Polymorphic Variant in GATA3 gene Is a Hallmark of PAR1-Deleted BCP-ALL and Associates with Poor Prognosis Among Pediatric Patients Treated with the BFM Backbone Protocols

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1742-1742
Author(s):  
Joanna Madzio ◽  
Agata Pastorczak ◽  
Marcin Braun ◽  
Joanna Taha ◽  
Kamila Wypyszczak ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Risk Group ◽  
Early Response ◽  
Leukemic Cells ◽  
Response To Treatment ◽  
Pseudoautosomal Region ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Risk Of Death ◽  
Gata3 Mrna

Abstract Introduction Germline variant at rs3824662 in GATA3 gene was associated with early response to treatment as well as relapse risk in childhood BCP-ALL treated with COG protocols. This effect resulted from the strong link between the GATA3 polymorphism and the presence of somatic defects in leukemic cells including IKZF1 deletions, CRLF2 rearrangements and JAK2 gene mutations, which promote aggressive course of the disease. Aims The study aimed to evaluate an association between GATA3 gene polymorphism and clinical and biological features of pediatric BCP-ALL treated with the BFM backbone protocols. Methods Between November 2010 and June 2016, 957 consecutive children with newly diagnosed BCP-ALL were enrolled into the study. 822 patients treated according to ALL-IC BFM2009 protocol (n=594) and ALL-IC BFM2002 protocol (n=228) in 15 centers of the Polish Pediatric Leukemia/Lymphoma Study Group were enrolled into the study (median age 4.5 yrs, median follow-up time 2.5 yrs). Patients with BCR-ABL1 and MLL gene rearrangements were excluded from the analysis. The rs3824662 polymorphism of the GATA3 gene was genotyped using TaqMan probes. GATA3 mRNA expression level in leukemic cell was evaluated in BCP-ALL cases using qPCR with FAM-MGB probes (n=136). Targeted copy number screening of selected 23 loci was performed using the P335-B2 SALSA MLPA kit (MRC-Holland, Netherlands) in n=807 available DNA leukemia samples. MRD at day 15 and 33 was measured by flow cytometry with EuroFlow 8-color antibody panels. Results In the study group genotypes distribution withinrs3824662 of GATA3 was as follows: AA: n=44 (5.4%); CA: n=266 (32.4%); CC: n=512 (62.3%). Median MRD15 and MRD33 were 0.31% and 0.001% respectively. IKZF1 deletion were found in 18%, PAX5 in 20%, PAR1 in 12%, CDKN2A in 24%, CDKN2B 20%, BTG1 in 6.3%, ETV6 in 21%, EBF1 in 4% and RB1 in 6% of cases. Leukemic cells harbouring AA variant withinrs3824662 showed GATA3 mRNA expression 1.6 and 2.2 times higher compared to cells with CA and CC variants respectively, with the difference close to significant (ANOVA p=0.06). The presence of AA variant was not related to any gene deletion apart from microdeletions of the pseudoautosomal region PAR1 (Xp22 and Yp11) which occurred more frequently in AA carriers as compared to CA and CC carriers (11/41 vs. 34/242 vs. 52/468, p=0.013). We did not find any association of clinical features such as initial WBC, steroid response, sex and age at diagnosis among BCP-ALL patients with GATA3 genotype. However, AA carriers had a higher risk for MRD>10% at day 15 OR (95%CI)=3.93 (1.37-11.23) as well as MRD>0.01% at day 33, OR(95%CI)=2.95 (1.12-7.73) as compared CC carriers. Cox model of survival analysis was done for variables with univariate significance of p<0.15 (risk group, sex). The results of Cox regression showedthe AA genotype remained associated with an increased risk of death regardless of risk group (assigned based on ALL-IC BFM09 protocol), HR(95%C)=2.95(1.12-7.73), P=0.028). Conclusions We showed that carriers of AA genotype in GATA3 are prone to develop PAR1 -deleted BCP-ALL. Moreover our study confirmed an association of GATA3 AA rs3824662 homozygosity with poor early response to treatment as well as risk of death among pediatric BCP-ALL patients treated with the BFM backbone protocols. Disclosures Madzio: National Science Centre: Research Funding.

scholarly journals Trends in CRP, D-dimer and fibrinogen during therapy for HIV associated multidrug resistant tuberculosis

2018 ◽  
Author(s):  
Patrick G. T. Cudahy ◽  
Joshua L. Warren ◽  
Ted Cohen ◽  
Doug Wilson
Keyword(s):  
Early Response ◽  
Multidrug Resistant ◽  
Response To Treatment ◽  
Hiv Positive ◽  
Measurement Interval ◽  
Risk Of Death ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
D Dimer

