Kevin X. Liu

Length of hospital stay after craniotomy for tumor: a National Surgical Quality Improvement Program analysis.

OBJECT Although the length of hospital stay is often used as a measure of quality of care, data evaluating the predictors of extended hospital stay after craniotomy for tumor are limited. The goals of this study were to use multivariate regression to examine which preoperative characteristics and postoperative complications predict a prolonged hospital stay and to assess the impact of length of stay on unplanned hospital readmission. METHODS Data were extracted from the National Surgical Quality Improvement Program (NSQIP) database from 2007 to 2013. Patients who underwent craniotomy for resection of a brain tumor were included. Stratification was based on length of hospital stay, which was dichotomized by the upper quartile of the interquartile range (IQR) for the entire population. Covariates included patient age, sex, race, tumor histology, comorbidities, American Society of Anesthesiologists (ASA) class, functional status, preoperative laboratory values, preoperative neurological deficits, operative time, and postoperative complications. Multivariate logistic regression with forward prediction was used to evaluate independent predictors of extended hospitalization. Thereafter, hierarchical multivariate logistic regression assessed the impact of length of stay on unplanned readmission. RESULTS The study included 11,510 patients. The median hospital stay was 4 days (IQR 3-8 days), and 27.7% (n = 3185) had a hospital stay of at least 8 days. Independent predictors of extended hospital stay included age greater than 70 years (OR 1.53, 95% CI 1.28%-1.83%, p < 0.001); African American (OR 1.75, 95% CI 1.44%-2.14%, p < 0.001) and Hispanic (OR 1.68, 95% CI 1.36%-2.08%) race or ethnicity; ASA class 3 (OR 1.52, 95% CI 1.34%-1.73%) or 4-5 (OR 2.18, 95% CI 1.82%-2.62%) designation; partially (OR 1.94, 95% CI 1.61%-2.35%) or totally dependent (OR 3.30, 95% CI 1.95%-5.55%) functional status; insulin-dependent diabetes mellitus (OR 1.46, 95% CI 1.16%-1.84%); hematological comorbidities (OR 1.68, 95% CI 1.25%-2.24%); and preoperative hypoalbuminemia (OR 1.78, 95% CI 1.51%-2.09%, all p ≤ 0.009). Several postoperative complications were additional independent predictors of prolonged hospitalization including pulmonary emboli (OR 13.75, 95% CI 4.73%-39.99%), pneumonia (OR 5.40, 95% CI 2.89%-10.07%), and urinary tract infections (OR 11.87, 95% CI 7.09%-19.87%, all p < 0.001). The C-statistic of the model based on preoperative characteristics was 0.79, which increased to 0.83 after the addition of postoperative complications. A length of stay after craniotomy for tumor score was created based on preoperative factors significant in regression models, with a moderate correlation with length of stay (p = 0.43, p < 0.001). Extended hospital stay was not associated with differential odds of an unplanned hospital readmission (OR 0.97, 95% CI 0.89%-1.06%, p = 0.55). CONCLUSIONS In this NSQIP analysis that evaluated patients who underwent craniotomy for tumor, much of the variance in hospital stay was attributable to baseline patient characteristics, suggesting length of stay may be an imperfect proxy for quality. Additionally, longer hospitalizations were not found to be associated with differential rates of unplanned readmission.

Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma and Barretts esophagus epithelial cells commonly express PD-L2 in the setting of a Th2-skewed chronic inflammatory environment. Additional tumors express PD-L1 in immune cells. Evaluation of PD-1 inhibition and PD-L2 as biomarkers is warranted. Esophageal adenocarcinoma is an increasingly common disease with a dismal 5-year survival rate of 10% to 15%. In the first systematic evaluation of the PD-1 pathway in esophageal adenocarcinoma, we identify expression of PD-L2 in cancer cells in 51.7% of esophageal adenocarcinomas. Epithelial PD-L1 was expressed on only 2% of cases, although PD-L1+ immune cells were observed in 18% of esophageal adenocarcinomas. We also evaluated expression in the precursor lesion of esophageal adenocarcinoma, Barretts esophagus, which emerges following gastric reflux–induced esophageal inflammation, and found PD-L2 expression in Barretts esophagus but not in non–Barretts esophagus esophagitis. Because the progression from squamous esophagitis to Barretts esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines. These results suggest that the inflammatory environment in Barretts esophagus and esophageal adenocarcinoma may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in esophageal adenocarcinomas with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials. Cancer Immunol Res; 3(10); 1123–9. ©2015 AACR.

