Artykuły w czasopismach: „Quantification tumorale”

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Brulé, A., L. Matignon, N. Elie, J. Vigouroux, A. Roche, N. Lassau i P. Péronneau. "Acquisition 3D temps reel et quantification 3D de la perfusion tumorale par ultrasons". Journal de Radiologie 87, nr 10 (październik 2006): 1422. http://dx.doi.org/10.1016/s0221-0363(06)87456-1.

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Brulé, A., L. Matignon, N. Elie, J. Vigouroux, A. Roche, N. Lassau i P. Péronneau. "RECH2 Acquisition 3D temps reel et quantification 3D de la perfusion tumorale par ultrasons". Journal de Radiologie 87, nr 10 (październik 2006): 1552. http://dx.doi.org/10.1016/s0221-0363(06)87956-4.

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Ducreux, D., i P. Lasjaunias. "Mesures et quantification de la perfusion et de la perméabilité tumorale: une nouvelle approche méthodologique". Journal of Neuroradiology 34, nr 1 (marzec 2007): 11–12. http://dx.doi.org/10.1016/j.neurad.2007.01.049.

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Lassau, N., J. Pellier, J. Lacroix, V. Vilgrain, S. Taieb, R. Azziza, M. Cuinet, C. Labbe-Devilliers i A. Sarran. "ONCO-WS-12 Etude STIC : DCE-US avec quantification de la perfusion tumorale pour l’evaluation precoce des traitements anti-angiogeniques". Journal de Radiologie 90, nr 10 (październik 2009): 1557. http://dx.doi.org/10.1016/s0221-0363(09)76097-4.

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TARTA, Cláudio, Cláudio Rolim TEIXEIRA, Shinji TANAKA, Ken HARUMA, César CHIELE-NETO i Vinícius Duval da SILVA. "Angiogenesis in advanced colorectal adenocarcinoma with special reference to tumoral invasion". Arquivos de Gastroenterologia 39, nr 1 (marzec 2002): 32–38. http://dx.doi.org/10.1590/s0004-28032002000100007.

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Background - Angiogenesis is a crucial step in tumor growth and progression. Its quantification by microvessel counting has a prognostic value in several types of malignancies and recently has been appraised in gastrointestinal tumors. Aim - To assess the prognostisc significance of microvessel quantification in colorectal carcinomas, studying its association with hematogenous metastases, survival and clinicopathological variables such as size, histologic differentiation and depth of tumoral invasion. Patients/Methods - Forty eight patients with colorectal adenocarcinoma were included in this study. Histologic sections of invasion tumoral margin (4 µm) were analyzed and endothellined microvessels were immunostained with monoclonal mouse Von Willebrand Factor (anti-FVIII). The microvessel count was performed from the identification of the area with increased microvessel density - hot spots - and results of the mean in five of these fields. Results- The cut-off microvessel count was 14 microvessels/0,785 mm² , which divided the sample into hypovascular and hypervascular groups. While 2/8 (25%) tumors with muscularis propria invasion were classified as hypervascular, 11/15 (73%) tumors with serosa or perivisceral fat were classified as hypervascular. However, a non-significant statistical association was found between the angiogenesis quantification, hematogenous metastases, survival and clinicopathological variables such as size and histologic differentiation of the tumor. Conclusions - The findings of significantly increase of microvessel count in conformity with tumoral invasion depth supports the hypothesis that tumor progression might be related to angiogenesis. Although angiogenesis is an important step in the tumoral growth and during the metastatization process, other factors can be implicated.

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Sorbo, M. C., F. P. Antonucci, M. Manuelli, I. Lenci, D. Sforza, L. Carioti, M. C. Bellocchi i in. "Different Prevalence of HCV Resistance and HCV RNA Quantification Within Tumoral and Non Tumoral Liver Tissues in HCC/Transplanted Patients". Journal of Hepatology 64, nr 2 (2016): S416—S417. http://dx.doi.org/10.1016/s0168-8278(16)00668-1.

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Sorbo, M. C., F. P. Antonucci, M. Manuelli, I. Lenci, D. Sforza, L. Carioti, M. C. Bellocchi i in. "Different prevalence of HCV resistance and HCV quantification within blood and liver samples (tumoral and non tumoral tissues) of HCC/transplanted patients". Digestive and Liver Disease 48 (luty 2016): e56. http://dx.doi.org/10.1016/j.dld.2015.12.130.

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Richards, Cathy E., Katherine M. Sheehan, Elaine W. Kay, Charlotta Hedner, David Borg, Joanna Fay, Anthony O’Grady, Arnold D. K. Hill, Karin Jirström i Ann M. Hopkins. "Development of a Novel Weighted Ranking Method for Immunohistochemical Quantification of a Heterogeneously Expressed Protein in Gastro-Esophageal Cancers". Cancers 13, nr 6 (13.03.2021): 1286. http://dx.doi.org/10.3390/cancers13061286.

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High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically significant correlations between JAM-A/HER2 expression. Given the growing importance of immunohistochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients.

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Feki-Tounsi, Molka, Pablo Olmedo, Fernando Gil, Mohamed-Nabil Mhiri, Ahmed Rebai i Amel Hamza-Chaffai. "Trace metal quantification in bladder biopsies from tumoral lesions of Tunisian cancer and controls subjects". Environmental Science and Pollution Research 21, nr 19 (7.06.2014): 11433–38. http://dx.doi.org/10.1007/s11356-014-3099-x.

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Patruno, Rosa, Giuseppe Passantino, Carmelo Laface, Antonella Tinelli, Alfredo Zito, Roberta Ruggieri, Francesco Luposella i in. "Microvascular Density, Endothelial Area, and Ki-67 Proliferative Index Correlate Each Other in Cat Post-Injection Fibrosarcoma". Cells 10, nr 1 (28.12.2020): 31. http://dx.doi.org/10.3390/cells10010031.

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Soft tissue sarcomas are a large group of different tumor types both in humans and in animals. Among them, fibrosarcoma is the most frequent malignant mesenchymal tumoral form in cats, representing up to 28% of all cat skin tumors, while human fibrosarcoma, fortunately, only represents 5% of all sarcomas and 0.025% of the world-wide burden of tumors. This low incidence in humans leads to consideration of this group of tumoral diseases as rare, so therapeutic options are few due to the difficulty of starting clinical trials. In this context, the identification of research models for fibrosarcomas could be of great interest to deepen knowledge in this field and recognize new or possible biological pathways involved in tumor progression and metastasis. Angiogenesis is considered a fundamental scattering cause of tumor aggressiveness and progression in all forms of cancer, but only a few research parameters were developed and reported to express them quantitatively and qualitatively. The role in angiogenesis of microenvironmental stromal cells, such as fibroblasts, lymphocytes, mast cells, and macrophages, was largely demonstrated since this topic was first approached, while quantification of new vessels and their blood capacity in tumoral area is a relatively recent approach that could be well developed thanks to expertise in immunohistochemistry and image analysis. In this paper, a crossing study evaluating microvascular density (MVD), endothelial area (EA), and Ki-67 proliferative index was reported for a series of formalin-fixed and paraffin-embedded tissue samples from 99 cat patients, affected by cat post-injection fibrosarcoma, by using a till ×400 magnification light microscopy. We aim to demonstrate that cat pets may be considered a useful animal model for better studying the correspondent human diseases and we report, for the first time to our knowledge, experimental data in terms of correlation among MVD, EA, and Ki-67 strictly involved in aggressiveness and tumoral progression.

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Nakayama, G. "Quantification of p16 methylation in serum DNA as a new diagnostic tool for colorectal cancer". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 10050. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10050.

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10050 Background: The incidence of colorectal cancer (CRC), one of the commonest malignancies worldwide, is still increasing. Despite advances in the diagnostic procedure, a large number of patients with CRC still presents with advanced disease. More sensitive and efficient diagnostic technique would make an impact on the prognosis of CRC patients through improving their compliance to the screening program, hence allowing earlier detection of the disease. To test the hypothesis that p16 methylation may serve as a marker for the diagnosis of CRC, we quantified the methylation levels of p16 in the serum DNA of CRC patients. Methods: Fresh specimens of 168 CRC and corresponding noncancerous tissues were obtained surgically at the Department of Surgery II, Nagoya University Graduate School of Medicine, together with the corresponding serum samples obtained 1 week prior to surgery. We defined the p16 methylation rate (p16 MR, in %) as follows: CM/(CM + CU) × 100%. CM is the concentration of methylated p16 sequences and CU is the concentration of unmethylated p16 sequences measured by quantitative methylation-specific PCR (Q-MSP) after bisulfite conversion. The relationship between the p16 MR and clinicopathologic findings were evaluated. Results: Aberrant p16 promoter methylation was found in 59% (99 of 168) of surgically resected CRC tissues. None of the corresponding normal tissues had methylated p16 sequences. 37% (37 of 99) serum samples of the CRC patients with tumoral p16 methylation had the same alterations. p16 MRs of 99 serum samples with tumoral p16 methylation were 0 to 68.9 (mean was 5.43±11.01). p16 MRs were significantly correlated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.001) and venous invasion (P=0.020) of CRCs. p16 MRs increased significantly with tumor stage [stage I : 0.94 ± 1.68, stage II : 2.33 ± 5.19, stage III : 8.49 ± 14.22, stage IV : 10.03 ± 14.27 (P = 0.021)]. Moreover, the survival of patients with low p16 MR was significantly superior to those with high p16 MR (P=0.006). Conclusions: These results suggest that quantification of p16 methylation in the serum DNA might be a novel diagnostic tool and a prognostic factor for CRC. No significant financial relationships to disclose.

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Piñero-Madrona, Antonio, Guadalupe Ruiz-Merino, Laia Bernet, Begoña Miguel-Martínez, Francisco Vicente-García, María A. Viguri-Díaz i Julia Giménez-Climent. "Tumoral load quantification of positive sentinel lymph nodes in breast cancer to predict more than two involved nodes". Breast 23, nr 6 (grudzień 2014): 859–64. http://dx.doi.org/10.1016/j.breast.2014.09.005.

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Hülsen, Sabine, Eleonora Lippolis, Fulvia Ferrazzi, Wolfgang Otto, Luitpold Distel, Rainer Fietkau, Stefan Denzinger i in. "High Stroma T-Cell Infiltration is Associated with Better Survival in Stage pT1 Bladder Cancer". International Journal of Molecular Sciences 21, nr 21 (9.11.2020): 8407. http://dx.doi.org/10.3390/ijms21218407.

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Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies.

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Qin, Caipeng, Huaqi Yin, Huixin Liu, Feng Liu, Yiqing Du i Tao Xu. "The Significance of Fibrosis Quantification as a Marker in Assessing Pseudo-Capsule Status and Clear Cell Renal Cell Carcinoma Prognosis". Diagnostics 10, nr 11 (2.11.2020): 895. http://dx.doi.org/10.3390/diagnostics10110895.

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Fibrosis plays an important role in tumor growth and progression, and thus, we aimed to determine whether renal fibrosis is correlated with the clinical and pathological characteristics and prognosis of clear cell renal cell carcinoma (ccRCC). Fibrosis, including intra-tumoral fibrosis (ITF), pseudo-capsule (PC) fibrosis and adjacent normal renal interstitial fibrosis, was evaluated in 73 pairs of ccRCC specimens using second harmonic generation combined with two-photon excitation fluorescence (SHG/TPEF). The clinical and pathological characteristics of the patients who were eligible for the present study were recorded. The associations between fibrosis and clinicopathological parameters were analyzed using a Mann-Whitney U test or logistic regression analysis. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and a Cox regression model. High-resolution images of fibrosis were captured from unstained slides using the SHG/TPEF approach. Both ITF and PC fibrosis were associated with tumor progression in ccRCC. Multivariate logistic regression analysis revealed a significant inverse association between the PC collagen proportional area (CPA) and PC invasion (p < 0.05), suggesting that PC CPA is an independent risk factor or marker for PC invasion. A significant decrease in progression-free survival (PFS), determined by Kaplan-Meier curves, was observed for patients with higher PC CPA status compared with those with lower PC CPA status (p < 0.05). Similar results were observed in patients with PC invasion. In multivariate Cox regression analysis, PC invasion and intra-tumoral necrosis were identified as independent prognostic factors for PFS. Our data suggest that ITF and PC fibrosis are associated with ccRCC progression. In addition, PC fibrosis may act as a marker of PC invasion and an effective quantitative measurement for assessing prognosis.