ABSTRACTBackgroundHIV positive adults on treatment for multidrug-resistant tuberculosis (MDR-TB) experience high mortality. Biomarkers of HIV/MDR-TB treatment response may enable earlier treatment modifications that improve outcomes.MethodsTo determine whether trends in C-reactive protein (CRP), D-dimer and fibrinogen predict treatment outcome among those with HIV/MDR-TB co-infection we studied 20 HIV positive participants initiating therapy for MDR-TB. Serum CRP, fibrinogen, and D-dimer were measured at baseline and serially while on treatment. Results: At baseline, all biomarkers were elevated with median CRP 86.15 mg/L (IQR 29.25-149.32), D-dimer 0.85 μg/mL (IQR 0.34-1.80) and fibrinogen 4.11 g/L (IQR 3.75-6.31). CRP decreased significantly within 10 days of treatment initiation and fibrinogen within 28 days; D-dimer did not change significantly. 5 (25%) participants died. Older age (median age of 38y among survivors and 54y among deceased, p=0.008) and higher baseline fibrinogen (3.86 g/L among survivors and 6.37 g/L among deceased, p=0.02) were significantly associated with death. Higher CRP concentrations at the beginning of each measurement interval were significantly associated with a higher risk of death during that interval.ConclusionTrends in fibrinogen and CRP may be useful for evaluating early response to treatment among individuals with HIV/MDR-TB co-infection.

scholarly journals Surface Expression of CRLF2 Protein Is Associated with Lower Minimal Residual Disease (MRD) Among Children with IKZF1-deleted Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2400-2400
Author(s):  
Agata Pastorczak ◽  
Lukasz Sedek ◽  
Marcin Braun ◽  
Joanna Madzio ◽  
Alicja Sonsala ◽  
...  
Keyword(s):  
Protein Expression ◽  
Prognostic Significance ◽  
Surface Expression ◽  
Leukemic Cells ◽  
Study Cohort ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Childhood All ◽  
Lymphoma Study Group

Abstract * AP and LS contributed equally ^ TS and WM contributed equally as senior authors on behalf of the Polish Pediatric Leukemia/Lymphoma Study Group Background High MRD levels as well as adverse outcome characterize ‘’BCR-ABL 1-like’’ subtype of ALL. Nevertheless, from genetic abnormalities associated with this subtype of ALL, only IKZF1 deletions were unequivocally associated with high MRD and increased ALL relapse risk across the published studies. Prognostic significance of CRLF2 alterations still remains with discordant conclusions. To date, CRLF2 status has been determined based on CRLF2 mRNA expression or CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-CRLF2, CRLF2F232C) but not regarding protein expression. Aim The goal of this project was to investigate early response to treatment in patients with childhood ALL with respect to CRLF2 protein expression on leukemic cells at diagnosis. Methods Between August 2011 and March 2014, 384 consecutive children (median age 4.4 yrs; median follow-up 15±8.7 months), with newly diagnosed BCP-ALL treated according to ALL-IC BFM09 protocol in 15 centers of the Polish Pediatric Leukemia/Lymphoma Study Group were prospectively enrolled into the study. Targeted copy number screening of selected 23 loci was performed on available DNA samples (n=359) by using the P335-B2 and P202-A2 SALSA MLPA kits (MRC-Holland, Netherlands). CRLF2 protein expression on leukemic cells collected at diagnosis (n=384) was determined by flow cytometry (FCM) using anti-TSLP-R antibody (Biolegend, USA). CRLF2-P2RY8fusion was identified using RT-PCR with specific primers followed by direct sequencing. MRD was measured at day 15 of induction therapy using FCM with EuroFlow 8-color antibody panels (n=377). Results CRLF2 expression was present at diagnosis in 21 cases (21/384=5.4%), in 10 out of the 21 CRLF2-P2RY8 fusion was found. Among 359 patients, 54 (15%) harbored IKZF1 deletions which were significantly associated with CRLF2 expression (47/341=13.7% vs. 7/18= 38.8%, p=0.01). The presence of CRLF2 expression was also linked with Down syndrome (5/12=41.6% vs. 3/258=11.6, p<10-5). Median MRD levels at day 15 were significantly higher among patients with IKZF1 deletion, delIKZF1+=2.65(0.1-12)% vs. delIKZF1-=0.37(0.05-2.99)%, p=0.001; and in patients negative for CRLF2 expression, CRLF2-=0.45(0.06-3.8)% vs. CRLF2+= 0.01 (0.00-1.12)%, p=0.007]. Moreover, in conditional analysis MRD levels were lower among ALL cases with delIKZF1+CRLF2+ compared to delIKZF1+CRLF2-, 0.3 (0.02-5.6) vs. 2.7 (0.2-12) respectively, p=0.001; and patients double negative delIKZF1-CRLF2- showed even higher MRD level than patients delIKZF1-CRLF2+, 0.4 (0.05-3.1) vs 0.01 (0.00-1.75), p=0.001. Conclusions We reported for the first time clinical relevance of the CRLF2 protein surface expression with specific impact on MRD levels, which did not worsen induction response in patients with IKZF1 deletions. Considering relatively short follow-up, further prospective observation of events in the study cohort is indispensable to assess prognostic value of CRLF2 protein expression. Disclosures No relevant conflicts of interest to declare.

