Impact of PET-CT Response on Survival Parameters Following Autologous Stem Cell Transplantation Among Patients with Multiple Myeloma: Comparison of Two Cut-Off Values

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3983-3983 ◽  
Author(s):  
Meral Beksac ◽  
Mehmet Gunduz ◽  
Mehmet Ozen ◽  
Sule Mine Bakanay Ozturk ◽  
Ozlem Kucuk ◽  
...  
Keyword(s):  
Clinical Response ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Response Criteria ◽  
Cox Regression Analysis ◽  
Protein Levels ◽  
Pet Ct ◽  
Cross Tabulation ◽  
Definition Of

Abstract Background and Aim: PET is a useful tool that allows deeper assessment of response beyond that measured by M protein levels. It has been reported to predict outcome following both ASCT and recently non-transplant setting too. To be able to integrate PET-CT negativity to internationally accepted response criteria the cut-off level needs to be validated by independent investigators. This prospective study was initiated to elucidate the prognostic role of PET-CT in the ASCT setting testing the cut-off level 4.2 initially reported by Zamagniet al versus the cut-off (3.35) based on our results. Patients and Methods: 139 consecutive patients diagnosed and transplanted in Ankara University with pre- and post-transplant (Tx) PET-CT imaging were included. Patients were: Median age 56.5 +/- 8.7 (M/F: 79/60), ISS I/II/III: 50/55/34, renal impairment (10.8%), bone involvement (90.6%), del13q (40.9%), t(4;14) and/or p53(26.5%), LDH high(12.9%), induction with Bortezomib (73.4%). Pre-Tx clinical response ³VGPR: 52.9%, post-Tx clinical response ³VGPR: 77.5%. Overall Survival (OS): median: 33 months (4.2-141 months). PASW statistics for Windows program was used for statistical analysis. Results: ROC analysis revealed 3.35 as a significant cut-off level (p=0.005; OS). PET-CR was defined FDG uptake less than 4.2 or 3.35 depending on the analysis. Pre-Tx PET-CR:17.4%, post-Tx PET-CR: 69.6% (<4.2), 46.4% (<3.35). Cross tabulation of post-Tx clinical response versus PET response is summarized in Table 1. PET (>4.2) was predictive for PFS (p=0.05) but not OS (p=0.096). However PET (>3.35) was predictive for OS (p=0.037) but not PFS. PET (>4.2) was predictive for OS (p=0.014) and PFS (p=0.019)among only ³VGPR patients. Similarly PET (>3.35) among ³VGPR patients was also predictive for OS (p=0.05) and PFS (p=0.04). PET-CR was not predictive among ³CR patients significantly. Cox regression analysis for PFS, when PET (>4.2) is used, ISS was significant only (OR: 1.99, p=0.049) when post-Tx clinical response (OR: 0.46, p=0.022) is not included in the model. For OS, clinical response both pre-Tx (OR: 0.35, p=0.015) and post-Tx (OR: 0.18, p<0.001) is the only significant parameter. PET (>3.35) increased the predictive value of PET. In addition to clinical response, PET-CR appeared as a borderline significant factor for OS: pre-Tx (OR: 2.2, p=0.078), post-Tx (OR: 2.26, p=0.067). In conclusion both PET (<4.2) and PET (<3.35) recognizes deeper responses as manifested by extension of PFS (PET<4.2) and OS (PET<3.35). Both assessments were able to define patients with separate survival outcomes within the ³VGPR group. This effect could not be confirmed within the ³CR group due to the relatively smaller sample size. After multivariate analysis only PET (>3.35) approached significance. To be able to integrate PET-CR to response criteria definition of PET-CR needs to be confirmed. Table 1PET cut-off 4.2PET cut-off 3.35Number of patientsnegativepositivenegativepositive<PR2020PR155911VGPR39143122CR22141521< VGPR17511113 VGPR61284643< CR561942333 CR221415213 year PFS45.8%25.6%48.9%28.9%3 year OS91.6%76.1%94.9%79.5% Figure-1: PET(<3.35) and OS Figure-1:. PET(<3.35) and OS Figure-2. PET(<3.35) and OS within the ³VGPR patients Figure-2. PET(<3.35) and OS within the ³VGPR patients Disclosures No relevant conflicts of interest to declare.

