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Supplementary methods, figures, and tables Figure S1: Variant filters applied to Lymphopanel NGS data. Figure S2: Validation of variants according to SIFT and CADD scores. Figure S3: PMBL samples harbor more mutations than other DLBCL subtypes. Figure S4: Role of AID-induced SHM in DLBCL. Figure S5: Mutation frequency by subtype. Figure S6: Clustering of gene mutations according to subtype. Figure S7: Protein representations of observed mutations. Figure S8: Correlations between age and specific gene mutations. Figure S9: Prognosis according to IPI and subtype. Figure S10: Prognostic impact of gene mutations among the Lymphopanel. Table S1: Clinical characteristics of patients in our cohort. Table S2: Overview of the Lymphopanel used for NGS analysis. Table S3: Overview of pathway selection Table S4: Validation of variant filtering by an independent study of seven non-tumoral samples from DLBCL patients Table S5: Validated variants. Table S6: Lymphopanel NGS detection of genes with high AID target frequencies. Table S7: Prognostic impact of mutations in Lymphopanel genes

Supplementary Figures 1-10 Figure S1. MYD88 mutation VAF according to L265P or non-L265P variants. Figure S2. Age according to MYD88 mutation status and variant among ABC patients. Figure S3. Genomic profiles of DLBCL according to the presence of MYD88 L265P or non-L265P variants. Figure S4. Relative L265P allele expression level according to L265P VAF. Figure S5. Gene expression according to MYD88 status. Figure S6. NFkB pathway gene expression according to MYD88 mutational status. Figure S7. LPS score according to subtype and downstream NFkB alterations. Figure S8. Clustering according to expression levels of 27 genes involved in LPS response and differentially expressed according to MYD88 L265P. Figure S9. TNFAIP3 and CARD11 expression according to their copy number status. Figure S10. Additional survival analyses.

Clinical characteristics of the 17 patients with CNS relapse are provided, included time to CNS relapse, first-line treatment and response after first-line treatment. CR, Complete Response; PR, Partial Response; PD, Progressive Disease.

Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays.Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell–like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK–STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919–28. ©2016 AACR.See related commentary by Lim and Elenitoba-Johnson, p. 2829

All relevant clinical data is included. Immunohistochemical results for BCL2, CD10, BCL6, MUM1, FOXP1, IgM and MYC are transcribed: 0 indicates negativity and 1 indicates positivity. For BCL2 and MYC, positivity is according to a threshold of 50% or 40% respectively.

Purpose: MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.Experimental Design: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses.Results: Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P–mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same MYD88 mutation. We showed that associated CD79B and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P–mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated CD79B mutations significantly improved the survival of MYD88 L265P–mutant ABC DLBCL in our cohort.Conclusions: This study highlights the relative heterogeneity of MYD88-mutant DLBCL, adding to the field's knowledge of the theranostic importance of MYD88 mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. Clin Cancer Res; 23(9); 2232–44. ©2016 AACR.

Supplementary methods, supplementary figure & table legends, and supplementary tables 3, 4, 8 & 9. Table S3: Overview of the Lymphopanel used for NGS analysis. Table S4: Overview of pathway selection Table S8. Genes involved in the LPS score. Table S9. Expression levels of genes involved in response to LPS stimulation according to MYD88 L265P.

Statistically significant differences (p

This table presents all variants identified among our cohort by Lymphopanel NGS. Variant type and variant allele frequency (VAF) are indicated.

This table presents all CNVs identified among our cohort using the ONCOCNV software. Duplication was considered when copy number was superior to 2 and deletion was considered when copy number was inferior to 2. False discovery rate (FDR) cutoff was set at 0.01.

