Cases of transfusion-transmitted babesiosis occurring in nonendemic areas: a diagnostic dilemma.

BACKGROUND: Transfusion-transmitted babesiosis (TTB) has been rapidly increasing in incidence since the beginning of the 21st century. Asymptomatic individuals with Babesia infection are able to donate blood in the United States because of the lack of specific blood donation testing. Blood products collected in Babesia-endemic areas are distributed nationally; thus, clinicians in nonendemic states may fail to include babesiosis in the differential diagnosis of a patient who had a recent transfusion history and a fever of unknown origin. STUDY DESIGN AND METHODS: We report the details of two cases of clinical transfusion-transmitted babesiosis and one asymptomatic infection identified in red blood cell recipients in two nonendemic states (South Carolina and Maryland), which, when combined with three recent additional cases in nonendemic states, totals six recipient infections in three nonendemic states. RESULTS: Delayed diagnosis of transfusion-transmitted babesiosis places patients at risk for increased morbidity and mortality and may result in clinical mismanagement or unnecessary treatments. A peripheral blood smear should be reviewed in any patient with a recent transfusion and a fever of unknown origin. Prompt communication of the diagnosis among physicians is key to ensuring that patients with transfusion-transmitted babesiosis are treated expeditiously, and a transfusion service investigation is necessary to identify additional recipients from the same donor. CONCLUSION: TTB is appearing in traditionally nonendemic states because of blood product distribution patterns. Clinicians should include TTB on the differential diagnosis in any patient presenting who had a recent transfusion history and a fever of unknown origin, regardless of where the transfusion took place.

Recombinant Human Antithrombin in Pregnant Patients with Hereditary Antithrombin Deficiency: Integrated Analysis of Clinical Data.

OBJECTIVES: The purpose of this analysis was to evaluate the use of recombinant human antithrombin (rhAT) in preventing venous thromboembolism (VTE) in pregnant patients with hereditary AT deficiency (HATD). STUDY DESIGN: Data from two clinical trials were pooled. Dosing of rhAT was based on body weight and baseline AT activity, started up to 24 hours before scheduled induction or cesarean delivery, or at the onset of labor. RESULTS: A total of 21 pregnant HATD patients were enrolled. Mean rhAT therapy duration was 4.3 days and dose was 245.1 IU/kg/day. All patients achieved target mean AT activity (80-120% of normal) during rhAT therapy. There were no confirmed VTEs during rhAT treatment or within 7 ( ± 1) days after dosing. Two VTE events (one deep vein thrombosis and one pulmonary embolism) occurred 11 and 14 days after discontinuation of rhAT, in patients managed with prophylactic doses of heparin or low-molecular-weight heparin following delivery. CONCLUSION: rhAT was safe and effective in pregnant HATD patients when administered during the peripartum period, the period of highest VTE risk and a time when anticoagulation therapy is normally withheld. Pregnant HATD patients may benefit from therapeutic, rather than prophylactic, doses of anticoagulation after delivery to protect against postpartum VTE.

Pancytopenia after allogeneic bone marrow transplant due to copper deficiency.

Pancytopenia occurring 1 year or later after allogeneic bone marrow transplantation typically prompts a primary consideration for relapse. We present the case of a 15-year old-girl who underwent transplantation for therapy-related myelodysplasia secondary to Ewing sarcoma treatment who developed pancytopenia with myelodysplasia 1 year after transplant due to copper deficiency. Copper deficiency is an important consideration in the evaluation of pancytopenia and myelodysplasia in pediatric patients.

Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory syndrome that results from unrestrained immune cell activation. Despite significant advances in the understanding of the pathophysiology of HLH, interventions remain limited for this often-fatal condition. Secretory sphingomyelinase (S-SMase) is a pro-inflammatory lipid hydrolase that is upregulated in several inflammatory conditions, including HLH. S-SMase promotes the formation of ceramide, a bioactive lipid implicated in several human disease states. However, the role of the S-SMase/ceramide pathway in HLH remains unexplored. To further evaluate the role of S-SMase upregulation in HLH, we tested the serum of patients with HLH (n = 16; primary = 3, secondary = 13) and healthy control patients (n = 25) for serum S-SMase activity with tandem sphingolipid metabolomic profiling. Patients with HLH exhibited elevated levels of serum S-SMase activity, with concomitant elevations in several ceramide species and sphingosine, while levels of sphingosine-1-phosphate were significantly decreased. Importantly, the ratio of C16 -ceramide:sphingosine was uniquely elevated in HLH patients that died despite appropriate treatment, but remained low in HLH patients that survived, suggesting that this ratio may be of prognostic significance. Together, these results demonstrate upregulation of the S-SMase/ceramide pathway in HLH, and suggest that the balance of ceramide and sphingosine determine clinical outcomes in HLH. .