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Clément-Duchêne, C., M. Zysman, T. Qian, G. Faure, E. Luporsi, J. M. Vignaud i Y. Martinet. "Quantification des cellules tumorales circulantes (CTC) dans le cancer bronchique non à petites cellules (CBNPC) de stade avancé (CIRCUBRONCH)". Revue des Maladies Respiratoires 31 (styczeń 2014): A124. http://dx.doi.org/10.1016/j.rmr.2013.10.437.

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Ghouti, L., F. Courbon, M. Poirot, R. Guimbaud, B. Pradère i J. Selvès. "R167 - Oral, Club Mex-H Quantification du volume tumoral résiduel des cancers du rectum post-radiochimiothérapie par histomorphométrie quantitative". Bulletin du Cancer 97, nr 4 (październik 2010): S82. http://dx.doi.org/10.1016/s0007-4551(15)31088-2.

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Liu, Peter Y., Steven M. Pincus, Daniel M. Keenan, Ferdinand Roelfsema i Johannes D. Veldhuis. "Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion". American Journal of Physiology-Endocrinology and Metabolism 289, nr 1 (lipiec 2005): E160—E165. http://dx.doi.org/10.1152/ajpendo.00007.2005.

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The hypothalamo-pituitary-adrenal axis is a stress-adaptive neuroendocrine ensemble, in which adrenocorticotropin (ACTH) drives cortisol secretion (feedforward) and cortisol restrains ACTH outflow (feedback). Quantifying direction- and pathway-specific adjustments within this and other interlinked systems by noninvasive means remains difficult. The present study tests the hypothesis that forward and reverse cross-approximate entropy (X-ApEn), a lag-, scale-, and model-independent measure of two-signal synchrony, would allow quantifiable discrimination of feedforward (ACTH → cortisol) and feedback (cortisol → ACTH) control. To this end, forward X-ApEn was defined by employing serial ACTH concentrations as a template to appraise pair-wise synchrony with cortisol secretion rates and vice versa for reverse X-ApEn. Coupled hormone profiles included normal ACTH-normal cortisol, high ACTH-high cortisol, and high ACTH-low cortisol concentrations in 35 healthy subjects, 21 patients with tumoral ACTH secretion, and 9 volunteers given placebo and a steroidogenic inhibitor, respectively. We used forward and reverse X-ApEn analyses to identify marked and equivalent losses of feedforward and feedback linkages (both P < 0.001) in patients with tumoral ACTH secretion. An identical analytical strategy revealed that ACTH → cortisol feedforward synchrony decreases ( P < 0.001), whereas cortisol → ACTH feedback synchrony increases ( P < 0.001), in response to hypocortisolemia. The collective outcomes establish precedence for pathway-specific adaptations in a major neurohormonal system. Thus quantification of directionally defined joint synchrony of biologically coupled signals offers a noninvasive strategy to dissect feedforward- and feedback-selective adaptations in an interactive axis.

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Lassau, N., S. Koscielny, M. Chebil, L. Chami, R. Bendjilali, A. Roche, B. Escudier, A. LeCesne i J. Soria. "Functional imaging using DCE-US: Which parameter for the early evaluation of antiangiogenetic therapies?" Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 3524. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3524.

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3524 Background: The early evaluation of anti-angiogenic treatments is a challenge in oncology. Functional imaging methods based on the measure of tumoral vascularization have been developed using different modalities (CT, MRI, US). We analyzed the response in four studies using different targeted treatments with dynamic contrast enhanced-ultrasonography (DCE-US). Seven parameters characterizing tumoral perfusion were estimated. The objective of the study was to determine which parameter is the most appropriate to confirm earlier the efficacy of treatments. Methods: A total of 823 DCE-US were performed in 117 patients included in 4 following studies (multikinase inhibitor targeting angiogenic-receptor with a cytotoxic or thyrosine-kinase inhibitor targeted angiogenic-receptor and C-kit or monoclonal antibody anti-VEGFR). Each DCE-US was performed using contrast agent (Sonovue, Bracco) with perfusion and quantification softwares (Toshiba) from raw linear data with a high temporal resolution: 4 frames per second during 3 minutes. Seven quantitative parameters of perfusion were estimated: peak intensity (PI) and area under the total curve (AUC), area under the wash-in (AUWI), area under the wash-out (AUWO), time to peak intensity, mean transit time (MTT), wash-in slope. DCE-US were performed before treatment and after D3, D 8, 15, 21 (according each study design) and every 2 months. Patients were classified in good responders and bad responders according the response (RECIST on CT-scan) after 2 cycles or 2 months. Results: Among the 7 parameters, 2 parameters related to the blood volume studies (AUC and AUWO) were always earlier significantly modified (p = 0.04 to p = 0.004). One was never modified: MTT. For the 4 others, it's depending of each study. Conclusions: DCE-US appears as a sensitive tool to evaluate tumoral response to anti-angiogenic drugs. Functional parameters related to the blood volume are more pertinent and represent a key add value to early evaluation of these therapies studies. No significant financial relationships to disclose.

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Veyer, David, Maxime Wack, Marion Mandavit, Sonia Garrigou, Stéphane Hans, Pierre Bonfils, Eric Tartour i in. "HPV circulating tumoral DNA quantification by droplet‐based digital PCR: A promising predictive and prognostic biomarker for HPV‐associated oropharyngeal cancers". International Journal of Cancer 147, nr 4 (18.12.2019): 1222–27. http://dx.doi.org/10.1002/ijc.32804.

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Sukhotska, I., L. García-Alonso, R. Sirera, G. Sarrión, E. Jantus Lewintre, M. Gil, A. Cabrera, A. Berrocal, J. Bagán i C. Camps. "Investigation of infiltrating regulatory T lymphocytes in tumor areas in oral cancer lesions". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): e22070-e22070. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22070.

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e22070 Background: HLA-G is a human non-classical MHC molecule, mainly expressed in the trophoblast whose main function is to suppress immunologic activity that allows maternal tolerance to phoetus. On the other hand, infiltrating regulatory T lymphocytes (Treg) could promote peripheral inmunotolerance fo oncogenic transformation. Methods: We performed real-time PCR in frozen oral cancer specimens from untreated patients who had undergone surgical resection (n=22) and in normal oral mucosa from healthy subjects (n=10). Samples were processed for mRNA extraction and quantification of gene expression was expressed as relative concentration by an endogenous gene. To asses the presence of infiltrating Treg we analysed CTLA-4, Foxp-3, IL-10, TGF-beta, CD4, CD8, CXCR4, CD127 and CD25 and also we determined HLA-G levels. We correlate the expression of immunologic mediators with clinical variables. Results: Patients presented squamous carcinomas of the tongue (n=12) or gum (n=10) and stages ranged from I to IV (stage I=4; II=9; III=4; IV=5). 10 patients presented well-differentiated lesions and the other 12 moderately-differentiated cells. Eight patients received post- surgery chemo and radiotherapy. Our results show that tumor samples had significant higher expression of the CTLA-4, Foxp-3, TGF-beta and CD127 genes than normal tissue. However, those data showed no correlation between the levels of expression and clinico-pathologic variables. When patients were grouped according to tumor size, there was a trend in the way that bigger tumoral lesions expressed relative higher amounts of Treg. By contrast we could not observe an increase of the expression of HLA-G in patients. Conclusions: Our results reveal that there is an increase in the expression of Treg in oral cancer patients. These Treg in tumoral tissues might contribute to the impairment of immunological rejection of the neoplasic transformation. Conversely we have not been able to demonstrate tumoral expression of HLA-G as a strategy to escape from immunosurveyance. Further analysis of this cells and their function is important in order to develop new therapeutic strategies. No significant financial relationships to disclose.

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Calvo, B., A. Muñoz, M. Jangi, U. Aresti, A. Garcia, A. Alonso, I. Marrodan, A. Moreno, G. Lopez-Vivanco i S. Carrera. "Effect of id1 and id2 proteins (inhibitors of dna binding) expression in human colorectal cell lines". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): e22179-e22179. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22179.

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e22179 Background: Id1 and Id2 proteins are negative regulators of basic helix-loop-helix transcription factors, a family of components in the transcriptional network regulating cell growth and differentiation. Id1 and Id2 are overexpressed in human colorectal carcinoma and might play a critical role in the malignant cell phenotype. Methods: Two cell-lines were use for the analysis. NCM460: immortal non-tumoral cells from colon mucosa, and Caco-2: epithelial cells from colorectal carcinoma. Cell-lines were transfected with different constructs based on pLXSN vector (Clontech) to overexpress or inhibit the expression of the Id1 and Id2 genes, and then cultured for the analysis. Quantification of Id1 and Id2 expression were assessed by RT-PCR and Western-blot, respectively. A gene expression profile using oligonucleotide microarrays (Agilent Technologies) was performed in each cell line. Results: NCM460 cells and Caco-2 cells overexpressing Id1 (NCM460-Id1 and Caco-2-Id1) showed a statistically significant higher proliferation, invasion and migration, compared with both normal and Id1 inhibited cells. Id2 overexpression was related with a higher invasion capability only in NCM460 cells, without significant effect on proliferation and migration. NCM460-Id1 cells showed overexpression of PTMA, TYMS and LMNB1 genes, whereas HOXB8, LRP1, MMP17, NDRG1, MAP3K10, SCGb3A1 and BBC3 were upregulated. PTP4A1 and DKK1 were overexpressed in Caco-2-Id1 cells, and NDRG1, LRP1, FMOD and ENO1 were repressed. Conclusions: Id-1 expression is associated with proliferation, migration and invasion in both normal and tumoral colonic cell lines, and it is related with regulation of several genes implicated in colorectal cancer phenotype. Id proteins might be a potential target for the development of new antineoplastic agents. No significant financial relationships to disclose.

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Ding, Shengli, Zhaohui Wang, Marcos Negrete Obando, Grecia rivera Palomino, Tomer Rotstein, Ian Williamson, Shiaowen David Hsu i Xiling Shen. "Patient-derived micro-organospheres recapitulate tumor microenvironment and heterogeneity for precision oncology." Journal of Clinical Oncology 39, nr 15_suppl (20.05.2021): 3076. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3076.

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3076 Background: Preclinical models that can recapitulate patients’ intra-tumoral heterogeneity and microenvironment are crucial for tumor biology research and drug discovery. In particular, the ability to retain immune and other stromal cells in the microenvironment is vital for the development of immuno-oncology assays. However, current patient-derived organoid (PDO) models are largely devoid of immune components. Methods: We first developed an automated microfluidic and membrane platform that can generate tens of thousands of micro-organospheres from resected or biopsied clinical tumor specimens within an hour. We next characterized growth rate and drug response of micro-organospheres. Finally, extensive single-cell RNA-seq profiling were performed on both micro-organospheres and original tumor samples from lung, ovarian, kidney, and breast cancer patients. Results: Micro-organospheres derived from clinical tumor samples preserved all original tumor and stromal cells, including fibroblasts and all immune cell types. Single-cell analysis revealed that unsupervised clustering of tumor and non-tumor cells were identical between original tumors and the derived micro-organospheres. Quantification showed similar cell composition and percentages for all cell types and also preserved functional intra-tumoral heterogeneity.. An automated, end-to-end, high-throughput drug screening pipeline demonstrated that matched peripheral blood mononuclear cells (PBMCs) from the same patient added to micro-organospheres can be used to assess the efficacy of immunotherapy moieties. Conclusions: Micro-organospheres are a rapid and scalable platform to preserve patient tumor microenvironment and heterogeneity. This platform will be useful for precision oncology, drug discovery, and immunotherapy development. Funding sources: NIH U01 CA217514, U01 CA214300, Duke Woo Center for Big Data and Precision Health

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Pitruzzella, Alessandro, Letizia Paladino, Alessandra Vitale, Stefania Martorana, Calogero Cipolla, Giuseppa Graceffa, Daniela Cabibi i in. "Quantitative Immunomorphological Analysis of Heat Shock Proteins in Thyroid Follicular Adenoma and Carcinoma Tissues Reveals Their Potential for Differential Diagnosis and Points to a Role in Carcinogenesis". Applied Sciences 9, nr 20 (15.10.2019): 4324. http://dx.doi.org/10.3390/app9204324.

