologie Médicale, Dijon), C Daniel (Institut Curie, Service d’Oncologie Médicale, Paris), F De Fraipont (Institut de Biologie et Pathologie, Centre Hospitalier Universitaire, Service Biochimie des Cancers et Biothérapies, La Tronche), R Descourt (H?pital Morvan, Centre Hospitalier Régional Universitaire, Service
d’Oncologie Médicale, Brest), J Dubrez (Clinique Lafourcade, Service Chirurgie Thoracique et Cardiovasculaire, Bayonne), E Fabre (H?pital Européen Georges Pompidou, Assistance Publique H?pitaux de Paris, Paris), M Filaire (Centre Jean Perrin, Service de Chirurgie Thoracique, Clermont-Ferrand), F Forest (Centre Hospitalier Universitaire, Service Anatomie et Cytologie Pathologiques, Saint Etienne), P Foucher (Bocage Central, Centre Hospitalier Universitaire, H?pital de Semaine Cardiologie Pneumologie, Dijon), R Gervais (Centre Francois Baclesse, Service de Pneumologie, Caen), D Gossot (Institut Montsouris, Département Chirurgie Thoracique, Paris), J P Gury (Centre Hospitalier Intercommunal de la Haute-Sa?ne, Service de Pneumologie, Vesoul),
P Hofman (H?pital Pasteur, Centre Hospitalier Universitaire, Laboratoire de Pathologie Clinique et Expérimentale, Nice), I Huet (H?pital Larrey, Centre Hospitalier Universitaire, Service de Pneumologie, Toulouse),
H Janicot (H?pital Gabriel Montpied, Centre Hospitalier Universitaire, Service de Pneumologie, Clermont-Ferrand), J Jougon (H?pital Haut-
Lévêque, Centre Hospitalier Universitaire, Service de Chirurgie Thoracique, Pessac), L Karayan-Tapon (Centre Hospitalier Universitaire, Service de Cancérologie, Poitiers), F Labrousse (H?pital Dupuytren, Centre Hospitalier Universitaire, Service d’Anatomie Pathologique, Limoges), R Lacave (H?pital Tenon, Assistance Publique H?pitaux de Paris, Service d’Histologie, Embryologie, Cytogénétique Biologie Tumorale et Génétique Moléculaire, Paris), L Lacroix (Institut Gustave Roussy, Département de Biologie et Pathologie Médicales, Villejuif),
J J La? tte (H?pital Albert Calmette, Centre Hospitalier Régional Universitaire, Service d’Oncologie Thoracique et Pneumologie, Lille),
T Le Chevalier (Institut Gustave Roussy, Service de Médecine, Villejuif, Paris), G Le Gac (H?pital Morvan, Centre Hospitalier Universitaire, Laboratoire de Génétique Moléculaire et d’Histocompatibilité, Brest),
J Lehmann-Che (H?pital Saint-Louis, Assistance Publique H?pitaux de Paris, Molecular Oncology Unit and University Paris-Diderot, Paris),
B Léotard (H?pital Brabois, Centre Hospitalier Universitaire, Service de Génétique, Vandoeuvre-Les-Nancy), K Leroy (H?pital Henri Mondor, Université Paris Est Créteil, Département de Pathologie, INSERM U955, équipe N°9, Créteil), M Marcq (Les Oudairies, Centre Hospitalier
Départemental, Roche-sur-Yon), L Martin (H?pital Fran?ois Mitterand, Centre Hospitalier Universitaire, Service de Pathologie & CRB Ferdinand Cabanne, Dijon, France), M Martin (Centre Hospitalier d’Angoulême, Service d’Oncologie, Angoulême), Y Martinet (H?pital Brabois, Centre Hospitalier Régional Universitaire, Vandoeuvre-lès-Nancy), P Merle
(H?pital Gabriel Montpied, Centre Hospitalier Universitaire, Service de Pneumologie, Clermont-Ferrand), L Moreau (H?pital Pasteur, H?pitaux Civils de Colmar, Service de Pneumologie, Colmar), A Morel (Institut de Cancérologie de L’Ouest Site Paul Papin, Service d’Oncologie Biologie, Angers), D Moro-Sibilot (H?pital Michallon, Centre Hospitalier Universitaire, Service de Pneumologie, La Tronche), C Mougin (H?pital Jean Minjoz, Centre Hospitalier Régional Universitaire, Laboratoire de Biologie Cellulaire et Moléculaire, Besan?on), C Nocent Ejanaini (Centre Hospitalier C?te Basque, Service de Pneumologie, Bayonne), L Oua?(Institut Curie, Département de Biopathologie, Paris), J C Pagès (H?pital Trousseau, Centre Hospitalier Régional Universitaire, Service de Biochimie et Biologie Moléculaire, Tours), F Pedeutour (Faculté de
Médecine, Laboratoire de Génétique des Tumeurs Solides, Nice),
M Poudenx (Centre Antoine Lacassagne, Service de Pneumologie, Nice), D Pouessel (H?pital Saint Louis, Assistance Publique H?pitaux de Paris, Service d’Oncologie Médicale, Paris), J F Régnard (H?pital Cochin, Assistance Publique H?pitaux de Paris, Service de Chirurgie Thoracique, Paris), N Richard (H?pital de la C?te de Nacre, Centre Hospitalier Universitaire, Service de Génétique, Caen), J M Rodier (H?pital Bichat—Claude-Bernard, Assistance Publique H?pitaux de Paris, Service de
Cancérologie, Paris), J Solassol (H?pital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire, Université Montpellier 1, Laboratoire de Biopathologie, Montpellier), I Soubeyran (Institut Bergonié, Service de Biopathologie, Bordeaux, France), P J Souquet (Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Service de Pneumologie, Pierre-Bénite),
L Thiberville (H?pital Charles Nicolle, Centre Hospitalier Universitaire, Service de Pneumologie, Rouen), V Thomas De Montpréville (Centre Chirurgical Marie Lannelongue, Service d’Anatomie Pathologique,
Le Plessis Robinson).
Declaration of interests
FB reports grants and personal fees from AstraZeneca, Eli Lilly Oncology, F Ho? mann-La Roche Ltd, Novartis, P? zer, and Pierre Fabre, and personal fees from Boehringer Ingelheim, Daiichi-Seiko, and GlaxoSmithKline, outside the submitted work. HL reports grants and non-? nancial support from Roche, personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Pierre Fabre Oncology, and personal fees and non-? nancial support from P? zer and Lilly, outside the submitted work. VW reports personal fees and other from Lilly and Roche, and personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. ALe reports personal fees from Roche, AstraZeneca, P? zer, and Boehringer Mannheim, and non-? nancial support from Boehringer Mannheim and Roche, outside the submitted work. Additionally, ALe has a patent pending (13306589.6 du 21/11/2013). RV reports personal fees from Boehringer Ingelheim, Roche, and AstraZeneca, outside the submitted work. CA-V reports grants, personal fees, and non-? nancial support from Roche, Boehringer Ingelheim, and Novartis, and personal fees and
non-? nancial support from Lilly, P? zer, AstraZeneca, and Amgen, outside the submitted work. PPB reports honoraria from AstraZeneca and Roche, outside the submitted work. J-CSa reports personal fees from Boehringer Ingelheim and AstraZeneca, and grants and personal fees from Roche, outside the submitted work. GZ reports grants from French NCI, grants and non-? nancial support from Roche-France and AstraZeneca, and grants from Boehringer-France and P? zer, during the conduct of the study.
