Do Alarmins Have a Role in Multiple Myeloma?

Objective: Calprotectin (CLP), S100A6, and high mobility group nucleosome-binding protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to investigate the relationships of serum CLP, S100A6, and HMGN1 levels with the clinical and laboratory findings of patients with multiple myeloma (MM) and their roles in the pathogenesis of MM. Materials and Methods: We measured the serum CLP, S100A6, and HMGN1 levels of 55 newly diagnosed patients and 32 healthy controls using the sandwich enzyme-linked immunosorbent assay method. The medical records of the patients were also reviewed. Results: Serum CLP, S100A6, and HMGN1 levels were significantly decreased in MM patients compared to the control group (p=0.012, p=0.001, and p=0.030, respectively). Receiver operating characteristic analysis was used to determine diagnostic cut-off values for serum CLP, S100A6, and HMGN1 of <98 ng/mL (area under the curve [AUC]: 0.663, 95% confidence interval [CI]: 0.554-0.761, p=0.009), <1174.5 pg/mL (AUC: 0.706, 95% CI: 0.598-0.799, p=0.001), and <440.18 pg/mL (AUC: 0.640, 95% CI: 0.530-0.740, p=0.03), respectively. CLP levels were found to be statistically significantly higher in patients with light chain MM (91.58±22.57 ng/mL) compared to heavy chain MM (79.42±15.83 ng/mL) (p=0.03). A negative correlation was observed between CLP and M protein, immunoglobulin G, globulin, and beta-2 microglobulin (correlation coefficients: -0.361, -0.370, -0.279, -0.300, respectively; p=0.024, p=0.06, p=0.04, p=0.0033). Conclusion: In this study, we found that serum CLP, S100A6, and HMGN1 levels were statistically lower in patients with newly diagnosed MM compared to the control group. These results suggest that CLP may bind to the paraprotein produced by heavy chain MM in the blood, causing its blood levels to be low. Additionally, low levels of HMGN1, which is involved in DNA repair, suggest that HMGN1 may contribute to the complex genetic abnormalities found in cases of MM.

Correction to: Efects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma.

[This corrects the article DOI: 10.1007/s12288-022-01574-6.].

Effects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma.

Purpose: The receptor for advanced glycation end products (RAGE) upregulated during the onset and progression of cancer and bone-related pathologies. In this study, we aimed to investigate the role of serum advanced glycation end products (AGEs), soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1), in multiple myeloma (MM). Methods: AGEs, sRAGE and HMGB1 concentrations of 54 newly diagnosed MM patients and 30 healthy volunteers were measured by ELISA. The estimations were done only once at diagnosis. The medical records of the patients were evaluated. Results: There was no significant difference between the AGEs and sRAGE levels between the patient and control groups (p = 0.273, p = 0.313). In ROC analysis, a HMGB1 cutoff value of > 9170 pg/ml accurately discriminated MM patients (AUC = 0.672, 95% CI 0.561-0.77, p = 0.0034). AGEs level was found to be significantly higher in early-stage disease and HMGB1 in advanced disease (p = 0.022, p = 0.026). High HMGB1 levels were detected in patients whose with better first-line treatment response (p = 0.019). At 36 months, 54% of patients with low AGE were alive, compared to 79% of patients with high AGE (p = 0.055). Patients with high HMGB1 levels tended to have a longer PFS (median 43 mo [95% CI; 20.68-65.31] ) compared to patients with low HMGB1 levels (median 25 mo [95% CI; 12.39-37.6], p = 0.054). Conclusion: In this study, a significant elevation of serum HMGB1 level was found in MM patients. In addition, the positive effects of RAGE ligands on treatment response and prognosis were determined.

Eltrombopag in patients with chronic immune thrombocytopenia in Asia-Pacific, the Middle East, and Turkey: final analysis of CITE.

