Upper outer boundaries of the axillary dissection. Result of the SENTIBRAS protocol: Multicentric protocol using axillary reverse mapping in breast cancer patients requiring axillary dissection.

BACKGROUND: Two thirds of node-positive breast cancer patients have limited pN1 disease and could benefit from a less extensive axillary lymph node dissection (ALND). METHODS: 172 breast cancers patients requiring an ALND were prospectively enrolled in the Sentibras Protocol of Axillary Reverse Mapping (ARM). Radioisotope was injected in the ipsilateral hand the day before surgery. ALND was standard. Removed lymph nodes were classified into non radioactive nodes and radioactive nodes (ARM nodes). Among ARM nodes, nodes located in the upper outer part of the axilla, above the second intercostal brachial nerve and lateral to the lateral thoracic vein were identified as "zone D ARM nodes". The main objective was: feasibility of identification of the zone D ARM nodes. Secondary objectives were: metastatic involvement and lymphedema rate. RESULTS: 100% of patients had ARM nodes identified. The "zone D ARM nodes" were identified in 92% of cases. The rate of metastatic nodes was 60% in the all cohort, 31% in ARM nodes and 9% in zone D ARM nodes. Among those, metastatic rate was 6% in patients undergoing ALND for a positive sentinel node biopsy, 6% in case of primary ALND versus 14% after neo-adjuvant chemotherapy (p < 0.05). After 34 months of median follow up, 27% of interviewed patients had a lymphedema. CONCLUSION: The ARM technique reliably identifies the "zone D ARM nodes". These nodes can also easily be identified using knowledge of axillary anatomy. In selected patients, a selective ALND sparing the zone D ARM nodes could be performed.

Quality indicators in ovarian cancer surgery: report from the French Society of Gynecologic Oncology (Societe Francaise d'Oncologie Gynecologique, SFOG).

BACKGROUND: Based on registries, the European experience has been that <50% of patients are treated according to protocols and/or benefit from the minimum required surgery for ovarian cancer. The French Cancer Plan 2009-2013 considers the definition of qualitative indicators in ovarian cancer surgery in France. This endeavour was undertaken by the French Society of Gynaecologic Oncology (SFOG) in partnership with the French National College of Obstetricians and Gynecologists and all concerned learned societies in a multidisciplinary mindset. METHODS: The quality indicators for the initial management of patients with ovarian cancer were based on the standards of practice determined from scientific evidence or expert consensus. RESULTS: The indicators were divided into structural indicators, including material (equipment), human (number and qualification of staff), and organizational resources, process indicators, and outcome indicators. CONCLUSIONS: The enforcement of a quality assurance programme in any country would undoubtedly promote improvement in the quality of care for ovarian cancer patients and would result in a dramatic positive impact on their survival. Such a policy is not only beneficial to the patient, but is also profitable for the healthcare system.

A nomogram to predict individual prognosis in node-negative breast carcinoma.

BACKGROUND: Currently, the benefit of chemotherapy (CT) in node-negative breast carcinoma (NNBC) is discussed. The evaluation of classical clinical and histological factors is limited to assess individual outcome. A statistical model was developed to improve the prognostic accuracy of NNBC. METHODS: A total of 305 node-negative breast carcinomas who underwent surgery (+/- radiotherapy) but no adjuvant treatment were selected. Putative prognosis factors including age, tumour size, oestrogen receptor (ER), progesterone receptor (PgR), Scarff-Bloom-Richardon (SBR) grading, urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and thymidine kinase (TK) were evaluated. The developed model was internally validated using Harrell's concordance index. A prognosis index (PI) was proposed and compared with Adjuvant! Online program. RESULTS: Age (p < 0.001), pathological tumour size (pT) (p < 0.001), PgR (p = 0.02), and PAI-1 (p ≤ 0.001) were included in the Cox regression model predicting Breast cancer specific survival (BCSS) at 5-years. Internal validation revealed a concordance index of 0.71. A PI score was derived from our nomogram. The PI score was significantly associated with BCSS (hazard ratio (HR): 4.1 for intermediate, p=0.02, HR: 8.8, p < 0.001 for high group) as compared to Adjuvant! Online score (HR: 1.4, p=0.14). CONCLUSION: A nomogram can be used to predict probability survival curves for individual breast cancer patients.