GZ reports grants, personal fees, and non-? nancial support from
Roche-France, AstraZeneca, P? zer-France, and Lilly-France, and grants and non-? nancial support from Boehringer, outside the submitted work.
All other authors declare no competing interests.
Articles
Acknowledgments
This study was sponsored by the French Cooperative Thoracic Intergroup (IFCT) and was funded by an unrestricted grant from the French National Cancer Institute (INCa). We thank the following individuals from INCa (Paris, France) for their constant support: D Maraninchi (past President), A Buzyn (President), F Calvo (past Head of Research Department), and F Nowak. We also thank A Deroy and S Dos Santos (Intergroupe Francophone de Cancérologie Thoracique, Paris, France) for their participation in data collection, monitoring, and computing.
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凡尔赛宫与卢浮宫的区别 卢浮宫与凡尔赛宫的区别从收集的资料上看 比较明显 虽同处法国 年代相当 风格有所类似但是也属于小同大异的一类 下面将从建设年代。地点、过程、面积，建 筑内外面风格，用途。。。这几点出发总结。另外我重点研究凡尔赛宫还会对其重点 景观进行论述。 一、建设年代、地点、过程、面积。 凡尔赛宫：1624年法国国王路易十三以1万里弗尔的价格买下了117法亩荒地， 在这里修建了一座二层的红砖楼房，用作狩猎行宫。由于16至17世纪的巴黎市民不 断发生暴动路易十四决定将王室宫廷迁出混乱喧闹的巴黎城。经过考察和权衡，他决 定以路易十三在凡尔赛的狩猎行宫为基础建造新宫殿。为此征购了6.7平方公里的土 地。这些土地面积可以给大家一个想象117亩的土地加上6.7平方公里的土地进行换 算相当于986个11人的足球场，及6.4个湖北工业大学的校园占地。是很大的! 1682 年5月6日，路易十四宣布将法兰西宫廷从巴黎迁往凡尔赛。凡尔赛宫主体部分的建 筑工程于1688年完工，而整个宫殿和花园的建设直至1710年才全部完成，1833年， 奥尔良王朝的路易·菲利普国王才下令修复凡尔赛宫，将其改为历史博物馆。 卢浮宫：卢浮宫比凡尔赛宫建设要早，始建于 12世纪末由法王腓力二世（“奥古斯都”）下令修建，最初是用作防御的城堡，边长约90米，四周有城壕，其面积大致相当于今卢浮 宫最东端院落的四分之一。当时的卢浮宫堡并不是法国国王的居所，而是被用来存放王室财 宝和武器。14世纪，法王查理五世觉得卢浮宫堡比位于塞纳河当中的城岛（西岱岛）的王 宫更适合居住，于是搬迁至此。其后不断进行修建与改造改建工作从1624年持续到1654 年。1682年法国宫廷移往凡尔赛宫后，卢浮宫的扩建再度终止。拿破仑即位后，开始了对 卢浮宫的大规模扩建，直到拿破仑三世时期完成了卢浮宫建筑群。现在出杜伊勒里宫在1871 年5月，巴黎公社面临失败时将其烧毁之外其余建筑全部幸存。前后将近600年。
安全管理编号：LX-FS-A28240 中国矿产资源特点 In the daily work environment, plan the important work to be done in the future, and require the personnel to jointly abide by the corresponding procedures and code of conduct, so that the overall behavior or activity reaches the specified standard 编写：_________________________ 审批：_________________________ 时间：________年_____月_____日 A4打印/ 新修订/ 完整/ 内容可编辑
中国矿产资源特点 使用说明：本安全管理资料适用于日常工作环境中对安全相关工作进行具有统筹性，导向性的规划，并要求相关人员共同遵守对应的办事规程与行动准则，使整体行为或活动达到或超越规定的标准。资料内容可按真实状况进行条款调整，套用时请仔细阅读。 （一）能源矿产资源中国能源矿产资源比较丰富，但结构不理想，煤炭资源比重偏大，石油、天然气资源相对较少。煤炭资源的特点是：蕴藏量大，但勘探程度低；煤种齐全，但肥瘦不均，优质炼焦用煤和无烟煤储量不多；分布广泛，但储量风度悬殊，东少西多，北丰南贫；资源赋存东深西浅，露采煤炭不多，且主要为褐煤；煤层中共伴生矿产多。油气资源的特点是：石油资源量大，是世界可采资源量大于150亿吨的10个国家之一；资源的探明程度低，陆上探明石油地质储量仅占全部资源的1／5，近海海域的探明程度更低；分布比较集中，大于10万平方
城 市 设 计 论 文 城市设计案例分析——巴黎 摘要 本文对巴黎地区发展及沿历史改革进行城市的分析总结，主要对1965年前后的改造，对巴黎的规划主要内容，措施及成效进行分析阐述，巴黎地区规划实现了从是去想市郊的发展，从遏制城市膨胀箱引导城市空间合理转变，解决了交
