Ligue Nationale Contre Le Cancer Research Articles

Predictive genomic and transcriptomic analysis on endoscopic ultrasound-guided fine needle aspiration materials from primary pancreatic adenocarcinoma: a prospective multicentre study

We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p=0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p=0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p=0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p=0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p=0.019). The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

Les forums de discussion dédiés au cancer du sein peuvent-ils être utiles aux soignants ? Analyse des messages initiaux du forum de la Ligue nationale contre le cancer pendant une année

ObjectivesForums are a source of health information and exchange. They can be studied to determine patients’ needs and improve caregivers’ practices. The aim of this study was to identify the needs of breast cancer patients based on messages posted on a discussion forum. MethodsInitial messages posted in 2021 on the Ligue nationale contre le cancer (LNCC) breast cancer forum were analyzed quantitatively. Message content was classified into three categories: testimonial, request for advice or request for medical opinion. The tone of the message (positive, neutral, or negative) was recorded. The temporality of the illness during which the patient expressed herself was defined. Analysis was carried out on the initial messages using the Chi2, Fisher, and Kruskal-Wallis tests, with a significance level of<0.05. ResultsIn 2021, 640 initial messages posted on the LNCC forum dedicated to breast cancer were analyzed. Messages were posted by 312 authors, including 275 patients and 37 family members. Three main types of messages were identified: requests for medical advice (n=339), advice (n=164), and testimonials (n=137). Requests for medical advice elicited fewer responses than testimonials (P<0.001). A need for supportive care was identified in 42.8% of messages, mostly concerning social (17.3%) and psychological (13%) care. ConclusionOur study revealed a need for more information especially regarding the social impact of the disease and the side-effects of treatment. The period of greatest need of information was the diagnostic waiting time. However, patients using discussion forums are not representative of all women with breast cancer and our results should not be generalized to all patients treated for breast cancer.

Patients' contribution to the review of research protocols

Involvement of patients in the ethical management of research protocols began by patients' associations involved in the fight against AIDS in France in the 1990s. It was the first step towards recognizing the major role of patients in research that concerns them. This article aims describing this emancipation and its consequences on the evolution of research by drawing on two experiences: 1) The one of the «Comité de patients pour la recherche clinique» founded in 1998 by the «Ligue nationale contre le cancer» and by the «Fédération nationale des centres de lutte contre le cancer»; 2) The one of the «Collège des relecteurs de l'Inserm» set up in 2007.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. Institut National du Cancer and Ligue Nationale Contre le Cancer.

Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial

Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC. In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling. Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported. The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures. French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology. For the French translation of the abstract see Supplementary Materials section.

Potential clinical activity of pembrolizumab monotherapy in ovarian sex cords, rare epithelial carcinoma, and other rare ovarian tumor histotypes: The French AcSé pembrolizumab study from Unicancer.