CITE was a prospective, noninterventional study in adult patients with chronic immune thrombocytopenia treated with eltrombopag under routine clinical care in Asia-Pacific, the Middle East, and Turkey. Data to assess eltrombopag usage, compliance, and outcomes were collected from May 2017 to December 2020. Platelet response was defined as platelet count ≥50 × 103/µL in the absence of rescue medications and splenectomy. Quality of life was evaluated using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire. Noncompliance was defined as the number of missed doses and number of days where the patient did not follow food instructions. A total of 231 patients were enrolled; the median (range) duration of eltrombopag treatment was 484.5 (1-642) days. Compliance to prescribed eltrombopag dose since the previous routine visit was high at ≥96.0%. Baseline median platelet count was 19.0 × 103/µL, which increased to ≥50 × 103/µL at month 2 and mostly fluctuated between 70 × 103/µL and 100 × 103/µL thereafter. The median time to first platelet response was 1.05 (95% confidence interval: 0.92-1.28) months, and the median (interquartile range) maximum duration of platelet response was 193 (57-456) days. FACIT-F scores improved from a mean (standard deviation) 34.4 (12.1) at baseline to 38.5 (9.1) at month 18. Adverse events occurred in 50.9% of patients (n = 116), the most common being upper respiratory tract infection (8.3%) and headache (6.6%). These findings confirmed the effectiveness of eltrombopag treatment in routine practice and reassured that real-world compliance to eltrombopag-prescribed doses and dietary instructions in Asia-Pacific, the Middle East, and Turkey were in line with current recommendations.

Programmed Cell Death Ligand 1 Expression Level and Prognostic Significance in Acute Myeloid Leukemia.

Purpose: We aimed to evaluate the expression level of programmed death ligand-1 (PD-L1) and its effects on prognosis in acute myeloid leukemia. Methods: The flow cytometry was used to detect PD-L1 expression on leukemic cells of 86 de novo acute myeloid leukemia patients with longitudinal follow-up. Results: Median follow-up was 13 (0-73) months. The mean of expression level was 3.22 ± 0.47 at diagnosis and ranged from 0 to 28%. PD-L1 expression tended to be lower in patients with acute promyelocytic leukemia (2.47 ± 1.08, p = 0.09) but there was no significant difference between neither diagnostic nor cytogenetic subgroups. There was no difference in PD-L1 levels between the patients who achieved complete remission (3.4 ± 0.61) and those who did not (2.91 ± 0.72, p = 0.94). The patients with low PD-L1 at diagnosis (median 25 mo [95% CI; 0-56.7]) had a longer overall survival compared with high PD-L1 (median 13 mo [95% CI; 5.52-25.17], p = 0.079). PD-L1 expression was lower at relapse (2.04 ± 0.79) compared to initial diagnosis (4.52 ± 0.93, p = 0.049). The patients who had overall survival longer than 1 year showed lower PD-L1 expression at relapse (0.66 ± 0.93) compared with who had not (5.06 ± 4.28, p = 0.052). A negative correlation between CD33 and PD-L1 (r = - 0.303, p = 0.005) was detected. Conclusion: Despite its low expression levels, PD-L1 appears to be a clinically important prognostic factor. The negative correlation determined between PD-L1 and CD33 supports the combination approach of PD-L1 inhibitors and CD33 targeted immunotherapies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-021-01473-2.

Prognostic Value of Serum Soluble Klotho and Fibroblast Growth Factor-23 in Multiple Myeloma Patients.

