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Infections due to human herpesvirus 6 (HHV-6) are frequent during early childhood. Usually, they have a favorable clinical course. Conversely, HHV-6 congenital infections occur in about 1% of neonates and may present with more severe clinical pictures. HHV-6 can be found in lung tissues and bronchoalveolar lavage (BAL) samples from patients with pneumonia and in immunocompromised patients can cause mild to severe pneumonia. In neonates, the role of HHV-6 in the genesis of severe pneumonia is poorly defined still now. We describe a healthy infant with a late-onset (15 days of life) severe interstitial pneumonia and heavy HHV-6 genome load, persistently detected in its BAL fluid. The baby underwent high-frequency oscillatory ventilation, hydroxychloroquine, steroids, and ganciclovir for 6 weeks and at 9 months she died. Next-generation sequencing of genes known to cause neonatal respiratory insufficiency revealed the presence of a "probably pathogenetic" heterozygous variant in the autosomal recessive DRC1 gene, a heterozygous variant of unknown significance (VUS) in the autosomal recessive RSPH9 gene, and a heterozygous VUS in the autosomal recessive MUC5B gene. HHV-6 infection should be considered in the differential diagnosis of late-onset severe respiratory distress in neonates and the co-occurrence of genetic predisposing factors or modifiers should be tested by specific molecular techniques. The intensity of HHV-6 genome load in BAL fluid could be an indicator of the response to antiviral therapy.

Outcomes for adults with soft tissue sarcoma are better when managed at referral centers. Care guidelines advise for 5 main criteria: 1-Imaging before biopsy; 2-Tumor biopsy before surgery; 3-Multidiscipinary team discussion (MTD) before biopsy; 4-Biopsy in "expert centers"; 5-Somatic molecular biology feasible. The aim is to describe and assess the prognostic impact of initial management of STS according to the type of referring centers and the number of optimal criteria.Monocentric retrospective analysis of the management of 127 youths (0-25 years) with localized STS treated from 2006 to 2015.Median age at diagnosis was 9.6 years (range: 025). Overall, only 41% patients had 5/5, 28% 3-4, 31% ≤2. No adequate imaging was performed before surgery/biopsy for 18% patients, no biopsy before treatment for 29%. Patients referred by "expert centers" had higher compliance to guidelines (P = 0.025). Upfront surgery was performed in 59/127 patients. Immediate re-operation was inversely related to the number of criteria (0% when 5 criteria vs. 14% for 3-4, 46% if ≤ 2; P 0.001). For malignant tumors, outcome was better when 5 criteria were reached: 5 year EFS 90.8% (81.4-100.0%) vs. 71.6 for (60.4-84.9%; ≤4 criteria; p = 0.033), OS 93.6% (85.5-100%) vs. 79.5% (68.9-91.8%; p = 0.11), and LRFFS 90.6% (81.0-100.0) vs. 73.1% (62.0-86.3%; p = 0.047).Less than half of the youths with STS are initially managed according to international guidelines, highlighting the need for better information about optimal management. These results plead for immediate management in reference centers to reduce initial burden of therapy.

Proof of concept studies has reported that circulating endothelial cell (CEC) count may be associated with the outcome of HER2-negative metastatic breast cancer (mBC) patients treated by chemotherapy and the anti-VEGF antibody bevacizumab. We report the results obtained in an independent prospective validation cohort (COMET study, NCT01745757). The main baseline criteria were HER2-negative mBC, performance status 0–2 and no prior chemotherapy for metastatic disease. CECs were detected by CellSearch® from 4 ml of blood at baseline and after 4 weeks of weekly paclitaxel and bevacizumab therapy. CEC counts (considered both as a continuous variable and using the previously described 20 CEC/4 ml cutoff) were associated with clinical characteristics and progression-free survival (PFS). CEC count was obtained in 251 patients at baseline and in 207 patients at 4 weeks. Median baseline CEC count was 22 CEC/4 ml (range 0–2231). Baseline CEC counts were associated with performance status (p = 0.02). No statistically significant change in CEC counts was observed between baseline and 4 weeks of therapy. High baseline CEC count was associated with shorter PFS in univariate and multivariate analyses (continuous: p

Background Outcome of HER2-positive metastatic breast cancer (MBC) patients has improved since the use of trastuzumab. However, most HER2-positive MBC patients will progress within 1 year of trastuzumab-based therapy. Only limited data are available concerning long-term responders. Methods The primary objective of this study was to compare overall survival (OS) of HER2+ MBC patients with long-term response to first-line trastuzumab with overall survival of those with non-long-term response, based on two institutional databases: the French Epidemiological Strategy and Medical Economics program and the Breast Database. Long-term responders (LTR) were defined as patients with non-progressive disease for ≥ 2 years on first-line trastuzumab. Secondary objectives included progression-free survival (PFS), and predictive factors for LTR status. Results From 2004 to 2014, 422 HER2-positive MBC patients received first-line trastuzumab. With a median follow-up of 48 months, median OS and PFS were 63 months (CI95%, 50-71), and 18 months (CI95%, 15-21) respectively. In 111 patients (26.3%) classified as LTR, median OS was 110 months (CI95%, 95-not reached) versus 56 months in non-LTR patients (CI95%, 47-68). In multivariate logistic regressions, the following factors were independently associated with LTR status: number of metastatic sites (≤ 2 versus > 2, p = 0.01); endocrine therapy for metastatic disease (p = 0.001) and taxane-based first-line chemotherapy (p = 0.003). Conclusion Several features are associated with long-term response to trastuzumab: few metastatic sites, taxane-based chemotherapy and maintenance endocrine therapy in HR+ patients. Further studies are needed to identify patients in whom trastuzumab can be stopped after several years of sustained response.

Background Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL–PCNSL. Patients and methods Patients with refractory/relapsed (R/R) DLBCL–PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20mg/day, D1-21 for cycle 1; and 25mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0=10%; P1=30%). Results Fifty patients were included. Forty-five patients (PCNSL, N=34; PVRL, N=11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9–51.2) in assessable patients and 32.0% (95% CI 21.9–51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2months (range 1.5–31), the median progression-free survival (PFS) and overall survival (OS) were 7.8months (95% CI 3.9–11.3) and 17.7months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS=9.5months (95% CI, 8.1–14.8] for CD4/CD8≥1.6; median PFS=2.8months, [95% CI, 1.1–7.8) for CD4/CD8 Conclusions The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. Clinical trials number NCT01956695.

Background High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). Methods The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. Results Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. Conclusion Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor., Highlights • This is the first large multicenter cohort reporting BMI’s effect on outcomes among patients with metastatic breast cancer. • Overweight or obese status does not negatively influence outcome of metastatic breast cancer patients, whatever the subtype. • Underweight is a strong negative independent prognostic factor on outcomes, whatever the subtype.

BACKGROUND: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. METHODS: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. FINDINGS: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. INTERPRETATION: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.

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

Background Conservative treatments of intraocular retinoblastoma often consist of chemotherapy and focal treatments. The protocols vary and currently may combine two or three drugs, with different number of cycles, associated to the ocular treatments. In case of macular/paramacular involvement, tumor location and retinal scars induced by focal treatments often have a major negative impact on final visual outcome. Methods This study aimed to include children affected by bilateral intraocular macular/paramacular retinoblastoma in a prospective phase II study. The protocol consisted of six cycles of a three-drug combination (vincristine, etoposide, carboplatin), and the addition of macula-sparing transpupillary thermotherapy (TTT) to the third cycle. The primary endpoint was the local control rate without external beam radiotherapy (EBR) and/or enucleation. Results Nineteen patients (26 eyes) were included from July 2004 to November 2009. Thirteen eyes belonged to group V of the Reese-Ellsworth classification and 10 to group D of the International Intraocular Retinoblastoma Classification. Macular/paramacular tumors were treated with chemotherapy alone in nine eyes, and with chemotherapy associated with macula-sparing TTT in 17 eyes. Four eyes experienced macular relapse. At a median follow up of 77 months, 23 eyes (88.5%) were saved without EBR, two were enucleated and one received EBR. The median visual acuity of the 24 saved eyes was 20/50. No severe adverse effect was observed. Conclusion Six cycles of a three-drug combination associated with macula-sparing TTT achieved good tumor control, improved eye preservation rates without EBR, and decreased macular damage, often providing satisfactory visual results with long-term follow up.

