Showing papers in "Bulletin Du Cancer in 2018"

Colorectal cancer cell-derived exosomes containing miR-10b regulate fibroblast cells via the PI3K/Akt pathway

Abstract: Summary Background Cancer-associated fibroblasts (CAFs) contribute to the proliferation of colorectal cancer(CRC) cells. However, the mechanism by which CAFs develop in the tumor microenvironment remains unknown. Exosomes may be involved in activating CAFs. Methods Using a miRNA expression profiling array, we determined the miRNA expression profile of secretory exosomes in CRC cells and then identified potential miRNAs with significant differential expression compared to normal cells via enrichment analysis. Predicted targets of candidate miRNAs were then assessed via bioinformatics analysis. Realtime qPCR, western blot, and cell cycle analyses were performed to evaluate the role of candidate exosomal miRNAs. Luciferase reporter assays were applied to confirm whether candidate exosomal miRNAs control target pathway expression. A CRC xenograft mouse model was constructed to evaluate tumor growth in vivo. Results Exosomes from CRC cells contained significantly higher levels of miR-10b than did exosomes from normal colorectal epithelial cells. Moreover, exosomes containing miR-10b were transferred to fibroblasts. Bioinformatics analysis identified PIK3CA, as a potential target of miR-10b. Luciferase reporter assays confirmed that miR-10b directly inhibited PIK3CA expression. Co-culturing fibroblasts with exosomes containing miR-10b significantly suppressed PIK3CA expression and decreased PI3K/Akt/mTOR pathway activity. Finally, exosomes containing miR-10b reduced fibroblast proliferation but promoted expression of TGF-β and SM α-actin, suggesting that exosomal miR-10b may activate fibroblasts to become CAFs that express myofibroblast markers. These activated fibroblasts were able to promote CRC growth in vitro and in vivo. Conclusion CRC-derived exosomes actively promote disease progression by modulating surrounding stromal cells, which subsequently acquire features of CAFs.

Exosomes of glioma cells deliver miR-148a to promote proliferation and metastasis of glioblastoma via targeting CADM1.

Abstract: Exosomes are now considered to be involved in mediating cell-to-cell communication to promote or inhibit tumor progression. However, the role and molecular mechanism of exosomes in promoting glioblastoma (GBM) metastasis remains elusive. Here, we found that circulating exosomal miR-148a levels were significantly higher in serum from GBM patients compared with serum from healthy volunteers. In T98G cells, inhibition of miR-148a suppressed cell proliferation and metastasis. In addition, we identified Cell adhesion molecule 1 (CADM1) as a target gene of miR-148a using luciferase reporter assay. Both protein and mRNA levels of CADM1 were decreased in tissues from GBM patients. There was a strong negative correlation between exosomal miR-148a and CADM1 mRNA levels in samples of patients. Moreover, miR-148a antagonist increased p-STAT3 protein level to activate STAT3 pathway. In conclusion, our findings indicated that miR-148a delivered by exosomes may promote cancer cell proliferation and metastasis via targeting CADM1 to activate STAT3 pathway, suggesting a predictor and therapeutic target role of exosomal miR-148a in GBM patients.

Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx

Abstract: Resume Les fluoropyrimidines restent les molecules anticancereuses les plus prescrites dans le traitement des tumeurs solides. Elles induisent des toxicites severes chez 10–40 % des patients et des toxicites letales chez 0,2–0,8 % des patients. Une abondante litterature a etabli le lien entre un deficit enzymatique en dihydropyrimidine deshydrogenase (DPD, enzyme qui degrade le 5-FU) et la survenue d’une toxicite severe sous fluoropyrimidine. Si les deficits complets en DPD sont rares (0,1–0,5 %), les deficits partiels sont retrouves chez 3–15 % des patients. La recherche du deficit en DPD peut etre realisee par phenotypage (mesure directe ou indirecte de l’activite enzymatique) ou par genotypage (recherche des principaux polymorphismes fonctionnels du gene DPYD). Actuellement, il n’existe pas d’obligation reglementaire pour le depistage du deficit en DPD avant l’administration de fluoropyrimidines. Sur la base des niveaux de preuve issus de la litterature, et des pratiques actuelles, le Groupe de Pharmacologie Clinique Oncologique (GPCO)-UNICANCER et le Reseau National de Pharmacogenetique hospitaliere (RNPGx) recommandent : (1) de rechercher un deficit en DPD avant la mise en route de tout traitement a base de 5-FU ou capecitabine ; (2) de realiser ce depistage par phenotypage en dosant en premiere intention l’uracile plasmatique (U) (eventuellement complete par le rapport dihydrouracil/U) et en y associant le genotypage des variants *2A, *13, p.D949V et HapB3 ; (3) de reduire si necessaire la posologie en fonction du statut DPD des la premiere cure et d’envisager une augmentation de dose aux cures suivantes en fonction de la tolerance. Actuellement en France, 17 laboratoires hospitaliers realisent en routine la recherche du deficit en DPD.