Epstein-Barr virus as a marker of biological aggressiveness in breast cancer.

PURPOSE: Although a potential role of the Epstein-Barr virus (EBV) in the pathogenesis of breast cancer (BC) has been underlined, results remain conflicting. Particularly, the impact of EBV infection on biological markers of BC has received little investigation. METHODS: In this study, we established the frequency of EBV-infected BC using real-time quantitative PCR (RT-PCR) in 196 BC specimens. Biological and pathological characteristics according to EBV status were evaluated. RESULTS: EBV DNA was present in 65 of the 196 (33.2%) cases studied. EBV-positive BCs tended to be tumours with a more aggressive phenotype, more frequently oestrogen receptor negative (P=0.05) and with high histological grade (P=0.01). Overexpression of thymidine kinase activity was higher in EBV-infected BC (P=0.007). The presence of EBV was weakly associated with HER2 gene amplification (P=0.08). CONCLUSION: Our study provides evidence for EBV-associated BC undergoing distinct carcinogenic processes, with more aggressive features.

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome.

BACKGROUND: c Kit (CD117) expression in tissues has been reported as a relevant target for specific therapy in some human malignancies, but has been poorly documented in breast carcinomas. METHODS: The prognostic significance of c Kit in a series of 924 breast carcinomas (mean follow-up, 79 months) was investigated using standardised high-throughput quantitative densitometry of immunohistochemical precipitates in tissue microarrays. RESULTS: c Kit was expressed in 14.7% breast carcinomas (and in 42 out of 586 node-negative tumours). In univariate analysis, (log-rank test) the score of c Kit expression correlated with poor patient outcome P=0.02 and particularly in node-negative cases (P=0.002). In multivariate Cox analysis, c Kit was an indicator of metastasis independent of 25 other concomitantly evaluated markers of prognosis. Logistic regression showed that c Kit ranked 10 out of 25 (P=0.041), and was included in a 10-marker signature that allowed 79.2% of the patients to be correctly classified in the metastatic or metastasis-free categories independently of hormone receptors and HER-2 status. Interestingly, c Kit was also a significant predictor of metastasis in node-negative tumours (2 out of 25 ranking, P<0.0001) and included in a six-marker signature of prognosis, correctly classifying 88.6% of the patients (P<0.0001). CONCLUSION: We concluded that, as assessed by quantitative immunohistochemistry, c Kit is an independent prognostic indicator that could also potentially serve as a target for specific therapy in breast carcinomas.

A nomogram predictive of non-sentinel lymph node involvement in breast cancer patients with a sentinel lymph node micrometastasis.

PURPOSE: Predictive factors of non-sentinel lymph node (NSN) involvement at axillary lymph node dissection (ALND) have been studied in the case of sentinel node (SN) involvement, with validation of a nomogram. This nomogram is not accurate for SN micrometastasis. The purpose of our study was to determine a nomogram for predicting the likelihood of NSN involvement in breast cancer patients with a SN micrometastasis. METHODS: We collated 909 observations of SN micrometastases with additional ALND. Characteristics of the patients, tumours and SN were analysed. RESULTS: Involvement of SN was diagnosed 490 times (53.9%) with standard staining (HES) and 419 times solely on immunohistochemical analysis (IHC) (46.1%). NSN invasion was observed in 114 patients (12.5%), whereas 62.3% (71) had only one NSN involved and 37.7% (43) two or more NSN involved. In multivariate analysis, significant predictive factors were: tumour size (pT stage < or = 10 mm or >11 and < or = 20 or >20 mm [odds ratio (OR) 2.1 and 3.43], micrometastases detected by HES or IHC [OR 1.64], presence or absence of lymphovascular invasion (LVI) [OR 1.76], tumour histological type mixed or not [OR 2.64]. The rate and probability of NSN involvement with the model are given for 24 groups, with a representation by a nomogram. CONCLUSION: One group, corresponding to 10.1% of the patients, was associated with a risk of NSN involvement of less than 5%, and five groups, corresponding to 29.8% of the patients, were associated with a risk < or = 10%. Omission of ALND could be proposed with minimal risk for a low probability of NSN involvement.

Concomitant intensive chemoradiotherapy induction in non-metastatic inflammatory breast cancer: long-term follow-up.

