Pretreatment prognostic factors for overall survival in primary resistant acute myeloid leukemia.

AIM: Primary resistant acute myeloid leukemia has a very poor prognosis. We assessed pretreatment parameters for their significance as prognostic factors in the overall survival (OS) of 53 acute myeloid leukemia (AML) patients who had failed to achieve complete remission (CR) after first-line standard-dose remission-induction therapy. RESULTS: During the period January 2005-December 2009, 53 with acute myeloid leukemia received two cycles of the 3+7 protocol as a first-line standard-dose remission-induction therapy (ARA-C, days 1-7 and daunorubicin, days 1-3). The HiDAC (5 patients), MiDAC (7 patients), and FLAG-IDA protocols (3 patients) were given as salvage therapy. None of these patients achieved CR. There were 27 (51%) males and 26 (49%) females (median age, 55 years, range 28-76). The median white blood cell count was 53 (range 0.9 -350)×10(9)/L, platelets 44 (range 3-856×10(9)/l) and bone marrow blasts 67%. HCT-IC comorbidity scores were 3 in two (3.8%) patients, 2 in 11 (20.8%), 1 in 12 (22.6%) and 0 in 16 (30.2%) patients. Median OS was 3.9 months (range 1 -20 months). The hepatomegaly, white blood cell count, ECOG PS, serum level of lactate dehydrogenase, dysplastic changes, coexpression of CD64, CD15, CD11b, comorbidities and disease cytogenetics influenced survival. CONCLUSION: This single-center study evaluated the significance of pretreatment factors, and found that patient age, comorbidities, ECOG performance status, leukocytosis, hepatomegaly, LDH, and the disease cytogenetics were factors which influenced the outcomes of primary resistant patients with acute myeloid leukemia. An understanding of these factors may help to predict OS in cases where CR has not been achieved and may help when making further treatment decisions.

Therapy-related myelodysplastic syndrome and acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide.

We retrospectively studied four cases of t-MDS/AML among 210 (1.9%) consecutive patients with CLL treated at a single center with fludarabine and cyclophosphamide (FC) either as the first- or second-line therapy. The median follow-up of the whole cohort of patients was 46months (range: 7-60). Two of these patients (2/130, 1.7%) had been treated with FC only, and two more (2/80, 2.3%) with CHOP and CHOP+FND, respectively, prior to FC. The median age was 61.5years (range: 49-71); three were male. They developed t-MDS/AML after a median latency period of 41months (range: 7-56) from the FC completion. Chromosomal aberrations with an adverse prognostic impact were present in the karyotype of all four patients, including abnormalities of chromosome 5 in three of them, and a rare chromosomal translocation in one patient. Median survival after t-MDS/AML diagnosis was 4months (range: 2-8). Although the agents administered prior to FC make it difficult to assess the risk of t-MDS/AML attributable to FC, this report might be a valuable addition to the literature.

Pure red-cell aplasia as the presenting feature of the carcionoid tumor of the thymus: case report.

Acquired pure red-cell aplasia (PRCA) is an uncommon disorder of erythrocytopoiesis that can develop in association with thymic tumors. We present the very rare case of a severely anemic 62-year-old man with PRCA and a concurrent neuroendocrine carcinoid tumor of the thymus. The anterior mediastinal thymus tumor was completely excised, and following histological and immunohistochemical analyses (showing positive staining for cytokeratin, chromogranin A, synaptophysin, and neuron-specific enolase) the diagnosis of a (grade I; T(1)N(0)M(0)) typical carcinoid tumor of the thymus was made. Postoperatively the anemia persisted despite no signs of residual tumor on CT chest. A hematological work up found: normocellularity with <0.5% erythroblasts and preserved megakaryocytopoiesis and granulocytopoiesis in a trephine biopsy; reduced numbers of Colony Forming Unit Erythroid (CFU-E) and normal numbers of Burst-Forming Unit Erythroid (BFU-E) in bone marrow colony-forming assays; a markedly increased level of serum erythropoietin; normal T and B-cell numbers with a normal CD4/CD8 ratio; and no clonal T-cell receptor -gamma and -delta gene rearrangement) The patient responded favorably to a therapeutic trial of glucocorticoid immunosuppressive treatment (prednisone 1 mg/kg/day) with a normalization of the reticulocyte count and hematocrit, suggesting an immunologic mechanism for the PRCA. Though the exact mechanisms underlying the association between the PRCA and the carcinoid tumor of the thymus remain unknown.

