Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia

PURPOSE: To determine, in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) on interferon alfa (IFNalpha), whether combining pretreatment characteristics and early response profiles would distinguish patients with differential benefits that would allow better decisions on subsequent therapy. PATIENTS AND METHODS: A total of 274 patients treated from 1982 through 1990 with IFNalpha regimens were analyzed. A second group of 137 patients treated with IFNalpha and low-dose cytarabine (ara-C) between 1990 and 1994 was later used to confirm the guidelines derived from the original study group analysis. Patients' pretreatment factors and response to IFNalpha therapy at 3, 6, and 12 months were analyzed in relation to subsequent achievement of major cytogenetic response. After univariate analysis of prognostic factors, a multivariate analysis selected, at 6 months, independent pretreatment factors that added to the response status in predicting subsequent outcome. The results were then applied at the 3- and 12-month periods and confirmed in the subsequent population. RESULTS: Response to IFNalpha therapy at 3, 6, and 12 months was a significant predictor of later major cytogenetic response. The presence of splenomegaly > or = 5 cm below the costal margin (BCM) or thrombocytosis > or = 700 x 10(9)/L pretreatment added significant independent prediction to response. At 6 months, patients with a partial hematologic response (PHR) or resistant disease had a less than 10% chance of achieving a later major cytogenetic response, as were those in complete hematologic response (CHR) and who had pretreatment splenomegaly and thrombocytosis. Applying the model at 3 months showed that only patients with < or = PHR and pretreatment splenomegaly or thrombocytosis at 3 months had such a low major cytogenetic response rate. Finally, at 12 months, patients with CHR still had a 15% to 25% chance of having a major cytogenetic response later if they did not have pretreatment splenomegaly and thrombocytosis. CONCLUSION: This analysis allows better selection of patients with Ph-positive CML on IFNalpha therapy for continuation of IFNalpha versus changing therapy early in the course of CML. For treatment programs that choose to change patients to other investigational therapies (eg, intensive chemotherapy and/or autologous stem-cell transplantation [SCT]), baseline outcome expectations are provided for patients continued on IFNalpha therapy, against which the results of new approaches can be compared.     

Correlation of thrombosis with increased platelet turnover in thrombocytosis

There are no readily applicable methods to routinely assess thrombosis risk and treatment response in thrombocytosis. Reticulated platelets (RP) define the most recently released platelets in the circulation, and the RP% has been shown to estimate platelet turnover in thrombocytopenic states. We examined whether increased RP values were associated with thrombotic complications in thrombocytosis. Platelet count, RP%, and absolute RP count were measured at presentation in 83 patients with chronic or transient thrombocytosis, 46 patients with deep vein (DVT) or arterial (ART) thrombosis and normal platelet counts, and 83 healthy controls with normal platelet counts. Chronic thrombocytosis patients presenting with thrombosis (n = 14) had significantly higher RP% (14.7% +/- 10. 1%, mean +/- SD) than asymptomatic chronic thrombocytosis patients (n = 23, RP% = 3.4% +/- 1.8%), healthy controls (3.4% +/- 1.3%), DVT patients (n = 21, 3.8% +/- 2.1%), or ART patients (n = 25, 4.5% +/- 4.1%, P < .05 for all comparisons). Chronic thrombocytosis patients with thrombosis also had significantly higher absolute RP counts than asymptomatic chronic thrombocytosis patients (98 +/- 64 x 10(9)/L [range, 54 to 249 x 10(9)/L] v 30 +/- 13 x 10(9)/L [range, 11 to 51 x 10(9)/L]; P = .0004), whereas healthy controls, DVT, and ART patients had similarly low absolute RP counts (6 +/- 6 x 10(9)/L, 9 +/- 7 x 10(9)/L, and 11 +/- 7 x 10(9)/L, respectively; P > .49). The RP% and absolute RP counts remained significantly higher in chronic thrombocytosis patients with thrombosis when patients were further subdivided into primary myeloproliferative disorders versus secondary thrombocytosis. Similarly elevated RP percentages and absolute counts were also noted in transient thrombocytosis patients with thrombosis (n = 6, 11.5% +/- 4.4% and 90 +/- 46 x 10(9)/L, respectively) when compared with asymptomatic transient thrombocytosis patients (n = 40, 4.5% +/- 2.7% and 35 +/- 16 x 10(9)/L, respectively) and to all control groups (P < .05 for all comparisons). In addition, 7 of 8 thrombocytosis patients who were studied before developing symptoms of thrombosis had elevated absolute RP counts compared with only 1 of 63 thrombocytosis patients who remained asymptomatic. Follow-up studies in seven chronic thrombocytosis patients showed that successful aspirin treatment of symptomatic recurrent thrombosis significantly reduced the RP% from 17.1% +/- 10.9% before therapy to 4.8% +/- 2.0% after therapy; absolute RP counts decreased from 102 +/- 67 x 10(9)/L to 26 +/- 10 x 10(9)/L (P < .01 for both). We conclude that thrombosis in the setting of an elevated platelet count is associated with increased platelet turnover, which is reversed by aspirin therapy. Measurement of reticulated platelets to assess platelet turnover may be useful in evaluating both treatment response and thrombotic risk in thrombocytosis.     

