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Purpose: We evaluated whether biomarkers on baseline [ 18 F]-FDG PET/CT are associated with recurrence after surgery in patients with invasive breast cancer of no special type (NST)., Methods: In this retrospective single-center study, we included consecutive patients with non-metastatic breast cancer of NST who underwent [ 18 F]-FDG PET/CT before treatment, including surgery, between 2011 and 2016. Clinicopathological data were collected. Tumor SUVmax, total metabolic tumor volume (TMTV), and spleen- and bone marrow-to-liver SUVmax ratios (SLR, BLR) were measured from the PET images. Cut-off values were determined using predictiveness curves to predict 5-year recurrence-free survival (5y-RFS). A multivariable prediction model was developed using Cox regression. The association with stromal tumor-infiltrating lymphocytes (TILs) levels (low if <50%) was studied by logistic regression., Results: Three hundred and three women were eligible, including 93 (31%) with triple-negative breast carcinoma. After a median follow-up of 6.2 years, 56 and 35 patients experienced recurrence and death, respectively. The 5y-RFS rate was 86%. In multivariable analyses, high TMTV (>20 cm3) and high SLR (>0.76) were associated with shorter 5y-RFS (HR 2.4, 95%CI 1.3-4.5, and HR 1.9, 95%CI 1.0-3.6). In logistic regression, high SLR was the only independent factor associated with low stromal TILs (OR 2.8, 95%CI 1.4-5.7)., Conclusion: High total metabolic tumor volume and high spleen glucose metabolism on baseline [ 18 F]-FDG PET/CT were associated with poor 5y-RFS after surgical resection in patients with breast cancer of NST. Spleen metabolism was inversely correlated with stromal TILs and might be a surrogate for an immunosuppressive tumor microenvironment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical ("OSNew") biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA- patients (p adj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy ( p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA- patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163-) mostly residing in osteolytic territories and osteoid-matrix-associated CD68-/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets., Competing Interests: The authors declare no conflict of interest.

Introduction: Inflammatory Breast Cancer (IBC) is the most aggressive form of breast carcinoma characterized by rapid onset of inflammatory signs and its molecular fingerprint has not yet been elucidated., Objectives: The objective of this study was to detect both gene expression levels and alternate RNA splice variants specific for IBC., Methods: W e performed splice-sensitive array profiling using Affymetrix Exon Array and quantitative RT-PCR analyses in 177 IBC compared to 183 non-IBC. We also assessed the prognostic value of the identified candidate genes and splice variants., Results: A 5-splice signature ( HSPA8 , RPL10 , RPL4 , DIDO1 and EVL ) was able to distinguish IBC from non-IBC tumors (p<10 -7 ). This splice signature was associated with poor metastasis-free survival in hormone receptor-negative non-IBC (p=0.02), but had no prognostic value in IBC. PAM analysis of dysregulated genes in IBC compared to non-IBC identified a 10-gene signature highly predictive of IBC phenotype and conferring a poor prognosis in non-IBC. The genes most commonly upregulated in IBC were 3 hemoglobin genes able to reliably discriminate IBC from non-IBC (p<10 -4 ). Hb protein expression in epithelial breast tumor cells was confirmed by immunohistochemistry., Conclusion: IBC has a specific spliced transcript profile and is characterized by hemoglobin gene overexpression that should be investigated in further functional studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

