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Purpose: To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. Experimental Design: We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression. Results: The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. Conclusions: MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.

Supplemental Figure 1.

Supplemental Figure 8.Relative MYLK mRNA expression by qPCR in GIST PDGFRA D842V PDXs treated with vehicle(Veh) or imatinib (IM) for 2 weeks.

Supplemental Figure 5.Short term culture of cells derived from PDGFRA D842V PDXs are tumor cells.

Supplemental Figure 3. GIST PDGFRA D842V PDXs are not sensitive to crenolanib.

Supplemental Figure 7.

Supplemental Figure 4.

Purpose:To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy.Experimental Design:We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression.Results:The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens.Conclusions:MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.

Supplemental Figure 6.Cell survival of GIST T1 cells treated with imatinib or avapritinib for 72h in complete media.Each data point represents an average of 10 wells.

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BackgroundThis study aimed to identify which emergency department (ED) factors impact door-to-needle (DTN) time in acute stroke patients eligible for intravenous thrombolysis. The purpose of analyzing emergency department factors is to determine whether any modifiable factors could shorten the time to thrombolytics, thereby increasing the odds of improved clinical outcomes.MethodsThis was a prospective observational quality registry study that included all patients that received alteplase for stroke. These data are our hospital data from the national Get With The Guidelines Registry. The Get With The Guidelines® Stroke Registry is a hospital-based program focused on improving care for patients diagnosed with a stroke. The program has over five million patients, and hospitals can access their own program data. The registry promotes the use of and adherence to scientific treatment guidelines to improve patient outcomes. The time of patient arrival to the ED was captured via the timestamp in the electronic health record. Arriving between Friday 6 p.m. and Monday 6 a.m. was classified as “weekend,” regardless of the time of arrival. Time to CT, time-to-lab, and presence of a dedicated stroke team were also recorded. Emergency medical services (EMS) run sheets were used to verify arrival via ambulance.ResultsForty-nine percent of the cohort presented during the day shift, 24% during the night shift, and 27% on the weekend. A total of 85% were brought by EMS, and 15% of patients were walk-ins. The median DTN time during the day shift was 37 min (IQR 26–51, range 10–117). The median DTN time during the night shift was 59 min (IQR 39–89, range 34–195). When a dedicated stroke team was present, the median DTN time was 36 min, compared to 51 min when they were not present. The median door-to-CT time was 24 min (IQR 18–31 min). On univariate analyses, arriving during the night shift (P < 0.0001), arriving as a walk-in (P = 0.0080), and longer time-to-CT (P < 0.0001) were all associated with longer DTN time. Conversely, the presence of a dedicated stroke team was associated with a significantly shorter DTN time (P < 0.0001).ConclusionFactors that contribute most to a delay in DTN time include arrival during the night shift, lack of a dedicated stroke team, longer time-to-CT read, and arrival as a walk-in. All of these are addressable factors from an operational standpoint and should be considered when performing quality improvement of hospital protocols.

Bradycardia is the most common terminal cardiac electrical activity in children, and early recognition and treatment is necessary to avoid cardiac arrest. Interventions such as oxygen, chest compressions, epinephrine, and atropine recommended by American Heart Association (AHA) Pediatric Advanced Life support (PALS) guidelines have been shown to improve outcomes (including higher survival rates) for inpatient pediatric patients with bradycardia. However, little is known about the epidemiology of pediatric prehospital bradycardia. We sought to investigate the incidence and management of pediatric bradycardia in the prehospital setting by emergency medical services (EMS).This was a retrospective study of 911 scene response prehospital encounters for patients ages 0-18 years in 2019 from the United States ESO Research Data Collaborative. We defined age-based bradycardia per the 2015 AHA PALS guidelines. We performed general descriptive statistics and a univariate analysis examining any PALS-recommended interventions in the presence of altered mental status, hypotension for age, and a first heart rate less than 60.Of 7,422,710 encounters in the 2019 ESO Data Collaborative, 1,209 patients met inclusion criteria. Most (58.5%) were male, and the median age was 2 years (interquartile range 0-13 years). One-quarter (24.7%) of patients received fluids, and bag-valve mask ventilation was the most common airway intervention (12.1% of patients). Receipt of any PALS-recommended interventions was associated with age-adjusted hypotension (odds ratio (OR) 4.0, 95% confidence interval (CI) 3.9-5.4) and altered mental status (OR 15.5, 95% CI 10.7-22.3), but not a first heart rate less than 60 bpm (OR 0.9, 95% CI 0.6-1.1).To our knowledge, this study is the first to examine the incidence and management of prehospital pediatric bradycardia. Incidence was rare, but adherence to PALS guidelines was variable. Further research and education are needed to ensure proper prehospital treatment of pediatric bradycardia.

