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Valganciclovir is an l-valyl ester pro-drug of ganciclovir that was initially used to treat cytomegalovirus (CMV)-associated retinitis in patients with human immunodeficiency virus. Currently, it is also indicated for the prevention of CMV disease in solid-organ transplantation. It is primarily eliminated via the kidneys through glomerular filtration and tubular secretion. Decreased renal function results in decreased drug clearance. Valganciclovir has been reported to cause usually mild to moderate hematologic adverse effects such as leukopenia, neutropenia, anemia, thrombocytopenia, and pancytopenia. Severe and fatal bone marrow depression has been described in 1 adult patient. Herein, we describe the cases of 4 patients with end-stage renal disease who underwent cadaveric renal transplantation and received valganciclovir prophylaxis for CMV at a standard dose of 900 mg/d despite persistant renal failure. This therapy resulted in severe bone marrow failure after 18 to 20 days in all 4 patients, with fatal infections in 2 patients. This report demonstrates the in vivo pharmacodynamics of valganciclovir overdose in terms of hematotoxicity in the setting of renal impairment. Valganciclovir, as its derivative ganciclovir, should be used cautiously in patients with renal impairment.

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AIM: Glucans are glucose polymers that constitute a structural part of fungal cell wall. They can stimulate the innate immunity by activation of monocytes/macrophages. In human studies it has been shown that beta glucan has an immunomodulatory effect and can increase the efficacy of the biological therapies in cancer patients. In this prospective clinical trial we assessed in vivo effects of short term oral beta glucan administration on peripheral blood monocytes and their expression of activation markers in patients with advanced breast cancer. METHODS: 23 female patients with advanced breast cancer were included in the study. Median age of the patients was 52 years. Sixteen healthy females with a median age of 48 years served as the control group for comparing the initial blood samples. Peripheral blood samples were drawn on day zero and patients started receiving oral 1-3, 1-6, D-beta glucan daily. Blood samples were recollected on the 15th day. In the initial samples mean lymphocyte count was significantly lower in the patients with breast cancer (1281+/-306/mm(3) versus 1930+/-573/mm(3), p=0.04). In the patients with breast cancer, mean monocyte count which was 326+124/mm(3) at the beginning, was increased to 496+194/mm(3) at the 15th day (p=0.015). Expression of CD95 (Apo1/Fas) on CD14 positive monocytes was 48.17% at the beginning, which was increased to 69.23 % at the 15th day (p=0.002). Expression of CD45RA on CD14 positive monocytes was 49.9% at the beginning; it was increased significantly to 61.52% on day 15 (p=0.001). CONCLUSION: Oral beta glucan administration seems to stimulate proliferation and activation of peripheral blood monocytes in vivo in patients with advanced breast cancer.

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Among the cutaneous manifestations, nodular lesions are rather common in Behçet syndrome. The histologic nature of these lesions has been a matter of controversy. To establish their distinguishing features, biopsy specimens from nodular lesions of 24 patients with Behçet syndrome, 25 with nodular vasculitis (NV), and 20 with erythema nodosum (EN) were compared. Statistical analysis revealed insignificant differences between most of the histologic features of Behçed syndrome and NV. However, neutrophil-predominating infiltrate in the subcutis was more common in Behçet syndrome, while necrosis and granuloma formation were encountered more frequently in NV. The differences between Behçed syndrome and EN were more significant. Septal panniculitis, lymphocyte-predominating infiltrate, absence of many vascular changes as well as vasculitis, and necrosis were features in favor of EN. Nodular lesions of Behçet syndrome are mainly neutrophilic vascular reactions with histologic features similar to NV but significantly differing from EN associated with other systemic diseases.

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A 25-year-old male with anemia, jaundice and liver dysfunction was admitted to our institution. Anisopoikilocytosis with tear-drop forms, polychromasia, basophilic stippling in peripheral blood smear, erythroid hyperplasia with megaloblastoid changes, binucleated cells and intranuclear bridging in bone marrow aspirate and spongy, unevenly condensed nuclear chromatin in electron microscopy studies indicated that he had congenital dyserythropoietic anemia (CDA) type I. As a rare finding in CDA, ringed sideroblasts were noted. It is proposed that this patient is an example for the designation 'variant congenital dyserythropoietic anemia with ringed sideroblasts'.