通，住房等要素向社会经济文化自然等多要素发展。及我们可以借鉴的经验。 历史回顾 法国首都巴黎是世界名城，素有“花都”之称。这一方面是由于它的繁荣奢华，另一方面也由于美丽动人的城市景观。和北京一样，巴黎也是一座具有800年历史的古城，但与北京不同的是它不象北京那样是按照城市设计统一建成。 巴黎是围绕塞纳河逐步扩大形成的。17世纪初亨利四世在位，为出尽工商业的发展，做了一些道路，桥梁，供水等城市建设工程，把巴黎昔日许多破烂房屋改成整齐一色的砖石联排建筑，17世纪下半叶路易十四统治时期，巴黎有了很大的发展，以卢浮宫为主的中心建筑群和以香榭丽舍田园大街为主轴线在那时已基本形成。卢浮宫和一大批古典主义大型建筑物都与主要干道，桥梁等联系起来，成为一个艺术标志。1724年，丢勒花园延伸向西，其轴线可到达星型广场。这条轴线后来成为巴黎中枢主轴，18世纪中叶至下叶完成了巴黎最壮观的林荫道——爱丽舍田园大道，这个时期最有代表性的广场是旺道姆广场。
这一时期建筑基本完成了对市政，道路建设，街道的改造，奠定了大都市的雏形。确立了城市中枢轴线，特别是凡尔赛宫的总布局对欧洲城市规划影响很大，三天笔直的放射形大道和对称严谨的大花园为其后一些城市的规划所借鉴。看下图 奥斯曼改造 1789年资产阶级革命爆发，种种矛盾出现，大工业生产方式大大刺激了商品经济的发展，城市盲目扩建，布局混乱，交通阻塞，建筑艺术衰退，1853年~1870年，拿破仑三世执政，由塞纳区行政长官奥斯曼主持，进行了大规模的改建工作——历史上著名的“奥斯曼改建”。 主要内容：（1）改造道路结构网，完成巴黎“大十字” 干道和两个环形路。 （2）城市中心区的改建。 （3）新建主要的基础设施。 （4）新建社会类城市服务设施。 （5）采用新城市行政结构，把重心分散成几个区中心。
法国古典主义园林之凡尔赛宫鉴赏美是人类永恒的追求，人类发展的历史，就是一部不断认识和创造美的过程。而高质量、高水平的园林工程建设，既是改善城镇生态环境和建设投资环境的需要，又是人民高质量生存、生活、工作环境的基础。 16-17世纪，意大利文艺复兴式园林传入法国。法国多平原，有大片天然植被和大量的河流和湖泊。17世纪后半叶，从路易十三开始，国王战胜了封建诸侯而同一法兰西。路易十四时（1661-1715年），是法兰西的极盛时代。路易十四为了满足他的虚荣，代表他的至尊玉权威，建造了雄伟的凡尔赛宫苑，在西方的建园建园史上解开了光辉灿烂的崭新一页。这个宫苑是法国最杰出的建造大师勒诺特设计和主持建造的。这座园林不仅是当时世界上最大的名园之一，也是法国绝对君权的象征。 艺术特征: 凡尔赛宫宫殿为古典主义风格建筑，立面为标准的古典主义三段式处理，即将立面划分为纵、横三段，建筑左右对称，造型轮廓整齐、庄重雄伟，被称为是理性美的代表。其内部装潢则以巴洛克风格为主，少数厅堂为洛可可风格。 正宫前面是一座风格独特的“ 法兰西式” 的大花园，园内树木花草别具匠心，使人看后顿觉美不胜收。而建筑群周边园林亦是世界著名。它与中国古典和皇家园林有着截然不同的风格。它完全是人工雕琢的，极其讲究对称和几何图形化。如果凡尔赛宫的外观给人以宏伟壮观的感觉，那么它的内部陈设及装潢就更富于艺术魅力，室内装饰极其豪华富丽是凡尔赛宫的一大特色。500 余间大殿小厅处处金碧辉煌，豪华非凡：内壁装饰以雕刻、巨幅油画及挂毯为主，配有17、18世纪造型超绝、工艺精湛的家具。大理石院和镜厅是其中最为突出的两处，除了上面讲到的室内装饰外，太阳也是常用的题目，因为太阳是路易十四的象征。有时候还和兵器、盔甲一起出现在墙面上。除了用人像装饰室内外，还用狮子、鹰、麒麟等动物形象来装饰室内。有的还用金属铸造成楼梯栏杆，有些金属配件还镀了金，配上各种色彩有大理石，显得十分灿烂。天花板除了象镜厅那样的半圆拱外，还有平的，也有半球形穹顶，顶上除了绘画也有浮雕。宫内随处陈放着来自世界各地的珍贵艺术品，其中有我国古代的精品瓷器。 著名景观：
中国矿产资源开发现状综述 姓名：班级：学号： 摘要：矿业是人类从事生产劳动古老的领域之一。矿业的发展与扩大矿产资源的开发利用，对人类社会文明的发展与进步产生了巨大的、无可替代的促进作用。目前在世界范围内，有95%以上的能源、80%以上的工业原料、70%以上的农业生产资料、30%以上的工农业用水均来自矿产资源，可以毫不夸张地说，矿产资源是人类的生命基石。人类使用矿产资源历史悠久，中国至少在50万年以前就开始利用矿产资源，矿产资源是一种重要的自然资源，是社会和经济发展的重要物质基础。矿产资源是社会经济持续发展的必要条件和物质基础，国民经济持续、快速的发展离不开矿产资源的快速稳定的供给。我国虽然是个矿产资源大国，但是我国人口基数大，而且当前我国正处在经济快速发展过程中，对矿产资源的依赖仍然很大。我们一定要做好国家矿产资源的宏观预测调控，健全制度，完善法规，转变观念，坚决关闭小矿业，加快技术进步，树立精品意识，实施全球资源战略，开发、利用、保护好我国现有的矿产资源，提高矿产资源的综合利用效率，实现“矿业强国”，并最终保证国家的可持续发展。 关键词：矿业开发，矿业分布与存储，矿业现状，矿业可持续发展 1.中国矿产资源储存分布情况 中国是世界上为数不多的、矿产资源种类较齐全的、矿产自给程度较高的国家之一。资源总量大，一部分矿种（矿组）的储量名列世界前茅或首位。中国现在已经发现171中矿产资源、其中已经查明储存量的有158种，其中能源矿产10种，金属矿产54种，水气矿产3种。面前已经拥有矿产地18000处，大中型的矿产有7000余处，是世界第三大矿产资源国。而人均占有量只有世界平均水平的58%，居第53位，个别矿种甚至居世界百位之后。 1.1 富矿少，贫矿多。 我国矿产资源，贫富矿兼有，而以贫矿居多，品位低，不能直接供冶炼和化工利用，而矿石在采选过程中，浪费也很严重。开采时采富弃贫，使矿石品位下降，富矿越来越少，选别时技术落后，富集率低，并形成大量尾矿，无法合理利用。 1.2 地区分布不平衡。 我国的煤炭贮量中，山西省占1/4，内蒙古自治区占1/5，而南方很少。石油也存在这种北多南少的状况，大庆、辽河、华北、胜利等几大油田都集中在北方，有色金属则是南多北少，如钨、锰、镍、铅、锌矿等。这种资源分布与生产力布局的不相匹配，长期形成了北煤南调、西煤东运的局面，大大提高了矿产开发的成本。[1] 1.3 共生、伴生矿床多，单一矿床少。 中国80%左右的有色矿床中都有共伴生元素，其中尤以铝、铜、铅、锌矿产多。而且不少矿石嵌布粒度细，结构构造复杂。中国有色矿产资源中，虽然共伴生元素多，若能搞好综合回收，可以提高矿山的综合经济效益，同时由于矿石组份复杂，势必造成选冶难度大、建设投资和生产经营成本高的现状。
