Integrative analysis of gene expression patterns predicts specific modulations of defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells.

To explore the mechanisms whereby estrogen and antiestrogen (tamoxifen (TAM)) can regulate breast cancer cell growth, we investigated gene expression changes in MCF7 cells treated with 17beta-estradiol (E2) and/or with 4-OH-TAM. The patterns of differential expression were determined by the ValiGen Gene IDentification (VGID) process, a subtractive hybridization approach combined with microarray validation screening. Their possible biologic consequences were evaluated by integrative data analysis. Over 1000 cDNA inserts were isolated and subsequently cloned, sequenced and analyzed against nucleotide and protein databases (NT/NR/EST) with BLAST software. We revealed that E2 induced differential expression of 279 known and 28 unknown sequences, whereas TAM affected the expression of 286 known and 14 unknown sequences. Integrative data analysis singled out a set of 32 differentially expressed genes apparently involved in broad cellular mechanisms. The presence of E2 modulated the expression patterns of 23 genes involved in anchors and junction remodeling; extracellular matrix (ECM) degradation; cell cycle progression, including G1/S check point and S-phase regulation; and synthesis of genotoxic metabolites. In tumor cells, these four mechanisms are associated with the acquisition of a motile and invasive phenotype. TAM partly reversed the E2-induced differential expression patterns and consequently restored most of the biologic functions deregulated by E2, except the mechanisms associated with cell cycle progression. Furthermore, we found that TAM affects the expression of nine additional genes associated with cytoskeletal remodeling, DNA repair, active estrogen receptor formation and growth factor synthesis, and mitogenic pathways. These modulatory effects of E2 and TAM upon the gene expression patterns identified here could explain some of the mechanisms associated with the acquisition of a more aggressive phenotype by breast cancer cells, such as E2-independent growth and TAM resistance.

Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer.

PURPOSE: The aims of this prospective study were to evaluate the outcome and the possibility of breast conservation therapy for patients with locally advanced noninflammatory breast cancer after primary chemotherapy followed by external preoperative irradiation. METHODS AND MATERIALS: Between April 1982 and June 1990, 97 patients with locally advanced nonmetastatic and noninflammatory breast cancer were treated. The median follow-up was 93 months from the beginning of treatment. The induction treatment consisted of four courses of chemotherapy (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative irradiation (45 Gy to the breast and nodal areas). A fifth course of chemotherapy was given after irradiation therapy. Three different loco-regional approaches were proposed, depending on the tumoral response. In 37 patients (38%) with residual tumor larger than 3 cm in diameter or located behind the nipple or with bifocal tumors, mastectomy and axillary dissection were performed. Sixty other patients (62%) benefited from conservative treatment: 33 patients (34%) achieved complete remission and no surgery was done but additional radiation boost was given to the initial tumor bed; 27 patients (28%) who had a residual mass less than or equal to 3 cm in diameter were treated by wide excision and axillary dissection followed by a boost to the excision site. After completion of local therapy, all patients received a sixth course of chemotherapy. A maintenance adjuvant chemotherapy regimen without anthracycline was prescribed (12 monthly cycles). RESULTS: The 5-year actuarial loco-regional relapse rate was 16% after radiotherapy alone, 16% following wide excision and radiotherapy, and 5.4% following mastectomy. The 5-year loco-regional relapse rate was significantly higher after conservative local treatment (wide excision and radiotherapy, and radiotherapy alone) than after mastectomy (p= 0.04). After conservative local treatment, the 5-year breast conserving rate of patients with loco-regional disease-free status was 84%. For all patients included in this study, the 5-year breast-conserving rate of those who were loco-regional disease-free was 52%. In multivariate analysis, the possibility of breast conservative treatment was significantly related to the initial tumor size and age (more conservative treatment for tumor size < 6cm and age < 50 years). Five- and 10-year overall survival rates and disease-free survival rates were 80, 69, 73, and 61% respectively. Five- and 10-year overall survival rates were not influenced by the local treatment (conservative vs. nonconservative local treatment, p = 0.9). On the other hand, local failure significantly decreased the 5- and 10-year overall survival rates (p , 0.0001). In multivariate analysis, three factors had a significant impact on overall survival and disease-free survival: tumor response after induction chemotherapy, initial tumor size, and clinical stage. Arm lymphedema was noted in 12.5% (8 out of 64) of the patients treated with axillary dissection and in 3% (1 out of 33) without axillary dissection. Cosmetic results were satisfactory in 79% of patients after wide excision and radiotherapy and in 71% of patients treated by radiotherapy alone. CONCLUSIONS: Induction chemotherapy followed by preoperative irradiation may permit the selection of some patients with locally advanced breast cancer for conservative treatment. However, the impact of this treatment modality on long-term survival remains to be established.