Luminal androgen receptor (LAR) breast cancer accounts for 10% of all triple-negative breast cancers (TNBC). Anti-androgen therapy for this subtype is in development, but yields only partial clinical benefits. In this study, we aimed to characterize the genomic alterations of LAR TNBC, to analyze activation of the PI3K signaling pathway and to compare the response to PI3K pathway inhibitors with that to anti-androgen therapy in patient-derived xenografts (PDX) of LAR TNBC. Methods : Four LAR PDX models were identified, on the basis of their transcriptomic profiles, in a cohort of 57 PDX models of TNBC. The expression of AR -related genes, basal and luminal cytokeratins and EMT genes was analyzed by RT-PCR and IHC. AKT1 and PIK3CA mutations were identified by targeted NGS, and activation of the PI3K pathway was analyzed with a reverse-phase protein array. Three LAR PDXs with a PIK3CA or AKT1 mutation were treated with the AR inhibitor enzalutamide, a PI3K inhibitor, a dual PI3K-mTOR inhibitor and a mTORC1-mTORC2 inhibitor. Finally, we screened a clinical cohort of 329 TNBC for PIK3CA and AKT1 hotspot mutations. Results : LAR TNBC PDXs were significantly enriched in PIK3CA and AKT1 mutations, and had higher levels of luminal-androgen-like gene expression and a higher PI3K pathway protein activation score than other TNBC subtypes. Immunohistochemistry analysis revealed strong expression of the luminal cytokeratin CK18 and AR in three LAR PDX models. We found that mTOR and PI3K inhibitors had marked antitumor activity in vivo in PDX harboring genomic alterations of PIK3CA and AKT1 genes that did not respond to the AR antagonist enzalutamide. PIK3CA mutations were detected in more than one third of AR+ TNBC from patients (38%), and only 10% of AR-negative TNBC. Conclusion : Our results for PDX models of LAR TNBC resistant to enzalutamide indicate that PIK3CA and AKT1 are potential therapeutic targets., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The French phase 3 trial (OS 2006) testing zoledronic acid, an osteoclast inhibitor, with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma (OS). To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 pre-therapeutic biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages (TAMs), CD8 + lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint were assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with better overall survival ( p = 0.0025) and longer metastasis progression-free survival (MPFS, p = 0.0315) independently of metastatic status ( p = 0.002). Only a trend was observed for patients with high CD68-positive cells ( p = 0.0582). CD8 + staining was positive in >50% of cases with a median staining of 1%. Lower CD8 + levels were associated with metastatic disease at diagnosis and the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients ( p = 0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated with outcome. Finally, CD163-positive TAMs and CD8 positive cells are crucial prognostic biomarkers in OS, whereas PD1/PDL-1 checkpoint plays a minor role. For the first time, we described a correlation between CD8 positive cells and survival in zoledronate-treated patients. The immunohistochemical analysis of the microenvironment in biopsies may represent a novel tool for therapeutic stratification.

The objective of this study was to establish that the denaturing fixative, formalin and acetic acid (AFA), is equivalent to neutral-buffered formalin (NBF) on the nCounter system using the Prosigna assay. Twenty-five previously resected tumors from breast cancer patients were apportioned and fixed with either NBF or AFA prior to embedding in paraffin. Differentially fixed and paraffin embedded tissue pairs were sectioned and pathological review was performed according to the Prosigna assay protocol. RNA was isolated using the Prosigna assay kit and analyzed using the NanoString nCounter Dx Analysis system. 47 of the 50 blocks (94%) passed RNA quality control (QC) criteria and were collectively designated as the analysis set. We found that RNA yield and purity (A260/A280) were not significantly different between the fixatives within the analysis set. In the analysis of ROR score, the tissue pairs had a Pearson Correlation Coefficient of 0.91, similar to the correlation observed between paired tissue blocks using a single fixative in previous studies. Subtype concordance between differentially fixed tissue pairs was high (K=0.80). No significant bias or variability in risk of recurrence (ROR) score attributable to fixative was detected in this study. Further analysis revealed that sample pairs with larger differences in ROR score were limited to nearly-depleted tissue blocks containing large amounts of normal tissue due to proximity of the tumor margin. The results of this study demonstrate that the fixative, AFA, does not contribute significantly to bias and variability of assay results., (Copyright © 2017. Published by Elsevier B.V.)

Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target., Competing Interests: Compliance With Ethical Standards Grant Support This work was supported by the Conseil régional d’Ile-de-France, the Cancéropôle Ile-de-France, the Comité départemental des Hauts-de-Seine de la Ligue Nationale Contre le Cancer and the Association pour la recherche en cancérologie de Saint-Cloud (ARCS), and by grant INCa-DGOS-4654. Conflict of Interest The authors declare no conflict of interest.

Background: Inconsistencies between mitotic index (MI) and Ki67 measures have been identified in many breast tumour samples. The aim of this study was to describe the prognosis of hormone receptor-positive (HR+) HER2- tumours having discrepant MI and Ki67., Methods: We included a cohort of breast cancer patients initially treated by surgery between 2001 and 2005 in the Institut Curie. Breast cancer-specific survival (BCSS) and disease-free survival (DFS) were analysed according to three proliferation groups: high MI/high Ki67 (MI=3, Ki67>20%), low MI/low Ki67 (MI<3, Ki67⩽20%) and discrepant (high MI/low Ki67 or low MI/high Ki67)., Results: Among the 1430 patients, 19.6% had discrepant Ki67 and MI, 11.6% had high markers and 68.8% had low markers. The 5-year BCSS was 95.8%, 95% CI (0.93-0.98) in the discrepant group, 99.3%, 95% CI (0.993-0.999) in the low-proliferation group and 91.8%, 95% CI (0.88-0.96) in the high-proliferation group. In multivariate analysis, the survival of the discrepant group was lower than that of the low-proliferation group: BCSS hazard ratio (HR)=3.01 (1.32-6.84; P=0.008) and DFS HR=2.07, 95% CI (1.31-3.26; P=0.002). Among grade 2 tumours in multivariate analysis, DFS of the discrepant group was lower than that of the low MI/low Ki67 group: HR=1.98, 95% CI (1.14-3.46), P=0.02. Regarding BCSS, the obtained results were similar., Conclusion: The prognosis of patients with discrepant MI and Ki67 appears intermediate between that of low MI/low Ki67 and high MI/high Ki67 groups. These markers should be jointly analysed to clarify prognosis.

