Dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in older patients with high-risk aggressive diffuse large B-cell lymphoma: A real-life multicenter study by the Croatian Cooperative Group for Hematologic diseases (KroHem).

PURPOSE: Dose-adjusted EPOCH and rituximab (DA-EPOCH-R) is a regimen used for the treatment of high-risk diffuse large B-cell lymphoma (DLBCL) designed to overcome resistance to standard R-CHOP by combining prolonged exposure of lymphoma cells to cytotoxic agents and dose-adjustment based on toxicity. Data on outcomes of older patients are scarce. PATIENTS AND METHODS: We collected data on patients with newly diagnosed high-risk DLBCL older than 60 years treated with DA-EPOCH-R. High-risk patients were defined by the age-adjusted international prognostic index score 2 or 3. RESULTS: A total of 120 patients were included. Median age was 69 years (range 60-82). Response rate was 74%; with 59% complete responses. Dose of DA-EPOCH-R was escalated in 50 patients (42%). Three-year progression-free survival (PFS) and overall survival (OS) was 53% and 58%, respectively, with treatment-related mortality (TRM) of 13%. In univariate analysis, favorable prognostic factors were performance status (PS) (0-2 vs. 3-4), age (<70 vs. ≥70 years), and center. In multivariate analysis, PS and center retained prognostic significance. Patients with PS 0-2 had 3-year PFS and OS of 58% and 64%, respectively, with TRM of 6%. CONCLUSION: DA-EPOCH-R is efficacious in sufficiently fit older high-risk DLBCL patients. Patients with poor PS have unacceptable toxicity and require less intensive therapy.

Psoas muscle index at the time of diagnosis might reflect the prognosis of classical Hodgkin's lymphoma patients.

We retrospectively investigated clinical and prognostic significance of psoas muscle index (PMI) calculated as total psoas muscle area at L3 vertebra level obtained from baseline computed tomography (CT) scans in 49 newly diagnosed classical Hodgkin's lymphoma (cHL) patients prior to specific treatment. Median PMI was 572.5 mm2/m2 and was significantly higher in males (P < 0.001), patients with higher body mass index (BMI, P < 0.001), absence of extranodal disease (P = 0.037), higher absolute lymphocyte count (P = 0.037), higher hemoglobin (P = 0.010) and lower lactate dehydrogenase (LDH, P = 0.050). There were no significant associations with age, disease subtype, presence of constitutional symptoms, Ann Arbor disease stage, presence of advanced disease or international prognostic score. Patients with lower PMI had significantly worse PFS (hazard ratio [HR] 4.91; P = 0.009). This phenomenon persisted in the multivariate model (HR = 5.09; P = 0.042) adjusted for International Prognostic Score (IPS) and chemotherapy type.

Prolonged methylprednisolone premedication prior to obinutuzumab in patients with chronic lymphocytic leukemia.

First obinutuzumab application is associated with infusion related reactions (IRRs) that may discourage further continuation of the drug. During our clinical practice we have observed that chronic lymphocytic leukemia (CLL) patients with autoimmune hemolytic anemia (AIHA) prolongedly receiving corticosteroids do not develop obinutuzumab IRRs. Therefore, we decided to apply prolonged corticosteroid premedication with methylprednisolone in dose 1-1.5 mg/kg for ≥7 days to all further obinutuzumab candidates. Here we present non-randomized comparison of 28 consecutive previously untreated CLL patients receiving prolonged corticosteroid premedication (15 patients) or standard premedication (13 patients) prior to the first obinutuzumab infusion. Prolonged corticosteroid premedication resulted in significant reduction of all-grade (20% vs 61.5%; p = .025) and grade III (0% vs 23.1%; p = .049) obinutuzumab IRRs. Prolonged corticosteroid premedication did not significantly affect occurrence of infective complications. Patients with CLL and AIHA receiving obinutuzumab showed continuous and stable increase in hemoglobin levels concomitantly with decrease in parameters of hemolysis.

Prognostic implications of low transferrin saturation in patients with primary myelofibrosis.