scholarly journals Systematic Construction of an Autophagic Risk Model in Bone Marrow for Prognostic Prediction in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4713-4713
Author(s):  
Lingling Shu ◽  
Han-Ying Huang ◽  
Yang Liu ◽  
Yang Li ◽  
Weida Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Regression Analysis ◽  
Risk Score ◽  
Risk Model ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Cox Regression Analysis

Abstract Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis, which plays critical role in the pathogenesis of multiple myeloma (MM). However, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, the ARGs were obtained from Gene Expression Omnibus datasets (accession GSE24080, GSE136337, GSE57317), which contains 1038 samples of patients with MM. Univariate Cox regression analysis identified 38 ARGs that were significantly associated with overall survival of MM. Furthermore, a risk score model with 11 prognosis-associated ARGs was developed using multivariate Cox regression analysis, including ARNT, ATG4D, BIRC5, BNIP3L, CDKN1A, EIF2S1, IRGM, ITGA3, NCKAP1, NRG1 and TM9SF1. The 3-year area under the curve (AUC) values for the receiver operating characteristic curves were 0.717(0.662, 0.758), 0.646(0.587, 0.703) and 0.906(0.694, 1.000) for GSE24080, GSE136337, GSE57317 prognosis predictions, respectively (Figure A-C). Using this prognostic signature, patients with MM could be separated into high- and low-risk groups with distinct clinical outcomes (Figure D-F). Moreover, autophagy risk score was an independent prognostic factor by multivariate analysis. KEGG revealed that most pathways were related to autophagy and metabolism. Furthermore, we validated the expression of 11 genes and ARNT in bone marrow of MM patients (Figure G-I) and showed the critical role of ARNT-mediated autophagy in the proliferation and drug resistance of bortezomib in myeloma cells (Figure J-M). In conclusion, we constructed ARGs-based prognostic model to predict the prognosis of MM, targeting specific autophagic gene such as ARNT might provide therapeutic clues for MM treatment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The Role of PET/CT in the Era of Immune Checkpoint Inhibitors: State of Art

2020 ◽  
Vol 13 (1) ◽  
pp. 24-31 ◽  
Author(s):  
Angelo Castello ◽  
Egesta Lopci
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Evaluation Criteria ◽  
Advanced Melanoma ◽  
Response Criteria ◽  
Response Evaluation ◽  
Pet Ct ◽  
18F Fdg ◽  
Fdg Pet Ct

Background: Immune checkpoint inhibitors (ICI) have achieved astonishing results and improved overall survival (OS) in several types of malignancies, including advanced melanoma. However, due to a peculiar type of anti-cancer activity provided by these drugs, the response patterns during ICI treatment are completely different from that with “old” chemotherapeutic agents. Objective: To provide an overview of the available literature and potentials of 18F-FDG PET/CT in advanced melanoma during the course of therapy with ICI in the context of treatment response evaluation. Methods: Morphologic criteria, expressed by Response Evaluation Criteria in Solid Tumors (RECIST), immune-related response criteria (irRC), irRECIST, and, more recently, immune-RECIST (iRECIST), along with response criteria based on the metabolic parameters with 18F-Fluorodeoxyglucose (18FFDG), have been explored. Results: To overcome the limits of traditional response criteria, new metabolic response criteria have been introduced on time and are being continuously updated, such as the PET/CT Criteria for the early prediction of Response to Immune checkpoint inhibitor Therapy (PECRIT), the PET Response Evaluation Criteria for Immunotherapy (PERCIMT), and “immunotherapy-modified” PET Response Criteria in Solid Tumors (imPERCIST). The introduction of new PET radiotracers, based on monoclonal antibodies combined with radioactive elements (“immune-PET”), are of great interest. Conclusion: Although the role of 18F-FDG PET/CT in malignant melanoma has been widely validated for detecting distant metastases and recurrences, evidences in course of ICI are still scarce and larger multicenter clinical trials are needed.