Triple-way therapeutic approach for paraganglioma-dependent erythrocytosis: drugs and surgery plus "multi-manner" apheresis.

Paragangliomas are tumors arising from the extra-adrenal paragangliar neural crest cells. The sympathoadrenal neuroendocrine system consists of extra-adrenal paragangliar cellular layer along the paravertebral and para-aortic axis, and the adrenal medullae. Paraganglioma should be included in the differential diagnosis of secondary erythrocytosis due to its possible ectopic erythropoietin (EPO) secretion. Thus, in this report we present a 24-year-old female patient with onset of unregulated ectopic EPO secretion, and consecutive erythrocytosis followed by hypertension, secondary to paraganglioma of multifocal retroperitoneal localization. Clinical, laboratory, and radiological investigations confirmed both an elevated EPO level and the presence of multiple paraganglioma. This paraneoplastic-mediated medical condition with high risk of cellular hyperviscosity syndrome (CHVS) requires prompt diagnosis and rapid therapeutic interventions. Initially, simple phlebotomy procedures were used; following that, tumors were surgically removed. In the course of the disease, this tumor relapsed, and urgent apheresis, as a treatment of life-threatening state, was used. The therapy performed resulted in a rapid blood viscosity depletion and a significant (P < 0.01) serum EPO reduction, as well as the general clinical benefit. Therefore, we conclude that the use of our own "multi-manner" apheresis (erythrocythapheresis plus plasma exchange), for long-time interval (until further causative therapy), effectively cross-bridged the possible hazards of EPO-dependent CHVS.

Systemic lupus Erythematosus and IgA multiple myeloma: a rare association?

The coexistence of systemic lupus Erythematosus (SLE) and multiple myeloma (MM) is uncommon and the pathogenetic mechanisms underlying this association remain unclear. We report the case of a woman who was diagnosed with SLE in 1993 aged 57, then developing IgA lambda type MM in the IIB clinical stage 7 years later. The SLE was treated successfully with methylprednisolone and chloroquine, and low dose maintenance steroid was continued with bisphosphonate protection until December 1994 when she suffered multiple vertebral fractures. She continued to receive 4 mg alternate day methylprednisolone and calcitonin until she decided to discontinue her own treatment 2 years later. In 2000, while still in stable SLE remission, she was diagnosed with MM. Protein electrophoresis revealed the IgA lambda paraprotein (40.5 g/l) and she had a Bence Jones (BJ) proteinuria of the lambda light chain type. Bone marrow trephine biopsy revealed a massive patchy infiltrate of abnormal plasmocytes (70%), while an extensive x-ray skeletal survey did not show any new fractures or osteolysis. The patient was treated according to the VMCP protocol without attaining a plateau phase. There was a similar poor clinical response to second and third line treatments (VAD, Thalidomide, Melphalan, and high dose dexamethasone). After 4 years of refractory disease the patient died from severe bilateral pneumonia. This case is discussed with reference to the literature.

Littoral-cell angioma as a rare cause of splenomegaly.

We report the case of a littoral-cell angioma of the spleen, a recently described benign vascular tumour, whose imaging and pathological characteristics have been discussed only by a few authors. The diagnosis was made after elective splenectomy. The CT images, scintigraphy and histological specimens are presented, and differential diagnoses discussed.

[Endoscopic ultrasound (EUS) in initial assessment and follow-up of patients with MALT lymphoma treated drug therapy].

