Langerhans cell histiocytosis is a neoplasm and consequently its recurrence is a relapse: In memory of Bob Arceci

Langerhans cell histiocytosis (LCH) remains a poorly understood disorder with heterogeneous clinical presentations characterized by focal or disseminated lesions that contain excessive CD1a+ langerin+ cells with dendritic cell features known as “LCH cells.” Two of the major questions investigated over the past century have been (i) the origin of LCH cells and (ii) whether LCH is primarily an immune dysregulatory disorder or a neoplasm. Current opinion is that LCH cells are likely to arise from hematopoietic precursor cells, although the stage of derailment and site of transformation remain unclear and may vary in patients with different extent of disease. Over the years, evidence has provided the view that LCH is a neoplasm. The demonstration of clonality of LCH cells, insufficient evidence alone for neoplasia, is now bolstered by finding driver somatic mutations in BRAF in up to 55% of patients with LCH, and activation of the RAS‐RAF‐MEK‐ERK (where MEK and ERK are mitogen‐activated protein kinase and extracellular signal‐regulated kinase, respectively) pathway in nearly 100% of patients with LCH. Herein, we review the evidence that recurrent genetic abnormalities characterized by activating oncogenic mutations should satisfy prerequisites for LCH to be called a neoplasm. As a consequence, recurrent episodes of LCH should be considered relapsed disease rather than disease reactivation. Mapping the complete genetic landscape of this intriguing disease will provide additional support for the conclusion that LCH is a neoplasm and is likely to provide more potential opportunities for molecularly targeted therapies.     

Significant Publications for Pharmacy Nutrition Support Practice in 2013

Purpose:

To assist the pharmacy clinician engaged in nutrition support in staying current with the most pertinent literature.

Methods:

Several experienced board-certified clinical pharmacists in nutrition support compiled a list of publications published in 2013 that they considered to be important to their practice. The citation list was compiled into a Web-based survey whereby pharmacist members of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), GI-Liver-Nutrition Practice Research Network of the American College of Clinical Pharmacy, and the Pharmacy and Pharmacology Section of the Society of Critical Care Medicine were asked to rank each article according to level of importance in their practice.

Results:

A total of 30 articles were identified by the author group. Thirty-six participants responded to the survey. The top-ranked papers by participants from the Web-based survey were reviewed by the authors. Due to its high level of importance, the parenteral nutrition safety consensus recommendations article, to be published in 2014 by A.S.P.E.N., was also reviewed.

Conclusion:

It is recommended that the informed pharmacist, who is engaged in nutrition support therapy, be familiar with the majority of these publications.Key Words: consensus, enteral nutrition, guidelines, nutrition support, outcomes, parenteral nutritionStaying current with the literature is a requirement for the informed pharmacist who maintains an evidence-based clinical practice. This requirement has become increasingly more challenging to fulfill as a paradigm shift has changed the practice culture of a full-time pharmacy nutrition support specialist to a more integrated model whereby the clinical pharmacist provides pharmacotherapy services along with nutrition support responsibilities. This paradigm shift has arguably been partially attributed to the financially motivated decline in the provision of interdisciplinary nutrition support teams by US hospitals over the past couple of decades.¹As a result of this change, informed clinicians are responsible for staying abreast of numerous therapeutic areas that interface with their clinical practice in addition to nutrition support therapy. Keeping current with the nutrition support literature, even for the pharmacy nutrition support specialist, is a daunting if not overwhelming task. Because nutrition support therapy is integrated with many divergent specialized fields (eg, medicine, surgery, pediatrics, gastroenterology, oncology, nephrology, infectious disease, endocrinology, hepatology, transplantation, trauma, burns, home infusion, critical care, dietetics, nursing, and pharmacy), it is nearly impossible for one individual to screen the plethora of journals each month to seek out those clinical studies, position papers, or clinical guidelines that may enhance or change their clinical practice.     

The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells

Multiple signal transduction cascades, consisting of multiple interacting proteins, are activated following stimulation through most cell surface receptors, including the immunoglobulin receptor of B lymphocytes. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, resulting in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a lipid kinase that consists of an 85-kD regulatory subunit, bound to a 110-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that contains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 120-kD protein that is expressed in early B-lineage cells and in myeloid cells and is phosphorylated on tyrosine following receptor-mediated signaling in T and B lymphocytes. We demonstrate here that phosphorylated c-cbl complexes with CD19 and with PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active PI3K in anti-Ig- stimulated cells. Although we cannot differentiate between a three- component, c-cbl/CD19/p85 complex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct signal transduction pathways.     