Prognostic role of aberrant mTOR activation in patients with stage II and III colorectal cancer

2020 ◽  
Vol 14 (12) ◽  
pp. 1127-1137
Author(s):  
Tong-Tong Zhang ◽  
Yi-Qing Zhu ◽  
Hong-Qing Cai ◽  
Jun-Wen Zheng ◽  
Jia-Jie Hao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Poor Prognostic Factor ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Potential Biomarker ◽  
Risk Predictor

Aim: This study aimed to develop an effective risk predictor for patients with stage II and III colorectal cancer (CRC). Materials & methods: The prognostic value of p-mTOR (Ser2448) levels was analyzed using Kaplan–Meier survival analysis and Cox regression analysis. Results: The levels of p-mTOR were increased in CRC specimens and significantly correlated with poor prognosis in patients with stage II and III CRC. Notably, the p-mTOR level was an independent poor prognostic factor for disease-free survival and overall survival in stage II CRC. Conclusion: Aberrant mTOR activation was significantly associated with the risk of recurrence or death in patients with stage II and III CRC, thus this activated proteins that may serve as a potential biomarker for high-risk CRC.

scholarly journals Myocardial Metabolic Response Predicts Chemotherapy Curative Potential on Hodgkin Lymphoma: A Proof-of-Concept Study

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 971
Author(s):  
Cecilia Marini ◽  
Matteo Bauckneht ◽  
Anna Borra ◽  
Rita Lai ◽  
Maria Isabella Donegani ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cox Regression ◽  
Metabolic Response ◽  
Progression Free Survival ◽  
Disease Relapse ◽  
Cox Regression Analysis ◽  
Normal Tissues ◽  
Pet Ct ◽  
Genome Sharing

Genome sharing between cancer and normal tissues might imply a similar susceptibility to chemotherapy toxicity. The present study aimed to investigate whether curative potential of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predicted by the metabolic response of normal tissues in patients with Hodgkin lymphoma (HL). METHODS: According to current guidelines, 86 patients with advanced-stage (IIB-IVB) HL, prospectively enrolled in the HD0607 trial (NCT00795613), underwent 18 F-fluorodeoyglucose PET/CT imaging at diagnosis and, at interim, after two ABVD courses, to decide regimen maintenance or its escalation. In both scans, myocardial FDG uptake was binarized according to its median value. Death and disease relapse were recorded to estimate progression-free survival (PFS) during a follow-up with median duration of 43.8 months (range 6.97–60). RESULTS: Four patients (4.6%) died, while six experienced disease relapse (7%). Complete switch-off of cancer lesions and cardiac lighting predicted a favorable outcome at Kaplan–Mayer analyses. The independent nature and additive predictive value of their risk prediction were confirmed by the multivariate Cox regression analysis. CONCLUSION: Susceptibility of HL lesions to chemotherapy is at least partially determined by factors featuring the host who developed it.

FAM196B promotes proliferation and migration via regulating epithelial-mesenchymal transition in esophageal cancer

2021 ◽  
pp. 1-8
Author(s):  
Haifeng Xia ◽  
Fang Hu ◽  
Liangbin Pan ◽  
Chengcheng Xu ◽  
Haitao Huang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Western Blot ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis ◽  
Ec Cells ◽  
And Migration ◽  
Proliferation And Migration

BACKGROUND: EC (esophageal cancer) is a common cancer among people in the world. The molecular mechanism of FAM196B (family with sequence similarity 196 member B) in EC is still unclear. This article aimed to clarify the role of FAM196B in EC. METHODS: The expression of FAM196B in EC tissues was detected using qRT-PCR. The prognosis of FAM196B in EC patients was determined by log-rank kaplan-Meier survival analysis and Cox regression analysis. Furthermore, shRNA was used to knockdown the expression of FAM196B in EC cell lines. MTT, wound healing assays and western blot were used to determine the role of FAM196B in EC cells. RESULTS: In our research, we found that the expression of FAM196B was up-regulated in EC tissues. The increased expression of FAM196B was significantly correlated with differentiation, lymph node metastasis, stage, and poor survival. The proliferation and migration of EC cells were inhibited after FAM196B-shRNA transfection in vitro and vivo. The western blot result showed that FAM196B could regulate EMT. CONCLUSION: These results suggested that FAM196B severs as an oncogene and promotes cell proliferation and migration in EC. In addition, FAM196B may be a potential therapeutic target for EC patients.