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A t(14;18) translocation is closely associated with the follicular lymphoma but is also seen in diffuse B cell lymphomas with a previous history of a follicular lymphoma as well as de novo diffuse lymphomas. Estimation of the frequency of t(14;18) in follicular lymphoma vary widely from 33 to 89%. Furthermore, no extensive data have been published on the frequency of t(14;18) in Turkish cases of follicular lymphoma. Representative tissue blocks from 67 patients with follicular lymphoma, 12 cases of diffuse large B cell lymphomas and 11 cases of reactive hyperplasias were examined for the presence of this translocation using PCR. DNA probes capable of detecting rearrangement at both the major and minor break point regions were employed. We could detect t(14;18) in 46 out of 67 cases (68.7%) of follicular and 25% of diffuse large B cell lymphomas. In follicular lymphomas 64.2% of these break points were at mbr and 4.5% were at the mcr region. Review of the literature showed that comparable results have been obtained previously using molecular techniques. Our data showed that despite the relative infrequency of follicular lymphomas in the Turkish population these lymphomas share a common molecular pathogenesis with involvement of bcl-2 gene and background incidence of such rearrangement is similar in all populations, regardless the incidence of folicular lymphoma.

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The first Phase I Trial with a combination of IL-2 and IFN-alpha was published in 1989. There are still some questions though, concerning the in vivo effects of this combination on lymphocytes. We designed a prospective pilot study to evaluate in vivo effects of low dose IL-2 and IFN-alpha combination on expression of Bcl-2, FAS (Apo-1/CD 95), Fas Ligand, IL-2 receptor (CD25), and HLA-DR on peripheral lymphocytes in patients with advanced renal cell carcinoma. After initiation of the immunomodulating therapy, Bcl-2 expressing lymphocytes increased significantly on day 3 (p < 0.025), Fas (Apo-1/CD95) expressing lymphocyte increased significantly on day 5 (p < 0.003), Fas ligand expressing lymphocytes increased significantly on day 3 (p < 0.004), HLA-DR expressing lymphocytes increased significantly on day 5 (p < 0.003), and IL-2 receptor (CD25) expressing cells increased significantly on day 5 (p < 0.01). We conclude that immunomodulating therapy induces in vivo expression of Bcl-2, Fas (Apo-1) and Fas Ligand in lymphocytes significantly.

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Cutaneous vasculitis is a heterogeneous group of disorders, which can be confined to the skin or may be part of an associated systemic disease. Various aetiological agents as well as conditions that mimic skin vasculitis, usually present with similar clinical features; mainly palpable purpura. The skin biopsies usually show leukocytoclastic vasculitis. This poses a great diagnositc and therapeutic challenge for the physician. The aetiologies, clinical features, diagnosis and treatment modalities for each form (drugs, infections, malignancies, systemic vasculitides, connective tissue disorders. Schönlein-Henoch purpura, cryoglobulinaemia, cutaneous periarteritis nodosa, livedoid vasculitis, erythema elevatum diutinum and urticarial vasculitis) are reviewed.

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The prognostic value of clinicopathological parameters, recorded at diagnosis, in idiopathic myelofibrosis (IMF) was retrospectively analyzed in a consecutive series of 32 patients followed for a minimum of 5 and maximum of 134 months in the period 1983-1994. Of the 32 patients, 18 were males and 14 were females. The mean age was 59.8 years (S.D., 10.4; range, 44-78 years). At the time of closure of the study (May 1995), 10 patients were dead, 18 were alive, and four were lost to follow up. The mean survival was 41 months (range 2-130 months). Univariate analysis showed that the following features were associated with a significantly shorter survival: (1) anemia (hematocrit <30%), (2) platelet count < 100,000/mm3. Age, sex, size of spleen and liver, WBC count, increased reticulin and collagen fibrosis were not of prognostic significance. Clinicopathological correlation was found between the sinusal hemopoiesis and the number of WBC precursors in peripheral blood, and between WBC precursors and spleen size. Medullary fibrosis was found to be associated with striking predominance of large and very mature megakaryocytes. Erythroid hyperplasia in the bone marrow correlated negatively with WBC precursors and spleen and liver size, and positively with reticulocyte count.