Protein-tyrosine kinase p72syk in Fc gamma RI receptor signaling

In this report we show that gamma-interferon (IFN) induces the expression of the nonreceptor protein tyrosine kinase, p72syk, and that cross-linking the Fc gamma RI receptor in IFN-differentiated U937 cells (U937IF cells) results in the activation of syk kinase. We show that syk is tyrosine phosphorylated (12-fold increase) after Fc gamma RI cross-linking. In vitro kinase assays demonstrate that the specific kinase activity of syk increased eightfold after Fc gamma RI cross- linking. The activation of signal transduction through the Fc gamma RI receptor, as measured by the respiratory burst, is associated with the tyrosine phosphorylation and catalytic activation of the syk kinase. We show that syk coprecipitates with the gamma subunit of the Fc gamma RI, Fc gamma RI gamma. The data suggest that p72syk is involved in signal transduction through the Fc gamma RI receptor, involving the Fc gamma RI gamma subunit.     

Maternal administration of granulocyte colony-stimulating factor improves neonatal rat survival after a lethal group B streptococcal infection

Maternally administered recombinant human granulocyte colony- stimulating factor (rhG-CSF) has been shown to cross the placenta and induce a peripheral neutrophilia and increases in the marrow and spleen neutrophil storage pools in fetal and newborn rats. In the present study, we have used this model system to investigate the efficacy of prenatally administered rhG-CSF on neonatal defense to a lethal challenge with Group B-beta hemolytic Streptococcus (GBS). Pregnant rats were injected with rhG-CSF twice daily beginning 6 days before parturition. At birth, all pups were infected with a dose of GBS that is lethal for 90% of infected pups (LD90). Survival was monitored daily for 5 days. Survival of infected pups from saline-treated mothers beyond 60 hours after infection was 10%. No difference in survival was observed among pups from mothers treated 2 and 4 days before parturition. In contrast, we determined that survival was 82.5% among infected pups from mothers treated for 6 days before parturition with rhG-CSF. Our results demonstrate that maternal administration of rhG- CSF augments neonatal defenses against a lethal bacterial challenge.     

Accuracy of endoscopic optical coherence tomography in the detection of dysplasia in Barrett's esophagus: a prospective, double-blinded study

BACKGROUND: Endoscopic optical coherence tomography (EOCT) is a high-resolution, cross-sectional tissue-imaging technique that provides microscopic morphologic information. EOCT should detect dysplasia in Barrett's epithelium, but this has not been established in a prospective blinded study. This study evaluated the accuracy of EOCT for the diagnosis and the exclusion of dysplasia in patients with Barrett's esophagus. METHODS: A 2.4-mm diameter EOCT probe was modified for use with a cap-fitted, two-channel endoscope. Pairs of EOCT image streams and jumbo biopsy specimens were obtained. Endoscopy/EOCT procedures were performed by 4 endoscopists who separately reviewed the EOCT digital images for the absence or the presence of dysplasia (low grade, high grade, or cancer) for each biopsy specimen obtained. The endoscopists were blinded to the interpretation of the pathology. An experienced pathologist blinded to the endoscopic/EOCT findings evaluated each biopsy for the absence or the presence of dysplasia. The setting of the study was a major academic medical center. Adult patients with documented Barrett's esophagus greater than 2 cm were included in the study. The main outcome measurement was the accuracy of EOCT in the detection of dysplasia in patients with Barrett's esophagus. RESULTS: A total of 314 usable EOCT image stream/biopsy pairs were obtained in 33 patients. By using histology as the standard, the performance of EOCT was sensitivity, 68%; specificity, 82%; positive predictive value, 53%; negative predictive value, 89%; and diagnostic accuracy, 78%. Diagnostic accuracy for the 4 endoscopists ranged from 56% to 98%. Limitations of the study were the variability in endoscopists' accuracy rates, difficulty in real-time interpretation, and the need for refined criteria of dysplasia by EOCT imaging. CONCLUSIONS: The current EOCT system has an accuracy of 78% for the detection of dysplasia in patients with Barrett's esophagus. EOCT could be used to target biopsies to areas of Barrett's epithelium with a higher probability for the presence of dysplasia. However, further modifications, including increased resolution and identification of further potential OCT characteristics of dysplasia, are needed before EOCT can be used clinically.     

