Acute Splenic Infarction at an Academic General Hospital Over 10 Years: Presentation, Etiology, and Outcome.

Few case series provide a current, comprehensive, and detailed description of splenic infarction (SI), an uncommon condition.Retrospective chart review complemented by imaging evaluation and patient follow-up.All adult patients with a confirmed diagnosis of acute SI discharged over 10 years from a single academic center were studied. A systematic literature review was done to compile a complete list of SI etiologies.SI was found in 32 patients, 0.016% of admissions. Ages ranged from 18 to 86 (median 64) years. Cardiogenic emboli were the predominant etiology (20/32, 62.5%) and atrial fibrillation was frequent. Other patients had autoimmune disease (12.5%), associated infection (12.5%), or hematological malignancy (6%). Nine of the patients (28%) had been previously healthy or with no recognized morbidity predisposing to SI. In 5 of 9 hitherto silent antiphospholipid syndrome or mitral valve disease had been identified. Two remained cryptogenic. Most patients presented with abdominal pain (84%), often felt in the left upper quadrant or epigastrium. Associated symptoms, leukocytosis or increased serum lactate dehydrogenase occurred inconsistently (∼25% each). Chest X-ray showed suggestive Lt. supra-diaphragmatic findings in 22%. Thus, the typical predisposing factors and/or clinical presentation should suggest SI to the clinician and be followed by early imaging by computed tomography (CT), highly useful also in atypical presentations. Complications were rare and patients were discharged after 6.5 days (median) on anticoagulant treatment. The systematic literature review revealed an extensive list of conditions underlying SI. In some, SI may be the first and presenting manifestation.SI is a rare event but should be considered in predisposed patients or those with any combination of suggestive clinical features, especially abdominal pain CT evaluation is diagnostic and the outcome is good.

Serum immunoglobulin levels at diagnosis have no prognostic significance in stage A chronic lymphocytic leukemia: a study of 1113 cases from the Israeli CLL Study Group.

OBJECTIVES: Hypogammaglobulinemia, commonly encountered in chronic lymphocytic leukemia (CLL), is one of the main causes of morbidity and mortality; however, its prognostic significance in patients diagnosed in early stages of disease remains uncertain. The aim of this study was to evaluate the predictive power of hypogammaglobulinemia at Bonet stage A. METHODS: Using the database of the Israeli CLL Study Group, we analyzed the relationship between low serum levels of IgG, IgA, and IgM; the presence of paraproteinemia, as well as other well-recognized prognostic markers in CLL; and time to first treatment (TTT) and overall survival. A total of 1113 patients consecutively diagnosed during the last 25 yrs with Binet stage A CLL were evaluated, and baseline information on serum immunoglobulin levels was found in 857 of the cases. RESULTS: Overall survival times correlated with age >65 yr, male gender, the presence of lymphadenopathy, high serum beta 2-microglobulin (b2m), CD38 and ZAP-70 expression, but not with low levels of immunoglobulin or the presence of paraproteinemia. By univariate analysis, patients with low IgA levels had a shorter TTT; however, on multivariate analysis, the presence of lymphadenopathy (P 0.02), b2m (P 0.04), CD38 (P < 0.001), and ZAP-70 (P < 0.001) was the only laboratory parameters with prognostic significance. CONCLUSIONS: In our cohort of patients with early-stage CLL, baseline hypogammaglobulinemia and the presence of paraproteinemia were not found to correlate with prognosis.

Pathogenesis, prevalence, and prognostic significance of cytopenias in chronic lymphocytic leukemia (CLL): a retrospective comparative study of 213 patients from a national CLL database of 1,518 cases.