5572 Background: AcSé Pembrolizumab is a Phase 2, non-randomized parallel arms, multicentric basket trial investigating the efficacy and safety of pembrolizumab monotherapy in different cohorts of patients with rare cancers (NCT03012620). Here we report the results in the rare ovarian tumors cohort. Methods: Selected histotypes were all rare ovarian cancers (incidence &lt; 6/100,000/year). Main inclusion criteria were age &gt; 18, ECOG PS≤1, resistant disease to platinum based chemotherapy, and systematic histological central review by expert pathologist from TMRG network. Patients (pts) received pembrolizumab 200 mg IV on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1 at 12 weeks. Secondary endpoints included best response rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. The 7 subgroups of pts analyzed were carcinosarcoma (CS), clear cell carcinoma (CCC), low grade serous carcinoma (LGSC), mucinous carcinoma (MEOC), sex cord tumors (SCT), germ cell tumor (GCT), and smarcA4 deficient hypercalcemic ovarian tumor (SCHOCCT). Results: 62 pts from 22 centers, were included from 08/2017 to 12/2020. Median Age was 53.5 years old [36-64]. Median number of previous lines of chemotherapy was 2 (range 1-4). The median number of cycles was 8 (range, 1-35) with 44 pts (70.9%) who discontinued the trial after a mean number of 6.8 cycles. There were 2 pts (3.2%) with partial response (PR) at 12 weeks. The best response in ITT was complete response (CR) in 1 patient (1%), PR in 3 (14.3%), and stable disease (SD) in 21 (33.8%). The occurrence of best response depended on the histotype with 1 CR (33%) in GCT (cancerized teratoma), 2 PR (20%) in CCC, and 1 PR (4%) in LGSC. 4/4 pts (100%) reported PD as best response in SCOOHT (Table 1). Median duration of response or stabilized disease was 7.8 months [IQR, 4.1 to 9.0]. At the data cut off, 6-month PFS was 29% [19.7-42.8] and 6-month OS was 77.8% [67.7-89.3] on the overall population. Outcomes differed according to subgroups and will be presented. There were a total of 62 adverse events (AEs) reported in 28 pts. For 5 pts (8%) AEs lead to drug discontinuation. AEs were of grade 1 (n = 9), grade 2 (n = 8), or grade ≥ 3 (n = 45: 42 grade 3, 2 grade 4, and 1 grade 5). Conclusions: Pembrolizumab is safe and well tolerate in this population of rare ovarian cancer pts. AcSé study reports prolonged responses in very selected subtypes of rare ovarian tumor (CCC, cancerized teratoma, and LGCS). Acknowledgements: TMRG (national cancer network dedicated to rare gynecological tumors), GINECO group for partnership, La Ligue Nationale contre le Cancer, INCa and MSD. Clinical trial information: NCT03012620. [Table: see text]

LTi-like type 3 innate lymphoid cells are associated with the transient induction of tertiary lymphoid structures in inflamed pulmonary tissue

Abstract Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates observed in inflamed tissues. Their presence in pulmonary tissue has been associated with good prognosis in patients with lung cancer. Although TLS formation shares common features with secondary lymphoid organogenesis, the mechanisms underlying this process are yet to be fully elucidated. Presence of ILC3 in the vicinity of tumor-associated TLS correlates with the density of lymphoid structures. We hypothesized that RORγt+ ILC3 play a major role in TLS induction in inflamed lungs, as do RORγt+ fetal lymphoid tissue inducer cells (LTi) during lymph node formation. We developed a murine model of pulmonary inflammation induced by LPS intranasal instillation that triggers TLS formation. ILC3 presence in lungs was observed with a specific flow cytometry antibody panel. Three RORgt+ILC3 subsets (NCR− CCR6−, NCR−CCR6+, NCR+CCR6−) were detected. In particular, NCR−CCR6+ LTi-like cells represented about 25% of CD117+CD127+ILC (ILC2/ILC3) and less than 0.04% among CD45+ cells. Analyses of ILC subsets at different time points following LPS instillation showed an increase in the number and % (up to 0.59%) of ILC3 among CD45+ cells, as well as an increase in the % of LTi-like ILC3 among CD45+ cells, that peaked around day 10 (from 0.02% up to 0.15%). Quantification of TLS by histochemistry showed that they are induced in lung tissue in an LPS dose-dependent manner. TLS density increases between days 3 and 10 and decreases thereafter. They were no longer detected at day 25, while LTi-like ILC3 % returned to baseline. Gene expression analysis and functional assays of sorted LTi-like ILC3 are essential to determine if these cells are key players in TLS induction. Supported by grants from La Ligue Nationale contre le cancer (TAHG21042) and Fondation ARC (R19232DD).

Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma.

Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma.