Vascular rings (VR) may cause severe tracheomalacia and upper airway obstruction (UAO). Increased pulmonary artery pressure and cardiac dysfunction have been described in patients with chronic UAO, but has not been investigated in infants with obstruction associated with VR. The aim of this study is to evaluate myocardial strain in infants with UAO due to VR.Demographic characteristics, respiratory symptoms, percentage of tracheal obstruction measured and classified using Computer Tomography, and lung function testing (LFT) were collected. Left (LV) and right ventricle (RV) systolic functions were measured using speckle tracking echocardiography longitudinal strain analysis (LS). Pulmonary artery pressure was evaluated using maximal tricuspid regurgitation jet velocity (TR) and LV end-systolic eccentricity index (EI).Fifteen cases were included in the study, six had mild tracheal obstruction (50%), nine moderate-severe obstruction (≥50%). LV LS and RV LS were significantly reduced in cases with moderate to severe airway obstruction cases compared to those with mild airway obstruction (LV LS -15.9 versus -19.9%; RV LS -15.7 versus -20.5%,In cases of VR with severe tracheomalacia RV and LV myocardial strain is reduced, suggesting secondary cardiac dysfunction.

Background: Breast cancer (BC) management in older women requires an individual approach and is becoming increasingly topical given the aging population. Postoperative radiation therapy (RT) is a standard treatment of BC after breast-conserving-surgery in most patients but its relative benefit may be counteracted by potential side-effects, especially in elderly. The aim of this study was to assess acute and long-term radiation-induced toxicities and the impact of comorbidities on outcomes in the older women treated by RT for non-metastatic breast cancer. Materials and Methods: Women aged ≥ 70 years at diagnosis, who received exclusive or postoperative RT for primary non-metastatic breast cancer, including carcinoma in situ, between 2003 and 2009 were retrieved from the Institut Curie registry. We calculated the Charlson Comorbidity Index (CCI) for each patient and collected the cardiovascular risk factors other than age (hypertension, dyslipidemia, smoking status). We analyzed overall survival (OS), progression free survival (PFS) and acute and late toxicities according to the CTCAE (Common Terminology Criteria for Adverse Events) v3.0. Results: A total of 817 patients was included in this study. Median age at diagnosis was 76.6 years [70 – 93.3]. Most patients had HR+ (hormone-receptor positive) HER2- breast cancer (83.9 %). 517 patients (62.7%) had at least one cardiovascular risk factor. With a median follow-up of 6.7 years [0.5 - 13], OS at 5 years was 86.3% CI95%[83.8 - 88.8], and PFS was 84.5% CI95%[81.9 – 87.1]. OS at 5 years was statistically different according to the Charlson index: 90.2% CI95%[87.2 – 93.3] for a CCI of 0, 84.6 % CI95%[80.5 – 88.8] for a CCI of 1, and 78% CI95%[70.5 – 86.2] for a CCI ≥ 2 (p < 0.001, log-rank test), respectively. Similar results were found for PFS (p < 0.001, log-rank test). 22.6% of patients had no toxicity; of those who experienced toxicity, most was limited to grade I or II. Only five cases (0.6%) of radiation – induced pneumonitis were reported after a median time of 16.4 months (grade I, n = 1; grade II, n = 2). One case (0.1%) of myocardial ischemia was described 14.5 months after RT. Women older than 80 years were less likely to have acute dermatitis (OR = 0.62; CI95%[0.45 - 0.85]), long-term breast pain (OR = 0.31; CI95%[0.14 - 0.62]), and long-term breast deformation (OR = 0.63; CI95%[0.42 - 0.93]) compared to patients younger than 80 years. There was no significant association found between other cardiovascular risk factors and toxicities. Conclusion: Radiation therapy for breast cancer in the older women is well-tolerated. An extended follow-up is planned in order to assess toxicities at a longer time horizon. Further studies could be envisaged to assess the quality-of-life during and after RT for breast cancer in the older patient population. Citation Format: Cao KI, Salviat F, Fourquet A, Falcou M-C, Laki F, Beuzeboc P, Savignoni A, Bazire L, Poortmans P, Kirova YM. Tolerability and outcomes of radiation therapy for breast cancer in older women: A retrospective study in 817 patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-20.

Background About 20% of breast cancer (BC) patients will develop distant metastases. HER2-positive (HER2+) disease is associated with poorer prognosis. However, outcome of HER2+ BC patients has dramatically improved since the use of trastuzumab. Although most HER2+ metastatic BC (MBC) patients will eventually develop progressive disease within one year of trastuzumab-based treatment, some are long-term responders (LTR). Few data on these patients are available. Methods The primary objective was to assess overall survival (OS) of HER2+ MBC patients treated with trastuzumab as 1st-line at the Institut Curie, based on institution-specific data included in the French Epidemiological Strategy and Medical Economics (ESME) program for MBC patients established in 2014 by Unicancer. Long-term responders (LTR) were defined as having a non-progressive disease for at least 2 years under 1st-line trastuzumab. Secondary objectives included progression-free survival (PFS), disease-free interval (DFI), prediction factors for LTR status by univariate and multivariate analysis: characteristics of patients (age, BMI, menopausal status), of primary tumour (e.g. hormone receptor (HR) status), of treatment (e.g. endocrine therapy, partner for trastuzumab combination), number and type of metastases. Results From 2008 to 2014, 2990 MBC patients were identified in the Curie-ESME MBC database. Of these, 460 had HER2+ disease. Sixteen patients with second primary malignancy were excluded. Of the 444 remaining patients, 340 received 1st-line trastuzumab and could be analyzed. With a 42.5-month median follow-up time, the mean age at metastatic diagnosis was 55.7 years, 59.4% had a HR-positive disease and 43.2% had de novo metastases or occurring within 6 months after adjuvant treatment. DFI was >24 months in 47.9% of patients, and 78.5% received 1st-line trastuzumab combined with taxane-based chemotherapy (CT). In 87 patients (25.6%) classified as LTR, median PFS was 56.2 months (CI95% 41.53-not reached) vs. 10.9 months in non-LTR (CI95% 9.46-11.8). Median OS in LTR is not reached versus 44.3 months in non-LTR (CI95% 37.9-49.1). Median age, menopausal status, BMI, pathological characteristics and treatment for primary BC were similar in both groups. The following factors were predictive of LTR status by univariate analysis: number of metastatic sites ( 3, p=0.022); endocrine treatment for metastatic disease (p=0.002); absence of central nervous system metastases (p=0.035); and taxane-based 1st- line CT (p=0.032). In multivariate analysis, only number of metastatic sites and taxane-based 1st-line CT were predictive of LTR status. In contrast, age, DFI, visceral disease, and adjuvant trastuzumab-based treatment did not influence outcome. Although not statistically significant, HR+ status was more frequent in LTR versus non-LTR patients (66.7% versus 56.9%). Conclusions With a median follow-up of 42.5 months, we found that more than 95% of LTR to 1st-line trastuzumab were still alive and could achieve a median PFS longer than 4.6 years. Although some clinical factors are clearly associated with better outcome, further investigations are needed to identify the mechanisms of resistance or sensitivity to trastuzumab. Citation Format: Kaczmarek E, Saint-Martin C, Pierga J-Y, Brain E, Rouzier R, Dubot C, Savignoni A, Mouret-Fourme E, Simon G, Carton M, Lerebours F. Long-term survival in HER2-positive metastatic breast cancer treated with first-line trastuzumab: Real-life results from the Curie ESME database [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-14.