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Hsp27, Hsp60, Hsp70, and Hsp90 are chaperones that play a crucial role in cellular homeostasis and differentiation, but they may be implicated in carcinogenesis. Follicular neoplasms of the thyroid include follicular adenoma and follicular carcinoma. The former is a very frequent benign encapsulated nodule, whereas the other is a nodule that infiltrates the capsule, blood vessels and the adjacent parenchyma, with a tendency to metastasize. The main objective was to assess the potential of the Hsps in differential diagnosis and carcinogenesis. We quantified by immunohistochemistry Hsp27, Hsp60, Hsp70, and Hsp90 on thin sections of human thyroid tissue with follicular adenoma or follicular carcinoma, comparing the tumor with the adjacent peritumoral tissue. Hsp60, Hsp70, and Hsp90 were increased in follicular carcinoma compared to follicular adenoma, while Hsp27 showed no difference. Histochemical quantification of Hsp60, Hsp70, and Hsp90 allows diagnostic distinction between follicular adenoma and carcinoma, and between tumor and adjacent non-tumoral tissue. The quantitative variations of these chaperones in follicular carcinoma suggest their involvement in tumorigenesis, for instance in processes such as invasion of thyroid parenchyma and metastasization.

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Barmpoutis, Panagiotis, Matthew Di Capite, Hamzeh Kayhanian, William Waddingham, Daniel C. Alexander, Marnix Jansen i Francois Ng Kee Kwong. "Tertiary lymphoid structures (TLS) identification and density assessment on H&E-stained digital slides of lung cancer". PLOS ONE 16, nr 9 (23.09.2021): e0256907. http://dx.doi.org/10.1371/journal.pone.0256907.

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Tertiary lymphoid structures (TLS) are ectopic aggregates of lymphoid cells in inflamed, infected, or tumoral tissues that are easily recognized on an H&E histology slide as discrete entities, distinct from lymphocytes. TLS are associated with improved cancer prognosis but there is no standardised method available to quantify their presence. Previous studies have used immunohistochemistry to determine the presence of specific cells as a marker of the TLS. This has now been proven to be an underestimate of the true number of TLS. Thus, we propose a methodology for the automated identification and quantification of TLS, based on H&E slides. We subsequently determined the mathematical criteria defining a TLS. TLS regions were identified through a deep convolutional neural network and segmentation of lymphocytes was performed through an ellipsoidal model. This methodology had a 92.87% specificity at 95% sensitivity, 88.79% specificity at 98% sensitivity and 84.32% specificity at 99% sensitivity level based on 144 TLS annotated H&E slides implying that the automated approach was able to reproduce the histopathologists’ assessment with great accuracy. We showed that the minimum number of lymphocytes within TLS is 45 and the minimum TLS area is 6,245μm2. Furthermore, we have shown that the density of the lymphocytes is more than 3 times those outside of the TLS. The mean density and standard deviation of lymphocytes within a TLS area are 0.0128/μm2 and 0.0026/μm2 respectively compared to 0.004/μm2 and 0.001/μm2 in non-TLS regions. The proposed methodology shows great potential for automated identification and quantification of the TLS density on digital H&E slides.

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Nascimento, Bruno A. C., Luiz G. Gardinassi, Inaê M. G. Silveira, Marília G. Gallucci, Mariana A. Tomé, Júlia Fernanda D. Oliveira, Mirella R. A. Moreira i in. "Arctium lappa Extract Suppresses Inflammation and Inhibits Melanoma Progression". Medicines 6, nr 3 (29.07.2019): 81. http://dx.doi.org/10.3390/medicines6030081.

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Background: Arctium lappa has been used as popular medicinal herb and health supplement in Chinese societies. Bioactive components from A. lappa have attracted the attention of researchers due to their promising therapeutic effects. In this study, we investigated the effects of A. lappa hydroalcoholic extract (Alhe) during different models of inflammation, in vivo. Methods: The anti-inflammatory activity was evaluated through the air pouch model. For this, mice received an inflammatory stimulus with lipopolysaccharide (LPS) and were later injected with Alhe. To assess anti-tumoral activity, the animals were inoculated with B16F10 cells and injected with Alhe every 5 days, along the course of 30 days. Controls were submitted to the same conditions and injected with the vehicle. Peritoneal or air pouch fluids were collected to evaluate leukocyte counting or cellular activation via quantification of cytokines and nitric oxide. Results: Alhe injection reduced the neutrophil influx and production of inflammatory mediators in inflammatory foci after LPS or tumor challenges. Furthermore, Alhe injection reduced tumor growth and enhanced mice survival. Conclusions: Collectively, these data suggest that Alhe regulates immune cell migration and activation, which correlates with favorable outcome in mouse models of acute inflammation and melanoma progression.

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Kontopodis, Eleftherios, Georgia Kanli, Georgios C. Manikis, Sofie Van Cauter i Kostas Marias. "Assessing Treatment Response through Generalized Pharmacokinetic Modeling of DCE-MRI Data". Cancer Informatics 14s4 (styczeń 2015): CIN.S19342. http://dx.doi.org/10.4137/cin.s19342.

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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enables the quantification of contrast leakage from the vascular tissue by using pharmacokinetic (PK) models. Such quantitative analysis of DCE-MRI data provides physiological parameters that are able to provide information of tumor pathophysiology and therapeutic outcome. Several assumptive PK models have been proposed to characterize microcirculation in the tumoral tissue. In this paper, we present a comparative study between the well-known extended Tofts model (ETM) and the more recent gamma capillary transit time (GCTT) model, with the latter showing initial promising results in the literature. To enhance the GCTT imaging biomarkers, we introduce a novel method for segmenting the tumor area into subregions according to their vascular heterogeneity characteristics. A cohort of 11 patients diagnosed with glioblastoma multiforme with known therapeutic outcome was used to assess the predictive value of both models in terms of correctly classifying responders and nonresponders based on only one DCE-MRI examination. The results indicate that GCTT model's PK parameters perform better than those of ETM, while the segmentation of the tumor regions of interest based on vascular heterogeneity further enhances the discriminatory power of the GCTT model.

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Jantus-Lewintre, Eloisa, Marta Usó, Elena Sanmartin, Sandra Gallach, Rafael Sirera, Ana Blasco, Cristina Hernando i in. "Ratios between VEGF ligands and receptors in tumor and stroma have impact on the outcome in resectable NSCLC." Journal of Clinical Oncology 31, nr 15_suppl (20.05.2013): e22147-e22147. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22147.

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e22147 Background: In tumor angiogenesis there is a complex interplay between endothelial, stromal and tumor cells. Some key regulators of this process are the members of the vascular endothelial growth factor (VEGF) family of ligands and receptors and the neuropilins (NRP). This study analyzes the correlations between the expression of these angiogenic factors in tumor cells and tumor stroma, and their prognostic role in tissue samples from resected non-small cell lung cancer (NSCLC) patients. Methods: Representative tumor and stroma areas from FFPE tissue samples of 125 early-stage NSCLC patients were carefully micro-dissected. RNA isolated from the samples was retrotranscripted and preamplified. RTqPCR was performed using hydrolysis probes (TaqMan, Applied Biosystems) and relative quantification was calculated using GAPDH and CDKN1B as endogenous controls. Results were normalized against a human cDNA (Clontech) as a reference. All statistical analyses were considered significant at p<0.05. Results: Paired Wilcoxon test revealed differences between tumor and stroma gene expression for VEGFB (p<0.0001), VEGFC (p<0.0001), VEGFR-1 (p<0.0001), VEGFR-2 (p=0.020), VEGFR-3 (p< 0.0001), NRP-1 (p=0.001) and NRP-2 (p< 0.0001). Survival analyses showed that those patients with higher levels of the Ratio Stromal-VEGFA/ Tumoral-VEGFR-2 had worse time to progression (TTP) (median 26.23 months vs NR, p=0.013) and overall survival (OS) (median 29.50 months vs NR, p=0.001). Similarly, those patients with higher levels of the Ratio Stromal-VEGFC/Tumoral-VEGFR-3 had worse TTP (median 23.30 vs 70.53 months, p=0.015) and OS (median 37.20 months vs NR, p=0.023). Conclusions: Our results show significant differences in the expression of VEGF family members between tumor and stromal cells. This may indicate the importance of the tumor-stroma interaction when trying to understand the angiogenic process. Furthermore, the combination of the ligands expression in stroma and their receptors in tumor may have a prognostic value in NSCLC patients. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII.

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Renzetti, P., R. C. Parodi, C. Ottonello, F. Zandrino, M. Cossu, M. P. Sormani i F. Sardanelli. "La gadodiamide come mezzo di contrasto in tomografia computerizzata cranio-encefalica". Rivista di Neuroradiologia 15, nr 6 (grudzień 2002): 705–11. http://dx.doi.org/10.1177/197140090201500606.

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L'elevato peso atomico del Gd giustifica l'ipotesi di un utilizzo in tomografia computerizzata (TC) di mezzi di contrasto (MdC) già clinicamente in uso in risonanza magnetica (RM). Il potenziamento TC determinato dalla Gadodiamide (Gd-DTPA-BMA, Omniscan, Nycomed-Amersham), MdC paramagnetico non ionico, è stato valutato e quantificato in vitro e in vivo. Due serie di soluzioni scalari di Gadodiamide e di MdC iodato (Iopamiro 370, Bracco) sono state sottoposte a scansione TC per la quantificazione densitometrica in unità Hounsfield (UH). Sette pazienti affetti da neoplasia intracranica sono stati sottoposti a TC prima e dopo somministrazione endovenosa di 0,3 mmol/Kg di Gadodiamide; sono stati rilevati i valori medi di densità pre- e postcontrasto a livello dell'arteria basilare e della massa tumorale. Nello studio in vitro, a parità di concentrazione molare del MdC, è risultata maggiore la densità media della soluzione di gadodiamide rispetto al MdC iodato, superiorità statisticamente significativa (test F, p < 0,0001), a conferma del fatto che il Gd ha caratteristiche fisiche che lo rendono utilizzabile in MdC per TC. Nello studio in vivo, la gadodiamide ha determinato incrementi densitometrici medi (postcontrasto /precontrasto) del 71,05% per l'arteria basilare e del 45,23% per la lesione tumorale, consentendo una sufficiente apprezzabilità soggettiva dell'enhancement. La Gadodiamide può essere utilizzata come MdC in TC in pazienti con dubbia o asserita diatesi allergica per i MdC iodati allorquando non sia praticamente disponibile la RM (urgenze!) o sussistano importanti controindicazioni (pacemaker, ecc.). L'osmolarità medio-bassa (780 mOsm/Kg) e il profilo tossi-cologico favorevole della Gadodiamide permettono di ipotizzare l'utilizzo di dosi anche più elevate. Tali risultati preliminari rafforzano l'ipotesi della messa a punto di MdC per TC a base di Gd; più atomi di Gd potrebbero ad esempio essere contenuti all'interno della molecola con il duplice effetto di ridurre la tossicità ed elevare il peso atomico del MdC. Gadolinium (Gd) high atomic weight can enable us to use the Gd-chelates as contrast agents (c.a.) in computed tomography (CT). CT contrast enhancement (c.e.) due to Gadodiamide (Gd-DTPA-BMA, Omniscan, Nycomed-Amersham), a non-ionic paramagnetic c.a. used in magnetic resonance (MR) imaging, was evaluated and quantified through an in vitro and in vivo study.

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Uhlig, Johannes, Lorenz Biggemann, Amar Sheth i Rohini Sharma. "Imaging and Radiomics of Immuno-oncology of Primary and Secondary Gastrointestinal Malignancies". Digestive Disease Interventions 04, nr 04 (19.11.2020): 373–81. http://dx.doi.org/10.1055/s-0040-1721404.

