Haluk Demiroglu

Risk Factor Assessment and Prognosis of Eye Involvement in Behçet's Disease in Turkey

BACKGROUND Behcets disease (BD) shows great regional differences in clinical manifestations and prognosis, including eye involvement. Thus, it is hard to predict in which patient the eyes will be involved and what the outcome will be. In this study we assessed various risk factors for eye involvement and attempted to predict the visual outcome in our patient population in Turkey. METHODS Data from a total of 224 patients with BD, diagnosed between 1982 and 1996, were analyzed retrospectively. A detailed physical examination and ophthalmologic work up were performed on each patient. Factors that might contribute to eye involvement were investigated, after which prognostic factors for vision were evaluated. RESULTS Eighty-eight patients had eye involvement during a median follow-up of 32 months. The risk of involvement was highest within the first year of diagnosis. Young age was the most significant factor for eye involvement (P < 0.0001), but vascular thrombosis, central nervous system (CNS) involvement, and male gender were other risk factors (P < 0.001; P < 0.01; and P < 0.05, respectively). The most important determinant for the prognosis of vision was CNS involvement (P < 0.0001). Vascular thrombosis and an age of < or = 32 were other risk factors for visual impairment (P < 0.001 and P < 0.05, respectively). The risk of eye involvement and prognosis for vision were similar with different treatment regimens (P > 0.05). CONCLUSION It is suggested that the first 2 years after diagnosis is the most critical period for eye involvement, and conventional forms of therapy generally are unsuccessful in preventing such involvement. It seems reasonable to treat patients who are at increased risk for eye involvement more aggressively, especially within the first 2 years of disease onset.

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial

BACKGROUND Sight-threatening eye involvement is a serious complication of Behçets disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. METHODS Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. FINDINGS Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. INTERPRETATION Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçets disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

ERYTHROCYTE AGGREGABILITY IN PATIENTS WITH CORONARY HEART DISEASE

Erythrocyte aggregation (EA) rates were measured at stasis (M) and at 3 sec- 1 (Ml) in four groups: healthy controls (HC) and three groups of coronary heart disease (CHD); stable angina pectoris (SAP), unstable angina pectoris (USAP) and post myocardial infarction (PostMI) patients. All CHD patients had similar risk factors. EA values were significantly higher. at M and M1 in USAP and PostMI groups than HC and SAP (p O.05). Since EA is higher in more severe forms of CHD (USAP and PostMI) and atherosclerosis is more common in men than women before menopause, it is possible that EA might play a role in the development of especially severe forms of CHD.

Bone marrow fibrosis may be an effective independent predictor of the ‘TKI drug response level’ in chronic myeloid leukemia

Abstract Objectives The aim of this study was to assess bone marrow (BM) fibrosis and dysplasia in chronic myeloid leukemia (CML) patients receiving the first-generation tyrosine kinase inhibitor (TKI), imatinib, or second-generation TKIs, dasatinib, and nilotinib. We further investigated whether CML under TKI is associated with dysplastic BM changes during the clinicopathological course of the disease. Methods In total, pre-treatment BM paraffin blocks of biopsy specimens were available for 41 adult patients diagnosed with chronic phase CML. Post-treatment BM aspirate clot and core biopsy samples were reviewed for fibrosis and dyshematopoiesis. Results Overall, 13 (31.7%) patients achieved a complete cytogenetic response with imatinib treatment, with no events. In 25 patients, imatinib was discontinued owing to primary or secondary resistance. In patients with initial dysmyelopoiesis, the rate of BM fibrosis was 82.4 versus 47.6% for other patient groups (P = 0.02). Overall, 24 patients with newly diagnosed CML showed marrow fibrosis, among which 19 (79.1%) had imatinib resistance. However, only 5 out of 15 patients (33.5%) without marrow fibrosis had imatinib resistance (P = 0.08). Discussion Our findings indicate that BM fibrosis is an independent predictor of the ‘TKI drug response level’ in CML and support its inclusion as a critical pathobiological parameter for decision-making with regard to TKI drug selection de novo, calculation of prognosis at the onset of disease, and monitoring response to TKI in the long-term disease course of CML.