Background: Most of the studies regarding the surgical treatment of severe laryngomalacia (LM) have been aimed at describing the efficacy of the treatment in terms of improvement of clinical symptoms or anatomical findings. There are no studies specifically aimed at analyzing the changes in breathing patterns following surgical treatment for severe LM. Objective: To review the breathing pattern changes before and after corrective surgery in infants with severe LM. Study design: A series of retrospective cases at a tertiary referral children’s hospital. Methods: Retrospective chart review of 81 infants who underwent supra-glottoplasty (SGP) for severe laryngomalacia between 2011 and 2020 at Bambino Gesù Children’s Hospital of Rome, Italy. Among the patients, 47 (58%) were male and 34 (42%) were female. Twenty-one patients (26%) had one or more comorbidities condition. The data collected included age, symptoms, a polysomnography/pulse oximetry study, growth rate, the findings from flexible endoscopy, pre- and post-supra-glottoplasty (SGP) pulmonary function tests (PFTs) and, when indicated, 24 h pH-metry. Breathing patterns were studied during restful, normal sleep, using an ultrasonic flow-meter (Exhalyzer, Viasys) which measured: Tidal Volume (Vt), Respiratory Rate (RR), time to peak expiratory flow/expiratory time ratio (tPTEF/Te, an index of the patency of the lower airways) and mean expiratory/mean inspiratory flow ratio (MEF/MIF, an index of the patency of the upper airways) evaluated before surgical procedure (T1) and 3–6 weeks after (T2). Pre- and post-operative mean data were calculated and comparisons made with a Student T-test. Results: The surgical procedure was well tolerated by all infants and no intraoperative or post-operatory long-term complications were noted. In T1, breathing patterns were characterized by low tidal volume and high tPTEF/Te and MEF/MIF ratios, suggesting a severe reduction in the patency of the upper airways in all patients. After surgery (T2), all the previously mentioned variables significantly improved, reaching normal values for the child’s age. Conclusions: Supra-glottoplasty, as already described in several studies, is a safe and efficient procedure to treat severe laryngomalacia during infancy. The improvement in breathing patterns after surgery was reliably confirmed by a lung function test in our study, which showed the diagnostic value of testing respiratory functionality in the laryngomalacia and comparing them to clinical and endoscopic data. Moreover, considering the results obtained, we also propose the use of this available, dependable test to verify its therapeutic effects (post-surgery) and to monitor future respiratory development in these infants. Moreover, we believe that further studies will provide detailed grading guidelines for gravity of the LM, based on these functional lung tests.

Background The long-term survival of germline retinoblastoma patients is decreased due to the risk of second primary tumors (SPTs) that occur years after the diagnosis of retinoblastoma. This risk is related to genetic predisposition and other factors, such as the treatment of retinoblastoma by external beam radiotherapy (EBRT). Procedure We studied the incidence, risk factors, and prognosis of specific craniofacial SPTs developed within the margins of radiation field in a cohort of 209 patients with germline retinoblastoma treated with EBRT at our institution between 1977 and 2010. Clinical characteristics, survival, incidence, and histology of craniofacial SPTs were recorded. Results Fifty-three of the 209 patients developed 60 distinct craniofacial SPTs in irradiated field with a median time from EBRT of 16.9 years (4-35) and a median follow-up of 24.8 years (5.3-40). Osteosarcoma (33.3%) and undifferentiated sarcoma (23.3%) were the more prevalent histological entities. Benign tumors (16.7%) also occurred. The cumulative incidence of craniofacial SPTs reached 32.6% at 35 years after EBRT, and the median survival after diagnosis was five years. In our series, irradiation under 12 months of age, bilateral EBRT, or previous treatment of retinoblastoma with chemotherapy did not significantly increase the risk of craniofacial SPTs. Conclusions This work presents a strong argument to avoid EBRT in the management of retinoblastoma and emphasizes the high risk and poor prognosis of specific craniofacial SPTs. This study also points to the question of the need and benefits of special programs for early detection of craniofacial SPTs in survivors of irradiated germline retinoblastoma.

Background After treatment of primary ocular uveal melanoma (UM), up to 50% of patients will develop metastases, mostly in the liver. Systemic treatments do not provide any overall survival benefit for these patients and surgery remains the most effective therapy for selected patients. Radiofrequency ablation (RFA) alone or in combination with surgery is frequently used to spare hepatic parenchyma. When patients relapse after treatment of their first metastases, and when the liver recurrence is limited, new local liver treatment is questionable. Methods A total of 14 patients with liver metastases from uveal melanoma (LMUM) were retrospectively evaluated. All patients had a complete first liver resection and a second treatment with RFA. Overall survival, recurrence-free interval after the first and the second treatment was evaluated. Results Treatment of hepatic recurrence was percutaneous RFA for ten patients and per-operative RFA for four patients associated with new metastasectomy. The median time to onset of LMUMs after ocular UM treatment was 50 months, and the median time to recurrence of hepatic metastasis after the first liver treatment was 20 months. The overall survival was 70% at five years and 35% at ten years. The recurrence-free interval was 50% and 56% at two years after the first and the second treatment, respectively. Conclusion Prolonged survival can be achieved by exclusive and iterative local treatment combining surgery and RFA in a small proportion of patients with a first recurrence of isolated LMUM.

Background and purposeFew data are available concerning the safety of bevacizumab (B) in combination with locoregional radiation therapy (RT). The objective of this study was to evaluate the 5-year late toxicity of concurrent B and RT in non-metastatic breast cancer.Materials and methodsThis multicentre prospective study included non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT versus RT alone. All patients received neoadjuvant or adjuvant chemotherapy and normofractionated breast or chest wall RT, with or without regional lymph node RT. B was administered at an equivalent dose of 5 mg/kg once a week for 1 year. The safety profile was evaluated 1, 3 and 5 years after completion of radiotherapy.ResultsA total of 64 patients were included between November 2007 and April 2010. Median follow-up was 60 months (12-73) and 5-year late toxicity data were available for 46 patients. The majority of tumours were triple-negative (68.8%), tumour size ConclusionConcurrent B and locoregional RT are associated with acceptable 5-year toxicity in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed.

Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A nomogram was developed based on a Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan&ndash, Meier curve, and calibration plots. The median follow-up was 49.2 months (range, 0.6&ndash, 70.9). The survival rates at 6, 12, and 24 months were 0.88 (0.95 CI [0.84&ndash, 0.93]), 0.68 (0.95 CI [0.62&ndash, 0.75]), and 0.26 (0.95 CI [0.21&ndash, 0.33]), respectively. The four factors selected for the nomogram with a worse prognosis were: A disease-free interval between the UM and LMUM groups of less than 6 months (HR = 3.39, 0.95 CI [1.90&ndash, 6.05]), more than 10 LMUM (HR = 3.95, 0.95 CI [1.97&ndash, 4.43]), a maximum LMUM of more than 1200 mm2 (HR = 2.47, 0.95 CI [1.53&ndash, 3.98]), and a lactate dehydrogenase (LDH) value greater than 1.5 (HR = 3.72, 0.95 CI [2.30&ndash, 6.00]). The model achieved relatively good discrimination and calibration (C-statistic 0.71). This nomogram could be useful for decision-making and risk stratification for therapeutic options.

Background Vascular anomalies (VA) may cause severe tracheomalacia in some cases. Chronic upper airway obstruction (UAO) is the most common symptom. Increased pulmonary pressure and cardiac dysfunction have been described in patients with chronic UAO, but not in infants with VA. Aim The aim of this study was to evaluate myocardial strain in infants with VA. Method Demographics characteristics, respiratory symptoms, and the percentage of tracheal obstruction measured on CT were collected. Left and right ventricle (LV, RV) systolic function were measured with speckle tracking longitudinal strain (LS) analysis. Pulmonary artery pressure was evaluated on tricuspid regurgitation (TR) jet and quantified by end-systolic eccentricity index (EI). Conclusion Of 15 cases, 6 had tracheal obstruction 50%. LS LV and RV was significantly reduced in cases with obstruction > 50% compared to those with 50%. There are no significant data for TR and EI. Results In cases with VA with severe tracheomalacia RV and LV myocardial strain is reduced, suggesting myocardial impairment. Further studies with larger sample size are needed to confirm these data and investigate cardiac function. Association with lung function test may be investigated too.