Type I gastric neuroendocrine tumors (GNETs) are typically managed either expectantly or endoscopically. In contrast, locoregional surgery has been recommended for patients with type III GNETs because of the risk of metastasis. This study aimed to identify predictors of outcome independent of type in a contemporary cohort of GNET patients. A single-institution retrospective cohort study of 121 patients with a pathologic diagnosis of primary GNET between January 2009 and June 2019 was performed. GNETs were designated as type 1 (n = 74) if atrophic gastritis was present, or as type III (n = 47) in the absence of atrophic gastritis. Demographic, clinical, and histopathologic factors were examined using Kaplan–Meier and multivariable Cox regression to assess the impact of various factors on recurrence and overall survival. Median follow-up for the entire cohort was 62.7 months. While there was no difference in OS in patients with different GNET types (p = 0.10), higher tumor grade (p = 0.02) and presence of nodal or distant metastases (p = 0.02) predicted worse survival on multivariable analysis. Among type III GNET patients, those with small (< 0.5 cm), grade 1 lesions (“low-risk”) were less likely to develop metastases (0% versus 33%, p < 0.01) and more likely to survive (100% versus 67%, p < 0.01) at 5 years. Size and tumor grade predict recurrence and survival in patients with GNETs irrespective of type. Small, low-grade type III GNETs are associated with minimal risk of progression and may be managed accordingly.

Background In this paper, the authors review the safety and practicality of elastomeric respirators for protecting themselves and others from the novel coronavirus or COVID-19. They also describe the safe donning and doffing procedures for this protective gear. Main text Due to the shortage of personal protective equipment (PPE), the CDC has recommended ways to conserve disposable N95 masks, including re-use and extended use, and reserving N95 masks for aerosol-generating procedures. However, these were never made to be re-used. Although the modes of transmission of COVID-19 are not fully understood, based on what we know about severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), droplets and aerosolized droplets contribute to the spread of this virus. More evidence from Wuhan, China, has demonstrated that COVID-19 viral particles are aerosolized and found in higher concentrations in rooms where PPE is being removed. Thus, it is best for all healthcare providers to have full aerosol protection. Conclusion Given the shortage of PPE for aerosols, it is logical to utilize reusable elastomeric respirators with filter efficiency of 95% or higher. A single elastomeric respirator may replace hundreds to thousands of new disposable N95 masks.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Despite initial clinical responses, long‐term efficacy is not possible because of acquired resistance to these therapies. We have developed EGFR TKI drug‐tolerant (DT) human lung cancer cell lines as a model for de novo resistance. Mass spectroscopic analysis revealed that the cytochrome P450 protein, CYP51A1 (Lanosterol 14α‐demethylase), which is directly involved with cholesterol synthesis, was significantly upregulated in the DT cells. Total cellular cholesterol, and more specifically, mitochondrial cholesterol, were found to be upregulated in DT cells. We then used the CYP51A1 inhibitor, ketoconazole, to downregulate cholesterol synthesis. In both parental and DT cells, ketoconazole and EGFR TKIs acted synergistically to induce apoptosis and overcome the development of EGFR tolerance. Lastly, this combination therapy was shown to shrink the growth of tumors in an in vivo mouse model of EGFR TKI resistance. Thus, our study demonstrates for the first time that ketoconazole treatment inhibits upregulation of mitochondrial cholesterol and thereby overcomes EGFR‐TKI resistance in lung cancer cells.

ImportanceLocalization of subcentimeter ground glass opacities during minimally invasive thoracoscopic lung cancer resections is a significant challenge in thoracic oncology. Intraoperative molecular imaging has emerged as a potential solution, but the availability of suitable fluorescence agents is a limiting factor.ObjectiveTo evaluate the suitability of SGM-101, a carcinoembryonic antigen–related cell adhesion molecule type 5 (CEACAM5) receptor–targeted near-infrared fluorochrome, for molecular imaging–guided lung cancer resections, because glycoprotein is expressed in more than 80% of adenocarcinomas.Design, Setting, and ParticipantsFor this nonrandomized, proof-of-principal, phase 1 controlled trial, patients were divided into 2 groups between August 1, 2020, and January 31, 2022. Patients with known CEACAM5-positive gastrointestinal tumors suggestive of lung metastasis were selected as proof-of-principle positive controls. The investigative group included patients with lung nodules suggestive of primary lung malignant neoplasms. Patients 18 years or older without significant comorbidities that precluded surgical exploration with suspicious pulmonary nodules requiring surgical biopsy were included in the study.InterventionsSGM-101 (10 mg) was infused up to 5 days before index operation, and pulmonary nodules were imaged using a near-infrared camera system with a dedicated thoracoscope.Main Outcomes and MeasuresSGM-101 localization to pulmonary nodules and its correlation with CEACAM5 glycoprotein expression by the tumor as quantified by tumor and normal pulmonary parenchymal fluorescence.ResultsTen patients (5 per group; 5 male and 5 female; median [IQR] age, 66 [58-69] years) with 14 total lesions (median [range] lesion size, 0.91 [0.90-2.00] cm) were enrolled in the study. In the control group of 4 patients (1 patient did not undergo surgical resection because of abnormal preoperative cardiac clearance findings that were not deemed related to SGM-101 infusion), the mean (SD) lesion size was 1.33 (0.48) cm, 2 patients had elevated serum CEA markers, and 2 patients had normal serum CEA levels. Of the 4 patients who underwent surgical intervention, those with 2+ and 3+ tissue CEACAM5 expression had excellent tumor fluorescence, with a mean (SD) tumor to background ratio of 3.11 (0.45). In the patient cohort, the mean (SD) lesion size was 0.68 (0.22) cm, and no elevations in serum CEA levels were found. Lack of SGM-101 fluorescence was associated with benign lesions and with lack of CEACAM5 staining.Conclusions and RelevanceThis in-human proof-of-principle nonrandomized controlled trial demonstrated SGM-101 localization to CEACAM5-positive tumors with the detection of real-time near-infrared fluorescence in situ, ex vivo, and by immunofluorescence microscopy. These findings suggest that SGM-101 is a safe, receptor-specific, and feasible intraoperative molecular imaging fluorochrome that should be further evaluated in randomized clinical trials.Trial RegistrationClinicalTrials.gov identifier: NCT04315467

