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Objectives The aim of our investigation was to establish normal pediatric reference intervals (PRIs) for rotational thromboelastometry (ROTEM) Delta assays in a representative group of healthy children, 0 to 18 years of age, at our institution. Methods This was a prospective study of healthy pediatric patients undergoing elective minor surgery requiring placement of an intravenous cannula. The sample size for patients was 20 per age group of either sex from 5 different age groups based on coagulation system maturity: 0 to 6 or fewer months, more than 6 to 12 or fewer months, more than 1 year to 5 or fewer years, more than 5 to 11 or fewer years, and more than 11 to 18 or fewer years. ROTEM Delta assays assessed include the EXTEM, INTEM, and FIBTEM. Results We defined 2 sets of ROTEM PRIs for our patient population: one for patients 11 years or younger and one for children more than 11 years of age. For those 11 years or younger, the PRIs were derived from the 2.5th and 97.5th percentiles from the 0 to 11 age groups. For those older than 11 years, previously published adult reference intervals validated internally with adult normal samples were used. Conclusions The 2 sets of PRIs were embedded into our electronic medical record, allowing clinicians to easily interpret their patient’s ROTEM results against age-verified reference ranges, enabling them to make informed transfusion decisions.

BACKGROUND Chondroblastomas (CBs) are rare benign bone tumors that are often difficult to treat because of their locations. CBs can be even more challenging to successfully manage when they present alongside aneurysmal bone cyst (ABC)-like changes. To minimize operative morbidity, especially in hard-to-reach lesions, percutaneous approaches for both lesions have been individually described. We present a skull base CB with associated ABC-like changes treated by combining two different previously described percutaneous modalities. OBSERVATIONS The authors report successful percutaneous treatment of a skull base CB with adjacent ABC-like changes in a 17-year-old male. The CB was treated with radiofrequency ablation (RFA) and the adjacent ABC area with doxycycline sclerotherapy. After 3 years of follow-up, there has been no clinical or radiological evidence of recurrence. LESSONS CBs occur in the skull base and, as elsewhere in the body, can be associated with ABC-like changes. Successful percutaneous treatment of such a CB with ABC-like changes is possible by combining previously described techniques of RFA and doxycycline sclerotherapy.

Objective To test the hypothesis that early RBC transfusion is associated with duration of organ dysfunction in critically ill septic children. Design Secondary analysis of a single-center prospective observational study. Multivariable negative binomial regression was used to determine relationships between RBC transfusion within 48 hours of sepsis onset and number of days in 14 with organ dysfunction, or with multiple organ dysfunction syndrome. Setting A PICU at a quaternary care children's hospital. Patients Children less than 18 years old with severe sepsis/septic shock by consensus criteria were included. Patients with RBC transfusion prior to sepsis onset and those on extracorporeal membrane oxygenation support within 48 hours of sepsis onset were excluded. Interventions None. Measurements and main results Ninety-four patients were included. Median age was 6 years (0-13 yr); 61% were male. Seventy-eight percentage had septic shock, and 41 (44%) were transfused RBC within 48 hours of sepsis onset (early RBC transfusion). On multivariable analyses, early RBC transfusion was independently associated with 44% greater organ dysfunction days (adjusted relative risk, 1.44 [1.04-2.]; p = 0.03), although risk differed by severity of illness (interaction p = 0.004) and by shock severity (interaction p = 0.04 for Vasoactive Inotrope Score and 0.03 for shock index). Relative risks for multiple organ dysfunction syndrome days varied by shock severity (interaction p = 0.008 for Vasoactive Inotrope Score and 0.01 for shock index). Risks associated with early RBC transfusion were highest for the children with the lowest shock severities. Conclusions In agreement with previous studies, early RBC transfusion was independently associated with longer duration of organ dysfunction. Ours is among the first studies to document different transfusion-associated risks based on clinically available measures of shock severity, demonstrating greater transfusion-associated risks in children with less severe shock. Larger multicenter studies to verify these interaction effects are essential to plan much-needed RBC transfusion trials for critically ill septic children.

Papillary thyroid carcinoma (PTC) is the most common differentiated thyroid cancer in children; and the follicular variant is the second most common variant after the classic subtype. The histological appearance of follicular variant of papillary thyroid cancer (FVPTC), can be mimicked by benign follicular nodules. Pediatric pathologists encountering such lesions with FVPTC-like appearance may err on diagnosing the benign lesions as malignant. In adult patients, several immunohistochemical markers have emerged recently as a useful adjunct to distinguish differentiated thyroid carcinomas from benign follicular lesions. We undertook an inter-institutional retrospective study to establish the diagnostic utility of immunohistochemical staining for HBME-1, Galectin-3 and CD56 in differentiating FVPTC from its benign mimics, follicular adenoma and adenomatoid nodules, in children. Our specific aim of the project was to define the sensitivity and specificity of the three antibodies in FVPTC. Based on institutional diagnoses, a total of 66 cases were obtained: 32 FVPTC and 34 benign follicular nodules that comprised of 23 follicular adenoma and 11 adenomatoid nodules. Five investigators, who were blinded to the original diagnoses, independently reviewed the slides following pre-determined criteria and semi-quantitatively scoring the immunohistochemical staining. The immunohistochemical staining revealed that a combination of positive HBME-1 and negative CD56 result gave 100% specificity and positive predictive value in distinguishing FVPTC from benign follicular nodules. However, the antibody combination suffered from a lower sensitivity (50%). We used a cutoff of 25% positivity of tumor cells in determining positivity of tumor cells to an antibody. In conclusion, our study found a very high specificity and strong positive predictive value for the combination of HBME-1 and CD56 immunohistochemical stains in distinguishing FVPTC from benign follicular lesions.