以巴黎和北京城为例浅析轴线式构图城市中西方差异 北京和巴黎, 作为代表东西方文化的两座世界闻名的历史古城,具有相似的历史背景和城市性质。两者均为国家的首都、政治和文化中心。都具有悠久的历史和灿烂的文化, 巴黎是沉淀西方文化最深厚的城市北京是蕴涵东方文化最富饶的地方。尽管受到不同文化与规划理论的影响但两个城市在空间形态及其布局上表现出许多相似之处,最著名的就是两座城市的轴线构图。 作为东西方两个历史悠久的古城,北京和巴黎在旧城布局上也有很多相似之处。其范围均由历史上形成的最外圈城墙确定(原先的城墙已改成了环路) 市中心布置王宫和重要的宗教建筑(北京为故宫;巴黎为城岛上的圣母院和塞纳河右岸的卢浮宫) 并采用了轴线构图(尽管轴线的表现方式及形成历史各有千秋) , 旧城区周围布置有大片的绿化环境(北京的颐和园、圆明园: 巴黎的布洛涅和班森诺公园)。 城市的轴线不仅是对城市主要道路的一种升华，而且是城市设计的高潮部 分，使得很多城市的道路、建筑及景观布置均围绕着它展开。北京和巴黎的轴 线有很多共同的特点，比如，它们都蕴含着悠久的历史和深厚的文化底蕴；它 们的型式都很清晰清晰且规模宏大；它们都有宫廷建筑统领的建筑群，并且空 间有序，高潮迭起；它们都经过人工的精心规划设计，将城市中心归于其上， 而非自然堆砌形成。但是，由于它们不同的形成过程、不同的体态，所以给人 的感觉也各不相同。下面我们将就此分别对北京和巴黎两条城市主轴线的特点 3.3.1两种形成过程——两种结果 北京和巴黎的轴线有着不一样的形成过程。北京的轴线是通过城市的整体 规划自上而下形成的，更多的反映了统治者的意志，除了使用功能以外更加注 重象征意义，给人带来一种庄严神圣的感觉。而巴黎的轴线则不然，虽然也是 自上而下形成的，但是其产生的过程并非一蹴而就，而是分时期逐渐形成，所 以其演化过程除了君主意志以外，也将民众的使用考虑在其中，除了给人以奢 华之感以外也将城市的浪漫融入其中。 轴线的概念和定义 轴线是一种历史悠久的而且现在仍被普遍运用的设计思想与方法，其内涵丰富而外延广泛，狭义上的轴线指的是中轴线，尤指中国传统城市中统领全城布局的对称轴，《土木建筑工程词典》认为，轴线是建筑群体或一栋建筑的布局中可分成对称或均衡两部分间的中线，就是狭义上给轴线下的定义；《建筑：形式·空间与秩序》指出：连接空间中的两点得到的一条线，形式和空间等要素沿线排列。作者以为城市的轴线式构图，关注的是轴线与城市结构的关系，故可理解为均衡与统领城市功能布局和空间形态构成的线型结构性要素。 轴线的作用 通过定义，不难发现轴线在城市中的意义就是可以统领城市空间的形态构成，使城市布局均衡有序，具体而言，可表现为以下几点：①控制城市空间格局——城市空间轴线的性状决定城市的基本格局（网状、放射状）；②组织城市空间序列——轴线上虚与实的组合与交替构成了城市的空间序列；③形成城市天际轮廓线——城市天际线的形成与发展往往依赖于城市轴线的构架；④展现城市标志——壮丽的城市空间轴线本身就兼具城市景观与认知地标的作用。 城市发展比较 回顾两座城市的发展的发展历程都具有悠久的历史。北京有80多年的建都史和3000多年的建城史，最早是在燕山脚下的一片平原上发展起来的。最初进行都城规划是在元代，其后经明清两朝修建逐步完善，但轴线式的城市构图始终没有发生过根本性改变。而巴黎的建都史则长达1200多年。最初是从塞纳河上的城岛发展起来的, 城岛之所以成为最早的居民点主
城市规划和可持续发展 --大巴黎 规划规划新方法之新方法之新方法之尝试尝试 为了更好的规划大巴黎城市群,法国政府在五十年的时间里对其进行不同尺度、不同领域的规划。包括从区域，省，城市以及到城镇各个尺度，街区; 涵盖从土地利用，住宅及设施建设，气候，大气环境，能源方面各个方面。 一、规划城市和规划城市和治理交通治理交通治理交通同步进行同步进行 众所周知，城市发展和交通之间的存在着最本质、最密不可分的联系。 在大巴黎地区，1965年编制的总体规划包括， 5个新城规划， 4条放射线路的快速铁路系统（RER ）规划，以及高速公路系统的规划，根据此规划，线路服务于700万局民，并且其辐射地区将在30内年吸引700万新的居民。 如今--五十年之后 ，大巴黎地区正在规划，8项国家级建设项目，6条高速铁路以及一个双核心“8"字形的快速铁路交通系统。此系统服务于1200万居民，并在20年时间里，吸引100万新居民。此系统沿线新车站附近地区（之前为城市建成区或是农业用地）的开发建设，得到国家法律，与当地政府或者区域联合政府土地开发合同的共同保障。 二、新的政策和手段新的政策和手段：：@d aménagement durable? 短短几年，可持续发展这一新的思想已经深刻地改变了大巴黎地区的发展面貌。 巴黎700万甚至900万居民的日常消费，投资及生活模式直接影响其所在城市的发展。针对可持续发展的三个重要方面——经济可持续，生活可持续，环境可持续， 提出一个综合的研究方案是非常必要的。我们必须关注于决策者，这些决策者包括城市居民，公司，政府和其行政部门。总的来说，大巴黎区域内包括500万决策人， 他们可能是个人或集体，可能是代表大众的，也可能是私人， 每个决策人都有自己的决定，其中的一些可能受到政策，及国家行政手段的影响。 如何整合这大量的独立决策人对于可持续发展的观点和看法是一个非常重要的问题。 作为国家法律法规，政策和监督的补充，建立一种机制，一种手段以使所有的决策人更好了解可持续发展 ，以地方的利益出发做出一个慎重的、有远见的决定是非常必要的。 因此我们提出@d aménagement durable?这一工作方法，从地区的利益为出发点，将重要问题归纳简化成12 个可以量化指标体系。应用这种方法有两个主要优势，第一，它可使决策者--居民，企业，当权政府及行政部门更易了解相关问题并做出选择；第二，从资金投入到项目实施，总资金的管理以及土地使用，此方法可以在项目进程的各个阶段综合考量项目的各个方面，以做出最好的决策。 因此，我们将各地市长、区域长官也作为影响当地决策的关键要素予考量。和当地其他他决策者--居民、公司等一起以生态环境为出发点，决定当地的政策实施,包括政府资金的投入，信息传播，主要工程建设等。 具体来说，这个评价系统包含12 个主要的评价方面，
