Benign Hematologic Disorders Research Articles

Infections caused by mycobacterium tuberculosis in patients with hematological disorders and in recipients of hematopoietic stem cell transplant, a twelve year retrospective study

BackgroundTuberculous infections in patients with hematological disorders and hematopoietic stem cell transplant vary in incidence, complications and response to treatment.Methods and materialsA retrospective study of patients with various benign and malignant hematological disorders and recipients of hematopoietic stem cell transplant who were treated at Riyadh Armed Forces Hospital, Saudi Arabia between January 1991 and December 2002 and who developed tuberculous infections was conducted.ResultsTuberculous infections occurred in eighteen patients with hematological disorders and hematopoietic stem cell transplant. The main associated factors were: reduced immunity due to the primary hematological disorder, age more than 50 years and the administration of cytotoxic chemotherapy, steroids or radiotherapy. These infections frequently involved the lungs and predominantly occurred in males and in patients with chronic myeloproliferative disorders, myelodysplastic syndrome and acute myeloid leukemia. In patients treated with intravenous cytotoxic chemotherapy, tuberculous infections tended to occur earlier and also tended to be more disseminated compared to infections occurring in patients treated with oral chemotherapy. Anti-tuberculous treatment was given to 16 patients and it was successful in 15 of these patients.ConclusionTuberculous infections cause significant morbidity and mortality in patients with various hematological disorders and in recipients of hematopoietic stem cell transplant. The early administration of anti-tuberculous therapy and compliance with drug treatment are associated with successful outcomes while delayed management, drug resistance and the presence of miliary infections are associated with poor prognosis and high mortality rates.

Handheld gamma probe used to detect accessory spleens during initial laparoscopic splenectomies

Preoperative determination of the accessory spleen still is a major factor in the failure of both laparoscopic and conventional techniques. This study aimed to evaluate the practicability and efficacy of a handheld gamma probe in identifying accessory spleens at the initial intervention. This study evaluated 17 patients undergoing laparoscopic splenectomy attributable to benign hematologic disorders. All the patients had preoperative ultrasonography, computed tomography (CT) scan, and nuclear scintigraphic examination of the abdominal cavity to assess the size of the spleen, and to determine the existence of the accessory spleen or spleens. For all the patients, a handheld gamma probe count was used intraoperatively as an adjuvant method to define the presence and location of the accessory splenic tissue. Control nuclear scintigraphic examinations of all the patients were performed 1 month after the surgical procedure. In two cases, intraoperatively accessory splenic tissue was detected by gamma probe, confirming the preoperative CT findings for the patients. One of these patients had three accessory spleens, although preoperative CT scan showed only two of them. However, by the help of the gamma probe, a third spleen located retroperitoneally was defined. For two patients, laparoscopic exploration and handheld gamma probe count did not identify any accessory splenic tissue, although preoperative CT scan indicated accessory spleens. For detecting accessory splenic tissue, the sensitivities of the studied techniques were 0% for ultrasonography, 75% for CT scan, 0% for preoperative nuclear scintigraphy, 75% for laparoscopic exploration, and 100% for perioperative gamma probe examination. Preoperative imaging methods for accessory spleen determination still have limited benefits because of their limited sensitivity. Thus, the handheld gamma probe technique may be an adjuvant method for laparoscopic exploration ensuring that no accessory splenic tissue is missed during the initial surgical treatment of benign hematologic disorders.

