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Preoperative anemia is common and associated with adverse postoperative outcomes. Assessment of hemoglobin concentrations may facilitate optimization prior to surgery. However, phlebotomy-based hemoglobin measurement may contribute to patient discomfort and iatrogenic blood loss, which makes non-invasive hemoglobin estimation attractive in this setting.This is a prospective study of adult patients presenting for preoperative evaluation before elective surgery at a tertiary care medical center. The Masimo Pronto Pulse CO-Oximeter was utilized to estimate blood hemoglobin concentrations (SpHb), which were then compared with hemoglobin concentrations obtained via complete blood count. Receiver operating curves were used to identify SpHb values maximizing specificity for anemia detection while meeting a minimum sensitivity of 80%.A total of 122 patients were recruited with a median (interquartile range) age of 66 (58, 72) years. SpHb measurements were obtained in 112 patients (92%). SpHb generally overestimated hemoglobin with a mean (± 1.96 × standard deviation) difference of 0.8 (-2.2, 3.9) g/dL. Preoperative anemia, defined by hemoglobin12.0 g/dL in accordance with institutional protocol, was present in 22 patients (20%). The optimal SpHb cut-point to identify anemia was 13.5 g/dL: sensitivity 86%, specificity 81%, negative predictive value 96%, and positive predictive value 53%. Utilizing this cut-point, 60% (73/122) of patients could have avoided phlebotomy-based hemoglobin assessment, while an anemia diagnosis would have been missed in3% (3/122).The use of SpHb devices for anemia screening in surgical patients is feasible with the potential to reliably rule-out anemia despite limited accuracy.

High titers of cold agglutinins jeopardize the quality of an apheresis product meant for autologous or allogeneic transplant. Management of transplant patients with cold agglutinin disease (CAD) is often experience-based and under reported, yet decisions must be made quickly to optimize product management and patient outcomes. There remains a lack of data quantifying cell recovery and viability when using various warming methodologies.To expand the published experimental data on this subject, our human cellular therapy lab compared cellular recoveries and viabilities after manipulation of cryopreserved apheresis products through various warming methodologies: (1) extended warming in a water bath, (2) warming via blood warmer and infusion pump, and (3) warming in a water bath followed by infusion pump as a control to assess potential shear stress effects.The presented studies demonstrate that all methods of product warming produce the same rates of recovery of total and viable cells across vital cell types prior to patient administration. Statistically, use of an extended water bath protocol provided a marginal benefit in recovery of total nucleated cells, though this effect is diminished when products are held for an extended period to simulate a delay in administration.These results can inform decisions to improve patient care and minimize product manipulation and loss. Centers are encouraged to use this information to guide proactive measures to establish a standard operating procedure to manage CAD cases.

PurposeSplenectomies though well-established in the successful management of several resistant haemoglobinopathies, have not been studied in detail in the paediatric population to assess the outcomes. We conducted this review to primarily assess the surgical and anaesthetic outcomes of paediatric splenectomies and secondarily highlight factors predictive for a high-risk splenectomy.MethodsA 5 year retrospective chart review was made, and patient follow-up was done jointly using the hospital electronic medical records and telephonic calls. A p value of ResultsAmong the 69 splenectomised children, 61% were male and the overall mean age was 10.2 years. The cohort consisted of thalassemia’s(46%), ITP’s(30%), haemolytic anemias(19%) and 1 child each with lymphoma, splenic cyst and Kassabach Meritt syndrome. Most(96%) were electively operated and 23% were performed laparoscopically. 61% received intravenous analgesia and the mean volume of fluid administered intra-operatively was 21ml/kg. There was no documented OPSI, and there was one mortality. The mean follow-up period was 43 months.ConclusionSplenectomy was associated with a promising overall outcome with a survival rate of 98.5%. A greater pre-operative transfusion requirement, a larger sized spleen and increased fluid administration intra-operatively, were associated with a worse outcome.

Patients with chronic gastrointestinal, hepatic, and renal disease are frequently encountered in clinical practice. This is due in part to the rising prevalence of risk factors associated with these conditions. These patients are increasingly being considered for surgical intervention and are at higher risk for multiple perioperative complications. Many are able to safely undergo surgery but require unique considerations to ensure optimal perioperative care. In this review, we highlight relevant perioperative physiology and outline our approach to the evaluation and management of patients with select chronic gastrointestinal, hepatic, and renal diseases. A comprehensive preoperative evaluation with a multidisciplinary approach is often beneficial, and specialist involvement should be considered. Intraoperative and postoperative plans should be individualized based on the unique medical and surgical characteristics of each patient.

Supplemental Figure 1. Histograms for Flow Cytometry Analysis. Supplemental Figure 2. DHA alters ABPs subcellular distribution.