A glycosyltransferase gene signature to detect pancreatic ductal adenocarcinoma patients with poor prognosis.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by an important heterogeneity, reflected by different clinical outcomes and chemoresistance. During carcinogenesis, tumor cells display aberrant glycosylated structures, synthetized by deregulated glycosyltransferases, supporting the tumor progression. In this study, we aimed to determine whether PDAC could be stratified through their glycosyltransferase expression profiles better than the current binary classification (basal-like and classical) in order to improve detection of patients with poor prognosis.MethodsBioinformatic analysis of 169 glycosyltransferase RNA sequencing data were performed for 74 patient-derived xenografts (PDX) of resected and unresectable tumors. The Australian cohort of International Cancer Genome Consortium and the microarray dataset from Puleo patient's cohort were used as independent validation datasets.FindingsNew PDAC stratification based on glycosyltransferase expression profile allowed to distinguish different groups of patients with distinct clinical outcome (p-value = 0.007). A combination of 19 glycosyltransferases differentially expressed in PDX defined a glyco-signature, whose prognostic value was validated on datasets including resected whole tumor tissues. The glyco-signature was able to discriminate three clusters of PDAC patients on the validation cohorts, two clusters displaying a short overall survival compared to one cluster having a better prognosis. Both poor prognostic clusters having different glyco-profiles in Puleo patient's cohort were correlated with stroma activated or desmoplastic subtypes corresponding to distinct microenvironment features (p-value < 0.0001). Besides, differential expression and enrichment analyses revealed deregulated functional pathways specific to different clusters.InterpretationThis study identifies a glyco-signature relevant for a prognostic use, potentially applicable to resected and unresectable PDAC. Furthermore, it provides new potential therapeutic targets.FundingThis work was supported by INCa (Grants number 2018-078 and 2018-079), Fondation ARC (Grant number ARCPJA32020070002326), Cancéropôle PACA, DGOS (labelization SIRIC, Grant number 6038), Amidex Foundation and Ligue Nationale Contre le Cancer and by institutional fundings from INSERM and the Aix-Marseille Université.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial

Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis

Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies and Myeloma

Background: Multiple myeloma remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Methods: We studied thirteen patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma with previous HCV infection. Viral load was quantified using the VERIS MDx system. The antigen specificity of purified monoclonal immunoglobulins was determined using the INNO-LIA HCV Score, dot-blot assays, and a multiplex infectious-antigen microarray. Findings: The target of the purified monoclonal immunoglobulin was identified for 8/13 patients. The monoclonal immunoglobulin from 6/8 patients reacted against HCV. Four of the patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with multiple myeloma in third relapse achieved complete remission with minimal residual disease negativity, as assessed by next generation multiparameter flow cytometry. Two patients did not receive antiviral treatment and progressed. For the two additional patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or multiple myeloma disease. Interpretation: Our results suggest a causal relationship between HCV infection and MGUS and multiple myeloma progression. When HCV is eliminated, chronic antigen-stimulation disappears, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and multiple myeloma. Funding Statement: This work was supported by grants to S.H. from the Ligue Nationale contre le Cancer (Comites Departementaux 44, 56, 29, 85, 35) and International Myeloma Foundation (IMF) (Brian D. Novis senior grant). We acknowledge of Instituto de Investigacion Hospital 12 de Octubre (i+12), CIBERONC, AECC (Accelerator Award), and the CRIS foundation for their help. M.L. had a postdoctoral fellowship from the Spanish Ministry of Economy and Competitiveness (FPDI-2013-16409) and a grant from the Spanish Society of Hematology Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by our Institutional Review Board and the patients provided written informed consent in accordance with the Declaration of Helsinki.

1271P - High clinical benefit rates of pembrolizumab in very rare sarcoma histotypes: First results of the AcSé pembrolizumab study