Visceral larva migrans and the hypereosinophilia syndrome

This is a case of visceral larva migrans and hypereosinophilia syndrome with persistently elevated white blood cell count despite adequate medical therapy in a 4-year-old boy with leukocytosis and splenomegaly. Medical history included reactive airway disease and geophagia (pica). Serology for Toxocara canis revealed elevated IgG and IgM titers. Ophthalmologic evaluation ruled out ocular larva migrans. After 5 days of thiabendazole therapy, leukocytosis persisted, and a second course of anthelmintics was prescribed. Two weeks later, a decrease in leukocytosis was noted. Thiabendazole therapy was continued for 15 more days. Repeated serology for T canis revealed a decreased IgM titer and a further elevated IgG titer. Follow-up showed increased physical activity, improved respiratory status, and resolution of splenomegaly.     

Characterization of the Ca2+ -dependent and -independent interactions between calmodulin and its binding domain of inducible nitric oxide synthase

We reviewed the prevalence of thrombocytosis (platelet count >/=400, 000/microL) and its association with outcome in 135 consecutive endometrial carcinoma patients and compared the platelet count with other prognostic factors. Nineteen of 135 patients (14%) had thrombocytosis. Thrombocytosis was significantly more frequent in advanced disease (stage II-IV), unfavorable grade (G2 and G3), deep myometrial invasion, and lymph-vascular space invasion. The overall 5-year survival rate was 92%. The 5-year survival rate of the 19 patients with thrombocytosis was significantly worse than that of the patients without thrombocytosis (61 vs 96%, P < 0.0001). The recurrence rate was significantly higher in patients with thrombocytosis than in those with a platelet count <400,000/microL (7 vs 32%, P < 0.005). In a multivariate analysis, thrombocytosis continued to be a predictor of worse prognosis. In conclusion, we found thrombocytosis to be a prognostic factor for survival in patients with endometrial carcinoma.     

Age at onset in geriatric bipolar disorder. Effects on clinical presentation and treatment outcomes in an inpatient sample

Incisional complications following infrainguinal vein bypass remain a formidable challenge to the vascular surgeon. A retrospective analysis of 250 infrainguinal vein bypass grafts (214 patients) was undertaken to identify risk factors for the development of incisional complications and determine the impact of incisional complications on outcome. Incisional complications occurred in 47 (19%) of the bypasses. The mean age was 67.8 years and 155 (62%) of the bypasses were performed in men. The patients were divided into two groups based on the presence or absence of an incisional complication. By univariate analysis, the contributing factors for an incisional complication were: veteran hospital status, dialysis dependence, anemia, obesity, leukocytosis, and hypoalbuminemia (p < 0.05). By multivariate analysis, veteran hospital status, female gender, leukocytosis, and prior ipsilateral bypass were independent risk factors for incisional complications (p < 0.05). The increased incidence of incisional complications in the veteran's hospital group was associated with anemia, leukocytosis, decreased lymphocyte count, and increased incidence of tissue loss (p < 0.05). By life-table analysis, incisional complications did not influence primary patency (p = 0.73), secondary patency (p = 0.91), limb salvage (p = 0.69), or survival (p = 0.92). However, a significant suppurative soft-tissue infection ultimately resulted in a high rate of major amputation.     