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽  
2021 ◽  
Author(s):  
Peng Wang ◽  
Chen Luo ◽  
Peng-jie Hong ◽  
Wen-ting Rui ◽  
Shuai Wu
Keyword(s):  
Cox Regression ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Lower Grade ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

scholarly journals P1764 A unifying concept for the quantitative definition of functional mitral regurgitation

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
P Bartko ◽  
H Arfsten ◽  
G Heitzinger ◽  
N Pavo ◽  
A Toma ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Cox Regression ◽  
Expert Consensus ◽  
Functional Mitral Regurgitation ◽  
Complex Nature ◽  
P Value ◽  
Intermediate Risk ◽  
Cox Regression Analysis ◽  
Definition Of ◽  
Quantitative Definition

Abstract Background Diverging guideline definitions for the quantitative assessment of severe secondary mitral regurgitation (sMR) reflect the lacking link of the sMR spectrum to mortality and has introduced a source of uncertainty and continuing debate. Objectives The current study aimed to define improved risk-thresholds specifically tailored to the complex nature of sMR that provide a unifying solution to the ongoing guideline-controversy. Methods We enrolled 423 heart failure patients under guideline directed medical therapy and assessed sMR by effective regurgitant orifice area (EROA), regurgitant volume (RegVol) and regurgitant fraction (RegFrac). Results Measures of sMR severity were consistently associated with 5-year mortality with a HR for a 1-SD increase of 1.42 (95%CI 1.25-1.63, P &lt; 0.001) for EROA, 1.37 (95%CI 1.20-1.56, P &lt; 0.001) for RegVol and 1.50 (95%CI 1.30-1.73, P &lt; 0.001) for RegFrac. Results remained statistically significant after bootstrap- or clinical confounder-based adjustment. Spline-curve analyses (Figure 1A-C) showed a linearly increasing risk enabling to stratify in low-risk (EROA &lt; 20mm2 and RegVol &lt; 30ml), intermediate-risk (EROA 20-30mm2 and RegVol 30-45ml) and, high-risk (EROA≥30mm2 and RegVol≥45ml). In the intermediate-risk group, a RegFrac ≥50% as indicator for hemodynamic severe sMR was associated with poor outcome (P = 0.017). A unifying concept based on combined assessment of the EROA, the RegVol, and the RegFrac (Figure 1D) showed a significantly better discrimination compared to the currently established algorithms (Table 1). Conclusions Risk-based thresholds tailored to the pathophysiological concept of sMR provide a unifying solution to the ongoing guideline controversy. An algorithm based on the combined assessment of the unifying cut-offs for EROA, RegVol and RegFrac improves risk prediction compared to currently established grading. Table 1 Definition of severe sMR Cox regression analysis ROC analysis IDI analysis HR (95%CI) P-Value ROC P-Value-for-comparison IDI P-Value Unifying concept 3.76 (2.71-5.23) &lt;0.001 0.63 –- –- –- ACC/AHA definition 3.20 (2.14-4.78) &lt;0.001 0.57 &lt;0.001 0.06 &lt;0.001 ESC/EACTS definition 1.52 (1.10-2.09) 0.01 0.55 &lt;0.001 0.13 &lt;0.001 ACC/ASE expert consensus 1.89 (1.40-2.56) &lt;0.001 0.59 0.04 0.08 &lt;0.001 Comparison of the unifying concept with the ACC/AHA, ESC/EACTS and ACC/ASE expert consensus definitions of sMR by Cox regression, ROC, and IDI demonstrated the most powerfull prediction by the unifying concept with significantly higher ROC area under the curve and better discriminatory power by IDI. Abstract P1764 Figure 1 A-D