Introduction: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit receptor. While highly effective, tyrosine kinase inhibitors like imatinib are not curative. The natural ligand for the Kit receptor is Kit Ligand (KitL), which exists in both soluble and membrane-bound forms. We sought to determine the role of KitL in the oncogenic Kit signaling of GIST. Methods: KitV558Δ/+ mice, which spontaneously develop an intestinal GIST, were treated with imatinib or vehicle for 1 week, and sorted non-immune (CD45-) cells from tumors were submitted for single-cell RNA sequencing (n=3/group). GIST T1 cells were treated with KitL with or without imatinib and oncogenic Kit signaling was evaluated. KitV558Δ/+ mice were crossed with various KitL mutant and inducible models and tumor weights were measured (n=3-4/group). Human GISTs were stained for KitL expression by IHC, and an existing bulk RNA sequencing human GIST dataset with matched human serum was analyzed. Results: Unsupervised clustering revealed endothelial, smooth muscle, and tumor cells had high expression of KitL RNA in untreated tumors from KitV558Δ/+ mice. Imatinib therapy increased KitL RNA in all 3 cell types, suggesting that extra-tumoral KitL expression is dependent on oncogenic signaling (p Citation Format: Andrew D. Tieniber, Ferdinando Rossi, Andrew Hanna, Mengyuan Liu, Mark Etherington, Kevin Do, Laura Wang, Ronald P. DeMatteo. Multiple intratumoral sources of kit ligand promote oncogenic kit signaling in gastrointestinal stomal tumor [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A017.

Background There is large variability in the risk of sentinel lymph node (SLN) positivity among patients with intermediate thickness melanoma (ITM), with a subgroup of patients exhibiting a low risk of nodal disease. Objective To identify a group of patients with ITM for whom the risk of nodal disease is low. Methods A retrospective cohort of patients with ITM who underwent wide excision and nodal evaluation from 2010 to 2013 was identified by using the National Cancer Database and analyzed for the presence of nodal disease. Classification and regression tree analysis identified the most important factors used in a model to identify groups at low risk of SLN positivity. Results Of 23,440 patients, 14.7% were found to have nodal metastasis. On classification and regression tree analysis, patients older than 55 years without lymphovascular invasion and with a lesion thickness less than 1.7 mm had an SLN positivity rate of 4.9%. A model using age and thickness in nonulcerated patients identified a low-risk subgroup with a corresponding SLN positivity rate of 4.7%. Limitations This was a retrospective study, and the model developed requires prospective validation. Conclusions Patient age is an important factor in estimating risk of SLN in patients with ITM and may help identify patients without ulceration who may be safely spared an SLN biopsy.

Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation. See related Spotlight on p. 489

Gastric ischemia has been reported in the literature mainly as case reports and case series. It is uncommon because of its excellent blood supply. Patients with atherosclerosis and vascular insufficiency are at risk for gastric ischemia, especially with gastric distension. Workup may reveal radiographic findings that denote ischemia and would prompt surgical intervention. However, these patients with vascular insufficiency tend to be poor surgical candidates, which can present a dilemma. The authors report two cases where non-operative management for gastric ischemia was successfully accomplished.

Pediatric altered mental status is a commonly feared presentation of children in both the emergency department and prehospital setting. Given the usual difficulties we face when treating children, utilizing systematic tools can help us to remain thorough and consistent when evaluating any given child. By using a standardized method of evaluation and diagnosis, first responders and emergency physicians can set aside their worries of mismanagement and provide adequate care to children with undifferentiated altered mental status. This article reviews one of the many approaches toward assessing children's clinical status, walks through the elements that comprise it, and examines how it can be used to make emergency providers more confident.