KRAS mutation testing is mandatory for patients with metastatic colorectal cancer who are eligible for treatment with an epidermal growth factor receptor targeting agent, since tumors with a mutation are not sensitive to the drug. Several methods for mutation testing are in use and the need for external quality assurance has been demonstrated. An often little addressed but important issue in external quality assurance schemes is a low percentage of tumor cells in the test samples, where the analytical sensitivity of most tests becomes critical. Using artificial samples based on a mixture of cell lines with known mutation status of the KRAS gene, we assessed the reliability of a series of commonly used methods (Sanger sequencing, high resolution melting, pyrosequencing, and amplification refractory mutation system-polymerase chain reaction) on samples with 0, 2.5, 5, 10, and 15 % mutated cells. Nine laboratories throughout Europe participated and submitted a total of ten data sets. The limit of detection of each method differed, ranging from >15-5 % tumor cells. All methods showed a decreasing correct mutation call rate proportionally with decreasing percentage of tumor cells. Our findings indicate that laboratories and clinicians need to be aware of the decrease in correct mutation call rate proportionally with decreasing percentage of tumor cells and that external quality assurance schemes need to address the issue of low tumor cell percentage in the test samples.

Flat epithelial atypia (FEA) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. We retrospectively reviewed the data for 271 FEA cases among 5,555 breast core biopsies obtained over a 7-year period (January 2003-2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. The 271 FEA comprised 128 cases of pure FEA, 135 cases of FEA + atypical ductal hyperplasia, and 8 cases of FEA + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. The presence of FEA at biopsy warrants surgery.

Introduction: To decipher the interaction between the molecular subtype classification and the probability of a non-sentinel node metastasis in breast cancer patients with a metastatic sentinel lymph-node, we applied two validated predictors (Tenon Score and MSKCC Nomogram) on two large independent datasets., Materials and Methods: Our datasets consisted of 656 and 574 early-stage breast cancer patients with a metastatic sentinel lymph-node biopsy treated at first by surgery. We applied both predictors on the whole dataset and on each molecular immune-phenotype subgroups. The performances of the two predictors were analyzed in terms of discrimination and calibration. Probability of non-sentinel lymph node metastasis was detailed for each molecular subtype., Results: Similar results were obtained with both predictors. We showed that the performance in terms of discrimination was as expected in ER Positive HER2 negative subgroup in both datasets (MSKCC AUC Dataset 1 = 0.73 [0.69-0.78], MSKCC AUC Dataset 2 = 0.71 (0.65-0.76), Tenon Score AUC Dataset 1 = 0.7 (0.65-0.75), Tenon Score AUC Dataset 2 = 0.72 (0.66-0.76)). Probability of non-sentinel node metastatic involvement was slightly under-estimated. Contradictory results were obtained in other subgroups (ER negative HER2 negative, HER2 positive subgroups) in both datasets probably due to a small sample size issue. We showed that merging the two datasets shifted the performance close to the ER positive HER2 negative subgroup., Discussion: We showed that validated predictors like the Tenon Score or the MSKCC nomogram built on heterogeneous population of breast cancer performed equally on the different subgroups analyzed. Our present study re-enforce the idea that performing subgroup analysis of such predictors within less than 200 samples subgroup is at major risk of misleading conclusions.