[Physiopathological mechanisms of immune-related adverse events induced by anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies in cancer treatment].

Abstract: Recently, the emergence of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies called immune check-point inhibitors (ICPI) has modified the landscape of anti-cancer treatments These therapeutics are associated with immune related adverse events that affect many organs, most commonly skin, digestive tract, endocrine glands and lungs This review summarizes the main physiopathological hypotheses on the mechanisms of these toxicities In most cases, the T lymphocytes hyperactivation induced by ICPI generates a specific response directed against tumor antigens, leading to anti-tumor activity in tumor tissues but also side effects in normal tisues called "on-target" The CD8+ cytotoxic T lymphocytes-mediated cell lysis induces the release of neoantigens, tumor antigens and auto-antigens from normal tissues, respectively This phenomenon called "epitope spreading" leads to diversification of the T cell repertoire and thus to reduced immune tolerance, which is exacerbated by inhibition of regulator T lymphocytes Furthermore, the predominant activation of Th1 and Th17T lymphocytes mediated by ICPI induced an increased production of pro-inflammatory cytokines such as interferon-γ (IFNγ) and interleukine-17 (IL-17) These two mechanisms are responsible for the so called "off-target" toxicities The roles of cross-reactivity with the intestinal microbiota, hypersensitivity and the specific effect of PD-L2 remain to be determined Better knowledge of these mechanisms will improve patient care and help predict patients at risk of developing severe toxicities to ICPIs

Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma.

Abstract: Summary Background The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC. Methods Ninety patients with pathologically confirmed HBV-associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis. Results Tim-3 or/and PD-1 was up-regulated expressed on CD4+ and CD8+ TILs in HBV-HCC patients and a higher proportion of TILs expressed PD-1 alone. Tim-3+ and PD-1+ TILs greatly decreased secretion of IFN-? and TNF-a. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-? and TNF-a. Conclusion Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC.

Recommandations françaises du Groupe Génétique et Cancer pour l’analyse en panel de gènes dans les prédispositions héréditaires au cancer du sein ou de l’ovaire

Abstract: Resume Introduction Dans le contexte d’une suspicion de predisposition aux cancers du sein et de l’ovaire, le sequencage haut debit permet desormais d’analyser de nombreux genes simultanement. Ainsi, de nouveaux « panels de genes sein/ovaire » ont ete developpes en France, avec une grande diversite dans leur composition, ainsi que dans la prise en charge medicale des personnes porteuses de mutations, faute de referentiels. Une homogeneisation des pratiques est indispensable. Methodes Le Groupe Genetique et Cancer (GGC) – Unicancer a conduit un travail exhaustif bibliographique sur 18 genes d’interet, et retenu les publications avec des estimations de risque de cancer non biaisees. Resultats Cette expertise a permis de definir un panel de 13 genes identifies d’utilite clinique : risque relatif de cancer superieur a 4, possibilites de prise en charge medicale et de tests genetiques presymptomatiques dans les familles. Ainsi devant toute suspicion de predisposition aux cancers du sein et de l’ovaire, le GGC recommande l’analyse de BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, EPCAM. Les raisons pour ne pas inclure les genes NBN, RAD51B, CHEK2, STK11, ATM, BARD1, BRIP1 sont presentees. Les preconisations de depistage, de prevention et de conseil genetique associees a tous les genes expertises sont revues. Discussion Les connaissances evoluant rapidement, une mise a jour annuelle de la bibliographie est prevue par le GGC pour faire evoluer le panel, et des etudes d’epidemiologie genetique se mettent en place afin d’estimer plus precisement les risques de cancers associes aux genes non retenus.

PTBP1 promotes tumorigenesis by regulating apoptosis and cell cycle in colon cancer

Abstract: Increased expression of polypyrimidine tract-binding protein 1 (PTBP1) has been observed in human ovarian tumors, glioblastomas, and breast cancer, but its biological roles in tumorigenesis is not fully clear. In the present research, we investigated the biological role of PTBP1 in colon cancer. We found that PTBP1 was overexpressed both in colon cancer cell lines and tissues. Tissue microarray analysis (TMA) indicated that low PTBP1 expression predicted a favorable overall survival for colon cancer patients. Using small interfering RNA technology, we found that down-regulation of PTBP1 significantly inhibited colon cancer cell growth/proliferation, and induced cell cycle arrest as well as apoptosis in vitro. Western blot analysis showed that siRNA PTBP1 could up-regulate the expression of cytoC, p53 and Bax as well as down-regulated p85, p-AKT, cyclinD1, CDK4 and Bcl2 compared to the control. Furthermore, Caspase-3 and PARP1 were activated when PTBP1 is knockdown. This study implies that PTBP1 plays an important role in tumorigenesis of colon cancer.

[WHO classification of head and neck tumours 2017: Main novelties and update of diagnostic methods].