The aim of this study was to evaluate with a long follow-up the efficacy of concomitant chemoradiotherapy in non-metastatic inflammatory breast cancer (IBC) and to evaluate the breast conservation rate. Between 1990 and 2000, 66 non-metastatic patients with IBC were treated with chemotherapy and concomitant irradiation. The induction chemotherapy consisted of epirubicine, cyclophosphamide and vindesine, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and 5-fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and six cycles of epirubicine, cyclophosphamide and fluorouracil. Hormonal treatment was given if indicated. Mastectomy was not systemic. Among 65 evaluable patients, 57 (87.6%) achieved a complete clinical response and had a breast conservation. Only six loco regional relapses were noted in six patients with a delay of 20 months and with concomitant metastatic dissemination in four cases. Median disease-free survival (DFS) was 28 months. Median overall survival (OS) was 63 months and median follow-up was 55.5 months. Induction chemotherapy and concomitant irradiation is feasible in patients with IBC, permitting a breast conservation with a high rate of local control with an OS comparable to that of the best recent series.

c-Met overexpression in inflammatory breast carcinomas: automated quantification on tissue microarrays.

Inflammatory breast carcinoma (IBC) is a rare but aggressive tumour associated with poor outcome owing to early metastases. Increased expression of c-Met protein correlates with reduced survival and high metastatic risk in human cancers including breast carcinomas and is targetable by specific drugs, that could potentially improve the prognosis. In the present study, we compared c-Met expression in IBC (n=41) and non-IBC (n=480) immunohistochemically (Ventana Benchmark autostainer) in two tissue microarrays (TMA) along with PI3K and E-cadherin. The results were quantified through an automated image analysis device (SAMBA Technologies). We observed that (i) c-Met was significantly overexpressed in IBC as compared with non-IBC (P<0.001), (ii) PI3K was overexpressed (P<0.001) in IBC, suggesting that the overexpressed c-Met is functionally active at least through the PI3K signal transduction pathway; and (iii) E-cadherin was paradoxically also overexpressed in IBC. We concluded that overexpressed c-Met in IBC constitutes a potential target for specific therapy for the management of patients with poor-outcome tumours such as IBC. Automated image analysis of TMA proved to be a valuable tool for high-throughput immunohistochemical quantification of the expression of intratumorous protein markers.

[Regression models for crude and relative survival: a comparative review]. / Revue comparative des modèles régressifs de survie brute et de survie relative.

BACKGROUND: Statistical analysis of lifetime data is frequently used in the biomedical area. Our objective was to present a comparative review of the different regression models according to the survival concept (crude survival or relative survival) in order to express guidelines. METHODS: From a methodological point of view, we compared a regressive crude survival model (Cox model) and regressive relative survival models for grouped data (Hakulinen and Tenkanen) and for individuals data (Esteve et al.). We illustrated our work with an analysis of survival data of 3,355 incident cases of breast cancer identified by a hospital registry. Comportment of the models was studied in situation where censors rates ranged from 31.7 to 96.5%. RESULTS: Because relative survival analysis takes into account natural mortality, the risk of death was smaller for women older than 50 years than for women aged from 35 to 49; this was not demonstrated in the crude survival analysis (Cox). Estimations obtained from Cox model were more accurate than those obtained from both studied regressive relative survival models. Estimations obtained from Esteve et al. model were not very different from those obtained from Hakulinen and Tenkanen model and they were more accurate. CONCLUSION: By definition, analysis of relative survival is more appropriate to estimate survival to a specific cause of death. It is preferable to use models based on individual estimation when data set is small or when the number of individual per strata is small.

[Breast carcinoma diagnosed from surgical specimens. Retrospective study on three years]. / Cancer du sein diagnostiqué par la réduction mammaire. Etude rétrospective sur une période de trois ans.