Association of Interphase Fluorescence in Situ Hybridization (IP-FISH) Response Criteria with Conventional Metaphase Cytogenetics in CML Patients On Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4707-4707
Author(s):  
Thomas Schenk ◽  
Martin C Müller ◽  
Alice Fabarius ◽  
Philipp Erben ◽  
Thomas Ernst ◽  
...  
Keyword(s):  
Bone Marrow ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Conflicts Of Interest ◽  
False Negative ◽  
Response Criteria ◽  
Interphase Cells ◽  
Definition Of ◽  
Fish Response

Abstract Abstract 4707 The Philadelphia (Ph) chromosome and its molecular equivalent, the BCR-ABL fusion gene, represent the pathogenetic cause and a useful marker for diagnosis and follow up monitoring of chronic myeloid leukemia (CML). Cytogenetic analysis of bone marrow metaphases (Cy) has been established as the standard method. In contrast, interphase fluorescence in situ hybridization (IP-FISH) has been increasingly applied in many studies due to recent optimization of the technique but is not represented in current treatment guidelines. We therefore sought to define IP-FISH response criteria which correspond best with complete (CCyR) and major cytogenetic responses (MCyR). In order to quantitatively compare results of both methods 1,749 consecutive non selected bone marrow samples from 748 CML patients at different stages of CML were analyzed in parallel with Cy and IP-FISH. 5 patients with Ph negative/BCR-ABL positive CML were excluded from the analysis. 643 patients in chronic phase (CP) were analyzed during imatinib based therapy, ten patients received interferon alpha. 74 patients at different stages of the disease received 2nd generation tyrosine kinase inhibitors: nilotinib, n=18 (CP, n=13; accelerated phase, AP, n=2; blast crisis, BC, n=3); dasatinib, n=56 (CP, n=41; AP, n=4; BC, n=11). 21 patients received no therapy or the therapy was not evaluable. The correlation between Ph positive metaphases and the proportion of FISH positive interphase cells was determined using the Spearman's rank correlation coefficient. The chi-square test was used to compare IP-FISH and Cy data. The optimally separating threshold value between Cy and IP-FISH was chosen as cut-off point. Cy and IP-FISH data correlated well (r=0.89; p<0.0001). The following cut-off values were defined: '30% IP-FISH positivity was found to correspond best with MCyR ('35% Ph+ metaphases); <6% IP-FISH positivity was concordant with CCyR (0% Ph+ metaphases). Of 1,163 samples of patients in CCyR, 99.1% showed a percentage of <6% IP-FISH positive cells. 82 of 1,163 samples (7.0%) with 0% Ph+ metaphases by Cy were IP-FISH positive (median 3%, range, 1-21% positive interphases). IP-FISH showed false negative results in 10 of 1,090 samples (0.9%) with a median of 8% Ph+ metaphases (range, 4-40%). Using these IP-FISH cut-off points, the diagnostic specificity for the definition of CCyR was 93.8% for all patients and 93.7% for CP pts only and for the definition of MCyR 89.4% for all patients and 88.4% for CP patients only, respectively. In conclusion, BCR-ABL FISH data derived from bone marrow interphase cells are comparable with metaphase cytogenetics but the cut-off points differ. IP-FISH might be used instead of Cy in order to assess the achievement of response milestones in CML patients during therapy. The prognostic value of IP-FISH data, however, should be analyzed in prospective controlled trials. Disclosures: No relevant conflicts of interest to declare.

Identification of Rab5 as a Gene Involved in Chronic Myeloid Leukemia (CML) Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3470-3470
Author(s):  
Daniela Cilloni ◽  
Monica Pradotto ◽  
Francesca Messa ◽  
Francesca Arruga ◽  
Enrico Bracco ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Western Blot ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Small Gtpases ◽  
Loss Of Function ◽  
Imatinib Resistance ◽  
Protein Levels