Abstract: The publication of the new WHO classification of head and neck tumours in 2017 brought major modifications. Especially, a new chapter is dedicated to the oropharynx, focusing on the description of squamous cell carcinoma induced by the virus Human Papilloma Virus (HPV), and new entities of tumors are described in nasal cavities and sinuses. In this article are presented the novelties and main changes of this new classification, as well as the updates of the diagnostic methods (immunohistochemistry, cytogenetics or molecular biology).

[Psychological impact of ostomy on the quality of life of colorectal cancer patients: Role of body image, self-esteem and anxiety].

Abstract: Surgery accounts for an important part of the therapeutic arsenal of colorectal cancer treatment. In digestive cancers, ostomy devices induce the loss of anal function and control. This medical appliance generates changes affecting all aspects of patients' lives. This study explores, on the one hand, the psychological impact of colostomy on colorectal cancer patients' quality of life and on the other hand, it analyzes the correlational links between body image, self-esteem and anxiety during the stoma. Thirty-five patients with colorectal cancer participated in the study, divided into 2 subgroups: 23 were carriers of a definitive stoma and the 12 others with a temporary stoma. All completed the Functional Assessment Cancer Therapy (FACT-C), the Body Image Scale (BIS), the State Trait Anxiety Inventory (STAI-Y) and the Self Esteem Scale (ETES). Analysis revealed the quality of life of temporary ostomates is more affected than that of the definitive ones. All three of them, body image, self-esteem and anxiety negatively affect the quality of life regardless of the type of stoma. This study highlights the prevalence of physical self-esteem for temporary ostomy; the role of a good body image and substantial emotional self-esteem for the permanent ostomy. Future studies are required to explore the underlying causes of the acceptance of this equipment and the mediating role of care devices.

[Management of uveal melanomas, guidelines for oncologists].

Abstract: Uveal melanomas are the most frequent primary malignant eye tumor. Enucleation was historically the gold standard. Since then, several studies showed that conservative treatments did not increase the risk of metastasis or survival. Choroidal melanomas are both radioresistant and located close to visual structures (the optic nerve and macula) of the eye, which may be preserved in some settings without compromising tumor control, as this is the first priority. Different types of radiation therapy may be used for such tumors: brachytherapy and charged particles, including proton beam therapy. If visual prognosis is dependent to the local treatment, the vital prognosis is dependent on the metastatic risk, with a risk of liver involvement in 20 to 50% of patients, depending on tumor size and genomics. Median survival after the discovery of liver metastases is about 15 months. The management of these patients is often complex. Systemic therapies (chemotherapy, targeted therapies, immunotherapy, etc.) yield limited response rates and although local treatments of liver metastases are promising, they are only feasible in selected patients. The mission of the MELACHONAT national network is to improve the management of patients regardless of the stage of the disease. The patient association ANPACO is dedicated to help uveal melanoma patients in their health care path and to promote knowledge dissemination within the patient community. The aim of this review is to focus on the local treatments of uveal melanomas as well as the management of their metastatic evolution.

Precision medicine and bladder cancer heterogeneity.

Abstract: Summary Bladder cancer is a widespread and highly heterogeneous malignancy. Moreover, bladder cancer recurrence and treatment failure are common, making this disease a challenge for genito-urinary surgeons. Precision medicine represents a new medical concept and model. It is based on personalized medicine, and employs genomics, proteomics, and other omics and cutting-edge medical technologies to classify disease at the molecular level, enabling accurate identification of its cause and therapeutic targets, ultimately offering precise, personalized medicine. The existence of heterogeneity in bladder cancer, resulting in different molecular phenotypes, constitutes a huge challenge for precision medicine. Studying phenotypic differences will be of substantial clinical significance and far-reaching research value with respect to the natural history of tumor development, reduction of drug resistance, the early diagnosis and prognosis of patients with bladder cancer, and the realization of fully developed precision medicine. This paper reviews the possible mechanisms underlying tumor heterogeneity and their impact on precision medicine. The manner in which precision medicine may be performed in the presence of bladder cancer heterogeneity and the prospects of this discipline are also discussed.

Préservation de la fertilité, contraception et traitement hormonal de la ménopause chez les femmes traitées pour tumeurs malignes rares de l’ovaire : recommandations du réseau national dédié aux cancers gynécologiques rares (TMRG/GINECO)

