Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.

Severe hypercalcaemia and extensive osteolytic lesions in an adult patient with T cell acute lymphoblastic leukaemia.

Hypercalcaemia is a rare feature of acute lymphoblastic leukaemia (ALL) in adults, particularly of the T cell type. We report on a 24-year-old patient with T-ALL, who presented with symptoms of hypercalcaemia (vomitus, acute renal failure), bone pain, extensive osteolytic lesions and normal white cell count without circulating blasts. An increased serum tumor necrosis factor (TNF-alpha) concentration of 35 pg/ml was found; it remained elevated at 52 pg/ml four weeks later, after having achieved haematological remission. Serum concentrations of IL-1beta, IL-6 and IL-2 were within the control range. The pathophysiology of hypercalcaemia in malignancy and possible mediators of bone resorption, in particular TNF-alpha, are discussed.

Platelet dysfunction as the presenting feature of atypical myelodysplastic syndrome with monosomy 7, normal blood counts and no bleeding tendency.

A 71-year-old male patient with atypical myelodysplastic syndrome showing monosomy 7 is described. He presented with severe foot pains, trophic skin and nail changes, loss of distal pulses, all compatible with peripheral arterial occlusive disease. He had completely normal blood counts and no bleeding tendency. Prolonged bleeding time was disclosed by chance, during routine haemostatic studies. An acquired platelet dysfunction was considered, with prolonged bleeding time and large platelets that failed to aggregate in response to arachidonic acid and that had impaired response to collagen and adrenaline. The bone marrow was hypercellular, with numerous dysplastic megakaryocytes and two other slightly dysplastic myeloid lines. Cytogenetic analyses of the bone marrow cells showed a mosaic karyotype: 46,XY/45,XY,-7. On angiography, bilateral thrombosis of the iliac, superficial femoral and popliteal was disclosed. The patient was prepared with platelet transfusions. Arterial thrombectomy and amputation of the left calf were performed. Ten months later, his blood counts showed mild pancytopenia. He died at home. The authors discuss some clinical and pathogenetical aspects of such presentations of myelodysplastic syndromes.

Incidence and prognostic significance of karyotypic subgroups in older patients with acute myeloid leukemia: the Swedish population-based experience.

The Swedish population-based acute myeloid leukemia registry contains data from 3251 patients (excluding acute promyelocytic leukemia) diagnosed between 1997 and 2006. Informative cytogenetic data from 1893 patients were retrospectively added, including 1054 patients aged between 60 and 79 years. Clonal abnormalities were found in 57% of the informative karyotypes. Karyotypic patterns differed by age: t(8;21), inv(16) and t(11q23) were more common in younger patients, whereas loss of 5q, 7q and 17p, monosomal karyotype (MK) and complex karyotypes were more common in older patients. Loss of 5q, 7q and 17p often occurred together within MK. Patients with 5 chromosome abnormalities had worse overall survival than those with fewer abnormalities or normal karyotype in all age groups. Loss of 5q, 7q and/or 17p had, in contrast to MK, a further negative impact on survival. Multivariable Cox regression analyses on risk factors in patients <80 years with cytogenetic abnormalities and intensive treatment revealed that age and performance status had the most significant impact on survival (both P<0.001), followed by sex (P=0.0135) and a karyotype including -7/del(7q) (P=0.048).

Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry.

Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100,000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

[Administration of intravenous immunoglobulins in adult patients with hematologic diseases]. / Primjena imunoglobulina za intravensku upotrebu kod odraslih osoba s bolestima krvi.

Abnormalities in serum immunoglobulin levels or in antibody production may develop as a result of many different diseases. Antibody deficiency may occur in previously normal persons with haematologic malignancies or who received immunosuppressive agents in treatment of cancer or in anticipation of bone marrow transplantation. Effective regimens may develop in primary immunodeficiencies and secondary immunodeficiencies as well as in idiopathic thrombocytopenic purpura. Some reports and information about the other haematological indications were published in medical literature. However, the consensus conference on IVIG at the National Institutes of Health (Bethesda--May 21, 1990) recommended treatment with IVIG in haematology only for CLL, ITP and after bone marrow transplantation, as a prevention for GVHD. The adverse effects of IVIG therapy are minimal, but they exist. The other important subject is the cost of widespread use of IVIG; therefore the indications must be carefully concerned and documented before therapy is started.