BackgroundAcSé Pembrolizumab is a Phase II, non-randomized parallel arm, open-label, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with rare cancers (NCT03012620). Here we report the first results of pembrolizumab in the sarcoma arm including chordomas, alveolar soft part sarcoma (ASPS), rhabdoid tumors, SMARCA4 deficient sarcomas and desmoplastic small round cell tumors (DSRCT). MethodsSelected histotypes were all rare sarcomas (incidence <0.2/100000/year). Main inclusion criteria were age>18, PS≤1, and advanced disease resistant to standard treatment. Patients received pembrolizumab 200mg IV as a 30-minute infusion on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1. Secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results21 patients with a primary diagnosis of chordoma (n=12, 57%), ASPS (n=6, 28%), or DSRCT, rhabdoid tumor and SMARCA4-deficient sarcoma (n=3, 15%) were included from October 2017 to October 2018. The median number of cycle was 11 (range 1-23) with 9 (42.9%) patients who discontinued the trial after a median of 5 cycles. Three patients died after a median of 2 cycles due to progression (n=2) or an unrelated cause (n=1, trauma). For the population, the complete response/partial response (PR)/stable disease (SD) rates was 85% with 3 (15%) patients who achieved PR (DSRCT, rhabdoid, chordoma) and 16 (80%) with SD, after a median follow-up of 7.7 months (range 0-15.2). The median PFS was 11.5 months, the 6-month PFS was 61.5% and the 6-month OS was 85.2%. In subgroup analyses, the median PFS was 5.7 months for patients with chordoma and not reached for patients with ASPS. The 6-month OS rate was 75% in chordomas and 100% in the ASPS cohort. The basal clinical (histology) or biological (potassium, C-reactive protein, and lymphocyte levels) parameters tested were not predictive factors of PFS. The toxicity profile was similar to that observed in other cancers. ConclusionsPembrolizumab shows high levels of prolonged activity in selected subtypes of rare sarcomas. Clinical trial identificationNCT03012620 EudraCT 2016-002260-14. Legal entity responsible for the studyR&D UNICANCER. FundingLa Ligue Nationale contre le Cancer, Institut National du Cancer (INCa), MSD. DisclosureJ. Blay: Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Innate. C.M. Chevreau: Advisory / Consultancy: MSD. J. Soria: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Gritstone; Advisory / Consultancy: Astex; Advisory / Consultancy: Clovis; Advisory / Consultancy: GSK; Advisory / Consultancy: GammaMabs; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Mission Therapeutics; Advisory / Consultancy: Merus; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Takeda. C. Massard: Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: CelGene; Advisory / Consultancy: Debiopharm; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy: Lilly; Advisory / Consultancy: MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Orion; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Merck; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: CelGene; Advisory / Consultancy: Debiopharm. All other authors have declared no conflicts of interest.

178PD - Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the HER2-positive subgroup

BackgroundLong term information on the risk/benefit ratio of currently available therapies remains crucial for treatment decisions. In the PACS04 phase III trial, patients (pts) with node-positive (N+) breast cancer (BC) were double-randomized to concomitant taxane-anthracycline versus standard FEC, as well as 1-year trastuzumab versus nill in the HER2+ subpopulation. Methods3009 pts (20% HER2+, 12% triple negative (TNBC) BC) were randomly assigned to receive 6 cycles of fluorouracil 500mg/m2, epirubicin 100mg/m2 and cyclophosphamide 500mg/m2 (FEC) or epirubicin 75mg/m2 and docetaxel 75mg/m2 (ED). Pts with HER2+ tumors were randomized to either trastuzumab (TRA) for one year, or observation (OBS). The primary endpoint was disease-free survival (DFS). ResultsAfter a median 115-month follow-up, DFS was not different in the ED compared to the FEC arm (70% vs 68% respectively, HR=0.88 [95% CI: 0.77-1.01]; p=0.064), nor was OS: 80% with FEC and 81% with ED (HR=0.97 [95% CI: 0.81-1.16]; p=0.729). Subgroup analysis suggested better DFS with ED in non-TNBC pts [HR=0.82 (0.71-9.96) p=0.02]. In the 528 pts with HER2+ BC, there was trend for a higher DFS in the TRA arm (68%; [95% CI: 61-74]) versus the OBS arm (60%; [95% CI: 54-66]); HR=0.77 [95% CI:0.57-1.03]; p=0.079 (intent to treat population). In the per protocol population, DFS, but not OS, was significantly higher in the TRA arm (HR: 0.69 [95%CI: 0.51-0.94]; p=0.0156). ED led to more neurological and hematological toxicities (31% vs 11% febrile neutropenia) and led to 5 versus 1 treatment-related deaths. During follow-up, 75 pts developed a second non-breast primary cancer (43 with FEC and 32 with ED); 12 were hematologic malignancies (7 with FEC and 5 with ED). Long term cardiac deaths were rare (3 with FEC and 1 with ED). ConclusionsThis study did not show superiority of the concomitant anthracycline-taxane arm, which was more toxic in high-risk N+ BC pts. Long-term results of the HER2+ subpopulation are in line with the other adjuvant TRA trials but less striking probably due to lack of power. Long term cardiac toxicity and second primary cancer rate are similar to what has been reported by others. Clinical trial identificationNCT00054587. Legal entity responsible for the studyUNICANCER. 101 rue Tolbiac, 75013 Paris, France. FundingRoche, Ligue Nationale Contre le Cancer. DisclosureAll authors have declared no conflicts of interest.