Single-fraction stereotactic radiotherapy: a dose-response analysis of arteriovenous malformation obliteration.

PURPOSE: Stereotactic radiotherapy delivered in a high-dose single fraction is an effective technique to obliterate intracranial arteriovenous malformations (AVM). To attempt to analyze the relationships between dose, volume, and obliteration rates, we studied a group of patients treated using single-isocenter treatment plans. METHODS AND MATERIALS: From May 1986 to December 1989, 100 consecutive patients with angiographically proven AVM had stereotactic radiotherapy delivered as a high-dose single fraction using a single-isocenter technique. Distribution according to Spetzler-Martin grade was as follows: 79 grade 1-3, three grade 4, 0 grade 5, and 18 grade 6. The target volume was spheroid in 74 cases, ellipsoid in 11, and large and irregular in 15. The targeted volume of the nidus was estimated using two-dimensional stereotactic angiographic data and, calculated as an ovoid-shaped lesion, was 1900 +/- 230 mm3 (median 968 mm3; range 62-11, 250 mm3). The mean minimum target dose (Dmin) was 19 +/- 0.6 Gy (median 20 Gy; range: 3-31.5). The mean volume within the isodose which corresponded to the minimum target dose was 2500 +/- 300 mm3 (median 1200 mm3; range 75-14 900 mm3). The mean maximum dose (Dmax) was 34.5 +/- 0.5 Gy (median 35 Gy; range 15-45). The mean angiographic follow-up was 42 +/- 2.3 months (median 37.5; range 7-117). RESULTS: The absolute obliteration rate was 51%. The 5-year actuarial obliteration rate was 62.5 +/- 7%. After univariate analysis, AVM obliteration was influenced by previous surgery (p = 0.0007), Dmin by steps of 5 Gy (p = 0.005), targeted volume of the nidus (< or = 968 mm3 vs. >968 mm3; p = 0.015), and grade according to Spetzler-Martin (grade 1-3 vs. grade 4-6; p = 0.011). After multivariate analysis, the independent factors influencing AVM obliteration were the Dmin [relative risk (RR) 1.9; 95% confidence interval (CI) 1.4-2.5; p < 0.0001] and grade distribution according to Spetzler-Martin (RR 1.4; 95% CI 1.1-1.7; p = 0.010). Delayed complications were observed in eight patients. The 5-year actuarial rate of delayed complications was 7.4%. CONCLUSION: After stereotactic radiotherapy delivered in a single high dose using a single-isocenter technique, the success rate for complete obliteration is independently correlated to Dmin but does not seem to be influenced by Dmax and the targeted volume of the nidus.

Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer.