Introduction: Targeted therapy with tyrosine kinase inhibitors (TKI) including imatinib is effective in treating gastrointestinal stromal tumor (GIST), but resistance often develops within 18 months. Despite a robust immune T cell infiltrate, combining TKIs with immune checkpoint inhibitors has largely been unsuccessful in treating advanced GIST. The superagonist IL15/1L15Rα has shown promise in a number of cancer types. The objective of this study was to determine the effects of TKI therapy on intratumoral T cells in GIST and evaluate IL15/1L15Rα as an adjunctive therapy. Methods: KitV558Δ/+ mice were treated with imatinib (600mg/L in water) and/or IL15/IL15Rα (2ug/12ug/dose, 3x/week), for 1-4 weeks and evaluated by TCRB sequencing (Immunoseq), RNA-seq, and flow cytometry (n=4-5/group). Intratumoral immune cells from KitV558Δ/+ mice were evaluated by single cell RNA sequencing (scRNAseq) (n=3). Results: RNA-seq of sorted CD8 T cells following 1 week of imatinib treatment suggested intratumoral CD8 T cells gain antigen experience but lose their effector profile, as cd44, sell, and tcf7 increased while gzmb and tnfrsf9 decreased (p Citation Format: Andrew Tieniber, Andrew Hanna, Benjamin Medina, Kevin Do, Lillian Levin, Ferdiando Rossi, Ronald DeMatteo. Oncogenic kinase therapy restricts CD8 T cell differentiation and clonal expansion [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P050.

The natural history of hiatal herniation of small and/or large bowel post-esophagectomy (HHBPE) in the current era of improving long-term survival and evolving surgical technique is unknown. The aim of this study was to describe the rate and risk factors of HHBPE at our hospital.Patients undergoing esophagectomy between January 2011 and June 2017 were included if both follow-up information and axial imaging were available beyond 3 months post-esophagectomy. Patient characteristics, disease information, and treatment factors were all included in univariate analysis comparing patients with and without HHBPE, and multivariate regression was used to identify significant independent risk factors associated with HHBPE.Of 310 esophagectomy patients analyzed, 258 patients were included in the study, with 79 patients (31%) showing evidence of an HHBPE and an overall median follow-up of 24 months; 44 of 79 patients (56%) had symptoms possibly referable to HHBPE and 17 of 79 patients (22%) underwent surgical repair. On univariate analysis, neoadjuvant therapy (n = 176), higher clinical stage, minimally invasive approach (n = 154), and transhiatal esophagectomy (n = 189) were significant predictors of HHBPE (p0.05). On multivariate analysis, neoadjuvant therapy and transhiatal approach remained significant independent predictors (p 0.05). The rate of HHBPE was 44% in the 131 patients (51%) that had both factors.HHBPE in the current era of neoadjuvant therapy and minimally invasive esophagectomy is common. HHBPE can cause gastrointestinal symptoms, but operation to repair HHBPE is uncommon on intermediate follow-up. Additional study and long-term follow-up are required to fully assess the impact of HHBPE and to potentially modify surgical practice to prevent or minimize HHBPE.

Objective: Mindfulness-based interventions (MBIs) have shown promise in cultivating resilience and are widely accepted as efficacious in the treatment of a range of psychological disorders. This paper explores the feasibility of a Mindful-Awareness and Resilience Skills Training (MARST) program to enhance mindfulness and resilience, as a means of increasing psychological well-being and alleviating burnout and compassion fatigue in human service professionals. Method: In this randomised control trial, 46 human service professionals were randomly allocated to either a MARST group or to a no intervention, control group. Results: Multivariate analysis of covariance (MANCOVA), with pre-test scores as the covariates, revealed that the MARST intervention resulted in significant improvements in mindfulness, resilience, compassion satisfaction, and psychological well-being, and significant reductions in burnout and compassion fatigue; at post-intervention. These results were maintained at one month follow-up, with the exception of compassion satisfaction which was non-significant. Mediation analysis using a bootstrap resampling method indicated that mindfulness fully mediated changes in resilience and psychological well-being, as a result of the MARST intervention. Self-reported reductions in burnout following the intervention were mediated by mindfulness and resilience, and decreased compassion fatigue was mediated by resilience. Conclusions: The results of this study suggest that the MARST program may assist in developing resilience and ameliorating burnout and compassion fatigue in human service professionals. The study also provides evidence for the potential of mindfulness-based approaches to enhance resilience.

