160 research outputs found
Thérapie radionucléidique personnalisée des tumeurs neuroendocrines
Cette thĂšse de doctorat porte sur le traitement personnalisĂ© des tumeurs neuroendocrines (TNE) en utilisant la thĂ©rapie radiomĂ©tabolique par Âčâ·â·Lu-octrĂ©otate. Comme la plupart des TNE surexpriment des rĂ©cepteurs de la somatostatine (RSST)s, les analogues de la somatostatine radiomarquĂ©s sont utilisĂ©s dans le diagnostic des TNE par imagerie molĂ©culaire, ainsi que pour la radiothĂ©rapie interne en utilisant des radionuclĂ©ides Ă©metteurs bĂȘta (PRRT : peptide receptor radionuclide therapy). Les protocoles actuels de la PRRT impliquent lâadministration de 4 cycles dâune activitĂ© fixe de Âčâ·â·Lu-octrĂ©otate (p. ex. 7,4 GBq), ce qui donne des doses de radiation absorbĂ©e trĂšs variables pour les organes critiques et les lĂ©sions tumorales. Les faibles taux de toxicitĂ© sĂ©rieuse rĂ©nale et hĂ©matopoĂŻĂ©tique (< 1 %) aprĂšs traitement au Âčâ·â·Lu-octrĂ©otate suggĂšrent que la plupart des patients reçoivent un traitement sous-optimal. La mise en place dâune personnalisation de lâactivitĂ© administrĂ©e en fonction de la dosimĂ©trie individualisĂ©e par imagerie molĂ©culaire quantitative pourrait donc permettre de maximiser la rĂ©ponse chez chaque patient, comparativement au rĂ©gime empirique, et ce, en augmentant la dose tumorale absorbĂ©e sans dĂ©passer les seuils de toxicitĂ© aux organes critiques. Les objectifs de cette thĂšse Ă©taient donc, (i) de simuler un rĂ©gime de PRRT personnalisĂ©e (P-PRRT) Ă partir dâune cohorte de patients atteints de TNE traitĂ©s par PRRT empirique, (ii) de rapporter les premiers rĂ©sultats dosimĂ©triques, dâefficacitĂ© et de toxicitĂ© de notre essai prospectif de PRRT personnalisĂ©e (NCT02754297) et finalement (iii) dâĂ©valuer lâexactitude et la reproductibilitĂ© interobservateurs des protocoles simplifiĂ©s de dosimĂ©trie Ă deux temps (Jour 1 et 3) ou Ă un temps unique (Jour 3) basĂ©s sur la tomographie quantitative par Ă©mission de photon (QSPECT : quantitative single-photon emission computed tomography) effectuĂ©e aprĂšs chaque administration de thĂ©rapie. Un autre objectif de la derniĂšre Ă©tude Ă©tait la mise Ă jour de notre protocole personnalisĂ© de prescription de lâactivitĂ© injectĂ©e (AI). (i) Pour rĂ©pondre au premier objectif, nous nous sommes basĂ©s sur une Ă©tude rĂ©trospective afin de concevoir un protocole personnalisĂ© de PRRT basĂ© sur les calculs dosimĂ©triques. Par la suite, une simulation de ce protocole a Ă©tĂ© effectuĂ©e rĂ©trospectivement chez des patients atteints de TNE traitĂ©s par PRRT depuis 2012 Ă lâHĂŽpital de lâHĂŽtel-Dieu de QuĂ©bec. Selon notre rĂ©gime personnalisĂ© de PRRT, la dose rĂ©nale absorbĂ©e par AI Ă©tait prĂ©dite en fonction de la surface corporelle (SC) et le taux de filtration glomĂ©rulaire (TFG) pour le premier cycle de traitement, et par la dosimĂ©trie rĂ©nale du cycle prĂ©cĂ©dent (ou la moyenne de la dosimĂ©trie rĂ©nale des deux derniers cycles) pour les cycles suivants. En normalisant la dose rĂ©nale absorbĂ©e administrĂ©e pendant les cycles dâinduction, notre approche personnalisĂ©e a dĂ©montrĂ© une augmentation moyenne significative de 1,48 fois la dose cumulative maximale absorbĂ©e par la tumeur par rapport au rĂ©gime empirique, augmentant potentiellement le bĂ©nĂ©fice thĂ©rapeutique sans dĂ©passer le seuil de toxicitĂ© rĂ©nale.Cette thĂšse de doctorat porte sur le traitement personnalisĂ© des tumeurs neuroendocrines (TNE) en utilisant la thĂ©rapie radiomĂ©tabolique par 177Lu-octrĂ©otate. Comme la plupart des TNE surexpriment des rĂ©cepteurs de la somatostatine (RSST)s, les analogues de la somatostatine radiomarquĂ©s sont utilisĂ©s dans le diagnostic des TNE par imagerie molĂ©culaire, ainsi que pour la radiothĂ©rapie interne en utilisant des radionuclĂ©ides Ă©metteurs bĂȘta (PRRT : peptide receptor radionuclide therapy). Les protocoles actuels de la PRRT impliquent lâadministration de 4 cycles dâune activitĂ© fixe de 177Lu-octrĂ©otate (p. ex. 7,4 GBq), ce qui donne des doses de radiation absorbĂ©e trĂšs variables pour les organes critiques et les lĂ©sions tumorales. Les faibles taux de toxicitĂ© sĂ©rieuse rĂ©nale et hĂ©matopoĂŻĂ©tique (< 1 %) aprĂšs traitement au 177Lu-octrĂ©otate suggĂšrent que la plupart des patients reçoivent un traitement sous-optimal. La mise en place dâune personnalisation de lâactivitĂ© administrĂ©e en fonction de la dosimĂ©trie individualisĂ©e par imagerie molĂ©culaire quantitative pourrait donc permettre de maximiser la rĂ©ponse chez chaque patient, comparativement au rĂ©gime empirique, et ce, en augmentant la dose tumorale absorbĂ©e sans dĂ©passer les seuils de toxicitĂ© aux organes critiques. Les objectifs de cette thĂšse Ă©taient donc, (i) de simuler un rĂ©gime de PRRT personnalisĂ©e (P-PRRT) Ă partir dâune cohorte de patients atteints de TNE traitĂ©s par PRRT empirique, (ii) de rapporter les premiers rĂ©sultats dosimĂ©triques, dâefficacitĂ© et de toxicitĂ© de notre essai prospectif de PRRT personnalisĂ©e (NCT02754297) et finalement (iii) dâĂ©valuer lâexactitude et la reproductibilitĂ© interobservateurs des protocoles simplifiĂ©s de dosimĂ©trie Ă deux temps (Jour 1 et 3) ou Ă un temps unique (Jour 3) basĂ©s sur la tomographie quantitative par Ă©mission de photon (QSPECT : quantitative single-photon emission computed tomography) effectuĂ©e aprĂšs chaque administration de thĂ©rapie. Un autre objectif de la derniĂšre Ă©tude Ă©tait la mise Ă jour de notre protocole personnalisĂ© de prescription de lâactivitĂ© injectĂ©e (AI). (i) Pour rĂ©pondre au premier objectif, nous nous sommes basĂ©s sur une Ă©tude rĂ©trospective afin de concevoir un protocole personnalisĂ© de PRRT basĂ© sur les calculs dosimĂ©triques. Par la suite, une simulation de ce protocole a Ă©tĂ© effectuĂ©e rĂ©trospectivement chez des patients atteints de TNE traitĂ©s par PRRT depuis 2012 Ă lâHĂŽpital de lâHĂŽtel-Dieu de QuĂ©bec. Selon notre rĂ©gime personnalisĂ© de PRRT, la dose rĂ©nale absorbĂ©e par AI Ă©tait prĂ©dite en fonction de la surface corporelle (SC) et le taux de filtration glomĂ©rulaire (TFG) pour le premier cycle de traitement, et par la dosimĂ©trie rĂ©nale du cycle prĂ©cĂ©dent (ou la moyenne de la dosimĂ©trie rĂ©nale des deux derniers cycles) pour les cycles suivants. En normalisant la dose rĂ©nale absorbĂ©e administrĂ©e pendant les cycles dâinduction, notre approche personnalisĂ©e a dĂ©montrĂ© une augmentation moyenne significative de 1,48 fois la dose cumulative maximale absorbĂ©e par la tumeur par rapport au rĂ©gime empirique, augmentant potentiellement le bĂ©nĂ©fice thĂ©rapeutique sans dĂ©passer le seuil de toxicitĂ© rĂ©nale. (ii) Sur la base de notre Ă©tude rĂ©trospective, et en appliquant le protocole de PRRT personnalisĂ©e dĂ©veloppĂ© aux patients atteints de TNE mĂ©tastatique traitĂ©s depuis avril 2016 Ă lâHĂŽpital de lâHĂŽtel-Dieu de QuĂ©bec, nous avons rapportĂ© les premiers rĂ©sultats dosimĂ©triques sur lâefficacitĂ© et la toxicitĂ© de notre essai prospectif de PRRT personnalisĂ©e. Notre approche personnalisĂ©e a dĂ©montrĂ© une augmentation significative de la dose tumorale absorbĂ©e mĂ©diane de 1,26 fois par rapport au rĂ©gime de PRRT empirique simulĂ© sans augmenter le taux