Body habitus, serum albumin, and the outcomes after craniotomy for tumor: a National Surgical Quality Improvement Program analysis

OBJECTIVE Although there is a growing body of research highlighting the negative impact of obesity and malnutrition on surgical outcomes, few studies have evaluated these parameters in patients undergoing intracranial surgery. The goal of this study was to use a national registry to evaluate the association of body mass index (BMI) and hypoalbuminemia with 30-day outcomes after craniotomy for tumor. METHODS Adult patients who underwent craniotomy for tumor were extracted from the prospective National Surgical Quality Improvement Program registry. Patients were stratified by body habitus according to the WHO classification, as well as by preoperative hypoalbuminemia (< 3.5 g/dl). Multivariable logistic regression evaluated the association of body habitus and hypoalbuminemia with 30-day mortality, complications, and discharge disposition. Covariates included patient age, sex, race or ethnicity, tumor histology, American Society of Anesthesiology class, preoperative functional status, comorbidities (including hypertension and diabetes mellitus), and additional preoperative laboratory values. RESULTS Among the 11,510 patients included, 28.7% were classified as normal weight (BMI 18.5-24.9 kg/m2), 1.9% as underweight (BMI < 18.5 kg/m2), 33.4% as overweight (BMI 25.0-29.9 kg/m2), 19.1% as Class I obese (BMI 30.0-34.9 kg/m2), 8.3% as Class II obese (BMI 35.0-39.9 kg/m2), 5.5% as Class III obese (BMI ≥ 40.0 kg/m2), and 3.1% had missing BMI data. In multivariable regression models, body habitus was not associated with differential odds of mortality, postoperative stroke or coma, or a nonroutine hospital discharge. However, the adjusted odds of a major complication were significantly higher for Class I obese (OR 1.28, 99% CI 1.01-1.62; p = 0.008), Class II obese (OR 1.53, 99% CI 1.13-2.07; p < 0.001), and Class III obese (OR 1.67, 99% CI 1.19-2.36; p < 0.001) patients compared with those of normal weight; a dose-dependent effect was seen, with increased effect size with greater adiposity. The higher odds of major complications was primarily due to significantly increased odds of a venous thromboembolism in overweight and obese patients, as well as of a surgical site infection in those with Class II or III obesity. Additionally, 41.0% of patients had an albumin level ≥ 3.5 g/dl, 9.6% had hypoalbuminemia, and 49.4% had a missing albumin value. Hypoalbuminemia was associated with significantly higher odds of mortality (OR 1.91, 95% CI 1.41-2.60; p < 0.001) or a nonroutine hospital discharge (OR 1.46, 95% CI 1.21-1.76; p < 0.001). CONCLUSIONS In this National Surgical Quality Improvement Program analysis evaluating patients who underwent craniotomy for tumor, body habitus was not associated with differential mortality or neurological complications. However, obese patients had increased odds of a major perioperative complication, primarily due to higher rates of venous thromboembolic events and surgical site infections. Preoperative hypoalbuminemia was associated with increased odds of mortality and a nonroutine hospital discharge, suggesting that serum albumin may have utility in stratifying risk preoperatively in patients undergoing craniotomy.

A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia

We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium–potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.

A Practical Approach to the Diagnosis and Management of Hair Loss in Children and Adolescents

Hair loss or alopecia is a common and distressing clinical complaint in the primary care setting and can arise from heterogeneous etiologies. In the pediatric population, hair loss often presents with patterns that are different from that of their adult counterparts. Given the psychosocial complications that may arise from pediatric alopecia, prompt diagnosis and management is particularly important. Common causes of alopecia in children and adolescents include alopecia areata, tinea capitis, androgenetic alopecia, traction alopecia, trichotillomania, hair cycle disturbances, and congenital alopecia conditions. Diagnostic tools for hair loss in children include a detailed history, physical examination with a focused evaluation of the child’s hair and scalp, fungal screens, hair pull and tug test, and if possible, light microscopy and/or trichoscopy. Management of alopecia requires a holistic approach including psychosocial support because treatments are only available for some hair loss conditions, and even the available treatments are not always effective. This review outlines the clinical presentations, presents a diagnostic algorithm, and discusses management of these various hair loss disorders.