In the wake of three consecutive cases of microscopical examination of resection specimens following breast reduction revealing an adenocarcinoma, we wanted to point out the interest of a complete preoperative senological examination including mammography and postoperative anatomopathological examination. A retrospective study concerning 837 patients over a three-year period was conducted. We found seven patients (0.83%) with malignant breast cancer diagnosed on anatomopathological examination, which is comparable to the incidence found in literature. Of these seven cases there were four ductal adenocarcinomas (0.47%), all of them in situ (DCIS), and three lobular adenocarcinomas (0.36%) of which one invasive (ILA), one in situ (LCIS) and one mixed. The majority was aggressive, multifocal and bilateral. Treatment consisted of mastectomy with or without adjuvant therapy with curative intent in five out of seven cases, and this within two months after a esthetic surgery. In our opinion this shows that breast reduction can help in tracking down breast cancer and underlines the need for systematic and meticulous microscopic examination of resection specimens after breast reduction.

Prediction of metastasis risk (11 year follow-up) using VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 expression in breast cancer (n=905).

Neoangiogenesis in tumours contributes to the development of blood-borne metastases, and can be evaluated by markers of activated endothelial cells in preference to panendothelial markers. Our purpose was to document the prognostic significance of VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 immunoexpression in breast carcinoma frozen samples (n=905, follow-up=11.7 years). We observed that: (i). CD105 (P=0.001) and Tie-2/Tek (P=0.025) (but not VEGF-R1 and VEGF-R2) overexpression correlated with a shorter survival, and were (Cox's model) independent histoprognostic indicators; (ii). only CD105 marked expression correlated (P=0.035) with a shorter survival of node-negative patients; (iii). three markers - CD105 (P=0.001), Tie-2/Tek (P=0.01), VEGF-R1 (P=0.001), but not VEGF-R2 - correlated with metastatic risk in node-negative patients in univariate analysis; and (iv). VEGF-R1 (P=0.01) expression correlated with high local recurrence risk. It is concluded that CD105 and to a lesser extent Tie-2/Tek and VEGF-R1, but not VEGF-R2 are endowed with prognostic significance that may be useful for patient monitoring, particularly CD105 expression for selecting node-negative patients for more aggressive postsurgery therapy.

Mutation analysis in the coding sequence of thymidine kinase 1 in breast and colorectal cancer.

We report the first mutational study of thymidine kinase 1 (TK1) performed in human solid tumors. We sequenced cDNAs representing the complete coding region of TK1 in human breast (n=22) and colorectal (n=26) cancer. Codon 106 near the ATP binding site constantly differed (ATG --> GTG; Met --> Val) from the one deposited by Bradshaw and Deininger in the Genbank database (Accession number NM_003258). Silent polymorphisms at codon 11 (CCC --> CCT; Pro --> Pro) and codon 75 (GCG --> GCA; Ala --> Ala) were frequently detected in tumors as well as in normal tissues. In breast cancer the two polymorphisms were observed in 63.6% of the samples analyzed. No significant association could be found between polymorphisms and TK activity. In colorectal cancer the incidence of the two changes was 73.1% and 69.2%, respectively. Interestingly, one colon cancer with high cytosolic TK activity displayed two missense mutations located in and near the putative phosphorylation site by tyrosine kinase (s) (TAT --> CAT; Tyr --> His) and by cAMP-, cGMP-dependent protein kinase (TAC --> TGC; Tyr --> Cys), respectively; adjacent normal mucosa showed no mutation. This may open new avenues that imply TK1 activity in tumor cell proliferation.

Bayesian population model of methotrexate to guide dosage adjustments for folate rescue in patients with breast cancer.

BACKGROUND: Methotrexate (MTX) infusions may induce severe side-effects, and alkaline hydration along with folinic acid rescue is a common way to reduce such toxic risks. The purpose of this study was to develop an adaptive rescue strategy based upon the early detection of patients with impaired MTX elimination. METHODS AND RESULTS: In this study, we propose a simple population-based Bayesian approach for predicting MTX plasma concentration from a limited number of samples, so as to adapt both duration and dosage of the rescue agent to be used next. Ten kinetic profiles obtained after 10 courses of MTX (1.5 g/m2) in seven patients with inflammatory breast cancer were used to establish the population pharmacokinetic parameters (Cl, 8.16 L/h; t1/2, 12.7 h). This population was next involved in the Bayesian estimation of MTX individual pharmacokinetic parameters from only two blood samples (T24 and T36 h), thus allowing one to forecast the elimination of this drug by predicting MTX levels at 48 h. According to the MTX concentrations predicted during the elimination phase, folinic acid rescue was then prolonged in patients likely to be overexposed. CONCLUSION: The Bayesian estimation presented in this study was an easy and convenient method to efficiently detect patients with impaired MTX elimination in routine clinical practice. This information enabled the introduction of strategies for minimizing the risk of severe drug toxicity.