[Idiopathic congestive splenomegaly--Banti's disease]. / Idiopatska kongestivna splenomegalija--Bantijeva bolest.

Banti's disease is a condition where congestive splenomegaly can be observed in the absence of intrahepatic or extrahepatic obstruction. The diagnosis is established by splenectomy, but it is necessary to exclude liver diseases or portal vein obstruction before surgery. The advanced stage of Banti's disease may be complicated by upper gastrointestinal haemorrhages; so splenectomy has both diagnostical and therapeutical benefits. Primary lesions of the small splenic arterioles are one of the offered explanations. A patient with no intrahepatic or extrahepatic obstruction, is described. We also excluded diseases which might be complicated by splenomegaly, part of them after splenectomy. Cytogenetics showed normal female pattern. The histologic examination revealed no liver disease, but the spleen was congestive with reduced lymphoid tissue. Immunohistologically, the reduced spleen white-pulp nodules were composed of polyclonal B-cells and T-cells in a normal distribution, discarding indolent lymphoprolipherative disorder. Over one year after splenectomy the patient had no trouble. In conclusion, we believe that Banti's disease is a condition clearly separated from Banti's syndrome. We also believe that splenectomy is the treatment of choice.

Familial Myelodysplastic Syndrome/Acute Myeloid Leukaemia With Monosomy 7: Report of a New Kindred.

Familial juvenile myeloid disorders are uncommon, but better understanding of their basis may lead to crucial advances in the study of leukemogenesis. We report a family with three siblings who died of myelodysplasia and/or acute myeloid leukemia at the age of 10, 11 and 16 years, respectively. Two children died of a fulminant generalized varicella. No somatic constitutional abnormalities were found and histories of exposure to common environmental or occupational mutagens were unremarkable. One of the two tested patients had monosomy of the chromosome 7 in all examined metaphases. Therefore, the clinical and genetic findings are consistent with the "Familial Monosomy 7". A constitutional pericentric inversion of chromosome 9 (p11q13) was detected in the karyotype of the father and both analyzed siblings. In addition, clustering of breast cancer was observed in maternal relatives. As the mode of inheritance and the molecular basis of this disease remain obscure, we believe that it is important to report new cases and attempt to study them as thoroughly as possible. We discuss possible mechanisms of familial tendency to myeloid malignancies.

[Hereditary deficiency of antithrombin III, protein C, protein S and factor XII in 121 patients with venous or arterial thrombosis]. / Nasledni nedostatak antitrombina tri, proteina C, proteina S i XII faktora kod 121 bolesnika s venskom ili arterijskom trombozom.