Utilizing the database of the Israeli CLL Study Group, we investigated the prevalence and prognostic significance of anemia and thrombocytopenia in patients with chronic lymphocytic leukemia (CLL). Of 1,477 patients, 113 had anemia and thrombocytopenia associated with "infiltrative" marrow failure, median survival of 41 and 86 months, respectively. Autoimmune cytopenias were diagnosed in 100 patients, autoimmune hemolytic anemia (AIHA) in 80, and immune thrombocytopenia (ITP) in 31, while 11 had both co-existent. Median survival of patients with AIHA and ITP, from CLL diagnosis, was 96 and 137 months, respectively, but 29 and 75 months from onset of cytopenia. Patients with AIHA from the time of CLL diagnosis had a significantly shorter survival than those without anemia (p < .0001). Survival was similar for patients with AIHA or anemia due to "infiltrative" bone marrow failure (p = .44). The presence of positive antiglobulin test even without hemolysis was associated with worse outcome. Overall survival of patients with ITP and those without cytopenias (p = 0.94) were similar. In conclusion, laboratory or clinical evidence of AIHA has a significant negative impact on the survival of patients with CLL. Outcome for cases with ITP and patients without cytopenias was similar.

[Decitabine treatment in myelodysplastic syndromes--results of a compassionate patient program in Israel].

INTRODUCTION: Hypermethylation of tumor suppressor genes (TSG) has been recognized as an important factor in the pathogenesis of malignancies, including myelodysplastic syndromes (MDS). Decitabine (trade name Dacogen; 5-aza-2'-deoxycytidine) is a cytosine analog which inhibits the enzyme DNA methyltransferase (DNMT), inducing hypomethylation and activates TSG, leading to tumor cell growth inhibition. In clinical trials with hypomethylating agents in advanced MDS, a total response rate of 30-73% has been observed, with a complete response (CR) of 9-37%, partial response (PR] of similar rate and a hematologic improvement (HI] in 20-48% of the patients. AIM: We report the results of a national Israeli compassionate program of decitabine administration to patients with advanced MDS. PATIENTS AND METHODS: From July 2007 through August 2008, under the joint sponsorship of The Israel Society of Hematology and Blood Transfusions and Janssen, Israel, a compassionate program was conducted. Decitabine was administered to patients with advanced MDS who were not candidates for any other anti-MDS treatment, except for supportive care. The selected regimen was a 5-day intravenous administration of 20 mg/m/d, every 28 days. After the program had been completed, an approval of the institutional Helsinki committees was obtained, and the data were collected in an attempt to evaluate the results of this novel treatment. The standard response criteria, i.e. total response, CR, PR and HI were applied. Toxicity, survival and leukemic transformation rate were also analyzed. RESULTS: Twenty-four patients with advanced MDS participated in the program but evaluable information could be collected only on 17 patients. The median number of therapeutic cycles was two per patient. Twelve patients were transfusion-dependent at program onset, of whom 7 either benefited from reduced transfusion requirements or became transfusion-free. The overall response rate was 26%, with 23% PR and 13% HI. Two patients (13%) demonstrated leukemic transformation. The median overall survival was 17 months and the median event-free survival was 13 months. Nine out of 12 patients, who could be evaluated, experienced 3-4 degree bone marrow suppression. A single patient suffered from vocal cord paralysis, apparently, unrelated to the treatment. DISCUSSION AND CONCLUSIONS: The overall response rate was 26% in this national compassionate program of decitabine administration to patients with advanced MDS. Although somewhat low, this is similar to other reports. Possible reasons for the relatively low response rate include a small number of patients, the nature of a compassionate program, the limited number of therapeutic cycles, and the very advanced degree of the disease in most patients who had been on several treatment lines prior to the program. Nevertheless, understanding the role of epigenetics in the pathogenesis of neoplasms and MDS, which led to the introduction of hypomethylation agents such as decitabine into clinical practice, is an encouraging step towards better care of cancer, including MDS.

Cell surface expression of CD25 antigen (surface IL-2 receptor α-chain) is not a prognostic marker in chronic lymphocytic leukemia: results of a retrospective study of 281 patients.