Chemotherapy and concomitant irradiation in inflammatory breast cancer.

The purpose of this study was to evaluate the efficacy of concurrent chemotherapy and irradiation in inflammatory breast cancer (IBC). Between January 1990 and December 1998, forty-eight non-metastatic patients with clinical or occult IBC were treated with chemotherapy and irradiation. The induction chemotherapy consisted of epirubicin, cyclophosphamide and vindesin, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and 6 cycles of epirubicin, cyclophosphamide and fluorouracil Hormonal treatment was given routinely but mastectomies were not routinely performed. A high rate of locoregional control was obtained in 47 evaluable patients of whom 93.6 % achieved a complete clinical response. Three patients had locoregional relapses, always with concomitant metastatic dissemination. In 47 patients, 21 developed metastatic dissemination with a median delay of 23 months. Median disease-free survival (DFS) was 45 months. Median overall survival (OS) has not yet been reached after a median follow-up of 44.5 months. The 3-year DFS rate was 53 % and the 3-year OS rate was 71 %. Toxicity was mainly hematological. During the induction therapy, grade 3 or 4 neutropenia occurred in 54 % of patients, grade 3 or 4 thrombocytopenia in 23 % and grade 3 or 4 anemia in 8 %. The administration of induction chemotherapy and concomitant irradiation is feasible in patients with IBC. The hematological toxicity of this treatment approach is significant but nevertheless, the treatment achieves a high degree of locoregional control and improved survivaL

[Evaluation and treatment of endometrial cancer]. / Evaluation et traitement des cancers de l'endomètre.

Endometrial cancer is the most common gynaecologic cancer and its incidence increases with age. Prognosis is good because in over 80% of cases the cancer is discovered early. Preoperative work-up should include definition of the operability of such patients, who are often elderly with frequent co-morbidity. Preoperative evaluation and operative findings allow guiding the treatment and evaluating the prognosis. Main determinants are local extension, penetration into the myometrium, histologic stage of the tumour and involvement of lymph modes or peritoneum. Surgery is the first approach since it establishes the evaluation and comprises the first step of treatment. When necessary, subsequent treatment uses irradiation. Treatment with hormones or antimitotic drugs is less effective and is used for forms that are locally advanced, metastatic or recurrent after initial treatment.

Frequency and genome load of Epstein-Barr virus in 509 breast cancers from different geographical areas.

Since the few data exploring a possible association between Epstein-Barr virus (EBV) and breast cancer are conflicting, we investigated this association together with the influences of geographical areas. 509 breast cancers were sampled from areas with varying risks of nasopharynx carcinoma (NPC) such as North Africa (Algeria and Tunisia, high-risk area); southern France (Marseille, intermediate-risk area); and northern Europe (northern France, the Netherlands and Denmark; low-risk areas). Polymerase chain reaction (PCR) of a subregion of EBV BamHIC encoding the EBERs demonstrated that 31.8% of the tumours contained the viral genome. No significant differences were observed among the geographical areas. However, positive samples showed higher loads of the EBV genome in the NPC high- and intermediate-risk areas than in the low-risk areas. EBV type 1 was the dominant strain. In situ hybridization studies using a(35)S-labelled riboprobe for EBER1 and a laser capture microdissection, combined with quantitative PCR, showed that EBV localization was restricted to some tumour epithelial cell clusters. EBV could not be detected in the stroma. Considering the whole population covered, the presence of the EBV genome was not correlated with age, menopausal status, tumour, size, nodal status or histological grade.

Idiopathic ocular neuromyotonia: a neurovascular compression syndrome?

Ocular neuromyotonia in the muscles innervated by the right oculomotor nerve was diagnosed in a patient without a history of radiation therapy. Electromyography of the levator palpebrae showed continuous motor unit activity. Brain MRI disclosed a close contact between the right third cranial nerve and a basilar artery dolichoectasia. The patient partly benefited from carbamazepine therapy. This unique finding suggests that neurovascular compression syndrome could be an hitherto unrecognised cause of ocular neuromyotonia.