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AbstractIn recent years, systemic cancer treatment has been revolutionized with the advent of immunotherapy, which utilizes the body's immune system to target cancer cells and results in unique and novel imaging patterns of cancer response and therapy-associated toxicities. Hyperprogression is defined as a rapid tumor progression after treatment initiation. In contrast, pseudoprogression is defined as a tumor response after an initial increase in tumor burden, or appearance of new tumor lesions, and observed in <10% of patients undergoing PD-1/PD-L1 immunotherapy. Since traditional radiological strategies might not fully capture tumor response of patients receiving immunotherapy, several efforts have been made to better quantify specific immuno-oncological imaging patterns, including immune-related response criteria, immune-related RECIST, immunotherapy RECIST, and modified RECIST. These criteria account for potential pseudoprogression, and thus may prevent preemptive immunotherapy cessation. Immunotherapy is also associated with specific immune-related adverse events, including colitis (8–22% of patients), hypophysitis (8–13%), pneumonitis (<4%), lymphadenopathy (5–7%), hepatitis (1–7%), and pancreatitis (2%). Quantification of imaging studies using radiomic features has shown promising results in immuno-oncology, including prediction of individual patient's treatment response and survival, as well as characterization of tumoral expression of immunotherapy-relevant targets.

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Murdocca, Michela, Francesco Torino, Sabina Pucci, Manuela Costantini, Rosamaria Capuano, Chiara Greggi, Chiara Polidoro i in. "Urine LOX-1 and Volatilome as Promising Tools towards the Early Detection of Renal Cancer". Cancers 13, nr 16 (21.08.2021): 4213. http://dx.doi.org/10.3390/cancers13164213.

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Renal cell carcinoma (RCC) represents around 3% of all cancers, within which clear cell RCC (ccRCC) are the most common type (70–75%). The RCC disease regularly progresses asymptomatically and upon presentation is recurrently metastatic, therefore, an early method of detection is necessary. The identification of one or more specific biomarkers measurable in biofluids (i.e., urine) by combined approaches could surely be appropriate for this kind of cancer, especially due to easy obtainability by noninvasive method. OLR1 is a metabolic gene that encodes for the Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), implicated in inflammation, atherosclerosis, ROS, and metabolic disorder-associated carcinogenesis. Specifically, LOX-1 is clearly involved in tumor insurgence and progression of different human cancers. This work reports for the first time the presence of LOX-1 protein in ccRCC urine and its peculiar distribution in tumoral tissues. The urine samples headspace has also been analyzed for the presence of the volatile compounds (VOCs) by SPME-GC/MS and gas sensor array. In particular, it was found by GC/MS analysis that 2-Cyclohexen-1-one,3-methyl-6-(1-methylethyl)- correlates with LOX-1 concentration in urine. The combined approach of VOCs analysis and protein quantification could lead to promising results in terms of diagnostic and prognostic potential for ccRCC tumors.

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Beltran, Brady, Renzo Salas, Ausberto Chunga, Eduardo M. Sotomayor i Jorge J. Castillo. "Quantification of EBV DNA In Whole Blood In Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma". Blood 116, nr 21 (19.11.2010): 3102. http://dx.doi.org/10.1182/blood.v116.21.3102.3102.

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Abstract Abstract 3102 Introduction: Epstein-Barr virus (EBV) is a well-known oncogenic virus associated with the development of several lymphoproliferative disorders. The quantification of EBV viral load in plasma and peripheral blood mononuclear cells has been reported as a useful biomarker for EBV-associated non-Hodgkin lymphoma (NHL). The role of EBV in diffuse large B-cell lymphoma (DLBCL) is unclear at this time. METHODS: In the present prospective study, using real-time quantitative polymerase chain reaction (RQ-PCR), whole blood specimens from patients with a new diagnosis of DLBCL were used to quantitatively determine EBV viral load. Consecutive patients who presented from January 1, 2009 to December 30, 2009 were selected for this study. The pathological samples from the patients showing elevated EBV DNA levels were then investigated for the presence of EBV-encoded RNA (EBER) using a chromogenic in situ hybridization (CISH) technique. Clinical data from these patients was collected and analyzed, and will be presented using descriptive statistics. Overall survival estimates were obtained using the Kaplan-Meier method. Results: Forty six patients with a new diagnosis of DLBCL were included in our study; from which five cases showed elevated levels of EBV DNA by RQ-PCR (10.8%). These five patients (100%) were positive for EBER expression within the tumoral cells by EBER CISH. One patient was evaluated at the end of treatment and blood EBV DNA level was undetectable. All EBV DNA-positive cases were male with a median age of 69 years (range 25–73 years); only one case was younger than 50 years. The median EBV DNA viral load was 59 copies/uL (range 0.225–43200 copies/uL). Three patients (60%) presented with advanced clinical stage (III or IV) and three patients (60%) had a primary extranodal site of involvement. Four patients (80%) received CHOP-based chemotherapy regimens. The three patients with advanced stage have deceased with a survival of <3 months. The two patients with early stage experienced a complete response with immunochemotherapy and are alive 6 and 9 months after diagnosis, respectively. The median overall survival is 4 months. Conclusions: These results, although preliminary, suggest that whole blood EBV DNA quantification might be useful at detecting patients with EBV-positive DLBCL. Further studies are needed to investigate the potential diagnostic and/or prognostic value of EBV DNA in DLBCL. Disclosures: No relevant conflicts of interest to declare.

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Salas, S. Bastien, Nicolas Macagno, Nicolas Penel, Florence Duffaud, Isabelle Nanni, Corinne Bouvier, Raquel Rouah i in. "Circulating cell free tumor DNA detection as novel biomarkers to monitor desmoid tumors evolution." Journal of Clinical Oncology 35, nr 15_suppl (20.05.2017): 11063. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11063.

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11063 Background: Since desmoid tumors (DT) exhibit an unpredictable clinical course, with stabilization and/or spontaneous regression, an initial “wait-and-see” policy is the new standard of care to select best indications of active treatments in case of significant evolution. Therefore, translational research is crucial to identify predictive factors of progression. Most DT are characterized by CTNNB1 mutation (CM) in exon 3 (T41A, S45F, S45P). Circulating cell-free tumoral DNA (ctDNA), named "liquid biopsy", has emerged as a new promising non-invasive tool to detect biomarker in several cancers. Methods: We present a method of detection of DT-specific CM using a targeted strategy digital droplet PCR (ddPCR) on cell-free DNA (cfDNA) extracted from blood samples of 31 DT patients (pts). T41A, S45P, S45F and their respective CTNNB1 wild-type probe were designed for ddPCR. Furthermore, we analyzed the correlation of cfDNA levels (CTNNB1 wt/ml plasma) and evolution of the tumor. Results: Initial DT CM statuswas known for 28 pts and unknown for 3 pts. 24 pts presented a CM (17 pts T41A, 6 pts S45F and 1 pt S45P), 2 pts a mutation of APC, 2 pts were wild-type, and 3 pts were undetermined. Among pts with a CM, CTNNB1 mutants were detected in the cfDNA of 6 patients (19.4%). CM detection was not correlated with the quantity of cfDNA analyzed (p = 0,7263–Mann-Whitney (MW)). Absolute quantification of cfDNA (CTNNB1 wt) normalized by mL of plasma displayed higher levels for patients with progressive DT (p = 0,0009 - MW), this difference of cfDNA quantity was also present between progressive, stable and self-regressive DT (p = 0,0012 - MW). A threshold of 875 CTNNB1 copies/mL predicted DT progression with a sensibility of 100% (CI95%: 59-100) and a specificity of 76.5% (CI95%: 50.1-93.2). Absolute cfDNA quantity was also higher in patients harboring multiple desmoids (p = 0.0292 - MW). Conclusions: The absolute quantification of normalized cfDNA is correlated with evolution of the disease, independently of the initial tumor type of CM. This study opens the perspective of using cfDNA as a genomic biomarker to assess the tumor dynamics at initial diagnosis, and to monitor treatment strategy in case of tumor evolution.

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Sabatino, Maria Eugenia, Juan Pablo Petiti, Liliana del Valle Sosa, Pablo Anibal Pérez, Silvina Gutiérrez, Carolina Leimgruber, Alexandra Latini, Alicia Inés Torres i Ana Lucía De Paul. "Evidence of cellular senescence during the development of estrogen-induced pituitary tumors". Endocrine-Related Cancer 22, nr 3 (19.03.2015): 299–317. http://dx.doi.org/10.1530/erc-14-0333.

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Although pituitary adenomas represent 25% of intracranial tumors, they are usually benign, with the mechanisms by which these tumors usually avoid an invasive profile and metastatic growth development still remaining unclear. In this context, cellular senescence might constitute a plausible explanation for the benign nature of pituitary adenomas. In this study, we investigated the emergence of cellular senescence as a growth control mechanism during the progression of estrogen-induced pituitary tumors. The quantification of Ki67-immunopositive cells in the pituitaries of estrogenized male rats after 10, 20, 40, and 60 days revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the expression of cellular senescence features, such as the progressive rise in the enzymatic senescence-associated b-galactosidase (SA-b-gal) activity, IL6, IL1b, and TGFb expression, was observed throughout pituitary tumor development. Furthermore, tumoral pituitary cells also displayed nuclear pATM expression, indicating activated DNA damage signaling, with a significant increase in p21 expression also being detected. The associations among DNA damage signaling activation, SA-b-gal expression, and p21 may provide a reliable combination of senescence-associated markers for in vivo pituitary senescence detection. These results suggest a role for this cellular process in the regulation of pituitary cell growth. Thus, cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation.

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Pincus, Steven M., Mark L. Hartman, Ferdinand Roelfsema, Michael O. Thorner i Johannes D. Veldhuis. "Hormone pulsatility discrimination via coarse and short time sampling". American Journal of Physiology-Endocrinology and Metabolism 277, nr 5 (1.11.1999): E948—E957. http://dx.doi.org/10.1152/ajpendo.1999.277.5.e948.

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Pulsatile hormonal secretion is a ubiquitous finding in endocrinology. However, typical protocols employed to generate data sets suitable for “pulsatility analysis” have required 60–300 samples, rendering such studies largely research methodologies, due primarily to considerable assay expense. One successful mathematical strategy in calibrating changes in pulsatility modalities is approximate entropy (ApEn), a quantification of sequential irregularity. Given the degree of differences between ApEn values in pathophysiological subjects vs. healthy controls reported in several recent studies, we queried to what extent coarser (less frequent) and shorter duration time sampling would still retain significant ApEn differences between clinically distinct cohorts. Accordingly, we reanalyzed data from two studies of 24-h profiles of healthy vs. tumoral hormone secretion: 1) growth hormone comparisons of normal subjects vs. acromegalics, originally sampled every 5 min; and 2) ACTH and cortisol comparisons of normal subjects vs. Cushing's disease patients, originally sampled every 10 min. By multiple statistical analyses, we consistently and highly significantly ( P < 0.0001) established that serum concentration patterns in tumor patients are more irregular than those of controls, with high sensitivity and specificity, even at very coarse (e.g., 60 min) sampling regimens and over relatively short (2–4 h) time intervals. The consistency of these findings suggests a broadly based utility of such shorter and/or coarser sampling methodologies. Substantial reduction in sampling requirements holds the potential to move analysis of pulsatile hormone release from a primarily research tool to a clinically applicable protocol, in appropriate diagnostic and therapeutic contexts.

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Goisnard, Antoine, Pierre Daumar, Clémence Dubois, Corinne Aubel, Manon Roux, Marie Depresle, Jean Gauthier i in. "LightSpot®-FL-1 Fluorescent Probe: An Innovative Tool for Cancer Drug Resistance Analysis by Direct Detection and Quantification of the P-glycoprotein (P-gp) on Monolayer Culture and Spheroid Triple Negative Breast Cancer Models". Cancers 13, nr 16 (11.08.2021): 4050. http://dx.doi.org/10.3390/cancers13164050.

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P-gp is the most widely studied MDR protein conferring cellular resistance to many standard or targeted therapeutic agents. For this reason, P-gp chemoresistance evaluation, established before or during chemotherapy, can be very relevant in order to optimize the efficacy of treatments, particularly for aggressive tumoral subtypes such as triple-negative breast cancer (TNBC). In this context, our team developed an innovative cell-permeant fluorescent probe called the LightSpot®-FL-1, which is able to specifically localize and quantify the P-gp in cells or cell masses, as evidenced on different TNBC cell models. First, flow cytometry analysis showed LightSpot®-FL-1 cell penetration and persistence in time, in TNBC cells. Then, LightSpot®-FL-1 staining was compared to anti-P-gp immunostaining by fluorescence microscopy on five TNBC cell lines. Results showed a clear similarity of P-gp localization and expression level, confirmed by Pearson’s and Mander’s colocalization coefficients with 92.1% and 100.0%, and a strong correlation coefficient of R2 = 0.99. In addition, the LightSpot®-FL-1 staining allowed the quantification of a P-gp induction (33% expression increase) following a 6-hour spheroid model exposure to the anti-PARP Olaparib. Thus, the new LightSpot®-FL-1 cell-permeant probe, targeting P-gp, appears to be an effective tool for drug resistance evaluation in preclinical models and shows promising possibilities for future use in clinical diagnosis.

