Anterior segment infiltration of acute lymphoblastic leukemia: case report and systematic review.

Acute lymphoblastic leukemia (ALL) relapse implies a poor prognosis and demands emergency treatment. Leukemic infiltration of the anterior segment can masquerade as intraocular inflammation; a high index of suspicion for this complication is essential. We describe a case of ocular relapse in a 2-year-old male on maintenance therapy for ALL. A systematic review of all known cases of similar leukemic infiltration of the anterior segment of the eye in ALL was performed. A total of 106 patients in 43 reports described leukemic infiltration of the eye as an initial presentation of ALL or relapse. Ocular relapse may be the first visible manifestation of systemic disease, with concurrent disease in the CNS, bone marrow, or testes. Prognosis for ALL patients with ocular relapse is poor, with death after initial presentation reported as early as 16 days. Patients with a history of ALL presenting with any sign of ocular inflammation should be assessed for relapse and leukemic infiltration. As soon as a diagnosis of relapse has been confirmed, appropriate leukemia therapy should be initiated.

B-lymphoblastic leukemia/lymphoma: overexpression of nuclear DNA repair protein PARP-1 correlates with antiapoptotic protein Bcl-2 and complex chromosomal abnormalities.

Poly(ADP-ribose) polymerase-1 (PARP-1) and Bcl-2 are emerging as therapeutic targets in various cancers. The former is a DNA repair protein associated with genomic stability and apoptosis, whereas the latter is an antiapoptotic protein having a DNA repair function through inhibition of PARP-1. Because genomic stability is critical for prognosis in B-lymphoblastic leukemia/lymphoma (B-ALL), we studied the expression of PARP-1 and Bcl-2 proteins in patients with B-ALL of different ages and compared the results with cytogenetic data. The PARP-1 protein was overexpressed in about two-thirds (61%) of patients with B-ALL. It had a nuclear location, whereas Bcl-2 protein was cytosolic. Expression of the 2 proteins showed a highly positive correlation (ρ = 0.367; P < .001). Overexpression of PARP-1 correlated with a complex karyotype (P = .030), and this correlation remained significant for coexpression of PARP-1 and Bcl-2 proteins (χ(2) = 7.498; P = .024) as well as after exclusion of pediatric patients (n = 9, P = .042). Overexpression of PARP-1 was not significantly more common in diploid versus aneuploid karyotypes (50% versus 59%, P = .610). The PARP-1 protein showed no correlation with specific chromosomal abnormalities associated with prognosis in B-ALL, as defined by the World Health Organization. In conclusion, high expression of the PARP-1 protein among patients with B-ALL is related to a complex karyotype and Bcl-2 positivity. Although these findings require validation in a larger population, the observations will be valuable in planning therapeutic trials (such as of PARP inhibitors and BH3 mimetics).

Hemolysis upon intravenous immunoglobulin transfusion.

Intravenous immunoglobulin (IVIG) is a mainstay of therapy in many disorders. An uncommon adverse side effect is IVIG-related hemolysis. Risk factors for IVIG-related hemolysis have been identified, including high dose IVIG given to non-O blood group recipients with an underlying inflammatory state. IVIG-related hemolysis has been linked to anti-A and anti-B hemagglutinins in the IVIG preparations and may involve both IgG and complement mediated hemolysis. A two-hit mechanism with threshold effect is proposed for IVIG-related hemolysis. Strategies exist to minimize or avoid IVIG-related hemolysis.

Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures.

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson's disease (PD), Crohn's disease and leprosy. As all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity isolated, CD14(+) monocytes, CD19(+) B cells, and CD4(+) as well as CD8(+) T cells. Up to 26% of PBMC from healthy donors and up to 43% of CD14(+) monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in (R1441C)lrrk2-mutant cells (<31%); and (iii) a significant up-regulation of lrrk2 mRNA (>fourfold) and protein after exposure to several microbial structures including bacterial lipopolysaccharide and lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with altered lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy. A pattern recognition receptor-type function for LRRK2 could explain its locus' association with Crohn's disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be relevant to the susceptibility of developing PD or its progression.