Context.—Cystoisospora belli is an intracellular parasite associated with gastrointestinal disease in immunocompromised hosts. Although infection has been classically associated with intestinal disease, studies have identified Cystoisospora in the gallbladder of immunocompetent patients based on hematoxylin-eosin morphology. Recently, the identity of this histologic finding as Cystoisospora has been questioned based on negative results of nucleic acid studies.Objective.—To determine the prevalence of this histologic feature in pediatric patients, we retrospectively reviewed all cholecystectomy specimens from a pediatric hospital during a 24-month period.Design.—In 180 cholecystectomy specimens, we identified 11 cases (6.1%) with classical histologic features previously described to represent Cystoisospora organisms. To further investigate these structures, we retrieved tissue from paraffin-embedded blocks and performed electron microscopy.Results.—Ultrastructural examination identified ovoid perinuclear cytoplasmic structures composed of dense fibrillar aggregates rather than organisms. Patients with positive cases were similar in age to controls (positive cases: mean patient age 13.4 years [range, 2–23 years]; negative cases: mean patient age 14.7 years [range, 12 weeks–31 years]; P = .35). There was no significant association of this finding with cholelithiasis (54.5% versus 65.1%, P = .52), cholesterolosis (0% versus 22.5%, P = .12), acute cholecystitis (9.1% versus 10.1%, P > .99), or chronic cholecystitis (45.5% versus 66.3%, P = .20).Conclusions.—To our knowledge, this is the first positive identification of these structures as cytoplasmic fibrillar aggregates rather than parasitic inclusions by ultrastructural examination, and the first study of this histologic finding in pediatric cholecystectomies.

Thyroid Imaging Reporting and Data System (TI-RADS) is validated in adults but not yet in children. The purpose of this study was to determine the sensitivity, specificity, and accuracy of TI-RADS in predicting thyroid malignancy for pediatric nodules, and to compare the diagnostic accuracy to the current American Thyroid Association (ATA) guidelines.A single institution retrospective review was performed of patients younger than 21 years who underwent thyroid nodule fine needle aspiration biopsy (FNAB). Two radiologists were blinded to the pathology and independently classified all biopsied thyroid nodules based on TI-RADS. ATA and TI-RADS guidelines were analyzed to determine the diagnostic sensitivity and specificity of both scoring systems.115 patients (median age 15.5 years, 90 females) with 138 nodules were scored using TI-RADS. There was moderate inter-rater agreement between radiologists (Kappa = 0.51; p 0.0001). Evaluating several potential TI-RADS criteria, 23.2%-68.1% of nodules were recommended for FNAB, compared to 82.6% of nodules using ATA guidelines. Using TI-RADS ≥ 3 (without size cutoff) as an indication for FNAB had 100% sensitivity with no missed suspicious or malignant nodules on cytology or pathology.Using TI-RADS for diagnostic management of pediatric thyroid nodules improves accuracy in predicting malignancy.

Adolescent and young adult (AYA) patients with Ewing sarcoma have inferior survival compared with pediatric patients even when treated with similar regimens. Investigation into specific explanations is lacking. A retrospective chart review of Ewing sarcoma patients at a single institution was performed, and 104 patients were identified, 45 were 15 to 39 years of age (AYA cohort) and 59 younger than 15 years (pediatric cohort). AYA patients demonstrated more metastatic disease (50% vs. 24%, P=0.009), peripheral tumor location (64% vs. 41%, P=0.025), percentage of male patients (76% vs. 51%; P=0.010), and tumor size ≥5 cm (93% vs. 70%, P=0.016) than pediatric patients. Five-year overall survival was 77.7% and 53.0% and event-free survival was 68.7% and 40.6% for pediatric versus AYA, respectively. Similar rates of toxicity and chemotherapeutic dose adjustments were demonstrated. In this cohort, increased AYA patient mortality appears to be related to disease characteristics rather than treatment-related differences.

Idiopathic acute eosinophilic pneumonia is a rare and potentially life-threatening condition that is defined by bilateral pulmonary infiltrates and fever in the presence of pulmonary eosinophilia. It often presents acutely in previously healthy individuals and can be difficult to distinguish from infectious pneumonia. Although the exact etiology of idiopathic acute eosinophilic pneumonia remains unknown, an acute hypersensitivity reaction to an inhaled antigen is suggested, which is further supported by recent public health risks of vaping (electronic cigarette) use and the development of lung disease. In this case, a patient with a year-long history of vaping in conjunction with tetrahydrocannabinol cartridge use who was diagnosed with idiopathic acute eosinophilic pneumonia with associated bilateral hilar lymphadenopathy is described.

Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient-specific risk factors. Unpacking these complexities requires an in-depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion-related immunomodulation and provide suggestions for future research directions.