Introduction Patients affected by esophageal atresia (EA) often faced airway problems, due to multifactorial dynamics (tracheomalacia, gastroesophageal reflex disorder, etc.). The aim of this study was to longitudinally evaluate the lung function test (LFT) in those infants to explore how the LFT modifies at mid-term follow-up. Methods Retrospective evaluation of lung functions in infants treated for EA (2010–2017) was performed at three time points: 6 months, 12 months, and 24 months. Tidal volume (Vt), respiratory rate (RR), and time to peak tidal expiratory flow as a percentage of total expiratory time (tPTEF/te) were analyzed. ANOVA test was used as appropriate. Results During the study period 172 patients were treated for EA. Of those 50 infants (28%) underwent LFT at 6 months, 30 at 12 months, and 11 at 24 months. Tracheomalacia was present in 20 infants (42%). Both Vt (6,79 ml/kg vs 7,82 ml/kg vs 8,37 ml/kg—p = 0,001) and RR (49,7 a/min vs 40,6 a/min vs 34,0 a/min—p = 0,020) significantly improved, while there was no significant difference for tPTEF/te (0,25 vs 0,26 vs 0,29—p = 0,62) despite the data showing an improvement trend. Conclusion The preliminary data suggest that, although EA patients may present impaired LTF in early infancy, lung function seems to improve over time, showing normal pulmonary function test at 24 months. The presence of selection bias and the retrospective nature of the study limit our result. Nonetheless, evaluation of lung function is warranted in EA infants to early detect respiratory symptoms, ideally reducing the impact on short- and long-term pulmonary outcomes.

Background There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium ( www.raids-fp7.eu ), conducted a prospectively monitored trial, [BioRAIDs ( NCT02428842 )] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Fund European Union's Seventh Program grant agreement No 304810.

To analyse long-term overall survival, relapse-free survival and late toxicities in a series of 675 patients treated between 1999 and 2003, with a median follow-up of 132 months.The cohort included low-risk patients and a selection of "favourable-intermediate" risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125 iodine seeds. Hormone therapy, consisting most often of an anti-androgen alone, was given in 393 patients (58%).The 10-year overall survival was 92% (95% confidence interval [CI]: 90-94) without a significant difference between the low and the select intermediate-risk groups (P=0.17). The 10-year relapse-free survival rate for the entire cohort was 82% (95% CI: 79-85), and was significantly higher in the low-risk group than in the intermediate one (87 vs 71%; P0.0001). Twenty-six percent of the relapses observed in this series occurred after more than 10 years of follow-up. The 10-year cumulative incidence of grade 3-4 urinary toxicity (whatever the delay and the recovery) was 5.78%. The cumulative incidence of grades 3-4 rectal toxicity in the present series was 1.65% at 10 years. As for sexual toxicity, 61% of our patients retained an erectile capacity at 10 years (with or without oral medication), with age being a major factor.With a median follow-up of more than 11 years, this series appears to confirm the excellent long-term results of low-dose rate prostate brachytherapy, both in terms of survival and in terms of toxicity.

Purpose: To report the results of a randomised study comparing the efficacy of Hydrosorb® versus control (water based spray) in the topical treatment of grade 1 and 2 radiation dermatitis in population of patients treated for early stage breast cancer (BC) with normo fractionated radiotherapy (RT). Patients and Methods: Breast cancer patients with grade 1-2 radio-induced dermatitis during normo fractionated postoperative radiotherapy were eligible (according to the CTCAE v3 scale). They were randomised to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of radiotherapy because of skin radiotoxicity or and/or change of local cares for skin alteration. Secondary endpoints were the evaluation of skin colorimetry, pain, and quality of life. Pain was assessed according to two classes with a VAS cut-off of 2. Results: Two-hundred seventy eight patients were enrolled (A = 142, B = 136). There were 186 successfully treated patients (82 in Hydrosorb® arm, and 74 in the control arm). There were 60 "failures" in the Hydrosorb® arm, and 62 in the control arm (p = 0.72), but mostly without interruption of the radiotherapy. Twenty-four patients stopped the radiotherapy treatment for local cares (16 in Hydrosorb®, arm and 8 in control arm). No risk factors were associated with failure to local treatment. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively (p = 0.36). Forty-eight patients in the Hydrosorb® arm had a VAS > 2 versus 51 patients in the placebo arm, i.e. 34% and 38%, respectively (p = 0.45). A significant reduction of pain was observed on D7 (p = 0.04) and D21 (p = 0.01) in the Hydrosorb® arm. Sixty patients in the Hydrosorb® arm and 55 patients in the placebo arm had moderately to severely altered quality of life (p = 0.76). Conclusions: The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined. Citation Format: Bazire L, Fromentin I, Diallo A, de Lalande B, Pernin V, Dendale R, Fourquet A, Savignoni A, Kirova Y. Hydrosorb® versus control (water based spray) in the management of radio-induced skin toxicity: Results of multicentre controlled randomized trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-16.

BACKGROUND: The benefit of chemotherapy for patients with estrogen receptor(ER)+ HER2- breast cancers is an ongoing question. The evaluation of the tumor's proliferation by Ki67 may guide the indication but no consensual predictive cut-off has been set yet. MATERIALS AND METHODS: This study included women with a first ER+HER2- invasive breast cancer treated by primary surgery between 2003 and 2008. Data was collected prospectively. Ki67 cut-off was sequentially set each 1% from 5% to 30%. For each threshold, the interaction between Ki67 and adjuvant chemotherapy was integrated in a multivariate Cox model to determine when it became statistically significant in predicting distant-disease free survival (DDFS). Using different Ki67 cut-offs, we also compared DDFS of patients who had or not an indication of chemotherapy, depending on whether they actually received it or not. RESULTS: Among the 3221 breast cancers, median Ki67 was 10%, with a mean of 15% (S.D = 14). Ki67 was an independent prognosis factor whether the cut-off was set to 14% or to 20% (p CONCLUSION: In ER+ HER2- breast cancers, a Ki67 level of expression >= 20% was predictive of benefit from adjuvant chemotherapy. A threshold at 14% was not as discriminant. Based on this large cohort study, we recommend the use of a cut-off at 20% to decide whether patientes with ER positive tumors should receive chemotherapy or not/. Citation Format: Rouzier R, Rossi L, Lerebours F, Savignoni A, Falcou M-C, Bonneau C, Pierga J-Y, Guinebretière J-M. Ki67 cut-off point to predict the benefit of adjuvant chemotherapy in ER+ HER2- breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-63.

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013-2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median FU of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were 65*4% [CI95%: 60*2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulatorgene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harbouring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Funding: European Union's Seventh Program grant agreement No 304810. Declaration of Interest: All authors declared: No conflict of interest. Ethical Approval: Ethical review was conducted according to national requirements and in accordance with the Declaration of Helsinki. All tumour and serum samples and clinical data were registered in a common database using a unique barcode system assuring data privacy.

