Cytomegalovirus hepatitis after bone marrow transplantation: An autopsy study with clinical, histologic and laboratory correlates.

Mortality from cytomegalovirus disease after marrow transplantation can be reduced by treatment with antiviral drugs based on the detection of viremia and organ involvement. We examined autopsy liver specimens to determine the frequency, extent and outcome of cytomegalovirus hepatitis and whether cytomegalovirus hepatitis occurred in the absence of cytomegalovirus disease elsewhere. Autopsy specimens from 50 transplant patients were evaluated for cytomegalovirus-infected cells, in five groups of 10, according to extent of CMV during life and at autopsy.

Donor-derived hepatocytes in human hematopoietic cell transplant recipients: evidence of fusion.

Reconstitution of hepatocytes by hematopoietic stem cells-a phenomenon which occurs in rodents under highly selective conditions-results from infrequent fusion between incoming myelomonocytes and host hepatocytes, with subsequent proliferation. Human hematopoietic stem cell transplant recipients have been little studied, with some support for transdifferentiation (direct differentiation). We studied routinely obtained autopsy liver tissue of four female hematopoietic cell transplant recipients with male donors, using a highly specific conjoint immunohistochemistry in situ hybridization light microscopic technique.

Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates.

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells.

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19 cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability.

Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease.

Unlabelled: Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury.

Graft-versus-Host Disease of the Gut: A Histologic Activity Grading System and Validation.

The pathologic interpretation of gut biopsies in hematopoietic cell transplant recipients to assess graft-versus-host disease (GVHD) is well accepted and supplements clinical and endoscopic findings. However, the histologic activity grading of GVHD is controversial, with attempts to predict prognosis or response to treatment largely unsuccessful. GVHD is being diagnosed earlier in its course, raising the possibility that the pathologic grading system can be profitably modified.

Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies.

Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (3 bacteria and 25 viruses) by quantitative polymerase chain reaction and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls.

NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report.

The 2005 National Institute of Health (NIH) Consensus Conference outlined histopathological diagnostic criteria for the major organ systems affected by both acute and chronic graft-versus-host disease (GVHD). The 2014 Consensus Conference led to this updated document with new information from histopathological studies of GVHD in the gut, liver, skin, and oral mucosa and an expanded discussion of GVHD in the lungs and kidneys. The recommendations for final histological diagnostic categories have been simplified from 4 categories to 3: no GVHD, possible GVHD, and likely GVHD, based on better reproducibility achieved by combining the previous categories of "consistent with GVHD" and "definite GVHD" into the single category of "likely GVHD.

Prevalence of chromosomally integrated human herpesvirus 6 in patients with human herpesvirus 6-central nervous system dysfunction.

We identified 37 hematopoietic cell transplantation recipients with human herpesvirus 6 (HHV-6) central nervous system dysfunction and tested donor-recipient pairs for chromosomally integrated HHV-6 (ciHHV-6). One patient had ciHHV-6A with possible HHV-6A reactivation and encephalitis. There was no ciHHV-6 enrichment in this group, but larger studies are needed to determine if patients with ciHHV-6 are at increased risk for HHV-6-associated diseases or other complications.

Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS.

Clonal cytogenetic abnormalities are a major risk factor for relapse after hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). We determined the impact of the recently established 5-group cytogenetic classification of MDS on outcome after HCT. Results were compared with the impact of the International Prognostic Scoring System (IPSS) 3 cytogenetic risk groups, and the additional effect of a monosomal karyotype was assessed.

Keratinocyte dysplasia in hematopoietic stem cell transplantation recipients in the day-28-to-84 posttransplantation period.

Severe keratinocyte dysplasia (SKD) has been reported as a common event in the early posttransplantation period of hematopoietic stem cell transplantation patients. The purpose of our study is to determine the possible causes of SKD during the intermediate posttransplantation period and to ascertain its prevalence in skin biopsies. Skin biopsy slides, obtained from hematopoietic stem cell transplantation recipients who were days 28 to 84 posttransplantation, were evaluated for SKD.

The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation.