法国凡尔赛宫和中国北京故宫的建筑美学比较
由许多单体建筑结合配置组群而成的，如二大殿、后二宫等都是一座座单独的单层建筑，这与凡尔赛宫光荣殿宏大、庄重、多种建筑融于一体、呈3层结构的综合式建筑有鲜明的不同.单体建筑群其实也是我国古代建筑的一大共性。 紫禁城空间图式所反映的中轴对称、多重围合与附会风水模式的布局，是中国古代长期以来礼制思想要求的必然结果.与此相异，凡尔赛宫的规划设计则反映出具有中心感与放射性的格网布局的空间图式，可以说是西方基督教文化控制性与扩张性的物化反映. 总之，紫禁城的布局从整体而言，是一个富于礼制涵义的院落**.与之相比，凡尔赛宫的营建过程可谓是在古典比例控制下的立面格构的累积与延续.紫禁城的设计自始至终以象征乎法表达帝王至上的主题，注重宫殿严密的礼制规范与内涵.凡尔赛宫在设计上则注重建筑立面整体的延续性，借助优雅、明晰的古典格式表现绝对的秩序和理性的光辉.与紫禁城一致的是，凡尔赛宫在内部功能的排布与划分上亦十分清晰、明确、主次有别，但并无强烈的礼制观念和方位上的主从次序2以不同的形式表示至高无上—凡尔赛宫和故宫在建筑体制上的比较 凡尔赛宫是强调逻辑的，富于理念的，严格按照纵横各分3段的古典式处理:其正宫、南宫与北宫组成对称的几何图形，花园也是几何的。中央部分供国土和土后起居、工作之用;南翼为土了、亲王的府邸;北翼为王权办公处.凡尔赛宫就是法国古典主义建筑最著名的作品之一，其建筑严格对称，突出中轴线.总体特征是均衡、恬静安详、庄严典雅，有条不紊，秩序井然。 故宫建筑则处处体现着中华民族追求和谐的特点，富有生气，轻盈活泼.故宫建筑基本上是在平面空间上展开的，不像凡尔赛宫那样以单体建筑为基本单元向高空发展来增加建筑的体量，而是在四合院的基础上向前后延仲，所以故宫表现出硕大的建筑物的群体性，亭台楼阁一眼无尽.这种水平方向的仲展布局体现出一种序列空间美，一种人文的秩序和伦理的规定。所以，欣赏故宫的建筑艺术与欣赏凡尔赛宫的建筑艺术，一个明显差异在于:对于凡尔赛宫，可以像欣赏一座雕塑作品，任意把玩其作品的“细节”.而欣赏故宫的建筑则不然，故宫的建筑本身就是一个流动的过程.因此，欣赏者还必须围绕建筑走动，才能真正领略到故宫的建筑风貌.故宫可以制造了在空间对比变换中产生的意境.故宫就像是一个政教合一的地方，通过繁褥、神秘的各个通道，造成一种对人的心灵的震慑与崇敬感，令人的精神和理智臣服.因此完全可以认为，故宫的建筑空间是流动的，是具有时间性的空间。 3与自然和谐—凡尔赛宫和故宫在建筑材料与结构上的比较 现在，我们来看故宫与凡尔赛的宫殿建筑特点.由于建筑材料的不同，故宫与凡尔赛宫的建筑特点、建筑风格有鲜明的区别.西方古代建筑几乎都以石头为建筑材料，而我国是世界上少见的以木材为主要建筑材料的国家.以石头做建筑材料，是建筑呈现宏伟、厚重、稳固的特征.但石料也极大地限制了建筑内部空间.为了解放建筑内部空间，古希腊创造了著名的古典柱式，古罗马人发展了大跨度的稳重的石拱结构，这些都刻在凡尔赛宫单看到其影子.凡尔赛宫是法国古典主义建
世界矿产资源分布情况 Document number：NOCG-YUNOO-BUYTT-UU986-1986UT
世界矿产资源分布情况 矿产品种类繁多，分类方法也不少，但最基本的分类是两种：金属矿物和非金属矿物；燃料矿物和非燃料矿物。世界矿物原料消耗中，非金属矿物，尤其是砂石料等，所占的比重最大。 世界上应用较为广泛的矿物约有80多种，其中的铁、铜、铝土、铅、锌、镍、磷酸盐、锡和锰等9种，具有产值大，国际贸易量较多等特点，地位相当重要。世界矿物开采的集中性明显,70～75％集中在10余个国家里，特别是少数几个工业发达国家。前苏联和美国是世界上采矿业规模最宏大的两个国家，前者约占世界矿业开采值的18％，后者约占世界的15％。加拿大居世界第三位，估占世界的11％。澳大利亚和南非的采矿业，规模也很大。发展中国家，采矿业发达、规模较大的有中国、智利、赞比亚、扎伊尔、秘鲁、墨西哥、巴西和阿根廷等国家。 全世界#铁矿石#的探明储量约为3,500亿吨。高度集中是铁矿石在地域分布上的最大特点。铁矿资源主要集聚于10多个国家里。前苏联铁矿石的探明储量是1,140亿吨，占世界铁矿探明储量的30％多，是目前地球上探明储量超过1,000亿吨的唯一国家，比居世界第二位的巴西要多近400亿吨，为美国铁矿石探明储量的倍。除前苏联外，依次排列的顺序是巴西、中国、加拿大、澳大利亚、美国和波利维亚，以上7国的铁矿石储量计占世界铁矿石总储量的90％。另外，法国、瑞典、英国、委内瑞拉、南非、智利、德国和利比里亚等也是世界铁矿石储量较为丰富的国家。目前，世界上铁矿石的主要输出国是澳大利亚，年输出量达8,000万吨左右，列世界第一位。巴西的年输出量约为7,000万吨，列世界第二位。加拿大、印度、智利、前苏联、利比里亚、毛里塔尼亚、委内瑞拉和秘鲁等，也是世界铁矿石的重要输出国。铁矿石的主要输入国是西欧的比利时、法国、德国、英国和荷兰，以及东欧和中欧的波兰，捷克等，日本是最大的铁矿石输入国之一。美国的铁矿石资源丰富，年产量亦较多，
国内外优秀城市设计案例与实施分析 一、城市设计案例简析 古往今来，世界上优秀的城市设计实例为数不少。如按城市总体设计、中心广场设计、干道设计、绿化设计等去细分，更是不胜枚举。这里只能列举几个具有代表性的名城，加以分析。 城市设计资料图片 1.北京 北京是我国首都，又是著名的古都。北京的城市设计，无论在历史上，还是在当今世界城市设计实例中都是数一数二的。北京的古城基本上是明代建成的，她的前身是元大都城，就是按《周礼·考工记》的理想都城模式设计的。明北京城在元大都的基础上吸取了明初中都和南京的布局和形制的特点，使这种“左祖右社，面朝后市”的格局更加突出，城市轴线也延伸到外城，形成了长达8公里的雄伟庄严的南北中轴线。北京作为封建都城，城市设计的主题就是要突出封建帝王至高无上、君临天下的气势与威严。北京城市的整体布局和城市设计，无论在功能上还是在意识形态上都充分满足了这一要求。譬如在功能上满足了皇家政治（前朝）、生活（后寝）、游憩（御苑）以及礼制（坛、庙）、防御（城墙城楼）等方面的需要；在意识形态上，全城以皇宫为中心，中轴线为脊柱，左右对称，轴线上一重重城门，极力烘托出皇帝的权威，即所谓“非壮丽无以重威”。