scholarly journals The use of hyperpolarised 13C-MRI in clinical body imaging to probe cancer metabolism

2021 ◽  
Author(s):  
Ramona Woitek ◽  
Ferdia A. Gallagher
Keyword(s):  
Cancer Metabolism ◽  
Signal To Noise Ratio ◽  
Response Assessment ◽  
Early Response ◽  
Multiparametric Mri ◽  
Metabolic Reprogramming ◽  
Response To Treatment ◽  
Additional Information ◽  
Positron Emission ◽  
Breast And Prostate Cancer

AbstractMetabolic reprogramming is one of the hallmarks of cancer and includes the Warburg effect, which is exhibited by many tumours. This can be exploited by positron emission tomography (PET) as part of routine clinical cancer imaging. However, an emerging and alternative method to detect altered metabolism is carbon-13 magnetic resonance imaging (MRI) following injection of hyperpolarised [1-13C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised 13C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of 13C-pyruvate to 13C-lactate over time. The method has produced promising preclinical results in the area of oncology and is currently being explored in human imaging studies. The first translational studies have demonstrated the safety and feasibility of the technique in patients with prostate, renal, breast and pancreatic cancer, as well as revealing a successful response to treatment in breast and prostate cancer patients at an earlier stage than multiparametric MRI. This review will focus on the strengths of the technique and its applications in the area of oncological body MRI including noninvasive characterisation of disease aggressiveness, mapping of tumour heterogeneity, and early response assessment. A comparison of hyperpolarised 13C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.

scholarly journals Sernbo score predicts survival after intracapsular hip fracture in the elderly

2013 ◽  
Vol 95 (1) ◽  
pp. 29-33 ◽  
Author(s):  
EJC Dawe ◽  
E Lindisfarne ◽  
T Singh ◽  
I McFadyen ◽  
P Stott
Keyword(s):  
Hip Fracture ◽  
High Risk ◽  
Risk Group ◽  
Characteristic Curve ◽  
Social Situation ◽  
High Risk Group ◽  
Low Risk ◽  
Risk Of Death ◽  
Intracapsular Hip Fracture ◽  
The Mean

Introduction The Sernbo score uses four factors (age, social situation, mobility and mental state) to divide patients into a high-risk and a low-risk group. This study sought to assess the use of the Sernbo score in predicting mortality after an intracapsular hip fracture. Methods A total of 259 patients with displaced intracapsular hip fractures were included in the study. Data from prospectively generated databases provided 22 descriptive variables for each patient. These included operative management, blood tests and co-mobidities. Multivariate analysis was used to identify significant predictors of mortality. Results The mean patient age was 85 years and the mean follow-up duration was 1.5 years. The one-year survival rate was 92% (±0.03) in the low-risk group and 65% (±0.046) in the high-risk group. Four variables predicted mortality: Sernbo score >15 (p=0.0023), blood creatinine (p=0.0026), ASA (American Society of Anaesthesiologists) grade >3 (p=0.0038) and non-operative treatment (p=0.0377). Receiver operating characteristic curve analysis showed the Sernbo score as the only predictor of 30-day mortality (area under curve 0.71 [0.65–0.76]). The score had a sensitivity of 92% and a specificity of 51% for prediction of death at 30 days. Conclusions The Sernbo score identifies patients at high risk of death in the 30 days following injury. This very simple score could be used to direct extra early multidisciplinary input to high-risk patients on admission with an intracapsular hip fracture.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group

2015 ◽  
Vol 63 (3) ◽  
pp. 406-411 ◽  
Author(s):  
Hidemitsu Kurosawa ◽  
Akihiko Tanizawa ◽  
Chikako Tono ◽  
Akihiro Watanabe ◽  
Haruko Shima ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Lymphoma Study Group