Palbociclib, ribociclib, and abemaciclib have been investigated in combination with aromatase inhibitors as first-line therapy for metastatic hormone receptor-positive breast cancer (PALOMA-2, MONALEESA-2 and MONALEESA-7, MONARCH-3 trials, respectively); pivotal trials led to absolute median progression-free survival (PFS) gain of about 15 months. We aimed to estimate, for each trial, the statistical power to demonstrate a significant gain in overall survival (OS). Power was calculated with Freedman’s formula. Given the allocation ratio and the number of events, power was computed as a function of hazard ratio. We focused on four specific hazard ratio values (0.94, 0.89, 0.81, and 0.77), which are estimated to correspond to absolute 3, 6, 12, and 15 months gain in OS, respectively. For these calculations, the type I error rate was stated at 5% with a two-sided test, and we assumed that the risk of death was constant over time. PALOMA-2 and MONALEESA trials have an almost similar power despite different allocation ratios, while MONARCH-3 has a more limited power. Overall, the power of the four trials to demonstrate a statistically significant improvement in OS is less than 70% if the prolongation in median OS is ≤12 months, whatever the OS data maturity. This analysis shows that OS results are jeopardized by limited powers, and a meta-analysis might be required to demonstrate OS benefit. Conversely, if a significant OS improvement is observed in some but not at all trials, this discrepancy might be more attributable to chance than to a truly different drug efficacy.

Background: Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment. Methods: We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed. Results: pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P

Purpose To report the efficacy of Hydrosorb® versus control (water based spray) as topical treatment of grade 1–2 radiodermatitis in patients (pts) treated for early stage breast cancer (BC) with normo fractionated radiotherapy (RT). Patients and methods BC pts were randomized to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of RT because of skin radiotoxicity or change of local care because of skin alteration. Secondary endpoints were: evaluation of skin colorimetry, pain, quality of life. Results Two-hundred seventy-eight pts were enrolled. There were 186 successfully treated pts. There were 60 "failures" in the Hydrosorb® arm, and 62 in the control arm ( p =0.72), but mostly without interruption of the RT. Twenty-four pts stopped RT for local care. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively ( p =0.36). Forty-eight patients in the Hydrosorb® arm had a VAS >2 versus 51 pts in the placebo arm, i.e. 34% and 38%, respectively ( p =0.45). A significant reduction of pain was observed on D 7 and D 21 in the Hydrosorb® arm. Conclusions The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined. It seems that the most important part of the skin care is the prevention of skin reactions using new adapted techniques, as well as strict hygiene.

Summary Introduction To describe the results of retinoblastoma treatment from 1995–2009 in a single institution. Material and methods Retrospective review of the charts of patients treated for retinoblastoma. Clinical characteristics at diagnosis, treatments and outcomes in terms of survival and ocular preservation are described. Results During the study period 826 children were referred for retinoblastoma and 730 were managed in our institution. Four hundred and eleven children presented with unilateral retinoblastoma and 319 with bilateral retinoblastoma. Median follow-up is of 93 months. Global survival is 98.5% of children, 10 children presented with second tumors, 11 children died (6 of tumor-related causes). Of the 411 children with unilateral retinoblastoma enucleation was needed at diagnosis for 324 (78.8%). Conservative treatments were attempted for 87 patients (21.2%) and ocular preservation obtained for 65 patients (74% of eyes). Three hundred and nineteen patients presented with bilateral retinoblastoma. Three hundred and ten could be treated conservatively for at least one eye. Initial intravenous chemotherapy was necessary for 75% of them. Ocular preservation without external beam radiation was possible for 221 patients (70%). The use of EBR decreased significantly after 2004 (9.1% of eyes vs 25.1%: P Discussion Management and treatment of retinoblastoma are complex, adapted to the extent of the disease. Survival is good. Enucleation is still required for extensive ocular disease, especially for unilateral patients. Intravenous chemotherapy allows good tumor control and eye preservation and decrease the need of EBR. Conclusions Retinoblastoma treatment with intravenous chemotherapy and ocular adjuvant therapies is very effective on the local tumor control and eye preservation.

International audience; Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as os-teosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population. Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

Background To improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases (BM) from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. Patients and methods This phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal BMs from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy × 10–30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m2/day during the irradiation period. The primary end point was objective response rate (ORR) 6 weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary end points were progression-free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. Results Between February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years (29–79). Median follow-up was 9.4 months [1.0–68.1]. ORRs at 6 weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥grade 2 acute toxicity was reversible lymphopenia. Conclusion WBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer. Clinicaltrials.gov NCT00875355.

e14135 Background: Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC) and are associated with immune-related adverse events (irAEs). However, real-life data on type, occurrence and kinetics of irAEs, and their predictive value on treatment outcome are lacking. Here, we report on the relation between irAEs, including endocrine irAEs, and outcome to anti-PD-/L-1 (programmed cell death protein-/ligand-1) ICIs. Methods: A total of 147 patients (pts), with locally advanced/metastatic NSCLC, treated with anti-PD-1 (N 140; 95%) or anti-PD-L1 agents (N 7; 5%) as ≥ 2 line treatment were included in two independent, prospective, cohorts at the Institut Curie (ALCINA-NCT02866149) and at Biella Hospital (Italy). PD-L1 status was assessed by immunohistochemistry (clone 22C3, Dako). Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier curves. Results: Median follow-up of 147 pts was 10.2 (range: 0.7-42.8) months; median age, 66 (35-85) years; 100 men (68%). After treatment initiation, irAEs were observed in 72 pts (49%). Thirty one (43%) pts had only endocrine irAEs, mostly thyroid dysfunctions (N 44, 61%). Pre-existing thyroid disease was present in only 6 pts (4%). Dermatologic toxicity in 21 (29%) pts was the next most frequent irAE, 22 (30%) pts had other types of irAEs. Among patients with irAEs, 61 (85%) had ≤ 2 coexisting irAEs, and 13 (18%) pts had > 2 irAEs. Most irAEs were G1 (63%) and G2 (18%). Onset and kinetics differed according to irAE type. There was no association between PD-L1 status and irAE occurrence. Median PFS was 7.2 and 4.2 months in irAEs vs no-irAEs group, respectively [HR 0.70 (95% CI 0.46;1.08), p 0.11]. Median OS in the irAEs group was 18.1 months vs 13.6 months no-irAEs group [HR 0.64 (95% CI 0.37;0.98), p 0.039]. Median OS in the endocrine-irAEs group was 23.5 vs 13.6 months in the no-irAEs group [HR 0.58 (0.74;3.92), p 0.2]. Conclusions: In this study, we show that irAEs – including endocrine type – are frequent in NSCLC pts treated with ICIs and that their occurrence is associated with a survival benefit.

Background: Despite of therapeutics progress in advanced breast cancer, brain metastases occurrence remain a frequent and delicate situation. The efficacy of whole-brain radiation therapy (WBRT), still considered as the standard local treatment in case of multiple brain metastases, is limited. Recently, several phase II studies have shown some efficacy of the association of WBRT and temozolomide (TMZ), an oral alkylating agent already known as a radiosensitizer, with improved brain control rate (44 to 96%). Patients with breast cancer were underrepresented and none of these trials have studied this combined treatment issue in this specific population. The aim of this study was to assess the efficacy and safety of WBRT combined with temozolomide in the treatment of brain metastases from breast cancer. Materials and Methods: A prospective randomized multicenter phase II study was developed, using a modified two-stage Fleming design. Patients with newly diagnosed intraparenchymal brain metastases from breast cancer, not suitable for surgery nor radiosurgery, were included. All patients received conformational WBRT (3 Gy x 10 to 30 Gy). They were randomized to WBRT plus concomitant TMZ administered 75 mg/m2/day during radiation period versus WBRT alone. The primary endpoint was radiologic objective response at six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (WHO modified criteria). We also evaluated neurologic symptoms, tolerance, safety, progression free survival (PFS) and overall survival (OS) as secondary endpoints. A longer clinical-brain MRI follow-up was planned, each three months during a two-year period. All of the patients gave their written informed consent to be part of the study, which was approved by the local committee. Results: One hundred patients were enrolled between February 2008 and December 2010 (50 in the WBRT + TMZ arm, 50 in the WBRT arm). The median age was 55 [29 -79]. Eighty (80) patients had brain metastases as single secondary localization. About one third of patients had a triple negative breast cancer subtype (38,3% in the association arm and 35,71% in the WBRT alone arm). There were 26,7% and 14,6% of HER2 positive subtype respectively. The median follow-up was 30 months [range 6-60]. At six months from brain metastases diagnosis (three months after the end of the treatment), objective response rate seems better in the WBRT + TMZ arm: 52% versus 40% in the arm WBRT alone but was not statistically significant (p = 0,54). No complete response was observed. In the WBRT + TMZ group, median PFS and OS at six-months were respectively 55,6% [range 46-7 – 66,0] and 67,7% [range 59,1 – 77,6]. No improvement in neurologic symptoms was noticed. In multivariate analysis, initial TNM status was significantly correlated with PFS and OS. The concurrent use of TMZ with WBRT was well-tolerated. The most frequent upper grade II acute toxicity was reversible leucopenia in the association arm. Conclusion: The addition of temozolomide to WBRT in patients with brain metastases from breast cancer did not improve local control or survival at six months follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-01.