Quantification of siderophages in bronchoalveolar fluid in transfusional and primary pulmonary hemosiderosis

Transfusional iron overload may occur in the lungs. We hypothesized that quantitating siderophages in the bronchoalveolar fluid (BALF) of heavily transfused patients may prove to be a useful tool in determining lung iron overload in transfusion-dependent patients. The study included six patients (7-20 years) with thalassemia major (TM) who had received multiple blood transfusions, one with hereditary spherocytosis (four blood transfusions) and one with sickle cell disease (never transfused); they were compared to three children with idiopathic pulmonary hemosiderosis (IPH) (2.5-7.0 years) as positive controls. Fiberoptic bronchoscopy with bronchoalveolar lavage was performed in seven patients under general anesthesia for elective surgery and the rest were bronchoscoped electively under sedation. Spirometry was also performed in eight patients. There was no significant difference between children with TM and IPH in siderophages as percentage of total count (95% CI -31.0 to 1.5, P = 0.068). There were positive relationships between both mean serum ferritin values during the preceding year and the total number of units of transfused blood, and percent siderophage count among multiply transfused patients (P = 0.010, P = 0.052, respectively); similar findings were noted for the Golde score (P = 0.001, P = 0.031, respectively). None of the patients showed lung function impairment. In conclusion, in this small study, we found that the BALF of multiply transfused patients with benign hematological disorders contain similar numbers of siderophages to that of patients with IPH; this is strongly suggestive of secondary pulmonary hemosiderosis. The correlation between the patients' serum ferritin, and the BALF siderophages suggests that the later may serve as a marker of pulmonary iron overload in patients requiring blood transfusion and appear to be more sensitive than standard pulmonary function tests.

Incidence and Types of Constitutional Chromosomal Abnormalities in Patients with Hematologic Malignancies

It is important to distinguish between the constitutional and acquired chromosomal abnormality in bone marrow of the patients with the hematologic malignancies, since the constitutional chromosomal abnormality will be continuously observed, even though in remission status of the disease. In this study, we investigated the incidence and types of constitutional chromosomal abnormalities in patients with the hematologic malignancies. This study included 396 patients with benign hematologic disorders and 634 with hematologic malignancies. The cytogenetic analysis of bone marrow aspirates were performed by direct or/and short term culture (24-48 hours). The constitutional chromosomal abnormality was confirmed by phytohemagglutinin-stimulated 72 hour culture with peripheral blood lymphocytes. The incidence of constitutional chromosomal abnormalities was 2.8% in patients with benign hematologic disorders and 2.4% in patients with hematologic malignancies. Among the patients with constitutional chromosomal abnormalities and hematologic malignancies, 12 were males and 3 females. Eleven patients had an age greater than 20 years. One patient had trisomy 21, 1 reciprocal translocation, 1 robertsonian translocation, 3 sex chromosome aneuploidy and 9 inv(9). Two patients showed both constitutional and acquired chromosomal abnormalities on the same chromosome. The constitutional chromosomal abnormality was continuously observed in remission status of hematologic malignancies. The incidence of the constitutional chromosomal abnormalities was low in patients with hematologic malignancies, but the chromosome study with peripheral blood or skin fibroblasts may be necessary for determining accurate cytogenetic response during follow up.

Future Directions for the Use of Hypomethylating Agents

Epigenetics refers to heritable changes in DNA and chromatin that impact gene expression without a change in DNA sequence. Two major steps involved in epigenetic regulation of gene expression include methylation of the promoter region of the gene and deacetylation of specific lysine residues on promoter-associated histones leading to changes in chromatin structure. Promoter hypermethylation is the most extensively studied epigenetic process. Our expanding knowledge of this process has led to its application in the diagnosis, prognosis, and treatment of various hematologic and neoplastic diseases. Several agents, which reverse promoter methylation or inhibit histone deacetylases, are under development for use alone or in combination for a variety of neoplastic diseases. This review discusses the potential use of methylation reversing agents in the treatment of solid tumors and in benign hematologic disorders along with the rationale for combination therapies using hypomethylating agents.