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Cismașiu, R. S., R. M. Bîrluțiu, A. Tudor, D. Pop i C. I. Stoica. "Borderline Giant Cell Tumors (GCT) of Proximal Tibial Epiphysis - Onco-Orthopedic Management Between Possibilities and Limits". Romanian Journal of Orthopaedic Surgery and Traumatology 1, Supplement (1.06.2018): 52. http://dx.doi.org/10.2478/rojost-2018-0063.

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Abstract Intralesional tumoral procedures in giant cell tumor (GCT) are quoted as having a recurrence rate of up to 60%. Thus, a number of studies suggest that broad resection is associated with a lower local recurrence risk compared to intralesional curettage, increasing the free recurrence interval from 84% to 100%. The TCG involvement of the proximal tibia occupies a particular place through the relationship with the articular line, but especially through the frequent, direct, or indirect interest of the extensor mechanism of the knee. Purpose of the paper. Based on the unique tumor registry of “Foişor” Orthopedic Clinic, we proposed to follow all the cases of TCG with proximal tibial localized operation, beneficiaries of an “en bloc” resection and modular tumor prosthesis reconstructions - registering a number of 5 cases between 2009 and 2017. Material and method. The initial evaluation was performed by radiography, CT-scan and MRI investigations and recurrence cases in which histopathological reassessment became mandatory after post-intralesional techniques were also included in the study. The surgical technique followed tumor resection, tumor reconstruction, and the reconstruction procedure of the extensor of the knee, which involved the modulation of the modular tumor prosthesis with a rotary reversible flap of the medial gastrocnemius with the ankle of the patellar tendon to the prosthesis and flap. Quantification of functional outcomes required the use of the revised Muscle-Skeletal Society Score (rMTS) and postoperative complications were centralized; the most commonly reported being the peroneal nerve palsy. Results and discussions. The results obtained were compared to the orthopedic oncology literature data for such a procedure, following their superposition and discrepancy. The challenge of such an orthopedic oncology intervention is the reconstruction of the extensor, with definite functional implications of limiting the knee extension, as well as avoiding the peroneal nerve palsy. However, the results can be reproducible, with an absent relapse rate.

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Metro, G., Z. Zheng, A. Fabi, M. Mottolese, A. N. Monteiro, P. Vici, D. Boulware, S. Lara Rivera, F. Cognetti i G. Bepler. "In situ protein expression of RRM1, ERCC1, and BRCA1 in metastatic breast cancer patients treated with gemcitabine-including chemotherapy". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): 1129. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.1129.

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1129 Background: Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small cell lung cancer (NSCLC) and pancreatic cancer. We investigated the tumoral levels of RRM1 in a population of metastatic breast cancer (MBC) patients treated with gemcitabine-based regimens. The protein levels of the excision repair cross-complementation group 1 (ERCC1) and breast and ovarian cancer susceptibility gene 1 (BRCA1) were also measured. Methods: Fifty-five patients were treated and followed prospectively from September 2004 to December 2007. Treatment consisted of gemcitabine plus a taxane in 46 patients and gemcitabine plus pegylated liposomal doxorubicin in 9 patients. RRM1, ERCC1, and BRCA1 were determined by automated in situ protein quantification (AQUA v1.6) on a tissue microarray containing triplicate tumor specimens. Results: The average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6–2, 774.1, 74.0–410.3, and 54.4–1, 833.1, respectively. A statistically significant correlation between the levels of expression of all three markers (Spearman's rho > .36; P < 0.007) was observed. There was no significant association between RRM1, ERCC1, or BRCA1 levels and disease response, progression free survival, or overall survival. Conclusions: In tumor specimens from patients with MBC, RRM1, and BRCA1 had a range of expression and pattern of distribution that makes these markers potentially suitable for clinical decision making. In contrast, the relatively narrow range of ERCC1 expression might signify that ERCC1 protein levels are not useful predictors of platinum efficacy in MBC. Consistent with what has been shown in NSCLC, RRM1, ERCC1, and BRCA1 levels were significantly correlated, suggesting that the coexpression of such DNA repair proteins may be universal to epithelial malignancies. The lack of correlation between marker levels and clinical outcome may be explained by the specific chemotherapy combinations used. No significant financial relationships to disclose.

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Usó, M., R. Sirera, E. Jantus Lewintre, N. Mosquera, E. Zapater, A. Cabrera, E. Sanmartín, A. Berrocal, J. Basterra i C. Camps. "Expression of angiogenic mediators in head and neck cancer". Journal of Clinical Oncology 27, nr 15_suppl (20.05.2009): e17032-e17032. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e17032.

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e17032 Background: In cancer, systematic analysis of mRNA expression levels can contribute to define a molecular network of lung carcinogenesis and establish predictive and prognostic molecular markers. Altered mRNA expression in certain angiogenic and anti-angiogenic genes such as vascular endothelial growth factor family of ligands and their receptors together with other molecules implicated in angiogenesis could predict disease outcome and add prognostic information at diagnosis. Methods: We performed RT-qPCR in frozen head and neck cancer specimens from untreated patients who had undergone surgical resection (n = 23). Samples were processed for mRNA extraction following standard procedures and quantification of gene expression was expressed as relative concentration normalized by an endogenous gene. The following angiogenic genes were quantified: PDGF-A, PlGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D, COX-2, bFGF, HGF, IL-8; and anti-angiogenic genes: Angiomotin and endostatin. Results: Median age was 56.5 years, range (31–79), 17 patients presented squamous carcinoma of the larynx; 8 patients were stage III and the other 15 stage IV. None of the patients received pre-surgery chemo or radiotherapy and 10 patients reveived post-surgery treatment. Our results show that tumor samples had significant higher expression of PDGF, PlGF, COX-2, and IL-8 and a deep down-regulation of angiomotin. However, those data show no correlation between the levels of expression and stage of the disease. Conclusions: Our results reveal that there is an increase in the expression of the pro-angiogenic mediators PDGF, PlGF, COX-2, and IL-8 and a downregulation of angiomotin that may mediate the inhibitory effect of angiostatin on tube formation and the migration of endothelial cells toward growth factors during the formation of new blood vessels in the tumoral area. This data suggest that more research are needed in other angiogenic mediators that VEGF, that PlGF and angiomotin have some role in cancer progression and could be a promising new biomarker in head and neck cancer. No significant financial relationships to disclose.

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Fanning, S. R., S. Short, K. Coleman, S. Andresen, G. T. Budd, H. Moore, A. Rim, J. Crowe i D. E. Weng. "Correlation of dynamic infrared imaging with radiologic and pathologic response for patients treated with primary systemic therapy for locally advanced breast cancer". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 10696. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10696.

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10696 Background: Assessment of response to therapy for locally advanced breast cancer includes serial assessments of physical exam, radiologic imaging, or repeated biopsies. Expense, subjective assessment, and patient risk make these methods impractical. Dynamic infrared imaging (DIRI) utilizes a quantum well infrared photon (QWIP) sensor with software to analyze the emission patterns over time. DIRI can detect biological temperature gradients with sensitivity of 0.009ºC. Tumor-induced local tissue nitric oxide production can increase local capillary blood flow. Anti-tumor therapies have been shown to result in decreased peri-tumoral capillary blood flow. These changes in temperature, detected by serial DIRI imaging, may provide a low cost, non-invasive, easily reproducible objective tool for real-time clinical assessment. Methods: In this prospective pilot study, we are evaluating patients with locally advanced breast cancer using serial DIRI. Primary endpoints include: sensitivity, specificity, PPV, and NPV of DIRI in comparison to pathologic response, concordance of DIRI to physical exam, and concordance of DIRI to standard radiographic evaluation at initial diagnosis and prior to surgery. DIRI results are reported as quantification of changes in the 0.2Hz modulation of temperature over the breast during the course of treatment and measurement of area of average temperature in a region of interest compared between breasts. One hundred patients will be enrolled in this trial. Results: Sixteen patients have been enrolled. Six have proceeded to surgery. All but one patient exhibited evidence of tumor response by physical exam. These findings correlated with response when comparing initial to pre-surgical MRI. In all responding patients, DIRI results revealed a decrease in the number of regions over the breast in which the 0.2Hz frequency dominated. Similarly, DIRI evaluation according to area of average temperature in the region of interest compared between breasts was concordant in patients with response to therapy. Conclusions: Assessment of response by physical exam, MRI, and DIRI were consistent. Preliminary data reveals that serial DIRI imaging can be an effective adjunctive tool. No significant financial relationships to disclose.

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Dreyer, Stephan, Nigel Jamieson, Lisa Evers, Marc Jones, Sancha Martin, Fraser Duthie, Liz Musgrove i in. "Feasibility and clinical utility of EUS guided biopsy of pancreatic cancer for next-generation genomic sequencing." Journal of Clinical Oncology 35, nr 15_suppl (20.05.2017): e15755-e15755. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15755.

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e15755 Background: Next-generation sequencing (NGS) has made genomic profiling to guide therapy a reality for many cancer types. The aim of this study is to investigate the feasibility of genomic profiling using standard clinical endoscopic ultrasound (EUS) core biopsy samples of Pancreatic Cancer (PC) to allow personalised cancer care. Methods:Patients undergoing EUS and biopsy for suspicion of PC underwent additional biopsies which was snap frozen. En-face frozen section enabled targeted macro-dissection prior to DNA extraction, quantification and targeted sequencing using a commercially available 151 gene ClearSeq Comprehensive Cancer Panel. Matching formalin-fixed (FFPE) diagnostic EUS biopsy and fresh frozen surgical resection specimens underwent genomic profiling for comparison. Whole genome sequencing (WGS) was performed in 2 patients. RNA sequencing was performed in samples with sufficient RNA yield. Results: Known PC genes ( KRAS, GNAS, TP53, CDKN2A, SMAD4) were identified in 27 out of 30 (90%) patients with histological diagnosis of PC. Potentially actionable somatic mutations (BRCA1, BRCA2, ATM, BRAF, JAK3) were found in 6 (20%) patients. In the 2 samples selected, WGS of the EUS samples confirmed point mutations identified on panel sequencing and revealed relevant mutational signatures and structural variation patterns. Targeted panel sequencing was successful in all FFPE samples. In 1 chemotherapy naïve patient, sequencing of a matching trio of fresh frozen and FFPE EUS biopsies, and resection sample revealed evidence of spatial intra-tumoral heterogeneity. In another patient, pre-treatment biopsy revealed a somatic BRCA1 mutation, and patient had a near complete pathological response to platinum containing neoadjuvant therapy in the resected specimen. RNA sequencing segregated patients into key clinically relevant molecular PC subtypes based on transcriptome as recently described. Conclusions: We demonstrate here novel multi-omic analysis of pancreatic cancer using standard clinical EUS guided fine needle biopsies. Multi-omic analysis of EUS biopsies offers potential clinical utility to guide personalized therapy of PC in the neoadjuvant and advanced settings.

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Argenziano, Michael, Akshay Save, Deborah Boyett, Jack Grinband, Hyunsoo Yoon, Jing Li, Matei Banu i in. "OTEH-6. Algorithmic approach to characterize post-treatment recurrent glioma using RNA sequencing and quantitative histopathology". Neuro-Oncology Advances 3, Supplement_2 (1.07.2021): ii11. http://dx.doi.org/10.1093/noajnl/vdab070.045.

