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The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. In addition to its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B cells, T cells, natural killer T cells, and innate lymphoid cells. Many of these cell types are thought to visit the BM only transiently, but for others, like plasma cells and memory T cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points toward an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization, and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders and the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematologic disorders., (© 2021 by The American Society of Hematology.)

Neurotoxic treatments (including proteasome inhibitors, immunomodulatory drugs and vinca-alkaloids) are often used in the treatment of hematologic malignancy. Peripheral neuropathy can be part of a paraneoplastic syndrome accompanying the disease but more commonly is a consequence of treatment with neurotoxic therapies, and produces sensory, motor, autonomic nerve dysfunction or a combination, leading to pain, loss of sensation and functional disability. This review provides an update on peripheral neuropathy in hematologic malignancy, including risk factors, mechanisms and treatment options. We examine the clinical features and risk factors for peripheral neuropathy following bortezomib, thalidomide, brentuximab vedotin and vinca alkaloid treatment, as well as related compounds. We review the current data on pharmacogenetic risk factors for the development of toxicity and highlight areas of future research., Competing Interests: Declaration of competing interest Professor Lazarus is a consultant and promotional speaker for Seattle Genetics and Bristol-Myers Squibb and a consultant for Celgene Corporation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The field of malignant hematology has experienced extraordinary advancements with survival rates doubling for many disorders. As a result, many life-threatening conditions have since evolved into chronic medical ailments. Paralleling these advancements have been increasing rates of complex hematologic pain syndromes, present in up to 60% of patients with malignancy who are receiving active treatment and up to 33% of patients during survivorship. Opioids remain the practice cornerstone to managing malignancy-associated pain. Prevention and management of opioid-related complications have received significant national attention over the past decade, and emerging data suggest that patients with cancer are at equal if not higher risk of opioid-related complications when compared with patients without malignancy. Numerous tools and procedural practice guides are available to help facilitate safe prescribing. The recent development of cancer-specific resources directing algorithmic use of validated pain screening tools, prescription drug monitoring programs, urine drug screens, opioid use disorder risk screening instruments, and controlled substance agreements have further strengthened the framework for safe prescribing. This article, which integrates federal and organizational guidelines with known risk factors for cancer patients, offers a case-based discussion for reviewing safe opioid prescribing practices in the hematology setting., (© 2020 by The American Society of Hematology.)

Myeloproliferative neoplasms are acquired hematological malignancies, mainly affecting the adult and whose morbidity and mortality stems from haemostasis disorders. The most frequently encountered complications include thrombosis, affecting preferentially the arterial territory, but also atypical locations such as splanchnic vein thrombosis. The pathophysiology of these thromboses is complex and involves different actors: blood cells, endothelium and flow conditions. Numerous studies have been conducted to identify risk factors for thrombosis. To date, only two risk factors have been validated through prospective studies (age over 60 years old, history of thrombotic events) and allow classification of patients as "low risk" and "high risk" as the basis for current treatment recommendations. Haemorrhagic manifestations, less frequent than thrombosis, are mainly related to an alteration of primary haemostasis and are therefore manifested by mucocutaneous bleeding. In these patients, platelet dysfunctions and/or acquired Willebrand syndromes can be found. The pathophysiology of thrombosis and platelet dysfunction during myeloproliferative neoplasms remains to date partially unknown. In this review, we offer to focus on physiopathological mechanisms as well as the latest advances in their understanding., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: The aim of this study was to evaluate seizure outcome in children with hematological malignancies and PRES and to identify prognostic factors that could help manage the syndrome., Method: We retrospectively reviewed the report data of 21 patients diagnosed with hematological malignancy or aplastic anemia and PRES between 2008 and 2018. Basic demographic data, oncology treatment, presymptomatic hypertension before PRES manifestation, neurological status, seizure type, and EEG and MRI findings at PRES onset and at the one-year follow-up visit were studied. Patients who developed remote symptomatic seizures or epilepsy were identified., Results: We included 21 children (11 females and 10 males) in the study. Sixteen patients (76.2%) were diagnosed with ALL and the rest individually with AML, CML, T-lymphoma, Burkitt lymphoma, and severe aplastic anemia. Presymptomatic hypertension (PSH) was evaluated in 19 patients and was present in 18 (94.7%). The duration was 9 h and more in 16 patients (88.8%); the severity was grade II in 12 patients (66.7%). Seizures as the initial symptom of PRES were present in 17 patients (80.9%). Four patients (19.0%) were assessed with remote symptomatic seizures. Two of them (9.5%) had ongoing seizures at the one-year follow-up visit and were diagnosed with epilepsy. The presence of gliosis on follow-up MRI indicated worse outcome with development of epilepsy (without statistical significance)., Conclusions: PRES syndrome has an overall good prognosis and the evolution to epilepsy is rare. The severity and duration of PSH or seizure severity and EEG findings at PRES onsetwere not associated with worse neurological outcomes in this study., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: While some regard an association between motor neuron disease (MND) and malignancy as co-incidental, others have argued that it could represent a distinct clinical entity. The present study undertook in depth phenotyping along with assessment of cortical function to further explore disease pathophysiology in MND with malignancy (MND-M) patients., Methods: Clinical features along with assessment of peripheral and cortical function was undertaken in 13 MND-M and results were compared to sporadic and familial MND cohorts., Results: From a cohort 13 patients (10 males; aged 65.2 ± 2.0 years), 38.5% were diagnosed with a haematological malignancy. The lower motor neuron phenotype predominated in the in the MND-M patients (χ 2  = 10.8, P < 0.01), with the upper motor neuron (UMN) score being significantly reduced in MND-M patients compared to sporadic and familial MND cohorts (χ 2  = 6.84, P < 0.01). The neurological deficits did not respond to treatment of the underlying malignancy in the majority of MND-M (92%) patients, and as such there were no significant differences in survival between the cohorts. Despite a paucity of UMN signs, cortical hyperexcitability was evident in MND-M patients, as indicated by reduction in short interval intracortical inhibition (P < 0.01) and increase in motor evoked potential amplitude (P < 0.01), that were similar to findings in sporadic and familial MND cohorts., Conclusions: The present study suggests that MND-M falls within the spectrum of MND., Significance: The concept of a co-incidental association between MND and malignancy is supported through the present study by the presence of cortical dysfunction, combined with clinical findings that can be explained within the spectrum of abnormality evident in classical MND phenotypes., (Copyright © 2019 International Federation of Clinical Neurophysiology. All rights reserved.)