Laparoscopic Splenectomy: A Selected Retrospective Review

Previous investigators have suggested that laparoscopic splenectomy should be the procedure of choice for the treatment of benign hematologic disorders unresponsive to medical therapy. To evaluate the safety and utility of laparoscopic splenectomy for a variety of splenic disorders, we reviewed our collective experience at 2 institutions. We studied our 8-year experience by retrospective chart review. Patient demographic data, splenic pathology, intraoperative events, concomitant procedures, and all adverse perioperative events were recorded. A total of 131 patients had laparoscopic splenectomy, and there were 8 conversions to open surgery. Pathology included 63 with idiopathic thrombocytopenic purpura (ITP), 23 malignancies, 12 thrombotic thrombocytopenic purpura (TTP), 10 autoimmune hemolytic anemia (AIHA), and 23 others. Accessory spleens were noted in 21 patients (16%). Concomitant surgical procedures included 12 hepatic biopsies, 4 distal pancreatectomies, 4 cholecystectomies, and 7 others. Mean operative time was 170 minutes. There were 16 major complications in 16 patients and 2 deaths. Median postoperative length of stay was 3 days. Conversions, due mostly to bleeding, are related to splenic pathology and medical comorbidity and are not temporally related to surgical experience (learning curve). The morbidity, mortality, and conversion rates were low. Laparoscopic splenectomy permits an appropriate abdominal exploration and is associated with a short hospital stay. It is the procedure of choice for most indications for splenectomy.

Hemopoietic chimerism following stem cell transplantation

Hematopoietic chimerism is a measure of the number of donor and recipient cells in the host following stem cell transplantation (SCT). The type of conditioning therapy prior to SCT has a major impact on the chimeric status in the recipient. Different techniques of measurement have varying sensitivities. The use of polymerase chain reaction (PCR) of short tandem repeats (STR) using fluorescent amplification permits quantification using Genescan analysis. When SCT is used for malignant haematological disorders, measurement of chimeric status may indicate early relapse and in aplastic anemia graft rejection. Reduced intensity or T-cell depletion is associated with mixed haemopoietic chimerism. SCT for benign haematological disorders does not require complete donor chimerism for a successful outcome.

101 Laparoscopic splenectomies for the treatment of benign and malignant hematologic disorders

Background Laparoscopic splenectomy (LS) is the surgical approach of choice for patients with hematologic disorders requiring splenectomy. Patients with idiopathic thrombocytopenic purpura (ITP) have normal to slightly enlarged spleens and benefit the most from LS. Methods We reviewed the perioperative outcomes in 101 patients who underwent LS between May 1996 and December 2002. Patients were divided into three groups—ITP, other benign, and malignant hematologic disorders—and compared. Results The ITP patients (n = 48) had significantly smaller spleens and operative times compared with the other groups. Splenomegaly in the other benign (n = 23) and malignant hematologic disorders (n = 30) groups was responsible for higher open conversion rates and greater need for hand-assisted laparoscopic splenectomy (HALS). Conclusions Laparoscopic splenectomy and HALS can be performed with good results for benign and malignant hematologic disorders. The benefits of HALS are similar to LS, so there should be a low threshold for HALS in patients with large spleens.

Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders.

Tumor necrosis factor (TNF), originally identified as a factor produced in the serum of endotoxin-injected animals, is a cytokine that mediates tumor necrosis. To date, 20 different members of the TNF superfamily and 21 different receptors have been identified. All ligands of the TNF superfamily have been found to activate transcription factor NF-kappaB and c-Jun kinase. Members of this family have diverse biologic effects, including induction of apoptosis, promotion of cell survival, and regulation of the immune system. The current review focuses on four members that play important roles in regulating hematopoietic cells and are involved in the pathogenesis of several hematologic malignancies. The potential therapeutic use of these members also is discussed.

Absence of donor-derived keratinocyte stem cells in skin tissues cultured from patients after mobilized peripheral blood hematopoietic stem cell transplantation.

