mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients

Author(s):  
Christos K. Kontos ◽  
Panagiotis G. Adamopoulos ◽  
Sotirios G. Papageorgiou ◽  
Vassiliki Pappa ◽  
Andreas Scorilas

AbstractTissue kallikrein and kallikrein-related peptidases (KLKs) compose a family of serine endopeptidases with much clinical interest in oncology, as their potential as diagnostic and/or prognostic molecular biomarkers in several human malignancies has already been evidenced. However, none of the members of this family has ever been studied in hematological malignancies. Based on our preliminary results regarding the differential mRNA expression of severalTotal RNA was isolated from 69 CLL patients and 31 non-leukemic blood donors. After reverse transcription of poly(A)-RNA,According to ROC analysis,

2019 ◽  
Vol 9 (10) ◽  
Author(s):  
Vivek Kumar ◽  
Sikander Ailawadhi ◽  
Leyla Bojanini ◽  
Aditya Mehta ◽  
Suman Biswas ◽  
...  

Abstract With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17–1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12–1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5–1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41–1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003–2015 (SIR 1.36; 95% CI:1.3–1.42) as compared to 1973–1982 (SIR 1.19; 95% CI:1.12–1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31–1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13–1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.


Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Jennifer R. Brown

Abstract Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem associated with poor overall survival (OS). The traditional definition, which includes those patients with no response or relapse within 6 months of fludarabine, is evolving with the recognition that even patients with longer remissions of up to several years after CIT have poor subsequent treatment response and survival. Approved therapeutic options for these patients remain limited, and the goal of therapy for physically fit patients is often to achieve adequate cytoreduction to proceed to allogeneic stem cell transplantation (alloSCT). Fortunately, several novel targeted therapeutics in clinical trials hold promise of significant benefit for this patient population. This review discusses the activity of available and novel therapeutics in fludarabine-refractory or fludarabine-resistant CLL as well as recently updated data on alloSCT in CLL.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 745-745
Author(s):  
Grzegorz S. Nowakowski ◽  
James D. Hoyer ◽  
Tait D. Shanafelt ◽  
Diane F. Jelinek ◽  
Laura Z. Rassenti ◽  
...  

Abstract Background: Smudge cells are ruptured CLL cells seen on blood smears of CLL patients. For over a century, smudge cells were thought to represent an artifact of slide preparation. We recently showed that smudge cell formation was inversely proportional to leukemic B cell vimentin content. Vimentin is a cytoskeletal protein critical for lymphocyte rigidity and migration; high vimentin content is related to poor prognosis in CLL. Concordantly, in an initial small cohort of patients from a single institution, we found that patients with a low (<30%) percentage of smudge cells on a blood smear have a shorter time to treatment (Mayo Clin Proc.2007;82:449–53). In the current study, we evaluated the impact of smudge cell percentage on prognosis of patients with CLL seen at member institutions of the CLL Research Consortium (CRC). Methods: Archived blood smears from untreated patients with CLL were evaluated for smudge levels. All blood smears were prepared manually in a standard fashion from blood obtained by CRC Tissue Core and stained with WrightGiemsa stain. Smudge cells were defined as broken cells with no intact cytoplasm and a disrupted nuclear membrane. A total of 200 lymphocytes and smudge cells were counted on each slide and the results were expressed as the percent smudge cells. The association between the percentage of smudge cells, prognostic factors (IgVH status, CD38, ZAP-70 and FISH) and time to initial therapy (TTT) was examined. Results: We calculated smudge cell percentage on blood smears obtained prior to treatment for 337 CLL patients. The median smudge cell percentage was 32 (range 2–95%). The percentage of smudge cells was lower in CD38 positive patients (mean 33% vs. 38% in CD38 negative patients, p=0.04). No difference in smudge cell percentage was observed based on IgVH gene mutation status or Zap70 expression. Smudge cell percentage as a continuous variable was associated with prolonged TTT, exponential coefficient 0.98, p=0.04. Using our previously published cutoff of 30% to stratify patients in low and high risk categories, the estimated median time to first therapy of patients with smudge cell percentage ≤30% (n=178) was 7.8 years versus not reached in patients in patients with > 30% (n=159) of smudge cells, p=0.0036, (Figure 1). Ten years from diagnosis, 62% of patients with ≤30% of smudge cells versus 39% of patients with >30% of smudge cells required therapy. In multivariate analysis, the low percentage of smudge cells (≤30%) was an independent predictor of the shortened time to treatment (HR 1.86, 95%CI 1.09–3.16, p=0.02). Conclusion: This multicenter study confirms our initial finding that the percentage of smudge cells on a blood smear is an independent predictor of clinical outcome in patients with CLL. The estimation of smudge cell percentage on routine blood smear provides a simple and inexpensive prognostic test available to nearly all patients with a diagnosis of CLL worldwide. It also allows reanalysis and risk stratification of previously completed trials provided that blood smears have been archived. Further studies of the role of the cytoskeleton in CLL biology are warranted and ongoing in our laboratory. Figure Figure


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1587-1587
Author(s):  
Giulia Agnello ◽  
Susan Alters ◽  
Joseph Tyler ◽  
Jinyun Liu ◽  
Peng Huang ◽  
...  