Objective: Neuroimaging studies of hematologic cancer patients report altered activity in dorsal attention and central executive networks. To determine the consequences of these altered brain networks, we evaluated neurophysiological correlates of attention and working memory in hematologic cancer patients prior to initiating treatment., Methods: Hematologic cancer patients (19-80 years) were excluded for premorbid cognitive impairment, prior non-hematologic cancer diagnosis, and prior chemotherapy. Attention was manipulated by presenting an irrelevant spatial cue prior to visual search displays. Working memory was manipulated by presenting irrelevant distractors within memory displays. Electroencephalogram was recorded during task performance., Results: Patients (n = 28) and controls (n = 15) were balanced on age, gender, and education. Spatial cues evoked larger N2pc amplitudes, a correlate of spatial attention, in patients than controls (p < .05; Cohen's d > 0.7). Memory distractors evoked larger contralateral delay activity amplitudes, a correlate of working memory load, in patients (p = .028; Cohen's d = 1.1) but not controls (p = .64)., Conclusions: Prior to initiating treatment, hematologic cancer patients demonstrated poor control over spatial attention and working memory, consistent with altered dorsal attention and central executive network activity., Significance: Hematologic cancer patients may be at a higher risk for selecting, processing, and storing distracting information that would compete with more immediate goal-related behaviors., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background/significance: People with cancer can experience co-occurring related symptoms, labeled symptom clusters. Gastrointestinal (GI) symptoms are common side effects of chemotherapy, but little research has investigated GI symptom clusters. A further gap in symptom cluster research is the lack of studies reporting symptom clusters based on symptom distress ratings., Purpose: To identify distress-based GI symptom clusters and to investigate their relationship to symptom interference with daily life and quality of life (QoL)., Subjects: About 105 adults with hematologic malignancy receiving chemotherapy., Methods: On Day 1 of a cycle of chemotherapy, participants completed a modified version of the Memorial Symptom Assessment Scale assessing 30 clinically relevant symptoms, the M.D. Anderson Symptom Inventory Symptom Interference with Daily Life subscale, and the Fox Simple Quality of Life Scale. Exploratory factor analysis was used to identify distress-based symptom clusters. Symptom clusters with ≥50% GI symptoms were labeled GI symptom clusters. Linear mixed modeling explored relationships between GI symptom clusters and symptom interference with daily life and QoL., Results: Of the six distress-based symptom clusters found, the bloating cluster and appetite cluster were identified as GI symptom clusters. Both the bloating cluster and the appetite cluster were significantly related to symptom interference with daily life, but only the appetite cluster was significantly related to QoL., Conclusions: This research demonstrates the existence of distress-based GI symptom clusters and their relationship to symptom interference and QoL. Future work should explore predictors of distress-based symptom clusters and interventions to manage them., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Demographic and clinical characteristics associated with nonarteritic anterior ischemic optic neuropathy (NAION) are well described. Patients with hematologic neoplasms may share some of these characteristics, and it may be useful clinically to better understand this set of patients. Our objective is to review systematically the characteristics of patients with both hematologic malignancies and NAION., Design: Systematic review., Participants: Patients with NAION diagnosis related in time to a hematologic neoplasm., Methods: Data sources for the study included MEDLINE, Web of Science, LILACS, SciELO, and OpenGrey. The study eligibility criteria included case reports and case series., Results: We found 261 records, with 15 studies included plus our case report. A total of 19 patients (8 female) with mean age of 54.6 years (range, 12-87) were analyzed: 37% (7) non-Hodgkin lymphoma; 26% (5) myeloproliferative neoplasms; 21% (4) myelodysplasia; 16% (3) leukemias. The limitations included verification bias, inability to test statistical association between NAION and hematologic neoplasms, the small number of cases, and confounding factors related to medical history and specific interventions in each case limited the robustness of our conclusions., Conclusions: Our results identified the characteristics of patients with NAION and hematologic neoplasms related in time. Additional observational studies may enlighten the importance of looking for evidence of an occult neoplastic disorder in patients presenting with NAION. A prompt diagnosis would be of invaluable significance for the best management, in terms of follow-up and therapeutics., (Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the reliability of G8 screening tool and the prognostic value of clinical parameters within the Comprehensive Geriatric Assessment (CGA) in clinically fit older patients with hematological malignancies., Materials and Methods: This study was performed to assess the reliability of G8 as a screening tool and to determine the predictive value of CGA items in terms of 1-year overall survival (OS). G8 and CGA were proposed to 107 consecutive patients (65-89 years) with hematological malignancies assessed by their physicians as clinically fit, meaning not exhibiting geriatric syndromes and/or irreversible comorbidities significantly impairing their daily function, and thus able to receive chemotherapy., Results: Out of 107 patients, 90 patients were evaluable and completed both scales; 72% and 80% were defined as "vulnerable" when evaluated with G8 (≤ 14.5) or CGA (≥ 2 impairments) respectively. The area under ROC-curve of G8 compared to CGA was 0.749±0.051. Neither G8 nor CGA total scores were predictive of 1-year OS. However, age (HR=1.105, 95% CI: 1.016-1.202; p=0.019), diagnosis (HR=5.208, 95% CI: 1.895-14.310; p=0.001) and cognitive status (HR=3.260, 95% CI: 1.043-10.194; p=0.042) were predictive of OS., Conclusions: We conclude that in our selected hematological patients: 1) the G8 score does not help selecting patients for CGA, 2) the G8 and CGA total scores do not predict OS, and 3) in addition to the age and disease itself, cognitive impairment appears to be a powerful prognostic factor., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background Aims: The number of hematopoietic stem cells (HSCs) is critical for transplantation. The ex vivo expansion of mobilized peripheral blood (MPB) HSCs is of clinical value for reconstitution to meet clinical need., Methods: This study proposed a simple, defined, stromal-free and serum-free culture system (SF-HSC medium) for clinical use, which is composed of Iscove's modified Dulbecco's medium, cytokine cocktails and serum substitutes. This study also characterized the cellular properties of expanded MPB CD133(+) HSCs from patients with hematologic malignancies and healthy donors by surface antigen, colony-forming cell, long-term culture-initiating cell, gene expression and in vivo engraftment assays., Results: The expanded fold values of CD45(+) white blood cells and CD34(+), CD133(+), CD34(+)CD38(-), CD133(+)CD38(-), CD34(+)CD133(+), colony-forming and long-term culture-initiating cells at the end of 7-day culture from CD133(+) MPB of hematologic malignancies were 9.4-fold, 5.9-fold, 4.0-fold, 35.8-fold, 21.9-fold, 3.8-fold, 11.8-fold and 6.7-fold, and values from healthy donor CD133(+) MPB were 20.7-fold, 14.5-fold, 8.5-fold, 83.8-fold, 37.3-fold, 6.2-fold, 19.1-fold and 14.6-fold. The high enrichment of CD38(-) cells, which were either CD34(+) or CD133(+), sustained the proliferation of early uncommitted HSCs. The expanded cells showed high levels of messenger RNA expression of HOBX4, ABCG2 and HTERT and had the in vivo ability to re-populate NOD/SCID mice., Conclusions: Our results demonstrated that an initial, limited number of MPB CD133(+) HSCs could be expanded functionally in SF-HSC medium. We believe that this serum-free expansion technique can be employed in both basic research and clinical transplantation., (Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Monitoring minimal residual disease (MRD) is useful to evaluate therapeutic response and risk of relapse in patients with hematologic malignancy. Currently available quantitative MRD assays are fluorescence in situ hybridization of chromosomal aberrations; multiparameter flow cytometry of leukemia-associated immunophenotypes; and quantitative polymerase chain reaction (qPCR) analysis of fusion genes, immunoglobulin/T-cell receptor gene rearrangements, genetic alterations, or over-expressed genes. Among the PCR-based markers, genetic alterations are found in acute myelogenous leukemia patients with cytogenetically normal karyotype and can be considered as applicable targets for monitoring of MRD. Screening, confirmation and quantification procedures are important to develop the patient- or tumor-specific MRD assays using the PCR-based markers. Wild-type blocking PCR or coamplification at lower denaturing temperature-PCR is suited for screening of low-abundant genetic alterations, and allele-specific qPCR using primers including mismatched base and locked nucleic acids can quantify not only insertion and duplication of several nucleotides but also single nucleotide mutation in the presence of an excess amount of wild-type nucleotides. In addition to the well-established MRD markers, such as immunoglobulin/T-cell receptor gene rearrangements and fusion genes, utilizing potential MRD markers such as genetic alterations may expand the spectrum of patients in whom MRD can be monitored., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Chronic GVHD is one of the most severe complications of allogeneic HSCT. The sclerotic skin manifestations of cGVHD (ScGVHD) result from inflammation and fibrosis of the dermis, subcutaneous tissue, or fascia, leading to significant functional disability. Risk factors and clinical markers associated with ScGVHD remain largely unexamined. By using a single-visit, cross-sectional design, we evaluated 206 patients with cGVHD at the National Institutes of Health. Most patients manifested severe (ie, 63% National Institutes of Health score "severe"), refractory disease (median treatments = 4). ScGVHD was detected in 109 (52.9%) patients. ScGVHD was associated with greater platelet count (P < .001) and C3 (P < .001), and decreased forced vital capacity (P = .013). Total body irradiation (TBI) was associated with development of ScGVHD (P = .002). TBI administered in reduced-intensity conditioning was most strongly associated with ScGVHD (14/15 patients, P < .0001). Patients with ScGVHD had significant impairments of joint range of motion and grip strength (P < .001). Greater body surface area involvement was associated with poorer survival (P = .015). We conclude that TBI, particularly in reduced-intensity regimens, may be an important risk factor for ScGVHD. Widespread skin involvement is associated with significant functional impairment, distressing symptoms, and diminished survival. This trial is registered at http://www.clinicaltrials.gov as NCT00331968.