北京城由于经过整体设计，全城空间布局井然有序，更可贵的是有六海园林水系与之相陪衬，使规整中见自然，严肃中有活泼，这是历代都城中少见的。1983年7月中共中央、国务院在对《北京城市建设总体规划方案》的重要批复中指出：“北京是我国的首都，又是历史文化名城。北京的规划和建设，要反映出中华民族的历史文化、革命传统和社会主义国家首都的独特风貌。对珍贵的革命史迹、历史文物、古建筑和具有重要意义的古建筑遗址，要妥善保护。在其周围地区内，建筑物的体量、风格必须与之相协调”。我们应该很好地继承并发展北京城市规划与设计的优秀传统。 2.华盛顿 华盛顿（Washington D.C.）是美国首都，也是世界名城，1791年由法国工程师朗方（L’anfant）规划。她的主题思想是体现美国在战胜英国殖民统治后，建成民主、自由、独立的新兴资产阶级国家这一国体和立法、司法、行政三权分立的政体。城市设计巧妙地利用地形，以国会山高地为标志，设计了纵横两条轴线。主轴东西向，以国会为全市中心，南北轴线以总统府（白宫）为重点，两条轴线交叉点上建立华盛顿纪念碑（方尖塔），城市主轴以宽阔绿化为主。城市设计方案以后又经过补充完善，在主轴线两端建成
凡尔赛宫详细介绍 驰名世界的凡尔赛宫坐落在巴黎西南18千米的凡尔赛镇，它是人类艺术宝库中一颗灿烂的明珠。 凡尔赛宫建于路易十四〔路易十四（1643—1715）〕时代。在位期间加强专制统治，强化中央集权。两次进行战争，晚年国库空虚，农民起义此伏彼起，法国封建专制制度开始走向没落。1661年动土，1689年竣工，至今约有330多年的历史。全宫占地111万平方米，其中建筑面积为11万平方米，园林面积100万平方米。宫殿建筑气势磅礴，布局严密、协调。正宫东西走向，两端与南宫和北宫相衔接，形成对称的几何图案。宫顶建筑摒弃了巴洛克〔巴洛克是17～18世纪发展起来的一种建筑和装饰风格。其特点是外形自由，追求动态效果，喜好富丽的装饰和雕刻以及强烈的色彩，常用曲线穿插和椭圆形空间〕的圆顶和法国传统的尖顶建筑风格，采用了平顶形式，显得端正而雄浑。宫殿外壁上端，林立着大理石人物雕像，造型优美，栩栩如生。 凡尔赛宫宏伟、壮观，它的内部陈设和装潢富于艺术魅力。五百多间大殿小厅处处金碧辉煌，豪华非凡。内部装饰，以雕刻、巨幅油画及挂毯为主，配有17、18世纪造型超绝、工艺精湛的家具。宫内还陈放着来自世界各地的珍贵艺术品，其中有远涉重洋的中国古代瓷器。由皇家大画家、装潢家勒勃兰和大建筑师孟沙尔合作建造的镜廊是凡尔赛宫内的一大名胜。它全长72米，宽10米，高13米，连结两个大厅。长廊的一面是17扇朝花园开的巨大的拱形窗门，另一面镶嵌着与拱形窗对称的17面镜子，这些镜子由400多块镜片组成。镜廊拱形天花板上是勒勃兰的巨幅油画，挥洒淋漓，气势横溢，展现出一幅幅风起云涌的历史画面。漫步在镜廊内，碧澄的天空、静谧的园景映照在镜墙上，满目苍翠，仿佛置身在芳草如茵、佳木葱茏的园林中。 正宫前面是一座风格独特的法兰西式大花园。园内树木花草的栽植别具匠心，景色优美恬静，令人心旷神怡。站在正宫前极目远眺，玉带似的人工河上波光粼粼，帆影点点，两侧大树参天，郁郁葱葱，绿阴中女神雕塑亭亭而立。近处是两池碧波，沿池的铜雕塑丰姿多态，美不胜收。 凡尔赛宫的修建，有一段历史轶（yì）事世人不大知道的事情，多指不见于正式记载的。1661年，居住在陈旧的凡赛纳宫和枫丹白露宫的路易十四，应财政总监大臣富盖邀请，去他新建的府第赴宴。富盖府第的富丽堂皇触怒了路易十四。三周之后，路易十四以贪污营私之罪将富盖投入监狱，并判处无期徒刑。嫉妒的心理促使路易十四作出兴建一座豪华皇宫的计划。凡尔赛宫的建造者，几乎全部是给富盖修建府第的人马，因此无论构造还是风格，两座建筑有异曲同工之妙。 历史上一度曾是法国政治、文化中心的凡尔赛在大革命后变得默默无闻了，到了19世纪下半叶，它又成为全世界瞩目的政治中心。1870年，普鲁士军队占领凡尔赛，第二年德
城市设计论文
城市设计案例分析——巴黎 摘要 本文对巴黎地区发展及沿历史改革进行城市的分析总结，主要对1965年前后的改造，对巴黎的规划主要容，措施及成效进行分析阐述，巴黎地区规划实现了从是去想市郊的发展，从遏制城市膨胀箱引导城市空间合理转变，解决了交通，住房等要素向社会经济文化自然等多要素发展。及我们可以借鉴的经验。 历史回顾 法国首都巴黎是世界名城，素有“花都”之称。这一方面是由于它的繁荣奢华，另一方面也由于美丽动人的城市景观。和北京一样，巴黎也是一座具有800年历史的古城，
但与北京不同的是它不象北京那样是按照城市设计统一建成。 巴黎是围绕塞纳河逐步扩大形成的。17世纪初亨利四世在位，为出尽工商业的发展，做了一些道路，桥梁，供水等城市建设工程，把巴黎昔日许多破烂房屋改成整齐一色的砖石联排建筑，17世纪下半叶路易十四统治时期，巴黎有了很大的发展，以卢浮宫为主的中心建筑群和以香榭丽舍田园大街为主轴线在那时已基本形成。卢浮宫和一大批古典主义大型建筑物都与主要干道，桥梁等联系起来，成为一个艺术标志。1724年，丢勒花园延伸向西，其轴线可到达星型广场。这条轴线后来成为巴黎中枢主轴，18世纪中叶至下叶完成了巴黎最壮观的林荫道——爱丽舍田园大道，这个时期最有代表性的广场是旺道姆广场。
这一时期建筑基本完成了对市政，道路建设，街道的改造，奠定了大都市的雏形。确立了城市中枢轴线，特别是凡尔赛宫的总布局对欧洲城市规划影响很大，三天笔直的放射形大道和对称严谨的大花园为其后一些城市的规划所借鉴。看下图
奥斯曼改造 1789年资产阶级革命爆发，种种矛盾出现，大工业生产方式大大刺激了商品经济的发展，城市盲目扩建，布局混乱，交通阻塞，建筑艺术衰退，1853年~1870年，拿破仑三世执政，由塞纳区行政长官奥斯曼主持，进行了大规模的改建工作——历史上著名的“奥斯曼改建”。 主要容：（1）改造道路结构网，完成巴黎“大十字” 干道和两个环形路。 （2）城市中心区的改建。 （3）新建主要的基础设施。 （4）新建社会类城市服务设施。 （5）采用新城市行政结构，把重心分散成几个区中心。