OBJECTIVES: Transferrin saturation (TSAT) 20% or less is considered to represent functional iron deficiency in the context of malignant disease, phenomenon mediated through inflammatory changes of iron homeostasis. We aimed to investigate clinical and prognostic significance of low TSAT in patients with primary (PMF) and secondary myelofibrosis (SMF), malignant diseases characterized by strong inflammatory milieu. METHODS: We retrospectively analyzed 87 patients with myelofibrosis and compared TSAT with disease specific parameters. RESULTS: One-third of patients had TSAT ≤20%. Lower TSAT was significantly associated with Janus-kinase-2 (JAK2) mutation (P = 0.007), transfusion independency (P = 0.003), higher platelets (P = 0.004), lower mean-corpuscular-volume (P < 0.001), lower ferritin (P < 0.001), higher absolute-neutrophil-count (P = 0.027), lower absolute-lymphocyte-count (P = 0.041) and lower albumin (P = 0.018). PMF patients presenting with low TSAT (≤20%) experienced significantly shorter overall-survival (OS) (HR = 2.43; P = 0.017), whereas TSAT did not affect OS of SMF patients (HR = 1.48; P = 0.623). Low TSAT remained significantly associated with inferior OS in PMF in a series of multivariate Cox regression models comparing its properties to anemia, transfusion dependency, ferritin and Dynamic-International-Prognostic-System (DIPSS). CONCLUSIONS: Low TSAT has detrimental effect on survival of PMF patients. This effect is independent of anemia and of ferritin levels that seem to be better at representing iron overload in PMF patients.

Increased mean platelet volume (MPV) is an independent predictor of inferior survival in patients with primary and secondary myelofibrosis.

Neoplastic megakaryopoiesis is a dominant feature of Philadelphia-chromosome-negative myeloproliferative neoplasms (Ph- MPNs), and elevated mean-platelet-volume (MPV) is a common finding in these diseases. The clinical and prognostic significances of MPV in patients with primary (PMF) and secondary myelofibrosis (SMF) have not been reported. We retrospectively analyzed 87 patients with myelofibrosis (66 with PMF, 21 with SMF) treated at our institution. MPV was recorded in addition to other hematological and clinical parameters. MPV was elevated in both PMF and SMF patients in comparison to controls, whereas there was no statistically significant difference between PMF and SMF. Elevated MPV was associated with lower platelets (P = 0.016), higher white blood cells (P = 0.015), higher percentage of circulatory blasts (P = 0.009), higher lactate dehydrogenase (P = 0.011), larger spleen size (P = 0.014) and higher Dynamic International Prognostic score category (P = 0.027), while there was no statistically significant association with driver mutations or degree of bone marrow fibrosis. Higher MPV was univariately associated with inferior overall survival in the whole cohort (HR = 3.82, P = 0.006), PMF (HR = 4.35, P = 0.007) and SMF patients (HR = 7.22, P = 0.034). These associations remained significant in multivariate analyses adjusted for DIPSS. Higher MPV is associated with more aggressive disease features and exhibits powerful independent prognostic properties in both PMF and SMF settings.

Rituximab with dose-adjusted EPOCH as first-line treatment in patients with highly aggressive diffuse large B-cell lymphoma and autologous stem cell transplantation in selected patients.

AIM: To assess the benefit of rituximab with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-DA-EPOCH) regimen as a first-line treatment for patients with diffuse large B-cell lymphoma (DLBCL) presenting with unfavorable or aggressive features, and autologous stem cell transplantation (ASCT) as a part of the first-line treatment for selected DLBCL patients with additional aggressive features. METHODS: We retrospectively analyzed 75 newly diagnosed DLBCL patients with Ki-67+≥80% or International Prognostic Index ≥2 who were treated with R-DA-EPOCH between 2005 and 2015. Of 24 DLBCL patients with additional aggressive features (Ki-67+≥90% or age-adjusted IPI≥2) who were planned to receive consolidation with ASCT, 17 patients underwent the procedure. We determined the overall response rate (ORR), complete remission (CR), partial remission (PR), 5-year overall survival (OS), and progression free survival (PFS) in all DLBCL patients and specifically those planned to receive ASCT. RESULTS: All 75 patients included in the analysis started one or more cycles of therapy. The ORR, CR, and PR rates were 80%, 55%, and 25%, respectively. The response was non-evaluable in 10 of 75 patients due to treatment discontinuation. The OS and PFS rates for all 75 patients were 70% and 61%, respectively, and 80% and 79%, respectively, for 24 planned-to-receive-ASCT patients. Age (≤65 vs >65 years) had no prognostic impact on OS and PFS (P=0.994 and P=0.827, respectively). CONCLUSION: Our retrospective analysis of one of the largest DLBCL patient cohorts outside the US National Cancer Institute showed that R-DA-EPOCH is a very effective therapeutic option as a first-line treatment of DLBCL patients with unfavorable prognostic features irrespective of their age. ASCT provided additional benefit for DLBCL patients with additional aggressive features.