Objectives: M-ficolin (ficolin-1) is a complement-activating pattern-recognition molecule structurally related to mannan-binding lectin. It is produced by monocytes and neutrophils, and is found in serum. Its biological role is largely unknown. We assessed M-ficolin concentration in serum from pediatric cancer patients. The aim of this study was to explore association of M-ficolin with clinical and hematological parameters, and to investigate whether the risk of chemotherapy-related infections was related to M-ficolin concentrations in serum., Methods: M-ficolin was measured by time-resolved immunofluorometric assay in serum taken at cancer diagnosis and was correlated with peripheral blood counts and bone marrow examinations performed at the same time., Results: Median M-ficolin concentration in 94 children with cancer was 1.6 μg/mL (interquartile range, 0.57-2.7; range, 0.055-25.8), and was not different from age-matched controls (median, 1.7 μg/mL; p=0.92). M-ficolin was strongly associated with absolute counts of neutrophils (Spearman's rho, 0.45; 95%-CI, 0.26-0.65; p<0.001), monocytes (0.34; 0.12-0.55; p<0.001), and thus phagocytes (0.42; 0.20-0.63; p<0.001) in peripheral blood. Similarly, M-ficolin correlated strongly with neutrophils (0.36; 0.14-0.59; p=0.002) and phagocytes (0.31; 0.08-0.54; p=0.009) in bone marrow. Low serum M-ficolin (≤0.5 μg/mL) was not associated with an increased incidence of fever in neutropenia during chemotherapy (multivariate Poisson rate ratio, 1.04; 95%-CI, 0.68-1.60; p=0.85)., Conclusions: The concentration of M-ficolin in serum from children with cancer was strongly associated with neutrophil and monocyte counts in blood and bone marrow. These results suggest that M-ficolin concentrations in serum reflect the pool of phagocytes., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Background Aims: A phase I trial examined the ability of immunotherapy to mobilize progenitor and activated T cells., Methods: Interleukin (IL)-2 was administered subcutaneously for 11 days, with granulocyte (G)-colony-stimulating factor (CSF) (5 mcg/kg/day) and granulocyte-macrophage (GM)-CSF (7.5 mcg/kg/day) added for the last 5 days. Leukapheresis was initiated on day 11. Thirteen patients were treated (myeloma n = 11, non-Hodgkin's lymphoma n = 2)., Results: Toxicities were minimal. IL-2 was stopped in two patients because of capillary leak (n = 1) and diarrhea (n = 1). Each patient required 2.5 leukaphereses (median; range 1-3) to collect 3.2 x 10⁶ CD34+ cells/kg (median; range 1.9-6.6 x 10⁶/kg). Immune mobilization increased the number of CD3+ CD8+ T cells (P = 0.002), CD56+ natural killer (NK) cells (P = 0.0001), CD8+ CD56+ T cells (P = 0.002) and CD4+ CD25+ cells (P = 0.0001) compared with cancer patients mobilized with G-CSF alone. There was increased lysis of myeloma cells after 7 days (P = 0.03) or 11 days (P = 0.02). The maximum tolerated dose of IL-2 was 1 x 10⁶ IU/m²/day., Conclusions: Immune mobilization is well tolerated with normal subsequent marrow engraftment. As cells within the graft influence lymphocyte recovery, an increased number of functional lymphocytes may result in more rapid immune reconstitution.