Abstract: Resume Introduction Les tumeurs malignes rares de l’ovaire regroupent les tumeurs borderline complexes, les tumeurs germinales, les tumeurs des cordons sexuels et les tumeurs epitheliales rares. Les indications et modalites de preservation de la fertilite, la prise en charge d’une infertilite, les possibilites de contraception et de traitement hormonal de la menopause sont des questions frequentes en pratique clinique. Un groupe d’experts du reseau national dedie aux cancers gynecologiques rares (TMRG/TMRO) associe a des experts nationaux de la fertilite, des traitements hormonaux et de la contraception se sont reunis pour proposer des recommandations nationales. Methodes Un panel de 39 experts de differentes specialites a participe a l’elaboration des recommandations, en suivant la methode DELPHI (consensus formalise d’experts). Apres revue systematique de la litterature, des recommandations ont ete redigees puis soumises a deux tours successifs de cotations. Resultats Trente-cinq recommandations ont ete retenues, precisant les indications de preservation de la fertilite, les situations contre-indiquant une stimulation ovarienne (en preservation de la fertilite ou dans la prise en charge d’une infertilite), les possibilites de contraceptions (notamment hormonales) et de traitement hormonal de la menopause pour chaque type tumoral. De facon generale, une prudence a ete retenue pour les tumeurs potentiellement hormonosensibles comme les tumeurs des cordons sexuels, les adenocarcinomes sereux et endometrioides de bas grade, ainsi que pour les tumeurs borderline avec criteres histologiques pejoratifs. Discussion Dans le contexte d’une litterature pauvre, ces recommandations etablies via consensus formalise d’experts devraient constituer une aide aux cliniciens dans la prise en charge de ces patientes.

Opioid switch and change of route of administration in cancer patients treated by morphine

Abstract: Resume Un groupe de travail nomme par les 3 societes impliquees dans la prise en charge de la douleur du cancer, a etabli des recommandations selon la methodologie HAS, en revision des Standards Options Recommandations datant de 2002 et emises par la Federation des centres regionaux de lutte contre le cancer. Apres un rappel des proprietes pharmacologiques et du metabolisme de la morphine, et selon l’AMM francaise de chacun des opioides pour le traitement de la douleur due au cancer, les coefficients de conversion ont ete revus dans le cadre du changement d’opioides de et vers la morphine (oxycodone, hydromorphone, fentanyl, methadone, tapentadol et en fonction de la voie d’administration orale, sous-cutanee ou intraveineuse). Les experts ainsi ont recommande d’abandonner la notion de dose d’equiantalgie utilisee dans la rotation des opioides, car pouvant etre a l’origine de graves erreurs de sur- ou de sous-dosage. Cela, au profit de la notion de changement de traitement opioide selon des coefficients beaucoup plus rigoureux, issus de la litterature parue depuis 2002, pour ensuite proceder a une nouvelle equilibration si l’intensite de la douleur residuelle ou les effets indesirables le requierent. Une application smartphone OpioConvert® sera disponible.

Methylation analysis for multiple gene promoters in non-small cell lung cancers in high indoor air pollution region in China

Abstract: Summary Aim The prevalence and mortality rates of lung cancer in Xuanwei, Yunnan, China, are the highest in the world. The severe indoor air pollution caused by smoky coals with high benzo (a)pyrene (BaP) and quartz levels is the main environmental factor. The aim of this study was to investigate methylation profiles of promoters in eight genes in primary non-small cell lung cancers (NSCLC) exposed to smoky coals. Materials and methods Candidate genes including CDKN2A, DLEC1, CDH1, DAPK, RUNX3, APC, WIF1 and MGMT were determined for the promoter methylation status using Nested methylation-specific PCR (nMSP) in primary 23 NSCLC tissues and in circulating tumor DNA (ctDNA) isolated from 42 plasma samples (9 matched to tissues) as well as 10 healthy plasma samples, using Sanger sequencing to verify the results. Results Seven of the 8 genes, except MGMT, had relatively high methylation frequencies ranging from 39%–74% in tissues. Moreover, methylation frequencies in five genes identified in lung cancer plasma were 45% for CDKN2A, 48% for DLEC1, 76% for CDH1, 14% for DAPK, 29% for RUNX3, with a relatively good concordance of methylation among 9 tissues and paired plasma. However, the genes from all healthy plasma showed no methylation. Conclusions A panel of genes including CDKN2A, DLEC1, CDH1, DAPK and RUNX3 may be used as potential epigenetic biomarkers for early lung cancer detection. CDH1 promoter methylation was associated with lung cancer metastasis in areas of air pollution from buring of smoky coals. DLEC1 and CDH1 exhibited specific high methylation frequencies, different from previous reports.

Knockdown of miR-299-5p inhibits the progression of hepatocellular carcinoma by targeting SIAH1.