BACKGROUND: Endoscopic ultrasonography (EUS) is an important tool for diagnosis and pretreatment staging of primary gastric lymphoma. The aim of the study was to evaluate the diagnostic importance of endosonography (EUS) in gastric lymphoma; to assess the depth of tumoral infiltration in low-grade gastric lymphoma of mucosa-associated lymphoid tissue (MALT) and to assess EUS response to medical treatment (Cyclophosphamid/Mabtera and/or anti-Helicobacter pylori therapy). METHODS: 26 patients with MALT gastric lymphoma were investigated by EUS. Six of them were evaluated after the eradication of Helicobacter pylori infection and 20 after and during the cyclophosphamide/Mabtera and anti H. pylori treatment. EUS staging was compared with histopathology. Tumours were staged according to the 2000 TNM and modified Ann Arbor classification. RESULTS: Six patients were treated with anti - Helicobacter pylori eradication therapy. Full regression of lymphoma was observed in 2 of 6 (33.3%) patients, which was endoscopicaly and histologicaly proved. EUS correlated with histology in all (6/6). In 20 patients treated with cyclophosphamide/Mabtera therapy, EUS revealed regression of lymphoma in 14 cases. Positive correlation with histology was found in 11 patients (11/14; 78%). The initial EUS showed an increased wall thickness more than 5mm in 24 of 26 patients (92%). The thickening was predominantly of mucosa and submucosa and in 11 patients extended the muscularis propria. After the therapy, the gastric wall thickening returned to normal in 14 patients, however, 3 of them still had positive histology findings. In 2 cases, during the follow-up, the EUS showed remained thickening of gastric wall, whereas biopsies were negative. Six months later histology revealed progressive low-grade MALT lymphoma in this cases. CONCLUSION: EUS appears to be a sensitive procedure for initial staging and assessment of treatment response and long-term follow up in patients with gastric lymphoma. The importance of EUS lies in abbility to detect relapse early, too.

Acute panmyelosis with myelofibrosis: clinical, immunophenotypic and cytogenetic study of twelve cases.

The clinical, cytogenetic, and immunophenotypic features in 12 adult patients with acute panmyelosis with myelofibrosis (APMF; ICD-0-3: 9931/3; C42.1) are reported (median age: 57 years; f/m = 1.4). The white cell count (WBC) was normal in 3 patients; 9 had leucopenia. The median hemoglobin value was 64.5 g/l, and median platelet count 12 x 10(9)/l. Bone marrow biopsy showed a hypercellular marrow in 10/12 patients with a significant infiltration of pathological blasts (range: 30 - 60%). All the cases had marked reticulin fibrosis. Immunophenotyping of bone marrow blast cells showed the expression of early (CD34) and lineage-unspecified antigens (HLA-DR) in 6/7, and 7/7 patients, respectively. "Early" myeloid antigens (CD13, CD33) were seen in 6/7 and 4/6 patients respectively. Monocyte antigen (CD14) was expressed in 3/7 patients. Megakaryocyte antigen (CD61) and erythroid cell antigen (GpA) were each expressed in only 1 patient. Two patients had expression of CD34, HLA-DR and "early" myeloid antigens by their bone marrow blast cells and 1 of these also had a co-expression of the antigens from a differentiated monocytic cell proliferation (lysozyme+, CD68+). Nonspecific chromosomal aberrations were recorded in 8/10 patients. The median survival was 2 months. These findings suggest an immature myeloid phenotype of blast cells in APMF. In 6/9 patients a leukemic cell differentiation into monocytic, megakaryocytic or erythroid lineage was also demonstrated.

Immunohistochemical analysis of cyclin D1 and p53 in multiple myeloma: relationship to proliferative activity and prognostic significance.

Conflicting data are reported on the clinical significance of cyclin D1 deregulation in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of cyclin D1 expression and p53 mutations in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of cyclin D1 and p53 was analyzed using standard immunohistochemical method of B5-fixed and routinely processed paraffin-embedded bone marrow specimens. Cyclin D1 was overexpressed in 14/59 (27%) and p53 in 5/59 (8.5%) specimens. There was no significant correlation between cyclin D1 overexpression and age, gender, clinical stage (Durie-Salmon classification), extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, C-reactive protein, and beta2-microglobulin. No association was observed between the expression of cyclin D1 and the extent of bone marrow infiltration, histological grade, proliferative activity index (measured with Ki-67 immunoreactivity) and response to therapy. No significant difference was observed regarding overall survival between cyclin D1 positive and cyclin D1 negative patients (29 vs 36 mo, p = 0.76). Results of this study did not revealed prognostic significance of cyclin D1 overexpression in multiple myeloma. Mutations of p53 gene are rare events in myeloma, suggesting their limited role in the pathogenesis of the disease.