Purpose To analyse the rate of secondary malignancies observed in a series of 675 prostate cancer patients who underwent a permanent implant brachytherapy between 1999 and 2003, and to compare the incidence with the expected rate in a matched general French population. Material and methods The cohort included low-risk patients and a selection of “favourable-intermediate” risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125-iodine seeds and a prescription dose of 145 Gy. The mean follow-up was 132 months. Results The 10-year overall survival for the entire cohort was 92% (95% confidence interval [CI]: 90–94). The 10-year relapse-free survival rate was 82% (95% CI: 79–85). Overall, 61 second cancers were registered. When comparing with a matched general French population, the standard incidence ratio (SIR) for bladder cancer was 1.02 (95% CI: 0.46–1.93). For colorectal cancer, the SIR was 0.45 (95% CI: 0.19–0.89). For lung cancer, the SIR was 0.38 (95% CI: 0.17–0.76). The SIR for all cancers was 0.61 (95% CI: 0.47–0.79). When excluding secondary colorectal and lung cancers (both with low SIRs in this series), the SIR for all cancers was 1.06 (95% CI: 0.77–1.29). Conclusion With a mean follow-up of more than 11 years, this series does not detect any excess risk of second cancers associated with permanent implant prostate brachytherapy. However, due to power limitation, a small increase in the risk of secondary malignancies cannot be totally ruled out.

International guidelines have set the frame and methods of patients’ surveillance after early breast cancer (BC) treatment. Since 1998, delegation of low-risk BC patients follow-up to nonhospital practitioners has been developed within a care network in the Paris region. We used the Gynecomed care network digital database to describe the characteristics of oncological events which occurred in the cohort, and to assess the quality of BC follow-up in relapsing patients. Events were defined as any local, contralateral, or metastatic recurrence, as well as second cancer or death due to any cause. We developed a ranked evaluation method of our surveillance program. Among the 3019 patients followed in the network, 116 (4.3%) patients had 116 events. Median follow-up was 7.1 years (0-51). First events were local-regional relapses, contralateral BCs, metastatic events, second primaries in respectively 52, 26, 14, 24 cases. During the first 5 years, 68.4% of surveillance visits were performed on time, 13.5% were behind schedule and 18.1% were not performed, while 79.1% of mammographies were performed on time, 7.7% behind schedule, and 13.2% were not performed. On schedule examinations allowed diagnosis of 77% of the local-regional, ipsilateral relapses or contralateral BCs, including 38 (69%) discovered by mammographies and 17 (31%) by clinical examination. A nonhospital practitioner care network is able to comply with good surveillance practices and deliver high quality surveillance, in accordance with international guidelines. Delegation of low-risk BC surveillance to nonhospital practitioners is reliable.

Estimating the prognostic effect of a time-dependent covariate could be tricky using a classical Cox model, despite adjustment on other known prognostic factors. This study evaluated and compared the performance of a Cox model including the covariate occurring over time as a time-dependent covariate and the so-called 'illness-death' multistate model, which is usually used to describe event-history data. We assess breast cancer prognosis related to a subsequent pregnancy occurring over time after cancer treatment in young women. We generated simulations. We considered constant and time-varying prognostic hazard ratios ( HR(t)) between patients undergoing the intermediate event and those who did not. We used both the classical Cox model and the multistate model to estimate the prognostic effect of the intermediate event HR(t). We also used the latter to estimate the covariate effect on each transition (exp(β(ij) )), thus helping to interpret HR(t) by taking into account the disease history. We applied these approaches to a female cohort treated and followed up in eight French Hospitals since 1990.

Pulmonary hypoplasia and hypertension account for significant morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). Whether CDH is associated with surfactant dysfunction remains controversial. Therefore, we measured disaturated phosphatidylcholine (DSPC) and surfactant protein (SP)-B concentration in tracheal aspirates and their synthesis rate in infants with CDH compared to infants without lung disease. (2)H2O as a precursor of DSPC and 1-(13)C-leucine as a precursor of SP-B were administered to 13 infants with CDH and eight controls matched for gestational age. DSPC and SP-B were isolated from tracheal aspirates, and their fractional synthesis rate was derived from (2)H and (13)C enrichment curves obtained by mass spectrometry. DSPC and SP-B amounts in tracheal aspirates were also measured. In infants with CDH, SP-B fractional synthesis rate and amount were 62±27% and 57±22% lower, respectively, than the value found in infants without lung disease (p

Purpose To report clinical and pathologic characteristics and outcome of breast cancer (BC) after irradiation for Hodgkin's lymphoma (HL) in women treated at the Institut Curie, with a special focus on the breast-conserving option. Methods and Materials Medical records of 72 women who developed either ductal carcinoma in situ or Stage I–III invasive carcinoma of the breast after HL between 1978 and 2009 were retrospectively reviewed. Results Median age at HL diagnosis was 23 years (range, 14–53 years). Median total dose received by the mediastinum was 40 Gy, mostly by a mantle-field technique. Breast cancers occurred after a median interval of 21 years (range, 5–40 years). Ductal invasive carcinoma and ductal carcinoma in situ represented, respectively, 51 cases (71%) and 14 cases (19%). Invasive BCs consisted of 47 cT0–2 tumors (82%), 5 cN1–3 tumors (9%), and 20 Grade 3 tumors (35%). Locoregional treatment for BCs consisted of mastectomy with (3) or without (36) radiotherapy in 39 patients and lumpectomy with (30) or without (2) adjuvant radiotherapy in 32 patients. The isocentric lateral decubitus radiation technique was used in 17 patients after breast-conserving surgery (57%). With a median follow-up of 7 years, 5-year overall survival rate and locoregional control rate were, respectively, 74.5% (95% confidence interval [CI], 64–88%) and 82% (95% CI, 72–93%) for invasive carcinoma and 100% (95% CI, 100 –100%) and 92% (95% CI, 79–100%) for in situ carcinoma. In patients with invasive tumors, the 5-year distant disease-free survival rate was 79% (95% CI, 69–91%), and 13 patients died of progressive BC. Contralateral BC was diagnosed in 10 patients (14%). Conclusions Breast-conserving treatment can be an option for BCs that occur after HL, despite prior thoracic irradiation. It should consist of lumpectomy and adjuvant breast radiotherapy with use of adequate techniques, such as the lateral decubitus isocentric position, to protect the underlying heart and lung.

