Guner Hayri Ozsan

Plasma levels of free tissue factor pathway inhibitor in patients with various thyroid disorders

Various coagulation abnormalities occur in thyroid disorders and its range may vary from subclinical laboratory abnormalities to clinically significant disorders of coagulation. Tissue factor pathway inhibitor (TFPI), which inhibits the initial reaction of tissue factor mediated coagulation pathway, is reported to be increased in patients with Graves disease (GD) in one study. Hyperthyroid (n=10), hypothyroid (n=10) and subclinical hypothyroid (n=10) patients and control cases (n=16) were evaluated for free and total tissue factor pathway inhibitor (tTFPI), plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) levels in disease and euthyroid states. Free TFPI levels were significantly higher in hyperthyroid patients compared with the control group and subclinic hypothyroid patients (p<0.001), but not with hypothyroid patients (p>0.05). After the euthyroid state was obtained in the hyperthyroid group, the levels of total TFPI (p<0.05), free TFPI (fTFPI) (p<0.005), t-PA (p<0.005) and PAI-1 (p<0.02) decreased significantly. In hyperthyroid patients, there was a strong correlation between thyroid functions and free TFPI levels. In conclusion, we hypothesize that coagulation abnormalities seen in thyroid disorders cannot be explained directly with the impaired fibrinolytic activity but also with the elevated fTFPI levels. Both increased plasma fTFPI and PAI-1 levels could be markers of the peripheral activity of thyroid hormones.

Prognostic significance of immunohistochemical classification of diffuse large B-cell lymphoma

Abstract Aim: To evaluate the clinical significance of immunoperoxidase staining for CD10, bcl-6, mum-1 and bcl-2 to subdivide DLBCL into prognostic subgroups, we analysed 50 DLBCL cases using immunohistochemical methods. Methods and results: Fifty DLBCL patients were evaluated retrospectively. The expression of CD10 was associated with better OS (p=0·04) whereas expression of mum-1 was associated with worse OS (p=0·009). There were no significance of OS in case of expression of bcl-6 (p=0·05) and bcl-2 (p=0·3). They were subclassified using CD10, mum-1, bcl-6 as germinal center B-cell like (GCB) lymphoma (30%) and non-GCB lymphoma (70%). The OS and EFS (event free survival) were longer in GCB group (p=0·002) and 5-year OS for GCB group was 92% compared with only 44% for the non-GCB group (p=0·02). The OS of the GCB group also was longer compared to that of the non-GCB group in low IPI subgroup (p=0·01). Conclusion: The existance of survival differences between GCB a non-GCB group also in the patients with low IPI score, showed the importance of prognostic classification in the risk-adaptive treatment approaches. The classification as GCB and non-GCB based immunostains may enable to define more accurate prognostic groups in DLBCL.

Hematopoietic recovery kinetics predicts for poor CD34+ cell mobilization after cyclophosphamide chemotherapy in multiple myeloma†

Autologous stem cell transplantation is an important part of therapy in patients with multiple myeloma. Some patients fail to collect the desired number of stem cells while others require multiple apheresis to reach the desired apheresis target. The aim of this study was to determine the predictive factors and if the hematopoietic kinetics of recovery were predictive for outcome of stem cell mobilization in cyclophosphamide + growth factor (CY‐GF) mobilized patients. Three hundred and ninety six consecutive CY‐GF mobilization attempts between January 2000 and December 2009 at Mayo Clinic, Rochester, MN were analyzed. Patients were divided into three groups: optimal (>5 × 106 CD34/kg), suboptimal (2–5 × 106 CD34/kg) and poor (<2 × 106/kg CD34+ cells) mobilization groups. About 86% of patients had optimal stem cell collection, whereas 8% had suboptimal collection and 6% had poor (or failed) collections. Age, Hb, WBC, and platelet levels had an impact on mobilization results. Time to peripheral blood (PB) CD34+cells >10/μL predicted for efficiency of collection and the interval between recovery of WBC>1 post‐CY to PB CD34+ cells>10 was shorter in the optimal collection groups. These findings suggest that for patients with a PB CD34+ cell count below 10/μL on Day 13 following CY or 1 day after the WBC>1 × 109/L, addition of plerixafor may be helpful to salvage the mobilization attempt. Am. J. Hematol., 2012.