Abstract: Summary Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. MiR-299-5p has been demonstrated to play important roles in multiple human cancers. Nevertheless, little is known about the detailed function and molecular mechanism of miR-299-5p on HCC progression. Methods Quantitative real-time PCR (qRT-PCR) assay was used to assess the expression patterns of miR-299-5p and siah E3 ubiquitin protein ligase 1 (SIAH1) in HCC tissues and cell lines. Loss-of-function experiments were performed to explore the effect of miR-299-5p on HCC progression in vitro and in vivo. Target predicted by software algorithms, the connection between miR-299-5p and SIAH1 was verified by dual-luciferase reporter assay, qRT-PCR and western blot analysis. Subsequently, anti-miR-299-5p and si-SIAH1 were cotransfected into LM9 and Huh-7 cells to further explore whether the regulatory effect of miR-299-5p on HCC was mediated by SIAH1. Results qRT-PCR assay revealed that miR-299-5p was upregulated and SIAH1 was downregulated in HCC tissues and cell lines. Moreover, miR-299-5p knockdown suppressed HCC progression in vitro and in vivo. In addition, anti-miR-299-5p-mediated regulatory effect on HCC cells was abated following the restoration of SIAH1 expression. Conclusions MiR-299-5p knockdown suppressed the progression of HCC by targeting SIAH1, highlighting its role as a potential biomarker and therapeutic target of HCC.

Expression de PD-L1 et inhibiteurs de la voie PD-1/PD-L1 dans le cancer du sein

Abstract: Resume Le developpement recent des inhibiteurs de « checkpoints » immuns represente un progres majeur en oncologie. Les anticorps monoclonaux diriges contre PD-1 ou son ligand (PD-L1) fournissent un controle durable de la maladie, en particulier dans le melanome, et les cancers du poumon, des reins, de la vessie et ORL. Le but de cette revue est de synthetiser les donnees actuelles sur l’expression de PD-L1 dans le cancer du sein et sur le developpement des inhibiteurs de PD-1/PD-L1 dans les contextes metastatiques et (neo) adjuvants. Dans le cancer du sein, l’expression de PD-L1 est heterogene et generalement associee a la presence de lymphocytes infiltrant la tumeur ainsi qu’a la presence de facteurs de mauvais pronostic, tels qu’un âge jeune, un grade eleve, une negativite de recepteurs aux œstrogenes, une negativite de recepteurs a la progesterone et une surexpression d’HER-2, un indice de proliferation eleve et des sous-types moleculaires agressifs (triple negatif, « basal-like », « HER-2-overexpressing »). Sa valeur pronostique reste controversee lorsqu’elle est evaluee par immunohistochimie, alors qu’elle semble favorable dans les cancers triple negatif lorsqu’elle est evaluee au niveau de l’ARN. Les premiers essais cliniques avec les inhibiteurs de PD-1/PD-L1 dans le cancer du sein ont montre une efficacite en termes de reponse tumorale et/ou de stabilisation de la maladie dans les formes metastatiques refractaires, notamment dans le sous-type triple negatif. De nombreux essais sont en cours, a la fois dans le cadre metastatique et neo-adjuvant. Une question cruciale est l’identification des biomarqueurs predictifs de la reponse aux inhibiteurs de PD-1/PD-L1.

Body image disorder in 100 Tunisian female breast cancer patients

Abstract: Resume Introduction Les objectifs de cette etude etaient de rechercher la prevalence du trouble de l’image du corps dans une population de femmes tunisiennes suivies pour un cancer du sein et les facteurs qui lui sont associes. Patients et methodes L’etude de type transversal, a concerne 100 patientes suivies pour un cancer du sein a l’institut tunisien Salah-Azaiez. Le questionnaire a porte sur la vie de couple et la sexualite des femmes ainsi qu’a leurs caracteristiques sociodemographiques, cliniques et therapeutiques. Les echelles utilisees etaient le BIS, le HADS et le FSFI. Resultats La prevalence du trouble de l’image du corps selon le BIS etait de 45 % avec une moyenne de 11,5 ± 11,2 parmi les femmes interrogees dont 24,7 % ont rapporte une alteration de leur relation de couple et 47 % de leurs relations sexuelles. En analyse univariee, le trouble de l’image du corps etait associe au soutien familial, a l’alteration de la relation de couple et aux troubles anxiodepressifs. Le trouble de l’image du corps et la dysfonction sexuelle etaient interrelies : chaque trouble a augmente la prevalence de l’autre. En analyse multivariee, l’activite professionnelle en etait un facteur independant predictif et l’absence d’anxiete le facteur independant protecteur. Le trouble de l’image du corps etait un facteur independant predictif de la depression et de l’anxiete. Discussion La qualite de la relation de couple et de la sexualite ainsi que la relation avec l’entourage de la patiente sont determinants pour proteger ou alterer l’image de son corps.

Urothelial carcinoma in children: A case series.