Still disease in adults

Adult onset Stills disease (ASD), an adult variant of systemic onset juvenile rheumatoid arthritis, is a rare disease entity. The diagnosis is solely a clinical one and often difficult. Clinical and laboratory features are not pathognomonic. The diagnosis of ASD has to be considered in patients with high spiking fever, transient rash, arthralgias, oligo- or polyarticular arthritis, leukocytosis, sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction and high serum ferritin levels. We give a brief review of the clinical features, differential diagnosis, treatment and prognosis.     

Leukemic phase of mantle cell lymphoma presenting as anemia: diagnosis by combining flow cytometry and cytomorphology

We report a case of mantle cell lymphoma in leukemic phase, which was diagnosed by a bone marrow biopsy performed as part of a workup for chronic anemia in a patient without lymphadenopathy. The patient, a 79-year-old man with diabetes mellitus, hypertension, chronic renal failure, congestive heart failure, and atherosclerosis, presented with claudication. On admission, he also had an 8-month history of anemia, during which time he experienced a 18-kg weight loss. On presentation, the patient had normal vital signs, anemia, leukocytosis (as well as an absolute lymphocytosis), and splenomegaly; as mentioned, lymphadenopathy was absent. A bone marrow biopsy showed an increase in small to intermediate-sized, slightly irregular lymphocytes in interstitial nodules. Flow cytometric immunophenotyping of the bone marrow identified a monoclonal population of cells, representing 25% of cells within the bone marrow, with expression of CD19, CD20, immunoglobulin M/D, lambda light chain, HLA-DR, and CD5; reactions for CD10 and CD23 were absent. Based on morphologic and immunophenotypic analysis of the bone marrow, as well as morphologic review of the peripheral blood smear, a diagnosis of mantle cell lymphoma involving the bone marrow and in leukemic phase was made. Subsequent polymerase chain reaction analysis of DNA from peripheral blood identified a population of cells with the bcl-1 rearrangement. This case is unique in that the diagnosis of mantle cell lymphoma was made without lymph node or spleen analysis and the patient, although exhibiting bone marrow and peripheral blood involvement by mantle cell lymphoma at presentation, did not have lymphadenopathy.     

Reversible thrombocytosis and anemia due to miconazole therapy

Miconazole was administered intravenously in six consecutive patients with, active coccidioidal infection. Such treatment was associated with progressive anemia and thrombocytosis. The hematological abnormalities appeared to be dose related and potentially reversible. Bone marrow studies demonstrated erythroid hypoplasia and increased or active platelet production in three subjects. No hemorrhagic or thrombotic episodes were identified. It is suggested that careful hematological monitoring be performed in subjects undergoing systemic miconazole therapy.     

Salmonella typhi infections. A 10-year retrospective study

Enteric fever is still a common health problem in many countries, especially in children. Thus a ten-year retrospective study was carried out to evaluate the clinical and laboratory properties of enteric fever and the incidence of antimicrobial resistance in children. Throughout the past 10 years, Salmonella was isolated in 105 patients by blood culturing, 27 of which were Salmonella typhi. Most of the patients were above the age of two. Besides the typical symptoms and signs of enteric fever, 29.2% of the patients had some neurologic findings. Besides, 68.5% had elevated liver enzymes while only 44.4% had hepatomegaly with or without splenomegaly. Anemia was present in 44%, leukopenia in 16% and leukocytosis in 11.1% of the cases. The emergence of antimicrobial resistance during the last five years against ampicillin, chloramphenicol and trimetoprim-sulfamethoxazole has created a challenge in treating these infections.     