1678PD - Immune classification of soft tissue sarcoma predicts clinical outcome

BackgroundSoft tissue sarcomas (STS) form a group of rare cancers which accounts for around 1% of tumours. Although up to 15% of patients respond in immunotherapy trials, there are no biomarkers predicting response of STS to checkpoint blockade therapies yet. MethodsWe analysed transcriptomic data of 4 publicly available cohorts, accounting for more than 600 STS. We used MCP-counter, a deconvolution method to estimate the tumour microenvironment (TME) composition Based on MCP-counter estimates, we established a robust immune classificationof STS tumors into 5 Sarcoma Immune Classes, labelled A, B, C, D and E. These classes exhibited different type and extents of TME. We validated the profiles of these 5 groups on a 72-patients cohort using immunohistochemichal (IHC) stainings for CD3, CD8, CD20 and CD34. ResultsOne group (A: 23.3% of tumours) exhibits a very low to low immune infiltrate for all TME cell types. Another class (C: 14.5% of all tumours) displays moderate immune infiltrate and a strong presence of endothelial cells. Finally, another group (E: 15.6%) is highly infiltrated by all immune cell types. The two remaining groups (B: 27.4% and D: 19.4%) are heterogeneous, respectively rather highly and lowly infiltrated. The immune high group E is associated with an overexpression of several immune checkpoint genes: PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), LAG3, HAVCR2 (TIM-3), CTLA4. On 72 patients, we showed that the immune-high group could be identified by the IHC-visible presence of tertiary lymphoid structures (TLS), defined as T cell aggregates juxtaposing B cell aggregates. The immune-high group also exhibited prolonged overall survival as compared with other groups. Using data from a phase II clinical trial with pembrolizumab, we show that responders can be identified as class E tumours, therefore allowing patient selection. ConclusionsWe have defined a novel immune-based classification of STS into 5 classes, among which an immune-high group characterized by a strong infiltration by all immune cell and expression of immune checkpoints, presence of TLS and longer overall survival. This class groups responders to PD-1 blockade in a phase II clinical trial. Legal entity responsible for the studyINSERM. FundingInstitut National de la Santé et de la Recherche Médicale, the University of Paris, Sorbonne University, the Programme Cartes d’Identité des Tumeurs (CIT) from the Ligue Nationale Contre le Cancer, Institut National du Cancer (HTE-INSERM plan cancer, C16082DS), Association pour la Recherche sur le Cancer (ARC), Cancer Research for Personalized Medecine programme, “FONCER contre le cancer” programme, Labex Immuno-Oncology, the National Institute of Health, Moon Shot program at MD Anderson Cancer Center, Ministry of Education and Ministry of Science and Technology of Taiwan, National Taiwan University, Merck, Inc, SARC, Sarcoma Foundation of America, and the QuadW Foundation. DisclosureT.W. Chen: Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy: Lilly. M.A. Burgess: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Eisai. J. Wargo: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Illumina. H.A. Tawbi: Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self): Celgene; Research grant / Funding (self): GSK. W.H. Fridman: Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.