INTRODUCTION: Hereditary thrombophilia is caused by various inherited disorders which lead to familial tendency to recurrent venous thrombosis usually at an early age and with spontaneous onset. In the studies reported so far, the different prevalence of hereditary thrombophilia among patients with venous thrombosis was found, greatly depending on criteria for selection of patients. Arterial thrombosis is most often the consequence of arteriosclerosis but the prevalence of hereditary thrombophilia among young patients with arterial thrombosis and without recognized risk factors for arteriosclerosis is not known . In this study, the frequency of hereditary deficiencies of antithrombin III (AT III), protein C (PC), protein S (PS), plasminogen (PLMG), factor XII (F XII) and dysfibrinogenaemia was investigated over a 2-year period in 121 patients with venous or arterial thrombosis selected according to the recommendations of the British Committee for Standards in Haematology. PATIENTS AND METHODS: The study included total a of 121 patients (58 males and 63 females) with documented venous or arterial thrombosis. Table 1 shows patient's characteristics regarding gender, age and clinical manifestation of thrombosis. Each patient fulfilled at least one of the following criteria: a) venous thrombosis prior to the age of 45; b) arterial thrombosis prior to the age of 30, without risk factors for arteriosclerosis; c) recurrent thrombosis; d) familial tendency to thrombosis; e) thrombosis of unusual localization. A detailed history was taken from each patient on earlier personal or familial occurrence of thrombosis. For the purpose of this study, thrombophilia was characterized as congenital when the deficient protein was constantly below normal value and when the same deficiency was confirmed in a close family member; acquired when the acquired disorder predisposing to thrombosis was present in absence of constant protein deficiency; and idiopathic when the cause of thrombosis was unknown. All tests were performed in plasma obtained after centrifugation of venous blood anticoagulated with 0.129 mol/1 sodium citrate. Concentrations of fibrinogen, PT, PTT and F XII were measured by standard clotting methods. At III, PC and plasminogen activity were determined by chromogenic methods using commercial reagents (Boehring, Marburg, Germany). AT III, PC and total PS antigen were assayed by Laurell immunoelectrophoresis. The presence of lupus anticoagulant was investigated by recommended tests. RESULTS: A total of 15 patients (12.4%) fulfilled criteria for hereditary thrombophilia. Seven of them (5.8%) had AT III deficiency, five (4.1%) PC deficiency, two (1.6%) PS deficiency, and one patient had F XII deficiency. Secondary thrombophilia was found in 21.5% of patients and the cause of thrombosis in 66.1% of patients was not elucidated. A high frequency of hereditary thrombophilia has been found in patients with arterial thrombosis (40%). Among patients with hereditary thrombophilia thrombosis occurred at significantly younger age (29.9 vs. 42.2 and 40.9 yr.) compared to the patients with secondary and idiopathic thrombophilia, respectively. Patients with hereditary thrombophilia had also a higher occurrence of positive family history related to thrombosis (66.7% vs. 7.7% and 27.5%). DISCUSSION: The prevalence of hereditary thrombophilia in nonselected patients with venous thrombosis is relatively low, and for that reason the selection of patients, according recommended criteria, in whom the screening tests for congenital thrombophilia should be performed, is strongly suggested by many authors. In our study we used the generally accepted recommendations for investigation of patients with venous and arterial thrombosis. The presence of congenital thrombophilia was found in 15 (12.4%) of 121 studied patients, what is in accordance with results of other similarly designed studies. (ABSTRACT TRUNCATED)

[Splenic lymphoma with circulating villous lymphocytes]. / Silenicni limfom s cirkulisucim viloznim limfocitima.

Splenic lymphoma with circulating villous lymphocytes (SLVL) is a special kind of lymphoproliferative disease characterized by specific clinical, haematological, histomorphological and immunophenotypic features that make it different from hairy cell leukaemia, prolymphocytic leukaemia and non-Hodgkin lymphoma. Four patients suffering from SLVL, 3 men and 1 woman, 62 years in average (range 55-67 years), are presented. All patients had anaemia and splenomegaly. One patient had huge pseudocyst of the spleen, two had mild lymph-adenopathy, while 3 patients had thrombocytopenia. The number of WBC ranged from 13-29 x 10(9)/l with lymphocytes ranging from 62-80%. Monoclonal IgM paraprotein was found in 3 patients. Immunophenotyping showed cells with features of mature B lymphocytes. Splenectomy was carried out in three patients. They all recovered and stayed symptomfree. One patient refused surgery. In our opinion SLVL is not a rare disease as it was thought; it should especially be taken into diagnostic consideration in elder patients, particularly in males with splenomegaly and lymphocytosis.

[Diagnosis and follow-up of secondary erythrocytosis in a patient with adenocarcinoma renis by bone marrow culture]. / Dijagnostika i pracenje bolesnika sa sekundarnom eritrocitozom i adenokarcinomom bubrega kultivisanjem eritroidnih prethodnika metodom in vitro.

The paper deals with a patient with secondary erythrocytosis as concequence of renal carcinoma. Although the diagnosis was clear, it was confirmed by bone marrow culture. The colony-forming results were in accordance with secondary erythrocytosis. This case is a good example of high sensitivity of the above mentioned method. The second reason for this paper was the assertion that bone marrow culture can be used as a sensitive follow-up method.

Successful treatment of refractory pure red cell aplasia secondary to chronic lymphocytic leukaemia with cyclosporine A: correlation between clinical and in vitro effects.