Background Aims: Mesenchymal stromal cells (MSC) are the most popular cells used in regenerative medicine and biotechnology. The clonogenic potential of these cells is defined by colony-forming unit-fibroblasts (CFU-F). It is well known that there is an interaction between hematopoietic cells and stromal cells in disease formation pathogenesis. Therefore we hypothesized that there should be a quantitative and qualitative relationship between MSC colonies (CFU-F) and hematopoietic stem cell colonies (colony-forming unit-granulocyte-macrophages; CFU-GM) among patients with and without hematologic diseases., Methods: Forty-two patients were included in this study. Patients were divided into three groups: group A, patients with hematologic malignancies (n =20); group B, patients with bone marrow (BM) failure (n =11); group C, patients without hematologic diseases (n =11). BM aspirates were plated in different densities for CFU-F culture. The plating density was the same for CFU-GM culture., Results: CFU-GM colonies grew in 90% of group A cells and all of group B and C cells (P= 0.0001). CFU-F colonies became visible on the ninth day of plating in group A and on the eight day in groups B and C. There was no statistically significant difference between the groups for the duration of CFU-F colony formation (P= 0.12). There were differences in the morphology of the colonies among the groups., Conclusions: This is the first study that has compared the clonogenic potential of stromal cells and hematopoietic stem cells in the same subjects with and without hematologic diseases. No correlation was shown between the clonogenic potential of stromal cells and hematopoietic cells.