Recent studies suggest that primitive bone marrow-derived cells contribute to regeneration of many tissues, including muscle, endothelium, myocardium, neural tissues, liver, and skin. Conversely, primitive cells resident in muscle and other tissues have been reported to reconstitute hematopoiesis. We investigated the contribution of cells with a primitive hematopoietic phenotype to human epidermal skin formation in recipients of allogeneic mobilized peripheral blood hematopoietic stem cell (HSC) transplantation. Our study population included female patients who had received granulocyte colony-stimulating factor mobilized peripheral blood HSC transplants from male donors for a variety of benign and malignant hematologic disorders at least 6 months before study entry, with a history of skin graft-vs-host disease. Epidermal skin cells (keratinocytes) obtained from punch biopsies of the skin were cultured under conditions specific for growth and expansion of homogenous populations of keratinocytes from keratinocyte stem cells. After multiple passages, DNA was extracted from cultured cells and evaluated by two different polymerase chain reaction (PCR) method for detection of Y chromosome specific sequences. Neither sensitive PCR-based technique revealed the presence of male donor-derived keratinocyte stem cells in keratinocytes cultured from skin biopsies of female allogeneic transplantation recipients. We could not confirm the contribution of donor mobilized peripheral blood hematopoietic stem cells to keratinocyte stem cell populations after HSC transplantation. These results cannot explain the presence of donor-derived cells with keratinocyte phenotypic markers in tissue sections of HSC transplant recipients.

The cure of thalassemia by bone marrow transplantation

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative option for children with various malignant and non-malignant diseases. Most reports studied all age groups amongst children. Herein we analyzed our data in children transplanted at or less than 2-years of age.We reviewed medical charts of 618 patients who underwent 666 transplantation at our center between 1993 and 2015. There were 340 boys and 278 girls. Median age was 0.7 years (range 0.04–2). Stem cell source was bone marrow (BM) in 492 (73.9%), unrelated umbilical cord blood (UCB) in 161 (24.2%) followed by peripheral blood stem cell (PBSC) in 13 (2%) patients. Matched siblings were the most common donors (n = 356, 53.5%), followed by unrelated (n = 161, 24.2%) with haploidentical family member donors in 29 (4.4%) transplants. Disease groups were categorized as benign hematology (Thalassemia, Fanconi, Aplastic anemia etc.), benign neoplasm (Langerhans cell histiocytosis, Hemophagocytic Lymphohistiocytosis etc.), non-neoplasms (metabolic disorders, immunodeficiency disorders etc.) and Leukemia/lymphomas (myeloid and lymphoid malignancies etc.)Cumulative incidence of acute GvHD (I-IV) was 31.5% (n = 210) and grade III-IV GvHD was 8.7% (n = 58). At median follow-up of 115.1 months, the cumulative probability of overall survival (OS) at 5 years was 70.0% ± 1.9%. Our mortality rate was 31.2% (n = 193). The five-year OS was significantly better in patients transplanted for benign hematological disorders (P = .001). Patients transplanted using BM/PBSC as source of stem cells fared significantly better compared to those in which CB was used (P<.001). Post-transplant graft failure remains the leading cause requiring further transplants in this age group. In conclusion, the cumulative probability of OS at 5 years was about 70.0% for all with an OS of 61% in our haploidentical recipients.Analyzing our institutional data over time has enabled us to develop tentative strategies to minimize transplant related toxicities in very young children who are candidates for allo-HCT.

Laparoscopic splenectomy by the "Essen-manoeuvre" for treatment of benign and malignant haematological diseases

Despite its early description, laparoscopic splenectomy has not yet reached the level of a standard operation as a therapeutic option for haematological disease, especially for malignant disorders. We performed laparoscopic splenectomies in a modified 4 port technique and dissection of the splenic vessels by the "Essen-Manoeuvre" and report on 68 attempted laparoscopic splenectomies for benign (n = 42) and malignant (n = 26) haematological disorders. Conversion rate was 9 %, 30-days-mortality was 1.4 %, perioperative morbidity was 11 %, respectively. Accessory spleens were found and resected in 17 % of our patients. Laparoscopic splenectomy is a new minimally invasive option for patients with benign and malignant haematological disease fraught with a special risk of intraoperative bleeding.