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OBJECTIVE: To evaluate the frequency of vasculitis, mainly in the forms of Henoch-Schönlein purpura and polyarteritis nodosa (PAN), and to investigate the presence of occult blood in the first stool specimens after an abdominal attack in Turkish patients with familial Mediterranean fever (FMF). METHODS: Review of the charts of 207 patients with FMF seen between 1983 and 1993 with respect to clinical vasculitis. A prospective study designed to test the presence of occult blood in the first stool specimens obtained after abdominal attack and at least one week later in 36 patients with FMF compared with healthy and diseased controls. RESULTS: There were 15 patients with Henoch-Schönlein purpura (7%), 2 with definite and one with probable PAN (1%), one of whom developed perirenal hematoma. The diagnosis of FMF was made after the onset of Henoch-Schönlein purpura in 9 and subsequent to the development of PAN in one patient. Occult blood was positive in the first stool specimens obtained after an attack in 17 of the 36 patients with FMF (47%), a finding not reported previously. CONCLUSION: Vasculitis seems to be an important but not a widely recognized feature of FMF.

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The incidence of aplastic anemia among hospitalized adult patients was prospectively determined in this first study in Turkey. New cases of aplastic anemia among patients 14 years and older who were admitted to the study centers were included in a 3 year survey. Seventy-three patients fulfilled the diagnostic criteria, yielding a mean annual incidence rate of 1.14 cases in 10(3) admissions. The male-to-female ratio of the cases (1.6:1) differed from the almost equal ratio of the larger population of Turkey. The median age was 30 years and females were younger at diagnosis. The age distribution of the cases was different from that of the population; showing two incidence peaks in both sexes. The majority of the patients (89%) had severe disease.

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The translocation t(8;21) is one of the most common structural aberrations in acute myeloid leukemia (AML). Excellent response rates and a better relapse-free survival have been described. We analyzed specific morphologic and cytochemical features including dysplasia and other prognostic factors in 41 patients with AML and t(8;21) who underwent aggressive chemotherapy in two national cooperative group studies. Five patients were classified as AML M1 and 36 as AML M2 according to the FAB criteria. Auer rods were detected in 28 patients (68%), however in only 16 patients were they "thin and elongated" as has been described as typical for t(8;21). The presence or absence of Auer rods did not appear to be associated with disease-free survival in this sample. Dysgranulopoiesis was detected in 31/41 patients (90%); five of these patients additionally had dyserythropoiesis (12%). In six cases (15%), dysmegakaryopoiesis was seen in combination with dysgranulopoiesis. Only one patient had trilineage dysplasia. Dysplastic features had no influence on prognosis. Additional cytogenetic abnormalities were detected in 24/41 patients. Twelve male (48%) and four female (25%) had a loss of a sex chromosome. This was correlated with a better disease-free survival (p = 0.039). The complete remission rate (CR) to chemotherapy was 90%. The early death rate was 10%. Disease-free survival of the complete responders was 60% at two years with no relapses observed in ten patients with 2-6 years of follow up. This favorable disease-free survival was observed with a variety of post-induction regimens and t(8;21) had been detected as an independent factor for good prognosis. The need for very intensive therapy, such as bone marrow transplantation, is unanswered at this time.

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Toxoplasmic lymphadenitis generally involves a solitary lymph node in the head and neck regions, without systemic symptoms. In order to determine the frequency of toxoplasmic lymphadenitis, we reviewed the histological sections of 731 consecutive patients with reactive lymph node hyperplasia. Amongst 731 patients, 112 had histological features supporting a diagnosis of toxoplasmic lymphadenitis (15.3 per cent). In 80 of these patients (71 per cent), either Indirect Haemaglutination test (IHA), in 37 cases, or the Enzyme-Linked Immunosorbent Assay (ELISA) for detecting toxoplasmic IgG or IgM antibodies, in 43 cases, were performed. In 76 out of 80 patients (95 per cent), histological features correlated well with serological studies. The IHA test was positive in 30 patients with a titre of 1/64 or higher. The IgG-ELISA test was positive in 11 whereas the IgM-ELISA test was positive in 28 patients. These results provide further evidence of the distinctive nature of the histological changes in toxoplasmic lymphadenitis, which should enable the clinician to make a confident diagnosis of acute acquired toxoplasmosis.

