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.

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.

Study for the Diagnostic Screening of Paroxysmal Nocturnal Hemoglobinuria in Older Patients with Unexplained Anemia and/or Cytopenia.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematopoietic stem cell disease that may lead to weakness and death of patients, if unrecognized and untreated. Although consensus guidelines were reviewed recently for the diagnostic screening of PNH with multi-parameter flow cytometry (FCM), until now, no study has investigated the efficiency of such clinical indications in older patients. METHODS: Overall, 20 centers participated in the study and a total of 1,689 patients were included, 313 of whom were at geriatric age and 1,376 were aged 18 - 64 years. We evaluated the efficiency of consensus clinical indications for PNH testing using FCM in peripheral blood samples and compared the results of older patients and patients aged 18 - 64 years. RESULTS: PNH clones were detected positive in 7/313 (2.2%) of the older patients. Five (74.4%) of the patients with PNH clones had aplastic anemia, 1 had unexplained cytopenia, and 1 patient had myelodysplastic syndrome (MDS) with refractory anemia. PNH clones were not detected in any older patients who were screened for unexplained thrombosis, Coombs (-) hemolytic anemia, hemoglobinuria, and others (e.g., elevated lactate dehydrogenase (LDH), splenomegaly). We detected PNH clones in 55/1376 (4%) samples of the patients aged under 65 years. Forty-two (76.4%) patients with PNH clones had aplastic anemia, 2 patients had Coombs (-) hemolytic anemia, 3 patients had unexplained cytopenia, 1 patient had MDS with refractory anemia, 1 patient had hemoglobinuria, and 6 (10.9%) had others (e.g., elevated LDH, splenomegaly). PNH clones were not detected in any patients who were screened for unexplained thrombosis. There was no statistical difference between the geriatric population and patients aged 18 - 64 years in terms of clinical indications for PNH screening with FCM (p = 0.49). CONCLUSIONS: Our results showed that the current clinical indications for PNH screening with FCM were also efficient in older patients. We suggest that older patients with unexplained anemia, myelodysplastic syndrome with refractory anemia, and unexplained cytopenia should be screened for PNH with FCM to identify patients who would benefit from treatment.

Study for the diagnostic screening of paroxsymal nocturnal hemoglobinuria in Turkey: Prospective multicentric evaluation of suspected patients.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease presenting with variable and various clinical findings. PNH might be overlooked and diagnosis may be delayed due to low awareness about PNH. This is the first multicenter study in Turkey, investigating the efficiency of diagnostic screening of PNH by multiparameter flow cytometry (FCM) according to consensus guidelines. METHODS: We evaluate the efficiency of consensus clinical indications for PNH testing with FCM in 1689peripheral blood samples from 20 centers between January 2014 and December 2017. RESULTS: Overall, at the 20 centers contributing to this study, PNH clone were detected in 62/1689 samples (3.6%) by FCM test. 75.8% (n = 47) of patients with PNH clone had aplastic anemia, 3.2% (n = 2) had Coombs (-) hemolytic anemia, 6.5% (n = 4) had unexplained cytopenia, 3.2% (n = 2) had MDS with refractory anemia, 1.6% (n = 1) had hemoglobinuria and 9.7% (n = 6) had others (elevated LDH, splenomegaly, etc.). In contrast, we detect no PNH clone test in patients who were screened for unexplained thrombosis. CONCLUSIONS: Our study showed that current clinical indications for PNH testing are highly efficient and diagnostic screening of suspected patients for PNH with FCM is recommended. However, advanced screening algorithms are required for patients presenting with unexplained thrombosis and normal complete blood count.

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.

A comparison of the efficacy of piperacillin-tazobactam and cefoperazone-sulbactam therapies in the empirical treatment of patients with febrile neutropenia / Eficacia de piperacilina-tazobactam y cefoperazona-sulbactam en el tratamiento de pacientes con neutropenia febril

Introduction. Empirical antibiotic therapy in neutropenic patients presenting with fever plays a significant role in reducing mortality related to infection. Empirical therapies with broad-spectrum intravenous bactericidal, anti-pseudomonal antibiotics are accepted treatments for febrile neutropenic patients. The aim of this study was to compare the efficacy of piperacillin-tazobactam (PIP-TAZO) and cefoperozone-sulbactam (CS) therapies in adult patients with haematological malignancies presenting with neutropenic fever in a prospective study design. Methodology. Patients with haematological malignancies (leukaemia, lymphoma, multiple myeloma, and myelodysplastic syndrome) were recruited from June 2010-May 2013. Participants were over 18 years old, with an absolute neutrophil count (ANC) of less than 500/mm³ following chemotherapy or expected to have an ANC less than 500/mm³ in the first 48 h post-chemotherapy, and with an oral body temperature ≥ 38.3°C at a single measurement or 38.0°C after 1-h monitoring. Patients were randomised to the two treatment groups. The initial empirical therapy comprised PIP-TAZO (4.5 g/6 h/day, IV) and CS (2 g/8 h/day, IV). Results. The overall success rate was 61% with CS and 49% with PIP-TAZO (p =0.247). Factors affecting the treatment success included a neutrophil count <100/mm3, being in the relapse/refractory stage of malignancy, and the presence of a microbiologically documented infection (p <0.05). Conclusion. PIP-TAZO and CS monotherapies are equally effective and safe for the empirical treatment of febrile neutropenic patients (AU)