569P - FUSAFE individual patient data meta-analysis (MA) to assess the performance of dihydropyrimidine dehydrogenase (DPD) gene polymorphisms for predicting grade 4-5 fluoropyrimidine (FP) toxicity

BackgroundDespite decades of research, performance of DPYD genotyping to predict FP toxicity (tox) is poorly documented. GPCO-UNICANCER and RNPGx groups initiated the FUSAFE MA on individual patient data (IPD) to assess the prognostic value of consensual deleterious DPYD variants on grade (G) 4-5 FP tox. MethodsEligibility criteria included unbiased recruitment of Caucasian patients (pts) without FP dose adjustment based on DPD status. Main endpoint was 12 weeks hematological or digestive G4-5 tox. Age, sex, body mass index (BMI), advanced stage (M- vs M+), FP drug (5FU vs capecitabine), FP administration (bolus±continuous vs continuous alone or p.o.) and associated anticancer drugs (AAD) were collected. Multivariable logistic models were applied. Performance was assessed by AUC and diagnostic indices maximizing Youden index. ResultsFrom the 18 identified eligible studies (10230 pts), 14 were included (9030 pts), with complete IPD collected for 6403 pts (84% colorectal, 16% M+, 66% 5FU, 80% AAD). G4-5 tox prevalence was 8% (518 events). DPYD variants *2A, D949V, *13 and HapB3 were carried by 0.9%, 1.2%, 0.2% and 3.9% of pts, respectively. The clinical model (M1) retained age, sex, BMI, FP-administration, AAD. Adding variants *2A/D949V/*13 (at least one mutated allele) significantly (p<.0001) improved the model (M2). Further adding HapB3 did not improve the model (p=.24, M3). M3-adjusted OR (95%CI) was 10.0 (6.9-14.7) for the 3 variants *2A/D949V/*13 and 2.1 (1.4-3.0) for HapB3. Similar results were observed on colorectal pts only, or when excluding bolus administration alone.Table569PTableModelAUC (area under the curve)SensitivitySpecificityPositive predictive valueNegative predictive valueM10.72569.7%65.4%15.1%96.1%M20.75075.5%62.8%15.2%96.7%M30.75276.4%61.9%15.0%96.8% ConclusionsThis is the largest MA on DPYD genotyping and toxicity. It shows the relevance of clinical variables and of the 3 consensual DPYD variants. Despite its association with tox, HapB3 does not improve the discriminant ability to identify pts at risk of G4-5 toxicity. Legal entity responsible for the studyCentre Antoine Lacassagne, Nice, France (Dr Marie-Christine Etienne-Grimaldi, coordinator). FundingFrench Cancer Institute (INCa) funding (PHRC-K 14-193 FUSAFE) and French Ligue Nationale Contre le Cancer. DisclosureV. Boige: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Prestizia; Advisory / Consultancy: Eisai; Travel / Accommodation / Expenses: Sanofi. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre. D. Meulendijks: Full / Part-time employment: AstraZeneca UK. C. Palles: Advisory / Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing / Royalties: Robert Bosch GmbH. M. Boisdron-Celle: Speaker Bureau / Expert testimony, Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: ODPM. A. Marinaki: Full / Part-time employment: Viapath. E. Gross: Licensing / Royalties: Klinikum Rechts der Isar der Technischen Universitat Munchen. All other authors have declared no conflicts of interest.

1239P - High level of activity of nivolumab anti-PD-1 immunotherapy and favorable outcome in metastatic/refractory MSI-H non-colorectal cancer: Results of the MSI cohort from the French AcSé program