Post-treatment Lyme disease syndrome (PTLDS) is a pain disorder for which there remains no gold standard treatment option. Here, we report a case of PTLDS in a female patient whose pain was refractory to treatment options such as radiofrequency ablation, vitamin infusion therapy, opioid analgesics, and other pharmacotherapies. The patient commenced an experimental intravenous ketamine infusion therapy at the Florida Spine Institute (Clearwater, FL, USA) and achieved relief from her chronic pain, an improved quality of life, reduced depression and suicidal ideation, and reduced opioid consumption., Video abstract

BACKGROUND: Hamstring autografts with a diameter of less than 8 mm for ACL reconstruction have an increased risk of failure, but there is no consensus regarding the best method to predict autograft size in ACL reconstruction. QUESTIONS/PURPOSES: (1) What is the relationship between hamstring cross-section on preoperative MRI and intraoperative autograft size? (2) What is the minimum hamstring tendon cross-sectional area on MRI needed to produce an autograft of at least 8 mm at its thickest point? METHODS: This was a retrospective cohort study of 68 patients. We collectively reviewed patients who underwent ACL reconstruction by three separate fellowship-trained surgeons at the Carilion Clinic between April 2010 and July 2013. We searched the patient records database of each surgeon using the keyword “ACL”. A total of 293 ACL reconstructions were performed during that time period. Of those, 23% (68 patients) had their preoperative MRI (1.5 T or 3 T magnet) performed at the Carilion Clinic with MRI confirmation of acute total ACL rupture. Exclusion criteria included previous ACL reconstructions, multiligamentous injuries, and history of acute hamstring injuries. After applying the exclusion criteria, there were 29 patients in the 1.5 T magnet group and 39 in the 3 T group. Median age (range) was 29 years (12 to 50) for the 1.5 T group and 19 years (9 to 43) for the 3 T group. The patients were 41% female in the 1.5 T group and 23% female in the 3 T group. Use of 1.5 T or 3 T magnets was based on clinical availability and scheduling. The graft’s preoperative cross-sectional area was compared with the intraoperative graft’s diameter. The MRI measurements were performed by a single musculoskeletal radiologist at the widest point of the medial femoral condyle and at the joint line. Intraoperative measurements were performed by recording the smallest hole the graft could fit through at its widest point. Pearson’s correlation coefficients were calculated to determine the relationship between graft size and tendon cross-sectional area. A simple logistic regression analysis was used to calculate the cutoff cross-sectional areas needed for a graft measuring at least 8 mm at its thickest point. Intrarater reliability was evaluated based on re-measurement of 19 tendons, which produced an overall intraclass correlation coefficient (ICC) of 0.96 95% (CI 0.93 to 0.98). A p value < 0.05 was considered significant. RESULTS: In general, the correlation between MRI-measured hamstring thickness and hamstring graft thickness as measured in the operating room were good but not excellent. The three measurements that demonstrated the strongest correlation with graft size in the 1.5 T group were the semitendinosus at the medial femoral condyle (r = 0.69; p < 0.001), the semitendinosus and gracilis at the medial femoral condyle (r = 0.70; p < 0.001), and the mean semitendinosus and gracilis (r = 0.64; p < 0.001). These three measurements had correlation values of 0.53, 0.56, and 0.56, respectively, in the 3 T MRI group (all p values < 0.001). To create an 8-mm hamstring autograft, the mean semitendinosus plus gracilis cutoff values areas were 18.8 mm(2) and 17.5 mm(2) for the 1.5 T and 3.0 T MRI groups, respectively. CONCLUSIONS: Imaging performed according to routine knee injury protocol can be used to preoperatively predict the size of hamstring autografts for ACL reconstructions. In clinical practice, this can assist orthopaedic surgeons in graft selection and surgical planning. LEVEL OF EVIDENCE: Level II, diagnostic study.

This case report describes a patient who presented with acute left facial numbness and eyelid weakness prompting work-up, which demonstrated low suspicion for new stroke but revealed hypomagnesaemia as a potential differential diagnosis. Patient initially presented to the emergency department with left upper extremity weakness and was diagnosed with right basal ganglia infarction. Two weeks after transfer to the acute rehabilitation unit, patient suddenly complained of left facial numbness and eyelid weakness. However, brain imaging did not show any new acute infarct. Instead, laboratory results showed hypomagnesaemia at 1.50 mg/dL. Patient was therefore treated with intravenous magnesium leading to resolution of his symptoms. Up to 30% of acute stroke presentations are stroke mimics. Although hypomagnesaemia is less frequently seen as a mimic, its neuromuscular manifestations may present with similar symptoms. Patients will always benefit from a comprehensive evaluation for stroke symptoms, but it is important to consider the mimics as well.