Long-term survival in acute lymphoblastic leukaemia in adults treated according to the LALA 87 protocol.

BACKGROUND: Between January 1989 and July 1995, a prospective study of the therapeutic efficacy of the LALA 87 protocol in adult acute lymphoblastic leukaemia (ALL) has been conducted. METHODS: A total of hundred and twelve patients with ALL have been analysed. The median age of the patients was 40 years (range: 15-65), the gender ratio (M/F) was 66/46, and the morphologic FAB (French-American-British) profile was L1 in 30 (26.9%) patients, L2 in 71 (63.3%) and L3 morphology in 11 (9.8%) of the patients. The LALA 87 protocol includes five phases: induction, consolidation, reinforcement, maintenance and central nervous system (CNS) prophylaxis with intrathecal methotrexate and irradiation. The induction phase comprised daunorubicin 50 mg/m(2) (days 1-3), cyclophosphamide 600 mg/m(2) (days 1 and 8), vincristine 1.5 mg/m(2) (on days 1, 8, 15 and 22) and daily oral prednisone on days 1-21. Maintenance therapy was given for 2 years and consisted of different drugs as reinforcement, daily 6-mercaptopurine and weekly methotrexate. RESULTS: Complete remission (CR) was achieved in 81 (72.3%) of the patients. The causes of induction failure were partial response in 10 (8.9%), and hypoplastic death in 12 patients (10.7%), and 9 were non-responders (8.0%). Of the 81 patients who achieved CR, 62 relapsed (76%). Among the relapsed patients, 9 developed CNS disease in spite of CNS prophylaxis during induction chemotherapy. Median follow-up for the living patients was 110 months. Median disease-free survival (DFS) was 16 months; 19 patients are still in remission with an estimated 10-year DFS (24%). Adverse prognostic factors were >50 years of age, immunologic subtype and cytogenetic profile. CONCLUSION: The results support the strategy of applying more effort and other treatment modalities in the therapy of ALL.

In vitro sensitivity of hematopoietic progenitors to tiazofurin in refractory acute myeloid leukemia and in the blast crisis of chronic myeloid leukemia.

The effect of Tiazofurin (TR) on the in vitro growth of bone marrow (BM) and peripheral blood (PB) leukemic progenitors was investigated in 29 patients. Nineteen of the patients were suffering the blast crisis of chronic myeloid leukemia (bcCML) and ten patients refractory acute myeloid leukemia (AML). PB and BM mononuclear cells were cultured in methylcellulose alone or with concentrations of TR ranging between 10 and 200 microM. TR produced a dose dependent inhibition of colony forming unit (CFU)-blast growth in all the samples tested from BM and PB. The most effective concentrations of TR used were 150 and 200 microM, while concentrations of less than 50 microM TR were not adequate for 50% inhibition of cell growth (IC50). Differences were found in the response of CFU-blasts to TR related to the type of underlying leukemia. Inhibition of CFU-blast growth was more pronounced in bcCML than in AML in both the BM and PB samples. The concentration of TR required to induce IC50 in bcCML was 50 microM, while the same effect in AML required a concentration of 150 microM. Analysis of the control samples also revealed that CFU-blasts from bcCML produced smaller numbers of colonies, though these differences were not statistically significant. It has therefore been demonstrated that TR has strong in vitro anti-leukemic activity, more pronounced in bcCML than in refractory AML. We thus feel this study gives further rationale for the clinical application of TR, and would strongly support this.

Case-control study of multiple myeloma with special reference to diet as risk factor.