Active immunization of murine allogeneic bone marrow transplant donors with B-cell tumor-derived idiotype: a strategy for enhancing the specific antitumor effect of marrow grafts

Persistence of the underlying malignancy remains the major obstacle limiting the success of high-dose chemoradiotherapy with allogeneic bone marrow transplantation (BMT) for lymphomas and multiple myeloma. We used the C3H 38C13 murine B-cell lymphoma, which expresses and secretes clonally derived Ig, the idiotype of which can serve as a tumor-specific antigen, to test the principle of transfer of tumor idiotype-specific immunity with BM. BALB/c marrow donors were twice immunized with 38C13-derived Ig, or with an isotype-matched control Ig, conjugated to keyhole limpet hemocyanin. Lethally irradiated C3H recipients reconstituted with marrow from idiotype immune, but not nonspecifically immune, donors demonstrated protection against subsequent lethal tumor challenge. The immunoprotective effect of immune allogeneic marrow was abrogated by T-cell depletion of the marrow graft before infusion. Low levels of serum anti-idiotypic antibody remained unaltered in recipients of T-cell-depleted immune marrow, consistent with a primary role for T-cell immunity in the cellular mechanism of this phenomenon. A modest therapeutic effect of immune allogeneic marrow was observed against 10 day, 1 cm established subcutaneous tumors, but only in combination with a booster immunization of the recipient post-BMT. These results provide the rationale for a novel strategy for enhancing the specific antitumor effect of allogeneic marrow grafts.     

Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.     

Treatment and outcome of traumatic biliary injuries in children

Background/Purpose

Traumatic biliary tract injuries in children are rare but may result in significant morbidity. The objective of this study was to review the occurrence of traumatic biliary tract injuries in children, management strategies, and outcome.

Methods

We conducted a retrospective review of patients with biliary tract injury using the trauma registry at our level 1 pediatric trauma center from 2002–2012.

Results

Twelve out of 13,582 trauma patients were identified, representing 0.09% of all trauma patients. All were secondary to blunt trauma. Mean age was 9.7 years [range 4–15], and mean Injury Severity Score was 31 ± 14, with overall survival of 92%. Biliary injuries included major ductal injury (6), minor ductal injury with biloma (4), gallbladder injury (2), and intrahepatic ductal injury (1). Major ductal injuries were managed by endoscopic retrograde cholangiopancreatography (ERCP) and biliary stent (5) and Roux-en-Y hepaticojejunostomy (1). Associated gallbladder injury was managed by cholecystectomy. In addition, the associated biloma was managed with percutaneous drainage (7), laparoscopic drainage (2), or during laparotomy (3). Two patients with ductal injuries developed late strictures after initial management with ERCP and stent placement. One of the two patients ultimately required a left hepatectomy, and the other has been managed conservatively without evidence of cholangitis. Two patients required placement of additional drains and prolonged antibiotics for superinfection following biloma drainage.

Conclusion

Biliary tract injuries are rare in children, and many are amenable to adjunctive therapy, including ERCP and biliary stent placement with or without placement of a peritoneal drain. Patients with a discrete ductal injury are at higher risk for stricture and require close follow up. Hepaticojejunostomy remains the definitive repair for large extrahepatic biliary tract injuries or transections.     

【特刊综述】雄激素对骨骼肌的作用：对乏力的发展和治疗的意义

雄激素对骨骼肌合成有明显影响,随着年龄增大,雄激素的下降常伴随肌量和肌力的下降。这种肌量和肌功能的下降,被称为少肌症或肌体老化,是老年人体质弱化（男性化减退）进展的关键事项。也是导致快速机能衰退及其不良后果的关键。雄激素水平下降对老年男性体质弱化（男性化减退）的潜在影响和对躯体功能的促进治疗作用无疑已经引起了相当的关注。本综述概述了近期关于肌肉老化、少肌症、老年体质弱化的概念、定义,并评估了关于雄激素和老年体质弱化的研究进展。近期源于观测性和介入性研究的证据强烈支持雄激素对老年男性肌量的作用,但雄激素对肌力和特有的躯体功能的效用并不明确。研究显示,雄激素治疗在老年男性中通常有良好的耐受性,而近期的研究则关注于雄激素的高剂量治疗和对于心血管风险较高人群的治疗。雄激素受体调节剂（SARMs）的初期试验研究显示传统雄激素治疗对于老年患者在肌量和肌功能方面有相同的效用。将来的重要研究方向包括利用这类雄激素治疗并结合适用于不同老年患者群体促进躯体功能的运动训练,同时将更多地关注近期关于激素水平、身体成分及躯体功能间关系的观测性（回顾性）研究。