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Background To distinguish new primary breast cancers from true recurrences, pangenomic analyses of DNA copy number alterations (CNAs) using single-nucleotide polymorphism arrays have proven useful. Methods The pangenomic profiles of 22 pairs of primary breast carcinoma (ductal or Iobular) and ipsilateral breast cancers from the same patients were analyzed. Hierarchical clustering was performed using CNAs and DNA breakpoint information. A partial identity score developed using DNA breakpoint information was used to quantify partial identities between two tumors. The nature of ipsilateral breast cancers (true recurrence vs new primary tumor) as defined using the clustering methods and the partial identity score was compared with that based on clinical characteristics. Metastasis-free survival was compared among patients with primary tumors and true recurrences as defined using the partial identity score and by clinical characteristics. All statistical tests were two-sided. Results All methods agreed on the nature of ipsilateral breast cancers for 14 pairs of samples. For tive pairs, the clinical definition disagreed with both clustering methods. For three pairs, the two clustering methods were discordant and the one using DNA breakpoints agreed with the clinical definition. The partial identity score confirmed the nature of ipsilateral breast cancers as defined by clustering of DNA breakpoints in 21 of 22 pairs. The difference in metastasis-free survival of patients with new primary tumors and those with true recurrences was not statistically significant when tumors were defined based on clinical and histologic characteristics (5-year metastasis-free survival: 76%, 95% confidence interval [CI] = 52% to 100% for new primary tumors and 38%, 95% CI = 17% to 83% for true recurrences; P = .18; new primary tumor vs true recurrence, hazard ratio = 2.8, 95% CI = 0.6 to 13.7), but the difference was statistically significant when tumors were defined using the partial identity score (5-year metastasis-free survival: 100% for new primary tumors and 29%, 95% CI = 11% to 78% for true recurrences; P= .01). Conclusions DNA breakpoint information more often agreed with the clinical determination than CNAs in this population. The partial identity score, which was calculated based on DNA breakpoints, allows statistical discrimination between new primary tumors and true recurrences that could outperform the clinical determination in terms of prognosis.

Abstract: Women from hereditary breast cancer families with BRCA1/2 germline mutation are at increased risk for contralateral breast cancer (BC) and for ovarian cancer (OC). It is less clear whether [...]

To determine prospectively the efficacy and to assess potential side effects of melphalan selective ophthalmic artery chemotherapy (SOAC) as first-line treatment for unilateral retinoblastoma.

IMPORTANCE: Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies. OBJECTIVE: To assess the association between genotype and phenotype in patients with RB. DESIGN, SETTING, AND PARTICIPANTS: This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018. MAIN OUTCOMES AND MEASURES: RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group). RESULTS: Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01). CONCLUSIONS AND RELEVANCE: These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers.

IMPORTANCE: Studies on uveal melanomas (UMs) have demonstrated the prognostic value of 8q gain and monosomy 3, but the prognosis of UMs with partial deletion of chromosome 3 remains to be defined. OBJECTIVE: To examine the association of partial chromosome 3 deletion in UMs with metastasis-free survival. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study of 1088 consecutive comparative genomic hybridization arrays performed from May 1, 2006, to July 31, 2015, assessed patients presenting with UMs with and without partial loss of chromosome 3 at a referral center. Data analysis was performed from September 1, 2017, to November 30, 2017. EXPOSURE: Uveal melanoma with or without partial loss of chromosome 3. MAIN OUTCOMES AND MEASURES: Metastasis-free survival and overall survival at 60 months. RESULTS: Of the 1088 consecutive comparative genomic hybridization arrays that were performed, 43 UMs (4.0%) in 43 patients (median age, 58 years [range, 12-79 years]; 22 [51%] female) carried partial deletions of chromosome 3. Median follow-up was 66 months (range, 1.2-126.2 months). Metastasis-free survival at 60 months was 33.6% (95% CI, 15.8%-71.4%) for UMs that carried a deletion of the BAP1 (BRCA1 associated protein 1) locus (BAP1del; 24 tumors) and 80.5% (95% CI, 64.8%-100%) for UMs without the loss of the BAP1 locus (BAP1 normal [BAP1nl]; 19 tumors) (log-rank P = .001). Overall survival at 60 months was 64.5% (95% CI, 43.5%-95.8%) in the BAP1del group vs 84.1% (95% CI, 69.0%-100%) in the BAP1nl group (log-rank P < .001). In these 43 cases, metastasis-free survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 70.0% (95% CI, 50.5%-96.9%) for UMs that carried 1 of these alterations, and 12.5% (95% CI, 2.1%-73.7%) for those that carried both (log-rank P < .001). Similarly, overall survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 80.8% (95% CI, 63.3%-100%) for UMs that carried 1 of these alterations, and 46.7% (95% CI, 23.3%-93.6%) for those that carried both (log-rank P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that partial deletion of chromosome 3 encompassing the BAP1 locus is associated with poor prognosis. A cytogenetic classification of UMs could be proposed based on the status of the BAP1 locus instead of the chromosome 3 locus, while also taking chromosome 8q into account.