Background: We studied HER-2 expression in paired serum and tissue samples, in 157 selected cases from 701 consecutive primary breast cancer patients with pre-treatment HER-2 extracellular domain (ECD) > or = 10 ng/ml, or < 10 ng/ml but showing a HER-2 ECD lead time before first metastasis., Patients and Methods: HER-2 ECD was measured by the Immuno 1 automated ELISA (Bayer). Tumour tissue was analysed by immunohistochemistry (IHC) with Dako A 0485 and CB 11 antibodies and scored with the Dako scoring system., Results: Mean HER-2 ECD was 12.48+/-7.08 ng/ml and 21/157 (13.4%) sera were > or = 15 ng/ml (cut-off). Forty tumours (25.48%) showed both invasive and intraductal components, 3 (1.91%) were pure in situ carcinomas and 114 (72.61%) were pure invasive tumours. Elevated HER-2 ECD concentration was related only to pT (p=0.0008), histological grade (p=0.0465), presence of comedonecrosis (p=0.0123) or comedo-type carcinoma (p=0.041) and was unrelated to the presence of an intraductal component. HER-2 ECD was > or = 15 ng/ml in 48% of Dako 3+ and 60% of CB 11 2+ and 3+ tumours. By logistic regression analysis, the significant parameters associated with HER-2 ECD concentration were pT (p=0.0038) and Dako 3+ scores (p=0.0005). In Dako 3+ or CB 11 2+3+ tumours, elevated mean HER-2 ECD concentrations were observed only when pT exceeded 28-30 mm (p=0.0062 and p=0.0036, respectively)., Conclusion: In breast tumours, a threshold in size and HER-2 overexpression is necessary to observe elevated concentrations of HER-2 ECD at diagnosis. This information may be useful when the primary tumour is not available for IHC.

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy.

Purpose: To describe the pathologic characteristics and prognostic factors of primary breast sarcomas (PBSs)., Patients and Methods: We reviewed the clinical records and pathologic slides of 83 women with PBS treated in our institution between 1954 and 1991, with a median follow-up of 7.8 years. The majority of patients had undergone surgical treatment., Results: The main histologic type was malignant fibrohistiocytoma (n = 57). For the whole population, the 10-year overall survival (OS) and disease-free survival (DFS) rates were 62% and 50%, respectively. For Fédération Nationale des Centres de Lutte Contre le Cancer grade 1, 2, and 3 tumors, the 10-year OS and DFS rates were 82% and 61%, 62% and 51%, and 36% and 25%, respectively (P =.00007 and.004, respectively). For tumors measuring less than 5 cm, 5 to 10 cm, and more than 10 cm, the 10-year OS and DFS rates were 76% and 66%, 68% and 55%, and 28% and 15%, respectively (P =.002 and.009, respectively). In the multivariate analysis, the tumor size and histologic grade were correlated with the 10-year DFS rate (P =.04 and.01, respectively), but only the histologic grade was correlated with OS (P =.01). Angiosarcoma was the only histologic type significantly associated with a poorer outcome in the multivariate analysis., Conclusion: PBSs have the same clinical history and prognostic factors as sarcomas arising at other sites. Therefore, it is legitimate to use a similar treatment strategy for PBS as for other sarcomas.

Background: Liver metastases (LM) from breast cancer are generally considered as disseminated disease with a poor prognosis. However in selected patients hepatectomy may be an important adjunct to systemic treatment., Methods: Fifty-four breast cancer patients (mean age 49.2 +/- 5.2 years) with LM as the sole site of metastatic disease (except for bone metastases in 3 patients) underwent hepatectomy between 1986 and 2000. The mean number of LM was 4.0 +/- 8. All patients presented either a stable disease or an objective response to chemotherapy. The last 25 patients also underwent hepatic artery catheter installation in order to receive postoperative hepatic artery infusion chemotherapy (HAIC)., Results: The postoperative morbidity was 12.9%. There was no postoperative mortality. R0 and R1-R2 resections were obtained in, respectively, 81.5% and 18.5% of patients. After a median follow-up of 32 months the median survival was 34 +/- 9 months, with 3- and 5-year overall survival rates of 50% and 34%, and 3- and 5-year disease-free survival rates of 42% and 22%, respectively. The number of LM, the presence of hilar lymph nodes (33%), and the completeness of resection had no significant prognostic impact. The only factor influencing survival in both the univariate and multivariate analysis was the hormone receptor status (P = 0.03): the relative risk of death was increased by 3.5-fold when negative. In the HAIC group, the liver recurrence rate decreased from 60.5% to 31.2% without any impact on global survival., Conclusions: Hepatectomy is beneficial for selected patients with isolated LM. Indications should be based more on technical (low operative risk, probable R0 resection) than on oncologic criteria. The decision is simple for young patients but more difficult for older patients in whom a negative hormone receptor status appears to be a contraindication.