PURPOSE: To identify predicting factors for local failure and increased risk of distant metastases by statistical analysis of the data after breast-conserving treatment for early breast cancer. METHODS AND MATERIALS: Between January 1976 and December 1993, 528 patients with nonmetastatic T1 (tumors < or = 1 cm [n = 197], >1 cm [n = 220]) or T2 (tumors < or = 3 cm [n = 111]) carcinoma of the breast underwent wide excision (n = 435) or quadrantectomy (n = 93) with axillary dissection (negative nodal status [n-]: 396; 1-3 involved nodes: 100; >3 involved nodes: 32). Radiotherapy consisted of 45 Gy to the entire breast via tangential fields. Patients with positive axillary lymph nodes received 45 Gy to the axillary and supraclavicular area. Patients with positive axillary nodes and/or inner or central tumor locations received 50 Gy to the internal mammary lymph node area. A boost dose was delivered to the primary site by iridium 192 Implant in 298 patients (mean total dose: 15.2+/-0.07 Gy, range: 15-25 Gy) or by electrons in 225 patients (mean total dose: 14.8+/-0.09 Gy, range: 5-20 Gy). The mean age was 52.5+/-0.5 years (range: 26-86 years) and 267 patient were postmenopausal. Histologic types were as follows: 463 infiltrating ductal carcinomas, 39 infiltrating lobular carcinomas, and 26 other histotypes. Grade distribution according to the Scarff, Bloom, and Richardson (SBR) classification was as follows: 149 grade 1, 271 grade 2, 73 grade 3, and 35 nonclassified. The mean tumor size was 1.6+/-0.3 cm (range: 0.3-3 cm). The intraductal component of the primary tumor was extensive (EIC = IC > or = 25%) in 39 patients. Tumors were microscopically bifocal in 33 cases. Margins were assessed in the majority of cases by inking of the resection margins and were classified as positive in 13 cases, close (< or = 2 mm) in 21, negative (>2 mm tumor-free margin) in 417, and indeterminate in 77. Peritumoral vascular invasion was observed in 40 patients. Tamoxifen was administered for at least 2 years in 176 patients. At least six cycles of adjuvant systemic chemotherapy were administered in 116 patients. The mean follow-up period from the beginning of the treatment was 84.5+/-1.7 months. RESULTS: First events included 44 isolated local recurrences, 8 isolated axillary node recurrences, 44 isolated distant metastases, 1 local recurrence with synchronous axillary node recurrence, 7 local recurrences with synchronous metastases, and 2 local recurrences with synchronous axillary node recurrences and distant metastases. Of 39 pathologically evaluable local recurrences, 33 were classified as true local recurrences and 6 as ipsilateral new primary carcinomas. Seventy patients died (47 of breast carcinoma, 4 of other neoplastic diseases, 10 of other diseases and 9 of unknown causes). The 5- and 10-year rates were, respectively: specific survival 93% and 86%, disease-free survival 85% and 75%, distant metastasis 8.5% and 14%, and local recurrence 7% and 14%. Mean intervals from the beginning of treatment for local recurrence or distant metastases were, respectively, 60+/-6 months (median: 47 months, range: 6-217 months) and 49.5+/-5.4 months (median: 33 months, range: 6-217 months). After local recurrence, salvage mastectomy was performed in 46 patients (85%) and systemic hormonal therapy and/or chemotherapy was administered to 43 patients. The 5-year specific survival rate after treatment for local recurrence was 78+/-8.2%. Multivariate analysis (multivariate generalization of the proportional hazards model) showed that the probability of local control was decreased by the following four independent factors: young age (< or = 40 yr vs. >40 yr; relative risk [RR]: 3.15, 95% confidence interval [CI]: 1.7-5.8, p = 0.0002), premenopausal status (pre vs. post; RR: 2.9, 95% CI: 1.4-6, p = 0.0048), bifocality (uni- vs. bifocal; RR: 2.7, 95% CI: 2.6-2.8,p = 0.018), and extensive intraductal component (IC <25% vs. IC > or = 25%; RR: 2.6, 95% CI: 13-5.2, p = 0

Adenocarcinoma of the endometrium treated with combined irradiation and surgery: study of 437 patients.

