Background Pheochromocytomas are malignant in ∼10% of patients. The histologic differentiation between benign and malignant tumors is difficult, the latter diagnosed by the presence of metastatic ...disease or recurrence. Aim To determine if postoperative histologic evaluation using the previously proposed Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and cell cycle/apoptosis markers can predict patients at risk for recurrence. Methods Using the Memorial Sloan-Kettering Cancer Center adrenal database, we identified 48 patients with 51 resected pheochromocytomas (1987–2006). A senior endocrine pathologist, blinded to clinical outcome, reviewed the histopathologic characteristics of all cases using the PASS system. This pheochromocytoma scoring system is based on the presence of 12 different histologic parameters, including tumor necrosis, mitotic rate, tumor cell spindling, and the presence of large cell nests. In addition, we constructed a tissue microarray of all 5 malignant tumors and 41 of the benign tumors. By immunostaining of the tissue microarray, we assessed the expression of 7 different cell cycle/apoptosis–related genes (p53, Ki-67, Bcl-2, mdm-2, cyclin D1, p21, and p27). Results Forty-three patients had a benign clinical course while 5 patients harbored a clinically malignant pheochromocytoma. Tumor necrosis (focal or confluent) was a particularly powerful indicator of malignancy present in 4 of 5 patients (80%) with malignant tumors, but only in 3 of 42 cases (7%) with benign neoplasms ( P = .0009). The presence of a high mitotic rate (>3/10 high power fields) and tumor cell spindling significantly correlated with malignancy ( P = .026 and .041, respectively). High cellularity was more often present in the malignant lesions ( P = .050). There was a highly significant difference in PASS scores between benign and malignant cases ( P = .0003). All malignant pheochromocytomas had a PASS score ≥6, well above the previously proposed ≥4 cutoff value. Two of the 4 patients testing positive for Ki-67 (>2% nuclear staining) had a clinically malignant course while only 3 (7%) of the 41 cases with lower Ki-67 positivity rate behaved in a malignant fashion ( P = .055). Ki-67-positive tumor had a significantly higher chance of harboring tumor necrosis than Ki-67-negative neoplasms ( P < .01). There was no difference in staining between benign and malignant pheochromocytomas using p53, Bcl-2, mdm-2, cyclin D1, p21, and p27. Conclusions (1) A PASS score of <4 predicted benign pheochromocytomas. (2) All malignant pheochromocytomas had a PASS score ≥6, which was significantly higher compared with the benign lesions. Patients with a PASS score ≥4 should be followed closely for recurrence. (3) p53, Bcl-2, mdm-2, cyclin D1, p21, and p27 appear to have no role in predicting the behavior of pheochromocytomas. Ki-67 may help identify those neoplasms at risk for recurrence by prompting the pathologist to look aggressively for adverse histologic features.
Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a syndrome involving multiple systems. Liver injury is the most common visceral manifestation. Objective The purpose of ...this study was to investigate the types of liver injury and factors associated with DRESS. Methods A retrospective cohort study was conducted in Taiwan using a DRESS database compiled from December 2000 to March 2013. Results Seventy-two cases were included in this study. Among them, 62 (86.1%) cases involved liver injury, 6 of which (9.7%) were liver injury before skin presentation. The distribution of liver injury patterns at initial presentation was 23 cholestatic type (37.1%), 17 mixed type (27.4%), and 12 hepatocellular type (19.4%). Patients with hepatocellular-type injuries were younger, with a median age of 31.5 ( P = .044). Individuals with liver function results more than 10 times the upper limit were more likely to have fever ( P = .026), took more time to recover, and had fewer eosinophils in the dermis ( P = .002). Limitations The study was a retrospective cohort study with limited cases. Conclusions Liver injury is common in DRESS and frequently associated with atypical lymphocytosis. The cholestatic type is the most common type. Patients with cholestatic-type injuries were older and more frequently had interface changes in skin pathology.
Background Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease ...activity, although 85% of cases begin by 5 years. Blood phenotyping shows only TH 2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies. Objective We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD. Methods Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects. Results In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3+ , CD11c+ , and FcεRI+ ) than adults with AD. Similar to adults, strong activation of the TH 2 (IL-13, IL-31, and CCL17) and TH 22 (IL-22 and S100As) axes and some TH 1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of TH 17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), TH 9/IL-9, IL-33, and innate markers (IL-8) than adults ( P < .02). Despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children. Nonlesional skin in pediatric patients with AD showed higher levels of inflammation (particularly IL-17A and the related molecules IL-19 and LL37) and epidermal proliferation (keratin 16 and S100As) markers ( P < .001). Conclusion The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess TH 2 activation characterizes both, TH 9 and TH 17 are highly activated at disease initiation. Increases in IL-19 levels might link TH 2 and TH 17 activation.