Die laparoskopische Splenektomie: Neue Techniken und Indikationen

Over the recent years laparoscopic splenectomy has become the preferred approach for the treatment of many conditions requiring splenic removal. At first limited to small spleens and to benign hematologic disorders, this procedure is now used for a variety of indications. Enlarged spleens are possible to be removed laparoscopically, although this is still a demanding procedure. Two factors facilitated the technique and contributed to its wide acceptance: 1) Change in the technique originally used, by positioning the patient in right lateral decubitus, and approaching the spleen from a postero-lateral direction. 2) The development of new technologies to dissect and divide tissues and vessels, including the ultrasonic shears and the laparoscopic linear stapler. In this article we review the current indications for laparoscopic splenectomy, as well as the techniques to accomplish this procedure.

Decreased CD10-positive mature granulocytes in bone marrow from patients with myelodysplastic syndrome.

We retrospectively examined the maturation of the granulocytic cell lineage in bone marrow specimens from patients with myelodysplastic syndrome (MDS) by flow cytometry using both light scatter and surface marker characteristics, including CD10 and myeloid lineage-associated antigens. The 7 MDS cases we studied included 2 patients with refractory anemia (RA), 3 with RA with ringed sideroblasts, 1 with RA with excess of blasts, and 1 unclassified case. Another 7 patients matched for age and sex who received bone marrow aspirates for lymphoma staging (all negative for lymphoma involvement or any other hematologic abnormalities) were selected as the control group. The percentage of CD10(+) mature granulocytes was significantly lower in patients with MDS than in control patients. Additionally, all patients with MDS had less than 50% CD10(+) cells in the granulocytic lineage. In contrast, only 1 of the 7 control patients had less than 50% CD10(+) cells (P <.01). These results suggest that flow cytometry might be a useful adjunct in the assessment of patients with suspected MDS. Further studies to correlate CD10(+) mature granulocytes from MDS cases with other benign hematologic disorders are indicated to confirm our evaluation.

Laparoscopic splenectomy in patients with hematologic malignancies

Background: Although laparoscopic splenectomy (LS) for benign hematologic disease is well accepted, its role in hematologic malignancies is not clearly defined. This study examined the efficacy and feasibility of LS for hematologic malignancies.Methods: Records were reviewed from patients who underwent LS at two university hospitals. Charts from 77 open splenectomies for malignancy (OM) during the same period were also reviewed.Results: Fifty-three patients underwent LS, 22 for hematologic malignancies (LM) and 31 for benign hematologic disorders (LB). Median splenic weight was greater in the LM group (930 g) than in the LB group (164 g, P = 0.001). LM was associated with longer operations and greater blood loss than was LB. LM had a 41% conversion rate. Morbidity, mortality, and transfusion rates were similar. Median hospital stay was shorter for LM (4 days) than for OM (6 days, P = 0.001).Conclusions: LS is feasible in hematologic malignancies but is associated with increased operative time and blood loss and a high conversion rate. Morbidity and mortality, however, was similar. Shorter hospital stays for LM compared with OM may translate into earlier recovery and initiation of antineoplastic therapy.

Familial Aggregation of Nonhematological Malignancies in Relatives of Patients with Hematological Neoplasms

Familial aggregation of nonhematological malignant disorders (NHMD) was compared in 189 families of patients with hematological neoplasms (HN) with a control group of 36 families of patients with benign hematological disorders and a second group of 33 families of patients with diabetes mellitus. A self-administered questionnaire was used requesting from each family a full list of first- and second-degree relatives, their vital status, current age or age at death, and a list of their chronic diseases, including all malignant disorders. There was no evidence of a significantly increased tendency for developing NHMD among relatives of patients with HN as compared to controls (adjusted odds ratio of 0.88; 95% confidence interval 0.61–1.27). Moreover, in the HN group, no significant difference in the frequency of NHMD was found between the families with and without familial aggregation of HN. Based on the present analysis and our previous observations on familial aggregation of HN, we conclude that the increased aggregation of malignant disorders among relatives of patients with HN is unique to the hematopoietic system and might result from a genetic predisposition to HN in these families.

Ocular manifestations of cardiovascular and hematologic disorders.