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OBJECTIVE: To make a retrospective and prospective analysis of the frequency of symptomatic inflammatory bowel disease in patients with Behçet's syndrome (BS). METHODS: The medical records of the first 1000 patients with BS were reviewed retrospectively for past or present history of diarrhoea. The past and present history of diarrhoea was also elicited prospectively among 147 consecutive patients with BS and 78 diseased controls (42 with rheumatoid arthritis, 17 with systemic lupus erythematosus, seven with seronegative spondylarthropathy, and 12 with miscellaneous rheumatic diseases). Inflammatory mucosal changes were sought in rectal biopsy specimens from 75 patients with BS, 47 diseased controls (29 with nephrotic syndrome, eight with rheumatoid arthritis, six with familial Mediterranean fever, and four with ankylosing spondylitis), and 14 patients with ulcerative colitis. RESULTS: In chart review there were only seven Behçet's patients with diarrhoea; none of them had inflammatory bowel disease. In the prospective survey there were no significant differences between the BS and control groups in the past and present history of diarrhoea. There were no significant differences in the rectal mucosal histology between patients with BS and controls, while patients with ulcerative colitis showed pronounced differences. CONCLUSION: Symptomatic inflammatory bowel disease is not common in BS patients from Turkey.

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Inflammatory pseudotumor of lymph nodes (IPT) is a rare, recently described benign cause of lymphadenopathy. The IPT is composed of a proliferation of spindle cells, small vessels and inflammatory cells without atypia and formed by high and poor cellular areas. This study reports a case of IPT. It was a 50-years-old man in whom the abdominal mass was an incidental finding during exploratory laparatomy. The mass was a lymphadenopathy measuring 12 x 10 x 5 cm in diameters. Histologic examination revealed IPT of the lymph nodes. The patient has remained asymptomatic for more than 10 months following surgery without any treatment. In conclusion, IPT of the lymph nodes is being recognized increasingly and should be considered in the differential diagnosis of lymphadenopathies. Inflammatory pseudotumor (IPT) of the lymph nodes resembling the IPT of other organs was recently described as a possible cause of lymphadenopathy. Histologically, the process showed a proliferation of spindle cells associated with a mixture of polymorphic inflammatory cells and small blood vessels involving the connective tissue framework (hilum, trabecula, capsule) of the lymph node. In this report, the case of a patient with IPT of pelvic lymph nodes is presented with the clinical and pathological features.

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To determine whether hypocellular MDS differs from normo/hypercellular MDS, we attempted to identify hypocellular MDS cases either by correcting the bone marrow (BM) cellularity by age (28 patients) or by using a single arbitrary value of BM cellularity (25 patients) and compared these two groups of hypocellular cases to the normo/hypercellular MDS cases (72 patients). 18 patients were common to both hypocellular groups. Patients with hypocellular MDS in both of these selected groups have similar features with regard to age and sex distribution, peripheral blood and bone marrow parameters, FAB subtypes, karyotypes, leukaemic transformation, and survival. However, the median age of patients in < 30% BM cellularity group was higher than those patients in the age-corrected group (69 years v 62 years). The selection of < 30% cellularity excluded 10 cases in the age group < 70 years but included another seven patients in the age group of > 70 years. However, correction of BM cellularity by age revealed that those included patients (selected for < 30% cellularity) who had normocellular BM by their age. Therefore we recommend the age-correcting grouping to ensure comparable series for comparison, for response to treatment, and survival. Finally, BM cellularity does not appear to be an important factor on prognosis in MDS, because patients with hypocellular MDS in both selected groups have similar prognosis to those with normo/hypercellular MDS patients.