Cutaneous presentation of T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is the most common mature T-cell leukemia (MTCL). Cutaneous involvement is a characteristic symptom of T-PLL and appears in up to one-third of cases; however, T-PLL is a relatively unknown disease in the field of dermatology. In this article, we seek to increase awareness and educate physicians about the clinical manifestations of T-PLL. Hopefully, an increased awareness of this disease will lead to more prompt diagnoses and better prognoses for affected patients.

Update on anemia and neutropenia in copper deficiency.

PURPOSE OF REVIEW: Copper deficiency is an under-recognized cause of reversible refractory anemia and leukopenia, particularly neutropenia, often misdiagnosed as myelodysplastic syndrome (MDS). Clinicians and hematopathologists need to be aware of distinct morphologic findings to distinguish these entities including cytoplasmic vacuolization of both erythroid and myeloid precursors, excess iron stores, ringed sideroblasts, iron incorporation in plasma cells, and variable marrow cellularity. In contrast, the findings in MDS do not include myeloid lineage vacuolization, abnormal nuclear lobulation of both erythroid and myeloid precursors, nuclear/cytoplasmic dyssynchrony, or dysmegakaryopoiesis with abnormalities of nuclear lobulation and size. RECENT FINDINGS: The mechanism of neutropenia remains unknown; however, the study by Peled and coworkers suggests that copper deficiency results in the inhibition of differentiation and self-renewal of CD34(+) hematopoietic progenitor cells. A number of recent studies have reported on the association of copper deficiency with the development of concomitant neurologic deficits manifested as peripheral neuropathies and myeloneuropathy indistinguishable from the findings seen in vitamin B12 deficiency. SUMMARY: Patients presenting with refractory anemia and leukopenia with or without associated neurologic deficits should have copper and ceruloplasmin levels measured as part of their diagnostic evaluation.

Scalp Metastasis as an Initial Manifestation of Squamous Cell Carcinoma of the Lung: Case Report of an Extremely Rare Entity.

Cutaneous metastasis of primary visceral neoplasm is an unusual phenomenon. However, cutaneous metastasis as an initial presentation of clinically silent visceral neoplasm is exceedingly rare. We are reporting a unique case of an elderly male patient who presented with a solitary scalp metastasis as an initial manifestation of underlying lung cancer. Further diagnostic evaluation revealed neoplastic primary lung disease. This case report emphasizes the importance of physicians being aware of these unusual clinical presentations of visceral malignancies. It is also critical to order appropriate diagnostic tests promptly to establish an accurate diagnosis and begin the proper treatment for a better prognosis. Skin lesions can be a diagnostic manifestation of lung cancer and predict a poor prognosis. We conclude that in patients with a history of smoking or lung cancer who present with cutaneous lesions, the possibility of skin metastasis of primary lung cancer should always be considered in the differential diagnosis.

Disseminated neuroendocrine carcinoma in a pediatric patient: a rare case and diagnostic challenge.

A previously healthy 16-year-old female presented with 1-month history of fever, cough, extremity pain, left upper quadrant pain, and night sweats. Imaging studies revealed mediastinal lymphadenopathy, lung and liver masses, and bony lesions. Liver and bone marrow biopsies revealed small tumor cells with a high nuclear cytoplasmic ratio, stippled chromatin, and inconspicuous nucleoli surrounded by bands of collagen. Immunohistochemically, the tumor cells were positive for epithelial (epithelial membrane antigen and cytokeratin AE1/AE3) and neuroendocrine markers (chromogranin and synaptophysin), and negative for other antigens tested, including vimentin, desmin, CD99, and WT-1. The morphologic features and immunohistochemical profile was consistent with neuroendocrine carcinoma. Despite several chemotherapeutic regimens, the patient had progressive disease and enrolled in a phase 1 trial. Thorough histopathologic evaluation, including immunohistochemical stains is a crucial component for diagnosing this rare, aggressive tumor in children and adolescents.

Clinically silent massive fetomaternal hemorrhage: important lessons from an illustrative case.