de toxicitĂ© sĂ©rieuse des organes critiques liĂ©e au traitement. Le traitement personnalisĂ© a donnĂ© un taux de rĂ©ponse partielle ou mineure de 59 % avec une stabilitĂ© dans 33,3 % des cas. En particulier, la PRRT personnalisĂ©e a induit une rĂ©ponse partielle ou mineure chez 84,6 % des patients atteints de TNE dâorigine pancrĂ©atique (pTNE). Finalement, le profil de sĂ©curitĂ© est similaire Ă celui du rĂ©gime empirique alors quâaucun patient nâa prĂ©sentĂ© d'insuffisance rĂ©nale sĂ©vĂšre. (iii) La dosimĂ©trie, obtenue Ă lâaide de petits volumes dâintĂ©rĂȘt pour l'Ă©chantillonnage de concentration dâactivitĂ© pour le rein, la moelle osseuse et la tumeur dominante, est basĂ©e sur trois temps (Jour 0, 1 et 3) selon la pratique courante. Toutefois, en raison de la complexitĂ© de cette procĂ©dure, des mĂ©thodes de dosimĂ©trie plus pratiques mais robustes sont nĂ©cessaires pour une adoption clinique Ă©tendue. Nous avons dĂ©montrĂ© quâun protocole simplifiĂ© de dosimĂ©trie basĂ© sur des images QSPECT Ă deux temps fournit des estimations de dose reproductibles et plus prĂ©cises que les techniques basĂ©es sur un seul temps. Nous avons aussi observĂ© une excellente reproductibilitĂ© interobservateurs, en particulier pour la dose rĂ©nale, en utilisant les deux mĂ©thodes les plus prĂ©cises basĂ©es sur trois ou deux temps avec des erreurs moyennes < 1 % et des Ă©carts-types †5 %. Finalement, nous avons mis Ă jour notre protocole de P-PRRT : la dose rĂ©nale absorbĂ©e peut ĂȘtre normalisĂ©e en personnalisant lâAI en fonction du produit du TFG avec la SC pour le premier cycle et de la dosimĂ©trie rĂ©nale prĂ©cĂ©dente pour les cycles subsĂ©quents. En conclusion, nous avons conçu et validĂ© un protocole de personnalisation de la PRRT au 177Lu-octrĂ©otate basĂ© sur la dosimĂ©trie, dans lequel la dose absorbĂ©e au rein est contrĂŽlĂ©e et normalisĂ©e. La personnalisation de la PRRT permet dâaugmenter de façon significative la dose absorbĂ©e Ă la tumeur, et ainsi la probabilitĂ© dâobtenir une meilleure rĂ©ponse thĂ©rapeutique, tout en limitant le risque de toxicitĂ© aux organes critiques. Nous proposons Ă©galement un protocole de dosimĂ©trie simplifiĂ©e, basĂ© sur l'imagerie QSPECT en deux temps, en utilisant des petits volumes dâintĂ©rĂȘt. Cette mĂ©thode donne des rĂ©sultats de dosimĂ©trie prĂ©cis, notamment pour les reins et la tumeur, et une reproductibilitĂ© interobservateur Ă©levĂ©e.(ii) Sur la base de notre Ă©tude rĂ©trospective, et en appliquant le protocole de PRRT personnalisĂ©e dĂ©veloppĂ© aux patients atteints de TNE mĂ©tastatique traitĂ©s depuis avril 2016 Ă lâHĂŽpital de lâHĂŽtel-Dieu de QuĂ©bec, nous avons rapportĂ© les premiers rĂ©sultats dosimĂ©triques sur lâefficacitĂ© et la toxicitĂ© de notre essai prospectif de PRRT personnalisĂ©e. Notre approche personnalisĂ©e a dĂ©montrĂ© une augmentation significative de la dose tumorale absorbĂ©e mĂ©diane de 1,26 fois par rapport au rĂ©gime de PRRT empirique simulĂ© sans augmenter le taux de toxicitĂ© sĂ©rieuse des organes critiques liĂ©e au traitement. Le traitement personnalisĂ© a donnĂ© un taux de rĂ©ponse partielle ou mineure de 59 % avec une stabilitĂ© dans 33,3 % des cas. En particulier, la PRRT personnalisĂ©e a induit une rĂ©ponse partielle ou mineure chez 84,6 % des patients atteints de TNE dâorigine pancrĂ©atique (pTNE). Finalement, le profil de sĂ©curitĂ© est similaire Ă celui du rĂ©gime empirique alors quâaucun patient nâa prĂ©sentĂ© d'insuffisance rĂ©nale sĂ©vĂšre. (iii) La dosimĂ©trie, obtenue Ă lâaide de petits volumes dâintĂ©rĂȘt pour l'Ă©chantillonnage de concentration dâactivitĂ© pour