Multiple myeloma is the plasma cell malignancy in which bone involvement is common. The Fibroblast growth factor-23 (FGF-23)/Klotho pathway plays a major role in mineral metabolism that FGF-23 is mineralization inhibitory. Klotho also has anti-apoptotic and anti-tumor effects by acting as a tumor suppressor gene. There is a negative correlation between serum FGF-23 and serum soluble Klotho (sKL) levels. As such, there can be considerable interest in investigating sKL and FGF-23 as a biomarker in patients with MM. We used an enzyme-linked immunosorbent assay to measure serum FGF-23 and sKL levels in 55 newly diagnosed MM patients and 23 healthy controls. We determined significantly high serum FGF-23 and low serum sKL levels in MM patients when compared to healthy controls. Serum sKL levels correlated negatively with a p53 positive mutation status, with high ISS, elevated lactate dehydrogenase, C-reactive protein, Beta-2 microglobulin levels. Serum FGF-23 levels are associated negatively with serum phosphorus and positively only light chains and p53 mutation. Patients with high serum FGF-23 levels had significantly shorter median overall survival than those with low serum FGF-23 levels (p = 0.008). Additionally, low sKL levels were related to decreased overall survival, but they didn't reach statistically significant (p = 0.072). There is a significant correlation between low serum sKL, high FGF-23 levels, and known prognostic factors in MM patients. We conclude that low sKL and high FGF-23 levels are a probable prognostic biomarker for poor MM patient outcomes.

The Role of Interim PET/CT on Survival in Diffuse Large B Cell Lymphoma.

BACKGROUND: Diffuse large B cell lymphoma is the most frequent aggressive non-Hodgkin lymphoma. Predicting response and estimating prognosis earlier makes management of this heterogeneous lymphoma more satisfying. Interim PET response is established in Hodgkin Lymphoma to tailor the therapy but results for non-Hodgkin Lymphoma is unconvincing. In the current study evaluation of interim PET and survival outcomes of 103 DLBCL patients is performed. PATIENTS AND METHODS: About 103 Patients with DLBCL followed up in a single center between 2009 and 2019 were enrolled the study. All patients received R-CHOP chemoimmunotherapy at first line. Interim PET was performed after at least one or more cycles. All PET scans were performed with 18F-FDG isotope as PET/CT. PET scoring results were evaluated according to the 5-Point Deauville Scoring system defined in the National Comprehensive Cancer Network clinical guidelines for iPET and eotPET. 5-P DS of scores of 1 to 3 were defined as negative scans, and scores of 4 to 5 were considered to be positive scans. RESULTS: Forty-six (44.7%) Female and 57 (55.3%) male aged between 25 and 83 (median 57) years newly diagnosed DLBCL patients were enrolled in the study. Median PFS was 21 (interquartile range 8.5-53.7) months and median OS was 33.5 (interquartile range 12.5-62.9) months for the total cohort. Positive predictive value of interim PET according to Deauville scoring system was 65.4% and negative predictive value was 77.9%. CONCLUSION: Our study showed that according to Deauville 5 point scale (D 5PS) scoring system, interim PET-positive patients have shorter both PFS and OS than iPET-negative patients.

Evaluation of a Generic Bortezomib Molecule in Newly Diagnosed Multiple Myeloma Patients

Objective: Constantly increasing health expenditures lead to the use of generic molecules and generic versions of bortezomib have been used for a long time. The aim of this study is to retrospectively examine the effectiveness, side effects, and reliability of generic bortezomib in newly diagnosed multiple myeloma (MM) patients. Materials and Methods: The data of 95 patients who received four cycles of bortezomib as first- or second-line therapy in a single center were retrospectively recorded. Treatment responses, side effects, and progression-free survival (PFS) rates were calculated and compared. Results: Of the 95 patients, 42 used the original and 53 used the generic molecule. Epidemiological data, MM types, genetic risk groups, laboratory values at diagnosis, and bortezomib treatment lines (as a first line or second) were evaluated and there was no statistical difference between the two groups. When the response rates were evaluated according to International Myeloma Working Group criteria, there was no significant difference (p=0.42). Rates of partial response and higher responses were similar (81% vs. 79.2%, p=0.84). PFS rates were 42.8 months with the original and 37.8 months with the generic molecule (p=0.68). Side effects were seen in 44.2% of all patients, and the most common side effects were neuropathy, cytopenia, and infection. These rates were similar in the two groups (p=0.55). Conclusion: Although this retrospective study is limited in scope, it is the first study comparing the original molecule of bortezomib with a generic version. There were no statistical differences between the two groups in terms of treatment responses, PFS, or side effects. However, large-scale evaluations will help obtain more data on this subject.