Background/aims: Clotting of haemofiltration circuits is a major complication of continuous renal replacement therapies (CRRT), yet systemic anticoagulation risks haemorrhage. Traditionally, patients with liver failure are managed with no or minimal anticoagulation, because of abnormal clotting tests and the perceived, increased bleeding risk., Methods: We retrospectively reviewed CRRT circuit life in 50 patients; 3 groups of liver failure patients treated with CRRT (acute liver failure (ALF), acute on chronic liver disease (ACLD) and post-elective liver transplantation (LTx)), with two control groups; systemic sepsis (SS) and haematological malignancy (Haem)., Results: CCRT circuit life was significantly greater in the Haem group, compared to the others; 24.3+/-23.9h, vs. 11+/-10.5 ALF, 11.6+/-6.6 ACLF, 7.4+/-5.1 LTx and 9.2+/-6.5 SS, p<0.05, with Haem group requiring fewest new CCRT circuits within 48h; 2.4+/-1.0 vs. 4.3+/-1.3 ALF, 4.2+/-2.1 ACLF, 5.3+/-1.5 LTx and 4.6+/-1.5 SS, p<0.05 and least blood transfusions; 1.2+/-1.3 vs. 4.8+/-4.2 ALF, 4.2+/-4.1 ACLF, 2.2+/-2.1 LTx and 3.0+/-1.5 SS. Transmembrane pressures were higher in those CCRT circuits with haemofilter/dialyzer clotting, compared to other causes, such as access dysfunction (123+/-74 vs. 71.8+/-29.3 mm Hg, p=0.009). In those patients in whom anticoagulation was started due to repeated filter clotting, circuit life improved from 5.6+/-3.4 to 19+/-12.7h, p<0.01., Conclusion: Despite abnormal laboratory coagulation tests and thrombocytopenia, CCRT circuits clot frequently in liver failure patients. Anticoagulation did improve CRRT circuit survival without an obvious increase in bleeding or blood transfusion requirement. Thus anticoagulation should be considered in these patients with repeated circuit clotting.

