Diagnostic Significance of Exosomal miRNAs in the Plasma of Breast Cancer Patients

Poster Session AbstractsBackground and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for 25% (up-regulation) and 15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis.link_to_OA_fulltex

Intégration des mesures intermédiaires de survie dans les évaluations économiques en cancer du sein métastatique

De nos jours, il est de plus en plus fréquent de recourir à des mesures intermédiaires d’efficacité telles que la survie sans progression (SSP) et le temps avant la progression de la tumeur (TPT) afin d’estimer l’efficacité d’un nouvel agent anticancéreux. Cependant, l’absence de mesures finales comme la survie globale (SG) complexifie la prise de décision par rapport au remboursement des nouveaux traitements anticancéreux. Ainsi, cette thèse se concentre sur différents aspects de l’intégration des mesures intermédiaires d’efficacité dans les évaluations économiques en oncologie, spécifiquement en cancer du sein métastatique. Une première étude a évalué la relation entre la SSP/TPT et la SG dans le contexte du cancer du sein métastatique. Une revue systématique de la littérature a identifié les études cliniques randomisées portant sur l’efficacité d’un traitement anticancéreux chez les femmes atteintes d’un cancer du sein métastatique et rapportant des données de SSP/TPT et de SG. Les résultats de cette étude ont démontré qu’il existe une relation statistiquement significative, d’une part, entre la SSP/TPT médiane et la SG médiane (r = 0.428; p ≤ 0,01), et d’autre part, entre l’effet de traitement sur la SSP/TPT et l’effet de traitement sur la SG (r = 0.427; p ≤ 0,01). Selon les résultats obtenus, la SSP/TPT pourrait être considérée comme un substitut valide de la SG, justifiant ainsi son utilisation dans les évaluations économiques en cancer du sein métastatique. Une deuxième étude a évalué l’utilisation des mesures intermédiaires de survie dans les évaluations économiques en cancer avancé et identifié les méthodes utilisées pour intégrer ces mesures en l’absence de données de SG. Une revue systématique de la littérature a été réalisée pour recenser les évaluations économiques de type coût-efficacité et coût-utilité ayant intégré des mesures intermédiaires de survie. Cette étude a démontré l’ampleur de l’utilisation des mesures intermédiaires de survie dans les évaluations économiques en cancer avancé. Par ailleurs, plusieurs approches ont été identifiées pour pallier l’absence de données de SG, notamment l’utilisation d’un risque de décès post-progression équivalent pour les groupes à l’étude, le recours à des comparaisons indirectes basées sur de nombreuses hypothèses, l’utilisation d’une mesure intermédiaire comme proxy de la SG, le recours à l’opinion d’experts et l’utilisation de données associées à un traitement différent ou une ligne de traitement différente. Enfin, une troisième étude s’est penchée sur le développement d’un modèle pharmacoéconomique générique canadien intégrant les mesures intermédiaires de survie en cancer du sein métastatique. Ce modèle de Markov inclut des paramètres spécifiques aux traitements sous évaluations (coût de traitement, données de survie et incidence des effets indésirables) de même que des paramètres globaux qui ne dépendent pas des traitements évalués (caractéristiques des patientes, valeurs d’utilité associées aux états de santé du modèle, pertes d’utilité et coûts des effets indésirables, coûts d’administration des traitements, coûts de suivi médical et coûts des soins prodigués en fin de vie). Le modèle a été validé en évaluant sa capacité à répliquer des résultats d’études existantes. Ce