Purpose To evaluate the rate of scapular dyskinesis and resulting patient outcomes after treatment of displaced midshaft clavicle fractures. Methods Skeletally mature patients with isolated, ...displaced midshaft clavicle fractures treated with or without surgery over a 16-month period were recruited. The minimum length of follow-up at study examination was 12 months. Patient outcomes were documented using the SICK (scapular malposition, inferomedial border prominence, coracoid pain and malposition, and dyskinesis of scapular movement) Scapula Rating Scale, the Simple Shoulder Test, 3 visual analog scales (VAS) for pain, and shoulder range-of-motion and strength measurements. Of the 32 eligible patients, 24 (75%) were successfully recruited. Results The mean participant age was 46 ± 17 years, with a mean length of follow-up at study evaluation of 1.7 ± 1 years. Surgical fixation was performed in 12 patients (50%). Scapular dyskinesis was present in 37.5% of patients (n = 9). Patients with scapular dyskinesis had worse SICK scapula scores (5.8 ± 2.2 vs 3.1 ± 2.4, P = .01), worse Simple Shoulder Test scores (10.5 ± 1.6 vs 11.7 ± 0.8, P = .029), higher maximum VAS pain scores (4.1 ± 3.1 vs 0.97 ± 1.2, P = .002), and worse average VAS pain scores in the week before the examination (2.7 ± 2.5 vs 0.2 ± 0.4, P < .001) compared with patients without scapular dyskinesis. Range of motion and abduction strength were similar between the groups. Scapular dyskinesis developed in 1 patient treated with surgery (8% 1 of 12) compared with 8 patients treated nonoperatively (67% 8 of 12) ( P = .009). Conclusions Scapular dyskinesis is common after displaced middle-third clavicle fractures, and these patients have more pain and worse functional outcomes compared with patients without scapular dyskinesis. Surgical treatment may reduce a patient’s risk of scapular dyskinesis developing and improve short-term outcomes.
Objectives The objective of this study was to test the hypothesis that gastric bypass surgery (GBS) would favorably impact cardiac remodeling and function. Background GBS is increasingly used to ...treat severe obesity, but there are limited outcome data. Methods We prospectively studied 423 severely obese patients undergoing GBS and a reference group of severely obese subjects that did not have surgery (n = 733). Results At a 2-year follow up, GBS subjects had a large reduction in body mass index compared with the reference group (−15.4 ± 7.2 kg/m2 vs. −0.03 ± 4.0 kg/m2 ; p < 0.0001), as well as significant reductions in waist circumference, systolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, and insulin resistance. High-density lipoprotein cholesterol increased. The GBS group had reductions in left ventricular (LV) mass index and right ventricular (RV) cavity area. Left atrial volume did not change in GBS but increased in reference subjects. In conjunction with reduced chamber sizes, GBS subjects also had increased LV midwall fractional shortening and RV fractional area change. In multivariable analysis, age, change in body mass index, severity of nocturnal hypoxemia, E/E′, and sex were independently associated with LV mass index, whereas surgical status, change in waist circumference, and change in insulin resistance were not. Conclusions Marked weight loss in patients undergoing GBS was associated with reverse cardiac remodeling and improved LV and RV function. These data support the use of bariatric surgery to prevent cardiovascular complications in severe obesity.
To prevent unintentional transmission of bloodborne pathogens through organ transplantation, organ procurement organizations (OPOs) screen potential donors by serologic testing to identify human ...immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. Newly acquired infection, however, may be undetectable by serologic testing. Our objective was to estimate the incidence of undetected infection among potential organ donors and to assess the significance of risk reductions conferred by nucleic acid testing (NAT) versus serology alone. We calculated prevalence of HIV and HCV—stratified by OPO risk designation—in 13 667 potential organ donors managed by 17 OPOs from 1/1/2004 to 7/1/2008. We calculated incidence of undetected infection using the incidence‐window period approach. The prevalence of HIV was 0.10% for normal risk potential donors and 0.50% for high risk potential donors; HCV prevalence was 3.45% and 18.20%, respectively. For HIV, the estimated incidence of undetected infection by serologic screening was 1 in 50 000 for normal risk potential donors and 1 in 11 000 for high risk potential donors; for HCV, undetected incidence by serologic screening was 1 in 5000 and 1 in 1000, respectively. Projected estimates of undetected infection with NAT screening versus serology alone suggest that NAT screening could significantly reduce the rate of undetected HCV for all donor risk strata.