Background: Epstein-Barr virus (EBV) may be a cofactor in the development of different malignancies, including several types of carcinomas. In this study, we investigated the presence of EBV in human breast cancers., Methods: We used tissues from 100 consecutive primary invasive breast carcinomas, as well as 30 healthy tissues adjacent to a subset of the tumors. DNA was amplified by use of the polymerase chain reaction (PCR), with the primers covering three different regions of the EBV genome. Southern blot analysis was performed by use of a labeled EBV BamHI W restriction fragment as the probe. Infected cells were identified by means of immunohistochemical staining, using monoclonal antibodies directed against the EBV nuclear protein EBNA-1., Results: We were able to detect the EBV genome by PCR in 51% of the tumors, whereas, in 90% of the cases studied, the virus was not detected in healthy tissue adjacent to the tumor (P<.001). The presence of the EBV genome in breast tumors was confirmed by Southern blot analysis. The observed EBNA-1 expression was restricted to a fraction (5%-30%) of tumor epithelial cells. Moreover, no immunohistochemical staining was observed in tumors that were negative for EBV by PCR. EBV was detected more frequently in breast tumors that were hormone-receptor negative (P =.01) and those of high histologic grade (P =.03). EBV detection in primary tumors varied by nodal status (P =.01), largely because of the difference between subjects with more than three lymph nodes versus less than or equal to three lymph nodes involved (72% versus 44%)., Conclusions: Our results demonstrated the presence of the EBV genome in a large subset of breast cancers. The virus was restricted to tumor cells and was more frequently associated with the most aggressive tumors. EBV may be a cofactor in the development of some breast cancers.

Rationale and Objectives: To determine the capacity of color and spectral Doppler ultrasonography (US) to quantify angiogenesis in vivo and to characterize low-resistance intratumor blood flow., Methods: Thirty-two tumors, xenografted into mice, were studied with Doppler US. The number of intratumor vessels visualized with color Doppler US was compared with the density of microvessels and the number of vessels >100 microm determined by histologic examination. The resistance index and the peak systolic velocities were evaluated., Results: The number of intratumor vessels visualized by color Doppler US was correlated with the number of vessels >100 microm (P<0.001) determined histologically. When vessel density was >30, intratumor vessels were always detected by color Dopper US. The resistance index and peak systolic velocities were significantly lower in intratumor than in peritumor vessels., Conclusions: Color Doppler US evaluated tumor angiogenesis accurately. Spectral analysis confirmed the low resistance of intratumor blood flow.

Objective: To quantitate initial mammographic signs and to describe post-therapeutic patterns of inflammatory breast cancer., Material and Methods: Two radiologists retrospectively analyzed the initial clinical and mammographic findings of 92 patients with inflammatory breast carcinoma. The post-therapeutic mammogram (n = 75) was considered abnormal when focal opacity and or malignant-type microcalcifications were still visible., Results: Redness of the skin, "peau d'orange' and increased temperature were the most common findings. A palpable mass was noted in 97% with axillary lymph node involvement in 83% of cases. All initial mammograms were abnormal. Isolated inflammatory signs were observed in 14% and malignant signs in 86% of patients (opacity = 77% and/or malignant-type microcalcifications = 47%). Skin thickening was seen in 93.5%, nipple inversion in 56.5%, increased breast density in 93.5%, stromal coarsening in 85% and hypervascularisation in 32.5% of mammograms. On post-therapeutic mammograms, 35 patients (46.5%) were suspected of having residual disease. During follow-up, 19 patients (25.3%) relapsed locally: 75% had abnormal post-therapeutic mammograms., Conclusion: The presence of isolated inflammatory signs on the mammogram is sufficient to suspect inflammatory breast carcinoma and biopsy must be performed in doubtful cases. Radical surgery is indicated when persistent malignant signs are still visible on mammogram after conservative treatment.

The existence of two subgroups of BRCA1-associated breast cancer (BC) families has been recently posited: the first with highly proliferating tumors, and the second composed of cases with a low proliferation rate. Our aim was to test whether the proliferation rate of BRCA1-associated breast cancers was affected by the site of the germ line mutation in the BRCA1 gene. We analyzed the distribution of the mitotic index, a histoprognostic grade component shown to segregate in families, matching for germ line mutation location in a series of 28 breast cancers from 20 kindreds. We observed a prevalence of highly proliferating tumors when the mutation occurs in the two terminal conserved domains of the BRCA1 protein, ie., in the amino and carboxyl termini (P = 0.0024). Our data provide evidence for a genotype-phenotype correlation and along with their strong conservation during evolution argue for the importance of these two regions in the control of mammary cell growth.