modèle permet d’uniformiser l’évaluation économique des nouveaux traitements en cancer du sein métastatique et pourrait par conséquent, devenir un outil d’aide à la décision de référence pour les organismes responsables du remboursement des médicaments au Canada. Bref, les résultats de ces trois études répondent à une problématique importante dans l’évaluation économique des traitements en oncologie et pourront contribuer à faciliter la prise de décision en santé.Nowadays, intermediate endpoints such as progression-free survival (PFS) and time to progression (TTP) are frequently used in clinical trials of advanced cancer. However, use of such endpoints instead of overall survival (OS) poses a significant challenge in the economic evaluation of anticancer drugs. This thesis focuses on different aspects of the integration of intermediate endpoints in the economic evaluation of anticancer drugs, especially in the context of metastatic breast cancer. A first study assessed the relationship between PFS/TPT and OS in metastatic breast cancer using a trial-based approach. A systematic review of the literature was performed to identify randomized clinical trials of metastatic breast cancer therapy reporting both PFS/TTP and OS data. Results of this study indicated a statistically significant relationship between the median PFS/TTP and the median OS (r = 0.428; p < 0.01), and between the treatment effect on PFS/TTP and the treatment effect on OS (r = 0.427; p < 0.01). Findings of this study suggest that PFS/TTP may be considered as a potential surrogate for OS, thus justifying its use in cost-effectiveness or cost-utility analyses of metastatic breast cancer therapy. A second study evaluated the use of intermediate endpoints in the economic evaluation of new treatments for advanced cancer and the methodological approaches adopted when OS data are unavailable or of limited use. A systematic review of the literature was conducted to identify cost-effectiveness and cost-utility analyses using an intermediate endpoint as an outcome measure. This study showed that intermediate endpoints are widely used in the economic evaluation of new treatments for advanced cancer. Several approaches are used in the absence of OS data such as assuming an equal risk of death for all treatment groups, using indirect comparison based on numerous assumptions, using of a proxy for OS, using unpublished external information (consultation with clinical experts), and using published external information from different treatment settings. Finally, a third study aimed to develop a global economic model to assess the cost-effectiveness of new treatments for metastatic breast cancer in Canada. This Markov model, which integrates intermediate endpoints, includes parameters specific to the treatments under evaluation (drug treatment, survival outcomes, and incidence of treatment-related adverse events (AEs)), as well as global parameters that are consistent regardless of the treatment under evaluation (patient characteristics, health states utilities, disutilities and costs associated with treatment-related AEs, as well as costs associated with drug administration, medical follow-up, and end-of-life care). The model was validated by assessing its ability to replicate results of existing studies. This model standardizes the economic evaluation of new therapies for metastatic breast cancer, and could thus be used as a benchmark by drug reimbursement authorities in Canada. In summary, the results of these three studies address an important challenge encountered in the economic evaluation of anticancer drugs, and therefore, can be very valuable for decision-making purposes