Inflammatory myofibroblastic tumor in children

The authors presented the cases of two children with inflammatory myofibroblastic (IMF) tumor and reviewed the literature to facilitate the preoperative recognition, delineate the clinical features, and describe the natural history of this entity. The first child had IMF tumor arising from the mesentery of the small intestine. He presented with an abdominal mass associated with severe inflammatory response manifested by fever, impaired growth, thrombocytosis, and microcytic, hypochromic anemia. After surgical resection, his fever resolved and his growth rate and the laboratory abnormalities normalized. Five months after initial diagnosis, the fever, anemia, and thrombocytosis recurred along with two tumors arising from the omentum and the abdominal soft tissue. After the second surgery, he remains free of recurrent disease for 30 months. The second child presented with a lung mass that was radiologically indistinguishable from pulmonary sequestration. After surgical resection, she remains free of recurrent disease for 18 months. IMF tumor should be considered in any solid tumor that occurs in association with a chronic inflammatory response. IMF tumor should also be considered in the differential diagnosis of pulmonary sequestration.     

Laboratory diagnosis of idiopathic myelofibrosis. Review of the literature and presentation of 15 cases

We report on 15 patients affected by myelofibrosis. The main clinical aspects were hepatosplenomegaly, anemia and leukocytosis. Immature cells and anisopoikilocytosis of the erythrocytes were frequently found in the peripheral blood. At bone biopsy, various aspects of panhyperplasia, increase in the reticular fibers, myeloid fibrosis and osteosclerosis were observed. Leukocyte alkaline phosphatase was frequently elevated. The clinical and laboratory course of the disease, causes of death and the possible etiopathogenetic aspects of this disease are considered and discussed.     

Clinical study on effect of bushen shengxue paste in treating renal anemia patients

OBJECTIVE: To evaluate the therapeutical mechanism of Bushen Shengxue Paste (BSSXP) on anemia. METHODS: Chronic renal failure induced anemia patients were treated with BSSXP, clinical manifestation, anemia and renal function as indicators were observed in patients. The erythropoietin (EPO) and inhibition of colony-forming unit-erythrocyte (CFU-E) in patients' serum were determined by CFU-E in vitro. RESULTS: The patients' symptoms, renal function and anemia were improved after administration with BSSXP 1-2 course. EPO in serum was slightly increased. The inhibition of CFU-E in patient's serum was significantly decreased. CONCLUSIONS: BSSXP could improve the anemia degree, its mechanism might be through clearing the inhibitor of CFU-E in serum.     

Adult-onset Still's disease associated with G6PD deficiency: a case report and literature review

A 37-year-old man presented with symptoms consistent with adult-onset Still's disease. Fever and leukocytosis were prominent, and the patient was started on high-dose aspirin for possible acute rheumatic fever. He developed severe anemia as a result of glucose-6-phosphate dehydrogenase deficiency. His treatment was changed to naproxen, and he recovered with restoration of his hematologic parameters. Although Still's disease is frequently accompanied by mild-to-moderate anemia, the development of severe anemia should raise the possibilities of hemolysis secondary to glucose-6-phosphate dehydrogenase deficiency.     

Adult-onset Still's disease and its characteristic rash

Still's disease was originally described as one form of rheumatoid arthritis in children beginning with fever and other systemic symptoms. In rare cases it may also begin in the adult and is then referred to as adult-onset Still's disease. The diagnostic criteria include typical rash, arthralgias, bouts of fever, and leukocytosis, as well as lymphadenopathy or splenomegaly, liver dysfunctions, noninfectious angina, and absence of rheumatoid factor and antinuclear antibodies. We report two adult patients with longstanding disease whose exanthema guided us to the correct diagnosis. The rash is a finding with high sensitivity. It is characterized by red macules with distinct borders and is evanescent. During an acute flare of the rash, gentle friction induces erythematous, isomorphic (Koebner) phenomena, which, as we describe here for the first time, may persist longer than the remainder of the fleeting rash.     

Lymphangiomatosis with splenic involvement

Severe splenomegaly and anemia developed in a 5-year-old girl with diffuse lymphangiomatosis of the upper part of the body. Radioisotope scanning and celiac angiography demonstrated lymphangiomatosis of the spleen, a rare but diagnosable condition. Intractable infection in areas of ulcerated skin led to her death from overwhelming sepsis.     