Abstract Abstract 3470 Poster Board III-358 The role of Bcr-Abl in the pathogenesis of Chronic Myeloid Leukemia (CML) is well established, however, the mechanisms leading to CML progression remain poorly understood. By using our model of transgenic Drosophila Melanogaster (Dm) for human Bcr-Abl driven CML we have identified Rab5 as a gene involved in the regulation of CML progression. The Rab5 is a member of gene family small GTPases which are involved in the regulation of vesicular transport. Lately several important reports have linked some members of the Rab family to invesivness and migration of cancer cells. Rab5 is associate with alpha-integrin subunits and modulates their endosomal traffic and subcellular localization. We have observed that a loss of function of Rab5 gene have induced a worsening of the CML phenotype generated by hBcr-Abl expression. In contrast, Rab gain of function rescued Bcr-Abl phenotype. The aim of the study was to evaluate the expression of Rab5 in CML cells to better understand if a potential correlation with progression, which has been observed in the model, could be confirmed in patients. Methods Rab5 gene expression was measured by Real Time PCR in 90 samples from 80 CML patients (32 PB and 58 BM). Among those, 53 are collected at diagnosis (19 of 53 patients have been enrolled in TOPS study). In addition, 9 samples from in CP patients have been collected at the time of imatinib resistance, 7 in accelerated phase and 11 in BC. In 14 patients, genes expression was analyzed during remission as, well. In parallel, 21 healthy donors (10 PB and 11 BM) have been evaluated. Rab5 protein expression was investigated by Western Blot and Immunofluorescence. We have also utilized K562 transfected with Rab5 plasmid, which we have generated to gain insight about the effects of Rab5 on cell proliferation and apoptosis. Results Rab5 transfection and overexpression in K562 significantly reduced proliferation and affected apoptosis. We found that in CML patients Rab5 expression levels were significantly decreased in either BM or PB (p<0.001 and p<0.0001) as compared to healthy subjects. Furthermore, in blast crisis samples we have found Rab5 transcripts levels to be further decreased. In contrast, at the time of remission, the transcript levels were comparable to normal values. Our preliminary analysis of samples from TOPS trial have shown a trend that Rab5 levels are lower among those patients achieving MMR by 12 months, when compared to the group of patients non achieving MMR on 400 mg, but that difference was not statistically significant (p=0.2). Among those randomized to receive imatinib 800 mg the difference was statistically significant with a median value among those achieving MMR of 1.27 vs 2.14 in the group without MMR (p=0.04). The protein levels have been analyzed by Western Blot and immunofluorescence and allow us to show detectable levels of Rab5 in samples collected at remission, but undetectable levels in course of active CML disease. Although preliminary, our results show a significant decrease of Rab5 expression in blast crisis samples, when compared to CP CML and healthy volunteers, which suggest a role of Rab5 in slowing down or suppressing a progression. Surprisingly, among CP CML patients the responders to TKI therapy have been detected to express a lower level of Rab5 than non responders. We are conducting further studies to better explain these data, which we find intriguing and suggesting that molecular factors involved in the regulation of CML progression could be uncoupled from the mechanisms regulating response to TKI therapy. Supported by Novartis Oncology, Clinical Development, TOPS Clinical Correlative Studies Network Disclosures No relevant conflicts of interest to declare.

Role of Positron Emission Tomography (PET/CT) in Primary Mediastinal Large B Cell Lymphoma (PMLBCL): Preliminary Results of an International Phase II Trial (IELSG-26 Study) Conducted On Behalf of the International Extranodal Lymphoma Study Group (IELSG), the Fondazione Italiana Linfomi (FIL) and the UK NCRI Lymphoma Group

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1566-1566 ◽  
Author(s):  
Luca Ceriani ◽  
Emanuele Zucca ◽  
Pier Luigi Zinzani ◽  
Andrés J.M. Ferreri ◽  
Umberto Vitolo ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Liver Uptake ◽  
Cut Point ◽  
Large B Cell Lymphoma ◽  
Deauville Score ◽  
Pet Ct ◽  
Residual Masses ◽  
Definition Of