Nilotinib Does Not Alter the Secretory Functions of Carotid Artery Endothelial Cells in a Prothrombotic or Antithrombotic Fashion

Background: There have been concerns about the possible prothrombotic effects of nilotinib, especially in patients having cardiovascular risk factors. The potential mechanism behind the increased risk of thromboembolic events is still not clear. Objectives: In this study, we aimed to evaluate possible harmful effects of nilotinib on endothelial cells. To this aim, we examined proliferative capacity and secretory functions of healthy human carotid artery endothelial cells (HCtAECs) in response to nilotinib. Methods: 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation method was used to determine antiproliferative effects of nilotinib on HCtAECs. The HCtAECs were incubated with 5, 10, and 100 nmol/L doses of nilotinib for 72 hours. Then, in order to assess the endothelial function, levels of nitric oxide (NO), von Willebrand factor (vWF), tissue plasminogen activator, plasminogen activator inhibitor 1 (PAI-1), and endothelin 1 (ET-1) were evaluated using enzyme-linked immunosorbent assay from tissue culture supernatants. Results: There were slight but statistically significant decreases in cell proliferation in response to nilotinib. Nilotinib increased the secretion of t-PA, PAI-1, and vWF in a dose-dependent manner when compared with the untreated control group. The ET-1 secretion was lower in 5 nmol/L and higher in 10 and 100 nmol/L nilotinib-treated cells as compared to untreated cells. Regarding NO secretion, lower levels were observed in 5 and 10 nmol/L, and higher levels were detected in 100 nmol/L nilotinib-treated cells as compared to untreated control group cells. Conclusion: Considering the results obtained in our study, nilotinib does not affect the functions of endothelial cells either in a prothrombotic or an antithrombotic fashion, despite a dose-dependent decline in cell viability.

Fatal disseminated mucormycosis in a patient with mantle cell non-hodgkin's lymphoma: an autopsy case

A patient with mantle cell non-Hodgkins lymphoma presented herself with fever, nausea, right upper quadrant pain on the 7th day of R-CHOP chemotherapy. After hospitalization with the suspicion of acute cholecystitis, she received antibiotherapy with G-CSF because of emerging neutropenia at the 10th day of chemotherapy. Abdominal computed tomography revealed small infarcts in the spleen and kidneys. The ecchymotic lesion which developed on her right lateral malleolus, became bullous in the following days and treated as ecthyma gangrenosum. Although the patient was afebrile with a normal neutrophil count on the third day of antibiotherapy, she developed acute renal failure and deteriorated rapidly. The patient underwent hemodialysis but expired on the 10th day of hospitalization. Post mortem autopsy findings showed ischemic infarction and necrosis of parenchyma due to mycotic thrombosis of arteries and veins of many organs (heart, lung, diaphragm, kidneys, spleen, gut mucosa) as well as invasion of vessel walls and parenchyma by mucor. We reviewed mucormycosis in the light of this case.

Is the BFM Regimen Feasible for the Treatment of Adult Acute Lymphoblastic Leukemia? A Retrospective Analysis of the Outcomes of BFM and Hyper-CVAD Chemotherapy in Two Centers

Multiple induction regimens have been developed for adult patients with acute lymphoblastic leukemia (ALL). However, there have been no prospective randomized trials that directly compare these regimens. In this study, we wanted to evaluate the outcome of 50 adult ALL patients treated with BFM (i.e. Berlin-Frankfurt-Munster, n = 20) and hyper-CVAD (n = 30) protocols between March 2006 and October 2012. The median age was 25 years in the BFM group and 30.5 years in the hyper-CVAD group with a male/female ratio of 15:5 and 17:13, respectively. Forty-five percent of the patients in the BFM group and 30.3% in the hyper-CVAD group were <25 years old. The majority of cases were B cell in origin (80% in the BFM group and 70% in the hyper-CVAD group). Complete remission after induction therapy was achieved in 95 and 96% of the patients, respectively. The median follow-up time was 37 months. The 5-year survival rate was higher in the BFM group than in the hyper-CVAD group (59 vs. 34%). There were also no complications which could cause a delay during the hyper-CVAD regimen. Both chemotherapies were well tolerated. None of the patients died from drug-related toxicity. Only mild liver enzyme elevations were seen as toxicity in the BFM group; these did not cause any delay in therapy. The BFM regimen seems to be feasible for adult patients with ALL in terms of tolerability and efficacy, especially in young adults.