Serum calprotectin (S100A8/A9) levels as a new potential biomarker of treatment response in Hodgkin lymphoma.

INTRODUCTION: Hodgkin lymphoma (HL) is unusual among malignancies, with inflammation playing such a prominent role in its pathogenesis. S100A8/A9 (calprotectin) is a heterodimeric protein, which has a role in the inflammatory response and oncogenesis. In this study in HL patients, the correlation between serum S100A8/A9 levels and treatment responses was investigated along with whether this marker is correlated with other inflammatory markers. MATERIALS AND METHODS: Thirty-three HL patients and 20 healthy volunteers were included. Demographic and clinical characteristics were recorded. Calprotectin levels were measured with Human S100A8/A9 Heterodimer Quantikine ELISA kit. Calprotectin levels were measured twice in patients, before and after treatment, and once in the control group. Treatment responses were evaluated with positron emission tomography-computed tomography (PET-CT). RESULTS: The mean age of patients was 44.3 ± 18.1 (66.3% male). The median (IQR) values of S100A8/A9 before and after treatment in the patient group were 4.98 (2.6-7.8) and 1.87 (1.1-4.8)µg/mL. Median (IQR) S100A8/A9 concentration in the control group was 1.41 (0.98-2.73)µg/mL. In patients, pretreatment values were significantly higher than in controls (P < .001). However, median values of patients after treatment and controls were similar. Patient median S100A8/A9 levels were significantly lower post-treatment compared with pretreatment values (P = .001). When inflammatory markers were examined within groups, no relationship was found between markers. In ROC analysis, a S100A8/A9 cutoff value of ≥3.31µg/mL accurately discriminated end-of-treatment PET positivity (AUC = 0.78; 95% CI 0.58-0.98; accuracy = 76.2%). CONCLUSION: S100A8/A9 may be a potential biomarker for treatment response in HL independent of inflammation. This is the first study to investigate and show this finding. However, further large-scale studies are still required.

A Multi-Center Study on the Efficacy of Eltrombopag in Management of Refractory Chronic Immune Thrombocytopenia: A Real-Life Experience

Objective: The aim of the present study was to evaluate the efficacy and safety of eltrombopag, an oral thrombopoietin receptor agonist, in patients with chronic immune thrombocytopenia (ITP). Materials and Methods: A total of 285 chronic ITP patients (187 women, 65.6%; 98 men, 34.4%) followed in 55 centers were enrolled in this retrospective cohort. Response to treatment was assessed according to platelet count (/mm3) and defined as complete (platelet count of >100,000/mm3), partial (30,000-100,000/mm3 or doubling of platelet count after treatment), or unresponsive (<30,000/mm3). Clinical findings, descriptive features, response to treatment, and side effects were recorded. Correlations between descriptive, clinical, and hematological parameters were analyzed. Results: The median age at diagnosis was 43.9±20.6 (range: 3-95) years and the duration of follow-up was 18.0±6.4 (range: 6-28.2) months. Overall response rate was 86.7% (n=247). Complete and partial responses were observed in 182 (63.8%) and 65 (22.8%) patients, respectively. Thirty-eight patients (13.4%) did not respond to eltrombopag treatment. For patients above 60 years old (n=68), overall response rate was 89.7% (n=61), and for those above 80 years old (n=12), overall response rate was 83% (n=10). Considering thrombocyte count before treatment, eltrombopag significantly increased platelet count at the 1st, 2nd, 3rd, 4th, and 8th weeks of treatment. As the time required for partial or complete response increased, response to treatment was significantly reduced. The time to reach the maximum platelet levels after treatment was quite variable (1-202 weeks). Notably, the higher the maximum platelet count after eltrombopag treatment, the more likely that side effects would occur. The most common side effects were headache (21.6%), weakness (13.7%), hepatotoxicity (11.8%), and thrombosis (5.9%). Conclusion: Results of the current study imply that eltrombopag is an effective therapeutic option even in elderly patients with chronic ITP. However, patients must be closely monitored for response and side effects during treatment. Since both response and side effects may be variable throughout the follow-up period, patients should be evaluated dynamically, especially in terms of thrombotic risk factors.