PurposeIntraocular retinoblastoma treatments often combine chemotherapy and focal treatments. A first prospective protocol of conservative treatments in our institution showed the efficacy of the use of two courses of chemoreduction with etoposide and carboplatin, followed by chemothermotherapy using carboplatin as a single agent and diode laser. In order to decrease the possible long-term toxicity of chemotherapy due to etoposide, a randomized neoadjuvant phase II protocol was conducted using vincristine–carboplatin vs etoposide–carboplatin.Patients and methodsThe study was proposed when initial tumor characteristics did not allow front-line local treatments. Patients included in this phase II noncomparative randomized study of neoadjuvant chemotherapy received vincristin–carboplatin (new arm) vs etoposide–carboplatin (our reference arm). They were subsequently treated by local treatments and chemothermotherapy. Primary end point was the need for secondary enucleation or external beam radiotherapy (EBRT) not exceeding 40% at 2 years.ResultsA total of 65 eyes in 55 children were included in the study (May 2004 to August 2009). Of these, 32 eyes (27 children) were treated in the arm etoposide–carboplatin and 33 eyes (28 children) in the arm vincristin–carboplatin. At 2 years after treatment, 23/33 (69.7%) eyes were treated and salvaged without EBRT or enucleation in the arm vincristin–carboplatin and 26/32 (81.2%) in the arm etoposide–carboplatin.ConclusionEven if the two treatment arms could be considered as sufficiently active according to the study decision rules, neoadjuvant chemotherapy by two cycles of vincristine–carboplatin followed by chemothermotherapy appear to offer less optimal local control than the etoposide–carboplatin combination.

To describe the results of retinoblastoma treatment from 1995–2009 in a single institution.

We sought to determine whether the levels of expression of 17 candidate genes were associated with locoregional control after breast-conserving treatments of early-stage breast cancers in young, premenopausal women. Gene expression was measured by using RT-PCR in the breast tumors of a series of 53 young (younger than 40 years), premenopausal patients. All treatments consisted of primary breast-conserving surgery followed by whole-breast radiotherapy (± regional lymph nodes) with or without systemic treatments (chemotherapy ± hormone therapy). The median follow-up was 10 years. The 10-year locoregional control rate was 70% (95% CI, 57% to 87%). In univariate analysis, no clinical/pathologic prognostic factors were found to be significantly associated with decreased locoregional control. Expression of three genes was found to be significantly associated with an increased locoregional recurrence rate: low estrogen-receptor β, low aromatase, and high GATA3. Two others were associated with only a trend (P< 0.10): low HER1and SKP2. In multivariate analysis, only the absence of aromatase was significantly associated with an increased locoregional recurrence rate (P= 0.003; relative risk = 0.49; 95% CI 0.29 to 0.82). Recent data give credit to the fact that breast cancer in young women is a distinct biologic entity driven by special oncogenic pathways. Our results highlight the role of estrogen-signaling pathways (mainly CYP19/aromatase, GATA3, and ER-β) in the risk of locoregional recurrence of breast cancer in young women. Confirmation in larger prospective studies is needed.