Avoidance of red blood cell (RBC) transfusions in patients awaiting heart transplantation (HTx) has been suggested to minimize the risk of allosensitization. Although recent studies have suggested that an immature immune system in younger HTx recipients may reduce risks associated with RBC transfusion, the role of age in moderating the influence of transfusion on HTx outcomes remains unclear. We used available data from a national transplant registry to explore whether the association between pre-transplant transfusions and outcomes of pediatric HTx varies by patient age. De-identified data were obtained from the United Network for Organ Sharing registry, including first-time recipients of isolated HTx performed at age 0-17 years in 1995-2015. The primary exposure was receiving blood transfusions within 2 weeks prior to HTx. Patient survival after HTx was evaluated using multivariable Cox proportional hazards, where age at transplant was interacted with exposure to pre-transplant transfusion. Age-specific hazard ratios (HRs) of pre-transplant transfusion were plotted across ages at transplant. There were 4883 patients meeting inclusion criteria, of whom 1258 died during follow-up (mean follow-up duration 6 ± 5 years). Patients receiving pre-transplant transfusions were distinguished by younger age, higher prevalence of prior cardiac surgery, greater likelihood of being in the intensive care unit, and greater use of left ventricular assist device bridge to transplant. In multivariable analysis, pre-transplant transfusions were associated with increased mortality hazard among infants

Purpose Many potential pediatric heart transplant (HT) recipients develop sensitization to potential donor Human Leukocyte Antigens (HLA) from prior tissue and blood product exposure. HT in the face of allosensitization carries elevated risk of morbidity and mortality. We sought to determine and compare the degree and timing of HLA-antibody removal between centrifuge-based plasmapheresis (cPP) and membrane-based plasmapheresis (mPP) during cardiopulmonary bypass (CBP). Methods Two mPP and two cPP systems were each incorporated into CPB circuits. The prime consisted of highly sensitized pooled donor whole blood. Blood was considered sensitized if any HLA-antibody exceeded 3000 mean fluorescence intensity (MFI) units by Luminex assay. Fresh frozen plasma was utilized to replenish the plasmapheresis circuits. Samples to determine the panel reactive antibody (PRA) were taken at baseline, then at 30 minute intervals until the end-point at 2 hours. Results The pooled donor blood was sensitized to HLA Class II but not Class I per institutional threshold. Reduction of anti-HLA class II antibody to below threshold levels (MFI Conclusion The incorporation of cPP or mPP systems into the CPB circuit can effectively reduce circulating HLA-antibodies. This can be accomplished within the time period of CPB for implantation before graft reperfusion and may be done more efficiently using cPP. This technology may have important utility for sensitized transplant recipients at increased risk for early antibody-mediated rejection.

The contribution of T-cells after lung transplant (LTx) remains controversial with no current consensus of their role concerning chronic lung allograft dysfunction. Using flow cytometry to assess T-cell subsets of bronchoalveolar lavage fluid (BALF) in 16 cystic fibrosis (CF) LTx recipients, we identified a decline in CD4+ T-cell frequency and an increase in CD8+ T-cell frequency in patients who developed severe bronchiolitis obliterans syndrome (BOS) (N = 10) when comparing baseline (6 months post-LTx) and follow-up (most recent bronchoscopy—clinical or surveillance per protocol). Comparing BOS to No BOS cohorts, significant differences were found in CD4+ T-cell frequency [17.4 (12.5, 28.2) vs 46.6 (44.4, 48.4), p = 0.003] and CD8+ T-cell frequency [65.6 (62.8, 75.3) vs 39.2 (32.2, 43.3), p = 0.014], respectively. The mean difference of the CD4:CD8 ratio was 0.87 units lower (95% CI − 1.44 to − 0.30, p = 0.006) than patients without BOS, while the median difference of the CD4:CD8 ratio was 0.92 units lower (95% CI − 1.83 to − 0.009, p = 0.048). Therefore, our results suggest that T-cell profiles measured through flow cytometry of BALF in the CF LTx population are associated with the development of severe BOS. Further work is needed in larger patient populations to validate our findings and to determine if this is useful for recipients who underwent LTx for other indications.

We compared the incidence of refractory thrombocytopenia (RT) and platelet transfusion requirements (PTR) in 35 children who developed veno-occlusive disease (VOD) with 35 matched control subjects who underwent hematopoietic stem cell transplant but did not develop VOD. RT developed in 100% of the VOD patients, at a median of 8 days before VOD diagnosis, as compared with 71.5% of the control group. VOD patients required more platelet transfusions than control subjects (median PTR, 6.9 mL/kg [range, .57 to 17.59] versus 3.57 mL/kg [range, 0 to 14.63], respectively) with a statistically significant difference (P.0001). The number of days with platelet requirements was significantly higher for VOD patients as compared with control subjects (median 68% versus 39%, P =.0001). The PTR peaked at ~12 mL/kg/day, 2 days before VOD diagnosis, whereas the PTR in the control population was 5 mL/kg/day. The positive predictive value of developing VOD was 88.9% (95% confidence interval, 66.5% to 97%) in patients who were given7 mL/kg/day of platelets during the at-risk period of days +3 to +13 after transplant. For patients who received8 mL/kg/day of platelets, the positive predictive value of developing VOD was 86.7% (95% confidence interval, 61.2% to 96.4%). There was no difference in the PTR in patients with mild to moderate VOD as compared with severe VOD; however, the PTR was higher in patients whose VOD did not resolve. The median daily PTR after the diagnosis of VOD in 17 patients who got defibrotide as compared with those who did not get defibrotide was 6.04 mL/kg and 5.72 mL/kg, respectively, but the difference was not statistically significant (P = .56). On univariate and multivariate analysis use of intravenous immunoglobulin was significantly associated with VOD (P = .0088) but was not significantly associated with fatal VOD. In conclusion, RT occurs in 100% of patients at a median of 8 days before VOD diagnosis. VOD should be suspected in any patient with RT after the exclusion of other causes of consumptive thrombocytopenia, especially if they require7 mL/kg/day of platelets.