Ocular relapse in acute myeloid leukemia (M4) with normal bone marrow

A patient with the rare occurrence of ocular relapse of acute myeloid leukemia (AML) M4 while the bone marrow was normal is reported in this paper. A 47-year-old woman with AML was treated with chemotherapy and went successfully into remission. Four months later, she presented with pain, redness, and a mass over the left eye. The ocular relapse involved the subconjunctival space and anterior chamber of the left eye and, presumably, the left lacrimal gland. There were also multiple subcutaneous nodules on both of her forearms. Incisional biopsy from the subconjunctival lesion was performed. Histopathological examination of the specimen showed diffuse blast cell infiltration. Her bone marrow was still in remission. Although exceedingly rare, ocular extramedullary relapse in AML M4 heralds bone marrow recurrence and, despite intensive chemotherapy, the prognosis is dismal.

Clinical and pathological correlations of marrow PUMA and P53 expressions in myelodysplastic syndromes.

p53 is a key regulator of apoptosis. p53 upregulated modulator of apoptosis (PUMA) is a critical mediator of p53‐dependent and independent apoptosis. The objective of this study was to evaluate the relationship of p53 and PUMA to the prognosis of MDS. Bone marrow biopsies of MDS patients at the time of diagnosis (n = 76) and at the time of transformation (n = 19) were included in the study group. The expression of p53 and PUMA was evaluated using immunohistochemistry. When compared to the control group, both p53 (p < 0.001) and PUMA (p = 0.012) expression levels were significantly higher in MDS group. In MDS group, there was a moderate positive correlation between p53 and PUMA expressions. PUMA expression was not correlated with event free and overall survival. However, overall survival was significantly lower in cases with p53 expression in more than 50% of the cells. There was an increase in PUMA expression in cases that showed transformation as compared to the initial diagnostic bone marrows but was not statistically significant. The correlation that existed between p53 and PUMA was lost in transformed cases. Our results showed that PUMA and p53 expressions are increased in MDS marrows compared to normal marrows. PUMA expression increases further during transformation while the expression of p53 is not significantly altered which suggests that PUMA alterations might be a late event during the evolution of MDS.

Ovarian relapse and cutaneous involvement in a case of acute lymphoblastic leukaemia.

Haluk Demiroğlu, Hacettepe Universitesi Tip Fakültesi, Hematoloji Departmant, TR-06100 Ankara (Turkey) A case of acute lymphoblastic leukaemia (ALL) presenting with an intraspinal mass was described by Hwang et al. [1] in this journal, thus adding another unusual extrame-dullary (EM) site of relapse in this disease. We report an ALL patient with an isolated ovarian relapse and cutaneous involvement. A 27year-old woman was hospitalized for weight loss, pallor, fatigue, anemia and hepatosplenomegaly in May 1991. After peripheral blood smear and bone marrow examination, ALL was diagnosed. Immu-nophenotyping was positive with CD20, CD10 and HLA-DR (pre-B cell ALL). She achieved complete remission with chemotherapy and then central nervous system (CNS) prophylaxis was applied with radiotherapy. In July 1992, after a 13-month remission, she was re-admitted to hospital with lower abdominal pain and swelling. Abdominal ultrasonography revealed a right ovarian mass and free ascites. Laparatomy and oophorectomy were performed. On pathological examination, the ovary and peritoneum were infiltrated with blasts; at the same time, the bone marrow was in remission. Her complaints subsided with systemic chemotherapy. Four months later, a 6 × 4 cm fixed tumoral mass appeared in the left pre-tibial region, infiltrating the cutaneous and subcutaneous tissues. An excision biopsy was performed, and pathological examination showed that the lesion was also infiltrated with blasts. Immunophenotyping revealed that these cells had the same surface markers as the original clone. This time too, the bone marrow was in remission. Systemic chemotherapy and local radiotherapy were applied and the mass disappeared gradually. Two months later, the patient had a CNS relapse, again without bone marrow involvement, and died within 2 weeks. Ovarian involvement in ALL is usually occult although it is detected in 3.2-36% of the cases at autopsy [2]. Cutaneous involvement is rare and is found in only 6% of the patients, including autopsy series [3]. Isolated EM relapse is unusual [4]. In such a condition, it is recommended to give systemic chemotherapy in addition to local therapy. In ALL, this kind of relapse usually occurs in ‘sanctuary sites’ like the testes and CNS [5]. Isolated ovarian relapse is an extraordinary finding and is reported in the literature as single case reports [2]. Skin involvement in ALL usually occurs when bone marrow and peripheral blood are full of blasts, and the

Chimeric antigen receptor T cell treatment in hematologic malignancies.