PURPOSE: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas. METHODS AND MATERIALS: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system (225 Stage IB, 107 Stage IC, 4 Stage IIA, 35 Stage IIB, 30 Stage IIIA, 6 Stage IIIB, and 30 Stage IIIC), underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of adjuvant RT was not randomized and depended on the usual practices of the surgical teams. Seventy-nine pts (Group I) received preoperative low-dose-rate uterovaginal brachytherapy (mean dose [MD]: 57 Gy). Three hundred fifty-eight pts (Group II) received postoperative RT. One hundred ninety-six pts received low-dose-rate vaginal brachytherapy alone (MD: 50 Gy). One hundred fifty-eight pts had external beam pelvic RT (MD: 46 Gy) followed by low-dose-rate vaginal brachytherapy (MD: 17 Gy). Four pts had external beam pelvic RT alone (MD: 47 Gy). The mean follow-up from the beginning of treatment was 128 months. RESULTS: The 10-year disease-free survival rate was 86%. From 57 recurrences, only 12 were isolated locoregional recurrences. The independent factors decreasing the probability of disease-free survival were as follows: histologic type (clear-cell carcinoma, p = 0.038), largest histologic tumor diameter >3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.005), and 1988 FIGO staging system (p = 9.10(-8)). In Group II, the addition of external beam pelvic RT did not seem to independently improve vaginal or pelvic control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were stage FIGO (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for Grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. External beam pelvic RT independently increased the rate for Grade 3 and 4 late complication (RR: 5.6, p = 0.0096). CONCLUSION: Postoperative external beam pelvic RT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in subgroup of "intermediate-risk" patients (Stage IA Grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with Stage III tumor are not satisfactory.

Kidney mobility during respiration.

Radiotherapy treatment planning needs optimum definition of the target volume in its relative position to normal tissue. The motion of the kidneys during respiration has not been well quantified. They move in a tilted coronal and sagittal plane. Using fast MRI while patients held their breath we quantified the movements of the kidneys. Fourteen patients volunteered for the study. Nine MRI images of the kidneys for one volunteer were done: three in the axial plane (all in deep inspiration) and six in the coronal plane (three in deep inspiration, three in deep expiration). The maximal vertical motion of the superior pole from its end-expiratory to its end-inspiratory position is 39 mm (43 mm for the inferior pole). In deep inspiration or deep expiration the positions of the right and left kidneys appear reproducible. The mean deviation of kidney movement is less than 4 mm in all three dimensions (range, 0-6.9). For tumors close to the kidney, we advocate respiration gated radiation therapy so as to minimize the movement of this very radiosensitive structure.

Epidermoid carcinoma of the anal margin: 17 cases treated with curative-intent radiation therapy.

Between 1973 and 1991, 17 patients with epidermoid carcinoma of the anal margin without evidence of distant metastasis were treated with curative-intent radiation therapy (RT). There were nine T1-tumors, six T2-, one T3- and one T4-tumor; two patients presented with inguinal node involvement: one N1 and one N3. Nine patients underwent prior incomplete local excision (six with microscopic involvement of surgical margins and two with macroscopic residual disease). The radiation dose to the tumor was 60-70 Gy; the radiation dose to the inguinal lymph nodes was 40-45 Gy in N0, and 50-60 Gy for involved inguinal nodes. The 5- and 10-year cancer-specific survival rates were 86.2% and 77.5%, respectively. The same probabilities were 100% and 100% for T1-tumors, 60% and 40% for T2-tumors. Severe complications occurred in two patients, one anal radionecrosis requiring a colostomy and one permanent anal incontinence after local excision, which was non-related to irradiation. For the cured patients, the sphincter preservation rate after 5 years was 82% (9/11). In univariate analysis and in Cox multivariate analysis, the cancer-specific survival rate was influenced by one factor: the tumor size.

Early breast cancer: influence of type of boost (electrons vs iridium-192 implant) on local control and cosmesis after conservative surgery and radiation therapy.

Between December 1981 and December 1988, 329 consecutive patients with stage I and II breast cancers who underwent wide excision (n = 261) or quadrantectomy (n = 68) with (n = 303) or without (n = 26) axillary dissection were referred to radiotherapy. Final margins of resection were microscopically free from tumor involvement in all cases. Radiotherapy consisted in 40-45 Gy over 4-4.5 weeks to the breast, with (n = 168) or without (n = 161) regional nodal irradiation of 45-50 Gy over 4.5-5 weeks. A mean booster dose of 15 Gy was delivered to the primary site by iridium-192 implant in 169 patients (group 1) or by electrons in 160 patients (group 2). Twenty-seven percent (n = 88) of patients received tamoxifen for > or = 2 years. Adjuvant chemotherapy was administered in 22% (n = 71) of patients. Groups 1 and 2 were not strictly comparable. Group 1 patients were significantly younger, had smaller tumors, were treated with cobalt at 5 x 2 Gy per week and axillary dissection was more frequently performed. Group 2 patients were more frequently bifocal and more frequently treated by quadrantectomy and tamoxifen, and irradiation used accelerator photons at 4 x 2.50 Gy per week. No difference in terms of follow-up and survival rates was observed between the two groups. For all patients the 5- and 10-year local breast relapse rates were 6.7% and 11%, respectively. No difference was observed regarding local control either by the electron or the iridium-192 implant boosts. Axillary dissection and age had an impact on the breast cosmetic outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary chemotherapy and preoperative irradiation for patients with stage II larger than 3 cm or locally advanced non-inflammatory breast cancer.