COO information according to the three techniques used in this study is given according to the various MYD88 variants present in our cohort.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Background CT and fluorine 18 (

Monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1), such as nivolumab and pembrolizumab, are associated with high response rates in patients with relapsed or refractory classic Hodgkin lymphoma (HL). To date, no prognostic factor for overall survival (OS) has been established with these agents in HL. We examined whether the first early response assessment evaluated using

Advanced soft-tissue sarcomas are usually resistant to cytotoxic agents such as doxorubicin and ifosfamide. Antitumor activity has been observed for gemcitabine and docetaxel combination. We conducted a retrospective study on 133 patients (58 males/75 females) with unresectable or metastatic soft-tissue sarcoma. The median age at diagnosis was 51.7 (18-82), with 76 patients with leiomoyosarcoma and 57 patients with other histological subtypes. The initial localizations were limb (44), uterine (32), retroperitoneal (23) and organs or bone (34). Patients received 900 mg/m2 of gemcitabine (days 1 and 8) over 90 min plus 100 mg/m2 of docetaxel (day 8), intravenously every 21 days. Gemcitabine/docetaxel combination was well tolerated with an overall response of 18.4% and with no clear statistical difference between leiomyosarcomas and other histological subtypes (24.2% versus 10.4% (p=0.06)). No difference was found between uterine soft-tissue sarcomas versus others. The median overall survival was 12.1 months (1-28). Better overall survival was correlated with leiomyosarcoma (p=0.01) and with the quality of the response, even for patients with stable disease (p

Announcement of diagnosis is a critical step in establishing a trust-based relationship of quality between patient and physician. Disclosing "bad news" is a difficult and sensitive task which has direct consequences on psychological, emotional and relational levels, as well as on therapeutic management. This is a potentially traumatic experience which requires a long process of integration and psychological adaptation. The hematologist-oncologist occupies a central position: He introduces the framework for a multidisciplinary care, while taking into account the personality and behavior of the teenager or young adult. We propose an analysis of doctor-patient interaction; an overview of psychological issues associate with diagnosis disclosure; suggestions to build and manage communication with patients; and a clarification of the role of the psychologist and of the psychological adjustment at the time of disclosure.

Summary Background Diffuse large B-cell lymphoma is a common cancer in elderly patients. Although treatment has been standardised in younger patients, no prospective study has been done in patients over 80 years old. We aimed to investigate the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab in elderly patients with diffuse large B-cell lymphoma. Methods We did a prospective, multicentre, single-arm, phase 2 study of patients aged over 80 years who had diffuse large B-cell lymphoma. Patients were included from 38 centres in France and Belgium. All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m 2 rituximab, 400 mg/m 2 cyclophosphamide, 25 mg/m 2 doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m 2 prednisone on days 1–5. The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01087424. Findings 150 patients were enrolled between Jan 9, 2006, and Jan 23, 2009 and 149 were included in the intention-to-treat analyses. Median age was 83 years (range 80–95). After a median follow-up of 20 months (range 0–45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49–67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3·2, 95% CI 1·4–7·1; p=0·0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38–56). 58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade ≥3 neutropenia in 59 patients; febrile neutropenia in 11 patients). Interpretation R-miniCHOP offers a good compromise between efficacy and safety in patients aged over 80 years old. R-miniCHOP should be considered as the new standard treatment in this subgroup of patients. Funding Groupe d'Etude des Lymphomes de l'Adulte (GELA).

To evaluate quality of life (QOL) after radial forearm free flap (RFFF) reconstruction of the oral cavity and oropharynx in head and neck cancer patients.Prospective study.Academic, tertiary referral centre.Between January 2004 and May 2005, 47 patients underwent immediate RFFF reconstruction of the oral cavity and oropharynx following ablative surgery for a previously untreated head and neck cancer and were initially included in this study. The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire and the EORTC Head and Neck Cancer Quality of Life Questionnaire were completed before surgery and at 6 and 12 months thereafter.QOL scores obtained at the three assessment dates. Predictive factors of QOL scores at 6 months researched among the following: age, gender, comorbidity, radiotherapy, tumour stage, and tumour site.Global QOL remained stable over time. Social and role functioning scores deteriorated significantly after treatment. Social eating and speech difficulties, trismus, and salivary problems increased significantly in the postoperative period and were among the main complaints of our patients.Despite some functional impairment, global QOL was preserved after RFFF reconstruction following extensive ablative surgery in patients with oral and oropharyngeal cancer.