Abstract Cancer cells experience higher intrinsic oxidative stress than their normal counterparts and acquire adaptive antioxidant mechanisms to maintain redox balance. This increased antioxidant capacity has been correlated to malignant transformation, metastasis and resistance to standard anticancer drugs. This enhanced antioxidant state also correlates with cancer cells being more vulnerable to additional oxidative insults, therefore disruption of adaptive antioxidant mechanisms may have significant therapeutic implications. Hematological malignancies including Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM) are critically dependent on the cellular antioxidant glutathione (GSH), consistent with the higher intrinsic oxidative stress. L-cysteine is the rate-limiting substrate for GSH biosynthesis and adequate levels of cysteine are critical to maintain the intracellular homeostasis of GSH. CLL and a subset of ALL cells have been reported to rely on the stromal supply of cysteine to increase the synthesis of GSH in order to maintain redox balance, which in turn promotes cell survival and fosters drug resistance. One approach to target this cancer specific dependency is by therapeutic depletion of amino acids via enzyme administration; a clinically validated strategy for the treatment of ALL. Aeglea BioTherapeutics Inc. has developed a bioengineered cysteine and cystine degrading enzyme (Cyst(e)inase, AEB3103) and evaluated its therapeutic efficacy against hematological malignancies in in vitro, ex vivo and in vivo pre-clinical studies. The TCL1-TG:p53 -/- mouse model exhibits a drug resistant phenotype resembling human CLL with unfavorable cytogenetic alterations and highly aggressive disease progression. AEB3103 greatly decreased the viability of TCL1-TG:p53 -/- cells cultured in vitro, whereas the CLL therapeutic, fludarabine, showed minimal cytotoxic effects. In vivo treatment of TCL1-TG:p53 -/- mice with AEB3103 resulted in an increase in median survival time (7 months, p<0.0001) compared to the untreated control group (3.5 months, p<0.001) and a fludarabine treated group (5.3 months, p<0.001). These results indicate a superior therapeutic effect of AEB3103 compared to fludarabine. Additionally, evaluation of AEB3103 in in vitro 2D cultures of patient-derived CLL and MM cells, and in ex vivo 3D cultures of cells derived from ALL and AML PDx models resulted in significant cell growth inhibition with therapeutically relevant IC50 values. Collectively these results demonstrate the sensitivity of hematological malignancies to modulation of GSH levels via AEB3103-mediated cyst(e)ine depletion. Disclosures Agnello: Aeglea BioTherapeutics: Employment. Alters:Aeglea BioTherapeutics: Employment, Equity Ownership. Tyler:Aeglea BioTherapeutics: Employment, Equity Ownership. Huang:Aeglea BioTherapeutics: Research Funding. Stone:Aeglea Biotherapeutics: Consultancy, Equity Ownership, Research Funding; University of Texas at Austin: Employment, Patents & Royalties: I am an inventor of technology related to this abstract. Georgiou:Aeglea Biotherapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Lowe:Aeglea BioTherapeutics: Employment, Equity Ownership. Rowlinson:Aeglea BioTherapeutics: Employment, Equity Ownership.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5337-5337 ◽  
Author(s):  
Zisis Kontoninas ◽  
Georgia D Kaiafa ◽  
Zoi Saouli ◽  
Christos G Savopoulos ◽  
Didangelos Triantafyllos ◽  
...  