Introducción. El tratamiento antibiótico empírico en pacientes neutropénicos con fiebre juega un papel importante en la reducción de la mortalidad asociada a la infección. El tratamiento empírico con antimicrobianos intravenosos de amplio espectro y antipseudomonas es el tratamiento aceptado para pacientes neutropénicos febriles. El objetivo de este estudio prospectivo fue comparar la eficacia de piperacilina-tazobactam (PIP-TAZO) y cefoperazona-sulbactam (CS) en pacientes neutropénicos febriles adultos con alteraciones hematológicas. Métodos. Pacientes con alteraciones hematológicas (leucemia, linfoma, mieloma múltiple y síndrome mielodisplásico) fueron reclutados desde junio 2010 a mayo 2013. Todos los pacientes fueron mayores de 18 años de edad, presentaban un recuento absoluto de neutrófilos (RAN) menor de 500/mm³ tras la quimioterapia o la expectativa de tener un RAN menor de 500/mm³ en la primeras 48 h después de la quimioterapia, una temperatura corporal oral ≥ 38,3°C o 38,0°C después de 1 h de monitorización. Los pacientes fueron aleatorizados en los dos grupos de tratamiento empírico inicial PIP-TAZO 4,5 g/6 h/día IV o CS 2 g/8 h/día IV. Resultados. La tasa de éxito total fue de 61% con CS y 49% con PIP-TAZO (p =0,247). Los factores que afectaron el éxito de tratamiento fueron un recuento de neutrófilos <100/mm3 y la presencia de una infección documentada microbiológicamente (p <0,05). Conclusión. El tratamiento en monoterapia de PIP-TAZO y CS son igual de eficaces y seguro para el tratamiento empírico de pacientes neutropénicos febriles (AU)

A comparison of the efficacy of piperacillin-tazobactam and cefoperazone-sulbactam therapies in the empirical treatment of patients with febrile neutropenia.

OBJECTIVE: Empirical antibiotic therapy in neutropenic patients presenting with fever plays a significant role in reducing mortality related to infection. Empirical therapies with broad-spectrum intravenous bactericidal, anti-pseudomonal antibiotics are accepted treatments for febrile neutropenic patients. The aim of this study was to compare the efficacy of piperacillin-tazobactam (PIP-TAZO) and cefoperozone-sulbactam (CS) therapies in adult patients with haematological malignancies presenting with neutropenic fever in a prospective study design. METHODS: Patients with haematological malignancies (leukaemia, lymphoma, multiple myeloma, and myelodysplastic syndrome) were recruited from June 2010-May 2013. Participants were over 18 years old, with an absolute neutrophil count (ANC) of less than 500/mm³ following chemotherapy or expected to have an ANC less than 500/mm³ in the first 48 h post-chemotherapy, and with an oral body temperature ≥ 38.3°C at a single measurement or 38.0°C after 1-h monitoring. Patients were randomised to the two treatment groups. The initial empirical therapy comprised PIP-TAZO (4.5 g/6 h/day, IV) and CS (2 g/8 h/day, IV). RESULTS: The overall success rate was 61% with CS and 49% with PIP-TAZO (p =0.247). Factors affecting the treatment success included a neutrophil count <100/mm3, being in the relapse/refractory stage of malignancy, and the presence of a microbiologically documented infection (p <0.05). CONCLUSIONS: PIP-TAZO and CS monotherapies are equally effective and safe for the empirical treatment of febrile neutropenic patients.

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.

Beta-2 microglobulin predicts the outcome after autologous stem cell transplantation in non-Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is an established therapeutic modality in the treatment of lymphomas, especially in the relapse setting. In the present study, we aimed to define pretransplantation factors including Beta-2 microglobulin (ß2m) that influence outcomes following ASCT in patients with non-Hodgkin lymphoma (NHL). We analyzed retrospectively 78 NHL patients who had undergone ASCT from August 2010 to January 2013. The 2-year overall survival (OS) was 70% and the progression-free survival (PFS) was 60%. While remission status less than complete remission (CR) emerged to be a poor prognostic factor for OS in univariate analysis, high ß2m levels and comorbidity indices revealed to be independent poor risk factors for both OS and PFS. The present study demonstrated that even if the patient is in CR before ASCT if he has high ß2m, the 2-year OS decreases from 100% to 49%. Moreover, lymphopenia for the first time was demonstrated to predict PFS in ASCT in NHL patients. Our findings suggest that ß2m at transplantation predict the outcome after ASCT in NHL and further investigation with larger sample sizes is warranted.

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.