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Abstract Introduction Distinguishing between tumor and treatment effect in post-treatment glioma, although crucial for clinical management, is difficult because contrast-enhancing regions are mixtures of recurrent tumor and reactive tissue, and definitive histopathological criteria do not exist. This study disentangles the marked intra-tumoral heterogeneity in the treatment-recurrent setting by developing an unsupervised framework to algorithmically categorize intraoperative MRI-localized biopsies into three clinically-relevant tissue clusters based on joint analysis of RNA sequencing and histopathological data. Methods A retrospective cohort of 84 MRI-localized biopsies from 37 patients with post-treatment recurrent glioblastoma underwent mRNA extraction and quantification via PLATEseq protocol. For 48 of 84 biopsies, a neighboring piece of tissue underwent quantitative histopathology based on labeling index (LI) for SOX2, CD68, NeuN, Ki67, and H&E. Correlation between LIs and gene expression for these 48 samples was performed. Genes significantly correlated (p<0.05) with ≥1 marker were used for hierarchical clustering of correlation matrix, identifying three mutually-exclusive tissue-specific gene sets. These sets were then used to perform ssGSEA to categorize each of 84 biopsies into one of three tissue types. Results Correlation analysis identified 7779 genes significantly correlated with ≥1 histopathological marker. Clustering revealed three gene sets associated with specific markers: SetA-3688 genes associated with SOX2/Ki67/H&E; SetB-2418 genes associated with CD68; SetC-1673 genes associated with NeuN. ssGSEA using these sets categorized each biopsy into one of three tissue types: 27 biopsies enriched in SetA, 28 in SetB, and 29 in SetC. Conclusions Using MRI-localized biopsies with both RNAseq and histopathological data, this algorithmic approach allows development of three orthogonal tissue-specific gene sets that can be applied to characterize the heterogeneity in post-treatment recurrent glioma: SetA: genes correlated with SOX2/Ki67/H&E, representing recurrent tumor; SetB: genes correlated with CD68 (microglia) representing reactive tissue consistent with treatment effect; SetC: genes correlated with NeuN (neurons), representing infiltrated brain.

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Plesa, Adriana, Christophe Roumier, Florent Dumezy, Delphine Manzoni, Pierre Sujobert, Sandrine Hayette, Isabelle Tigaud i in. "Stemness Signature in AML: GEP with 17 Genes Score Versus Leukemic Stem Cell (LSC) Quantification By Multiparameter Flow Cytometry (MFC)". Blood 132, Supplement 1 (29.11.2018): 4009. http://dx.doi.org/10.1182/blood-2018-99-119857.

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Abstract Background: Clonal heterogeneity of the AML blast cell population has been well documented using next generation sequencing (NGS) strategies. This heterogeneity extends to the presence of LSC fraction among the leukemic population: a dynamic compartment evolving to overcome cell selection pressure during disease progression and its treatment including allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, it remains difficult to discriminate between LSC and nHSC or other myeloid progenitors as MPP, LMPP or GMP. Here we present how to combine FLOWSom and KALUZA software to obtain robust identification among tumoral and normal progenitors. We compared the flowLSC Profile with stemness 17 genes score to identify patients with adverse outcome. Methods: 11 AML patients from ALFA07-01 clinical trial diagnosed in Lyon University Hospital between 2009-2010 were included in this study. The quantification of CD34+CD38- fraction at diagnosis from total bulk leukemia was made as previously described. To better discriminate between LSC and nHSC we designed MFC panel based on 2-tube antibody combinations to identify the pattern of LSC in the CD34+CD38- cell compartment. CD34/CD38/CD45/CD117« backbone » was used in both tubes, completed by lineage defined markers CD7/CD56/CD19/CD13/CD33/ and/or LSC identified markers CD123 +/- CD90/CD45RA, CLL1, TIM3, CD97. Results: As seeing in Table Nr 1, between 11 AML patients we observed a strong correlation identifying patients with adverse prognostic using previously published threshold by Flow (> 1% CD34+CD38- from bulk leukemia cells). 4 from 11 patients showed a discrepancy between GES 17 LSC and Flow CD34+CD38-: one from four patients (Nr 3) was classified as "high" by Flow (high CD34+ expression) and "low" by GES LSC 17 and three other patients (Nr 8, 10, 11) were classified inversely as "low" by Flow (<1% CD34+ expression) and "high" by GES LSC 17 scoring. Our preliminary data tend to show the relevance to establish a scoring system including the level of FlowLSC at diagnosis and GES LSC 17 to distinguish patients with high risk in patients with high CD34+ expression. Conclusion: In summary, we confirmed that the presence of the LSC CD34+CD38- subpopulation representing more than 1% of total "bulk leukemic cells" at diagnosis could help to identify patients with a poor outcome. Using more accurate analysis as FLOWsom "neural network" system we showed the better discrimination between nHSC and LSC pathway with better separation between CD34+CD38- and CD34+CD38lo fractions and between nHSC (Fig 1A) and LSC (Fig 1B). This unsupervised system could allow us to improve and harmonize the analysis of AML LSC flow signature at diagnosis. A high LSC17 score probably reflects biological properties of LSCs that confer resistance to standard AML therapy. The previous analysis of the ALFA- 0701 trial data demonstrates the utility of the LSC17 score as a tool for patient selection. Despite heterogeneity and complexity of the AML LSC compartment, we should still use LSC quantification as a biomarker of chemosensitivity of AML (Fig 1C). For the patients with high-level of LSC other therapeutic modalities should be chosen to eradicate LSC using targeting immunotherapy before allograft. Monitoring of the LSC fraction should be useful in most clinical trials to overcome chemoresistance of LSC. These results should be confirmed in a prospectively larger cohort of patients and could be considered as useful complementary prognostic parameter for risk-stratification AML patients in future clinical trials. Image: Fig1 A, B, C Table 1 Clinical Trial Registry: ALFA 0701 Conflict of Interest: No conflict Key-Words: LSC, flow cytometry, AML, LSC17 Scoring References: Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia : Monique Terwijn, et al, Gert J. Ossenkoppele1, Gerrit J. Schuurhuis ; PlosOne, 2014 Sep ; Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up. Boyer T, Gonzales F, Plesa A, et al, Roumier C, Preudhomme C, Cheok M; JoVE; March 2018; A 17-gene stemness score for rapid determination of risk in acute leukaemia: Stanley W. K. Ng1, John E. Dick & Jean C. Y. Wang; Nature, 2017 Dec; FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Van Gassen S, Callebaut B and Saeys Y (2017). Disclosures Dombret: CELLIPSE: Research Funding.

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Gould, Clare, Colm Keane, Valentine Murigneux, Harald Oey, Jonathan Ellis, Simone Birch, Jay Gunawardana i in. "B2M Gene Expression Reflects an Immunologically Active Tumor Microenvironment in DLBCL". Blood 134, Supplement_1 (13.11.2019): 2778. http://dx.doi.org/10.1182/blood-2019-126537.

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Introduction Interactions between tumor cells and the immune system play a critical role in regulating tumor development. Immune-based therapies have shown variable responses in diffuse large B-cell lymphoma (DLBCL) which suggests that the immune cell composition of the tumor microenvironment (TME) influences response to these agents. However, the key determinants of the immune TME are poorly understood. We have recently shown that indolent lymphomas can be stratified as immunologically 'hot' or 'cold' (Tobin et al J. Clin Oncol, in press) and sought to test for this in DLBCL. Also, given that beta-2-microglobulin (B2M) has a key role in antigen presentation and its loss is a frequent immune evasion mechanism in DLBCL, we determined the effect of B2M expression on the nature and magnitude of immune infiltration in the tumor microenvironment of DLBCL. Methods Ninety-seven de novo systemic DLBCL FFPE biopsies underwent targeted exon re-sequencing of B2M (Illumina) in addition to quantitative gene expression of Β2M, immune effector (CD4, CD8, CD56, CD137), immunosuppressive macrophage markers (CD68, CD163) and immune checkpoints (TIM3, LAG3, PD1 and PDL1) (Nanostring Technologies). B2M promoter methylation by mass array, immunohistochemistry for the above markers and high throughput T-cell receptor β sequencing (Adaptive Biotechnologies) were performed on a subset of cases. Genomic findings were validated in a whole exome and transcriptome cohort of approximately 1000 DLBCL samples (Reddy et al Cell 2017). Results Β2MMut were detected in 14/97 (14.4%) samples and had lower Β2M gene expression compared to Β2MWT (p = 0.0094) and all of these showed B2M protein loss. However, 29/40 (72%) of B2MWT samples tested also had B2M protein loss. There was no differential methylation of B2M promoter regions observed compared to lymph node controls. Results indicate that mechanisms other than mutation and methylation status contribute to loss of B2M surface expression and that a more comprehensive assessment of B2M expression within tumor tissues is achieved by B2M digital gene quantification. Consistent with this, there were no significant differences in expression of intra-tumoral immune markers between B2MMut and B2MWT tissues, whereas gene expression of B2M was significantly associated and positively correlated with the gene expression of CD4, CD8, CD56, CD137, CD68, CD163, PD1, PDL1, LAG3 and TIM3 (all p <0.01) and with the protein expression of CD8, CD56, CD137, PDL1 and LAG3 (all p <0.01), irrespective of their classification as an immune-effector, immune-checkpoint or macrophage markers. These observations are consistent with a co-ordinately regulated immune response, indicating an adaptive immune-checkpoint response to regulate immune-effector activation. In keeping with this, the housekeeper genes did not correlate with immune gene expression indicating that high or low co-ordinate expression of immune genes was not reflecting tissue RNA quality or quantity (Fig 1). Next, we tested the discovery cohort for relationships with the TCR repertoire. High B2M gene expression was significantly associated with reduced TCR diversity (p = 0.0101) compared to low B2M gene expression, suggesting that clonal T cell expansions are more likely with intact antigen presentation. The validation cohort also demonstrated that B2M gene expression correlated with immune cell infiltration and additionally showed that B2M positively correlated with the gene expression of HLA Class I//II molecules and a range of regulatory, transport and assembly molecules involved in the antigen presentation machinery pathway. However, no differential survival benefit was observed in patients with high versus low B2M. Conclusions In summary, digital gene expression is a robust measure of B2M quantification in the TME. Our data show that high B2M gene expression reflects an immunologically active or 'hot' tumor microenvironment in DLBCL characterised by higher levels of immune cell infiltration. These findings indicate that B2M gene expression level could be used as a biomarker of an active intra-tumoral immune response in DLBCL. Further studies are required to determine if B2M gene expression may have a role in stratifying the selection of patients in whom immune-based therapies are more likely to be effective. Disclosures Gould: NovoNordisk: Other: Travel funding - domestic flights to attend education, May 2018. Keane:MSD: Consultancy; BMS: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy, Other: Travel Grant. Hertzberg:Takeda: Consultancy, Honoraria; MSD: Consultancy; Roche: Consultancy, Honoraria. Gandhi:Gilead: Honoraria, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

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Kocdor, Mehmet A., Hakan Cengiz, Halil Ates i Hilal Kocdor. "Inhibition of Cancer Stem-Like Phenotype by Curcumin and Deguelin in CAL-62 Anaplastic Thyroid Cancer Cells". Anti-Cancer Agents in Medicinal Chemistry 19, nr 15 (10.01.2019): 1887–98. http://dx.doi.org/10.2174/1871520619666191004144025.

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Background: Anaplastic Thyroid Cancer (ATC) is one of the most lethal and aggressive human malignancies. Studies have shown that Cancer Stem-Cell (CSC) phenotype is mainly responsible for ATC aggressiveness. Cytostatic compounds are mostly ineffective because of multidrug resistance mechanisms driven by the CSC phenotype. Taxanes have limited efficacy. Recently, CSC inhibition using plant-derived, less toxic compounds, which have anti-cancer efficacy, has become a novel treatment modality. The aim of the study was to evaluate the anti-cancer activity of two natural compounds (curcumin and deguelin) on ATC cells and their CSC properties. In addition, the efficacies of these compounds were compared with that of docetaxel. Methods: Besides control, five treatment groups were formed. ATC cells (CAL-62) were treated with curcumin, deguelin, docetaxel, and their combinations (curcumin+docetaxel, deguelin+docetaxel) at previously determined IC50 doses. Stemness was analyzed by quantitative estimation of sphere formation in matrigel, expression of several cell surface markers (CD133, CD90, Nanog, and OCT3/4) using flow cytometry, and quantification of the hypoxic status [Oxidative Stress Index (OSI) and Superoxide Dismutase (SOD) activity]. The anti-cancer efficacies of these compounds and their combinations were evaluated by determining the alterations in the cell cycle, apoptosis, and tumoral cell migration. Results: Both the natural compounds (particularly curcumin) significantly suppressed the spheroid formation and cellular motility in matrigel as well as suppressed the accumulation of cells in the G0/1 phase, in which the maximum CSC activity is observed. The compounds did not suppress the expression of CSC markers, but twothirds of the cells expressed CD90. Deguelin was found to be particularly effective in inducing apoptosis similar to docetaxel at IC50 concentrations. Curcumin reduced the OSI and deguelin enhanced the SOD activity, even in docetaxel pre-treated cells. Conclusion: A large proportion of anaplastic tumors might consist of heterogeneous CSC population. Curcumin and deguelin have anti-cancer and several anti-stem cell activities against ATC cells. These natural compounds are capable of altering the aggressive behavior of ATC cells through the inhibition of the CSC phenotype. As a novel therapeutic target, CD90 should be investigated in other ATC cell lines and in vivo models.