Abstract Background Microsatellite instability-high (MSI-H) is observed in a large variety of cancer types. Immune checkpoint targeted therapies against PD-1 and CTLA-4 have demonstrated significant activity in metastatic colorectal cancer (mCRC) with nivolumab +/- ipilimumab. We aimed to demonstrate a clinical benefit of nivolumab in non-CRC MSI patients. Methods The AcSe immunotherapy program launched by the French National Cancer Institute (INCa) and sponsored by the French network of comprehensive cancer centers (Unicancer) is a nationwide exploratory program which has allowed access to anti-PD-1 therapies outside of their current approvals. A phase II, single arm, AcSe-nivolumab trial has been conducted to investigate the efficacy and tolerance of nivolumab in patients with metastastic/refractory rare tumor types. Here we report the results of the MSI cohort. Nivolumab (240 mg IV) was administered q2w for a max of 2 years or until disease progression (PD), or toxicity. The primary endpoint was the objective response rate (ORR) assessed by RECIST v1.1 at 12 weeks. Results From July 2017 to October 2018, 50 pts (mean age 63 years) were included. Primary locations were endometrial adenoCa (17), gastric (10), small bowel (7), pancreas (5), biliary (4), urothelial (2), ovary (2), and breast (2). 15 patients (30%) had a Lynch syndrome. All patients were pre-treated (mean of previous lines: 1.6) and had a MSI status locally determined by IHC and/or PCR (IHC 15 pts, PCR 4, both 31). The mean number of cycles/patients was 12.9. The ORR at 12 weeks was 38% (95%CI 24.6 to 52.8) and the best ORR at any time was 42% (95%CI, 28.2 to 56.8) with median time to response of 14 weeks. CR: n = 2; PR: n = 17; SD: n = 16; DCR=74%. Median PFS was not reached with a 6-mo PFS at 58.9% (95%CI, 46.5 to 74.6). At the date of analysis, 15 patients died (PD 13, drug related death 1, other 1), with a 6-mo OS rate at 80.3% (95%CI, 69.5 to 92.8). No unexpected adverse event of nivolumab has been observed. Conclusions Nivolumab as monotherapy is highly active in non-colorectal MSI patients, outperforming results of classical chemotherapy in this heavily pre-treated population. Clinical trial identification NCT03012581, EudraCT 2016-002257-37. Legal entity responsible for the study RD Honoraria (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (institution), Travel / Accommodation / Expenses: BMS. E. Saada-Bouzid: Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck Serono. D. Pouessel: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): A2; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: BMS. C. Le Tourneau: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: GSK. P. Augereau: Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca. J. Soria: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Gritstone; Advisory / Consultancy: Astex; Advisory / Consultancy: Clovis; Advisory / Consultancy: GSK; Advisory / Consultancy: GammaMabs; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Mission Therapeutics; Advisory / Consultancy: Merus; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Takeda. A. Marabelle: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Fondation MSD Avenir; Advisory / Consultancy: Oncovir; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy: eTheRNA; Advisory / Consultancy, Research grant / Funding (self): Lytix pharma; Advisory / Consultancy: Kyowa Kirin Pharma; Advisory / Consultancy: Novartis, Seattle Genetics, Molecular Partners; Advisory / Consultancy: Symphogen, Bayer, Partner Therapeutics; Advisory / Consultancy: Genmab, RedX pharma, OSE Immunotherapeutics; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen, Sanofi, Servier; Advisory / Consultancy: Biothera, Gritstone; Advisory / Consultancy: Nektar, Pierre Fabre; Advisory / Consultancy: GSK; Advisory / Consultancy: Oncosec; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca/MedImmune; Speaker Bureau / Expert testimony, Research grant / Funding (self): Roche/Genentech. All other authors have declared no conflicts of interest.

Risk Factors for Small Adult Height in Childhood Cancer Survivors

BACKGROUND: Between 10-20% of childhood cancer survivors (CCS) suffer impaired growth leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone (GH) deficiency among CCS. METHODS: The FCCSS holds data on 7670 cancers survivors treated before 2001. We analyzed self-questionnaire data from 2965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height <2 Standard Deviation Scores (SDS) of control values obtained from a French population health study. RESULTS: After exclusion of the 189 CCS treated with GH, 9.2% (254/2776) had a SAH. Being young at the time of cancer treatment (RR 0.91 [95% CI, 0.88-0.95], by year of age), small height at diagnosis ( 40 Gy RR 19.48 [95%CI, 8.73-43.48]), having received busulfan (RR 4.53 [95%CI, 2.10- 9.77]), or more than 300 mg/m² of lomustine ([300-600]mg/m² RR 4.21 [95%CI, 1.61-11.01], >600mg/m² RR 9.12 [95%CI, 2.75-30.24]) were all independent risk factors for SAH. Irradiation of seven or more vertebrae (>15 Gy on >90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 [95%CI, 2.77-7.72]. If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4. CONCLUSION: CCS are at high risk of SAH. Any CCS who has been treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency. FUNDING STATEMENT: This work was supported by the French Society of Childhood Cancer (SFCE), the PAIR Research Program “START - INCa-ARC-Ligue_11902, the PAIR Research Program “Mr Robot” – INCa-ARCLIGUE_11909, the Electricite de France (EDF), the Pfizer Foundation for childhood and adolescent health, the Ligue Nationale Contre le Cancer (LNCC), the Institut de Recherche en Sante Publique (IRESP), and the French “Agence Nationale Pour la Recherche Scientifique” (Hope-Epi Project). DECLARATION OF INTERESTS: All authors declared to have no conflict of interest with this study. ETHICS APPROVAL STATEMENT: The study has been approved by the French Data Protection Authority (CNIL) and the ethics committee of the National Institute of Medical Research and Health (INSERM).