The case-control study was conducted in Belgrade (Yugoslavia) during the period 1994-1998. The objective of the study was to investigate factors related to the occurrence of multiple myeloma (MM). The study group consisted of 100 newly diagnosed MM patients and the same number of matched hospital controls. In the analysis conditional univariate and multivariate logistic regression were applied. According to multivariate analysis the following factors were significantly related to MM: smoking > or =25 cigarettes per day (Odds ratio--OR=6.7, 95% confidence interval--95% CI=1.3-34.3); having more than two brothers (OR=2.7, 95% CI=1.3-5.3), rheumatoid arthritis in personal history (OR=4.2, 95% CI=1.2-14.8), and frequent (4-7 times per week vs. lower frequency) consumption of yogurt (OR=3.1, 95% CI=1.6-6.0) and vegetables (OR=0.4, 95% CI=0.1-1.0).

Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside.

Monocytoid B cell lymphoma (MBCL) is an immunologically and morphologically well-defined low-grade lymphoma with a predilection for lymph nodes of the parotid region. We describe an association of MBCL with anti-myelin-associated glycoprotein (MAG) polyneuropathy in a 53-year-old male. The diagnosis of stage IV MBCL with nodular bone marrow infiltration, Sjögren's syndrome and sensorimotor polyneuropathy was made in October 1996. Serum immunoelectrophoresis demonstrated IgMkappa paraprotein. This was then cross-reacted with epitopes of MAG and sulphated glucuronyl paragloboside (SGPG) on myelin sheaths, and detected by thin layer chromatography and Western blot. Direct immunofluorescence of a sural nerve biopsy showed loss of myelin fibres, segmental demyelinization and IgM deposits on the myelin sheaths. The cerebrospinal fluid was normal. After six cycles of chemotherapy (ChlVPP protocol), all the patient's haematological parameters normalized accompanied by an improvement in neurological signs. The improvement of the polyneuropathy after chemotherapy indicates that the autoimmune anti-MAG and anti-SGPG antibodies resulted from the neoplastic lymphoid proliferation.

Secondary myelofibrosis in visceral leishmaniasis--case report.

A 39-year-old woman with a history of travel to the Montenegrin coast presented with a 9-month long history of fever and weakness, and on examination was found to be emaciated with hepatosplenomegaly and pancytopenia. Marrow aspiration showed poor cellularity with abundant Leishman Donovan (LD) bodies in the macrophages. Bone marrow trephine biopsy revealed a marked myelofibrosis (Manoharan classification: grade III) with osteosclerosis. The impression smears of a trephine biopsy stained with Güiemsa also showed LD bodies. The patient did not exhibit evidence of any risk factors for visceral leishmaniasis (VL). She was treated with meglumine antimoniate (Glucantime) without any adverse effect. The spleen returned to a normal volume after 4 months and bone marrow trephine biopsy performed 6 months after initiation of the therapy had returned to normal. A diagnosis was difficult to establish as VL is rarely encountered in the continental parts of Yugoslavia, and with the presence of associated myelofibrosis it could easily have been mistaken for chronic idiopathic myelofibrosis. The association of myelofibrosis with visceral leishmaniasis has been reported in the literature only three times; we thus feel that documentation of this case is merited.

Diffuse primary plasmacytoma of the lung.

Primary plasmacytoma of the lung is a rare tumor, thus presenting a diagnostic challenge to the clinician. So far, approximately 20 cases have been verified by immunohistochemistry. We describe an elderly patient presenting with progressive dyspnea on exertion, dry cough, weight loss and malaise. The main finding on plain chest radiography was a diffuse infiltration of pulmonary parenchyma in the lower parts of both lungs and in the middle part of the right lung. The histology of the open lung biopsy of the right middle lobe revealed massive and diffuse infiltration by well differentiated plasma cells with extracellular deposits of amyloid. The plasma cells and amyloid expressed a monoclonal lambda light chain. No monoclonal spike was shown by serum and urine immunoelectrophoresis. A skeletal survey and bone marrow biopsy specimen excluded a disseminated disease and a diagnosis of extramedullary plasmacytoma was made. The patient was considered for VI courses of VMCP chemotherapy after which a complete regression on chest roentgenography was evident. Almost five years after the diagnosis the patient is still alive without any evidence of disease recurrence or dissemination.

Clinical, Immunophenotypic and Cytogenetic Features of Megakaryocytic Blast Crisis of Chronic Myeloid Leukemia: A Single Institution Study.