Identification of indeterminate melanocytic skin lesions capable of neoplastic progression is suboptimal and may potentially result in unnecessary morbidity from surgery. MicroRNAs (miRs) may be useful in classifying indeterminate Spitz tumors as having high or low risk for malignant behavior.RNA was extracted from paraffin-embedded tissues of benign nevi, benign Spitz tumors, indeterminate Spitz tumors, and Spitzoid melanomas in adults (n = 62) and children (n = 28). The expression profile of 12 miRs in adults (6 miRs in children) was analyzed by real-time polymerase chain reaction.Benign Spitz lesions were characterized by decreased expression of miR-125b and miR-211, and upregulation of miR-22, compared with benign nevi (p 0.05). A comparison of Spitzoid melanomas to benign nevi revealed overexpression of miR-21, miR-150, and miR-155 in the malignant primaries (p 0.05). In adults, Spitzoid melanomas exhibited upregulation of miR-21, miR-150, and miR-155 compared with indeterminate Spitz lesions. Indeterminate Spitz lesions with low-risk pathologic features had lower miR-21 and miR-155 expression compared with Spitzoid melanoma tumors in adults (p 0.05), while pathologic high-risk indeterminate Spitz lesions had increased levels of miR-200c expression compared with low-risk indeterminate lesions (p 0.05). Pediatric Spitzoid melanomas exhibited increased miR-21 expression compared with indeterminate Spitz lesions (p 0.05). Moreover, miR-155 expression was increased in indeterminate lesions with mitotic counts1 and depth of invasion1 mm, suggesting miR-155 expression is associated with histological characteristics.miR expression profiles can be measured in indeterminate Spitz tumors and correlate with markers of malignant potential.

Myoepithelial carcinomas (MC) represent aggressive tumors that occur in a myriad of ages and anatomic locations. The rarity and histologic similarity with other tumors make them difficult to diagnosis. We report an extremely rare case of a right ventricular outflow tract mass identified to be an intracardiac MC in a 4-month-old male infant. Pathology revealed an EWS-KLF15 translocation. Treatment included gross total resection and intensive chemotherapy. Recurrent cardiac mass with brain metastasis was seen 16 months after primary diagnosis. We describe the rarity of intracardiac MC in pediatric patients and the challenges encountered in the multimodal management of this patient.

BACKGROUND Restoration of a balanced innate immune response is paramount to recovery from critical injury. Plasma transfusion may modulate innate immune responses; however, little is known about the immunomodulatory potential of various plasma products. We conducted in vitro experiments to determine the effects of fresh frozen plasma, thawed plasma, solvent/detergent plasma, and an investigational spray-dried solvent/detergent plasma product on monocyte function. METHODS Monocytes were isolated from healthy adult volunteers and cocultured with aliquots of autologous plasma (control), fresh frozen plasma, thawed plasma, solvent/detergent treated plasma, or spray-dried solvent/detergent plasma. Monocyte function was assessed by cytokine production with and without lipopolysaccharide (LPS) stimulation, and flow cytometric assessment of HLA-DR cell surface expression. RESULTS Monocyte cytokine production was not significantly altered after exposure to fresh frozen plasma or thawed plasma. In the absence of LPS, spray-dried solvent/detergent plasma exposure resulted in markedly increased IL-8 production compared to other plasma groups and controls (p = 0.01, analysis of variance [ANOVA]). Likewise, spray-dried SD plasma exposure resulted in higher LPS-induced IL-8, TNFα, and IL-1β production compared with autologous plasma controls (p < 0.0001; p < 0.0001, p = 0.002, respectively; ANOVA). LPS-induced IL-8 and TNFα production was lowest after exposure to solvent/detergent plasma (p < 0.0001, ANOVA). CONCLUSION Exposure to spray-dried solvent/detergent plasma resulted in marked augmentation of monocyte inflammatory cytokine production. Solvent/detergent plasma exposure resulted in the lowest cytokine production, suggesting lower immunomodulatory potential. Further work is needed to determine how these in vitro findings may translate to the bedside.