Adoptive transfer of T cells that have genetically engineered chimeric antigen receptors (CARs) is an encouraging treatment modality in the hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens. There are a variety of reported, as well as ongoing studies on the utilization of CAR-T cells in the treatment of leukemia, myeloma, as well as B and T cell lymphomas. In this review, we aimed to highlight current understanding of this promising treatment modality, including its efficacy and adverse effects.

Rebound Thrombocytosis following Induction Chemotherapy is an Independent Predictor of a Good Prognosis in Acute Myeloid Leukemia Patients Attaining First Complete Remission.

There are very few data about the relationship between acute myeloid leukemia (AML) prognosis and bone marrow recovery kinetics following chemotherapy. In this study, we aimed to assess the prognostic importance and clinical associations of neutrophil and platelet recovery rates and rebound thrombocytosis (RT) or neutrophilia (RN) in the postchemotherapy period for newly diagnosed AML patients. De novo AML patients diagnosed between October 2002 and December 2013 were evaluated retrospectively. One hundred patients were suitable for inclusion. Cox regression analysis using need for reinduction chemotherapy as a stratification parameter revealed RT as the only parameter predictive of OS, with borderline statistical significance (p = 0.06, OR = 7; 95% CI 0.92-53), and it was the only parameter predictive of DFS (p = 0.024, OR = 10; 95% CI 1.3-75). In order to understand whether RT or RN was related to a better marrow capacity or late consolidation, we considered neutrophil recovery time and platelet recovery time and nadir-first consolidation durations in all patients in the cohort. Both the marrow recovery duration and the time between marrow aplasia and first consolidation were shorter in RT and RN patients. To our knowledge, this is the first study to report a correlation between RT/RN and prognosis in AML.

Vascular Thrombotic Problems in Behçet’s Disease

Halûk Demiroğlu, MD, Hosdere Cad. 80/19, Yukarι Ayranci, TR-06550 Ankara (Turkey), Tel. 312 4683576, fax 312 3114246, eMail demir@umich.edu We have read with great interest the case report by Sanchez-Burson et al. [1] on Behçet’s disease (BD) with deep vein thrombosis (DVT) and subsequent pulmonary embolism. They describe a 46-year-old female patient with a 6-month history of BD. She had uveitis and was being treated with corticoste-roids and thalidomide at the time of vascular complications. Although anticoagulant therapy was begun, she had recurrent DVT and pulmonary embolism within a week. That time she was treated successfully with the thrombolytic agent urokinase and at the end of the 2 years of therapy, she was free of thrombotic attacks. In a recent study, we have evaluated 224 patients with BD of which 36 had DVT of various systems [2]. The first 2 years of the disease were the most critical period for DVT. Other risk factors were an age < 30 years and the presence of ocular involvement [3]. Pulmonary arterial thrombotic complications generally occur in the presence of DVT of the calf veins and isolated involvement of the pulmonary artery is rare. In a previous retrospective study during 1968-1988, 3 patients with pulmonary arterial occlusion were reported from our institute [4]. These patients were symptomatic with chest pain and dyspnoea. Diagnosis was confirmed by angiographic examinations. Actually, thrombotic disease of the pulmonary arteries is much higher than expected as evidenced by abnormalities on perfusion scintigraphy, computed tomography scan and angiographic investigations in asymptomatic BD patients [5]. The main problem in BD is to prevent recurrent serious complications – such as vascular thrombotic disease and ocular involvement and their recurrences. It is hard to say that, with thrombolytic therapy, recurrences of DVT might be prevented. The course of BD is unpredictable and the disease generally leads a course with exacerbations and remissions. Not all patients with DVT are as lucky as the patient presented by Sanchez-Burson et al. [1]. In a large proportion of patients, BD runs a mild to moderate course, where conventional forms of therapy such as colchicine and thalidomide may control mucocutaneous and articular symptoms [6, 7]. However, these conventional drugs and corticosteroids have very little if any effect on the course of vascular thrombotic complications. In recent years, alpha-inter-feron (α-IFN) has been gaining popularity in the treatment of BD especially in severe forms of the disease with vascular and ocular complications. We have tried α-IFN in patients with vascular and ocular complications