High-dose therapy with allogeneic hematopoietic cell transplantation (HCT) offers effective control and potential cure of hematopoietic malignancies, but with the cost of associated morbidity that includes adverse effects on quality of life (QOL). A growing body of literature has characterized this impact. Longitudinal studies suggest early moderate impairments that largely return to pretransplantation levels by day 100; the majority of studies suggest that greater than 60% of patients report good to excellent QOL in years 1 to 4 after HCT. Comparisons of allogeneic HCT with autologous HCT and standard-dose chemotherapy suggest impairments in QOL and a different trajectory of recovery in allogeneic HCT, but these conclusions are limited by confounding variables. Cross-sectional studies suggest larger and more persistent decrements in QOL in comparison with matched noncancer controls and population normative data. Acute and chronic graft-versus-host disease (GVHD) are significant threats to QOL. Behavioral interventions show promise to maintain or improve quality of life after allogeneic HCT. The review concludes with recommendations to investigators and clinicians as the state of this research advances.

High dose chemotherapy and radiation have been found to impair the hematopoiesis-supportive capacity of bone marrow stroma. We now provide evidence for an important role of chemotherapy-induced alterations in stromal glycosaminoglycans (GAGs) in reduction of the supportive properties of stromal fibroblasts. Exposure to cytarabine resulted in a pronounced increase in hyaluronan, both in the cell/matrix (p<0.03) and supernatant fraction (p<0.05). Gene expression analysis showed a corresponding increase in gene expression of hyaluronan synthase 1, indicating that the increase in hyaluronan is at least partly under genetic control. Functionally, hyaluronan significantly inhibited the proliferation of early megakaryocytic progenitor cells in a dose dependent way (p=0.01). The increase in hyaluronan was confirmed in vivo by showing a >2-fold increase in bone marrow hyaluronan of patients after chemo- and/or radiotherapy as conditioning for an allogeneic stem cell transplantation, indicating physiologically relevance. Furthermore, there was a trend towards a decrease in the amount and sulfation of stromal heparan sulfate proteoglycans upon exposure to cytarabine, resulting in a 40% reduced binding of SDF1-alpha to stromal cells (p<0.05). In conclusion, there is a pronounced effect of cytarabine treatment on the expression of genes involved in GAG synthesis and degradation, affecting the synthesis and function of stromal GAGs. Our results indicate that chemotherapy-induced changes in stromal GAG profile are likely to affect normal hematopoiesis.

Apoptosis is an intrinsic cell death program that plays critical roles in tissue homeostasis, especially in organs where high rates of daily cell production are offset by rapid cell turnover. The hematopoietic system provides numerous examples attesting to the importance of cell death mechanisms for achieving homeostatic control. Much has been learned about the mechanisms of apoptosis of lymphoid and hematopoietic cells since the seminal observation in 1980 that glucocorticoids induce DNA fragmentation and apoptosis of thymocytes and the demonstration in 1990 that depriving colony-stimulating factors from factor-dependent hematopoietic cells causes programmed cell death. From an understanding of the core components of the apoptosis machinery at the molecular and structural levels, many potential new therapies for leukemia and lymphoma are emerging. In this review, we introduce some of the drug discovery targets thus far identified within the core apoptotic machinery and describe some of the progress to date toward translating our growing knowledge about these targets into new therapies for cancer and leukemia.

Besides its role as an essential regulator of physiologic and pathologic angiogenesis, vascular endothelial growth factor (VEGF) triggers growth, survival, and migration of leukemia and multiple myeloma cells; plays a pivotal role in hematopoiesis; inhibits maturation of dendritic cells; and increases osteoclastic bone-resorbing activity as well as osteoclast chemotaxis. Dysregulation of VEGF expression and signaling pathways therefore plays an important role in the pathogenesis and clinical features of hematologic malignancies, in particular multiple myeloma. Direct and indirect targeting of VEGF and its receptors therefore may provide a potent novel therapeutic approach to overcome resistance to therapies and thereby improve patient outcome.