le rein, la moelle osseuse et la tumeur dominante, est basĂ©e sur trois temps (Jour 0, 1 et 3) selon la pratique courante. Toutefois, en raison de la complexitĂ© de cette procĂ©dure, des mĂ©thodes de dosimĂ©trie plus pratiques mais robustes sont nĂ©cessaires pour une adoption clinique Ă©tendue. Nous avons dĂ©montrĂ© quâun protocole simplifiĂ© de dosimĂ©trie basĂ© sur des images QSPECT Ă deux temps fournit des estimations de dose reproductibles et plus prĂ©cises que les techniques basĂ©es sur un seul temps. Nous avons aussi observĂ© une excellente reproductibilitĂ© interobservateurs, en particulier pour la dose rĂ©nale, en utilisant les deux mĂ©thodes les plus prĂ©cises basĂ©es sur trois ou deux temps avec des erreurs moyennes < 1 % et des Ă©carts-types †5 %. Finalement, nous avons mis Ă jour notre protocole de P-PRRT : la dose rĂ©nale absorbĂ©e peut ĂȘtre normalisĂ©e en personnalisant lâAI en fonction du produit du TFG avec la SC pour le premier cycle et de la dosimĂ©trie rĂ©nale prĂ©cĂ©dente pour les cycles subsĂ©quents. En conclusion, nous avons conçu et validĂ© un protocole de personnalisation de la PRRT au Âčâ·â·Lu-octrĂ©otate basĂ© sur la dosimĂ©trie, dans lequel la dose absorbĂ©e au rein est contrĂŽlĂ©e et normalisĂ©e. La personnalisation de la PRRT permet dâaugmenter de façon significative la dose absorbĂ©e Ă la tumeur, et ainsi la probabilitĂ© dâobtenir une meilleure rĂ©ponse thĂ©rapeutique, tout en limitant le risque de toxicitĂ© aux organes critiques. Nous proposons Ă©galement un protocole de dosimĂ©trie simplifiĂ©e, basĂ© sur l'imagerie QSPECT en deux temps, en utilisant des petits volumes dâintĂ©rĂȘt. Cette mĂ©thode donne des rĂ©sultats de dosimĂ©trie prĂ©cis, notamment pour les reins et la tumeur, et une reproductibilitĂ© interobservateur Ă©levĂ©e.(ii) Based on our retrospective study and applying our developed personalized PRRT protocol to the patients with metastatic NET treated since April 2016 at lâHotel-Dieu de QuĂ©bec hospital, we reported the preliminary data on dosimetry, efficacy and safety from our prospective PRRT trial. Our personalized approach yielded a significant increase in the median absorbed tumor dose (1.26 fold) compared with the simulated empirical PRRT regimen, without increasing the rate of serious treatment-related toxicity for critical organs. The personalized treatment gave a partial or minor response rate of 59 % and stability in 33.3 % of cases. In particular, the personalized PRRT regime resulted in a partial or minor response in 84.6 % of patients with NET of pancreatic origin (pNET). Finally, the safety profile was similar to that of the empirical regimen whereas, no patient has had severe renal impairment. (iii) According to the current practice, the dosimetry, obtained using small volumes of interest activity for concentration sampling in the kidney, bone marrow and the dominant tumor, is based on three time points (day 0, 1 and 3). However, due to the complexity of this procedure, more practical yet robust dosimetry methods are required for extended clinical use. We have observed that a simplified dosimetry protocol based on two-time point QSPECT scanning on Day 1 and 3 after PRRT treatment provides reproducible and more accurate dose estimates than the techniques relying on a single time point for noninitial or all cycles. We also observed an excellent inter-observer reproducibility, in particular for the renal absorbed dose using the two most precise dosimetry methods based on three or two time points with mean relative errors < 1 % and standard deviations †5 %. In addition, we have