Intracranial hemorrhage in adult patients with hematological malignancies

ABSTRACT: BACKGROUND: Clinical characteristics and outcomes of intracranial hemorrhage (ICH) among adult patients with various hematological malignancies are limited. METHODS: A total of 2,574 adult patients diagnosed with hematological malignancies admitted to a single university hospital were enrolled into this study between 2001 and 2010. The clinical characteristics, image reports and outcomes were retrospectively analyzed. RESULTS: A total of 72 patients (48 men and 24 women) with a median age of 56 (range 18 to 86) had an ICH. The overall ICH incidence was 2.8% among adult patients with hematological malignancies. The incidence of ICH was higher in acute myeloid leukemia (AML) patients than in patients with other hematological malignancies (6.3% vs 1.1%, P = 0.001). ICH was more common among patients with central nervous system (CNS) involvement of lymphoma than among patients with CNS involved acute leukemia (P <0.001). Sites of ICH occurrence included the cerebral cortex (60 patients, 83%), basal ganglia (13 patients, 18%), cerebellum (10 patients, 14%), and brainstem (5 patients, 7%). A total of 33 patients (46%) had multifocal hemorrhages. In all, 56 patients (77%) had intraparenchymal hemorrhage, 22 patients (31%) had subdural hemorrhage, 15 patients (21%) had subarachnoid hemorrhage (SAH), and 3 patients (4%) had epidural hemorrhage. A total of 22 patients had 2 or more types of ICH. In all, 46 (64%) patients died of ICH within 30 days of diagnosis, irrespective of the type of hematological malignancy. Multivariate analysis revealed three independent prognostic factors: prolonged prothrombin time (P = 0.008), SAH (P = 0.021), and multifocal cerebral hemorrhage (P = 0.026). CONCLUSIONS: The incidence of ICH in patients with AML is higher than patients with other hematological malignancies. But in those with intracranial malignant disease, patients with CNS involved lymphoma were more prone to ICH than patients with CNS involved acute leukemia. Mortality was similar regardless of the type of hematological malignancy. Neuroimaging studies of the location and type of ICH could assist with prognosis prediction for patients with hematological malignancies.     

Immunological aspects of HBs antigenemia in patients with hematological malignancies

HBsAg positive sera of 70 patients with lymphoproliferative disorders were tested for hepatitis Be antigen (HBEAg) and antibodies to hepatitis B virus serum immunoglobulins: IgG, IgM and IgA were measured systematically in the whole group before and after acquisition of HBV infection. Sera of 37 patients with neoplastic disorders and of control group were also tested for antibodies to rubella virus (LRV). HBeAg was found in serum of 2 asymptomatic carriers of HBsAg, anti-HBs in serum of 2/70 patients who eliminated HBsAg from their serum within 3 months, anti-HBc were found in serum samples of all transient or persistent HBsAg positive patients. Substantial rise of IgG concentration was determined in the whole infected group irrespective of the clinical course. The percentage of patients without anti-RV was lower in HBsAg positive than in HBsAg negative patients. The differences in reactions to RV between cancer patients and control group were not significant. General impairment of humoral immunity or more specific defects are discussed as factors determining relative or absolute deficiency of anti-HBs and persistence of HBsAg in patients with lymphoproliferative disorders.     

Oral infections and septicemia in immunocompromised patients with hematologic malignancies.

To estimate the role of oral infections during septicemic episodes in immunocompromised patients with hematologic malignancies, 78 febrile episodes in 46 patients were monitored with daily clinical and microbiological investigations. The 19 septicemic episodes did not differ from the 59 other febrile episodes in the qualitative composition of the aerobic and facultatively anaerobic oral microflora or in the presence of teeth or acute oral infections on day 1. The oral prevalence rates of members of the family Enterobacteriaceae were higher on days 10, 11, and 12 in the febrile episodes with septicemia when compared with those of febrile episodes without septicemia. The prevalence of a probable oral focus in septicemia was 10.5%, and the prevalence of a probable or possible oral origin in septicemia was 31.6%. The results suggest that prevention and elimination of oral infections may reduce the morbidity and perhaps even the mortality in these patients.     