We report the experience of two French cancer centers in the treatment of oral cavity squamous cell carcinoma (SCC) in patients aged 80 years.Two hundred and sixty patients aged 80 years with a primary oral cavity SCC were included in this retrospective analysis.Sex ratio was near to 1. Tobacco or alcohol intoxication was the main risk factor for 66% of men and 16% of women and leukoplakia, lichen planus, or oral traumatism for 55% of women and 11% of men (p0.0001). Two hundred patients received a loco-regional (LR) treatment with a curative intent (surgery and/or radiotherapy), 29 with a palliative intent and 31 did not receive a LR treatment. Curative treatments were initially planned to be adapted to age in 118 patients (59%). The median disease-specific survival (DSS) was 29 months. In multivariate analysis, the independent prognostic factors for DSS were stage (HR=0.42 [0.24-0.72]), age (HR=0.43 [0.24-0.75]) and performance status (HR=0.50 [0.27-0.95]). The median overall survival (OS) was 14 months. In multivariate analysis, the independent prognostic factors for OS were age (HR=0.52 [0.35-0.79]), stage (HR=0.56 [0.38-0.84]), tumor differentiation (HR=0.60 [0.33-0.93]) and performance status (HR=0.6 [0.37-0.97]). In patients treated with a curative intent, treatment adapted to age was not associated with a decreased overall survival or disease-specific survival as compared with the standard treatment. However, prophylactic lymph node treatment in stages I-II tumors decreased the rate of nodal recurrence from 38% to 6% (p=0.01).This study emphasizes the need for prospective evaluation of standard and adapted schedules in elderly patients with oral cavity cancer.

Cancers of the upper aerodigestive tract cover the solid tumors of the oral cavity, pharynx and larynx. The principal risk factors identified are smoking and alcohol. Moreover, the combination of alcohol and smoking increases the relative risk by more than simple multiplication. The pretreatment work-up represents the starting point in the natural history of the patient's disease and conditions recovery and time course; it must be both specific and exhaustive. It leads to a TNM classification or staging that is a major prognostic factor and essential to determination of the appropriate therapy. Patients with cancer of the upper aerodigestive tract must receive cooperative multidisciplinary treatment. Conservative treatment strategies must be favored. Treatment is essentially surgical and radiological. Prognosis for survival is poor. For all stages and sites together, 5-year survival remains between 30 and 40%.

The adaptor molecule growth-factor-receptor-bound protein-2 (Grb2) plays a role in insulin action since it links tyrosine phosphorylated IRS–1 and Shc to the guanine-nucleotide-exchange factor, Sos, which initiates the mitogen-activated-protein (MAP) kinase cascade by producing Ras-GTP. Both IRS-1 and Shc are phosphorylated by the insulin-receptor tyrosine kinase. In the present study, we have investigated whether the tyrosine kinases of the Janus kinase family (JAK) could be involved in insulin signaling by acting on Grb2. In fibroblasts over-expressing insulin receptors we observed that two tyrosine-phosphorylated proteins interact with Grb2 and with a mutant of Grb2, which lacks the Src homology 2 (SH2) domain, indicating that these proteins associate with the SH3 domains of Grb2. Further, we found that both JAK1 and JAK2 constitutively associate with Grb2, through interaction with the SH3 domains of Grb2. Finally, insulin appears to induce the tyrosine phosphorylation of JAK1, but does not modify the tyrosine phosphorylation state of JAK2. In conclusion, our results suggest that the JAK proteins could participate in insulin signal transduction, and could therefore constitute an alternative pathway for mediating some of the pleiotropic responses induced by insulin.