Phyllodes tumors are rare fibroepithelial tumors of the breast. The pathologic grading of phyllodes tumors based on the aspect of the stromal component, is divided into 2 or 3 grades according to the system used. To determine whether genetic markers could be of use for improving the classification of phyllodes tumors and to provide a better knowledge of the genetic alterations in these tumors, we analyzed chromosomal changes detected by comparative genomic hybridization (CGH) in comparison with histological data, in a series of 30 cases. Recurrent chromosome imbalances were observed in 55, 91 and 100% of benign, borderline and malignant phyllodes tumors, respectively. The mean number of chromosome changes was one in benign, six in borderline, and six in malignant phyllodes tumors. Most frequent genetic imbalances were +1q (12/30), −13q (7/30), −6q (9/30), +5 (9/30) and −10p (8/30). Gains of 1q, present in only one of nine benign tumors, were found in 11/21 (51%) borderline or malignant tumors. Losses of 13q have 13q14.2 as smallest region of overlap, suggesting that the RB1 gene could be the target of deletions. Amplifications of 12q14, involving the MDM2 locus, and of 8p24, involving the MYC gene, were observed in one case each. Borderline and malignant phyllodes tumors could not be differentiated on the basis of their genomic imbalances (presence and number of chromosomal changes, presence of 1q gain and/or 13q loss). Conversely, benign tumors could be significantly differentiated from the group composed of borderline and malignant tumors (P<0.01). This study reveals two distinct patterns of genomic imbalance in phyllodes tumors: benign, with none or a few chromosome changes and malignant, with numerous recurrent chromosomal changes, in particular 1q gain and 13q loss. Helpful additional pathological criteria for differentiating the two genetic groups of phyllodes tumors are the nuclear size and the mitotic rate.Modern Pathology (2007) 20, 435–444. doi:10.1038/modpathol.3800756; published online 2 March 2007

Medullary breast carcinoma (MBC) is a rare pathological type of breast cancer. The rate of p53 protein accumulation is higher in MBC than in common invasive ductal carcinoma. Whether this particular feature of MBC influences the outcome after treatment is unknown. We retrospectively analyzed the characteristics, treatment and outcome of 71 patients with MBC treated between 1981 and 1996. The median age was 51 years (range 27–81) and the median clinical tumor size was 25 mm (range 0-70 mm). Breast-conserving treatment was offered when possible: 55 patients had undergone a tumorectomy and radiotherapy while 16 patients had undergone a mastectomy. p53 protein accumulation was determined by immunohistochemistry on paraffin-embedded tumor specimens from 58/71 samples available for this study. The median follow-up for the 56 survivors was 113 months (range 30–241). The 10-year survival and metastasis-free survival rates were 81% and 81.4%, respectively. The local recurrence rate was 16.4%. The two factors predicting outcome were pathological axillary node involvement in the 60 patients who underwent axillary dissection and adjuvant chemotherapy. p53 accumulation was found in 33/58 patients (57%). p53 status was not predictive of survival nor of distant or local recurrences. We confirm that medullary breast carcinoma has a favorable prognosis despite its aggressive pathological features. p53 protein accumulation, found in the majority of MBCs, was not related to outcome.

The efficacy and safety of a 3-day course of azithromycin oral suspension (10 mg/kg of body weight once daily) were compared with those of penicillin V (50,000 U/kg/day in two divided doses) in children aged 3 to 12 years for the treatment of symptomatic pharyngitis caused by the group A beta-hemolytic streptococcus (GABHS). For the 154 evaluable patients, the original infecting strain of GABHS was eliminated at the end of follow-up (34 to 36 days after treatment started) from 67 (85.8%) of 78 penicillin-treated patients and 41 (53.9%) of 76 azithromycin-treated patients (P < 0.0001). Overall clinical success was achieved in 71 (91.0%) of 78 penicillin V-treated patients and 57 (75.0%) of 76 azithromycin-treated patients (P < 0.05). Potential drug-related adverse events were reported for 5.5 and 8.6% of the penicillin V- and azithromycin-treated patients, respectively (P = 0.6). In the present study, a once-daily (10 mg/kg), 3-day oral regimen of azithromycin was as safe as a 10-day course of penicillin but did not represent an effective alternative to penicillin for the treatment of GABHS pharyngitis, even for those children with azithromycin-susceptible strains.

Among the various references which Athenaeus makes in his ?e?p??s?f?sta?to the encounter of Herakles with Helios, when he was going to the island of Erytheia, we find the following (Book xi. 39 ff):—Fe?e??d?? d? ?? t? t??t? t?? ?st????? p??e?p?? pe?? t?? ? O?ea????p?f??e? ? d? ??a???? ???eta? ?p? a?t?? t? t???? ?? ßa??? ?a? ? ?????pa?sas?a? ?e?e?e? ? d? de?sa? pa?eta?. ?´ ????? d? ??t? t??t?? d?d?s??a?t? t? d?pa? t? ???se?? ? a?t?? ?f??e? s?? ta?? ?pp??? ?p?? d?? d?? t??O?ea??? t?? ???ta p??? ???? ??? ???s?e? ? ?´ ????? ?pe?ta p??e?eta? ?? ??a???? ?? t? d?pa? t??t? t??t? ?? t?? ? ????e?a? ?.t.?.