Infectious complications in children treated for hodgkin and non-hodgkin lymphomas in polish pediatric leukemia/lymphoma study group: incidence, epidemiology and etiology

2018 ◽  
Vol 60 (1) ◽  
pp. 124-132 ◽  
Author(s):  
Olga Zajac-Spychala ◽  
Jacek Wachowiak ◽  
Anna Szmydki-Baran ◽  
Lukasz Hutnik ◽  
Malgorzata Salamonowicz ◽  
...  
Keyword(s):  
Infectious Complications ◽  
Study Group ◽  
Pediatric Leukemia ◽  
Lymphoma Study Group

scholarly journals A Prognostic Marker in Idiopathic Sudden Sensorineural Hearing Loss: Serum Calprotectin

2020 ◽  
Vol 13 (1) ◽  
pp. 36-40
Author(s):  
İhsan Kuzucu ◽  
Tuba Çandar ◽  
Deniz Baklacı ◽  
İsmail Güler ◽  
Rauf Oğuzhan Kum ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sudden Sensorineural Hearing Loss ◽  
Sensorineural Hearing ◽  
Response To Treatment ◽  
Control Group ◽  
Study Group ◽  
Cross Sectional ◽  
Historical Cohort ◽  
The Relationship

Objectives. Calprotectin, a protein released by neutrophils, has been used in many studies as a biomarker showing the presence of inflammation. In this study, it was aimed to investigate the relationship between serum calprotectin level and response to the treatment of idiopathic sudden sensorineural hearing loss (ISSHL).Methods. The present study is a prospective, cross-sectional historical cohort study. The study group consisted of 44 patients with ISSHL, and the control group consisted of 41 healthy volunteers without ear pathology. At the same time, patients in the study group were divided into three groups according to the response to ISSHL treatment (recovered, partially recovered, unrecovered). The relationship between the groups was statistically evaluated in terms of serum calprotectin levels.Results. The mean serum calprotectin value was 75.67±19.48 ng/mL in the study group and 50.24±29.14 ng/mL in the control group (<i>P</i>=0.001). Serum calprotectin value according to the severity of hearing loss in the mild, moderate and severe was 66.20±8.82, 70.35±16.77, and 91.23±19.73 ng/mL, respectively. Serum calprotectin value in the severe group was significantly higher compared to the moderate and mild groups (<i>P</i>=0.004, <i>P</i>=0.001, respectively). Serum calprotectin value according to the treatment response in the recovered, partially recovered and unrecovered groups was 63.36±11.54, 80.17±12.06, and 85.33±22.33 ng/mL, respectively. Serum calprotectin value in the recovered group was significantly lower compared to the partially recovered and unrecovered groups (<i>P</i>=0.002, <i>P</i>=0.001, respectively).Conclusion. Serum calprotectin value informs the clinician about both the severity of hearing loss and the response to treatment. Hence, serum calprotectin can be used as an important biomarker in ISSHL patients for the determination of the prognosis of disease.

scholarly journals Preliminary results using PET/MR in glioblastoma patients treated with regorafenib: an 18F-FET and DWI-ADC comparison

2021 ◽  
Author(s):  
Alessandro Spimpolo ◽  
Giuseppe Lombardi ◽  
Sara Berti ◽  
Cristina Campi ◽  
Maria Giulia Anglani ◽  
...  
Keyword(s):  
Early Response ◽  
Recurrent Glioblastoma ◽  
Response To Treatment ◽  
Fet Pet ◽  
Additional Information ◽  
Rano Criteria ◽  
Percentage Difference ◽  
Before And After ◽  
The Difference ◽  
Cancer Network

Abstract Introduction: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. DWI and 18F–FET PET are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in DWI/ADC- and 18F-FET PET-derived parameters in patients who underwent PET/MR at both baseline and soon after starting regorafenib. Method: We retrospectively selected 16 consecutive GBM patients who underwent 18F–FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze 4 SD patients who underwent a third PET/MR after another 4 cycles of regorafenib. 18F–FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and soon after treatment. A number of metrics were then derived and compared. Result: The average increases in FET and ADC pathological volumes were higher in PD than in SD patients, although in neither case did the difference reach significance. However, when the percentage difference in FET volumes was plotted against the corresponding percentage difference in ADC, a correlation was observed (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Conclusion: In recurrent glioblastoma patients treated with regorafenib, 18F-FET and ADC metrics, being obtained from completely different measures, could serve as semi-quantitative independent biomarkers of response to treatment. These promising parameters should be tested in a larger cohort of glioblastoma patients treated with regorafenib.