Objective: The purpose of this retrospective study was to evaluate sequelae and complications after dental extractions and to analyze their impact on medical treatment in patients with myelodysplastic syndrome, acute and chronic leukemia, and multiple myeloma during a 3-year period., Study Design: The study population included 388 patients with hematologic malignancies. All medical and dental charts were reviewed in a retrospective fashion to identify patients who received dental extractions. Preexisting dental disease and intervention (extraction) were evaluated, and parameters such as days of hospitalization and survival rate were compared with those of the remainder population who did not receive dental extractions., Results: Of the 388 patients, 69 underwent dental extractions and 9 had sequelae and complications after the intervention. The resulting complication rate of 13% was reported. Although some patients did experience delay of chemotherapy or bone marrow transplant (BMT), or both, no significant difference was found in the number of days in the hospital for BMT and the survival rate for the patients with sequelae and complications (n = 9) and for the remainder population (n = 319) ( >.05)., Conclusion: Dental extraction intervention provided in the prechemotherapy and pre-BMT time frame did not have a negative bearing on medical outcome.

Background: We have investigated a novel nonmyeloablative conditioning regimen in 44 patients with hematological malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant., Methods: Recipient conditioning consisted of CAMPATH-1H 20 mg/day on Days -8 to -4, fludarabine 30 mg/m(2) on Days -7 to -3 and melphalan 140 mg/m(2) on Day -2. Thirty-six recipients received unmanipulated G-CSF mobilized PBSC from HLA identical siblings and eight received unmanipulated BM from MUD. GvHD prophylaxis was with CYA alone for 38 patients and CYA plus MTX for six sibling recipients., Results: Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite PCR indicate that 18 of 31 patients studied were full donor chimeras, while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range, 3-29 months) 33 patients remain alive in CR, or with no evidence of disease progression. Seven patients relapsed or progressed post-transplant and four of them subsequently died. Four patients died from regimen-related complications. There were no cases of Grades III-IV acute GvHD. Only two patients developed Grade II acute GvHD and only one had chronic GvHD. The estimated probability of non-relapse mortality at 1 year was 11%.Results: Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity and low incidence of GvHD.

Background: The effect of allogeneic hematopoietic cell transplantation (alloHCT) on hematologic malignancies is based on the graft-versus-malignancy effect. Obtaining this effect with reduced toxicity has been possible by non-myeloablative (NMA) alloHCT. Once mixed chimeric status, and host versus graft with graft versus host tolerance are achieved, further strengthening of chimerism and graft-versus-malignancy effect can be obtained by donor lymphocyte infusions (DLIs) when needed., Methods: The patient group consisted of 13 patients with advanced hematological malignancies: seven had CML, four of them in blastic-, two in chronic- and the remainder in accelerated-phase; four patients with AML, refractory or in second remission state; one patient with primary refractory secondary AML; and one patient with ALL relapsed after alloHCT. Conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days and anti-T-lymphocyte globulin (ATG) 10 mg/kg/day for 4 days as immunosuppressive. Ara-C or Bu or melphalan were used as the cytoreductive component. All transplants were performed using HLA-identical sibling donors' peripheral blood hematopoietic cells, after priming with filgrastim. Post-transplant GvHD prophylaxis was achieved with CsA alone in 10 patients, and with CsA plus mycophenolate mofetil in the last three patients., Results: Median follow-up is 3 months (range, 0-20) for all the patients and 6 months (range, 2-15) for the live patients. Donor chimerism was shown in 10 patients, not regarding any pretransplant feature. DLIs were performed in seven patients after transplantation and two of them achieved complete chimeric status and molecular remission. Two CML patients in blastic phase (CML-BP), and the primary refractory secondary AML patient did not respond to procedure. In four patients, drug therapy in conventional doses was added to post-transplant DLIs for their relapsed or refractory diseases. Two patients with AML in second CR, and another CML-BP patient, relapsed or progressed after transplantation. A patient with CML-BP achieved CR and full donor chimerism after transplantation, but developed refractory post-transplant lymphoproliferative disease in the 19th month. Two patients with refractory AML, one patient with relapsed ALL and two patients with CML in chronic phase were in complete chimeric status and free of disease signs. Acute GvHD, Grade II-III, was observed in five patients, and two of them developed secondary progressive chronic GvHD subsequently. We observed one early death in a platelet transfusion refractory blastic phase CML patient due to intracranial hemorrhage. Procedure-related severe toxicity was not observed, either in standard-risk patients or stem-cell donors., Discussion: Establishing engraftment with donor chimerism was the first successful step in this approach. The second step, which was the result of the graft-versus-malignancy effect, could be seen in most of the patients, but was not sustained in all of them because of the aggressiveness of their malignancy. It can be suggested that the immunotherapeutic efficacy of this approach could be more successful, and with acceptable toxicity, when performed in patients with minimal residual disease. The role of NMA conditioning, and of the treatment in standard disease indications, remains to be determined in further studies.