Osteogenesis with hematopoiesis simulating infection in a hydroxyapatite orbital implant.

A 28-year-old woman underwent secondary orbital implant surgery with placement of a hydroxyapatite implant. Over the next 7 years she underwent 3 drilling procedures. She began having copious discharge 1 year after the last drilling procedure. She was seen on numerous occasions with socket discharge, unresponsive to a variety of topical and oral antibiotics. Clinically, with the conjunctiva diffusely inflamed, the implant tender to touch, and the presence of a pyogenic granuloma, implant infection was suspected and the implant subsequently removed. Histopathologic assessment revealed widespread lamellar bone formation, including focal areas of marrow with active extramedullary hematopoiesis. There was no evidence of an inflammatory process or infection. Postoperatively the patient's symptoms and signs resolved. Extramedullary hematopoiesis within hydroxyapatite implants is rare. Porous orbital implant infection is also rare. Osteogenesis with extramedullary hematopoiesis simulating implant infection has not previously been reported.

The effect of patient-controlled analgesia on coadministered red blood cells.

BACKGROUND: Patient-controlled analgesia (PCA) provides effective pain control. The possibility of administrating opioids in the same line as red blood cells (RBCs) for patients with poor venous access has been entertained. The literature on this approach is not extensive, but generally cautionary. STUDY DESIGN AND METHODS: Standard concentrations of morphine, hydromorphone (Dilaudid), and meperidine (Demerol) were used to determine the effect on RBCs. Three in vitro approaches were used: 1) continuous low-dose opioid infusion with a single bolus, 2) continuous infusion with multiple boluses, and 3) assessment of RBCs with different concentrations of opioids in test tubes. Samples were assayed for hemoglobin (Hb), mean corpuscular volume (MCV), plasma Hb, potassium, and lactate dehydrogenase, and a peripheral blood smear was made. RESULTS: Addition of each drug as a single or multiple bolus(-es) with continuous infusion showed the same effects as normal saline. In vitro exposure of Demerol at a 1:2 ratio (drug:blood) increased the MCV (110 fL), at 1:1 the MCV was 120 fL, and there was 4.5 percent hemolysis. At 2:1, hemolysis increased to 9.2 percent. Both morphine and Dilaudid had similar effects as normal saline. CONCLUSION: Morphine, Dilaudid, and Demerol, given as a bolus in the intravenous line, have the same effects as those seen with saline. When mixed directly with the blood for more than 1 hour, however, Demerol caused increasing RBC swelling and at high, nontherapeutic concentrations, caused hemolysis. Our study suggests that analgesia delivered via PCA may be safely coadministered with RBCs. Further clinical study is warranted.

Follicular hodgkin lymphoma: a histopathologic study.

Follicular Hodgkin lymphoma (FHL) is a form of classic Hodgkin lymphoma with morphologic similarity to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). We present the clinicopathologic features of 13 FHL cases and compare their morphologic features with 40 cases of NLPHL. Seven males and 6 females had FHL in the lymph nodes of the neck (6 patients), axilla (3 patients), groin (2 patients), and mediastinum (1 patient) and in the nasopharynx (1 patient). All FHLs had follicles with small, eccentric germinal centers (GCs) and expanded mantle zones containing classic Reed-Sternberg (RS) cells; reactive GCs also were seen in 6 of 13 cases. The RS cells were CD30+, fascin+ in 13 cases; CD15+ in 11 cases; CD20+ in 4 cases; CD79alpha+CD20- in 1 case; and negative for epithelial membrane antigen in 12 cases; they were surrounded by CD3epsilon+ and CD57+ rosettes in 13 and 2 cases, respectively. Morphologically, FHL may closely simulate NLPHL, and, thus, immunohistochemical analysis is essential to confirm the diagnosis. Clues helpful in diagnosing FHL include the presence offollicles with GCs, classic RS cells, and a relative absence of histiocytes.