Introduction :Le traitement par cetuximab a été récemment proposé dans les carcinomes épidermoïdes cutanés (CEC) localement avancés lorsque la chirurgie ou la radiothérapie ne peuvent pas être réalisées. Cependant, son efficacité est inconstante. Des biomarqueurs pourraient aider à sélectionner les patients potentiellement répondeurs au traitement par cetuximab. Objectifs :Déterminer l’incidence des mutations des gènes EGFR, HRAS, KRAS, NRAS et BRAF chez les patients atteints de CEC non résécables ou métastatiques traités par cetuximab en monothérapie et déterminer l’impact de ces mutations sur la réponse au cetuximab.Matériel et méthodes :Une étude rétrospective multicentrique a été conduite entre 2008 et 2014. Tous les patients avec un diagnostic de CEC non résécable ou métastatique traité par cetuximab en monothérapie et confirmé histologiquement ont été inclus.Résultats :Trente et un échantillons de CEC provenant de 31 patients ont été analysés. Seulement 2 échantillons mutés RAS (6.5 %) ont été identifiés. Le premier avait une mutation NRAS (c.35G>A) dans le codon 12 résultant d’une substitution p.G12D. Le second échantillon présentait une mutation HRAS (c.38G>T) dans le codon 13 résultant d’une substitution p.G13V. Nous n’avons pas identifié de mutations dans les gènes KRAS, BRAF et EGFR, dans les loci investigués. De manière surprenante, les deux patients avec les mutations NRAS et HRAS ont eu une réponse partielle et complète au cetuximab, respectivement.Discussion :Cette étude démontre que l’incidence des mutations HRAS, KRAS, NRAS, BRAF et EGFR est très faible dans les CEC et que le statut mutationnel de ces gènes n’est pas prédictif d’une mauvaise réponse au cetuximab.Conclusion :Ces résultats montrent que la détection des mutations HRAS, KRAS, NRAS, BRAF et EGFR avant l’instauration d’un traitement par cetuximab pour les CEC n’est pas nécessaire.

IntroductionLa Leucémie Aigue Myéloïde (LAM) est une pathologie rare avec un pronostic très sévère. Son pic de fréquence se situe entre 65 et 70 ans. Pour autant, la plupart des études sont menées chez des sujets jeunes et la prise en charge des LAM du sujet âgé et de ses facteurs pronostics reste peu connue. Matériel et Méthode Nous avons effectué une étude rétrospective unicentrique, en intention de traiter, incluant tous les patients âgés de 65 ans et plus, admis pour prise en charge d’une LAM. Nous avons recherché quels étaient les facteurs pronostics de survie globale et de rémission complète (RC) dans cette population et cherché à établir un modèle pronostic d’aide à la décision thérapeutique pour le clinicien. Résultats 163 patients ont été inclus au cours des 15 dernières années. Le taux de survie globale à un an est de 46,7% et de 24,4% à 2ans. 112 patients ont été induits, sur les 56 patients mis en RC on compte 39 rechutes. La SSR à 12 et 24 mois est de 44,4% et 18,9% respectivement. Les facteurs pronostics de SG sont l’âge inférieur à 75 ans (p=0,01 ; HR 0,44 [0,24-0,83]), le caryotype favorable (p=0,006 ; HR 0,3 [0,13-0,7]), un PS favorable (p=0,01 ; HR 0,4 [0,2-0,8] pour PS 0 ou 1 vs 2-4), un score de Charlson supérieur à 90% (p=0,03 ; HR 0,5 [0,3-0,9]), l’utilisation d’un traitement par Azacitidine (p=0 ,004 ; HR 2,4 [1,3-4,6]) et l’obtention d’une rémission complète (p75g/L), et le score de Charlson (p=0,02 HR 2,52 [1,1-5,4] pour Charlson à 1-2 vs >2). Un patient présentant plus de 2 de ces 4 facteurs (l’âge > 75 ans, le score de Charlson inférieur à 90%, le PS> à 1 et le caryotype défavorable ou intermédiaire) présente une différence mortalité importante (p=0,001). Conclusion Les patients âgés ont donc intérêt à bénéficier d’une induction lorsque leur état physique le permet mais les nouvelles thérapies constituent une piste intéressante augmentant grandement la SG en limitant les toxicités.