Background: Thiazole orange (TO) is a nucleic-acid-specific dye that enters cells without pretreatment. When it binds to either RNA or DNA, there is an increase in fluorescence emission. This property has been utilized to measure the amount of newly released platelets using flow cytometry. These newly released platelets differ from more mature platelets because they still contain residual amounts of RNA, and have become known as reticulated platelets., Methods: Peripheral blood samples were collected at least 48 h following platelet infusion. For validation, manual reticulocyte counts obtained in the laboratory were compared with results obtained using TO and flow cytometry. Following validation, experiments using platelet-rich plasma were performed to evaluate the presence of reticulated platelets in the sample., Results: Validation experiments comparing the manual and flow cytometric reticulocyte counts gave a strong relationship between the two values (r(2) = 0.92). Reticulated platelet studies performed on platelet-rich plasma samples yielded the following results. Patients who did not engraft within 4 days were significantly different from patients who did engraft within 4 days, idiopathic thrombocytoperic purpura (ITP) patients, and donor platelet segments (all P < 0.0008). Patients who engrafted within 4 days, ITP patients, and donor platelet segments were all statistically similar (all P > 0.08)., Discussion: The statistical difference between patients who did engraft within 4 days and those who did not suggests that this method could have an important clinical impact in determining those patients who are still in need of platelet support. However, great care must be taken when performing and analyzing the results.

The flt3 ligand (FL) is a growth factor for primitive hematopoietic cells. Serum levels of FL are inversely related to the number and proliferative capacity of early hematopoietic progenitors. We sought to elucidate the molecular mechanism underlying this regulation. Expression of FL was examined in peripheral blood (PB) and bone marrow (BM) cells under normal steady-state hematopoiesis and during transient BM failure induced by chemoradiotherapy in 16 patients with hematological malignancies. Using anti-FL antibodies in Western analysis, flow cytometry, and confocal microscopy, we detected high levels of preformed FL inside but not on the surface of T lymphocytes in steady-state hematopoiesis. Intracellular FL colocalized with giantin and ERGIC-53, indicating that it is stored within and close to the Golgi apparatus. After chemotherapy-induced hematopoietic failure, FL rapidly translocated to the surface of T lymphocytes and the levels of FL released to serum increased approximately 100-fold. Expression of FL mRNA was enhanced only about sevenfold; a similar, twofold to sixfold increase in mRNA was observed in the thymus and BM of mice with irradiation-induced aplasia. Upregulation of FL mRNA was delayed when compared with the appearance of cell surface-associated and soluble protein isoforms. The described changes in FL expression in response to chemotherapy-induced aplasia were observed in all patients, irrespective of the diagnosis and treatment regimen. Our data demonstrate that mobilization of preformed FL from intracellular stores rather than de novo synthesis is responsible for increased FL levels in BM failure.

Objective: To evaluate in a multivariate analysis the prognostic factors associated with hematopoietic recovery and the supportive care requirements after autotransplant of progenitor cells (PC) from various sources: bone marrow (BMPC), BMPC & peripheral blood (PBPC), and PBPC alone., Patients and Methods: A total of 570 patients with hematological malignancies and solid tumors underwent high-dose therapy followed by autotransplant. PBPC were obtained after mobilization with chemotherapy and/or cytokines. One-hundred five patients received BMPC, 217 received BMPC & PBPC and 248 PBPC alone; all of the patients received G-CSF or GM-CSF after infusion., Results: In a multivariate analysis the recovery of neutrophils was adversely associated with low numbers of nucleated cells infused (P < 0.13), bone marrow progenitor cell source, and diagnosis of multiple myeloma and acute leukemia (P < 0.001). The factors that adversely affected platelet recovery were low number of nucleated cells and diagnosis of multiple myeloma and acute leukemia (P < 0.001)., Conclusions: We conclude that BMPC adversely affect neutrophil recovery while low numbers of nucleated cells and diagnosis of multiple myeloma and acute leukemia adversely affect both neutrophil and platelet recovery.