A volumetric analysis of pre- and post-radiosurgery (PreSRS and PostSRS) edema in patients with cerebral metastases was performed to determine factors of a predictive model assessing the risk of developing increased edema relatively early after SRS. One-hundred-fourteen metastases in 55 patients were analyzed. Selection for this analysis required an MRI ≤ 30 days before SRS and an MRI ≤ 100 days after SRS. Tumor volumes were calculated on PreSRS, SRS, and PostSRS T1-weighted postgadolinium images while edema volumes were calculating using PreSRS and PostSRS fluid-attenuated inversion recovery MR images. An increase in edema was defined as an increase in measurable edema of at least 5%. We developed and evaluated a model predicting the relative risk (RR) of increased edema after SRS. Peritumoral edema increased in 18% (21/114) of the analyzed lesions. Melanoma/renal histology, recursive partitioning analysis class III, and prior WBRT carried RRs of developing postSRS edema increase of 2.45, 2.48, and 3.16, respectively (all P values

Background: In anterior cruciate ligament (ACL) reconstruction, hamstring tendon autografts Purpose/Hypothesis: The purposes of this study were to (1) determine whether routine magnetic resonance imaging (MRI) measurement of hamstring tendon cross-sectional area (CSA) can reliably be used by sports medicine fellowship–trained orthopaedic surgeons to predict graft size and (2) determine whether radiologists and sports medicine surgeons are able to discriminate grafts below a predetermined cutoff value. We hypothesized that radiologists will find a correlation between MRI measurement and intraoperative graft size. Similarly, orthopaedic surgeons will be able to correctly estimate the graft size based on MRI measurement. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Included in this study were 30 consecutive patients (15 women and 15 men) (mean age, 23 years [range, 13-43 years]) for whom MRI-determined hamstring tendon CSA and graft size measurements could be compared. Patients were included if they had a preoperative MRI demonstrating acute ACL rupture and were scheduled with 1 of 3 surgeons for a reconstruction performed using the ST and GR tendons. Operative data were collected over 1 year. Sectra imaging software was used to measure the CSA of the semitendinosus (ST) and gracilis (GR) tendons on the preoperative MRIs. Control measurements were performed intraoperatively using a graft sizing block with 0.5-mm increments. Simple linear regression analysis was used to evaluate the ability of MRI measurements to predict autograft size. Logistic regression was used to determine the minimum CSA for a graft of 8 mm. The intraclass correlation coefficient (ICC) was used to evaluate interrater reliability. Results: MRI CSA measurement of the average STGR (ST CSA added to the GR CSA) was a significant predictor of graft size (adjusted R 2 = 0.186; P < .001). The 3 measurements with the strongest correlations with graft size were the ST at the medial femoral condyle (MFC), the STGR at the MFC, and the average STGR. The minimum CSA for the average STGR on MRI to achieve a graft size of 8 mm was 17.168 mm2 ( P < .001). The area under the receiver operating characteristic curve was 0.765. The overall ICC was 0.977. Conclusion: Routine preoperative MRI can be used by both radiologists and orthopaedic surgeons to predict the expected ACL autograft size and identify those below a cutoff of 8 mm. This will help in preoperative planning and graft selection.

To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan–Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/− WBRT. 100 consecutive patients treated with SRS +/− WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson’s correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

Given the social burden and significant cost of dementia care in Australia, finding evidence-based approaches that improve outcomes, maintain independence, and reduce the impact on patients and families is essential. Finding effective ways to train and assist the healthcare staff who support these individuals is also critical, as they are considered to be at risk of workplace stress, burnout, and other psychological disturbances which negatively affects standards of care. The current paper describes a protocol for evaluating the effects of a Montessori-based approach to dementia care, in non-residential respite centres. An 18 month prospective observational, cohort controlled design is suggested that will compare participants from a community respite service that has undergone a Montessori-based workplace culture change and those from a service that provides a person-centred 'care as usual' approach. To achieve this, the protocol includes the assessment of participants across multiple variables on a monthly basis including the cognitive, behavioural, and emotional functioning of clients with dementia, levels of caregiver burden experienced by informal carers, and burnout, compassion satisfaction and workplace engagement among respite staff. The protocol also employs a qualitative evaluation of program fidelity. This approach will provide further insight into the potential benefits of early intervention with Montessori approaches for persons living with dementia in the community, their caregivers, and the staff and volunteers who assist them.

Our aim was to determine whether the establishment of a dedicated operating room team leads to improved process measure compliance and clinical outcomes in an Enhanced Recovery after Surgery (ERAS) program. Enhanced Recovery after Surgery programs involve the application of bundled best practices to improve the value of perioperative care. Successful implementation and sustainment of ERAS programs has been linked to compliance with protocol elements.Development of dedicated teams of anesthesia providers was a component of ERAS implementation. Intraoperative provider team networks (surgeons, anesthesiologists, and certified registered nurse anesthetists) were developed for all cases before and after implementation of colorectal ERAS. Four measures of centrality were analyzed in each network based on case assignments, and these measures were correlated with both rates of process measure compliance and clinical outcomes.Enhanced Recovery after Surgery provider teams led to a decrease in the closeness of anesthesiologists (p = 0.04) and significant increase in the clustering coefficient of certified registered nurse anesthetists (p = 0.005) compared with the pre-ERAS network. There was no significant change in centrality among surgeons (p = NS for all measures). Enhanced Recovery after Surgery designation among anesthesiologists and nurse anesthetists-whereby individual providers received an in-service on protocol elements and received compliance data was strongly associated with high compliance (0.6 of measures; p0.001 for each group). In addition, high compliance was associated with a significant reduction in length of stay (p 0.01), surgical site infection (p0.002), and morbidity (p0.009).Dedicated operating room teams led to increased centrality among anesthesia providers, which in turn not only increased compliance, but also improved several clinical outcomes.