Dual HDAC and PI3K Inhibition Abrogates NFκB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007-21. ©2018 AACR.

Eliminating Daily Shifts, Tattoos, and Skin Marks: Streamlining Isocenter Localization With Treatment Plan Embedded Couch Values for External Beam Radiation Therapy

PURPOSE The Radiation Oncology Incident Learning System demonstrated that incorrect or omitted patient shifts during treatment are common near-misses or incidents. This single pediatric hospital quality improvement experience evaluated a markless isocenter localization workflow to improve safety and streamline treatment, obviating the need for daily shifts. METHODS AND MATERIALS Patients undergoing radiation therapy were simulated and treated with indexed immobilization devices. User origins were established at simulation based on a limited set of fixed couch-top references. In treatment planning, shifts from the user origin to the planned isocenter were converted to absolute couch parameters and embedded in the setup field parameters. Thus, the first fraction did not require any shifts. Before kilovoltage imaging, setup verification was often supplemented with surface-guided imaging. After image guidance and final couch adjustments, couch parameters could be reacquired and used for subsequent treatments. No skin marks were used. RESULTS Over 3 years, approximately 300 patients were treated with over 5000 treatment fractions using this workflow. There were no wrong-site treatment errors. Approximately a dozen near-miss events related to the daily setup process occurred, largely on the first treatment. Root-cause analysis attributed errors to user origin misidentification, couch parameter miscalculation, incorrect immobilization device use, and immobilization device indexed at the wrong indexing position. Skin marks and tattoos were unnecessary. Continuous quality improvement added additional quality assurance checks, resulting in no near-miss incidents or adverse events in the preceding 12 months. CONCLUSION We minimized near-miss incidents by using limited simulation user origins, converting user origin-to-isocenter shifts to absolute couch parameters, and enforcing restrictive tolerance tables to limit delivery parameter changes, coupled with surface guidance and quality assurance tools. This technique can be applied across institutions, age ranges, and tumor types and with or without surface guidance. This workflow has removed a common treatment setup error and the need for skin marks.

Characterization of long-term outcomes for pediatric patients with epithelioid hemangioma

Epithelioid hemangioma (EH) is a rare benign vascular tumor that occurs in soft tissues and bone and presents between the third and sixth decades of life. Little is known about the clinical course and outcomes of pediatric EH. We report 11 patients diagnosed with EH at a median age of 14.4 years. One patient treated with interferon and one with sirolimus exhibited partial response for >2 years. Although a benign neoplasm, EH is difficult to manage without standard protocols and portends considerable morbidity. Our findings suggest medical management, particularly sirolimus, may benefit these patients; however, long‐term follow‐up is needed.

De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome

Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patients father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patients episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

Painful Ulcerative Lesions on Bilateral Lower Extremities.

A young black woman with a history of Graves disease presented with painful lesions on both legs. She reported chills, bilateral lower extremity swelling, and several small, painful, “pimple-like bumps” appearing on her bilateral lower legs, which ulcerated several days later. The ulcers progressed despite a recent course of trimethoprim-sulfamethoxazole for cultures growing methicillin-sensitive Staphylococcus aureus. The patient’s medications included methimazole and atenolol, which she had been taking since her diagnosis of Graves disease 1 year prior. She had not taken other over-the-counter medications or supplements. Physical examination of her bilateral lower extremities revealed pitting edema and multiple discrete, round, dry ulcers, most with central eschars, dusky gray borders, and collarettes of scale (Figure, A). Results from the initial laboratory workup revealed elevated levels of C-reactive protein and increased erythrocyte sedimentation rate. A punch biopsy specimen of an ulcer edge demonstrated a midand deep dermal marked lymphohistiocytic infiltrate with neutrophils and focal abscess, suggesting a nonspecific infection. The patient was initially treated with cephalexin, mupirocin, and conservative wound care, but the eruption later worsened, with new lesions appearing on her right leg. During follow-up, an intact 4-mm papular lesion was identified on her lower right leg (Figure, B). No pathergy at the previous punch biopsy site was observed. A biopsy of the new intact papule was performed (Figure, C and D). Round, dry ulcers A New papule B