Inherited bone marrow failure with macrothrombocytopenia due to germline tubulin beta class I (TUBB) variant.

Germline mutations in tubulin beta class I (TUBB), which encodes one of the ß-tubulin isoforms, were previously associated with neurological and cutaneous abnormalities. Here, we describe the first case of inherited bone marrow (BM) failure, including marked thrombocytopenia, morphological abnormalities, and cortical dysplasia, associated with a de novo p.D249V variant in TUBB. Mutant TUBB had abnormal cellular localisation in transfected cells. Following interferon/ribavirin therapy administered for transfusion-acquired hepatitis C, severe pancytopenia and BM aplasia ensued, which was unresponsive to immunosuppression. Acquired chromosome arm 6p loss of heterozygosity was identified, leading to somatic loss of the mutant TUBB allele.

Isolated Intraocular Rosai-Dorfman Disease.

BACKGROUND/AIMS: To report a case of Rosai-Dorfman disease (RDD) presenting as a solitary, choroidal mass, initially suspicious for uveal melanoma, in a 72-year-old woman. METHODS: Retrospective case report of a single patient. RESULTS: A 72-year-old woman presented with sudden vision loss in the right eye. A month prior, visual acuity was 20/40, but she was noted to have a choroidal mass confirmed with B-scan ultrasonography. Patient's vision deteriorated significantly a month later and a shallow retinal detachment was newly noted. Magnetic resonance imaging was obtained, demonstrating a hyperintense intraocular tumor on TI imaging. Patient underwent enucleation of the right eye for suspicion of a uveal melanoma. Pathology revealed a mixed cellular infiltrate with histiocytes, some exhibiting emperipolesis. Macrophage immunohistochemical stains were positive, while melanocytic markers were negative. A diagnosis of RDD was made. Subsequently, the patient had a negative workup for systemic involvement. A final diagnosis of intraocular RDD without extraocular and systemic involvement was determined. CONCLUSION: We describe a rare presentation of RDD as a solitary choroidal mass in an elderly patient with overlapping features of uveal melanoma. Definitive diagnosis could only be made on histology. RDD should be considered in the differential diagnosis of a choroidal lesion in the elderly.

Lymphoma Metastasis to Vertebral Body Hemangioma: Collision Tumor Causing Cord Compression.

BACKGROUND: Collision tumors of the spine are extremely uncommon. Prior reports have detailed intracranial collision tumors comprising meningiomas and astrocytomas, as well as metastases to meningiomas. Spinal collision tumors are even rarer, with only 5 cases in the literature, none involving the osseous spine. In this report, we highlight the salient features of a case of lymphoma metastasis to a preexisting benign osseous hemangioma, resulting in cord compression. CASE DESCRIPTION: An 81-year-old woman with a known typical T8 vertebral body hemangioma stable for over 6 years was evaluated for increasing back pain, new gait instability, and urinary retention. Magnetic resonance imaging showed a change in the appearance of the T8 hemangioma, with marrow replacement and new associated epidural soft tissue causing cord compression. A biopsy was performed, which showed diffuse large B-cell lymphoma within blood elements, consistent with lymphoma metastasis to a vertebral body hemangioma. The patient was treated with intravenous steroids and radiation therapy. CONCLUSIONS: Collision tumors of the spine are extremely rare. New or increasingly aggressive appearance of a previously benign spinal osseous lesion should prompt consideration for a collision tumor or malignant transformation of the benign tumor. Biopsy of the lesion should be strongly pursued whenever feasible, as the treatment strategy may vary depending on the histology of the tumor.

Infusion of CD3/CD28 costimulated umbilical cord blood T cells at the time of single umbilical cord blood transplantation may enhance engraftment.

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.

Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.

Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20-25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric-onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging-immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies.

Erythrodermic Leukemia Cutis in a Patient With Pre-B-Cell Acute Lymphoblastic Leukemia.

The clinical differential diagnosis of erythroderma is extensive and includes both benign and malignant causes. The authors present an exceptional case of erythroderma secondary to pre-B-cell lymphoblastic leukemia cutis, with diagnostic findings on biopsy.

Myelofibrosis 2012: it's complicated.

Major advances in myeloproliferative neoplasms in the last decade have cast light on their complexity. The identification of JAK2 (V617F) briefly promised a unifying mechanism of pathogenesis with a single pathway that could be efficiently targeted. Instead, there have been major advances in understanding acquired and background genetic and epigenetic contributors to this group of disorders, with refined risk prediction models and experimental therapeutics that have provided a more nuanced model of disease. In aggregate these observations likely explain the heterogeneity of these disorders and their generally unpredictable response to therapy. Molecular studies, beginning with the identification of JAK2 (V617F), have led to a concept of MPN subtypes existing on a continuum, and additional discoveries such as TET2 and EZH2 mutations have provided the molecular underpinnings to begin to explain overlapping phenotypes in myeloid malignancies more generally. In many ways the pace of molecular discovery is outstripping our ability to integrate these observations into clinical care, both in terms of molecular diagnostics and medical decision making. This review will attempt to summarize, within a clinical context, our evolving understanding of myeloproliferative neoplasms. It focuses on biology, histopathology, prognostic scoring systems, stem cell transplantation as well as selected clinical/preclinical therapeutic observations.

Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease.

Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4(+) and CD8(+) T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4(+) T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4(+) T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.

Cervical unicentric Castleman disease presenting as a neck mass: case report and review of the literature.

Castleman disease is an uncommon lymphoproliferative disorder that usually presents asymptomatically at a single site, most commonly the mediastinum; it is rare in the head and neck. Although Castleman disease may be mistaken for a malignant process such as lymphoma, it is a benign condition that is curable with complete surgical resection. We report the case of a 43-year-old man with the hyaline vascular type of unicentric Castleman disease who presented with an isolated neck mass.

Burkitt lymphoma of the oral cavity: an atypical presentation.

Burkitt lymphoma (BL) is an aggressive form of non-Hodgkin B-cell lymphoma with 3 variants: endemic, sporadic, and immunodeficiency-associated types. The sporadic form, most commonly involving the abdomen and ileocecal region, presents as an abdominal mass, rarely presenting in the orofacial region. A 36-year-old Indian female presented to the Hospital of the University of Pennsylvania for evaluation of a persistent intraoral swelling ulceration of the lower right mandibular alveolar ridge with minimal bony invasion. Progressive systemic symptoms of fatigue, weakness, and fever developed without resolution following treatment for a presumed odontogenic infection in the 4 weeks before presentation. An incisional biopsy revealed a diffuse proliferation of intermediate- to large-sized lymphocytes with multiple small peripheral nucleoli, scant cytoplasm, and nuclear pleomorphism. Nearly all cells displayed Ki67 expression. A final diagnosis of BL was rendered following confirmation of a cMYC translocation by fluorescence in situ hybridization. This article presents a case of the sporadic form of BL with atypical presentation clinically and morphologically, primarily involving the oral soft tissue.

Umbilical cord blood xenografts in immunodeficient mice reveal that T cells enhance hematopoietic engraftment beyond overcoming immune barriers by stimulating stem cell differentiation.

Clinical experience and animal models have shown that donor T cell depletion (TCD) adversely affects engraftment of hematopoietic stem cells (HSCs). Although it is known that donor T cells are acting to overcome residual host immune barriers, they may also exert effects independent of host resistance via direct or indirect interactions with donor stem cells, their microenvironment, or key differentiation events. To more precisely define the effect of T cells on engraftment, we have performed human umbilical cord blood (UCB) transplantation into immunodeficient mice under limiting dilution conditions. UCB mononuclear cells (MNC) or TCD UCB were transplanted into NOD/LtSz-scid/scid B2m(null) (NOD/SCID-beta(2)m(-/-)) mice. Cohorts of mice received UCB MNC or TCD UCB at 5 dose levels between 5 x 10(4) and 5 x 10(6) cells. At dose levels at or above 10(5) cells, engraftment was higher in the MNC recipients (n = 32) than the TCD recipients (n = 31) in a dose-dependent manner. Despite this difference, limiting dilution analysis to determine functional stem cell frequency revealed that SCID repopulating cells in TCD UCB was not significantly less than in CB MNCs, suggesting that T cells may facilitate engraftment at stages beyond the stem cell. Add-back of CD3/CD28 costimulated T cells restored and appeared to enhance engraftment, both in NOD/SCID-beta(2)m(-/-) as well as NOD/LtSz-scid IL2Rgamma(null) (NOG) recipients. These results, in a model where there are minimal host immune barriers to overcome, suggest T cells possess additional graft-facilitating properties. CD3/CD28 costimulation of UCB T cells represents a potential strategy for enhancing the engraftment of UCB.

A novel t(3;8)(q27;q24.1) simultaneously involving both the BCL6 and MYC genes in a diffuse large B-cell lymphoma.

Diffuse large B-cell lymphomas (DLBCLs) are a clinically and biologically heterogeneous group of hematologic malignancies. Specific genetic aberrations underlie some of this heterogeneity. These genetic events include distinct and separate translocations resulting in the dysregulated expression of either BCL6 protein with the t(3;14)(q27;q32) or c-MYC protein with the t(8;14)(q24;q32), as a consequence of the juxtaposition of these oncogenes with heterologous promoters or enhancers, such as those of the immunoglobulin heavy chain gene. Here, we report the case of a patient with DLBCL with a unique t(3;8)(q27;q24.1) that involves the BCL6 and MYC genes. We know of no previous report of this translocation in DLBCL, which simultaneously affects two key genes implicated in lymphomagenesis and may reflect a novel genetic mechanism in neoplastic transformation.