updated our P-PRRT protocol. In particular, renal absorbed radiation dose over a four-cycle induction PRRT course can be standardized by personalizing IA based on the product of estimated GFR with BSA for the first cycle, and on prior renal dosimetry for the subsequent cycles. In conclusion, we have designed and validated a personalized PRRT protocol with Âčâ·â·Lu-octreotate based on dosimetry, in which the absorbed dose to the kidney is controlled and standardized. The personalization of PRRT can significantly increase the dose absorbed to the tumor, and thus the probability of obtaining a better therapeutic response, while limiting the risk of toxicity to critical organs. We also proposed a simplified dosimetry protocol, based on two time-points QSPECT scans, using small volumes of interest. This method gives accurate dosimetry results, especially for the kidneys and the tumors, and high interobserver reproducibility.This doctoral thesis is focused on the personalized treatment of neuroendocrine tumours (NET) using Âčâ·â·Lu-octreotate radiometabolic therapy. Since NETs overexpress somatostatin receptors (SSRT)s, radiolabeled somatostatin analogues are used in the diagnosis of NETs by molecular imaging, and for internal radiotherapy using beta-emitting radionuclides (PRRT: peptide receptor radionuclide therapy). The existing protocols for PRRT involve the administration of 4 cycles of a fixed activity of Âčâ·â·Lu-octreotate (i.e., 7.4 GBq), which gives highly variable absorbed radiation doses to critical organs and tumor lesions. The low incidence of serious renal and hematopoietic toxicities (< 1 %) of Âčâ·â·Luoctreotate suggests that the majority of patients are undertreated. The personalization of the administered activity according to the individualized dosimetry obtained from quantitative molecular imaging could make possible to maximize the response in each patient, compared to the empirical regime, without exceeding the thresholds of toxicity to the critical organs. The objectives of this thesis were, therefore (i) to simulate a personalized PRRT (P-PRRT) regime in a cohort of patients with NET treated with empiric PRRT, (ii) to report the preliminary data on dosimetry, efficacy and safety from our prospective PRRT trial and (iii) to assess the accuracy and the inter-observer reproducibility of simplified two time points (Day 1 and 3) or one time point (Day 3) dosimetry protocols based on quantitative single-photon emission computed tomography (QSPECT) performed after each PRRT cycle. Another objective of the last study concerned the update of our P-PRRT protocol. (i) We first reviewed retrospective data on patients with NETs treated with PRRT since 2012 at lâHĂŽtel-Dieu de QuĂ©bec hospital. According to our P-PRRT regimen, the renal absorbed dose per injected activity (IA) was predicted by the body surface (BSA) and the glomerular filtration rate (GFR) for the first induction cycle, and by the renal dosimetry of the previous cycle (or the average renal dosimetry of the last two cycles) for the following cycles. By normalizing the absorbed renal dose administered during the induction cycles, our personalized approach resulted in an average 1.48-fold increase in the maximum cumulative tumour absorbed dose compared with the empiric regimen, potentially increasing the therapeutic benefit without exceeding the threshold of renal toxicity
The role of Micro-RNAs in Hepatocellular Carcinoma: From Molecular Biology to Treatment
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC
Insulin resistance and acne: a new risk factor for men?