Massive fetomaternal hemorrhage (FMH) >150 mL is rare and may occur in the absence of high-risk obstetrical events. The significance of FMH in Rh D-negative women is alloimmunization with an increased risk of hemolytic disease of the newborn in subsequent Rh D-positive pregnancies and adverse outcomes for the fetus/neonate. The Kleihauer-Betke (KB) acid elution test is used to quantify fetal erythrocytes in the circulation of Rh D-negative women postpartum and to calculate the dose of Rh immune globulin (RhIG) needed for prophylaxis against alloimmunization. In this case, the KB stain unexpectedly revealed 4.5% fetal cells, a finding consistent with a massive FMH of 225 mL, in the absence of a predisposing cause and clinical signs in the infant. This case underscores the importance of FMH quantification in all Rh D-negative women with Rh D-positive fetuses, uncomplicated pregnancies, and healthy newborns. We discuss factors that can affect KB test performance and caveats in interpretation.

Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature.

Hemophagocytic lymphohistiocytosis (HLH) is rare in adults and is usually fatal without treatment. We present a consecutive series of 18 adults with HLH diagnosed at our institution between 2004 and 2009. All diagnoses were confirmed by pathology. The median age at diagnosis was 56 years (range: 18-73 years), with a male: female ratio of 2:1. Patients uniformly presented with fever. Fifty-five per cent of the patients presented with evidence of hepatomegaly or splenomegaly. All of the patients had at least a bi- or trilineage cytopenia. Elevated liver enzymes, hyperferritinemia, hypertriglyceridemia and hyperfibrinogenemia were seen in 50, 100, 40 and 50% of patients, respectively. The presumed causes were as follows; haematological malignancies (n = 4), post-autologous stem cell transplant (n = 2), infection (n = 2), rheumatologic illness (n = 2), sickle cell disease (n = 1), post-orthotopic liver transplant (n = 1) and idiopathic (n = 3). The median time from suspicion to diagnosis was 5 days (1-27 days). Corticosteroids and/or cyclosporine were the most frequently used treatment regimen. Other agents used were etoposide, IVIG, cyclophosphamide and chemotherapy. The mortality rate was 72%, with multi-system organ failure being the most common cause of death. Median survival time from diagnosis was 35 days. Six patients are alive to date. In a univariate analysis, the presence of fever was the only factor that was statistically significant for predicting a poor prognosis (early mortality) (p = 0.05). In conclusion, a high index of suspicion is the critical factor for early diagnosis. Early treatment with immunosuppressant is warranted, and a thorough diagnostic evaluation to identify the underlying cause should be undertaken.

PAX-5: a valuable immunohistochemical marker in the differential diagnosis of lymphoid neoplasms.

OBJECTIVE: Undifferentiated tumors and hematolymphoid neoplasms can be diagnostically challenging due to potential overlap of morphologic features and variant antigen expression. PAX-5, a transcription factor expressed throughout B-cell maturation, is detected in most B-cell neoplasms including those that lack expression of mature B-cell markers, such as classical Hodgkin lymphoma (cHL), B-lymphoblastic leukemia and B-cell lymphomas following rituximab therapy. The lack of PAX-5 expression in most CD30-positive non-hematopoietic malignancies (embryonal carcinoma and seminoma) and T-cell lymphomas, such as anaplastic large cell lymphoma (ALCL), suggests that the absence of PAX-5 may be used to confirm non-B-cell lineage. The goal of this study was to retrospectively assess PAX-5 immunoreactivity in diagnostic samples of hematolymphoid and other non-hematopoietic malignancies. DESIGN: Diagnostic lymph node, decalcified core bone marrow biopsies and tissue sections from 111 archived paraffin-embedded tissue blocks and a tissue lymphoma microarray were immunostained using a monoclonal antibody to PAX-5. The corresponding hematoxylin and eosin stained tissue sections and additional immunostains were simultaneously evaluated. PAX-5 immunoreactivity in neoplastic cells was scored as positive or negative. This study was exempted by the Institutional Review Board for Human Research. RESULTS: Nuclear PAX-5 immunoreactivity was detected in 88% (36/41) of Hodgkin lymphoma, all cases of diffuse large B-cell lymphoma (n=72), small B-cell lymphomas (n=5), B-lymphoblastic leukemia/lymphoma and mixed phenotype acute leukemia with B-cell lineage (n=5). PAX-5 was not detected in ALCL (n=22), T-cell lymphoblastic leukemia/lymphoma, mixed phenotype acute leukemia with T-cell lineage (n=5), acute myeloid leukemia (n=4), carcinoid tumors with typical morphology (n=5), melanoma (n=3), and undifferentiated/metastatic tumors (n=8). Non-neoplastic bone marrow sections showed scattered nuclear staining in small B-cell lymphocytes/hematogones. The detection of PAX-5 immunoreactivity resulted in the reclassification of two cases of ALCL to cHL. CONCLUSION: Overall, our results demonstrate that including PAX-5 in a panel with other immunomarkers helps establish B-cell lineage and increases diagnostic yield.