BACKGROUND AND PURPOSE: To evaluate possibility of breast-conserving therapy and outcome for patients with locally advanced non-inflammatory breast cancer (LABC) and stage II >3 cm in diameter after primary chemotherapy (CT) followed by external preoperative irradiation (RT). MATERIALS AND METHODS: Between 1982 and 1990, 147 patients were treated by four courses of induction CT (doxorubicin, vincristine, cyclophosphamide, 5-fluorouracil) followed by preoperative RT (45 Gy to the breast and nodal areas) and a fifth course of CT. Three different loco-regional approaches were proposed depending on tumour characteristics and tumour response. After completion of local therapy, all patients received a sixth course of CT and a maintenance adjuvant CT regimen without anthracycline. RESULTS: Mastectomy and axillary dissection were performed in 52 patients, and conservative treatment in 95 patients (48 achieved complete remission and received additional radiation boost to initial tumour bed; 47 had a residual mass < or =3 cm in diameter and were treated by wide excision and axillary dissection followed by a boost to the excision site. Ten-year actuarial loco-regional failure rate was 20% after RT alone, 23% after wide excision and RT and 6% after mastectomy (P = 0.85). After multivariate analysis, possibility of breast-conserving therapy was related to initial tumour size. Ten-year overall survival rate was 66%; it was not influenced by local treatment (conservative vs. non-conservative local treatment, P = 0.89). However, local failure significantly decreased overall survival (P < 0.0001). After multivariate analysis, tumour response after induction CT and clinical stage had a significant impact on survival. CONCLUSIONS: The present data indicate that induction CT followed by preoperative RT may permit the selection of some patients with LABC or stage II >3 cm for conservative treatment. The impact of this treatment modality on long term survival remains to be established.

[Locoregional recurrence of adenocarcinomas of the rectum treated with irradiation combined with or without excision surgery]. / Rechutes locorégionales d'adénocarcinomes du rectum traitées par irradiation associée ou non à une chirurgie d'exérèse.

PURPOSE: Retrospective study to analyze the results of external beam radiation treatment with or without surgery for loco-regional recurrence of adenocarcinoma of the rectum following previous surgery without pre- or post-operative radiotherapy. PATIENTS AND METHODS: Between March 1973 and November 1991, 211 patients with loco-regional recurrence of rectum cancer were treated with external beam radiation treatment. Radical surgery was the only initial treatment modality. Surgical resection of local recurrence was done in 36 patients and only 17 patients could undergo complete resection. Forty-seven patients underwent radiotherapy (RT) combined with surgery and 164 received external beam radiation treatment alone to a mean total dose of 46 Gy. RESULTS: Among the 151 patients whose recurrence was revealed by pain, 64 (42%) were considered to have a complete symptomatic response after loco-regional treatment with radiosurgery or RT alone. The mean duration of response was 12 months. The 3-year overall survival rate was 16%. Five prognostic factors decreased the overall survival rate in multivariate analysis: high age, sex (male), concomitant distant metastasis, no tumor resection, and low total radiation dose with external beam radiation treatment alone. The 3-year overall survival rate for patients with completely resected recurrences was 39%. CONCLUSION: External beam RT treatment can only be considered a palliative symptomatic treatment. New techniques of early detection of local recurrence and new combined modalities approaches (radiation sensitizers or intra-operative radiotherapy) with surgical resection in some favorable cases should be studied.