Dans le cadre d’une étude rétrospective de patients atteints d’un cancer et exposés au cours de leur suivi à des dispositifs médicaux implantables (DMI), nous nous intéressons à l’analyse de l’impact d’une exposition dépendante du temps sur le risque de décès. Les modèles comme le modèle de Cox ou exponentiel par morceaux (Em) font l’hypothèse que le risque instantané d’évènement à l’instant t ne dépend que de l’exposition à t et non des expositions reçues jusqu’à t−. Le modèle WCE (« Weighted Cumulative Exposure ») permet de prendre en compte les expositions passées et d’en étudier l’effet cumulé en estimant une courbe pondérant les valeurs de ces expositions [1]. Ce modèle est semi-paramétrique, comme le modèle de Cox et contrairement au modèle Emqui suppose une fonction de risque instantané de base constante par morceaux. Il permet le calcul d’hazard ratios associés à différentes trajectoires d’expositions.

In 2014, the R&D Department of Unicancer, a national academic network of comprehensive cancer centers in France, launched the Epidemiological Strategy and Medical Economics (ESME) Research program to centralize real-world patient data in oncology. The program's first project concerns the construction of a comprehensive database on patients with metastatic breast cancer (MBC), called ESME MBC Database, using data obtained from the 18 French Comprehensive Cancer Centers. Among the studied issues, ESME MBC Database (NCT03275311) [https://clinicaltrials.gov/ct2/show/NCT03275311?titles=ESME&rank=2] has served to describe the Overall Survival (OS) in patients with HER2-negative MBC treated with first-line paclitaxel chemotherapy, with or without bevacizumab [1]. Nevertheless, results have been criticized due to the lack of randomized trials, and the eventual presence of bias due to unmeasured confounders. In this work, we investigated two methods to address this issue : instrumental variables (IV) [2]and quasi-trials analysis [3].

Background: Whether congenital diaphragmatic hernia (CDH) is associated with surfactant deficiency or dysfunction is controversial.Aims: To measure disaturated phosphatidylcholine (DSPC) and surfactant protein B (SP-B) synthesis and metabolism in infants with CDH.Methods: DSPC and SP-B amounts and kinetics were studied in tracheal aspirates (TA) of 12 infants with CDH (BW 2978±447g, GA 38±2 wk) and in 8 GA-matched control infants (BW 3160±350g, GA 38±2 wk). Seventeen infants received a 24h infusion of 13C-leucine, an i.v. bolus of 2H2O and 0.0625% of fluid intake as 2H2O every 12h over the next 48h. Three infants received only 13C-leucine infusion. DSPC and SP-B were isolated from TA. DSPC amounts, 2H-palmitate and 13C-leucine enrichments were measured by gas chromatography mass spectrometry.Results: DSPC amount and kinetics have been measured in 17 newborns, and SP-B kinetics in 18. DSPC median (interquartile range) fractional synthesis rate (FSR) was 5.0 %/day (3.5-8.5) in CDH patients vs 6.1 %/day (5.8-7.0) in controls (p=0.31). DSPC secretion time (ST) was 10.7h (6.9-11.5) vs 7.9h (5.2-14.0) (p=0.65).SP-B FSR was 33.4 %/day (28.4-42.9) vs 52.0 %/ day (40.0-83.4) (p=0.03); SP-B peak time was 26h (24-32) vs 18h (15-21) (p=0.02), both significantly lower in the CDH group. SP-B ST was 6.1h (4.0- 9.9) vs 2.7h (1.1-7.1) (p=0.24), and half life 7.5h (5.2-9.1) vs 11.1h (5.8-17.3) (p=0.33).Conclusions: Decreased and delayed SP-B synthesis was found in newborns with CDH compared to controls while DSPC kinetics was similar in both groups, which may contribute to severe respiratory failure in these patients.

Ghesquieres: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding; Mundipharma: Consultancy. Choquet:Celgene: Consultancy; Janssen: Consultancy. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Soussain:Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding.

Choquet: Janssen: Consultancy; Celgene: Consultancy. Thyss:Takeda: Research Funding; Millennium: Research Funding. Soussain:Pharmacyclics: Research Funding; Roche: Research Funding; Celgene: Research Funding.