Using the database of the Israeli CLL Study Group, we investigated the incidence and prognostic significance of CD25 expression on the surface of lymphocytic leukemia cells. Strong CD25 expression was found in 46 (16.4 %) of 281 tested cases and was correlated with the presence of splenomegaly (p = 0.04), expression of CD38 antigen (p = 0.001), and FMC-7 (p = 0.04). Age, gender, Binet stage, circulating lymphocyte count, presence of anemia or thrombocytopenia, atypical cell morphology, serum beta 2-microglobulin level, and ZAP-70 expression did not differ in patients with or without cell surface CD25. There was no correlation between CD25 expression and time to first treatment or overall survival. CD25 expression does not appear to be a prognostic factor in CLL.

Left pleural effusion and fever of unknown origin--a clue to thoracic arterial pathology.

The subset of patients who have both fever of unknown origin (FUO) and a nondiagnostic pleural effusion on presentation has not been previously investigated. A retrospective search of all patients classified as 'classic' FUO one week after admission to a department of general internal medicine identified 71 patients over 15 years. Seven were found to have associated pleural effusion(s) on admission (9.8%). In three patients thoracic large vessel pathology was diagnosed (chronic aortic dissection, giant cell arteritis and Takayasu arteritis). In these patients, the pleural effusion was predominantly left-sided, small to moderate in amount and nondiagnostic on thoracentesis. The effusions resolved spontaneously or with appropriate treatment. Thus, in patients with prolonged fever and systemic symptoms, a 'bland' left-sided pleural effusion may be a diagnostic clue to underlying inflammation of large thoracic arteries. Pleural irritation due to its anatomical proximity to the large arteries on the left side of the thorax may underlie the pathogenesis. Recognition of this sign may lead to a more timely diagnosis of occult thoracic large vessel pathology.

Survival trends among 1,325 patients with chronic lymphocytic leukemia seen over the past 40 years in Israel.

In the light of recent data showing survival improvement of patients with chronic lymphocytic leukemia (CLL), we investigated clinical characteristics and survival patterns of patients with CLL over the last 40 years in Israel. Demographic and clinical data collected in the database of the Israeli CLL Study Group were analyzed. Of the 1,325 patients, 221 were diagnosed during the time period 1968-1989, 456 during 1990-1999, and 639 during 2000-2010. There was shift toward older age (median, 71 vs. 68 vs. 66 years) and a higher proportion of patients at Binet stage A at diagnosis (77.6% vs. 66.7% vs. 60.3%) in the more recent time periods. Median survival for the entire cohort was 10.9 years; 12.2 years for patients diagnosed at Binet stage A, 8.5 years for stage B, and 6.4 years for stage C patients. Older age, high-beta 2-microglobulin level, and expression of ZAP-70 predicted shorter survival. There were no apparent changes over time regarding gender, age or different clinical stages. Young patients with Binet stage A had lower life expectancy than the general population; but, in older ages, the survival rates were comparable. There were increased proportions of CLL patients diagnosed in early stages, and, at older age, during the last decades, however, survival rates according to sex, age, or stage remained stable. CLL continues to be an incurable disease affecting survival even in patients diagnosed at early stages. Survival benefit shown in recent trials using chemoimmunotherapy has still to be proven in wider general practice.

Enhancing the action of rituximab in chronic lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab interactions & clinical results in refractory CLL.

Many patients with chronic lymphocytic leukemia (CLL) develop progressive treatment-resistant disease. Rituximab (RTX), a monoclonal antibody targeting CD20 on B lymphocytes and widely used in other indolent B-cell neoplasms is less efficacious in CLL, possibly because of associated complement deficiencies. Initial in vitro and in vivo observations support the central role of complement in rituximab-mediated loss of CD20(+) cells in CLL. In an open trial conducted in outpatient hematology clinics in Israel and Greece, we examined whether providing complement by concurrent administration of fresh frozen plasma (FFP) would enhance the effect of RTX in CLL. Five patients with severe treatment-resistant CLL were included in the trial. All had been previously treated with fludarabine, and three also failed treatment with RTX. Each patient was treated with two units of FFP followed with RTX 375 mg/m(2) as a single agent, repeated every 1-2 weeks as needed. A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. In conclusion, adding FFP to RTX may provide a useful therapeutic option in patients with advanced CLL resistant to treatment. Further studies are needed to confirm and study the efficacy of the FFP/RTX combination in advanced CLL, establish the mechanisms, and possibly extend its use to other B-cell-dependent pathologies, such as treatment-refractory autoimmune diseases.