[Endometrial adenocarcinoma treated with combined radiotherapy and surgery: 437 cases]. / Adénocarcinome de l'endomètre traité par association radiochirurgicale: à propos de 437 cas.

PURPOSE: To identify prognostic factors and treatment toxicity in a series of operable endometrial adenocarcinomas. PATIENTS AND METHODS: Between November 1971 and October 1992, 437 patients (pts) with endometrial carcinoma, staged according to the 1988 FIGO staging system, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy without (n = 140) or with (n = 297) pelvic lymph node dissection. The chronology of RT was not randomized and depended on the usual practices of the surgical teams. Group I: 79 pts received preoperative uterovaginal brachytherapy (mean total dose [MD]: 57 Gy). Group II: 358 pts received postoperative RT (196 pts received vaginal brachytherapy alone [MD: 50 Gy], 158 pts had external beam pelvis RT [EPRT] [MD: 46 Gy over 5 weeks] followed by vaginal brachytherapy [MD: 17 Gy], and 4 pts had EPRT alone [MD: 46 Gy over 5 weeks]). The mean follow-up was 128 months. RESULTS: The 10-year disease-free survival rate was 86%. From 57 recurrences, 12 were isolated locoregionally. Multivariate analysis showed that independent factors decreasing the probability of disease-free survival were: histologic type (clear cell carcinoma, p = 0.038), largest histologic tumor diameter > 3 cm (p = 0.015), histologic grade (p = 0.008), myometrial invasion > 1/2 (p = 0.0055), and 1988 FIGO staging system (p = 9.10(-8)). In group II, the addition of EPRT did not seem to improve locoregional control. The postoperative complication rate was 7%. The independent factors increasing the risk of postoperative complications were FIGO stage (p = 0.02) and pelvic lymph node dissection (p = 0.011). The 10-year rate for grade 3 and 4 late radiation complications according to the LENT-SOMA scoring system was 3.1%. EPRT independently increased the 10-year rate for grade 3 and 4 late radiation complications (R.R.: 5.6, p = 0.0096). CONCLUSION: EPRT increases the risk of late radiation complications. After surgical and histopathologic staging with pelvic lymph node dissection, in a subgroup of intermediate risk patients (stage IA grade 3, IB-C and II), postoperative vaginal brachytherapy alone is probably sufficient to obtain a good therapeutic index. Results for patients with stage III tumor are not satisfactory.

Automatic search for model to simulate the differentiation of T lymphocytes within the thymus.

The differentiation of T Lymphocytes within the thymus is an important biological phenomenon during which these cell acquire their functions to further control the immune system. Numerous experiments under various conditions have been devised to understand the different mechanisms involved in this complex process. Nevertheless, interpretation of these experiments lead to still contradictory debatable hypotheses. Modelisation of this process through classical simulation methods cannot be envisaged because they are not adapted to modifications of the model structure, which is the point of interest. For these reasons, we proposed a new approach of automatic search for model. The program consists of four independent connected modules: The generator produces model, based on the rationale of formal grammars. Protocol and experimental data are stored in a set of experiments. The simulator using a protocol and a model provides simulated results. Finally, the supervisor by comparing simulated results and experimental data, adapts the model parameters to increase their fit and either chooses a new experiment to explore, or modifies the model structure. Change of the model structure is performed among still unexplored models according to their "promise" level, which is iteratively evaluated relatively to previously explored models through a proposed model distance. The generator is written in Prolog and the other modules in C++. The architecture of the program allows us to modify or complete a module without changing anything in the other modules. As a consequence, the proposed modeling approach conceived to study T lymphocyte differentiation within the thymus remains independent of this biological phenomenon and can be applied to other biological problems.

"Iso-depth contour map" of a molecular surface.

The representation and display of protein surfaces are useful in many areas of molecular modeling, and surface shape study is particularly important in the analysis of protein-ligand interactions. We introduce here the notion of the molecular surface convex hull, allowing the depth of any molecular surface point to be defined. A two-dimensional (2D) map, the iso-depth contour map, and a three-dimensional (3D) representation, the iso-depth lines, allow the topography of a molecular surface to be displayed in terms of knobs (high depth) and holes (low depth).