The role of hepcidin, GDF15, and mitoferrin-1 in iron metabolism of polycythemia vera and essential thrombocytosis patients

Background/aim: GDF15, hepcidin and mitoferrin-1 (mfrn-1) are proteins involved in systemic iron regulation. There are no studies in the literature demonstrating the serum mfrn-1 levels in polycythemia vera (PV) and essential thrombocythemia (ET) patients. The aim of this study was to investigate GDF15, hepcidin and mfrn-1 levels in PV and ET patients. Materials and methods: Ten PV, 17 ET patients, and 27 healthy controls (HCs) were enrolled. GDF15, hepcidin and mfrn-1 values were measured with enzyme-linked immunosorbent assay (ELISA). Results: GDF15 levels were higher in the myeloproliferative neoplasm (MPN) group (P = 0.002). Hepcidin levels were not different between MPN patients and HCs. The mfrn-1 levels were lower in MPN patients (P = 0.039). Hepcidin, GDF15, and mfrn-1 levels were not different between PV and ET patients. mfrn-1 levels were lower in ET patients than HCs (P = 0.038). Conclusion: Increased erythropoiesis in MPNs may lead to high GDF15 levels in these patients. However, hepcidin was not suppressed despite the increased GDF15 levels and erythropoiesis in these patients. Decrease in mfrn-1 in MPNs can be the result of its increased turnover due to increased myelopoiesis. It can be hypothesized that similar hepcidin levels in patients and controls and low mfrn-1 levels in patients may be a defense mechanism against erythroid activity and thromboembolic complications.

Carfilzomib-induced tumor lysis syndrome in relapsed multiple myeloma: a report of two cases.

BACKGROUND: Tumor lysis syndrome (TLS) is a potentially fatal complication of cancer therapy characterized by severe electrolyte and metabolic abnormalities such as hyperphosphatemia, hyperkalemia, and hypocalcaemia. TLS usually occurs in aggressive hematologic malignancies such as Burkitt lymphoma and acute leukemia. TLS has rarely been observed in multiple myeloma (MM). CASE REPORT: We present 2 patients with relapsed MM who developed TLS after the first cycle of carfilzomib treatment. CONCLUSION: Carfilzomib is a next-generation proteasome inhibitor with proven efficacy in relapsed/refractory MM. Recently, increasing frequency of TLS has been reported in MM, especially after treatment with proteasome inhibitors. The potential complications of TLS should be considered especially during the first cycle of carfilzomib treatment.

Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura.

Most commonly seen side effects with Tyrosine kinase inhibitors (TKI's) are hematologic toxicities. Besides, with dasatinib autoimmune side effects can be seen. Thrombotic thrombocytopenic purpura (TTP) is a life- threatening disease that can be related to various causes mainly autoimmune disorders or antineoplastic drugs. Few cases of TKI associated secondary thrombotic microangiopathies (TMA) have been reported in literature. Most of cases were diagnosed as hemolytic uremic syndrome (HUS) rather than TTP. Herein, we describe a 37-year-old CML patient who was diagnosed as immune-mediated TTP related to dasatinib.

Isolated Breast Relapse of Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation.