Pharmacokinetic–pharmacodynamic analysis of voriconazole in Japanese patients with hematological malignancies

Voriconazole has been shown to be safe and effective for fungal infection. However, its population pharmacokinetics for patients with hematological malignancies remains unknown. We performed a population pharmacokinetics study of nine hematological patients with 36 points samples. We approximated the drug concentration curve using a linear one-compartment model. The distribution of volume (Vd), elimination rate constant, and clearance (CL) were 68.7 L, 0.163 h⁻¹, and 11.2 L/h, respectively. By coincidence, our study has verified that the current administration is enough to treat fungus infections by using Monte Carlo simulation. Our data demonstrated that the current administration method is appropriate and effective. Our results may prove to be useful as a basic reference for the clinical usage of voriconazole.     

Staphylococcus aureus bacteremia in patients with hematological malignancies and/or agranulocytosis

A total of 6,253 cases of Staphylococcus aureus bacteremia, including 274 (4.4%) endocarditis cases, were registered in Denmark in the period 1975-1984. Patients with hematological malignancies and/or agranulocytosis accounted for 479 of the bacteremia cases. The incidence of endocarditis in this group of patients was only 0.4% as compared to 4.7% in other patients with staphylococcal bacteremia (p less than 0.01). The lower incidence of endocarditis complicating bacteremia in these patients may justify a shorter course of therapy than usually recommended for suspected endocarditis. Patients with hematological malignancies and other patients with agranulocytosis had a higher mortality (49 and 46%, respectively) than other patients with S. aureus bacteremia (33%). The highest mortality was found in patients with multiple myeloma (71%, p less than 0.01), the lowest in patients with acute lymphocytic leukemia (28%, p less than 0.01). The higher mortality in these patients may indicate that empiric antibiotic regimens in granulocytopenic patients should include a specific anti-staphylococcal agent.     

Donor selection based on NK alloreactivity for patients with hematological malignancies

Natural killer (NK) cells are an important defender against infections and tumors. Their function is regulated by the balance of inhibitory and activating receptors. Among all inhibitory NK receptors: killer immunoglobulin-like receptors (KIR) and CD94/NKG2A recognize human leukocyte antigen (HLA) Class I molecules, allowing NK cells to be ‘licensed’ to avoid autoreactivity, but be fully functional at the same time. Licensed NK cells can target malignant cells with altered or downregulated/missing ‘self’ antigens. NK cell attacking malignant cells is one of the mechanisms of graft-versus-leukemia (GVL) effect. Numerous studies have demonstrated that NK cells improve hematopoietic stem cell transplantation (HCT) survival by reducing relapse mortality through GVL effect. Therapeutic strategies, such as adoptive alloreactive NK cell transfer, CAR-NK cells, antibodies against NKG2A and KIR2DL1-3, have been utilized to treat hematological malignancies in HCT. In this review, NK cell functions, NK cell receptors and ligands, as well as common alloreactive NK donor selection algorithms for patients with hematological malignancies in the setting of HCT are discussed. The goal of this review is to provide insights on the controversial results and provide better understanding and resources on how to perform alloreactive donor NK cell selection in HCT.     

Value of measurement of C-reactive protein in febrile patients with hematological malignancies

The maximum serum levels of C-reactive protein (CRP) in 126 patients with hematological malignancies who had 554 febrile episodes were analyzed retrospectively with regard to documented infections and fever of unknown origin. The CRP levels were significantly higher when the blood culture was positive than when it was negative (p=0.002). The CRP levels were significantly higher when the infection focus was identified than when it was not (p=0.010). In patients with fever of unknown origin the CRP was significantly lower than in patients with microbiologically documented infections (p<0.001). Cytotoxic treatment neither reduced nor enhanced the CRP reaction. The serial measurement of CRP is a reliable and readily available means for differentiating between bacterial infections and other causes of fever in patients with hematological malignancies, also during neutropenia and after cytotoxic treatment.     

Favorable outcome of chronic disseminated candidiasis in four pediatric patients with hematological malignancies

Four children were diagnosed with chronic disseminated candidiasis (CDC) during treatment for hematological malignancies. All presented with persistent fever, not responsive to broad-spectrum antibiotics, abdominal distension and hepatosplenomegaly. Two children needed artificial ventilation because of respiratory insufficiency. The time between onset of neutropenic fever and diagnosis of CDC ranged from 20-49 days. Ultrasound and computed tomography failed to demonstrate CDC during the neutropenic phase. All children needed a liver or spleen biopsy to establish the diagnosis of CDC. Three of four patients continued chemotherapy during treatment for the fungal infection. All patients had a favorable outcome, both in terms of the invasive Candida infections, as well as their underlying malignancies.     