早期[编辑] 巴黎是世界上最古老的城市之一，考古学家认为巴黎地区在公元前4200年就已经有人类居住在此[30]。凯尔特人当中的高卢人分支巴黎西人在公元前250年就已经居住在塞纳河沿岸[31][32]，所以巴黎市的核心就位于塞纳河上的西提岛（又译为“西岱岛”或“城岛”，?le de la Cité）。 公元前52年，罗马人征服了巴黎地区[30]。在此之前，巴黎地区只是一个名为巴黎西（Parisii）的凯尔特高卢人部落的聚居地。公元358年，罗马人在这里建造了宫殿，这一年被视为巴 黎建城的开始。罗马人起初将该这座城市命名为吕得斯（Lutetia），但是后来在四世纪时改名为巴黎。但是罗马时期高卢行省的中心是在巴黎南方的里昂，巴黎当时只是一个小规模的人类居住地，而且人口都集中在塞纳河左岸。巴黎在接下来的几个世纪中持续扩张，成为一个拥有宫殿、竞技场、浴场与花园的繁华城市[33]。 中古时期 公元508年，法兰克人占领了巴黎，国王克洛维一世将巴黎定为墨洛温王朝的首都，法兰 克人利用木板在这里建立教堂和宫殿。但是此时的法兰克人统治的国家不过是一个部落的聚合体，并无严谨的组织。克洛维一世死后，法兰克王国遭到他的儿子们瓜分，巴黎很快又沦为地方性城市。在加洛林王朝时期，法兰克王国的首都并不在巴黎，而是在亚琛等城市之间移动，巴黎地区当时是由“强者”罗贝尔来统治。公元9世纪，维京人入侵法国，并于公元845年进攻巴黎，于是巴黎人在城市周围建起了城墙抵御维京人侵略。因为加洛林王朝的最后一个国王胖子查理软弱无能，于是在抵抗维京人进攻中享有盛誉的巴黎伯爵奥多（Odo），同时也是罗贝尔之子，在公元888年由大领主们推选为西法兰克王国的国王。奥多的曾孙雨果·卡佩于987年加冕为法兰西国王，开创了卡佩王朝，同时巴黎也首次成为西法兰克王国的首都。 从公元11世纪开始，巴黎开始向塞纳河右岸发展。路易六世在右岸地区建立了市场和道路。腓力二世（奥古斯都）建设了首座环绕巴黎的城墙，还拓宽了城市道路，建设公共喷泉，同时修建了卢浮宫。巴黎于公元1348年遭到黑死病袭击，当时巴黎约有200,000人居住[34]，而这次黑死病曾经在一天之内就造成800人死亡，并在1466年再度造成40,000人死亡[35]。巴黎在百年战争中被英国和勃艮第公国的军队占领，但是后来瓦卢瓦王朝国王查理七世收复巴黎，在1453年结束了百年战争。1356年巴黎修建了第二道城墙。 1356年，王太子查理召开三级会议，筹备军资和赎金，却无意应答巴黎市民代表要求扩大三级会议权限、限制王权。1358年2月，巴黎市民艾蒂安·马赛（étienne Marcel）领导下起义，冲入王宫，查理出逃。后起义者联合扎克雷起义未果，查理调军围困巴黎，起义者遭镇压。 1436年，查理七世收复了巴黎。虽然巴黎恢复首都的地位，但是法国真正的权力中心仍然在卢瓦尔河流域[36]。 到了16世纪初（1528年），弗朗索瓦一世在巴黎周边建造了众多的城堡，法国的权力中 心才回到巴黎。1564年，凯瑟琳·德·美第奇王太后下令在城市中央修建杜伊勒里宫和花园，并将它与卢浮宫连接起来。1572年8月24日的圣巴托罗缪之夜，巴黎发生了天主教势力
国内外城市设计案例研究 ——以巴黎拉德芳斯新区为例 摘要：巴黎是法国的首都和最大的城市，也是法国的政治、经济、文化中心，同时又与美国纽约、英国伦敦和日本东京并列为四大世界级城市。随着城市人口逐渐增多，城市改造永远是一个不老的话题。城市改造主要有两条途径可走，一是改造旧城区，增高新建筑，增加建筑空间。二是合理规划，另建新城区。巴黎城市改造两条路都走，不仅对老城进行改造还在原来的荒野上建成一个新城区——拉德芳斯区。 关键词：城市设计拉德芳斯新城 巴黎，这座闻名世界的历史名城及现代化国际大都市，早在2000多年以前还是一个以西岱岛为中心、占地面积仅仅为0.5平方千米的渔民小村镇，经过时代变迁，现在已经发生了沧海桑田的变化，其独有的非凡的城市建设规划艺术在世界城建史上占有极其重要的地位。随着城市人口逐渐增多，城市改造永远是一个不老的话题。城市改造主要有两条途径可走，一是改造旧城区，增高新建筑，增加建筑空间。二是合理规划，另建新城区。巴黎城市改造两条路都走，不仅对老城进行改造还在原来的荒野上建成一个新城区——拉德芳斯区。巴黎城市改造，改造出一个举世瞩目的新区，并一举成为巴黎主要的商务区，是各国学习的楷模。 1.设计意图 从19世纪开始，巴黎城市规模发展迅猛，人口急剧增长。60年代初，巴黎大区的面积尽管仅为法国领土面积的2%，而人口却占了19%，法国大型的工商企业集团总部的70%设在巴黎地区。政府设置了一个城市规划研究中心来负责就巴黎大区的规划问题向政府提供咨询。1965年该中心提出巴黎大区规划，该规划明确提出在巴黎外围设立城市副中心，并在国际上首次提出新城的概念和卫星城的计划，以平衡城市布局，分散居住人口，解决用地压力，并都付诸了实施。 2.拉德芳斯新城 目前，这些规划中城市副中心和新城都已相继建成并具一定规模，使巴黎的经济结构与基础设施布局得到了重新组合，扭转了经济生活过于向中心城市集中地状况，缓解了市中心所面临的各种压力。其中，最引人注目的是拉德芳斯新城的建设，这座现代化的巴黎郊区卫星城被称为巴黎的“曼哈顿”。拉德芳斯区将艺术和视觉效果充分结合，加上现代城市的科学合理规划，体现出法国现代建筑艺术的魅力和震撼，世界许多建筑业人士都来拉德芳斯区观摩。 2.1拉德芳斯设计理念
世界矿产资源分布情况 矿产品种类繁多，分类方法也不少，但最基本的分类是两种：金属矿物和非金属矿物；燃料矿物和非燃料矿物。世界矿物原料消耗中，非金属矿物，尤其是砂石料等，所占的比重最大。世界上应用较为广泛的矿物约有80多种，其中的铁、铜、铝土、铅、锌、镍、磷酸盐、锡和锰等9种，具有产值大，国际贸易量较多等特点，地位相当重要。世界矿物开采的集中性明显,70～75％集中在10余个国家里，特别是少数几个工业发达国家。前苏联和美国是世界上采矿业规模最宏大的两个国家，前者约占世界矿业开采值的18％，后者约占世界的15％。加拿大居世界第三位，估占世界的11％。澳大利亚和南非的采矿业，规模也很大。发展中国家，采矿业发达、规模较大的有中国、智利、赞比亚、扎伊尔、秘鲁、墨西哥、巴西和阿根廷等国家。 全世界#铁矿石#的探明储量约为3,500亿吨。高度集中是铁矿石在地域分布上的最大特点。铁矿资源主要集聚于10多个国家里。前苏联铁矿石的探明储量是1,140亿吨，占世界铁矿探明储量的30％多，是目前地球上探明储量超过1,000亿吨的唯一国家，比居世界第二位的巴西要多近400亿吨，为美国铁矿石探明储量的6.5倍。除前苏联外，依次排列的顺序是巴西、中国、加拿大、澳大利亚、美国和波利维亚，以上7国的铁矿石储量计占世界铁矿石总储量的90％。另外，法国、瑞典、英国、委内瑞拉、南非、智利、德国和利比里亚等也是世界铁矿石储量较为丰富的国家。目前，世界上铁矿石的主要输出国是澳大利亚，年输出量达8,000万吨左右，列世界第一位。巴西的年输出量约为7,000万吨，列世界第二位。加拿大、印度、智利、前苏联、利比里亚、毛里塔尼亚、委内瑞拉和秘鲁等，也是世界铁矿石的重要输出国。铁矿石的主要输入国是西欧的比利时、法国、德国、英国和荷兰，以及东欧和中欧的波兰，捷克等，日本是最大的铁矿石输入国之一。美国的铁矿石资源丰富，年产量亦较多，但由于