BACKGROUND We have previously shown that critically ill children transfused with red blood cells (RBCs) of longer storage durations have more suppressed monocyte function after transfusion compared to children transfused with fresher RBCs and that older stored RBCs directly suppress monocyte function in vitro, through unknown mechanisms. We hypothesized that RBC-derived microvesicles (MVs) were responsible for monocyte suppression. STUDY DESIGN AND METHODS To determine the role of stored RBC unit–derived MVs, we cocultured monocytes with supernatants, isolated MVs, or supernatants that had been depleted of MVs from prestorage leukoreduced RBCs that had been stored for either 7 or 30 days. Isolated MVs were characterized by electron microscopy and flow cytometry. Monocyte function after coculture experiments was measured by cytokine production after stimulation with lipopolysaccharide (LPS). RESULTS Monocyte function was suppressed after exposure to supernatants from 30-day RBC units compared to monocytes cultured in medium alone (LPS-induced tumor necrosis factor-α production, 17,611 ± 3,426 vs. 37,486 ± 5,598 pg/mL; p = 0.02). Monocyte function was not suppressed after exposure to MV fractions. RBC supernatants that had been depleted of MVs remained immunosuppressive. Treating RBC supernatants with heat followed by RNase (to degrade protein-bound RNA) prevented RBC supernatant–induced monocyte suppression. CONCLUSION Our findings implicate soluble mediators of stored RBC-induced monocyte suppression outside of MV fractions and suggest that extracellular protein-bound RNAs (such as microRNA) may play a role in transfusion-related immunomodulation.

SummaryBackground The transfusion of blood products in the setting of uncontrolled bleeding is unquestionably lifesaving. However, in many instances, the decision to transfuse is based on physician gestalt rather than medical evidence. When indications for transfusion are unclear, the benefits of blood products must be balanced against their significant risks and associated costs. As our institution is a referral center for patients of Jehovah's Witness faith, this population has pushed our development of techniques to achieve the goal of bloodless surgery. Our practices in caring for this population have become our standard practice for managing all patients undergoing congenital cardiac surgery. Objectives To evaluate our success in minimizing the use of blood products during pediatric cardiac surgery. Methods After IRB approval, we retrospectively reviewed all patients who underwent cardiac surgery utilizing cardiopulmonary bypass (CPB), for biventricular repair procedures. The study was conducted at a single institution (Nationwide Children's Hospital (NCH)) during the period: January 1, 2013 and December 31, 2013. Results A total of 209 patients were included. Overall, 81 patients (38.8%) and 81 of 136 (59.6%) weighing more than 6 kg received no blood products (bloodless) during their entire hospital stay. Bloodless surgery was most successful in patients weighing more than 18 kg, followed by patients weighing 6–18 kg. All 73 patients who weighed

Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell function. These interactions can lead to both proinflammatory and immunosuppressive effects. Defining clinical outcomes related to immunomodulatory effects of RBCs in transfused patients remains a challenge, likely due to complex interactions between individual blood product characteristics and patient-specific risk factors. Unpacking these complexities requires an in-depth understanding of the mechanisms of immunomodulatory effects of RBC products. In this review, we outline and classify potential mediators of RBC transfusion-related immunomodulation and provide suggestions for future research directions.

Even though hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic cell transplantation (HCT), there is paucity of research on the management of associated multiorgan dysfunction. To help provide standardized care for the management of these patients, the HCT Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium, collaborated to develop evidence-based consensus guidelines. After conducting an extensive literature search, in part 2 of this series we discuss the management of fluids and electrolytes, renal dysfunction; ascites, pleural effusion, and transfusion and coagulopathy issues in patients with VOD. We consider the available evidence using the GRADE criteria.

Background Fibroepithelial polyps (FEPs) are benign tumors, of possibly hormone-dependent nature, found in the vulvovaginal region of women of reproductive age. Case A 15-year-old adolescent girl, receiving hormonal contraceptive therapy, who presented with multiple vulvar masses with histopathology consistent with FEP. Summary and Conclusion The spectrum of the morphology of FEPs might make their diagnosis challenging. We describe a rare presentation of vulvar FEPs in an adolescent girl receiving hormonal contraceptive therapy.

Background Our previous in vitro work showed that stored red blood cells (RBCs) increasingly suppress markers of innate immune function with increased storage time. This multicenter prospective observational study tests the hypothesis that a single RBC transfusion in critically ill children is associated with immune suppression as a function of storage time. Study Design and Methods Blood samples were taken immediately before and 24 (±6) hours after a single RBC transfusion ordered as part of routine care. Innate and adaptive immune function was assessed by ex vivo whole blood stimulation with lipopolysaccharide (LPS) and phytohemagglutinin, respectively. Monocyte HLA-DR expression, regulatory T cells, plasma interleukin (IL)-6, and IL-8 levels were also measured. Results Thirty-one transfused critically ill children and eight healthy controls were studied. Critically ill subjects had lower pretransfusion LPS-induced tumor necrosis factor-α production capacity compared to healthy controls, indicating innate immune suppression (p