Idiopathic and symptomatic hypereosinophilic syndromes (their comparative characteristics based on 14 cases)

Clinical, hematological, cytogenetic and pathohistological findings in 14 patients with high eosinophilia allowed the authors to distinguish 2 groups of patients: with symptomatic (secondary) and idiopathic hypereosinophilic syndromes (6 and 8 patients, respectively). The latter was characterized by hepato- and splenomegaly, specific cardiac lesion (thromboplastic endocarditis), non-infectious fever, anemia and thrombocytopenia, marked hypercellularity of the bone marrow with inhibition of erythro- and megakaryocytopoiesis. Ph'-chromosome occurred in 2 out of 8 cases. Biopsy and autopsy histology in all cases of idiopathic hypereosinophilic syndrome were typical for myeloproliferative diseases. In symptomatic hypereosinophilic syndrome the above features were not registered.     

The O'Brien filter test in the differential diagnosis of disorders with high-grade thrombocytosis

In the differential diagnosis of primary and secondary thrombocytosis, platelet function test can be used. We have examined the possible role of O'Brien's filter test in the differentiation of primary and secondary thrombocytosis in 53 patients with myeloproliferative diseases with primary thrombocytosis and in 21 patients with other disorders complicated by secondary thrombocytosis. By using heparin as an anticoagulant, the sensitivity of O'Brien's filter test proved to be 75%, and it's specificity was 85.7%. In blood samples anticoagulated with citrate, the sensitivity was 100% and specificity 83.3%. Based on these studies we suggest the use of O'Brien's filterometer as a screening test in the differential diagnosis in patients with elevated (> 400 x 10(9)/L) platelet count. In case of normal results, the causes of reactive thrombocytosis should be cleared first, while with pathologic results, haematological examination of the patients should be performed.     

Familial myeloproliferative syndrome

Familial chronic myeloproliferative syndrome (CMS) was observed in five members from two different generations of the same kindred. Diagnosis included agnogenic myeloid metaplasia (case 1), polycythemia vera (case 2), and essential thrombocythemia (cases 3-5). Cases 1-3 were siblings, case 5 was the daughter of case 1, and case 4 was the cousin of cases 1, 3. Age at diagnosis ranged from 28 to 75 years, cases 1 and 3 were male, and the others were female. The diagnosis was made after an episode of cerebral thrombosis in one patient, during a study for headache and dizziness in another, and fortuitously in the three remainders. All patients had splenomegaly and varying degrees of thrombocytosis. The cytogenetic exam was normal in all four cases. A woman patient was treated with interferon during a pregnancy. Fetal growth was retarded, and the newborn showed bone and genital malformations. No environmental leukemogen factor was found. This familial case strengthens Dameshek's theory of a common pathogenesis of CMS and suggests a genetic and hereditary etiology.     

Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis

We wished to test whether thrombopoietin (TPO) is entirely regulated by receptor binding or if other factors may play a role in the mechanism of TPO regulation. Therefore, we analyzed the TPO serum levels in 43 patients with reactive (secondary) thrombocytosis and in 37 with myeloproliferative thrombocytosis. Thrombocytosis was defined as a platelet level greater than 440 x 10(9)/l. Forty-two patients (98%) with reactive thrombocytosis had high concentrations of IL-6 correlating with elevated C-reactive protein levels. Twenty-three patients (53%) in this group had TPO serum concentrations of more than 300 pg/ml (normal: below 300 pg/ml). Only nine patients (24%) with myeloproliferative thrombocytosis had TPO serum levels above normal range, whereas 28 patients (76%) had normal levels of TPO. No correlation between the TPO serum levels and the concentrations of IL-6 or EPO was established. The other investigated thrombopoietic cytokines (IL-3, IL-11, GM-CSF) were unmeasurable; therefore, a correlation could not be assessed. We conclude that TPO concentrations are not strictly inversely related to platelet count. TPO serum levels are elevated especially in a considerable percentage of patients with reactive thrombocytosis, arguing for the existence of additional mechanisms of TPO regulation.