Abstract: Summary Objective To report a series of 5 patients with urothelial bladder cancer (UBC) three of them with a history of exposure to amines and only two with gross hematuria. Materials and methods After obtaining ethical and legal authorization, we performed a restrospective monocentric study. We collected information of patients with UBC over a period of 10 years. We recorded: age, sex, reason for presentation, familial history and risk factors, preoperative assessment, surgical details, histological type and grade, follow-up. Results 2 children came to our attention for hematuria and 3 for incidental bladder mass finding, at a median age of 11.8 years. We performed microscopically complete transurethral resection of the tumor (TURB). Median tumor size was 1.8 cm. No further therapy was required. All cancers belonged to NMIBC (Non-muscle-invasive Bladder Cancer) considering the 2004 WHO classification: 2 urothelial papillomas, 2 papillary tumors with low grade malignancy (PUN-LPM) and 1 papillary urothelial carcinoma of low histological grade (LG-PUC Ta, N0, M0). There was not any complications and no relapse occurred during follow-up (median 30 months). Conclusions In this study, UBCs presenting at a young age were low-grade and have not recurred in follow-up. This confirms the results of other series reported in Literature. Therefore there might be the space to perform a follow-up dedicated to children.

Rôle du pharmacien hospitalier dans le circuit d’une catégorie de Médicament de Thérapie Innovante : les lymphocytes T exprimant un Récepteur Chimérique à l’Antigène.

Abstract: Resume Les lymphocytes T exprimant un Recepteur Chimerique a l’Antigene (CART) appartiennent a une nouvelle classe de medicaments, les medicaments de therapies innovantes, tels que definis par le reglement Europeen 1394/2007, et plus precisement a la categorie des medicaments de therapie genique. Leur statut de medicament ainsi que d’organismes genetiquement modifies impose un circuit particulier a l’hopital tout en maintenant un passage par la Pharmacie a Usage Interieur du Centre Hospitalier. La manipulation de cellules genetiquement modifiees n’est pas habituelle en pharmacie. Elle necessite, en plus de l’acquisition de nouvelles competences, une reorganisation non negligeable des equipes et des locaux de la pharmacie ainsi qu’une formation adaptee du personnel. Une bonne communication est indispensable entre les differents intervenants du circuit. Le pharmacien hospitalier joue un role primordial dans la mise en place d’un circuit adapte a ce nouveau type de medicament. Le present article a pour but d’identifier les roles du pharmacien hospitalier et plus generalement de la pharmacie a usage interieur dans la prise en charge des CART. Nous detaillerons les specificites de ce type de medicament a chaque etape du circuit et les adaptations necessaires a realiser afin de garantir la qualite et la securite du traitement par CART. Au-dela de la mise en place du circuit au sein de l’hopital, le pharmacien a un role important a jouer dans le suivi des patients apres administration au vu de la complexite des effets secondaires et un role certain dans la formation des equipes a ce nouveau medicament.

[High-risk neuroblastoma treatment strategy: The experience of the SIOPEN group].

Abstract: High-risk neuroblastoma comprises nearly half of cases of neuroblastoma and the long-term survival is less than 50% despite complex and intensive treatments. Studies conducted in Europe and in North America in the last two decades have identified a strategy based on four therapeutic phases: an intensive induction therapy, a local control by surgery and radiation, a consolidation phase with single or tandem high dose chemotherapy and autologous transplant, and immunotherapy to eliminate residual disease. Future treatment improvements are based on progress at each of these therapeutic steps and ultimately a better stratification of the strategy adapted to the type of risk. A more extensive tumor molecular profiling at diagnosis and relapse will help to develop new therapeutics and to guide risk-based strategies. Earlier use of immunotherapy and identification of more effective combinations in induction or in maintenance treatment, identification of indications of more intense consolidations using high-dose chemotherapy combined or not with metabolic irradiation by 131I-MIBG and the introduction of other targeted treatments are tracks being explored.

Dermatofibrosarcome : prise en charge

Abstract: Resume Les dermatofibrosarcomes de Darrier et Ferrand sont des tumeurs rares (1 a 4 cas/million d’habitants par an), dont l’extension tumorale est souvent sous-estimee. Le diagnostic anatomopathologique est parfois trompeur, on connait desormais un transcrit de fusion specifique (t(17;22)(q22;q13) (COL1A1;PDGFB)). Le risque metastatique est faible (et lie a la transformation en fibrosarcome), le risque de recidive locale est conditionne par la qualite de la chirurgie. La prise en charge des formes localisees repose sur une chirurgie large avec une evaluation meticuleuse des marges (avec ou sans technique de Mohs). Les formes localement avancees, inoperables ou metastatiques avec presence du transcrit de fusion specifique relevent d’un traitement par imatinib. Les formes localement avancees peuvent relever d’un traitement neoadjuvant par imatinib. La prise en charge de ces tumeurs releve d’equipes entrainees.