Purpose There is a scarce clinical experience about adjuvant helical tomotherapy (HT) in patients affected by malignant pleural mesothelioma (MPM) even though it appears as a useful technique to treat complex volume as the pleural cavity, and seems to have better dose distribution than the “classic” intensity modulated radiotherapy (IMRT). Methods and materials Twenty-four patients received adjuvant radiotherapy (RT) by HT from August 1st, 2007 to December 1st, 2009 at Curie Institute (Paris) and Rene Gauducheau Cancer Center (Nantes). Thirteen patients had neoadjuvant chemotherapy. Extrapleural pleuropneumonectomy (EPP) was done in 23 patients. Median dose to PTV was 50 Gy [48.7–55.9 Gy] (2 Gy/fraction). Acute and long term toxicities, disease free survival (DFS), overall survival (OS) and relapses are presented. Results Average follow up after RT was 7 months. The disease was staged mostly as T2–T3, N1–N2. Nineteen patients had epithelial type histology. Most patients tolerated radiotherapy with grade 1–2 side effects: redness of the skin, light cough or dyspnea, fatigue, nausea and odynophagia, mild increase of the post-operative thoracic pain. Grade 3 pneumonitis was suspected in 2 patients. Two grade 5 pneumonitis were also suspected. Eleven patients had a follow up of more than 6 months and no long term side effects related with HT were noted. At 24 months, 51.8% of patients were free of disease. Thirty percent of patients relapsed, with 2 patients presenting local relapses. Two patients died from recurrence. Conclusion With limited follow up, HT has comparable toxicity to those observed with traditional IMRT. Higher radiation dose and good coverage results in excellent local control.

Background: To identify ER+ve ERBB2-ve ductal T1T2N0 carcinomas associated with a poor prognosis remains challenging. We have previously demonstrated that the number of chromosomal breakpoints assessed by CGH could be a marker of worse outcome for breast carcinomas. Our aim was to validate the CGH based signature in a series of luminal ductal and T1T2 N0 carcinoma patients with long-term clinical follow-up. Patients and methods: We analyzed 214 patients treated for an invasive ductal ER+ve ERBB2-ve carcinomas, smaller than 30mm. The training set was composed of 109 patients (10.9 years of median follow-up; 30 cases associated with a metastatic event within less than 4 years/79 control cases with no metastastic event at 5 years) and the validation set of 105 patients (10.5 years of median follow-up; 30 relapses including contra-lateral breast carcinomas, loco-regional relapses and 8 metastatic events). None of the patient received adjuvant chemotherapy. 16 received an adjuvant hormonotherapy (10 in the training and 6 in the validation groups). We genotyped the sample set with the SNP6.0 affymetrix array. After RMA normalisation using Genotyping console, segmentation was performed according to the Zhang and Siegmund maximum method. In the training data set, the number of breakpoints was assessed, linked to outcome and the threshold optimising the sensitivity and specificity was determined (ROC curve). The threshold prognostic value was then tested on the validation series (Kaplan Meier analysis, log rank test, determination of relative risk and its confidence interval with a Cox model). Results: In the training set, median numbers of breakpoints were 7 in cases that experienced a metastatic event after more than 5 years and 40.5 in cases that experienced a metastatic event in less than 4 years. The threshold (Younden index ) was 34 breakpoints with a sensitivity of 0.57 and a specificity of 0.94 (AUC: 0.81[0.71;0.91]). In the validation set, the outcome of patients with more than 34 breakpoints was poorer than that of patients with less than 34 breakpoints (34 breakpoints: 11 events out of 22 patients with a median time to progression of 108 months; p34 versus 34 breakpoints: 4 events out of 22 patients with a median time to progression of 108 months; p=0.009 (logrank test); RR: 5.29 [1.32; 21.26]). Conclusion: We demonstated that patients with T1T2 ( Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-01.

Introduction: AdjuvantOnline is a web-based application designed to provide 10 years survival probability patients with breast cancer. Few validation studies have underlined some limitations, particularly an overestimation of the prognosis among certain subgroups of patients. Moreover, several predictors such as HER2 over expression status and proliferation markers have not been assessed in Adjuvant! original study. We provide the validation of AdjuvantOnline algorithm on two breast cancer datasets collected from two large European cancer centres, and we determined whether the accuracy of AdjuvantOnline is improved by others well known prognostic factors. Material and Methods: The French data set is composed of 456 women with early breast cancer, treated at the Institut Curie between 1995 and 1996. The dutch data set is composed of 295 women less that 52 years treated at the Netherlands Cancer Institute between 1984 and 1995. Agreement between observation and Adjuvant! prediction was checked by testing that the calibration slope was equal to 1. Logistic models were performed to evaluate whether risk factors adds significant prognostic information, including AdjuvantOnline a priori information as an offset. Results: Ten years survival status was known for 383 patients in the French data set and 247 patients in the Dutch data set. Adjuvant! prediction was globally well calibrated in the French data set (observed survival 86%, predicted survival 85%), but was overestimated in high grade, HER2 positive and Ki67 > 20% subgroups. HER2 status, Mitotic Index, Ki67 and treatment type were strongly associated with 10-year survival, even considering AdjuvantOnline a priori information. In the Dutch data set, the overall 10-year survival was overestimated by AdjuvantOnline (observed 66%, predicted 79%), particularly in patients less than 40 years old. Conclusion: AdjuvantOnline needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider candidates, such as Ki67, HER2 and Mitotic Index. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-13.

Mammalian cells possess two isoforms of the histone H3–H4 chaperone anti-silencing function 1 (Asf1), Asf1a and Asf1b. However to date, whether they have individual physiological roles has remained elusive. Here, we aim to elucidate the functional importance of Asf1 isoforms concerning both basic and applied aspects. First, we reveal a specific proliferation-dependent expression of human Asf1b unparalleled by Asf1a. Strikingly, in cultured cells, both mRNA and protein corresponding to Asf1b decrease upon cell cycle exit. Depletion of Asf1b severely compromises proliferation, leads to aberrant nuclear structures and a distinct transcriptional signature. Second, a major physiological implication is found in the applied context of tissue samples derived from early stage breast tumours in which we examined Asf1a/b levels. We reveal that overexpression of Asf1b mRNA correlate with clinical data and disease outcome. Together, our results highlight a distribution of tasks between the distinct Asf1 isoforms, which emphasizes a specialized function of Asf1b required for proliferation capacity. We discuss the implications of these results for breast cancer diagnosis and prognosis.

Polo S E, Theocharis S E, Grandin L, Gambotti L, Antoni G, Savignoni A, Asselain B, Patsouris E & Almouzni G (2010) Histopathology 57, 716–724 Clinical significance and prognostic value of chromatin assembly factor-1 overexpression in human solid tumours Aims: Chromatin assembly factor-1 (CAF-1), whose function is critical for maintaining chromatin stability during DNA replication and repair, has been identified as a proliferation marker in breast cancer. The aim was to investigate CAF-1 as a proliferation marker in a wide variety of solid tumours, and to assess its potential value in predicting clinical outcome. Methods and results: Using immunocytochemistry on paraffin-embedded tissue sections, the CAF-1 labelling index was compared with known proliferation markers Ki-67 and minichromosome maintenance (MCM), and its association with clinicopathological data and patients’ outcome analysed. CAF-1 expression showed a strong positive correlation with Ki-67, used routinely to detect proliferating cells, while it generally displayed weaker correlations with MCM markers, known to label cells with replicative potential. CAF-1 expression was associated significantly with histological grade in breast, cervical, endometrial and renal cell carcinomas, and with disease stage in endometrial and renal carcinomas. Furthermore, high expression of CAF-1 was an independent predictor of adverse clinical outcome in renal, endometrial and cervical carcinomas. Conclusions: CAF-1 is a proliferation marker in various malignant tumours with prognostic value in renal, endometrial and cervical carcinomas, which supports the value of CAF-1 as a clinical marker of cancer progression.