Isolated breast relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is less often seen. Chronic graft-versus-host disease (cGVHD) is effective in preventing marrow relapse, but cGVHD seems not to be effective extramedullary relapse (EMR). We report the case of isolated breast relapse after first allo-HSCT for acute lymphoblastic leukemia (ALL). A 47-year-old female was diagnosed with ALL achieved complete remission with salvage chemotherapy and underwent allo-HSCT from an HLA-matched sibling male donor. At 17 months post-transplant, she presented with a bilateral breast masses that confirmed the diagnosis lymphoblast involvement. She had no evidence of leukemia in her marrow that determined 100 % full-donor chimerism when she was relapsed in her both breasts.

Serum Angiopoietin Levels are Different in Acute and Chronic Myeloid Neoplasms: Angiopoietins do not only Regulate Tumor Angiogenesis.

Molecular balance between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) has important effects in tumor angiogenesis. Ang-2 was shown to be elevated and proved to be a prognostic factor in acute myeloid leukemia (AML). To date studies revealed increased angiogenesis in bone marrows (BMs) of both myeloproliferative neoplasm (MPN) and AML patients. We conducted this study to demonstrate circulating levels of Ang-1 and Ang-2 in MPN patients since no data exists in literature. Thirty-three newly diagnosed MPN, 27 newly diagnosed AML patients and 25 controls (HC) were enrolled and Angiopoietin levels were determined with ELISA. We found that Ang-1 levels were higher whereas Ang-2 levels were lower in MPN and HC when compared to AML. Our results suggest that though angiogenesis is increased in both AML and MPN, angiopoietin serum level profile of the two diseases are different, and MPN patients have similar Ang-1 and Ang-2 levels as HC. We conclude that, according to our results Ang-1 and Ang-2 do not only regulate tumor angiogenesis and the difference between angiopoietin levels of acute and chronic myeloid neoplasms could be a reflection of other effects of these growth factors on tumor malignancy.

The Role of Azacitidine in the Treatment of Elderly Patients with Acute Myeloid Leukemia: Results of a Retrospective Multicenter Study.

OBJECTIVE: In this study, we aimed to investigate the efficacy and safety of azacitidine (AZA) in elderly patients with acute myeloid leukemia (AML), including patients with >30% bone marrow (BM) blasts. MATERIALS AND METHODS: In this retrospective multicenter study, 130 patients of ≥60 years old who were ineligible for intensive chemotherapy or had progressed despite conventional treatment were included. RESULTS: The median age was 73 years and 61.5% of patients had >30% BM blasts. Patients received AZA for a median of four cycles (range: 1-21). Initial overall response [including complete remission (CR)/CR with incomplete recovery/partial remission] was 36.2%. Hematologic improvement (HI) of any kind was documented in 37.7% of all patients. HI was also documented in 27.1% of patients who were unresponsive to treatment. Median overall survival (OS) was 18 months for responders and 12 months for nonresponders (p=0.005). In the unresponsive patient group, any HI improved OS compared to patients without any HI (median OS was 14 months versus 10 months, p=0.068). Eastern Cooperative Oncology Group performance status of <2, increasing number of AZA cycles (≥5 courses), and any HI predicted better OS. Age, AML type, and BM blast percentage had no impact. CONCLUSION: We conclude that AZA is effective and well tolerated in elderly comorbid AML patients, irrespective of BM blast count, and HI should be considered a sufficient response to continue treatment with AZA.

Soluble Programmed Death 1 (PD-1) Is Decreased in Patients With Immune Thrombocytopenia (ITP): Potential Involvement of PD-1 Pathway in ITP Immunopathogenesis.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by dysregulation of T cells. Programmed death (PD) 1 and programmed death 1 ligand 1 (PD-L1) are cosignaling molecules, and the major role of the PD-1 pathway is the inhibition of self-reactive T cells and to protect against autoimmune diseases. We measured levels of serum soluble PD 1 (sPD-1) and serum soluble PD-L1 (sPD-L1) in 67 patients with ITP (24 newly diagnosed ITP [ndITP], 43 chronic ITP [cITP]) and 21 healthy controls (HCs). We determined decreased serum sPD-1 levels both in patients with ndITP and in patients with cITP when compared to HC. Moreover, there was a positive correlation between sPD-1 levels and platelet counts. The sPD-L1 levels were decreased in patients with ndITP when compared to patients with cITP. This is the first study investigating PD-1 signaling pathway in ITP. Decreased sPD-1 levels may have a role in ITP pathogenesis as without the inhibitory regulation of PD-1, sustained activation of T cells may cause inflammatory responses which is the case in ITP.