Prognostic Impact of 3-HM Concentration in Patients with Alcoholic or Viral Cirrhosis

The role of endotoxemia related to intestinal bacterial translocation in worsening liver disease is the subject of many studies, but its impact on cirrhosis mortality has not been well evaluated. In this study, 3-hydroxymyristate (3-HM) (specific lipid of lipopolysaccharides) was directly quantified by an innovative patented assay with the aim of assessing the impact on cirrhosis mortality. The 3-HM concentration was measured in 593 patients with alcoholic or viral cirrhosis in stable clinical condition. A Cox hazards regression model was used to evaluate association between 3-HM and its fractions bound or nor bound to lipoprotein and the mortality. The 3-HM concentration was increased in patients with more severe cirrhosis (p<0.001). After 5 years of follow-up, 271 (45.7%) patients had died. In multivariate analysis, high level of 3HM was strongly associated with high risk of death in patients with Child-Pugh A cirrhosis (Hazard ratio (HR)Tertile3vsTertile1(T3vsT1)=3.86, confidence interval to 95% (CI 95%) 1.66-6.04, p-trend<0.001), as well as the 3-HM fraction bound to lipoprotein (HR T3vsT1=2.32, CI 95% 1.31-4.13, p-trend=0.005), and not bound to lipoprotein (HR T3vsT1=2.86, CI 95% 1.61-5.08, p-trend<0.001). Such association did not exist in Child-Pugh B or C patients. In patients without liver complication before inclusion, 3-HM concentration was associated with the occurrence of at least one complication of cirrhosis (p<0.001) as occurrence of ascites (p=0.001) and encephalopathy (p=0.008) but not with gastrointestinal bleeding (p=0.56). Conclusion: This study revealed that a high concentration of 3-HM was strongly associated with 5-year mortality in patients with alcoholic or viral cirrhosis. Our results suggest that a high 3-HM concentration in cirrhosis patients leads to an irreversible chronic process of disease worsening independently of cirrhosis severity. Funding Statement: This work was supported by a French Government grant managed by the French National Research Agency under the program “Investissements d’Avenir” [reference ANR-11-LABX-0021], French National Cancer Institute, Canceropole Grand-Est, Ligue Nationale contre le Cancer, Fondation de France, Conseil Regional de Bourgogne, Fonds Europeen de Developpement Regional (FEDER). The first author was financed by a fund provided by the Regional Health Agency. Declaration of Interests: The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this paper Ethics Approval Statement: All patients gave written informed consent. The study was carried out in accordance with the principles of the Helsinki declaration and was approved in 2008 by the local ethics committee (agreement n°2008/09); the French drug safety agency (Agence Nationale de Securite des Medicaments et des Produits de Sante: agreement n° 2008-A00023-52) and the National Commission for Data Processing and Liberties. The CiRCE study was registered at clinicaltrials.gov as NCT01798173.

First person: Ali Bazarbachi, MD, PhD: The professor at the American University of Beirut has advanced the treatment of leukemia and cancer research in the Middle East and worldwide.

First person: Ali Bazarbachi, MD, PhD: The professor at the American University of Beirut has advanced the treatment of leukemia and cancer research in the Middle East and worldwide.