Abstract Purpose: Τo estimate the incidence of abnormal values of tumor markers CA 15-3, CA125, CA19-9 and CEA at diagnosis and relapse/deterioration or remission of patients with hematological malignancies. Also, correlating them with the burden of disease at diagnosis and relapse/deterioration or remission of the above diseases. Material-methods: Studied 268 patients, aged 16-95 years, who suffered from 14 hematological malignancies: myelodysplastic syndromes (MDS), idiopathic thrombocytosis, polycythemia vera, primary myelofibrosis, chronic myelogenous leukemia (CML), Hodgkin's and Non- Hodgkin's(NHL) lymphomas, chronic lymphocytic leukemia (CLL), multiple myeloma (M.M.), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis, hairy cell leukemia and hypereosinophilic syndrome. Tumor markers were determined by electrochemiluminescence immunoassay method, based on the principle of double immunofluorescence conducted by analyzer Hitachi Modular E170, subunit Elecsys. Results: Tumor marker CA15-3 showed pathological values at diagnosis of hematological malignancies, except MDS and AML, which correlate with high disease burden at diagnosis of essential thrombocytosis(p <0,05), polycythemia vera(p <0.05) and NHL(p <0,001). Tumor marker CA125 had abnormal values at diagnosis of NHL and M.M, which correlate with high disease burden at diagnosis of NHL(p <0,01). CA19-9 and CEA showed no pathological values at diagnosis of hematological malignancies. CA15-3 showed pathological values at relapse/ deterioration of hematological malignancies, except for AML and ALL. These values correlate with the degree of relapse/deterioration of MDS(p <0,001), idiopathic thrombocytosis(p <0,01), lymphoma Hodgkin's(p <0,05), NHL(p <0,001) and CLL (p <0,01). CA125 showed pathological values at relapse/deterioration of M.M, NHL and CLL. These values correlate with the degree of relapse/deterioration of NHL(p <0,01) and CLL(p <0,05). CEA had pathological values at relapse/deterioration of M.M. CA19-9 had no significant findings at relapse/deterioration of hematological malignancies. Pathological values of CA15-3 decreased to normal levels during the remission of hematological malignancies, apart from MDS, primary myelofibrosis and AML. Decline of these values correlate with the degree of remission of Hodgkin's lymphomas(p <0,05), NHL(p <0,001), CLL(p <0,01) and idiopathic thrombocytosis (p <0,01). Pathological values of CA125 decreased to normal levels during the remission of M.M, NHL and CLL. Decline of these values correlate with the degree of remission of NHL(p <0,01) and CLL(p <0,05). CA19-9 and CEA had no significant findings at remission of hematological malignancies. Conclusions: CA15-3 is a surrogate marker at diagnosis of hematological malignancies, other than MDS and AML. It can determine relapse/deterioration or remission in idiopathic thrombocytosis, MDS, NHL, Hodgkin's lymphomas and CLL. CA125 is a surrogate marker at diagnosis of NHL and M.M. It can determine relapse/deterioration or remission in NHL and CLL. CEA can help detect relapse/ deterioration in M.M. CA19-9 has no value in diagnosing and monitoring of hematological malignancies. Further studies in this area will likely bring new knowledge about tumor markers and their utility in current practice. Disclosures No relevant conflicts of interest to declare.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
F Banfi-Bacsardi ◽  
Z Ruzsa ◽  
A Lux ◽  
I Edes ◽  
L Molnar ◽  
...  

Abstract Introduction No-reflow (NR) phenomenon occurs, when myocardial perfusion is not re-established despite opening the coronary artery during percutaneous coronary intervention (PCI). Purpose Our aim was to identify no-reflow specific characteristics, its independent predictors, and to develop a clinically-adaptable risk score. Methods We have analysed 4085 patient data from two Hungarian cardiovascular centres. We included all STEMI/NSTEMI patients underwent PCI (n=3187). 158 patients treated with papaverine/adenosine formed NR group, while 3029 patients were in control (C) group. Anamnestic parameters, laboratory and operation data were compared. Statistical analysis was carried out with Mann-Whitney-, Fisher test, binary logistic regression and Kaplan Meier survival curve. Based on our results, we designed a risk estimation system, checking its applicability with ROC analysis. Results As for NR-specific characteristics, malignant ventricular arrhythmias (11% vs. 4%, p=0,0031; NR-C consequently) and complications (21% vs. 11%, p=0,064) showed their vulnerability. The increment of glucose (8,1 vs. 7,1 mmol/l, p=0,004), WBC (12,08 vs. 10,5 G/l, p=0,001), CRP (12,46 vs. 7,67 mg/l, p=0,051) and LDL levels (3,34 vs. 3,13 mmol/l, p=0,059) supported the pathomechanism of NR. Higher biomarker levels (troponinT: 2040 vs. 510,5 ng/ml; CK-MB: 100,4 vs. 63,65 U/l, p<0,0001) indicated severe perfusion disturbance. Tendency was seen in higher BMI (28,65 vs. 28,03 kg/m2, p=0,12). STEMI dominated in NR (83 vs. 59%, p<0,0001). Lower platelet level (213,3 vs. 228 G/l, p=0,107) and single vessel disease (46 vs. 25%, p=0,0042) characterized NR. 30-day survival was significantly different (85,1 vs. 93,54%, p<0,0001). The mortality rate of NR in STEMI was 69,7% (69,7% vs. 7,94%, p<0,0001) and in NSTEMI 3,7% (3,7% vs. 4,32%). From the significant differences, CRP was the independent predictor of NR (OR: 1,011, p=0,004; pro 1 mg/l change). Examining STEMI/NSTEMI separately, in STEMI CRP was the independent predictor (OR: 1,0092, p=0,036). In NSTEMI LDL (OR: 4,23, p=0,021) was the independent factor. In the risk score, the following 8 parameters were included: BMI>28 kg/m2, glucose>8 mmol/l, WBC>12 G/l, CK-MB>100 U/l, hs troponin T>2000 ng/ml, CRP>12 mg/l, LDL>3,3 mmol/l, STEMI (yes/no), thus maximum 8 points could be reached. Low (0–1 points, 5–20%), moderate (2–5 points, 55–70%) and high risk groups (6–8 points, 41–11%) were formed. Supervising the model with ROC analysis: AUC=0,69, p=0,0026, which indicates its ability to discriminate effectively between different risk levels of NR. Conclusions The specific characteristics of NR group were identified, from which CRP was the independent predictor - as well as in STEMI, while in NR-NSTEMI LDL was the independent factor. With the elaborated risk estimation system –using anamnestic and routine laboratory parameters– NR could be predicted and unsuccessful PCI could be reduced, resulting in positive therapeutic consequences.


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