La toxicité cardiaque des fluoropyrimidines : 5-fluorouracile, capécitabine, le composé S-1 et le trifluridine/tipiracil

Abstract: The incidence of cardiac toxicity of 5-flurorouracil (5-FU) IV and capecitabine varies from 1.2 to 18%. The physiopathology of this toxicity is still under study, various hypotheses are mentioned. In the absence of identified prophylactic treatment, reintroduction of this cytotoxic is at risk. A discussion between oncologists and cardiologists is essential to estimate the balance between benefit and risk and the careful reintroduction of treatment. An alternative compound might be raltitrexed which is currently the treatment recommended in case of intolerance to fluoropyrimidines. The compound S-1 does not have any cardiac toxicity. Of a total of 2910 patients in phase II or III studies, no grade III or IV cardiovascular events were reported. However, the treatment is not reimbursed in France and therefore not available. The trifluridine/tipiracil, for which approval from French authorities was obtained in November 2016 for patients with metastatic colorectal cancer in progress despite standard treatment lines, does not appear to have cardiac toxicity according to studies published to date. The pivotal phase III study (RECOURSE), that led to this marketing authorization, was performed in 800 patients with metastatic colorectal cancer refractory and only one patient (less than 1% of patients) treated with trifluridine/tipiracil presented an episode of cardiac ischemia. Thus, trifluridine/tipiracil, which is well tolerated, could be an alternative to raltitrexed for patients with cardiovascular history contraindicating or discouraging the use of fluoropyrimidines.

Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer

Abstract: Despite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi therapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Societe francaise de pharmacologie et de therapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.

Médecine de précision : une avancée majeure dans des situations spécifiques, un mythe dans les cancers réfractaires ?

Abstract: Resume Les dernieres annees ont vu se developper les techniques de sequencage a haut debit appliquees a la cancerologie, de nombreux essais cliniques se structurent actuellement autour de biomarqueurs qui peuvent guider le choix d’un traitement specifique. Cette approche est caracteristique de la medecine de precision, une notion initiee il y a plusieurs dizaines d’annees avec, par exemple, l’acide retinoique dans la leucemie promyelocytaire. Cette revue permettra de faire le point sur les differents types d’alterations moleculaires et d’analyses biologiques « -omiques », la notion de biomarqueurs, les outils bio-informatiques, les couples medicaments – biomarqueurs deja valides, la problematique ethique considerant que le genome entier d’un individu peut etre sequence dans le cadre d’une inclusion dans un essai clinique, et enfin les premiers resultats des essais de la medecine de precision. Le programme AcSe crizotinib, soutenu par l’Inca, est emblematique d’une reussite de cette medecine guidee par la genomique illustree par 4 points : la mise en evidence d’une cohorte de patients atteints de cancer du poumon avec un rearrangement du gene ROS1 caracteristique d’une sensibilite au crizotinib ; une mise a disposition rapide de cette innovation par la mise en place d’une recommandation temporaire d’utilisation (ANSM) ; l’obtention d’une AMM conditionnelle par l’industriel ; et enfin, la prise en charge par la solidarite nationale (HAS), malgre des donnees preliminaires et non comparatives. Dans le cas de cancers refractaires, au regard de notre systeme d’acces aux molecules illustre par l’essai PROFILER, cette approche ne permet d’envisager une therapeutique guidee par un evenement moleculaire que dans 7 % des cas, ce qui ne presage pas d’une reduction tumorale ou d’un avantage en survie. Laisser des patients etre inclus dans des essais qui identifient des cibles moleculaires pour « in fine » ne pas etre en capacite de proposer la molecule d’interet, est un evenement traumatisant pour ces malades qui vivent dans l’espoir d’un futur immediat. Dans la maladie refractaire, nous nous devons de repenser la medecine de precision dans une vision plus humaniste pour nos malades et non pas uniquement dans une dimension de promotion medico-industrielle. La mise en place d’un nouveau programme AcSe multi-drogues/multi-cibles moleculaires pourrait repondre a cette problematique.

Consumption of processed and pickled food and esophageal cancer risk: A systematic review and meta-analysis.

Abstract: Previous investigations yielded inconsistent results for association of esophageal cancer (EC) risk and intake of processed food (including pickled food) or pickled food alone. The aim of this study was to perform a systematic review and meta-analysis of data exploring association of EC risk and intake of processed food (including pickled food) or pickled food alone. We systematically searched on PubMed and Web of Science for association of EC risk and intake of processed and pickled food published from 1964 to April 2018. We computed the multivariate odd ratio (OR) or relative risk (RR) and 95% confidence intervals (CI), comparing the highest and the lowest categories of processed or pickled food intake. The present meta-analysis showed that the highest categories of processed food intake were associated with a 78% increase in EC risk compared with the lowest categories. In addition, meta-analysis results indicated that the combined OR/RRs (95%CI) of studies comparing the highest and lowest categories were 2.10 (1.64-2.69) for pickled food. Subgroup study indicated significant positive associations between EC risk and intake of processed food or pickled food in case-control studies (combined ORs: processed food: 1.93 (95%CI: 1.66-2.24), pickled food: 2.28 (95%CI: 1.93-2.70)), whereas no significant associations were detected between them in cohort studies (combined RRs: processed food: 1.24 (95%CI: 0.98-1.58), pickled food: 1.43 (95%CI: 0.85-2.42)). In conclusion, this study suggests that both a high consumption of processed and pickled food may increase the EC risk.