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Lassau, N., S. Koscielny, L. Chami, A. Roche, J. Soria, A. le Cesne, V. Boige i J. Armand. "Functional imaging by DCE-US as a surrogate for response in phase I/II of different targeted therapies by DCE-US: Which quantitative parameter and which timing". Journal of Clinical Oncology 25, nr 18_suppl (20.06.2007): 14093. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14093.

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14093 Background: The early evaluation of targeted treatments is a major challenge in oncology. Functional approaches based on the measure of tumoral vascularization have been developed using different modalities of imaging (CT, MRI, US). We analyzed the response of tumors in three studies using different targeted treatments with dynamic contrast enhanced-ultrasonography (DCE-US). Seven parameters characterizing tumor perfusion were estimated. The objective of the study was to determine which parameter is the most appropriate and when to use it to confirm earlier the efficacy of treatment. Methods: A total of 157 DCE-US were performed in 30 responding patients (PFS>3 months) selected from 3 following studies (multikinase inhibitor targeting angiogenic-receptor with a cytotoxic, thyrosine-kinase inhibitor targeted angiogenic-receptor and C-kit, VEGF monoclonal antibody). Each DCE-US was performed using contrast agent (Sonovue,Bracco) with perfusion and quantification softwares (Toshiba) from raw linear data. Seven quantitative parameters of perfusion were estimated: peak intensity (PI) and area under the curve (AUC), area under the wash-in (AUWI), area under the wash-out (AUWO), time to PI, mean transit time (MTT), wash-in slope. DCE-US were performed before treatment and after during 5 periods (P) : 1–12 days(P1), 13–22 days(P2), 23–43 days(P3), 44–110 days (P4), > 111 days(P5). Results: 1099 parameters have benefited a statistical analysis. Significant modifications (P<0.05) of 4 parameters (PI, AUC, AUWI, AUWO) were observed for the 3 treatments. The earliest significant modifications were observed during the 3rd period for the first 2 studies and during the 4th period for the 3rd study. Conclusions: DCE-US is a sensitive tool to evaluate early tumor response to targeted drugs. Four functional parameters were significantly modified patients responding to treatment: PI, AUC, AUWI, AUWO. Those modifications appear earlier for the multikinase inhibitor targeting angiogenic receptor and the thyrosine-kinase inhibitor targeted angiogenic receptor and C-kit ( (23–43 d) compared to VEGF monoclonal antibody (44 -110 d). DCE- US represent a key add value to early evaluation of targeted therapies. No significant financial relationships to disclose.

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Zareian, Nahid, Bella Patel, Lena Rai-Shetty, Clare Rowntree, Andrew McMillan, David I. Marks, Tobias Menne i in. "Evaluation Of IKZF1 Δ4-7 Deletion As a Suitable Marker For Minimal Residual Disease Monitoring; A Study Of 161 Consecutive Acute Lymphoblastic Leukaemia (ALL) Patients On The On-Going UKALL14 Trial". Blood 122, nr 21 (15.11.2013): 1335. http://dx.doi.org/10.1182/blood.v122.21.1335.1335.

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Abstract Minimal residual disease (MRD) testing is vital to risk assignment in acute lymphoblastic leukaemia (ALL). Quantification of patient-specific rearrangements of immunoglobulin and T-cell receptor (Ig/TCR) genes is the most standardised method in current use. Recent studies demonstrated that deletion in the IKZF1 gene is common and is prognostic of poor outcome. IKZF1 targets could offer potential for MRD monitoring in BCR-ABLnegative (neg) ALL. The 5' and 3' break points of this deletion are highly conserved, making it possible to design a universal PCR assay to amplify the fusion genomic sequence created by the deletion. With the initial aim of developing an MRD assay we studied the incidence of IKZF1 Δ 4-7 in 161 consecutive patients enrolled on the on-going adult ALL trial UKALL14, aged 25-59 years. We carried out PCR using breakpoint-specific primers designed as close as possible to the breakpoint. In order to ensure that the screening PCR enabled sensitive detection of the deletions, serial dilution of a positive control SUP-B15 cell line diluted into non-tumoral DNA was analysed. IKZF1 Δ 4-7 could be detected with a sensitivity of at least 10-4 (0.01%). PCR bands could be readily allocated to “strong” or “weak” on visual inspection; all PCR positive signals were confirmed as IKZF1 Δ 4-7 by Sanger sequencing of the PCR products and the breakpoints mapped. The frequency of the deletion in the total population studied was 80/161 (50%); 23/35 (66%) in the BCR-ABL positive (pos) subgroup and strikingly 57/126 (45%) in the BCR-ABLneg subgroup. The high rate of IKZF1 Δ 4-7 in the BCR-ABLneg patients was unexpected, being approximately double the reported incidence BCR-ABLneg adults. Real time quantitative (RQ)-PCR analyses to investigate the suitability of IKZF1 quantitation as the basis for an MRD assay was performed on 26 BCR-ABLneg cases, selected only on the basis of availability of follow-up material. Assays were assessed using the same criteria applied by EuroMRD for Ig/TCR quantification. On that basis, “limited testing” of PCR amplifications at the 10-2 (1%) and 10-4(0.01%) dilution points was performed on all 26 samples. To our surprise, only 5 samples gave acceptable data to qualify for a quantitative MRD assay. Notably, all the 21 cases that failed “limited testing” had yielded a weak PCR signal on initial screening, suggesting the PCR assay have detected intragenic deletions restricted to minor subclones. Although subclonal IKZF1 gene alterations are well described, the apparent high frequency of these events in our cohort (21/26 tested for RQ-PCR assay) was surprising. To further analyse this, we performed MRD-based genomic quantification of all 26 diagnostic specimens using SUP-B15 dilution series. The percentage of ALL cells bearing IKZF1 Δ 4-7 in the putative 21 subclonal cases was <0.01% compared to >90% in the putative 5 major clonal cases. In total, 82% of BCR-ABLneg cases gave a weak PCR band at initial screening, suggesting that most of the Δ 4-7 in BCR-ABLneg adult ALL are subclonal. In the 5 cases where a quantifiable IKZF1 Δ 4-7-based MRD assay could be developed, MRD analysis was performed on 12 follow-up samples and sensitivity and quantitative range of at least 10-4 (0.01%) and 5×10-4 (0.05%) were obtained, respectively. These parameters compare favourably with the performance of standard Ig/TCR assays. Notably in one sample MRD could only be quantified by the IKZF1 deletion approach (level= 7.79E-05, ∼ 0.008%). IKZF1 lesions are not leukaemia-initiating events, hence the stability of this alteration during the history of ALL is not clear. To address this, 14 diagnosis and relapse paired samples were analysed. Three different patterns emerged: in 5 cases the IKZF1 Δ 4-7 at diagnosis was preserved at relapse; in 3 cases the lesion was newly acquired at relapse; and in 3 cases the deletion was lost at relapse, notably all these 3 cases had showed a weak PCR signal, suggesting the deletion which was lost at relapse was subclonal at diagnosis. Theoretically this observation suggests that IKZF1deletion-based MRD monitoring carries a risk of missing a resurgent clone. In conclusion, IKZF1 Δ 4-7 can provide highly sensitive MRD assays and could be a potential candidate to add to the repertoire of currently available MRD markers. However, we have shown limited applicability due to many IKZF1 deletions occurring in putative subclones. The stability of these deletions in major clones remains to be determined. Disclosures: No relevant conflicts of interest to declare.

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Windschmitt, Johannes, Björn Jacobi, Yagmur Bülbül, Lilli Sester, Janine Tappe, Christof Hiebel, Christian Behl, Matthias Theobald i Markus Munder. "Arginine Depletion in Combination with Canavanine Supplementation Induces Massive Cell Death in Myeloma Cells By Interfering with Their Protein Metabolism and Bypassing Potential Rescue Mechanisms". Blood 132, Supplement 1 (29.11.2018): 3205. http://dx.doi.org/10.1182/blood-2018-99-113396.

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Abstract Introduction Although the therapeutic armamentarium against multiple myeloma has tremendously increased in recent years, it still remains an incurable disease. A highly promising novel anti-tumoral treatment strategy is to target specific non-redundant metabolic achilles heels of individual cancer entities. The semi-essential amino acid arginine can be synthesized from citrulline in most physiological tissues due to expression of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1). Various tumor entities do not express ASS1, therefore depend on the exogenous availability of arginine and pharmacological approaches to systemically deplete arginine are in phase I-III clinical development for such arginine-auxotrophic cancers. Cell death induction by arginine depletion can be dramatically enhanced by co-application of the arginine analogue canavanine. Canavanine can be used by the respective aminoacyl tRNA synthetase instead of arginine during protein translation and this leads to a highly toxic intracellular accumulation of misfolded proteins. In preliminary work we have seen that myeloma cells are largely arginine-auxotrophic and can be killed by arginine depletion and canavanine supplementation within hours, while ASS1 expressing cells are completely protected by their endogenous arginine rescue capability. Encouraging results of tumor control have already been seen in a murine myeloma model. Methods Human myeloma cell lines (NCI-H929_A2 and FD50, developed in our laboratory) were cultured and treated in RPMI-1640 medium with or without arginine. Protein levels were determinded by western blot analysis. Cell viability was measured by propidium iodide staining and flow cytometry analysis. RNA quantification was done by qRT-PCR. For autophagosome and aggresome quantification we used immunofluorescence staining (IF) and laser scanning microscopy (LSM). Results Arginine depletion and canavanine supplementation led to misfolded protein accumulation which was followed by massive apoptotic cell death. Both processes were further enhanced by co-treatment with the proteasome inhibitor bortezomib, indicated by an increase in intracellular polyubiquitinated proteins as well as higher cleaved caspase 3 levels and propidium-iodide positive cells after only 8-12 h in both tested cell lines. Unexpectedly, the endoplasmic reticulum (ER)-stress response was activated only very moderately. Expression of CHOP, a pro-apoptotic transcription factor that is highly translated under toxic ER stress, was not altered compared to control conditions. Tunicamycin-mediated induction of enhanced ER stress significantly improved the viability of arginine-starved and canavanine treated cells. This suggests that protein accumulation mainly takes place in the cytoplasm rather than the ER and tunicamycin might alleviate cell death by reduction of total protein translation. Despite severe arginine deficiency and induction of misfolded protein stress, the cells were not able to respond by an adequate upregulation of macroautophagy, as determined by an altered LC3 metabolism. The autophagic flux was significantly reduced compared to control conditions after 4-8 h of treatment. There was a strong induction of BAG3 and p62 proteins, which are both associated with chaperone-assisted autophagy as well as aggresome formation and are normally cleared via macroautophagy. Cytoplasmic aggresome formation was not detectable until onset of apoptosis. Also, no relevant modulation of phosphorylation of the autophagy inducer mTORC and the downstream kinase p70S6K1 was noted upon arginine depletion and canavanine co-treatment. Finally, ER stress induction via tunicamycin did not improve autophagic protein turnover, as determined by IF staining, LSM and western blot. Conclusions Arginine starvation in combination with canavanine supplementation induces fast and highly efficient cell death in arginine-auxotrophic myeloma cells. This novel strategy interferes with myeloma cellular metabolism by induction of misfolded protein accumulation. A relevant upregulation of potentially protective cellular strategies like ER stress responses, aggresome formation and autophagy are either not detectable or they remain insufficient. We hypothesize that our novel metabolic anti-tumor strategy is either too potent or too fast for the tumor cells to cope with its consequences. Disclosures No relevant conflicts of interest to declare.