Studies by the International Working Group showed that the prognosis of myelofibrosis patients is predicted by the Dynamic International Prognostic Scoring System (DIPSS) risk categorization, which includes patient age, constitutional symptoms, hemoglobin, leukocyte count, and circulating blasts. We evaluated the prognostic usefulness of the DIPSS in 170 patients with myelofibrosis, 12 to 78 years of age (median, 51.5 years of age), who received hematopoietic cell transplantation (HCT) between 1990 and 2009 from related (n = 86) or unrelated donors (n = 84).

Comparison of quantitative real time PCR with Sequencing and ribosomal RNA-FISH for the identification of fungi in formalin fixed, paraffin-embedded tissue specimens.

Background: Identification of the causative agents of invasive fungal infections (IFI) is critical for guiding antifungal therapy. Cultures remain negative in a substantial number of IFI cases. Accordingly, species identification from formalin fixed, paraffin embedded (FFPE) tissue specimens by molecular methods such as fluorescence in situ hybridisation (FISH) and PCR provides an appealing approach to improve management of patients.

Secondary pulmonary alveolar proteinosis: a confusing and potentially serious complication of hematologic malignancy.

Objective: We analyzed the computed tomography and clinical findings of pulmonary alveolar proteinosis secondary to hematologic malignancy.

Materials And Methods: Seven patients with hematologic malignancy and pathologically proven secondary pulmonary alveolar proteinosis were identified from 2000 to 2007. Six had chest computed tomography scans, which were analyzed retrospectively; medical records were also reviewed.

Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis.

Background And Objectives: Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults.

Design, Setting, Participants & Measurements: The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney.

Validation of a flow cytometric scoring system as a prognostic indicator for posttransplantation outcome in patients with myelodysplastic syndrome.

A total of 152 patients with myelodysplastic syndrome (MDS) receiving a first stem cell transplant had marrow cells prospectively analyzed to calculate the flow cytometric scoring system (FCSS) score. The FCSS scores were retrospectively compared with patient outcomes in both univariate and multivariate models. The cumulative incidence of posttransplantation relapse at 3 years was 15%, 10%, and 36% for patients with mild, moderate, and severe FCSS scores, respectively, with the hazard for relapse of 2.

Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen.

To reduce the incidence of graft-versus-host disease (GVHD), we added Thymoglobulin (THY) to dose-adjusted oral busulfan plus cyclophosphamide (targeted BUCY). The starting dose of THY was 4.5 mg/kg given over days -3, -2, and -1, escalated in steps of 1.

Minimal disease detection and confirmation in hematologic malignancies: combining cell sorting with clonality profiling.

Background: In this study we demonstrate the technical application of flow cytometry and cell sorting combined with gene-rearrangement clonality profiling to detect and confirm minimal disease in 2 leukemia and 2 lymphoma cases.

Methods: Specimens with low percentages (0.05%-5%) of abnormal lymphoid populations were identified by flow cytometry.

Soy protein containing isoflavones does not decrease colorectal epithelial cell proliferation in a randomized controlled trial.

Background: Soy isoflavones have numerous biological properties that suggest that they may protect against colorectal cancer. Colorectal epithelial cell proliferation has been used extensively as an intermediate endpoint biomarker for colorectal neoplasia.

Objective: We tested the hypothesis that supplementation with soy protein containing isoflavones decreases colorectal epithelial cell proliferation.

Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia.

We evaluated the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 43 patients with chronic myelomonocytic leukemia. Patients were classified according to the French-American-British and World Health Organization classifications, as well as the International Prognostic Scoring System and the M.D.

Molecular identification of an invasive gingival bacterial community.

A woman with neutropenia developed gingival hyperplasia. Biopsy showed invasion of gingival tissue with mats of filamentous organisms, and molecular analysis by polymerase chain reaction and fluorescence in situ hybridization revealed Capnocytophaga sputigena, Leptotrichia species, and Fusobacterium nucleatum. Oral bacterial flora may cause invasive gingival disease with hyperplasia in immunocompromised patients.

BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients.

We performed a case-control study to determine the association of BK plasma viremia with hemorrhagic cystitis (HC) in hematopoietic cell transplant (HCT) recipients. Thirty cases of HC (14 of which occurred after platelet engraftment with documented BK viruria [BK-HC]) were compared with matched controls. Weekly plasma samples were tested for BK virus DNA by polymerase chain reaction (PCR).