Abstract Abstract 1566 Background. Response-tailored management of PMLBCL is a major challenge in everyday practice, mostly due to the persistence of post-treatment residual masses of uncertain nature. PET/CT is now widely used in the definition of response and as a prognostic indicator, in Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL), while its role in patients with PMLBCL remains to be defined. Aim of the study. The IELSG-26 study was designed to prospectively evaluate the clinical role of PET/CT after rituximab and anthracycline-containing immunochemotherapy (R-CHT) in patients with PMLBCL. Methods. Between January 2007 and July 2010, 125 patients (pts) with PMLBCL were enrolled in 21 institutions and treated with R-CHOP-like (20 pts), R-VACOP-B (34 pts) or R-MACOP-B (71 pts) regimens according to the local policy; consolidation with mediastinal involved field radiotherapy (IFRT) as indicated by local guidelines was allowed. PET/CT scans were planned at baseline, at 3–4 weeks after R-CHT and at 12 weeks after radiotherapy. Central PET/CT review was performed at the end of treatment using the Deauville score (Meignan et al. Leuk Lymphoma 2009) and complete response (CR) was defined as a negative PET scan or one having minimal residual uptake lower than mediastinal blood pool (MBP) activity in regions which were FDG-PET positive at baseline according to the criteria of the International Harmonization Project in Lymphoma (Juweid et al. JCO 2007). Results. Treatment was administered as initially planned in 119 pts (including IFRT in 106); there were 6 early withdrawals (4 with early progression and 2 with stable disease receiving second-line chemotherapy). PET imaging was not done (n=2) or not evaluable due to technical problems (n=2) in 4 pts, therefore, central review of PET/CT was possible in 115/119 patients. PET/CT visual assessment at 3–4 weeks post-R-CHT showed metabolic CR in 54/115 patients (47%; 95% CI, 36%–56%): in 12 cases (10%; 95% CI, 6%–18%) PET/CT scan was completely negative (score 1 according to the Deauville criteria), while in 42 (37%; 95% CI, 28%–46%) there were small residual masses with an uptake less than MBP (score 2). PET/CT scans showed a positive residual mass after R-CHT in 61/115 pts (53%; 95% CI, 44%–62%). The residual uptake was higher than MBP but below the liver uptake (score 3) in 27 pts (23%; 95% CI, 16%–32%), slightly higher than the liver uptake (score 4) in 24 pts (21%; 95% CI, 14%–29%) and markedly higher than the liver uptake (score 5) in 10 pts (9%; 95% CI, 4%–15%). Despite only 47% of patients attaining a CR -defined by the uptake below MBP activity- after R-CHT, at a median follow-up of 2.8 years, the estimated 5-year overall survival (OS) and progression-free survival (PFS) rates were 96% (95% CI, 89%–98%) and 91% (95% CI, 84%–95%), respectively. The achievement of a CR at 3–4 weeks after R-CHT predicted a longer PFS (p=0.015) with high sensitivity but poor specificity (negative predictive value of 0.98 but positive predictive value of only 0.15) and showed a borderline impact (p=0.052) on OS. Patients with Deauville score 3 had a clinical outcome identical to that of ‘PET negative’ (score 1–2) pts and ROC analysis suggested that moving the cut-point for the definition of CR from the MBP to the liver uptake, will increase specificity while maintaining sensitivity. Indeed, defining the response using the liver uptake as a cutpoint is a better predictor for both PFS (p<0.001) and OS (p=0.001); of 10 pts with disease progression, 9 had score 4–5 and one score 2. The latter was one of the five pts with score 1–3 who were not irradiated. All the 4 recorded deaths occurred in the group of patients with score 4–5. Conclusions. Using the MBP cut-point, the PET-positive rate (Deauville score>2) after R-CHT in PMLBCL was higher (53%) than in DLBCL. However, more than 90% of pts are projected to be alive and progression-free at 5 years post treatment and a negative PET/CT after R-CHT is significantly associated with a longer PFS. Pts with score 4 and 5 had a significantly worse PFS and OS. Hence, the liver uptake may represent a more appropriate cut-point than MBP to identify poor-risk pts who may need early intensification of therapy. The frequent use of IFRT in this study precludes any clear conclusion about its role, but the new IELSG-37 randomized trial will assess whether mediastinal irradiation can be safely omitted in PMLBCL pts achieving a CR after R-CHT. Disclosures: No relevant conflicts of interest to declare.

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