Late-onset Anticonvulsant Hypersensitivity Syndrome Mimicking Lymphoma.

Anticonvulsant hypersensitivity syndrome is a fatal, idiosyncratic drug reaction that is caused by aromatic antiepileptic drugs. This cutaneous drug reaction is also called pseudolymphoma because of its clinical and histological similarities with malignant lymphoma. The primary clinical findings are fever, skin rashes, enlarged lymph nodes, single or multiple internal organ involvement and hematological abnormalities. Typically, anticonvulsant hypersensitivity syndrome occurs 1-8 weeks after drug administration. We herein present the case of a patient who had been on anticonvulsant therapy for five years and died from late-onset anticonvulsant hypersensitivity syndrome.

The Role of ß-Catenin in Bcr/Abl Negative Myeloproliferative Neoplasms: An Immunohistochemical Study.

INTRODUCTION: ß-Catenin is a multifunctional protein that acts as a central effector molecule in the Wnt signaling pathway. Aberrant activation of the Wnt/ß-catenin signaling pathway causes various diseases including cancer. In this study we evaluated ß-catenin expression in bcr/abl-negative myeloproliferative neoplasms (MPNs). MATERIALS AND METHODS: The expression of ß-catenin was evaluated in bone marrow using immunohistochemical methods in 66 patients with bcr/abl-negative myeloproliferative neoplasms (MPNs) and in 30 healthy control subjects. Immunreactive score (IRS; staining intensity × percentage of positive stained cells) was used for the evaluation of the cell staining reaction. RESULTS: IRS of megakaryocytes (IRSmega) was higher in essential thrombocytemia (ET) compared with the control group (P = .022) and primary myelofibrosis (PMF; P = .001). IRS of vascular endothelial cells (IRSvas) was higher in the bcr/abl negative MPN compared with the control group (P = .024). Also, IRSvas was higher in the PMF compared with the control group (P = .001), policythemia vera (PV; P = .005), and ET (P = .006). A positive correlation was detected between IRSmega and platelet counts (P = .019). CONCLUSION: Results of this study suggest that the Wnt/ß-catenin signaling pathway has a role in the angiogenesis of PMF and in the thrombopoiesis of PV and ET. Hence, targeting the Wnt/ß-catenin signaling pathway could open new avenues for novel therapeutic approaches in bcr/abl-negative MPNs.

Treatment of patients with multiple myeloma over 65 yr: more tolerability or better response?

OBJECTIVE: Two-thirds of newly diagnosed patients with multiple myeloma (MM) are over 65 yr and/or physically unfit. Such patients are not eligible for high-dose chemotherapy or stem cell transplantation. The treatment aims in these patients should be to prolong survival by obtaining the best possible response, while maintaining good tolerability. The aim of our study was to evaluate the response to treatment and treatment-related toxicities in patients treated with conventional and novel protocols. METHODS: The records of 138 elderly (≥65 yr) patients with MM were retrospectively evaluated. RESULTS: The median overall survival(OS) of the patients was 46 months. The median progression-free survival (PFS) was 18 months. The OS and PFS of the patients treated with the conventional protocols did not differ significantly from those treated with the novel protocols. The statistical analysis of the quality of the response to the treatment with the conventional and novel therapies showed that complete remission (CR), combined with a very good partial response (VGPR), was significantly higher in the latter. However, the toxicities were higher in the novel treatment group. CONCLUSION: The novel drug protocols significantly increased the quality of the responses of elderly patients with MM to therapy, but they did not increase the patients' tolerability.