Predicting evolution of small node-negative breast carcinoma is a real challenge in clinical practice. The aim of this study was to search whether qualitative or quantitative DNA changes may help to predict metastasis of small node-negative breast carcinoma. Small invasive ductal carcinomas without axillary lymph node involvement (T1T2N0) from 168 patients with either good (111 patients with no event at 5 years after diagnosis) or poor (57 patients with early metastasis) outcome were analyzed with comparative genomic hybridization (CGH) array. A CGH classifier, identifying low- and high-risk groups of metastatic recurrence, was established in a training set of 78 patients, then validated, and compared with clinicopathological parameters in a distinct set of 90 patients. The genomic status of regions located on 2p22.2, 3p23, and 8q21-24 and the number of segmental alterations were defined in the training set to classify tumors into low- or high-risk groups. In the validation set, in addition to estrogen receptors and grade, this CGH classifier provided significant prognostic information in multivariate analysis (odds ratio, 3.34; 95% confidence interval 1.01-11.02; P = 4.78 × 10(-2), Wald test). This study shows that tumor DNA contains important prognostic information that may help to predict metastasis in T1T2N0 tumors of the breast.

The objective of this study was to assess the prevalence and associated factors of sexual activity, sexual problems or sexual satisfaction in French early-stage breast cancer survivors (BCS).Eight hundred and fifty eligible, post-treatment (6 months-5 years) female patients, aged 18-70 years, randomly selected from a consultation list, were invited to fill in questionnaires exploring quality of life (EORTC QLQ-C30 and QLQ-BR23), body image scale, and sexuality (Sexual Activity Questionnaire-SAQ; Relationship and Sexuality Scale; French Sexual Behaviour Survey-CSF).Fifty-three percent of BCS agreed to participate. Participating women (n=378) were younger, more often premenopausal at diagnosis and with a more recent diagnosis than non-respondents. The prevalence of sexual problems was significantly higher in BCS compared with adjusted data from a French female representative sample (p0.0001). In logistic regression, no sexual activity (R(2) =0.37) or sexual dissatisfaction (R(2) =0.28) were associated with the feeling of emotional separation in the couple or of partner's fear of sexual intercourse, lower emotional functioning, poorer body image, or co-morbidities. In sexually active women (71% of respondents), lower frequency of sexual activity (R(2) =0.26), lower sexual pleasure (R(2) =0.22), or higher sexual discomfort (R(2) =0.22) were associated with the feeling of emotional separation in the couple or of partner's fear of sexual intercourse, lower emotional functioning, age (50 years), nausea, or insomnia (all Hosmer-Lemeshow tests: p=NS).Psychological factors including the perception of the couple relationship appeared prominent in BCS women's experience of sexual problems.

10555Background: Over the past twenty-five years, the introduction of systemic chemotherapy combined to local treatments has enabled to dramatically increase globe retention for retinoblastoma (RB)...

e21501Background: Prognosis of MUM is poor, with a median overall survival (OS) of 12 months (mo) and a 80% mortality rate within the first year. Rare patients (pts) achieve long-term survival, var...

Background Carboplatin plays an important role in the conservative management of retinoblastoma, but is associated with risk of ototoxicity in these young children whose sensory prognosis may be also compromised by their loss of vision. This retrospective study analyzed the impact of carboplatin on hearing in the context of conservative management of children with retinoblastoma. Methods Data for 175 children treated at the Institut Curie between 1994 and 2002 were analyzed. Results Median age at diagnosis was 8 months (0–60). Carboplatin was administered on 3 days (200 mg/m2/day) or 5 days (160 mg/m2/day) with etoposide and with diode-laser therapy at the dose of 560 mg/m2 (chemothermotherapy). Median cumulative dose of carboplatin was 2,880 mg/m2 (560–6,160). Ototoxicity was investigated by pure-tone audiometry and scored by Brock's grading scale before and after treatment. The median follow-up of hearing assessment was 5 years (1.8–11). Ototoxicity was detected in 8 children: 3 grade 1, 1 grade 2, and 2 grade 4. The two patients with grade 4 hearing-loss required a hearing aid. Two children developed bilateral high frequency hearing-loss, considered to be secondary to carboplatin but with less than Brock grade 1. Ototoxicity was observed for a median cumulative dose of carboplatin of 3,120 mg/m2 (1,200–5,830). Only one child developed ototoxicity during treatment. All other cases were discovered after the last dose of carboplatin with a median interval of 3.7 years (0–7.6). No other risk factor for ototoxicity was able to account for these lesions. Conclusion Children receiving carboplatin require long-term audiometric follow-up. Pediatr Blood Cancer 2009;52:637–643. © 2009 Wiley-Liss, Inc.

The literature reports low rates of breast conservation after neoadjuvant chemotherapy for operable breast cancers not amenable to initial breast-conserving surgery. This study aims to compare the outcome of lobular vs ductal carcinomas after neoadjuvant chemotherapy. Between 1989 and 1999, 750 patients with clinical stage II/IIIA ductal (672) or lobular (78) invasive breast carcinomas were treated at the Institut Curie with primary anthracycline-based polychemotherapy followed by either breast conservation (surgery and/or radiotherapy) or mastectomy. Median follow-up was 10 years. Clinical response to primary chemotherapy was significantly worse for lobular than for ductal carcinomas (47 vs 60%; P=0.04), but only histological grade remained predictive in multivariate analysis. Breast conservation was high for both ductal and lobular carcinomas (65 and 54%; P=0.07), due, in part, to the use of radiotherapy, either exclusive or preoperative, for respectively 26 and 40% of patients. The lobular type had no adverse effect, neither on locoregional control nor on overall survival, even in the group of patients treated with breast conservation.

OBJECTIVES: We compared the relative effect of hypertensive disorders of pregnancy and chorioamnionitis on adverse neonatal outcomes in very preterm neonates, and studied whether gestational age (GA) modulates these effects. METHODS: A cohort of neonates 23 to 30 weeks' GA, born in 2008 to 2011 in 82 hospitals adhering to the Italian Neonatal Network, was analyzed. Infants born from mothers who had hypertensive disorders (N = 2096) were compared with those born after chorioamnionitis (N = 1510). Statistical analysis employed logistic models, adjusting for GA, hospital, and potential confounders. RESULTS: Overall mortality was higher after hypertension than after chorioamnionitis (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.08–1.80), but this relationship changed across GA weeks; the OR for hypertension was highest at low GA, whereas from 28 weeks' GA onward, mortality was higher for chorioamnionitis. For other outcomes, the relative risks were constant across GA; infants born after hypertension had an increased risk for bronchopulmonary dysplasia (OR, 2.20; 95% CI, 1.68–2.88) and severe retinopathy of prematurity (OR, 1.48; 95% CI, 1.02–2.15), whereas there was a lower risk for early-onset sepsis (OR, 0.25; 95% CI, 0.19–0.34), severe intraventricular hemorrhage (OR, 0.65; 95% CI, 0.48–0.88), periventricular leukomalacia (OR, 0.70; 95% CI, 0.48–1.01), and surgical necrotizing enterocolitis or gastrointestinal perforation (OR, 0.47; 95% CI, 0.31–0.72). CONCLUSIONS: Mortality and other adverse outcomes in very preterm infants depend on antecedents of preterm birth. Hypertension and chorioamnionitis are associated with different patterns of outcomes; for mortality, the effect changes across GA weeks.

The characteristics of ipsilateral breast tumour recurrences (IBTRs) relative to those of their primary tumours (PTs) remain scarcely studied. Of 70 young (or =40 years) premenopausal women with IBTRs, we studied a series of 63 with paired histological data. Median follow-up since IBTR was 10 years. Rates of histological types, grades or hormonal receptors were not significantly different in PTs and in IBTRs. The concordance between IBTRs and their PTs was good for histological types. IBTRs with conserved histological types tended to occur more locally, but not significantly sooner than others. These IBTRs had good concordance for hormone receptors. In discordant cases there were as many losses as appearances of the receptors. The concordance was weak for grades, with equivalent numbers of IBTRs graded lower as higher than their PTs. The 10-year overall survival rate was 70%. Neither the conservation of histological type, location, nor of the two combined were associated with deaths. Early (2 years) IBTRs, tended to be associated with poorer survival (HR=2.24 (0.92-5.41); P=0.08). IBTRs did not display features of higher aggressiveness than PTs. Neither clinical nor histological definition of a true recurrence could be established other than the conservation of the histological type.