A Novel Case of Compound Heterozygous Type 3 Von Willebrand Disease.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder worldwide. Genetic mutations in the von Willebrand gene may result in either quantitative (Types 1 or 3) or qualitative defects (Type 2) of von Willebrand Factor (vWF). Type 3 is the rarest and most severe form of VWD, resulting in a virtual absence of vWF. Type 3 VWD follows autosomal recessive inheritance and is most often reported in patients who are homozygous for the same gene mutation. We report a patient with type 3 VWD who inherited two different mutations, one from each parent, resulting in compound heterozygosity.

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade.

Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.

Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations.

During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.

Pancytopenia with myelodysplasia due to copper deficiency.

We present a case of pancytopenia in a 9-month-old infant with total parenteral nutrition (TPN) dependence due to short bowel syndrome. Bone marrow examination revealed left-shifted myeloid maturation, erythroid and myeloid dysplasia with normal iron stores. Serum copper level was 2 microm/dl (normal range 90-190 mcg/dl). After supplementation, copper levels normalized at 143 mcg/dl, and the macrocytic anemia, neutropenia, and thrombocytopenia resolved. Copper deficiency should be considered in the differential diagnosis of cytopenias and myelodsyplasia, particularly in the growing number of pediatric patients with TPN dependency or malabsorption.

Testicular lymphoma: an update for clinicians.

Testicular lymphoma is a lethal disease with a median survival of approximately 12 to 24 months. It is the most common testicular malignancy in men older than 60 years of age. Testicular lymphoma has a predilection for widespread dissemination to unusual sites, including the central nervous system, contralateral testis, Waldeyer's ring, skin, and lung. Doxorubicin based chemotherapy with prophylactic intrathecal chemotherapy and radiation to the contralateral testis seems most promising. This review article will focus on the presentation, pathology, patterns of relapse and challenges in improving the outcome of this disease.

Validation of the STA-Liatest DDi assay for exclusion of proximal deep vein thrombosis according to the latest Clinical and Laboratory Standards Institute/Food and Drug Administration guideline: results of a multicenter management study.

: Recommended strategy for venous thromboembolism (VTE) diagnosis includes the use of sensitive D-dimer (DDi) assays along with pretest probability (PTP) assessment. The Clinical and Laboratory Standards Institute (CLSI) recently issued a guideline (US FDA endorsed) on DDi in VTE exclusion. Such guideline specifies the ideal D-dimer assay characteristics and target population. Demonstrate STA-LiatestD-Di performance combined with a PTP score for proximal deep vein thrombosis (pDVT) exclusion in a CLSI compliant study. International, multicenter, prospective nonrandomized, noninterventional clinical outcome management study conducted in a standard-of-care setting. DDi was measured in DVT-suspected consecutive low/moderate PTP outpatients, without conditions possibly impacting DDi values independently of thrombosis presence (age >80, pregnancy, postoperative, cancer) using a 0.5 µg/ml (FEU) threshold for DVT exclusion. Results were used to determine test performance. One thousand two hundred and thirty-four patients (17 centers) signed informed consent. Nine hundred and eighty (mean age: 55) with valid results (494 negative DDi) completed the study (DVT prevalence: 8.7%). STA-LiatestD-Di performance exceeded CLSI/FDA requirements: sensitivity: 100% (95% CI 95.8-100%), NPV: 100% (95% CI 99.3-100%). STA-LiatestD-Di associated with PTP score showed excellent performance for pDVT exclusion, as recently demonstrated for pulmonary embolism. The assay allows safe VTE exclusion, avoiding unnecessary imaging tests.

Trends in Bone Marrow Sampling and Core Biopsy Specimen Adequacy in the United States and Canada: A Multicenter Study.

OBJECTIVES: To assess bone marrow (BM) sampling in academic medical centers. METHODS: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. RESULTS: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. CONCLUSIONS: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

CD20 positive T-cell lymphoma/leukemia: a rare entity with potential diagnostic pitfalls.

Mature T-cell neoplasms are relatively uncommon, accounting for approximately 10% of all non-Hodgkin lymphomas. This category of hematopoietic neoplasms is clinically aggressive and shows a poor response to therapy and shortened survival. The antigen CD20 has long been thought to be a specific marker for B-cell lineage and has been used to help differentiate T-cell and B-cell neoplasms. We present two cases of a rare subset of T-cell leukemia/lymphoma having a unique immunophenotype, both being CD20+. The significance of CD20 antigen in T-cell lymphomas is yet to be determined, but may allow treatment with novel therapeutic agents (eg, rituximab, a recombinant anti-CD20 monoclonal antibody).