BACKGROUND Critical injury has been associated with reduction in innate immune function in adults, with infection risk being related to degree of immune suppression. This relationship has not been reported in critically injured children. HYPOTHESIS Innate immune function will be reduced in critically injured children, and the degree of reduction will predict the subsequent development of nosocomial infection. METHODS Children (≤18 years old) were enrolled in this longitudinal, prospective, observational, single-center study after admission to the pediatric intensive care unit following critical injury, along with a cohort of outpatient controls. Serial blood sampling was performed to evaluate plasma cytokine levels and innate immune function as measured by ex vivo lipopolysaccharide-induced tumor necrosis factor α (TNF-α) production capacity. RESULTS Seventy-six critically injured children (and 21 outpatient controls) were enrolled. Sixteen critically injured subjects developed nosocomial infection. Those subjects had higher plasma interleukin 6 and interleukin 10 levels on posttrauma days 1-2 compared with those who recovered without infection and outpatient controls. Ex vivo lipopolysaccharide-induced TNF-α production capacity was lower on posttrauma days 1-2 (P = 0.006) and over the first week following injury (P = 0.04) in those who went on to develop infection. A TNF-α response of less than 520 pg/mL at any time in the first week after injury was highly associated with infection risk by univariate and multivariate analysis. Among transfused children, longer red blood cell storage age, not transfusion volume, was associated with lower innate immune function (P < 0.0001). Trauma-induced innate immune suppression was reversible ex vivo via coculture of whole blood with granulocyte-macrophage colony-stimulating factor. CONCLUSIONS Trauma-induced innate immune suppression is common in critically injured children and is associated with increased risks for the development of nosocomial infection. Potential exacerbating factors, including red blood cell transfusion, and potential therapies for pediatric trauma-induced innate immune suppression are deserving of further study.

Background/purpose Fibrous soft tissue tumors (FSTT) of infancy and childhood present a challenge to surgeons due to ambiguous histological interpretation, propensity for local recurrence, and uncertainty regarding appropriate therapy. Methods Records were reviewed for patients diagnosed and treated for FSTT at our institution from 1992 to 2010. Data included demographics, tumor location, operative treatment, histopathology, margin status, mitotic index, and recurrence. Results Eighty-six patients underwent treatment of FSTT. Mean follow-up time was 62 months (range 1 to 201 months). There were 11 recurrences (13%), with a mean time to recurrence of 23 months. Extremity and digital lesions were most likely to recur with 21% of such lesions recurring compared to 7% of lesions located elsewhere. Recurrences were seen more frequently in older children. Despite the presence of positive margins in 92% of cases, margin status, histopathology, and mitotic index were not significant predictors of recurrence. Conclusions Digital and extremity fibrous soft tissue tumors and tumors of older children have an increased risk for local recurrence. Margin status did not predict recurrence rates in this series. While the surgical goal is to obtain complete local resection with clear margins, this may be challenging in particular locations and may not ultimately impact recurrence.

Transfusion-related immunomodulation (TRIM) in the intensive care unit (ICU) is difficult to define and likely represents a complicated set of physiologic responses to transfusion, including both proinflammatory and immunosuppressive effects. Similarly, the immunologic response to critical illness in both adults and children is highly complex and is characterized by both acute inflammation and acquired immune suppression. How transfusion may contribute to or perpetuate these phenotypes in the ICU is poorly understood, despite the fact that transfusion is common in critically ill patients. Both hyperinflammation and severe immune suppression are associated with poor outcomes from critical illness, underscoring the need to understand potential immunologic consequences of blood product transfusion. In this review we outline the dynamic immunologic response to critical illness, provide clinical evidence in support of immunomodulatory effects of blood product transfusion, review preclinical and translational studies to date of TRIM, and provide insight into future research directions.

Background The effect of pre-transplant transfusion of red blood cells on survival after lung transplantation (LTx) has not been studied. Methods The UNOS database was queried from 2005 to 2013 to compare survival in recipients receiving a transfusion while on the LTx waitlist. Results Of 12,283 adult patients undergoing single or bilateral LTx from May 2005 onwards, 11,801 met inclusion criteria, among whom 512 required transfusion while on the LTx waitlist. Transfusion was associated with a higher mortality hazard in unadjusted Cox proportional hazards analysis (HR=1.296; 95% CI: 1.124, 1.494; p

BACKGROUND: Reduced monocyte function is associated with adverse outcomes from critical illness. Red blood cells (RBCs) are thought to impair monocyte function but relationships between RBC storage solution and monocyte suppression are unknown. This study was designed to test the hypothesis that immunosuppressive effects of RBCs on monocytes are related to both storage time and preservative solution. STUDY DESIGN AND METHODS: Monocytes from healthy adult donors were co-cultured with RBCs that had been stored in AS-1, AS-3, or CPD only for 7, 14, or 21 days. Cells were then stimulated with lipopolysaccharide (LPS) and their supernatants assayed for tumor necrosis factor (TNF)-α and interleukin (IL)-10. Transwell experiments were performed to evaluate the role of cell-to-cell contact. Monocyte mRNA expression was quantified by real-time–polymerase chain reaction. RESULTS: LPS-induced TNF-α production capacity was reduced compared to controls for all groups, but CPD-only RBCs suppressed monocyte function more than RBCs stored in AS-1 (p = 0.007) and AS-3 (p = 0.006). IL-10 production was preserved or augmented in all groups. A longer storage time was associated with reduced TNF-α production capacity for AS-1 and AS-3 groups but not CPD. Preventing cell-to-cell contact did not eliminate the inhibitory effect of RBCs on monocyte responsiveness. RBC exposure was associated with decreased LPS-induced TNFA mRNA expression (p

Despite the utilization of bronchoalveolar lavage (BAL) in children since the early 1970s, several challenges remain once the procedure is complete. These include little documentation on normal controls, the limitations due to the size of the patient, and uniform processes for assessment. It was not until 1995 that a taskforce on pediatric BAL was formed by the European Respiratory Society, and to our knowledge, they remain the only committee evaluating the process [ 1 ]. We examined our procedures and reviewed the literature in an attempt to document the most fruitful practices that would allow improved data comparison and introduce possible investigations.