Vancomycin-resistant enterococci colonization in patients with hematological malignancies: screening and its cost-effectiveness

Background and objective

We evaluated the rates of vancomycin-resistant enterococci (VRE) colonization and VRE-related bacteremia in patients with hematological malignancies in terms of routine screening culture and its cost-effectiveness.

Materials and Methods

All patients of the hematology department who were older than 14 years of age and who developed at least one febrile neutropenia episode during chemotherapy for hematological cancers between November 2010 and November 2012 were evaluated retrospectively.

Results

We retrospectively analyzed 282 febrile episodes in 126 neutropenic patients during a two-year study period. The study included 65 cases in the first study-year and 78 cases in the second study-year. The numbers of colonization days and colonized patient were748 days of colonization in 29 patients (44%) in the first study-year and 547 colonization days in 21 patients (26%) in the second study-year, respectively. Routine screening culture for VRE cost $4516,4 (427 cultures) in the first study-year, $5082,7 (504 cultures) in the second study-year depending on the number of patients and their length of stay.

Conclusion

In line with our study results, routine screening of hematological patients for VRE colonization is not costeffective. Routine surveillance culture for VRE should be considered with respect to the conditions of health care setting.     

Prognostic significance of del(20q) in patients with hematological malignancies

Deletions of the long arm of chromosome 20 represent a common chromosomal abnormality associated with myeloid malignancies, in particular with myeloproliferative disorders (MPD), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Using G-banding cytogenetic techniques, we found clones with del(20q) in 36 patients with hematological malignancies examined in our laboratory during the years 2001–2003: in 23 patients as a sole cytogenetic aberration and in 13 patients together with other chromosomal changes. Fluorescence in situ hybridization (FISH) with a probe specific for the 20q12 region was used in all cases to confirm the presence of the clone with deletion. For patients with additional or complex chromosomal rearrangements, multicolor FISH (M-FISH) analysis was performed. Statistical evaluation of the prognostic impact of sex, age, diagnosis, and karyotype was performed. The survival time correlated with the type of chromosomal aberration; no significant differences in survival were found for sex, age, and diagnosis.     

Plasma NO-binding activity in patients with hematological malignancies: Suppressive effect of glucocorticoids

Plasma NO-binding activity was studied in patients with various forms of hematological malignancies. The method used in the study quantitatively evaluated the plasma capacity to bind NO, which reflects the intensity of NO production and the degree of patient’s stress resistance. Plasma NO-binding activity significantly decreases in patients with hematological malignancies. Glucocorticoid treatment promotes the decrease in plasma NO-binding activity, which was dose-dependent. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 11, pp. 562–565, November, 2006     

血管发生与恶性血液病

血管发生是一个极其复杂的过程,在很多生理和病理过程中起重要的作用,与恶性血液疾病的发生、发展有着密切关系。抗血管生成治疗已经成为治疗恶性血液疾病的重要策略。     

Fluorescence in situ hybridization confirmation of 5q deletions in patients with hematological malignancies

Fluorescence in situ hybridization (FISH) using specific probes for the 5q31-32 region and a whole chromosomal painting (WCP) probe for chromosome 5 were used to corroborate the results of classical cytogenetic examinations performed on G-banded chromosomes of 77 patients with hematological malignancies. Using classical cytogenetic methods, we suspected the presence of clones with a deletion 5q in 63 patients, and complex rearrangements with involvement of chromosome 5 in 14 other cases. Fluorescence in situ hybridization proved the occurrence of deletion 5q31 in 23 patients and ascertained translocations of part of the long arms of deleted chromosome 5 with missing region 5q31 in 12 patients. In 2 cases, the 5q31 region was translocated to other chromosomes as a part of complex rearrangements. The combination of classical cytogenetics and FISH with specific probes for the 5q31 band yielded cytogenetic results in 35 cases. Routine FISH detection of deleted regions was possible by commercially available cosmid probes for the 5q31 chromosomal band. The interpretation of small deletions and frequent involvement of the deleted chromosomes 5 in complex translocations were ascertained by WCP probes.     