scholarly journals Metabolic Tumor Volume for Early Response Assessment in Early-Stage Unfavorable Hodgkin Lymphoma Treated with Nivolumab in the GHSG Nivahl Phase II Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4020-4020
Author(s):  
Conrad-Amadeus Voltin ◽  
Jasmin Mettler ◽  
Horst Mueller ◽  
Michael Fuchs ◽  
Christian Baues ◽  
...  
Keyword(s):  
Survival Data ◽  
Research Funding ◽  
Early Stage ◽  
Response Assessment ◽  
Early Response ◽  
Percentage Change ◽  
Response To Treatment ◽  
Deauville Score ◽  
Group A ◽  
Group B

Background: Metabolic tumor volume (MTV) measured by FDG-PET/CT is becoming established as an independent risk factor for treatment failure in Hodgkin lymphoma (HL). Moreover, response to treatment with novel agents including checkpoint inhibitors may be better reflected by a decrease in MTV than by currently used response criteria. Our aim was to evaluate the early response to first-line HL treatment with the PD-1 inhibitor nivolumab using MTV. Methods: The analysis set included 59 patients with newly diagnosed, early-stage unfavorable HL treated within the prospective, multicenter, open label, randomized, phase II NIVAHL trial of the German Hodgkin Study Group (GHSG). Patients in NIVAHL were randomized to receive either four double cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine (4x Nivo-AVD, group A, n=31) or a sequential therapy starting with 4x nivolumab monotherapy followed by 2xNivo-AVD and 2x AVD (group B, n=28). Early response to treatment was assessed at a 1st interim restaging after either 2x Nivo-AVD or 4x nivolumab. All NIVAHL patients who underwent PET at both initial staging and early response assessment, with images available to the central review panel for quantitative analysis before April 30th 2019, were included. MTV was calculated using a fixed SUV threshold of 4 for both staging and restaging. Results: Patient characteristics of the MTV analysis subset presented here did not differ in any relevant way from the overall NIVAHL trial population. Median age of the 59 patients was 27 years (range 18-57) with a female predominance (61%). All patients presented with stage II disease (IIB 27%) and ≥3 involved areas was the most common risk factor (75%) followed by elevated erythrocyte sedimentation rate (51%), extranodal disease (17%) and large mediastinal mass (14%). Mean MTV at initial staging was 124 ml (range 4 - 578 ml) and 177 ml (11 - 581 ml) in groups A and B, respectively. In both groups a marked decrease in MTV was observed at the 1st interim restaging (Figure 1): After 2x Nivo-AVD all patients in group A showed a reduction of MTV >80% (mean percentage change in MTV -99.8%). In group B a reduction of MTV >80% was observed in 26/28 patients (93%), while in 2/28 patients an increase <10% was observed (mean percentage change in MTV -91%; Figure 1). The mean residual MTV at interim restaging after 2x Nivo-AVD was 0.4 ml (range 0 - 8) in group A and 11 ml after 4x nivolumab in group B (range 0 - 176). The reduction of MTV was observed irrespective of initial MTV with a similar mean percentage change in patients above and below the median MTV in both groups. When applying the Deauville score, however, the number of patients presenting with a Deauville score ≥4 was higher in the group with an initial MTV above the median MTV than in the group where initial MTV lay below the median value. Using the Lugano criteria and a Deauville score of 4 or higher as cut-off for PET-positivity, early interim complete remission was observed in 81% of patients after 2xNivo-AVD, as compared to 51% after 4x nivolumab monotherapy. Further analyses regarding MTV and response at the 2nd and end-of-treatment restaging as well as survival data are not yet available due to limited follow-up. These data will be available at the time of presentation and shown at the meeting. Conclusions: Marked reductions of MTV demonstrate an excellent early efficacy for both 2x Nivo-AVD and 4x nivolumab as 1st-line therapy for early-stage unfavorable HL. The unexpectedly and previously unreported high MTV reduction with nivolumab monotherapy indicates a relevant potential of anti-PD1 mono- or debulking-therapy in the 1st-line treatment of early-stage unfavorable HL. Early interim response assessment based on MTV may help to identify HL patients treated with anti-PD1 antibodies in whom a significant reduction or even omission of chemotherapy could be considered. MTV appears to have the potential to accurately measure response to immune checkpoint inhibition. However, correlation of early MTV reduction with response at the end of treatment or with survival data is pending. Disclosures Borchmann: Novartis: Honoraria, Research Funding. Bröckelmann:Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document