巴黎是法国的首都，也是法国最大的城市，是法国的政治经济文化商业中心，与纽约伦敦东京并称为国际四大都市。同时也是著名的旅游胜地，艺术之都。巴黎地处法国北部，巴黎盆地的中央，横跨塞纳河两岸。 广义的巴黎有小巴黎和大巴黎之分。小巴黎指大环城公路以内的巴黎城市内，面积105.4平方公里，人口200多万；大巴黎包括城区周围的上塞纳省等七个省，共同组成巴黎大区，面积达12000平方公里，人口约1100万，几乎占全国人口的五分之一。 接下来从巴黎的历史规划讲起。巴黎在历史时期主要有三次重要的历史阶段，对其城市规划起了重大的影响。 首先要介绍一下中世纪及文艺复兴时期的巴黎，整个欧洲都如出一辙的肮脏，而巴黎甚至可以被称作是最脏的城市。在中世纪，街道没有铺路石，满地都是垃圾粪便堆积成的泥浆，下雨天更是肮脏不堪。巴黎的所有下水道都直接通向塞纳河，而市民又直接从塞纳河取水饮用。当时居住在凡尔赛宫中的贵族都直接在房间内排泄，因此他们每隔一段时间就会换一个房间居住，弄脏的房间就有人来清洁。这样一个肮脏的时期持续了很长一段时间，基督教对人们精神的黑暗统治，城市规划的杂乱无章，疾病常发的社会现象促使城市改革发生。 15世纪前后，文艺复兴，资产阶级萌芽，基督教的统治地位被强烈动摇。16世纪的法国统治者致力于国家统一，到17世纪中叶成为欧洲最强大的中央集权王国。这一时期，城市建筑风格主要是为君主服务的“古典主义”。在建筑外形上显得端庄雄伟，但内部则极尽奢华，空间效果和装饰上带有强烈的巴洛克特征，到18世纪则演化成洛可可风格。在城市规划思想领域，”古典主义+巴洛克“的设计思想对后来的豪斯曼改建产生了重要影响。 在前文提到的绝对君权时期，道路桥梁供水等城市建设工程开始有了些发展，巴黎昔日破破烂烂的房屋被整改成了整齐一色的砖石联排建筑。这些改建工作多在广场或大街旁，形成完整的广场和街道景观。 绝对君权时期最伟大的产物是对着卢浮宫建立的一个大而深远的视线中轴。轴线一路向西延伸，于1724年其轴线到达星形广场，也称作戴高乐光场，矗立着闻名于世的凯旋门。巴黎于18世纪中叶至下叶完成了巴黎最壮观的林荫道—香榭丽舍大道。这条轴线成为了巴黎的中枢主轴，其上分别有卢浮宫，杜乐丽花园，协和广场，香榭丽舍大道和凯旋门。 与此同时，巴黎出现了分布在一条轴线上的广场系列的规划。纪念性的公共广场得到了很大发展，并且开始把绿化布置喷泉雕塑、建筑小品和周围建筑组成一个协调的整体，注重处理好广场大小和周围建筑高度的比例。广场周围的环境以及广场与广场之间的关系。这个时期最有代表性的广场是左边的旺道姆广场和右边的协和广场。 总的来讲，在绝对君权时期，巴黎完成了如下几条规划：1、基本完成了对市政、道路建设和建筑群、街道的改建，初步形成城市必需的基础设施和城市景观，基本奠定了大都市的雏形；2、确立了城市中枢轴线，为城市的面貌和发展起到引导和示范作用；3、广场建设的轴线变换、相互关系、尺度等系列处理手法极大地丰富和促进了城市设计的发展。比如说左边这张图的星形广场，以其为中心辐射出去了十二条对称的道路。 接下来讲到著名的奥斯曼改造。1789法国爆发资产阶级革命后，资本主义城市的迅速发展与城市分布的不平衡导致了城市建设的种种矛盾。拿破仑三世执政时期，由塞纳区行政长官奥斯曼主持，进行了大规模的改建工作。其改建的主要内容为以下六点：1、改建道路结构网，形成新的城市结构；2、城市中心区的建设；3、新建主要的基础设施；4、新建社会类城市服务设施；5、采用新的城市行政结构，从管理层次上变革；6、美化巴黎城市面貌。 奥斯曼改造的重要内容是完成了巴黎的“大十字”干道，就是如图的红十字。奥斯曼将
巴黎改建及巴黎总体规划的图示布局分析说明 一、巴黎改建 巴黎改建时间为18世纪初期，分为三个阶段，分别为：1.雅各宾时期；2.拿破仑时期；3.拿破仑第三时期。改建内容如下： 雅各宾时期：最下层的贫苦人民的专政，城市建设重点是第三等级和城市贫苦手工业和工业者的聚居区 ①改善城市交通，增辟几条交通干道，特别是为劳动人民居住区铺设街道和路面，增加供水水井，清除垃圾，添置街灯； ②将巴士底狱夷为平地，修建绿化广场，广泛绿化； ③提出建筑应该追求简单，体现“建筑就像平民的道德一样单纯的”原则。 拿破仑时期：大资产阶级的政治代表拿破仑建立军事独裁权，城市建设活动主要为发展资本主义经济以及为颂扬拿破仑对外战争的胜利服务。 ①出租牟利的多层公寓为居住建筑的主要类型 ②改建贵族，市中心纪念碑、纪念柱和纪念性建筑群点缀广场与街道，以控制帝都风貌 ③改善城市面貌，对街道两侧的建筑高度及坡度做了明确规定 ④修建协和广场，并以其为控制城市的中心 ⑤修建凯旋门和明星广场 拿破仑第三时期： 背景：法国国内国际铁路建成，成为欧洲的最大交通枢纽之一。城市迅速发展，使城市原 有功能结构由于急剧变化而产生城市现状与发展之间的尖锐矛盾 目的：城市的改建既有功能要求，又有改造市容、装点帝都的要求、还有政治目的：从市中心迁出无产阶级，改善贵族和上层阶级的居住环境，拓宽大道，疏导交通功能，消灭狭窄街巷，以便镇压起义者。功能要求、艺术要求、政治目的 内容： 1)完成了巴黎的“大十字”干道和两个环形路 2)在市中心开辟95公里顺直宽阔的道路 3)为美化巴黎城市面貌，对道路的宽度与两旁建筑高度，屋顶坡度都规定了一 定比例的限制 4)改建市中心大型公共建筑 5)为适应城市结构变化带来的分区要求，市中心分散为几个区中心 6)建造了完善的地下排水系统和其它市政设施，促进城市近代化 7)重视绿化建设，修筑大面积公园。 1.不足： 1)未能解决工业化提出的新要求，未能解决城市贫民窟问题 2)城市内外交通衔接问题 3)以巴洛克的风格对城市大拆大建，破坏了城市的原有面貌； 2.意义：