Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis.

Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.

Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], P = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], P = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], P = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, P = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.

Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis.

Pediatric patients with refractory multisystem Langerhans cell histiocytosis (LCH) have a poor prognosis despite aggressive chemotherapy. Salvage therapy with cytarabine and cladribine has shown promise as an effective treatment but is associated with significant toxicity. A previous report described two patients with refractory LCH who had a rapid response to single-agent clofarabine with minimal toxicity. In this report, we describe four children with refractory, risk-organ-positive LCH who were treated with clofarabine and provide follow-up for the two previously reported cases. The results support development of a formal trial evaluating clofarabine as front-line salvage for refractory LCH.

Clinician adherence to pharmacogenomics prescribing recommendations in clinical decision support alerts.

Thoughtful integration of interruptive clinical decision support (CDS) alerts within the electronic health record is essential to guide clinicians on the application of pharmacogenomic results at point of care. St. Jude Children's Research Hospital implemented a preemptive pharmacogenomic testing program in 2011 in a multidisciplinary effort involving extensive education to clinicians about pharmacogenomic implications. We conducted a retrospective analysis of clinicians' adherence to 4783 pharmacogenomically guided CDS alerts that triggered for 12 genes and 60 drugs. Clinicians adhered to the therapeutic recommendations provided in 4392 alerts (92%). In our population of pediatric patients with catastrophic illnesses, the most frequently presented gene/drug CDS alerts were TPMT/NUDT15 and thiopurines (n = 3850), CYP2D6 and ondansetron (n = 667), CYP2D6 and oxycodone (n = 99), G6PD and G6PD high-risk medications (n = 51), and CYP2C19 and proton pump inhibitors (omeprazole and pantoprazole; n = 50). The high adherence rate was facilitated by our team approach to prescribing and our collaborative CDS design and delivery.

Pre-clinical evaluation of a next-generation spray adhesion barrier for multiple site adhesion protection.

Intra-abdominal adhesions represent a major cause of postoperative morbidity, including chronic or recurrent pelvic pain and infertility in a significant percent of patients. The SprayShield™ Adhesion Barrier System (Covidien, Waltham, MA) is a next-generation sprayable adhesion barrier to prevent postoperative adhesions. Initially sprayed as a liquid, SprayShield™ solidifies within 2 seconds of contact with tissue through a polyethylene glycol (PEG) ester-Trilysine reaction to form an adherent, internal tissue barrier that protects the underlying tissues for several days after surgery. After tissue begins to heal, the adhesion barrier liquefies via hydrolysis and completely absorbs within 7 days. Safety testing has shown the product to be nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. SprayShield™ has been shown to adhere well to tissue, with the mechanism of adherence believed to be mainly due to tissue surface mechanical interlocking. In studies that compared SprayShield™ to good surgical technique, virgin hogs were randomized to receive SprayShield™ or good surgical technique (Control). Compared to Controls, SprayShield™ demonstrated a statistically significant reduction in the number of adhesions (46%, p=0.04) and in the area of adhesions (83%, p=0.012) to injured sites. With its ease of application, biocompatibility and adhesion prevention efficacy, SprayShield™ may be an effective next-generation adhesion prevention product for open and laparoscopic abdominopelvic procedures as an adjunct to good surgical technique.

Optimizing Drug-Drug Interaction Alerts Using a Multidimensional Approach.

OBJECTIVES: Excessive alerts are a common concern associated with clinical decision support systems that monitor drug-drug interactions (DDIs). To reduce the number of low-value interruptive DDI alerts at our hospital, we implemented an iterative, multidimensional quality improvement effort, which included an interdisciplinary advisory group, alert metrics, and measurement of perceived clinical value. METHODS: Alert data analysis indicated that DDIs were the most common interruptive medication alert. An interdisciplinary alert advisory group was formed to provide expert advice and oversight for alert refinement and ongoing review of alert data. Alert data were categorized into drug classes and analyzed to identify DDI alerts for refinement. Refinement strategies included alert suppression and modification of alerts to be contextually aware. RESULTS: On the basis of historical analysis of classified DDI alerts, 26 alert refinements were implemented, representing 47% of all alerts. Alert refinement efforts resulted in the following substantial decreases in the number of interruptive DDI alerts: 40% for all clinicians (22.9-14 per 100 orders) and as high as 82% for attending physicians (6.5-1.2 per 100 orders). Two patient safety events related to alert refinements were reported during the project period. CONCLUSIONS: Our quality improvement effort refined 47% of all DDI alerts that were firing during historical analysis, significantly reduced the number of DDI alerts in a 54-week period, and established a model for sustained alert refinements.

Application of a hydrogel sealant improves watertight closures of duraplasty onlay grafts in a canine craniotomy model.