This study investigated the relationship between tumor volume and outcomes in patients receiving trimodality therapy for locally advanced esophageal cancer.Between 2001 and 2012, 67 patients treated for esophageal cancer with chemoradiotherapy followed by esophagectomy who had available gross tumor volume (GTV) information were analyzed (35 node-negative, 32 node-positive patients with primary and nodal GTV contoured as separate regions of interest). All gross tumor volumes (GTVs) were contoured at the time of radiotherapy treatment planning. GTV optimal cutoff values were determined with receiver operating characteristic analysis and deemed significant when χ (2) analysis demonstrated differences in examined prognostic variables. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Cox proportional hazards model.GTVprimary (P = 0.034) and N stage were significant multivariate predictors for improved local control; GTVprimary was the only multivariate predictor of PFS (P = 0.0299) and OS (P = 0.001228) at 5 years. Univariate predictors of 5-year PFS and OS included GTVprimary, node number, and metastatic lymph node ratio. GTVprimary85 cc was the best predictor for local failure (33.3 %; 8.7 % if ≤85 cc). GTVprimary46 cc correlated with an increased risk of 5-year distant failure (37.1 %; 6.7 % if ≤46 cc).GTVprimary was a significant multivariate predictor for improved local control, PFS, and OS. GTVprimary is a more powerful predictor of patient outcomes than traditional TNM staging and should be part of the decision-making process when determining optimal local and systemic options for patients with locally advanced esophageal cancer.

Summary The study aimed to examine whether omission of 5-fluorouracil (5-FU)-containing chemotherapy alters pathological complete response rates in patients receiving trimodality therapy for locally advanced esophageal cancer. A total of 159 patients were identified. One hundred twenty-nine patients received platinum/5-FU concurrently with radiotherapy, and 30 received taxane/platinum-containing chemoradiotherapy prior to esophagectomy. Patients were staged using the 2002 American Joint Committee on Cancer staging system. Patients were matched between chemotherapeutic groups, with no significant demographic or clinical differences other than T stage (14% T2 in the 5-FU group; no T2 in the platinum/taxane group) and radiotherapy technique (8.5% received intensity-modulated radiotherapy in the 5-FU group; 60% in the platinum/taxane group). Pathological complete response rates for 5-FU and platinum/taxane-based groups were not significantly different (45% and 30%, respectively; P = 0.1548). Five-year overall survival and progression-free survival were not statistically different between the two groups. Significant predictors of pathological complete response included N stage (56% N0 and 33% N1; P = 0.0083), histology (37% adenocarcinoma and 59% squamous cell; P = 0.0123), tumor location (39% distal and 59% proximal/mid; P = 0.048), gastroesophageal junction involvement (33% involved and 55% uninvolved; P = 0.005), and radiotherapy end-to-surgery interval (50% < 55 days and 34% ≥ 55 days; P = 0.04). Grades 3–4 hematological toxicity was higher in the 5-FU group (36%) than in the paclitaxel-containing therapy group (17%; P = 0.0484). Use of paclitaxel-containing chemoradiotherapy did not result in inferior pathological complete response, overall survival, or progression-free survival rates, and resulted in less hematological toxicity than 5-FU treatment.

Purpose Numerous studies have shown that tooth size is an important key to ideal occlusion. Bolton (Angle Orthod 28:13, 1958; 48:504, 1962) described a constant ratio between the widths of the upper and lower teeth that must be present to achieve an optimal occlusion. The purpose of this study was to determine the incidence of Bolton discrepancies in patients with Class II malocclusion scheduled for mandibular advancement surgery. Patients and Methods This study included 126 patients (40 male, 86 female) with Class II malocclusion who had at least a mandibular advancement as part of their surgical treatment. The mesiodistal widths of the 6 anterior maxillary and mandibular teeth were measured on preoperative models using a caliper. The measurements were used to compute the anterior Bolton ratio. Results Seventy-three of 126 patients (57.9%) were found to have an anterior Bolton ratio greater than the Bolton norm, indicating too much lower tooth mass compared with the upper mass or too little upper tooth mass compared with the lower mass. Conclusion Tooth-size discrepancies are common in patients requiring mandibular advancement surgery. This can make it difficult to advance the mandible into a solid Class I relation at the time of surgery. Bolton discrepancies should be considered when planning treatment with presurgical orthodontics. In addition, if necessary, the width of the lower incisors should be decreased or a space distal to the maxillary lateral incisors should be created to allow the establishment of a solid Class I canine occlusion at the time of surgery.