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An in vitro skin explant model has been proposed for prediction of graft versus host disease and reported to be highly sensitive and specific for this purpose. In this study we have re-evaluated this model in both HLA full-matched BMT recipient-donor sibling pairs and also in HLA one haplotype-matched parent-children pairs. All assessments were made blindly by 3 independent observers. The predictive value of the test for the occurrence of clinical GvHD in 14 BMT patients was found to be less sensitive than reported previously (correlation coefficients were +0.019, +0.067 and -0.061 between clinical GvHD and in vitro primed allogeneic, primed mixed and unprimed allogeneic settings, indicating "poor" correlation). False positive and false negative results were high and there were also significant discrepancies between three blind observations in the grading of skin changes. Weighted kappa analysis revealed that there were "fair" correlations between the 3 observers (K = 0.25). These results indicated that the skin explant model is an unpredictable test system and there are great problems in standardization of the method.

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Multiple persistent vacuoles were seen in the neutrophils, monocytes and eosinophils of a 9 year old boy and his 10 year old sister. The siblings were both asymptomatic. In the bone marrow, the cytoplasmic vacuoles were also present in the promyelocytes, myelocytes and metamyelocytes, but not in the myeloblasts and they tended to be single and large in immature cells. The cytoplasmic vacuoles did not stain with PAS, Sudan Black or Oil Red O; Sudan III positivity of the vacuoles was found only in a very small number of granulocytes. The vacuoles appeared as round and bright bodies with phase contrast microscopy. By electron microscopy, the vacuoles contained material of low electron density and had no surrounding membrane. Granulocyte functions were unimpaired. Muscle biopsy showed normal morphology. This anomalous vacuolization of the leukocytes is consistent with familial Jordans anomaly.

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Fourteen patients with hypocellular acute leukemia (HAL) were reviewed. The median age was 72 years, with an equal male-to-female ratio. Severe granulocytopenia with marrow hypocellularity and increased marrow blasts and absence of physical findings were common features. The median peripheral blood blast count was 2%. All except 3 cases of erythroleukemia had marrow blast count that exceeded 30% of all nucleated marrow cells. All cases were classifiable with the FAB criteria. FAB classification revealed a preponderance of the M1 category followed by M2 and M6 types. The majority of blasts were type I and the median myeloperoxidase positivity was 14%. Immunophenotyping of bone marrow cells by flow cytometry in 9 cases showed expression of myeloid antigens (CD13, CD33); 6 cases also expressed CD34 antigen. Significant dysplasia involving erythroid and megakaryocytic lineages was seen in most of the cases. Trilineage dysplasia was observed in 5 cases. Median survival of the entire group was 10.5 months. Eleven patients underwent induction therapy consisting of daunorubicin and cytosine arabinoside +/- 6 thioguanine; 8 patients achieved complete remission (72.6%). Remission duration was 14.5 months. Three patients (27.4%) died secondary to infections during induction therapy. Higher frequencies of trilineage dysplasia and FAB M6 type together with low percentage of peripheral blasts and presence of antecedent hematologic disorders suggest that some of these cases might represent the hypocellular form of acute myeloid leukemia with trilineage dysplasia.

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We have reviewed the initial diagnostic bone marrow aspirate and biopsy specimens performed on the same date on 92 patients with acute myeloid leukaemia (AML), 100 patients with myelodysplastic syndrome (MDS), 24 patients with chronic granulocytic leukaemia (CGL), 19 patients with polycythemia vera (PV) and essential thrombocythemia (ET). An excellent assessment of cellularity by aspirate and biopsy was found. The estimation of BM cellularity for each group was utilized with and without age adjustment based on normal marrow biopsies. Without correcting the BM cellularity for age it was observed that the median BM cellularity was > 50% in AML, CGL, PV and ET. In contrast, the median BM cellularity was estimated at 40% for MDS. In the age group 70 years and beyond the median BM cellularity was not changed in CGL, PV and ET, and only slightly decreased (35%) in MDS. However, a trend from hypercellularity to normocellularity was observed in patients with AML in this age group. By utilizing anatomic comparisons with normal age the corrected data disclosed that all patients with CGL, PV and ET, 63% of patients with AML and only 35% of patients with MDS had hypercellular BM according to their age, while only two patients with AML and seven patients with MDS were found to be truly hypocellular by age. The optimal cut-off value for definition of hypocellular AML and hypocellular MDS, and differences between MDS and other myeloid stem cell disorders in terms of BM cellularity have been discussed.

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