OBJECT: The authors evaluated whether a polyethylene glycol-based hydrogel sealant system improved dural closures with collagen-based duraplasty onlay grafts. METHODS: Dural defects 1.5 cm in diameter were created in 12 canines and repaired with one of two commercially available duraplasty onlay products. In six animals, hydrogel was applied onto the dural onlays, and the other six animals underwent duraplasty only. Before bone flap replacement, watertight closure was assessed. Before the animals were killed, the craniotomy was reopened, adhesions were rated by a neurosurgeon blinded to the treatment groups, and dural integrity was assessed using pressure testing. RESULTS: The animals that received the hydrogel sealant in addition to the duraplasty withstood intraoperative Valsalva maneuvers up to 20 cm H2O without cerebrospinal fluid (CSF) leakage. The duraplasty-only animals leaked CSF at spontaneous pressures (p = 0.0022). Postoperatively, all six duraplasty-only dogs developed CSF subcutaneous accumulations, compared with only one (16.7%) dog who underwent hydrogel application (p = 0.0152). At the time of harvesting (8 weeks after implantation), duraplasty-only dogs had extensive scarring between the bone flap and the dura mater (median adhesion score 4, range 3-4). The animals receiving hydrogel showed minimal scarring (median adhesion score 0.5, range 0-2). In hydrogel-treated dogs, the mean adhesion score was 82.6% lower than the scores in duraplasty-only animals (p = 0.0043). In animals receiving hydrogel, the mean dural leak pressure was 56.8 +/- 2.5 cm H2O compared with 9.8 +/- 3.8 cm H2O in duraplasty-only dogs (p = 0.0392). Application of the hydrogel was not associated with neurotoxicity, delayed healing, degenerative changes, or increased dura-cortex adhesions. CONCLUSIONS: The hydrogel sealant applied to collagen-based dural grafts significantly reduced CSF leakage and functioned as an adhesion barrier. Such technology could be an important tool for cranial surgery.

Mutation of a novel gene results in abnormal development of spermatid flagella, loss of intermale aggression and reduced body fat in mice.

ROSA22 male mice are sterile due to a recessive gene-trap mutation that affects development of the spermatid flagellum. The defect involves the flagellar axoneme, which becomes unstable around the time of its assembly. Despite a subsequent complete failure in flagellar assembly, development of the spermatid head appears normal and the spermatid head is released at the correct stage in spermatogenesis. The mutation is pleiotropic. Although ROSA22 homozygote males have normal levels of circulating testosterone and display normal mating behavior, they do not exhibit intermale aggressive behavior and have reduced body fat. The mutated gene (Gtrgeo22) maps to mouse chromosome 10 and is closely flanked by two known genes, Madcam1 and Cdc34. Ribonuclease protection analysis indicates that expression of the flanking genes is unaffected by the mutation. Gtrgeo22 is expressed at low levels in epithelial cells in several tissues, as well as in testis and brain. Analysis of the peptide coding sequence suggests that Gtrgeo22 encodes a novel transmembrane protein, which contains dileucine and tyrosine-based motifs involved in intracellular sorting of transmembrane proteins. Analysis of the Gtrgeo22 gene product should provide novel insight into the molecular basis for intermale aggression and sperm flagellar development.

Identification of a novel, tissue-specific ABCG2 promoter expressed in pediatric acute megakaryoblastic leukemia.

ABCG2 encodes a transporter protein that is associated with multidrug-resistant phenotypes in many cancers, including acute myeloid leukemia (AML); high levels of expression are generally associated with a poor prognosis. To better understand how expression of ABCG2 is controlled in pediatric AML, we performed a detailed analysis of the ABCG2 transcript isoforms from a variety of tissue sources, including 85 pediatric AML samples. These studies revealed a complex 5' untranslated region (UTR) with 6 novel exons and multiple splice variants. Samples from children with acute megakaryoblastic leukemia (AML FAB-M7) not associated with Down syndrome showed uniformly higher levels of ABCG2 transcripts than samples from children with other AML subtypes. A novel 5' UTR identified 90kb upstream of the exon 2 translation initiation site was expressed only in M7 AML subtypes. An associated upstream promoter fragment was shown to be selectively expressed in megakaryoblastic leukemia cells but not in human epithelial cell lines. These findings identify a new tissue-specific ABCG2 promoter that is selectively expressed in pediatric M7 AML. We also show a relatively high incidence of ABCG2 mRNA expression in non-Down associated M7 AML, which may contribute to the relatively poor prognosis of the M7 AML subtype.

Application of a new hydrogel dural sealant that reduces epidural adhesion formation: evaluation in a large animal laminectomy model.