PurposeThe purpose of this paper is to determine whether and how much patients would be willing to pay for diabetes disease state management (DSM) services in community pharmacies, and also to determine the relationships between willingness to pay (WTP) and different clinical/socio/demographic characteristics of patients.Design/methodology/approachA sample of 130 diabetic patients recruited from 14 pharmacies across Sydney, Australia completed self‐administered questionnaires. SPSS 16.0 was used to assess WTP in four scenarios (50 and 100 percent improvement in diabetes control after a 30 minute initial and 30 minute follow‐up consultation, respectively). Descriptive and inferential statistical techniques (regression) were used to analyse data.FindingsPatients are willing to pay a median of AUS$30 for 50 percent improvement and AUS$40 for 100 percent improvement per 30 minute initial consultation, and AUS$20 for 50 percent improvement and AUS$30 for 100 percent improvement per 30 minute follow‐up consultation. Although results varied across scenarios, WTP generally increased when: patients' income is greater than AUS$150,000; frequency of patients' diabetes‐related hospitalizations is between 2 and 4; and patients' perceptions of pharmacists' ability are higher. The remainder of the variables tested are not significantly associated with WTP.Practical implicationsThe findings demonstrate that most patients are willing to pay for diabetes DSM services in community pharmacies, and there is a great opportunity for pharmacies to expand their clinical services in this area.Originality/valueThe key contribution to the literature is the data relating to the willingness of Australian diabetic patients to pay for pharmacy‐delivered disease management support, and how this varies across people with different clinical/socio/demographic characteristics.

Background Although laparoscopic Heller myotomy (LHM) has been the standard of care for achalasia, per oral endoscopic myotomy (POEM) has gained popularity as a viable alternative. This retrospective study aimed to compare patient-reported outcomes between LHM and POEM in a consecutive series of achalasia patients with more than 1 year of follow-up. Study design We reviewed demographic and procedure-related data for patients who underwent either LHM or POEM for achalasia between January 2011 and May 2016. Phone interviews were conducted assessing post-procedure achalasia symptoms via the Eckardt score and achalasia severity questionnaire (ASQ). Demographics, disease factors, and survey results were compared between LHM and POEM patients using univariate analysis. Significant predictors of procedure failure were analyzed using univariate and multivariate analysis. Results There were no serious complications in 110 consecutive patients who underwent LHM or POEM during the study period, and 96 (87%) patients completed phone surveys. There was a nonsignificant trend toward better patient-reported outcomes with POEM. There were significant differences in patient characteristics including sex, achalasia type, mean residual lower esophageal pressure (rLESP), and follow-up time. The only univariate predictors of an unsatisfactory Eckardt score or ASQ were longer follow-up and lower rLESP, with follow-up length being the only predictor on multivariate analysis. Conclusions There were significant demographic and clinical differences in patient selection for POEM vs LHM in our group. Although the 2 procedures have similar patient-reported effectiveness, subjective outcomes seem to decline as a result of time rather than procedure type.

PURPOSE/OBJECTIVES: Physician estimates of cancer patients' survival are notoriously inaccurate. A number of models have been developed in an effort to better predict patient lifespan based on clinical factors. The Graded Prognostic Assessment (GPA), most recently published in 2012 by Sperduto et al, estimates median survival (MS) for patients who had undergone treatment for new brain metastases from June 1993 to January 2010. While independently validated in numerous studies, we investigated the applicability of the GPA model in the modern era for a smaller cohort of patients with brain metastases who were specifically selected for SRS by retrospectively calculating the diagnosis-specific GPA predicted median survival for patients with brain metastases treated with SRS at our institution between 2006 and 2012. RESULTS: 100 patients underwent SRS; 73 received whole brain radiation therapy. Observed (O) and predicted (P) MS were 13.3 and 9.4 months. The difference between predicted and actual survival was computed for each patient, and the mean difference was 10.8 months (95% CI, 8.95 - 14.8 months); the mean actual/predicted ratio was 2.07 (95% CI, 1.64 - 2.50). Compared to the predicted, actual survival was 25/35/50% longer (an arbitrarily chosen yet clinically significant amount of time) in almost half (53/49/48%) of our patients. Even when KPS was overestimated (increasing GPA predicted survival), actual survival 25/35/50% longer than predicted survival was observed in 49/46/44% of patients. CONCLUSIONS: Our deliberate selection bias of recently treated patients with modern imaging and more advanced therapies confirms that clinical models such as the GPA must be used with awareness of the current clinical setting as well as a full understanding of the model and its derivation to be of greatest benefit.