This report presents the case of a patient with PRCA in CLL where in vitro culture studies correlated well with successful CS-A treatment. Before initiating CS-A therapy, coculture studies showed that T-cells from peripheral blood of the patient suppressed the formation of CFU-E and BFU-E colonies by normal bone marrow cells. Normal erythropoiesis reappeared in the bone marrow of the patient 3 weeks after the start of CS-A therapy. At this time, cocultures demonstrated that peripheral blood T-cells no longer inhibited the growth of normal BFU-E, although there was persistent suppression of CFU-E. Six months later the patient was in stable remission from PRCA on maintenance therapy with CS-A. Moreover, cocultures showed no T-cell inhibition of normal BFU-E or CFU-E colony formation. The strong correlation between in vitro culture studies and a beneficial clinical outcome observed in this case suggests that in vitro cultures could be used to monitor CS-A treatment in patients with PRCA in CLL.

[Ectopic spleen--2 case reports]. / Ektopija slezine--prikaz dva slucaja.

Wandering spleen occurs consequently to the embryonal disturbances in the development of ligaments connecting the spleen with surrounding tissue. It is rarely the cause of abdominal discomfort, which is usually mild, but nevertheless it can be expressed within the signs of acute abdomen. In our study, two cases of wandering spleen are presented, the diagnosis was put according to the intermittent pain in lower abdomen, echotomography, radionuclide imaging and selective angiography. Splenectomy revealed subjective discomfort. In women, wandering pelvic spleen might be mis-diagnosed as a gynecological disease.

The management of antiphospholipid syndrome.

This paper shows 21 patients with antiphospholipid syndrome, that were diagnosed after thrombosis, recurrent fetal loss or thrombocytopenia. Lupus anticoagulant was detected in 18, anticardiolipin antibodies in 15 and VDRL test was positive in 6 patients. Nine patients had recurrent venous thrombosis, 6 pulmonary embolus, 9 recurrent fetal loss and 15 were with low platelet count. Secondary prevention with oral anticoagulants was applied according to the level of INR 2.5-3.5. Only one patient relapsed due to deficient anticoagulation. Three pregnant patients were treated with aspirin, and low molecular weight heparin, alone or in combination with prednisone. All of them had recurrent spontaneous abortions between 20 and 28 weeks of gestation. In conclusion, early diagnosis of antiphospholipid syndrome is very important. Secondary prevention of thromboembolic complications is recommended according to the level of INR > or = 3. For the prevention of fetal loss we have not agreed upon treatment of all patients. Further studies are needed to define more precisely the optimal type, intensity, and the duration of therapy.

[Results of treatment of patients with advanced multiple myeloma with the vincristine-adriamycin-dexamethasone protocol]. / Rezultati lecenja bolesnika s napredovalim multipnim mijelomom primenom protokola vinkristin-adriablastin-deksametazon.