Modeling the hepatitis C virus epidemic in France.

A backcalculation approach allows a reconstruction of the history of hepatitis C virus (HCV) infection in France and predictions of mortality from hepatocellular carcinoma (HCC) related to the virus. The model uses information from the literature about the natural history of the disease, epidemiological data about infected subjects in three French cohorts, and mortality data from national statistics. It seeks to determine the annual transition probabilities from chronic hepatitis to cirrhosis and the HCV incidence per year in the past. These unknowns are found by fitting the observed deaths from HCC that are attributable to HCV. Optimal values for these unknowns then allow to project the number of HCC deaths attributable to HCV for each year through 2025 (for patients infected before 1996). The model traces the HCV epidemic in France back to around the 1940s. It predicts that HCC mortality related to HCV will continue to increase through 2020 in the absence of treatment, with a 150% increase in the yearly incidence among men and 200% among women. The model also confirms that progression to cirrhosis depends strongly on sex and age. At any age, the annual probability of progression is 10 times greater for men than for women. Moreover, for men aged between 61 and 70 years, this probability is 300 times greater than that for men aged between 21 and 40 years.

Assessment of genetic diversity in space by superimposition of a distorted geographic map with a spatial population clustering. Application to GM haplotypes of native Amerindian tribes.

The GM immunoglobulin (Ig) allotype distributions of 49 native Amerindian populations from North to South America were analysed by a new technique called 'Mobile Sites Method' (MSM). This allows the global interpretation of genetic diversity in space by means of a distorted geographic map called a 'genetic similarity map'. This approach has been improved by superimposing in the distorted geographic map both the haplotype set (represented by hypothetical populations having a 100% frequency of the haplotype considered) and the 'geography-genetics discontinuities' (i.e. the zones between homogeneous population clusters). This bidimensional representation completes the interpretation of the genetic distances between populations in terms of local genetic diversity and possible migrations. Our results concerning the spatial distribution of the Amerindian populations show: (i) a great interdependence of the geographic locations and the GM haplotype distributions (the importance of the geographic factor was checked with the usual technique of 'random sampling' and the percentage of explained distance variability decreases from 78% with the observed data to a level less than 67% with the random data); (ii) a parallelism between genetics and linguistics groups as indicated by the population clusters in the similarity map, and (iii) a complex distorted map revealing the presence of multiple population migrations and admixtures in the course of time. A particular distortion of South America suggests possible migrations by sea along the western and eastern coasts of Central America, or multiple migration waves without population admixture across Central America.

A strategy for finding regions of similarity in complete genome sequences.

MOTIVATION: Complete genomic sequences will become available in the future. New methods to deal with very large sequences (sizes beyond 100 kb) efficiently are required. One of the main aims of such work is to increase our understanding of genome organization and evolution. This requires studies of the locations of regions of similarity. RESULTS: We present here a new tool, ASSIRC ('Accelerated Search for SImilarity Regions in Chromosomes'), for finding regions of similarity in genomic sequences. The method involves three steps: (i) identification of short exact chains of fixed size, called 'seeds', common to both sequences, using hashing functions; (ii) extension of these seeds into putative regions of similarity by a 'random walk' procedure; (iii) final selection of regions of similarity by assessing alignments of the putative sequences. We used simulations to estimate the proportion of regions of similarity not detected for particular region sizes, base identity proportions and seed sizes. This approach can be tailored to the user's specifications. We looked for regions of similarity between two yeast chromosomes (V and IX). The efficiency of the approach was compared to those of conventional programs BLAST and FASTA, by assessing CPU time required and the regions of similarity found for the same data set. AVAILABILITY: Source programs are freely available at the following address: ftp://ftp.biologie.ens. fr/pub/molbio/assirc.tar.gz CONTACT: vincens@biologie.ens.fr, hazout@urbb.jussieu.fr

Conservative versus nonconservative treatment of epidermoid carcinoma of the anal canal for tumors longer than or equal to 5 centimeters. A retrospective comparison.