Expression of interleukin-11 receptor in CD38-positive cells from patients with multiple myeloma.

Interleukin-11, a cytokine with multiple biological activities, has been shown to stimulate the proliferation and to support the long-term growth of human myeloma cell lines. Despite this, no expression of the interleukin-11alpha receptor has so far been demonstrated in myeloma cells. We have investigated the expression of interleukin-11alpha receptor and interleukin-11 at the level of mRNA and protein product in bone marrow mononuclear cells isolated from patients with multiple myeloma using reverse-transcriptase polymerase chain reaction and flow cytometry. The mRNA for interleukin-11alpha receptor and/or the corresponding protein were identified in 9 of 15 patients with multiple myeloma. In contrast, the interleukin-11 was not detected in any of the patients examined.

Persistent anemia in otherwise asymptomatic severe aortic stenosis: a possible indication for valve replacement?

BACKGROUND: The indication for aortic valve replacement in patients with significant aortic stenosis is symptomatology. Aortic stenosis may be associated with bleeding from colonic angiodysplasia, resulting in anemia. Persistent anemia in such patients, despite lack of an identifiable source of bleeding, is not considered an indication for valve replacement. OBJECTIVES: To report our experience with two elderly female patients who suffered from severe asymptomatic aortic stenosis, low levels of large von Willebrand factor multimer (10% and 5% respectively) and persistent anemia requiring multiple blood transfusions. METHODS: Both patients underwent an intensive work-up, but a source of bleeding could not be identified. Aortic valve replacement was performed in both patients. RESULTS: Aortic valve replacement abolished the need for further blood transfusions during a follow-up period of 20 months with normalization of the vWF multimer level (20% and 30% respectively). CONCLUSION: We suggest that aortic valve replacement be considered in selected patients with severe, otherwise asymptomatic aortic stenosis, who suffer from persistent anemia requiring multiple blood transfusions, lack an identifiable source of bleeding and have low levels of large vWF multimers.

Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders.

INTRODUCTION: Patients with T-cell large granular lymphocytic leukemia (T-LGLL) have a high incidence of autoimmune disorders. The pathogenesis of associated T-LGLL and autoimmune abnormalities is not clear. In this study we have investigated the role of cytokines in the development of immune complications in LGLL. PATIENTS AND METHODS: We studied clinical and laboratory features of 15 patients diagnosed with T-LGLL. The patients had various autoimmune disturbances: persistent neutropenia, immune thrombocytopenia, pure red-cell aplasia, Hashimoto's thyroiditis, sicca syndrome, systemic lupus erythemathosus, systemic scleroderma. The T-LGLL cells obtained from these patients were activated by phytohemagglutinin and incubated for 3 days. Using ELISA technique we analysed the release of sIL-2R, IL-4, IL-6, IL-8, IL-10, IL-12 and TNF-alpha in the supernatant. RESULTS: Cytokine analysis of supernatants obtained from the LGLL T cells stimulated with PHA revealed increased sIL-2R production in 40% (six patients), TNF-alpha - in 47% (seven patients), IL-6 - in 67% (10 patients), IL-10 - in 47% (seven) and IL-8 - in 60% (nine) of patients. Levels of IL-4 and IL-12 were not elevated compared to controls. No correlation was found between LGL count, CD4 versus CD8 expansion, or in the clinical findings of the patients and cytokine release in vitro. CONCLUSION: Our findings showing the potential of LGLL cells for cytokine release in vitro suggests that these cells may play a major role in the immune disturbances observed in large granular lymphocytic leukemia accompanied by autoimmunity features.