Results from this study suggest that the risk of undetected HCV infection among potential organ donors can be significantly reduced by screening with Nucleic Acid Testing as opposed to serology testing for both normal‐ and high‐risk donors. See editorial by Pruett on page 1115.
Purpose:
Existing literature describes the interdependence between neurotrophic and vascular signals in the central nervous system. We hypothesize a similar crosstalk important to extremity healing ...involving the peripheral nervous system and angiogenic cells. Nerves are difficult to capture via axons found in the periphery alone. Thus, we have interrogated from publicly available single-nuclei transcriptomic data of peripheral nerve soma (dorsal root ganglia), injured by physical transection or chemically induced pain. We present a combined analysis of extremity polytrauma (burn/tenotomy HO model) and peripheral nerve (post-injury/pain DRG model) to determine if there is expression of vascular signals by nerves and reciprocal neurotrophic signals by cells local to the injury site.
Methods:
A 30% dorsal burn and Achilles transection was performed in C57/BL6J mice. The tendon site tissues were harvested from baseline (t0) and day 7, 42 after induction. Samples were prepared for library generation on a 10x Genomics Chromium Controller, sequenced on a Illumina HiSeq 4000, and analyzed with Cell Ranger Software for pre-processing and alignment to the mm10 genome. DRG analyses and clusters were abstracted from NIH-GEO (GSE154659). Downstream analyses including unsupervised clustering downstream analyses were performed with Seurat.
Results:
We first examined candidate neurotrophins and vascular signals in nerve (DRG), finding robust upregulation of
Bdnf
and
Vegfa
. In HO, the site of injury contains many cells that may potentially respond to these signals. Indeed, in sequencing data from the pre-HO anlagen, endothelium and smooth muscle cell populations express upregulation for receptors to the nerve-derived
Vegfa
via
Flt1
/VEGFR1. This population in addition to being sensitive to the VEGFA ligand, also demonstrates upregulation of
Ngf,
signifying a potential vasculo-neuro axis where a vascular signal induces endothelium/SMCs to produce neurotrophic signals. Completing the circuit, the original DRG cells and by logical extension, regenerating peripheral nerves, are highly enriched for the neurotrophin receptors:
Ntrk1/
TrkA (responsive to the SMC derived NGF),
Ntrk2/
TrkB (responsive to the nerve-autonomous BDNF), and
Ntrk3/
TrkC (partial combined NGF/BDNF response). This potentially signifies a feedforward loop where peripheral nerve induces angiogenesis which in return, promotes nascent nerve ingrowth in a cyclical process. Indeed, in targeted knockout of a local VEGFA source (
Vegfa
Prrx1
mice), the injury site demonstrates parallel reduction in vascular density (77%) and reduction in nerve fiber frequency (62%) within the HO site.
Conclusions:
These findings represent the first work characterizing the coordination between neurogenic and angiogenic transcription programs following extremity trauma. We demonstrate through NextGen sequencing, evidence of neuroangiogenic crosstalk following musculoskeletal/neural injury. This VEGFA/NGF axis involves vascular signaling as a potential source for additional proliferation of NGF expressing pericyte/SMCs. The presented data describe the potential nerve-driven regulation contributing to the formation of HO at the extremity that with antagonism or inhibition may lead to better treatments for aberrant extremity wound healing.
Objective To assess medical resource utilization associated with Prader-Willi syndrome (PWS) in the US, hypothesized to be greater relative to a matched control group without PWS. Study design We ...used a retrospective case-matched control design and longitudinal US administrative claims data (MarketScan) during a 5-year enrollment period (2009-2014). Patients with PWS were identified by Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 759.81. Controls were matched on age, sex, and payer type. Outcomes included total, outpatient, inpatient and prescription costs. Results After matching and application of inclusion/exclusion criteria, we identified 2030 patients with PWS (1161 commercial, 38 Medicare supplemental, and 831 Medicaid). Commercially insured patients with PWS (median age 10 years) had 8.8-times greater total annual direct medical costs than their counterparts without PWS (median age 10 years: median costs $14 907 vs $819; P < .0001; mean costs: $28 712 vs $3246). Outpatient care comprised the largest portion of medical resource utilization for enrollees with and without PWS (median $5605 vs $675; P < .0001; mean $11 032 vs $1804), followed by mean annual inpatient and medication costs, which were $10 879 vs $1015 ( P < .001) and $6801 vs $428 ( P < .001), respectively. Total annual direct medical costs were ∼42% greater for Medicaid-insured patients with PWS than their commercially insured counterparts, an increase partly explained by claims for Medicaid Waiver day and residential habilitation. Conclusion Direct medical resource utilization was considerably greater among patients with PWS than members without the condition. This study provides a first step toward quantifying the financial burden of PWS posed to individuals, families, and society.
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