BACKGROUND: The role of radiotherapy alone in the sterilization of anal canal epidermoid carcinomas of 5 cm or more remains to be assessed. Thus, the outcomes of patients treated with radiotherapy alone (RT) versus those treated with preoperative radiotherapy and surgery (RS) were compared retrospectively. METHODS: Between 1972 and 1990, 185 patients were treated with curative intent either with RT alone (n = 147) or with RS (n = 38). The Mean tumor length was 6.18 +/- 1.14 cm and was significantly longer in the RS group (6.55 +/- 1.29 cm) than in the RT group (6.08 +/- 1.08 cm) (P = 0.02). The median follow-up was 77 +/- 57 months and 93 +/- 60 months (P = 0.23) for the RT and RS groups, respectively. For the RT group, the first course of radiotherapy was 40 to 45 Gy in the pelvis for 4 to 5 weeks; after a rest of 4 to 6 weeks, radiotherapy was boosted an additional 15 to 20 Gy for 2 weeks. The RS patients received 40 to 45 Gy in the pelvis for 4 to 5 weeks, then received surgery after a median period of 54 days. RESULTS: The overall 10-year cancer specific survival rates were 58% in the RT group and 66% in the RS group (P = 0.48). The T-stage 10-year cancer specific survival rates were 68% in the RT group and 67% in the RS group for T2 tumors (P = 0.96); 57% in the RT group and 53% in the RS group for T3 tumors (P = 0.85); and 42% in the RT group and 40% in the RS group for T4 tumors (P = 0.05). In the RS group, the local control rate was 75% (3/4) for T2 tumors; 74% (17/23) for T3 tumors; and 82% (9/11) for T4 tumors. In the RT group, the local control rate was 77% (34/44) for T2 tumors; 70% (58/82) for T3 tumors; and 60% (12/20) for T4 tumors. In the RT group, the anal conservation rate was 61% (27/44) for T2 tumors, 59% (48/82) for T3 tumors, and 55% (11/20) for T4 tumors. Local tumoral control and a functioning anus were present in 72 out of 147 (49%) patients [52% (23/44) for T2 patients, 52% (43/82) for T3 tumors, and 30% (6/20) for T4 patients]. In the RS group, the grade 3 complication rate was 9% (13/146) and in the RS group, 5% (2/38). CONCLUSION: For patients with T4 tumors, preoperative radiotherapy and surgery seemed to be better in terms of survival and local tumor control rate, but the difference was not significant probably because the number of patients in the RS group was small. For these large tumors, the treatment should probably be more aggressive, combining chemotherapy and radiation therapy, but the increase of local control in relation with the addition of cytotoxic chemotherapy to irradiation is not proved.

Radiation therapy with or without surgery in the management of low-grade brain astrocytomas. A retrospective study of 120 patients.

From 1977 to 1988, 120 consecutive patients with a diagnosis of low-grade astrocytoma were referred to our department for radiotherapy. Fourty-one patients (group 1) underwent surgery and post operative external radiation therapy (2 gross total resections and 39 subtotal resections). Sixty-nine patients underwent exclusive external radiotherapy (group 2). In ten patients, the irradiation was delivered by stereotactic implantation of iridium-192 wires into the tumor with or without external irradiation (group 3). Ten had pilocytic astrocytomas (mean age, 24 years) and twenty had microcystic astrocytomas (mean age, 35.4 years). The 5- and 10-year survival rates were 55.6% and 44.4%, respectively and 55% and 48%. Ninety astrocytomas were classified as "ordinary" astrocytoma (mean age, 36.8 years). The 5- and 10-year overall survival rates were 51% and 20.5%, respectively. The same probabilities at 5 and 10 years were 65% and 37% respectively, for group 1, 38.8% and 12.7% for group 2 and, 78.8 and 22.5% for group 3. In multivariate analysis, two prognostic factors had a significant impact on overall survival: IK score (IK < 90 vs IK > or = 90, p = 0.0001), surgical resection (surgical resection and post operative radiotherapy vs radiation therapy alone, p = 0.012). However, the patients who underwent surgical resection were those in the best condition, having tumors that were easily accessible and less invasive.