Supplementary Data from Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy

Supplementary Table from Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy

Supplementary Data from Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy

Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacologic inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ataxia-telangiectasia mutated (ATM) activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized cross-talk between squalene metabolites, ER stress, and the DNA damage response. Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments.Significance:Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.

PDF file - 636KB, Supplemental Table S1: information of the GBM lines used in this paper. Supplemental Table S2: information of the patient clinical data for Figure 1. Supplemental Table S3: Percentage of cells positive for staining with PRMT5 in spontaneous high grade astrocytoma from Mut3 strain (GFAP-cre; cisNf1-/+; P53-/-) and normal brain tissue from wild-type control mouse stained by PRMT5 and ki-67 antibody. Supplemental table S4. GBM cell line (U251) was transfected by scramble control or si-PRMT5. Affymetrix microarray genechip was performed in three independent experiments to evaluate genes up-regulated with PRMT5 silencing.

PDF file - 1690KB, Supplemental Figure S1. PRMT5 is over-expressed in human GBM cell lines. Supplemental Figure S2: High grade astrocytomas Supplemental Figure S3: efficacy and specificity of PRMT5 knock-down by lead siRNA. Supplemental Figure S4: PRMT5 Knockdown promotes cell death of human GBM cells Supplemental Figure S5: si-PRMT5 induced cell death is P53-independent Supplemental Figure S6: Decreased ST7 expression correlates with worse survival in all glioma patients (grade I-IV). Supplemental Figure S7: Over-expression of ST7 in three GBM cell lines was confirmed by real-time PCR and western blot (top panels).

Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease. Cancer Res; 74(6); 1752–65. ©2014 AACR.

Careful consideration of the clinical history with traditional testing such as an antibody screen and direct antiglobulin test (DAT) allow for the categorization of most forms of autoimmune hemolytic anemia. Based on the initial findings, specialized testing can further categorize disease entities and increase the sensitivity of testing. In this section, we explain the diagnostic findings of both traditional and novel testing and how their appropriate interpretations help distinguish the forms of autoimmune hemolytic anemia (AIHA).

Background The rise of investigative and commercially available cell therapy products adds a new dynamic to academic medical centers; that is, the management of patient-specific cell products. The scope of cell therapy has rapidly expanded beyond in-house collection and infusion of cell products such as bone marrow and peripheral blood transplant. The complexities and volumes of cell therapies are likely to continue to become more demanding. As patient-specific “living drugs,” cell therapy products typically require material collection, product provenance, transportation and maintenance of critical quality attributes, including temperature and expiration dates. These requirements are complicated by variations in product-specific attributes, reporting requirements and interactions with industry not required of typical pharmaceuticals. Methods To manage these requirements, the authors set out to establish a framework within the Immune, Progenitor and Cell Therapeutics Lab, the Current Good Manufacturing Practice facility responsible for cell manufacturing at Mayo Clinic Rochester housed within the Division of Transfusion Medicine. The authors created a work unit (biopharmaceutical unit) dedicated to addressing the specialized procedures required to properly handle these living drugs from collection to delivery and housing the necessary processes to more easily integrate externally manufactured cell therapies into clinical practice. Results The result is a clear set of expectations defined for each step of the process, with logical documentation of critical steps that are concise and easy to follow. Conclusions The authors believe this system is scalable for addressing the promised growth of cell therapy products well into the future. Here the authors describe this system and provide a framework that could be used by other centers to manage these important new therapies.

Objective To compare the relative value of 3 analgesic pathways for total knee arthroplasty (TKA). Patients and Methods Time-driven activity-based costing analyses were performed on 3 common analgesic pathways for patients undergoing TKA: periarticular infiltration (PAI) only, PAI and single-injection adductor canal blockade (SACB), and PAI and continuous adductor canal blockade (CACB). Additionally, adult patients who underwent elective primary TKA from November 1, 2017, to May 1, 2018, were retrospectively identified to analyze analgesic (pain score, opiate use) and hospital outcomes (distance walked, length of stay) after TKA based on analgesic pathway. Results There was no difference in patient demographic characteristics, specifically complexity (American Society of Anesthesiologists score) or preoperative opiate use, between groups. Compared with PAI, total cost (labor and material) was 1.4-times greater for PAI plus SACB and 2.3-times greater for PAI plus CACB. The addition of SACB to PAI resulted in lower average and maximum pain scores and opiate use on the day of operation compared with PAI alone. Average and maximum pain scores and opiate use between SACB and CACB were not significantly different. Walking distance and hospital length of stay were not significantly different between groups. Conclusion Perioperative care teams should consider the cost and relative value of pain management when selecting the optimal analgesic strategy for TKA. Despite slightly higher relative cost, the combination of SACB with PAI may offer short-term analgesic benefit compared with PAI alone, which could enhance its relative value in TKA.