Lymphatic malformation is a common benign mass in children and adults and is representative of a derangement in lymphangiogenesis. These lesions have high recurrence rates and significant morbidity associated with surgery. Several sclerotherapy regimens have been developed clinically to treat lymphatic malformations; however, an animal model has not been developed that is adequate to test the efficacy of image-guided therapeutic interventions. To develop an animal model suitable for evaluation of percutaneous treatments of lymphatic malformations. Male Harlan Sprague-Dawley rats (n = 9) received two US-guided injections of Incomplete Freund’s Adjuvant (IFA) over a 2-week period. All nine rats were injected twice into the peritoneum (IP); a subgroup (n = 3) received additional injections into the neck. Three animals that received IP injections of saline were used as controls. The injection sites were monitored for the development of lesions by high-resolution ultrasonography at 2-week intervals for 100 days. High-resolution (4.7 Tesla) magnetic resonance imaging was then performed on two animals noted to have developed masses. The rats were sacrificed and histologic examination of the identified lesions was performed, including immunohistochemical staining for vascular (CD31) and lymphatic (Flt-4 and Prox-1) endothelium. All animals injected with IFA developed cystic lesions. The three animals injected at dual sites were noted to have both microcystic and macrocystic malformations in the neck and microcystic plaque-like lesions in the peritoneum. The macrocystic malformations (≥5 mm) in the neck were detected by ultrasonography and grossly later during necropsy. Histopathologic analysis revealed the cystic spaces to be lined by lymphatic endothelium supported by a connective tissue stroma. Control animals did not exhibit detectable lesions with either ultrasonography or necropsy. This model represents a promising tool for translational development of image-guided interventions for lymphatic malformations. It may also serve as a model for the study of lymphangiogenesis and the development of anti-lymphangiogenic therapies.

Morphologically, the distinction between undifferentiated embryonal sarcoma of the liver (UESL) and biliary tract rhabdomyosarcoma (RMS) can be uncertain because of some shared pathologic similarities. Patients with UESL have been consistently but erroneously enrolled in Children's Oncology Group (COG) treatment protocols because UESL was equated with RMS, despite the differing primary treatment modalities of these entities. Review of COG pathology files yielded 20 cases of UESL that were compared to 25 cases of biliary tract RMS. Clinicopathologic features including immunohistochemical staining were examined. In the UESL cases, the male:female ratio was 1:1 and the median age was 10.5 years. Histologically, hyaline globules and diffuse anaplasia were consistently present. The cases of RMS had a male:female ratio of 1.8:1 with a median age of 3.4 years and routinely lacked diffuse anaplasia and hyaline globules. Polyclonal desmin and muscle-specific actin were variably immunoreactive in UESL and RMS; however, myogenin and myogenic regulatory protein D1 (MyoD1) were uniformly negative in UESL and routinely positive in the majority of biliary tract RMS. Myogenin, in particular, was highly significant ( P = 0.0003) in distinguishing RMS from UESL. With a median follow-up of 8 months, 11 of 18 patients with UESL were still alive. The estimated 5-year survival for biliary tract RMS was 66%. Establishing the correct diagnosis of these distinct clinical and pathologic entities is important, as surgery alone may be curative in UESL, whereas initial chemotherapy is often recommended for the treatment of biliary tract RMS.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) offers standardized and widely understood diagnostic categories for reporting thyroid cytology diagnoses. We compared the utility of TBSRTC categories in pediatric cytology diagnoses and pediatric intraoperative frozen section diagnoses. We examined the experience of our primary and referral care center over a 20-year period. This included 182 thyroidectomy patients who underwent 64 preoperative fine-needle aspirations and 91 intraoperative frozen section evaluations, including 38 patients evaluated sequentially by each method. All diagnoses were retrospectively reclassified into TBSRTC categories and correlated with the final thyroidectomy diagnoses. For each sampling method, malignant final diagnoses were observed at similar frequencies to rates predicted by TBSRTC. Malignant final diagnoses following fine-needle aspiration or frozen section diagnoses in TBSRTC categories other than malignant or suspicious for malignancy most often resulted from difficulty in detecting papillary carcinoma, including difficulty detecting the nuclear characteristics of papillary carcinoma in frozen sections. The limitations of needle biopsy and frozen section evaluations differ, yet serial utilization of these procedures was rarely informative. Based on the experience of our institution, classification of cytology and frozen section diagnosis by TBSRTC predicts a risk of malignancy similar to the guidance offered by TBSRTC. We recommend including a TBSRTC category when reporting either thyroid cytology or frozen section diagnoses in children.