The purpose of this study is to investigate the relationship between acne and insulin resistance as well as other metabolic impairment in young males. Acne is a skin disease that can be influenced by endocrine abnormalities. In females, it is associated with polycystic ovary syndrome, with peripheral insulin resistance and hyperinsulinemia, whereas few data are available in males. For investigating this, 22 young males with acne have been compared to 22 controls of comparable age and gender. Acne was scored using the global acne grading system score. Clinical as well as biochemical parameters of glucose and lipid metabolism, circulating levels of androgens, and IGF-1 were evaluated. Oral glucose tolerance test was performed and homeostasis model assessment of insulin resistance was calculated. The results thus obtained are as follows, patients had higher BMI (p = 0.003), WC (p = 0.002), WHR (p = 0.02), SBP (p = 0.0001), DBP (p = 0.001), basal (p = 0.01) and 120 min. oGTT serum insulin concentrations (p = 0.002), basal glucose concentrations (p = 0.03), HOMA-IR (p = 0.016), and lower HDL-cholesterol than controls (p = 0.001). Among the subgroup of subjects with BMI <24.9, HDL-cholesterol (p = 0.05) and 120 min. oGTT serum insulin concentrations (p = 0.009) resulted to be independent predictors of acne at multivariate analysis. In conclusion, these findings highlight a metabolic imbalance in young males affected with acne. Insulin resistance seems to play the main role for the development of acne in these subjects. Insulin resistance could represent an effective target for therapy in male acne
Cancer Stem Cell Gene Profile as Predictor of Relapse in High Risk Stage II and Stage III, Radically Resected Colon Cancer Patients
Early Botulinum Toxin Type A injection for post-stroke spasticity: a longitudinal cohort study
Early management of spasticity may improve stroke outcome. Botulinum toxin type A (BoNT-A) is recommended treatment for post-stroke spasticity (PSS). However, it is usually administered in the chronic phase of stroke. Our aim was to determine whether the length of time between stroke onset and initial BoNT-A injection has an effect on outcomes after PSS treatment. This multicenter, longitudinal, cohort study included stroke patients (time since onset <12 months) with PSS who received BoNT-A for the first time according to routine practice. The main outcome was the modified Ashworth scale (MAS). Patients were evaluated before BoNT-A injection and then at 4, 12, and 24 weeks of follow-up. Eighty-three patients with PSS were enrolled. MAS showed a significant decrease in PSS at 4 and 12 weeks but not at 24 weeks after treatment. Among the patients with a time between stroke onset and BoNT-A injection >90 days, the MAS were higher at 4 and 12 weeks than at 24 weeks compared to those injected â€90 days since stroke. Our findings suggest that BoNT-A treatment for PSS should be initiated within 3 months after stroke onset in order to obtain a greater reduction in muscle tone at 1 and 3 months afterwards
Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab
Clinical observations suggested that a non negligible proportion of patients, ranging from 40% to 70%, does not seem to benefit from the use of anti-EGFR targeted antibodies even in the absence of a mutation of the K- RAS gene. The EGFR pathway activation via the Ras-Raf-MAP-kinase and the protein-serine/threonine kinase AKT could determine resistance to anti-EGFR treatment.We tested the interaction between phosphorylated AKT and MAPK expression in colorectal tumours and corresponding metastases and global outcome in K-RAS wild type patients receiving irinotecan-cetuximab.Seventy-two patients with histologically proven metastatic colorectal cancer, treated with Irinotecan and Cetuximab based chemotherapy, were eligible for our analysis.In metastases pAKT correlated with RR (9% vs. 58%, p\u2009=\u20090.004), PFS (2.3 months vs. 9.2 months p\u2009<\u20090.0001) and OS (6.1 months vs. 26.7 months p\u2009<\u20090.0001) and pMAPK correlated with RR (10% vs. 47%, p\u2009=\u20090.002), PFS (2.3 months vs. 8.6 months p\u2009<\u20090.0001) and OS (7.8 months vs. 26 months p\u2009=\u20090.0004). At multivariate analysis pAKT and pMAPK in metastases were able to independently predict PFS. pAKT in metastases independently correlated with RR as wellpAKT and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAKT and pMAPK metastases expression targeting these factors may be crucial
Front-line window therapy with cisplatin in patients with primary disseminated Ewing sarcoma: A study by the Associazione Italiana di Ematologia ed Oncologia Pediatrica and Italian Sarcoma Group
VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib
Background: Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.Methods:A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).Results:Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.Conclusions:In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitini
Lactate Dehydrogenase in Hepatocellular Carcinoma: Something Old, Something New
Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80-90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this disease
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