The past year's important advancements in the ocular manifestations of cardiovascular and hematologic diseases are reviewed. Systemic changes related to blood pressure and carotid artery disease are commonly manifested on the ophthalmic examination. Ocular ischemic changes have been observed in patients with unusual aortic or congenital cardiac disorders. The ophthalmologist plays an important role in the detection of patients who are at risk for cardiovascular and cerebrovascular events. The hematologic disorders affecting the eye are subdivided into benign and malignant categories. A spectrum of diseases that include sickle cell hemoglobinopathy, aplastic anemia, leukemia, lymphoma, and multiple myeloma are discussed. With increased patient survival time after bone marrow transplantation, secondary ophthalmic complications are being identified. Although the ocular findings in the hematologic maladies are diverse, they may be an indication of serious systemic complications and have significant visual consequences.

Granulocyte-monocyte and Granulocyte-Colony Stimulating Factors in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal disorders of hemopoiesis entailing hypoproliferative and ineffective hematopoiesis. The biology of MDS may relate to uncoupling of hemopoietic cellular differentiative and proliferative programs. The MDS provide a clinical setting for evaluating the evolution of relative benign hematologic disorders into frankly malignant diseases similar to acute myelogenous leukemia (AML). In vitro marrow hemopoietic cultures were utilized to evaluate the effect of granulocyte-monocyte colony-stimulating factor (GM-CSF) and granulocyte-colony stimulating factors (G-CSF) on proliferating differentiative and regenerative responsiveness of marrow cells from MDS patients. We determined possible differing effects of G-CSF and GM-CSF in morphological and cytogenetical subgroups of MDS patients. G-CSF was able to induce granulocytic differentiation of enriched hemopoietic precursors from MDS patients, generally without increased clonal self-generation. G-CSF has greater granulocytic differentiative and less proliferative activity for MDS marrow cells than GM-CSF in vitro, particularly for patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) and those with normal cytogenetics. These findings provided a biologic rationale for in vivo clinical trials using G-CSF in MDS patients. Prospective investigations will be necessary to determine the possible utility of such in vitro studies for designing future in vivo clinical trials with these colony stimulating factors.

Balloon-like platelets in myelodysplastic syndromes—a feature of dysmegakaryopoiesis?

Large bizarre platelets are a frequent finding in the peripheral blood of the myelodysplastic syndrome (MDS). In this study we describe a distinct subpopulation of platelets in MDS which by phase contrast microscopic examination seems to have a balloon-shaped bulge of the cell membrane. Increased numbers of these atypical platelets were found in 24 of 27 MDS patients (89%). Only 3 patients, all with ringsideroblastic anemia, had normal platelet morphology. The number of atypical platelets were negatively correlated ( r = 0.44; p = 0.021) to the peripheral platelet counts in MDS. Among 48 patients with acute leukemia, chronic lymphoproliferative or chronic myeloproliferative disorders, 13 (27%) had atypical platelets, Here, but not in the MDS group, atypical platelets seemed to be associated with recent chemotherapy. In a group of patients with benign hematological disorders abnormal platelet morphology was seen only occasionally. The described atypical platelets most likely reflect maturation disturbances of the megakaryopoiesis. An increased value (>1%) in a cytopenic patient would suggest a diagnosis of MDS, unless associated with recent cytotoxic therapy.

Serum lysozyme activity in children with hematological and malignant disorders.

Pretreatment serum lysozyme activity was high in 2 children with myelomonocytic leukemia, 800 and 1 000 mug/ml, normal in all 10 cases of acute lyelocytic leukemia and subnormal in 21 of 34 cases of acute lymphocytic leukemia. Normal values were found in all but one case of acute lymphocytic leukemia during complete remission including 8 cases after all therapy had been discontinued. All 8 are still in complete remission. Low serum lysozyme activity was found in 5 patients with acute lymphocytic leukemia in complete relapse, this could possibly be helpful in the diagnosis of early relapse. Activity was subnormal in 5 of 17 children with malignant tumours, and in 3 of 65 cases of various benign hematological disorders.