OBJECT: The aim of this study was to evaluate the application and effects of a novel, nonswelling, polyethylene glycol-based hydrogel adhesion barrier and sealant in a canine laminectomy model of CSF leakage and adhesion formation. METHODS: After full-width L-2 and L-5 laminectomies, 1-cm midline durotomies were created and sutured closed, except for the last 1-2 mm on the cranial end to create spontaneous CSF leakage. All 5 control animals received no further treatment. Experimental animals received hydrogel at both durotomy sites via either the Dual Liquid applicator (5 animals) or MicroMyst gas-assisted sprayer (5 animals). Sealing of the CSF leak was confirmed by Valsalva maneuver. At 2 months, 2 animals from each group were killed to evaluate dural healing and epidural adhesion formation. The remaining animals were similarly evaluated 4 months after surgery. One animal died at 66 days due to a cause unrelated to hydrogel treatment. RESULTS: In hydrogel-treated animals, all leaking durotomies were sealed intraoperatively. All animals recovered uneventfully. There were no treatment-related health effects. MicroMyst hydrogel application was more controlled, slower, and significantly less thick (p = 0.0094) than Dual Liquid application. All 5 control animals developed subcutaneous CSF accumulations under the incision within days of surgery, compared with only 1 of 10 hydrogel-treated animals (p = 0.002). At 2 and 4 months, control laminectomy sites showed extensive, dense epidural adhesions blending with neodura, compared with hydrogel-treated sites (p < 0.0001 and p = 0.0234, respectively). At 2 months in hydrogel-treated animals, gel filled the epidural space and no epidural adhesions were noted (p < 0.0001 relative to controls). At 4 months, the hydrogel was absorbed. The hydrogel space was filled with scant, loosely organized connective tissue. CONCLUSIONS: Hydrogel prevented CSF leakage and mitigated epidural scarring without affecting healing of the dura or laminectomy site. The safety profile of the hydrogel appears favorable due to its synthetic composition, polyethylene glycol chemistry, minimal local tissue response, and lack of neurological deficits. Controlled application of such hydrogel materials may reduce the incidence of postoperative leaks, prevent adhesion formation and thus improve recovery from spinal surgery, and improve identification of tissue planes for reoperations.

Loss of alpha-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function.

Microtubules function as molecular tracks along which motor proteins transport a variety of cargo to discrete destinations within the cell. The carboxyl termini of alpha- and beta-tubulin can undergo different posttranslational modifications, including polyglutamylation, which is particularly abundant within the mammalian nervous system. Thus, this modification could serve as a molecular "traffic sign" for motor proteins in neuronal cells. To investigate whether polyglutamylated alpha-tubulin could perform this function, we analyzed ROSA22 mice that lack functional PGs1, a subunit of alpha-tubulin-selective polyglutamylase. In wild-type mice, polyglutamylated alpha-tubulin is abundant in both axonal and dendritic neurites. ROSA22 mutants display a striking loss of polyglutamylated alpha-tubulin within neurons, including their neurites, which is associated with decreased binding affinity of certain structural microtubule-associated proteins and motor proteins, including kinesins, to microtubules purified from ROSA22-mutant brain. Of the kinesins examined, KIF1A, a subfamily of kinesin-3, was less abundant in neurites from ROSA22 mutants in vitro and in vivo, whereas the distribution of KIF3A (kinesin-2) and KIF5 (kinesin-1) appeared unaltered. The density of synaptic vesicles, a cargo of KIF1A, was decreased in synaptic terminals in the CA1 region of hippocampus in ROSA22 mutants. Consistent with this finding, ROSA22 mutants displayed more rapid depletion of synaptic vesicles than wild-type littermates after high-frequency stimulation. These data provide evidence for a role of polyglutamylation of alpha-tubulin in vivo, as a molecular traffic sign for targeting of KIF1 kinesin required for continuous synaptic transmission.

DuraSeal magnetic resonance and computed tomography imaging: evaluation in a canine craniotomy model.

OBJECTIVE: Several novel sealing materials have been proposed as an adjunct to sutured dural closure to help insure watertight closure, thus diminishing the risk of pseudomeningocele formation. This evaluation was undertaken to clarify the in vivo magnetic resonance imaging (MRI) and computed tomographic (CT) scan characteristics of one such sealant, which has a high water content, permitting similar imaging characteristics to pseudomeningoceles and inflammatory collections. METHODS: After a craniotomy in two canine subjects, we sprayed a novel, water-soluble, self-polymerizing, absorbable, hydrogel sealant onto the dura and the bone flap was replaced. After recovery, both animals underwent MRI and CT scans after 3 days and again at 2, 4, 6, 8, and 10 weeks after the craniotomy. The appearance of the gel at each timepoint was characterized and compared with the macroscopic and microscopic findings obtained 14 weeks after implantation. RESULTS: Both animals remained neurologically intact. Hydrogel sealant was readily apparent with all imaging techniques through Week 6. Diagnostic distinction from inflammatory collections and pseudomeningoceles was possible with MRI, using inversion recovery and contrast-enhanced sequences; such distinctions were occasionally challenging with a contrast-enhanced CT scan. Temporal absorption of the gel and subsequent closure of the remaining void was documented. Histopathology showed minimal changes, and excellent tissue compatibility of the gel was noted. CONCLUSION: The hydrogel sealant can be observed with cross sectional imaging and can be distinguished from cerebrospinal fluid using a CT scan, complemented by an occasional MRI scan. In addition, complete absorption of the hydrogel, with closure of the remaining void was noted. Histological examination found an unremarkable response with no neurotoxicity or space-filling defect.