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Sciancalepore, Patrizia, Barbara Castella, Chiara Riganti, Myriam Foglietta, Joanna Kopecka, Francesco Novelli, Giorgia Mandili i in. "ATP-Binding-Cassette A1 Regulates Extracellular Isopentenyl Pyrophosphate Release and Vγ9Vδ2 T-Cell Activation By Dendritic Cells". Blood 128, nr 22 (2.12.2016): 3709. http://dx.doi.org/10.1182/blood.v128.22.3709.3709.

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Abstract Introduction Phosphorylated metabolites of mevalonate (Mev) pathway like isopentenyl-pyrophosphate (IPP) induce proliferation of Vγ9Vδ2 T cells. Endogenous IPP levels can be lowered or increased by aminobisphosphonates (NBPs) such as zoledronic acid (ZA). We have previously shown that ZA-treated dendritic cells (DC) produce and release high amounts of soluble IPP and are strong Vγ9Vδ2 T-cell activators. However, the mechanisms regulating IPP release in DC and other cells are still unknown. Methods "DC generation": purified CD14+ cells were cultured in standard culture medium at 0.5-1.5 x 106cells/ml supplemented with GM-CSF (1000 U/ml) and IL-4 (500 U/ml) in flat-bottomed 24-well plates for 24 h. After 24 h, DC were left untreated (ZA-) or treated for further 24 h with 1 µM ZA (ZA+). DC were washed after incubation with ZA and re-plated with fresh medium for an additional 24 and 48 h (washed DC [w-DC]). In selected experiments, supernatants were collected for quantification of extracellular IPP levels. "Vγ9Vδ2 T-cell proliferation":on day 7, total counts of viable T cells were calculated with the trypan blue staining assay, and by flow cytometry. In selected experiments, PBMC from CTRL were stimulated for 7 days with supernatants obtained from autologous DCZA- and DCZA+and 10 IU/ml IL-2 to evaluate Vγ9Vδ2 T-cell proliferation. "IPP efflux":cells were radiolabelled with 1 microCi/ml [3H]-acetate; after 24 h, cell supernatants were collected, [3H]-IPP was extracted and resolved by thin layer chromatography. After separation, the spot corresponding to IPP was cut and solubilized, and the radioactivity was quantified by liquid scintillation count. "siRNA ABCA1": cells were incubated 96 h with a 20-25 nucleotide non targeting scrambled siRNA or specific ABCA1 siRNA (Accell Thermo Scientific), then lysed and subjected to the Western blot analysis of ABCA1 expression. "Proximity ligation assay (PLA)":the ABCA1-BTN3A1 interaction was measured by the PLA method with the DuoLink In Situ kit (Sigma Chemicals Co.), using a mouse anti-human ABCA1 (Abcam) and a rabbit anti-human BTN3A1 (Sigma Chemicals Co.) antibody, respectively, as per the manufacturer's instructions. Nuclei were counterstained with 4',5-diamidino-2 phenylindole dyhydrochloride (DAPI). Cells were examined using a Leica TCS SP2 AOP confocal laser-scanning microscope (Leica Microsystem, Wetzlar, Germany). Results We tested a variety of tumoral and non-tumoral cells for their ability to activate Vγ9Vδ2 T cells and correlated this ability with the release of extracellular IPP. We used samples from healthy donors included peripheral blood (PB) monocytes, monocyte-derived DCs, and bone marrow (BM) stromal cells; samples from cancer patients included myeloma cells, chronic lymphocytic leukemia (CLL) cells, and BM stromal cells from multiple myeloma (MM) and CLL patients; tumor cell lines included the monocytic THP1 and histiocytic U937 cells and the myeloma cell line SKMMI. We found that the activation of Vγ9Vδ2 T cells was proportional to the simultaneous efflux of IPP and to the activity/expression of ATP-binding cassette transporter A1 (ABCA1), a membrane transporter involved in the delivery of intracellular cholesterol to apolipoprotein A-I. We have demonstrated that the most potent IPP releaser cells had also the highest expression of ABCA1. Functional ABCA1 inhibition with probucol slightly increased intracellular IPP accumulation, but abrogated extracellular IPP release and Vγ9Vδ2 T-cell activation. Abca1 silencing experiments confirmed the key role played by ABCA1. ABCA1 is up-regulated by ZA viaLXRα transcriptional activation induced by intracellular IPP accumulation and inhibition of the PI3K/Akt/mTOR signaling pathway. Butyrophilin-3A1 (BTN3A1) is an immunoglobulin superfamily protein reported to be required for phosphoantigen presentation and target recognition by Vγ9Vδ2 T cells. We have also demonstrated that BTN3A1 is physically associated with ABCA1 and cooperates with ABCA1 in the activation of Vγ9Vδ2 T cells. Conclusions These results suggest that ABCA1 is involved in extracellular IPP release and Vγ9Vδ2 T-cell activation induced by ZA-treated DC and therefore play a crucial role as mediator of the immune response. Disclosures Boccadoro: SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding. Massaia:Roche: Other: advisory board, research support; Gilead: Other: advisory board; Janssen: Other: advisory board.

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Keane, Colm, Kimberly Jones, Clare Gould, David Hamm, Peter Wood, Simone Birch, Pauline Crooks i in. "The T Cell Receptor (TCR) Repertoire Is a Key Determinant of the Tumour Microenvironment (TME) in Diffuse Large B Cell Lymphoma (DLBCL)". Blood 126, nr 23 (3.12.2015): 3893. http://dx.doi.org/10.1182/blood.v126.23.3893.3893.

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Abstract Background: We have recently demonstrated that an 'immune score' is strongly and independently prognostic in de novo DLBCL treated with R-CHOP immuno-chemotherapy. The score quantifies the relative composition of immune effectors (T cells) and checkpoints (e.g. PD-1 axis molecules and M2 macrophages), as a measure of net anti-tumoral immunity within the TME. It is also known that a diverse TCR repertoire is a hallmark of a robust anti-HIV T cell immune response; conversely in metastatic melanoma treated with anti-PD-1 checkpoint blockade, narrow more clonal TCR repertoires are associated with favorable response. The relationship between the intra-tumoral TCR repertoire and the TME in DLBCL following R-CHOP immuno-chemotherapy is unknown. Methods High-throughput unbiased TCR β chain sequencing was performed on 116 nodal tissues (101 de novo DLBCL patients treated with R-CHOP with long-term follow-up including 8 EBV+DLBCL; and 15 age/gender matched healthy lymph nodes). Outcomes included measurement of productive uniques (a measure of the number of functional T cells with a distinct TCR rearrangement or 'richness'); entropy (a measure of TCR 'diversity'), 'clonality' (a measure of clonal expansions) and the 'maximal frequency' of the most highly expressed clone within tumor biopsies. Results were compared to digital quantification (by nanoString) of key immune effector and checkpoint genes within the TME, the immune score, malignant cell-of-origin (COO), R-IPI and patient survival. Results: First we compared the TCR repertoire in lymphomatous and healthy nodes. There was a marked increase in clonality, reduced diversity and high maximal frequency within DLBCL nodes relative to healthy nodal tissue (both p<0.0001), consistent with an abnormally narrow TCR repertoire of antigen-specific T cells. Next, we tested the relationship between TCR and the TME. Notably, there was modest (r=0.3-0.7) but highly significant (all p<0.001) positive correlations between both richness and diversity (but not clonality) with CD3/CD4/CD8 T cells, and a range of immune checkpoints including PD-L1, PD-L2, LAG-3, CSF-1 and TIM-3. These findings are strongly suggestive of an adaptive immune response, in which malignant B cells influence (i.e. 'adapt') the TME in an attempt to counter an effective anti-lymphoma T-cell response that is in part influenced by the breadth of the TCR repertoire. Then we investigated the TCR repertoire in the context of prognosis and overall survival (OS) following R-CHOP. There were no correlations between COO or R-IPI with any TCR parameter. However, the presence of a high maximal frequency in the tumour biopsy was associated with significantly inferior 5 year OS of 59% compared to 81% in patients without a high maximal frequency (p=0.03, Figure 1). As expected, the immune score stratified patients into highly disparate outcomes: high-score 5-year overall survival 96% versus 42% for low-score (p<0.0001). Interestingly, there were significant differences in the TCR repertoire between the two groups. There was a significant increase for both richness and diversity in high immune score lymphoma patients (p=0.015 and p=0.018 respectively). In keeping, clonality was not increased in high-immune score patients. The only samples associated with increased T cell clonality were those patients with very high levels of intratumoral EBV, potentially reflecting the latent viral antigens expressed by this lymphoma. In the group of patients with poor prognosis (5 year OS 59%), defined by high maximal frequency, the immune score stratified two groups with very different outcomes (5 year OS 90% vs. 30%, p=0.003). Conclusions: These findings indicate the TCR repertoire as a key parameter of the TME that the malignant B cell attempts to narrow. A broad TCR repertoire is associated with a good prognostic immune score (i.e. increased T cells relative to PD-1 axis molecules and M2 macrophages checkpoints) after R-CHOP immunoÐchemotherapy, whereas a more clonal T cell response is associated with significantly inferior outcome. Figure 1. Figure 1. Disclosures Hamm: Adaptive Biotech: Employment.

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Delfau-Larue, Marie-Helene, Isabelle Nel, Axel VAN Der Gucht, Gaelle Laboure, Benjamin Verret, Salma Hamdane, Philippe Gaulard i in. "Number of Circulating t(14;18) Tumor Cells at Diagnosis Is Related to, but Add to the Prognostic Value of Metabolic Tumor Burden in Follicular Lymphoma". Blood 126, nr 23 (3.12.2015): 3872. http://dx.doi.org/10.1182/blood.v126.23.3872.3872.

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Abstract Beside the rare true leukemic forms of follicular lymphoma (FL), low levels of circulating tumor cells (CTC) are detected by PCR in the vast majority of FL patients at diagnosis. By a regular recirculating process, those CTC could reflect the total solid tumor mass. Alternatively, they could represent a subpopulation of tumor cells with distinct molecular profile including adhesion molecules and, as such, could add to the prognostic value of solid tumoral mass previously reported in FL (Dupuis, JCO 2013). In order to address these issues, we retrospectively selected FL patients treated in our institution between 2007 and 2014 who were simultaneously evaluated for both t(14;18) cells in peripheral blood (PB) and FDG-PET/CT tumor mass at diagnosis or at relapse. Absolute quantification of t(14;18) positive cells was performed using quantitative droplet digital PCR (ddPCR). Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were calculated from FDG-PET/CT, and baseline clinical characteristics and outcomes were collected. One hundred fourteen patients fulfilled the inclusion criteria. Using a routine 10-4 sensitive biomed 2 t(14;18) PCR assay, 75 had a positive PCR, either in peripheral blood alone (n=37), in peripheral blood and tumor biopsy (n=27) or in tumor biopsy but not PB (n= 11). Absolute quantitative ddPCR was performed for the 56 t(14;18) MBR+ patients. Clinical characteristics are given in Table 1. Median CTC value (number of t(14;18) positive cells out of total peripheral blood nucleated cells) was 1.6 10-3 (range 0-0.96), with only 5 CTC (-) patients and 13 patients with >10% CTC . Median TMTV was 267 cm3 (range 4.61-1900) and median TLG was 1473 (range 10.24-5912). A positive correlation was found between number of CTC and TMTV (R2 = 0.49; P<0.001; Fig.1) and to a lesser extend with TLG (R2 = 0.38; P<0.001). With a median follow-up of 32 months, OS of FLIPI 0-2 patients was 100% vs 87% for FLIPI 3-4 patients (p=0.003). A number of CTC > 6%, TMTV > 432 cm3 and TLG > 2717 tend to be associated with poorer OS (Fig. 2). The combined presence of > 6% CTC and TLG > 2717 allowed to identify a group of patients with 3-year OS of 71%, compared with 100% when both criteria were negative or dissociated (P= 0.01) (Fig. 2). In the subset of 42 patients with an untreated and untransformed FL, incremental prognostic value of circulating mass and metabolic tumor burden remained significant (P=0.03). Disclosures Dupuis: ABBVIE: Membership on an entity's Board of Directors or advisory committees; ROCHE: Speakers Bureau.

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