Smoking and alcohol cessation programs in patients with head and neck cancer

Abstract: Most head and neck cancers are associated with smoking and alcohol exposure. Smoking and alcohol cessation (ASC) is associated with improved quality of life, cancer therapy efficacy, decreased treatment-related and cardiovascular risks, and is expected to decrease the risk of second primary tumor. It is therefore a high priority in the plan of care. However, results of current ASC programs are disappointing and understanding the reasons of this is critical. We started a qualitative study in 6 academic centers including 3 university hospitals, one regional hospital and one comprehensive cancer center. We first interviewed surgeons and care givers involved in the management of head and neck cancers. Poor communication between stakeholders, absence of alignment of care goals between patients, surgeons and other caregivers, and low level of understanding by patients of the benefits of ASC were felt to represent frequent obstacles to successful outcome. More work is ongoing within the context of our IHNPACT umbrella protocol to identify hurdles associated with successful ASC.

Bladder cancer knowledge in the Lebanese population: When ignorance could be harmful.

Abstract: According to the latest data of the World Cancer Research Fund International (2012), Lebanon has the second highest age-standardized incidence rate of bladder cancer worldwide, both for "men" and "both-sexes" categories. This study was designed to assess bladder cancer knowledge among the Lebanese population. Between November 2017 and January 2018, a cross-sectional study was directed, including patients and visitors of one of the largest university hospitals in the capital Beirut. A face-to-face questionnaire evaluated knowledge regarding, among others, the most important risk factor for bladder cancer and the most frequent revealing symptom. This survey also obtained information regarding smoking habits. A total of 701 participants completed the survey. A total of 49.1% were younger than 50 years, 56.3% were male, 56.6% had a college degree and 54.4% were ever smokers. Two-hundred and thirty-two (33.1%) of the 701 surveyed individuals have never heard about bladder cancer. 157 (33.5%) of the 469 individuals who have heard about bladder cancer were unaware that bladder cancer is different from prostate cancer. Overall, 312 (44.5%) individuals have heard about bladder cancer and knew that it is different from prostate cancer. Of these 312 subjects, 94 (30.1%) knew that tobacco smoking was the most important risk factor for bladder cancer, 166 (53.2%) associated blood in the urine with the most frequent revealing symptom of this disease and 66 (21.2%) considered that bladder cancer is frequent in Lebanon compared to other cancers. This study suggests the lack of knowledge of the Lebanese population towards bladder cancer, including its association with tobacco.

Actualités autour des inhibiteurs de checkpoints immunitaires : enseignements issus du congrès ASCO 2017 et perspectives

Abstract: Immune checkpoint inhibitors anti-PD-1, anti-PD-L1 and anti-CTLA-4 have been in development in several indications and have changed the face of cancer patients' management. Cancer immunotherapy was central in ASCO's meeting 2017. The identification of patients who could benefit most from immune checkpoint inhibitors is essential. The predictive value of PD-L1 status remains insufficient to select patients who could respond to immunotherapy. An extended search for new biomarkers predictive of response (INF-γ, mutational load) is ongoing, in order to better select responders. Immune checkpoint inhibitors have mainly been developed as monotherapy. However, the low response rate, between 10 and 30%, and the occurrence of resistance, contributes to the increment of new therapeutic strategies. This review summarizes the results of combination trials of two immune checkpoint inhibitors, combination of immunotherapy with conventional chemotherapy, radiotherapy or targeted therapies active on the oncogenic addiction pathway.

Radiation therapy in patients with inflammatory bowel disease. A review

Abstract: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are multifactorial diseases characterized by a chronic intestinal inflammation. Abdominal and pelvic irradiation can result in acute or chronic digestive toxicity. A few old studies on small population samples have suggested an increase of gastro-intestinal toxicities in patients with IBD in case of irradiation. Nevertheless, the physiopathology is unknown. More recent studies, including new irradiation techniques, have shown less toxicity events in these patients with IBD. There are no recommendations for irradiation in patients with IBD. This review aims to report recent data on this topic and discuss them regarding radiation parameters.

La réunion de concertation pluridisciplinaire onco-palliative : objectifs et préconisations pratiques

Abstract: Progress leads to increase life duration at the metastatic stage but metastatic disease is most often lethal. Decision-making is necessary for an increasing period of care, beyond evidence-based medicine, dealing with complexity and uncertain benefit/risk ratio. This requires to inform the patient realistically, to discuss prognostication, to develop anticipated written preferences. These changes mean to pass from a medicine based on informed consent to medicine based on respect of the patient wishes even if it can be complex to determine. A new multidisciplinarity is needed, centered on the meaning of the care, the proportionality of the care, the anticipated patient trajectory. The ASCO has published recommendations on early palliative care. The timing and the quality of the discussion between palliative care specialists and oncologists is crucial. We propose 10 steps to organize a multidisciplinary onco-palliative meeting, as it appears the key for the organization of care in non-curable disease.