Morphology and immunophenotyping in hematological malignancies

We evaluated 443 outpatients and inpatients in Keio University Hospital between 1994 and 1999. Morphologic features from peripheral blood and bone marrow aspiration were evaluated in our hematology laboratory, using Wright-Giemsa, peroxidase staining films and other cytochemistry. Immunophenotype was determined by cell surface antigen analysis by laser flow cytometry, FACscan, using various monoclonal antibodies. Information on cytogenetic and molecular genetic characteristics can be also integrated for diagnosis. One hundred fifty patients were diagnosed with acute leukemia, in which 59 cases were ALL and 91 cases were AML. Seventy-four cases were MDS, 76 cases were myeloproliferative disorders, 21 cases were CLL related disorders, 104 patients were malignant lymphoma, and 18 cases were multiple myeloma. The ratio of male to female was 1.7. The probability of diagnostic rate by Immunophenotyping was estimated by Discriminant analysis in 189 patients, using multivariate analysis of immunophenotype compared to morphology. The average probability by immunophenotypic analysis for diagnostic rate was 91.7%, in which the probability for NHL was very high of 97.1%. Thus, morphologic and immunophenotypic analysis is most essential and basic approach in laboratory hematology, from the perspective of rapid and precise diagnostic methods. Recent advance appreciates the rapid contribution for diagnosis by immunophenotypic analysis. Furthermore, Tele-hematology would contribute the standardization for morphologic method in the near future.     

Gene therapy for hematological malignancies

Since cancer is the result of genetic mutations, it should be well suited for correction through gene therapy. Hematological malignancies in which human gene transfer has been performed are leukemias, lymphomas, graft-versushost disease after allogeneic bone marrow transplantation in leukemia, and multiple myeloma. Gene therapy may be used to induce or enhance an antitumor immunological reaction, to correct a genetic defect in the tumor cells, to render the malignant disease more susceptible to conventional therapies, to make the normal host cells more resistant to conventional therapies, or to track cells used for therapy. Gene therapy will probably be most valuable for the eradication of minimal residual disease after the use of conventional therapies. Received: 10 February 2003 / Accepted: 24 February 2003 Correspondence to I.G.H. Schmidt-Wolf     

Impact of galactomannan testing on the prevalence of invasive aspergillosis in patients with hematological malignancies

Galactomannan (GM) is a polysaccharide component of the cell wall of Aspergillus spp. and is released into the host's circulation by growing hyphae. GM testing of patients with hematological malignancies has been rarely considered in recent epidemiologic studies of invasive mould infections (IMIs). The aim of the investigation was to analyze the impact of GM testing on the reported prevalence of IMI by comparing detection rates of IMI before and after the introduction of this diagnostic procedure. Prevalence of IMI was assessed by conducting a prospective single-centre study over seven months in 2010. Results obtained were then compared to those obtained with a representative collection of patients assessed by the same investigators at the same institution over seven months in 2007, i.e., prior to the introduction of GM testing. We found that, in general, detection rates of invasive aspergillosis (IA) and invasive mould infections increased significantly after the introduction of GM analysis. This study may therefore indicate that GM testing has a significant impact on the reported prevalence of IMI. Broad usage of such testing in patients with hematological malignancies may be able to produce a realistic picture of IMI rates when current diagnostic criteria are applied.     

Fungal pathogens and primary antifungal prophylaxis in patients with hematological malignancies: one year experience

Background

Febrile neutropenia (FN) is generally a complication of cancer chemotherapy in patients with hematological malignancies.

Objective

To evaluate the febrile neutropenia episodes of hematological patients and their outcomes with respect to fungal pathogens, primary antifungal prophylaxis antifungal therapy.

Methods

All consecutive patients older than 14 years of age and who developed febrile neutropenia episodes from September 2010 to November 2011 were incorporated into this study.

Results

In total, we retrospectively evaluated 86 consecutive patients and their 148 neutropenic episodes. Of the 86 patients, 45 were male and the mean age was 47,65±15,06 years (range: 17–82 years). The mean MASCC score was 18,72 ± 9,43. Systemic antifungal drug was initiated to 17 patients with probable fungal infection and 12 patients with possible fungal infection. Of seven patients who received posaconazole prophylaxis, five were treated with systemic fungal infection due to possible fungal infection.

Conclusions

It is obvious that more studies focused on primary prophylaxis are needed and primary or secondary antifungal prophylaxis should be evaluated in terms of provided benefits and disadvantages. Timely and appropriately initiated antifungal treatment is one of the most important factors for a good prognosis for recovery from a neutropenic phase.