Renal and neurological response with eculizumab in a patient with transplant associated thrombotic microangiopathy after allogeneic hematopoietic progenitor cell transplantation.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenge after allogeneic hematopoietic progenitor cell transplantation, considering the diagnostic uncertainties and lack of established treatment. We report a 43-year-old male patient who was diagnosed as TA-TMA after allogeneic progenitor cell transplantation for a progressive ALK negative anaplastic large cell lymphoma and responded to eculizumab with dramatically improving neurological status and renal function. Rapid neurological and renal recovery achieved after eculizumab could support a possible relationship between complement activation and TA-TMA. Eculizumab should be a reasonable treatment approach in patients with TA-TMA after allogeneic hematopoietic progenitor cell transplantation.

Ischemic stroke after recombinant factor VIIa treatment in acquired hemophilia A patient.

Acquired hemophilia is a rare, life-threatening coagulopathy in adults caused by the development of autoantibodies against factor VIII. Bypass agents such as recombinant factor VIIa (rFVIIa) are usually preferred for bleeding control; however, thromboembolic complications may occur. We report here a case that presented with extensive cutaneous and mucosal bleedings due to factor VIII inhibitors and was treated successfully with rFVIIa and steroid therapy, but was complicated with a life-threatening thromboembolic attack during follow-up.

Bortezomib-Induced Skin Lesion

Bortezomib treatment was initiated in a 79-year-old female patient due to refractory/relapsed multiple myeloma. She had been diagnosed as having a light chain multiple myeloma 2 years ago, and the hemodialysis program was continued because of a myeloma-related renal failure. Bortezomib was administered with a dosage of 1.3 mg/m 2 as an intravenous bolus injection twice weekly for 2 weeks. A dose modification was not made, but the drug was given on the day after dialysis. She was discharged in good health after the last dose for a 10-day rest period. When she was admitted to the hospital for the second treatment cycle, she was complaining of a skin lesion with a diameter of 0.5 ! 0.5 cm, covering a black scar, at the right ala of the nose ( fig. 1 ). The first dose of bortezomib was given during a skin biopsy. The biopsy specimen of the lesion revealed a superficial perivascular and interface dermatitis that was compatible with drug eruption ( fig. 2 ). She had been taking the same drugs (erythropoietin 15,000 IU/week, gabapentin 200 mg/day and digoxin 0.125 mg/day) for the past 2 months except bortezomib. The second dose was postponed. Two weeks later the lesion had disappeared and the treatment was initiated again. Because the new drug in the treatment regimen was clearly bortezomib and the lesion disappeared after postponing the therapy, bortezomib seemed to be responsible for the development of the lesion. Bortezomib (PS-341) was the first proteasome inhibitor to enter clinical trials in cancer patients. It was granted accelerated approval by the FDA for the treatment of advanced myeloma in May 2003 [1] . In the National Cancer Institute cytotoxicity screen, it demonstrated anticancer activity against a broad range of human tumors [2] . Although the exact mechanism by which bortezomib exerts its anticancer effects is currently unknown, evidence suggests that it involves a combination of effects on proapoptotic and antiapoptotic pathways [3] . Proteasome inhibitors restrain the degradation of cell cycle regulatory proteins and regulate cell cycle progression. They can also overcome drug resistance by surmounting NFB activation. In the literature it was shown that bortezomib directly induces the apoptosis of human multiple myeloma cells and abrogates the paracrine growth of myeloma cells in the bone marow via altering cellular interactions and cytokine secretion [4] . The most common adverse effects of bortezomib are gastrointestinal symptoms (diarrhea, nausea, constipation and vomiting) cytopenia, fatigue and peripheral neuropathy [5] . Thrombocytopenia, hypotension, fever, headache, pain and dehydration are other adverse effects found in clinical trials [6, 7] . Because bortezomib is a very new agent, we arefaced with different adverse effects. We present a case having a skin lesion as a side effect of bortezomib. Received: December 22, 2005 Accepted after revision: February 28, 2006

EBV-associated nasal-type T/natural killer cell lymphoma presenting with polyserositis and rhabdomyolysis

Nasal-type T/natural killer (NK)-cell lymphoma, a distinct clinicopathological entity is highly associated with Epstein-Barr virus which shows an aggressive course. We present a CD56+ nasal-type T/(NK)-cell lymphoma case with systemic manifestations of rhabdomyolysis and polyserositis who died of multiorgan failure shortly after his admission to hospital in spite of adequate chemotherapy and supportive care.