Canonical Wnt/ß-Catenin Signaling Pathway Is Dysregulated in Patients With Primary and Secondary Myelofibrosis.

INTRODUCTION: ß-Catenin is a central effector molecule of the canonical wingless-related integration site (Wnt) signaling pathway. It is important for maintenance of stem cell homeostasis and its aberrant activation has been implicated in a wide array of malignant hematological disorders. There are few reports suggesting its dysregulation in Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs). PATIENTS AND METHODS: We analyzed ß-catenin mRNA expression in bone marrow (BM) aspirates of 29 patients with primary (PMF) and 4 patients with secondary, post Ph- MPN, myelofibrosis (SMF) using quantitative real-time polymerase chain reaction (qRT PCR). The control group consisted of 16 BM aspirates from patients with limited-stage aggressive non-Hodgkin lymphoma without BM involvement. We compared relative gene expression with clinical and hematological parameters. RESULTS: Relative expression of ß-catenin differed significantly among groups (P = .0002), it was significantly higher in patients with PMF and SMF than in the control group, but did not differ between patients with PMF and SMF. A negative correlation was found regarding hemoglobin level in PMF (P = .017). No association according to Janus kinase 2 (JAK2) V617F mutational status or JAK2 V617F allele burden was detected. CONCLUSION: Our results show for the first time that ß-catenin mRNA expression is increased in patients with PMF and SMF and its upregulation might potentiate anemia. A number of inflammatory cytokines associated with PMF are capable of mediating their effects through increased ß-catenin expression. Accordingly, ß-catenin can induce expression of a number of genes implicated in processes of cell cycle control, fibrosis, and angiogenesis, which are central to the PMF pathogenesis. Therefore, ß-catenin might represent an interesting new therapeutic target in these diseases.

Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome.

OBJECTIVES: The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in MDS. METHODS: Thirty six newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene. RESULTS: Mutations were present in 11 out of 36 patients (31%), which were not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (P = 0.039) and lower TIBC (P = 0.018). Ferritin was found to be higher for the untransfused mutated patients (P = 0.017), but not for transfusion-dependent patients in whom ferritin levels correlated significantly with the number of blood units received (P = 0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival in addition to a poorer leukemia free survival (LFS) (P = 0.004 and P = 0.003, respectively). DISCUSSION: The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anemia. The effect of mutations on survival could be mediated by changes in iron metabolism. CONCLUSION: The HFE genotype may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy.

[The use of peripherally inserted central catheter (PICC) in patients with hematological malignancies--a single center experience]. / Upotreba periferno uvedenoga centralnog venskog katetera (picc) u bolesnika sa zlocudnim hematoloskim bolestima--prikaz vlastitih iskustava.

UNLABELLED: AIM. In this study we presented our experience with peripherally inserted central venous catheter (PICC) in patients with hematological malignancies. METHODS: In the period from 2009 to 2012, a total of 105 PICCs were inserted in 90 patients. Patients with Non-Hodgkin lymphoma treated with DA-EPOCH comprised almost 40% of the cohort. RESULTS: The total PICC in-dwell time was 14781 days with a median of 129 days (range 8-570 days). Malposition of the PICC occurred in 12 patients (11.4%) with a successful reposition or re-insertion. In 39 patients (37%) PICC was removed before the end of treatment due to suspected or proven infection (30 patients, 29%; 2.03 per 1000 PICC days), thrombosis associated with PICC in four patients (3.8%), occlusion of the PICC (two patients), misplaced catheter (two patients), and suspected thromboembolism in a single patient. CONCLUSION: PICC is a safe and convenient long-term venous access in patients with hematological malignancies.

Focal myositis of lower extremity responsive to botulinum A toxin.

Focal myositis is a rare, mostly benign disease (pseudotumor) of skeletal muscle, histopathologically characterized by interstitial myositis and tumorous enlargement of a single muscle. The etiology of focal myositis remains unknown; however, localized myopathy has been postulated to be caused by denervation lesions. This case report describes a patient that presented with clinical, laboratory, electromyoneurography, and magnetic resonance imaging features of focal myositis complicated with intervertebral disk protrusion in the lumbosacral spine affected with radicular distress. In most cases, focal myositic lesions show spontaneous regression, relapses are rare, and long-term prognosis is good. There is a wide spectrum of therapeutic options, from no therapy at all through nonsteroidal antirheumatics and glucocorticoids to radiotherapy, surgical excision, and immunosuppressants. In the patient presented, treatment with glucocorticoids, methotrexate, and surgical excision failed to produce satisfactory results. Clinical improvement, pain relief, and reduction in lower leg volume were only achieved by local infiltration of botulinum A toxin.