We describe a 15-year-old boy who developed pulmonary hyalinizing granuloma (PHG) and retroperitoneal fibrosis (RPF). His PHG and RPF were not associated with histoplasmosis or tuberculosis and appeared to represent idiopathic autoimmune phenomena. This is the first reported case of PHG in a pediatric patient and the fourth reported co-occurrence of PHG and RPF. The use of F-18 fluorodeoxyglucose positron emission tomography in the diagnostic and follow-up evaluation of PHG is reported.

We report on a 16-year-old white male presenting with a 4-month history of syncopal episodes and occasional headaches. The CT and MRI studies revealed numerous lytic lesions of the skull base and cervical spine; subsequently, similar lesions were demonstrated in all areas of the skeleton, and CT showed numerous lesions in the lungs, liver, and kidneys. Excisional biopsy from several sites confirmed the diagnosis of epithelioid hemangioendothelioma. We conclude that epithelioid hemangioendothelioma should be added to the differential diagnosis for lytic lesions of bone that are clustered in the same anatomic region and that might also present with visceral involvement.

The vagal nerve is the tenth cranial nerve (CN) and is the only CN to extend through the neck into the thorax and abdomen. As a component of the autonomic nervous system, the vagal nerve innervates the visceral organs, including the lung. The majority of the bronchopulmonary sensory nerves are unmyelinated (C-fiber) afferents of the vagal nerve. The cell bodies of the visceral afferent fibers of the vagus nerve are located bilaterally in the inferior ganglion—also termed the nodose ganglia (NG). More recently, transient receptor potential vanilloid type 1 (TRPV1) channels have been identified and are expressed on the vagal C-fiber afferents, which play an important role in the cholinergic reflex pathway [1–3]. TRPV1 channels are nonselective cation channels and polymodal transducers that are known to be activated by increasing temperature, acidity (hydrogen ion), and endogenous inflammatory mediators [1– 3]. Although differences exist between swine and human anatomy, the patterns of the vagal nerve are largely similar and closer in size than standard rodent models [4]. Data are limited on identifying autonomic neurons and associated cell bodies, including the NG in swine [5, 6]. The importance and study of pulmonary neurobiology in acute lung injury is gaining momentum and often requires the use of large animal models, including swine. With no previous reports of the identification and subsequent histopathologic confirmation of the NG and TRPV1 in swine, we provide our experiences in identifying the NG in common crossbred piglets used in an acute lung injury model investigating the benefits of extracorporeal membrane oxygenation. The vagal nerve was dissected based on anticipated location. Figure 1 outlines the two anatomical patterns of the vagal laryngeal branches as previously described by Ding et al. [4]. Figure 2 illustrates the NG structure of one animal on gross examination with this animal having anatomical pattern A from Fig. 1. Histopathologic assessment confirmed the NG on hematoxylin The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the Nationwide Children’s Hospital with strict adherence to the IACUC guidelines regarding humane use of animals.

Although the literature on infections transmitted via transfused blood focuses on viruses, Yersinia enterocolitica can also cause severe infections in patients receiving transfusions. A 13-year-old patient developed severe sepsis after an autologous blood transfusion contaminated with Y. enterocolitica . The patient was an otherwise healthy female undergoing posterior spinal fusion for congenital scoliosis. Prior to surgery, the patient donated blood for perioperative and postoperative use. A few days before the donation, she had complained of abdominal pain and was experiencing mild diarrhea. The patient received four units of packed red blood cells (PRBCs) during the surgery. Intraoperatively, the patient developed fever up to 103.6 °F, became hypotensive requiring epinephrine and dopamine, and developed metabolic acidosis with serum bicarbonate concentration dropping to 16 mmol/l. The surgery team believed the patient was experiencing malignant hyperthermia and attempted to cool patient during the procedure. Postoperatively, the patient was transferred to the pediatric intensive care unit and treated for severe shock of unknown etiology. The patient further developed disseminated intravascular coagulation. The patient received supportive care and was started on ampicillin/sulbactam on postoperative day (POD) one which was changed to clindamycin, ciprofloxacin and tobramycin on POD two when blood cultures grew gram-negative bacilli. On POD three, cultures were identified as Y. enterocolitica and antibiotics were changed to tobramycin and cefotaxime based on susceptibility data. Sequelae of the shock included adult respiratory distress syndrome requiring intubation and a tracheostomy and multiple intracranial hemorrhagic infarcts with subsequent seizure disorder. Due to severe lower extremity ischemia, she required a bilateral below the knee amputation. The cultures of the snippets from the bags of blood transfused to the patient also grew Y. enterocolitica . This case illustrates the importance of considering transfusion related bacterial infections in patients receiving PRBCs. All patients in shock following any type of transfusion may require aggressive antibiotic therapy, until the diagnosis and etiology are known.

A pediatric patient requiring venovenous (VV) extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation developed heparin-induced thrombocytopenia. Unfractionated heparin was discontinued, and a bivalirudin infusion was started. During the lung transplant evaluation, he was found to have allosensitization, requiring treatment with plasma exchange along with pulse methylprednisolone, rituximab, bortezomib, and pooled immunoglobulin infusion. We describe our experience with successful plasma exchange for allosensitization during bivalirudin anticoagulation on VV ECMO in a pediatric patient.