UNLABELLED: A very few treatment regimens have shown a benefit in patients with multiple myeloma resistant to conventional melphalan/prednosone therapy or similar combinations. The first "biologically designed" protocol for the treatment of advanced, refractory myeloma was a combination of vincristine, doxorubicin and intermittent high-dose dexamethasone, so called VAD regimen. This report summarizes our experience in VAD regimen in the treatment of advanced, refractory myeloma patients, initially treated with melphalan-based chemotherapy. METHODS: Between July 1989 and July 1995, 27 patients with high-tumour-mass stage (Durie Salmon staging system) of the disease were treated with VAD combination. Clinical characteristics of patients are shown in Table 1. There were 17 pts who never responded (9 pts) of who progressed during induction therapy (8 pts). The second group of 10 pts responded to induction therapy and relapsed. Five pts (four with progressive and one with resistant myeloma) were treated with VAD therapy particularly due to significant extramedullary infiltrates. All pts in this study were initially treated with VMCP induction therapy. Seven of them were additionally treated with ABP combination, and this subgroup of pts was characterized as "resistant to melphalan and doxorubicin". The VAD regimen consisted of four-day continuous infusions of vincristine (0.4 mg per day) and doxorubicin (9 mg/m2 per day) in addition to dexamethasone in a dose of 40 mg for four days, beginning od days 1.9 and 17 of each cycle. The response was defined as a reduction of serum myeloma-protein concentration exceeding 75 per cent, with disappearance of Bence-Jones protein excretion. RESULTS: "Good" response to VAD regimen was achieved in 12 of 27 pts (44 per cent), mainly after three cycles of chemotherapy (Table 2). The tumour reduction occurred rapidly (Table 3), without significant myelosuppression. Response-rate was significantly higher in relapsing myeloma pts than in pts with progressive or resistant disease (chi 2 = 4.2; p < 0.05). Neither previous treatment (Table 2) nor the type or paraprotein concentration, degree of marrow infiltration and cytologic type of plasma cells affected the response to VAD. Among 15 pts with "bad" response to VAD, seven died during first four months of treatment. All pts with significant extramedullary infiltrates failed to respond to VAD (chi 2 = 4.91; p < 0.05). Median survival of all pts was 16 months. In responsive pts remissions were of good quality and survival was significantly longer that that in whom treatment failed (Figure 1, left). In responsive pts the median duration of "plateau-phase" was 11 months (Figure 1, right). In three pts who relapsed after the treatment, reinstitution of VAD regimen restored the "plateau-phase". The most important complications of treatment with VAD combination were infections (8 pts) but, fortunately, serious forms (i.e. pneumonia) were observed only in two pts. DISCUSSION: The antitumour effect of VAD regimen originates from a combined effect of doxorubicin and vincristine continuous infusions and intermittent pulses of high-dose corticosteroids. The rationale for protracted administration of vincristine and doxorubicin was based on long generation time and low growth fraction of plasma cells in most patients, while the use of high-dose dexamethasone was based on well-known dose-depend antimyeloma effect of corticosteroids. Using this chemotherapy schedule, significant prolongation of survival was achieved in our responding patients comparing to patients with VAD-resistant myeloma. The major toxic effect of treatment was infection, which was attributed in part to intensive steroid program. Relapse of the disease could be expected about one year after completion of VAD therapy. Nevertheless, the second "plateau-phase" can be obtained upon reinitiation of VAD (ABSTRACT TRUNCATED).

Recurrent venous thrombosis in a patient with chronic lymphocytic leukemia and acquired protein S deficiency.

A patient with chronic lymphocytic leukemia and an undetectable plasma level of protein S (PS), associated with recurrent venous thrombosis, is described. The laboratory investigation revealed the concomitant presence of an inhibitor directed to PS and a monoclonal protein in the patient's plasma. After treatment with prednisone and cyclophosphamide both the inhibitor to PS and the monoclonal component disappeared.

The inhibitory effect of human macrophage inflammatory protein-1 alpha (LD78) on acute myeloid leukemia cells in vitro.

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) has recently been shown to inhibit proliferation of immature hemopoietic progenitors. In addition, significant inhibition of early and mature leukemic progenitors in acute myeloid leukemia (AML) has been obtained with MIP-1 alpha. We performed a study of 25 AML patients at diagnosis to evaluate the effect of a human homolog of MIP-1 alpha (LD78) on bone marrow (BM) and peripheral blood (PB) leukemic progenitors (colony-forming unit-AML [CFU-AML]) and AML cell proliferation. A methylcellulose culture system was used for CFU-AML and incorporation of 3H-TdR for AML cell proliferation. We found that LD78 inhibits CFU-AML colony formation up to 100% for the BM in 14/16 samples studied with the average maximal inhibition of 62.7 +/- 9.1% and up to 100% for the PB in 12/13 samples studied with the average maximal inhibition of 71.4 +/- 9.9%. In addition to this, LD78 inhibited AML cell proliferation up to 60% for the BM in 10/18 samples studied with the average maximal inhibition of 17.8 +/- 3.5%, and up to 87.1% for the PB cell proliferation in 10/16 samples studied with the average maximal inhibition of 27.5 +/- 6.8%. Our results have shown that LD78 is more active on AML progenitors than on AML cell proliferation. Inhibition of the AML cells, although less than that of the progenitors, indicates that more limited activity of LD78 on more mature leukemic cells is present in AML.