Phytochemical, in vitro and in silico analyses of hexanic alpinia galanga extract in cancer chemo-prevention study on breast cancer cells

Cancer is one of the major health concerns and leading causes of mortality worldwide. The major problem in the cancer chemotherapy is the drug-resistant of the established drugs. Therefore, the immediate search for anti-cancer agents from plant sources has been done intensively. The purpose of this study was to evaluate the anticancer effects of Alpinia galanga extracts against several breast cancer cell lines. The crude extracts were isolated via aqueous and different polarity of solvents such as hexane, acetone and ethanol using soxhlet extraction rotary evaporator. Cytotoxicity of crude extracts were screened by using MTT assay against normal human liver (WRL-68), and MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cell lines. Active crude extract with lowest IC50 value was selected for fractionated via column chromatography (CC) technique. Then, fractionates were re-evaluated for cytotoxicity profile and anti-migration activity. Further determination of active fraction induced cells death through cell cycle, apoptosis and pyroptosis was conducted flow cytometry and caspases bioluminescence studies. Their morphology structures were assessed under phase-contrast microscopy and inverted fluorescent-microscopy. Besides that, identification of bioactive molecules using gas chromatography-mass spectrophotometry (GC-MS) and prediction potential mechanism pathways was conducted through in silico molecular docking study. Active hexanic A. galanga extract with lowest IC50 value at 2.12 μg/mL and highest selectivity index (10.17) against MDA-MB-231 cells was fractionated. It was revealed that fraction F6-4 possessed potent anticancer and anti-migration activities. Interestingly, fraction F6-4 demonstrated both apoptosis and pyroptosis-induce cells death which involves ATP-dependent in MDA-MB-231 cells. The inhibition of MDA-MB-231 cells was characterized with apoptosis cells positive Annexin-V FITC due to exposure of phosphatidylserines (PS) on cell membrane after treatment and underwent cell cycle arrest at G0/G1 checkpoint. Further, the molecular mechanisms of inhibition of MDA-MB-231 cells by fraction F6-4 emphasizes on activation extrinsic and intrinsic caspases cascade, including inflammation caspase-1 (pyroptosis). Also, distinctly apoptosis and pyroptosis morphological changes were observed. Concomitantly, major bioactive compound was identified in both hexanic A. galanga and fraction F6-4 is 4-Chromanol. In silico molecular docking elucidated that 4-Chromanol induced apoptosis mechanisms through interaction between molecular extrinsic and intrinsic pathways, and also reveals as strong competitive inhibitor against Cdk2 and Cdk6. In conclusion, 4-Chromanol exhibited potent anticancer against triple negative breast cancer (TNBC) subtype and elucidate possible underlying mechanism(s) of apoptosis pathways

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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Understanding Time-Activity Curve and TimeIntegrated Activity Variations in Radiopharmaceutical Therapy:Experience from the TACTIC AAPM Grand Challenge 2023

Aim/Introduction: The process of determining time-activity curves (TACs) for radiopharmaceutical therapy (RPT) relies heavily on user- and site-specifc steps, impacting time-integrated activity (TIA) and, efectively, absorbed dose calculations. Despite TIA’sclinical signifcance, there is no consensus on data processing methods nor an understanding of how user-dependent TAC calculation afects personalized RPT dosimetry. In 2023, the TACTIC AAPM Grand Challenge was created to address these challenges. This work presents results and insights from the challenge. Materials and Methods: Launched in January 2023, the TACTIC challenge consisted of three phases: warm-up (P0), individual patient-based TAC ftting (P1), and population-based TAC ftting (P2). Participants were provided with pre-processed synthetic biokinetic data of [177Lu]Lu-PSMA-617 (kidney, blood, and tumor) and tasked with modeling the TAC and calculating TIA values for each target organ. Additionally, participants submitted information about the TAC type and parameters used for ft optimization. The best-performing team in P1 and P2 was determined by the lowest total root mean squared error (RMSE) error over the organs. Results: A total of 132 individuals from over 30 countries registered for the challenge, representing a diverse mix of highly experienced dosimetry groups, industryprofessionals, and newcomers to RPT dosimetry. Among them, 73 participants requested data, of which 35 (P0), 35 (P1) and 28 (P2) submitted their results. Across the three phases, 13 diferentft functions were utilized, with varying advanced model selection criteria and levels of uncertainty incorporation. Notably, the biexponential function was most prevalent, utilized in 51% (P1) and 32% (P2) of submissions, while the least square objective functionwas the primary choice for 40% of submissions (P1). Despite the challenge’s nature, only a minority of participants—6 in P1 and 8 in P2—incorporated uncertainty budgets into their TIAC calculations. Population-based information was utilized in only 7 submissions during P2. Interestingly, no correlations were found between choice of ft function, objective function, uncertainty i ncorporation, or population information use and participants’ performance. Winners in each phase employed diverse models and objective functions. However, the top-performing participants consistently integrated uncertainty information when selectingthe most suitable TAC model. A decrease in some participants’ performance from P1 to P2 when including uncertainty or population-based information suggests that more guidance and training is needed to use them efectively. Conclusion: The TACTIC challenge results ofer insights into global TAC modeling practices, revealing signifcant variations in result quality. This underscores the importance of education in TAC ftting methodologies