We present 15 patients with megakaryocytic (Mk) blast crisis (BC) of a Philadelphia (Ph) chromosome positive CML confirmed by immunophenotype analysis between 1989-2000. The primary aim of this study is to define clinical, immunological, cytogenetic and laboratory characteristics of Mk BC in Ph positive CML. We have done retrospective analysis regarding basic clinical findings, immunologic phenotype, cytogenetic studies and platelet functions. All patients had significant expression of CD61 (14/14) and CD34 (13/13) antigens, and a high frequency of expression of CD13 (9/12), CD33 (10/12) and CD11b (9/11). The BC in 6/15 patients was presented with thrombocytosis, 7/15 had a normal platelet count and two patients had thrombocytopenia. A grade IV myelofibrosis was present in 8/10 patients. Six patients evolved additional karyotypic abnormalities. Two patients had extramedullary BC. The serum activity of LDH (med. 1095.6) was elevated in all patients. A platelet dysfunction was documented in 4/5 patient tested. There are no clinical and hematological characteristics specific for Mk BC of CML. Normal or elevated platelet count (med. 427.4 x 109/L) in BC of CML with prominent expression of CD34 and CD61 antigens, and significant myelofibrosis (grade IV) are the most consistent clinical findings.

Fatal strongyloidosis following corticosteroid therapy in a patient with chronic idiopathic thrombocytopenia.

A patient with chronic idiopathic thrombocytopenia and fatal strongyloides hyperinfection syndrome following prolonged corticosteroid therapy is briefly described. Diagnosis was difficult to perform due to absence of eosinophilia and diarrhea at presentation, as well as to the negativity of multiple stool specimens examined by direct microscopy of saline smear, formol-ether concentration techniques, and Baermann's test. The striking hypoalbuminemia in the setting of the normal results of liver function tests and prothrombin time was assumed to be due to enteropathy. Therefore, an upper endoscopy was undertaken, revealing Strongyloides stercoralis (SS) larvae in the biopsy specimens of the gastric and duodenal mucosa. The SS larvae were also demonstrated in the multiple specimens of the concentrated sputum. Despite thiabendazol treatment, death ensued. On autopsy, SS larvae were recovered in the gastrointestinal tract and lungs. The importance of early diagnosis and of ruling out strongyloidosis prior to administration of corticosteroids are discussed, as well as the pathogenetic aspects of strongyloidosis in the patient under corticosteroids.

Hepatosplenic candidiasis after neutropenic phase of acute leukaemia.

Hepatosplenic candidiasis following granulocytopenic periods is a relatively recently recognised problem in immunocompromised patients, particularly in those with acute leukaemia. We present three patients in whom diagnosis of hepatosplenic candidiasis was suspected on the basis of ultrasonographic (US), computed tomographic (CT) findings and confirmed by laparoscopy and biopsy of liver lesions. All three patients were successfully treated briefly with amphotericin B, followed by a longer period of fluconazole. In one patient laparotomy and surgical evacuation of abscesses was performed. This condition could be more often recognised by careful follow-up of liver function test, C-reactive protein level, ultrasonography, CT and MRI after recovery from chemotherapy-induced neutropenia.

Pure red cell aplasia evolving through the hyperfibrotic myelodysplastic syndrome to the acute myeloid leukemia: some pathogenetic aspects.

The authors report a 58-year-old female who originally presented with acquired pure red cell aplasia (PRCA). At diagnosis, the karyotype was normal, the serum erythropoietin level was highly elevated and no T-cell mediated inhibition of erythropoiesis was demonstrated in coculture studies. Conventional immunosuppressive therapy proved ineffective. A year later a diagnosis of hyperfibrotic myelodysplastic syndrome was assessed. The sequential bone marrow examinations in the course of the three years showed a progressive increase in bone marrow fibrosis, erythroid hyperplasia and dysmegakaryocytopoiesis, terminating in the acute myeloid leukemia. This sequence of the events included the appearance of del(5)(q13q33), four years after setting a diagnosis of PRCA. The authors suggest that the absence of both cytogenetic abnormality and the signs of dyshematopoiesis at the diagnosis of PRCA does not exclude ultimately a "clonal" category of the disease. Thus, repeated hematological and cytogenetical reevaluations are recommended.