Diffuse skin hyperpigmentation in CD30+ lymphoproliferation.

CD30+ T-cell lymphoproliferative disorders (LD) comprise two main groups of diseases: CD30+ LD of the skin and systemic anaplastic large cell lymphoma (ALCL). The main feature of these disorders is the expression of CD30. We present a patient with an unusual clinical presentation of CD30+ lymphoproliferative disease in a 54-year old Caucasian male who presented with generalized lymphadenopathy and pronounced skin hyperpigmentation. In the lymph nodes and skin, CD30+ lymphoproliferation (ALCL) was diagnosed. The Prussian blue staining identified that the pigment responsible for the skin color was hemosiderin. Chemotherapy was started but the patient's condition progressively worsened and he died a week after the first cycle. The complete color transformation of the entire skin due to hemosiderin accumulation is, to the best of our knowledge, the first reported observation in a CD30+ lymphoproliferation/ALCL patient. We speculate that hemosiderin-loaded macrophages resulted from the paraneoplastic process by some still unknown mechanism.

Carotid endarterectomy unexpectedly resulted in optimal blood pressure control.

Resistant hypertension is defined as hypertension that remains above 140/90 mmHg despite the provision of three or more antihypertensive drugs in a rational combination at full doses and including a diuretic. It is associated with adverse clinical outcome and therefore requires aggressive medical treatment. We present a case of 70-year-old woman who was treated for resistant hypertension with a diuretic, ACE-inhibitor, calcium channel blocker, and with centrally acting antihypertensive, moxonodine. Despite of aggressive medical treatment her blood pressure remained above 160/90 mmHg continuously. Large diagnostic workup excluded common causes of secondary hypertension, but revealed significant carotid stenosis present on left internal carotid artery. Carotid endarterectomy was performed in order to improve cerebrovascular prognosis, but unexpectedly resulted in optimal control of her blood pressure. Two months after operation patient was on only one antihypertensive drug, having blood pressure below 130/85 mmHg. We suggest that in selected patients resistant hypertension could be associated with carotid stenosis and carotid sinus baroreceptor dysfunction. For definite conclusions further studies are warranted.

Medical students' clinical skills do not match their teachers' expectations: survey at Zagreb University School of Medicine, Croatia.

AIM: To evaluate self-assessed level of clinical skills of graduating medical students at Zagreb University School of Medicine and compare them with clinical skill levels expected by their teachers and those defined by a criterion standard. METHOD: The study included all medical students (n=252) graduating from the Zagreb University School of Medicine in the 2004-2005 academic year and faculty members (n=129) involved in teaching clinical skills. The participants completed anonymous questionnaire listing 99 clinical skills divided into nine groups. Students were asked to assess their clinical skills on a 0-5 scale, and faculty members were asked to assess the minimum necessary level of clinical skills expected from graduating medical students, using the same 0-5 scale. We compared the assessment scores of faculty members with students' self-assessment scores. Participants were grouped according to their descriptive characteristics for further comparison. RESULTS: The response rate was 91% for students and 70% for faculty members. Students' self-assessment scores in all nine groups of clinical skills ranged from 2.2-/+0.8 to 3.8-/+0.5 and were lower than those defined by the criterion standard (3.0-4.0) and those expected by teachers (from 3.1-/+1.0 to 4.4-/+0.5) (P<0.001 for all). Students who had additional clinical skills training had higher scores in all groups of skills, ranging from 2.6-/+0.9 to 4.0-/+0.5 (P<0.001 for all). Male students had higher scores than female students in emergency (P<0.001), neurology (P=0.017), ear, nose, and throat (P=0.002), urology (P=0.003), and surgery skills (P=0.002). Teachers' expectations did not vary according to their sex, academic position, or specialty. CONCLUSION: Students' self-assessed level of clinical skills was lower than that expected by their teachers. Education during clinical rotations is not focused on acquiring clinical skills, and additional clinical skills' training has a positive influence on students' self-assessed level of clinical skills. There was no consensus among teachers on the required level of students' clinical skills.