Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

BACKGROUND: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. METHODS: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. RESULTS: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. CONCLUSIONS: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

Dalotuzumab in chemorefractory KRAS exon 2 mutant colorectal cancer: Results from a randomised phase II/III trial.

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.

Pediatric malignant hyperthermia: risk factors, morbidity, and mortality identified from the Nationwide Inpatient Sample and Kids' Inpatient Database.

BACKGROUND: Malignant Hyperthermia (MH) is a potentially fatal metabolic disorder. Due to its rarity, limited evidence exists about risk factors, morbidity, and mortality especially in children. METHODS: Using the Nationwide Inpatient Sample and the Kid's Inpatient Database (KID), admissions with the ICD-9 code for MH (995.86) were extracted for patients 0-17 years of age. Demographic characteristics were analyzed. Logistic regression was performed to identify patient and hospital characteristics associated with mortality. A subset of patients with a surgical ICD-9 code in the KID was studied to calculate the prevalence of MH in the dataset. RESULTS: A total of 310 pediatric admissions were seen in 13 nonoverlapping years of data. Patients had a mortality of 2.9%. Male sex was predominant (64.8%), and 40.5% of the admissions were treated at centers not identified as children's hospitals. The most common associated diagnosis was rhabdomyolysis, which was present in 26 cases. Regression with the outcome of mortality did not yield significant differences between demographic factors, age, sex race, or hospital type, pediatric vs nonpediatric. Within a surgical subset of 530,449 admissions, MH was coded in 55, giving a rate of 1.04 cases per 10,000 cases. CONCLUSIONS: This study is the first to combine two large databases to study MH in the pediatric population. The analysis provides an insight into the risk factors, comorbidities, mortality, and prevalence of MH in the United States population. Until more methodologically rigorous, large-scale studies are done, the use of databases will continue to be the optimal method to study rare diseases.

Abdominoperineal resection and low anterior resection: comparison of long-term oncologic outcome in matched patients with lower rectal cancer.

PURPOSE: The current study aimed to compare the oncologic outcome and pattern of metastasis after abdominoperineal resection (APR) and low anterior resection (LAR) treating lower rectal cancer. METHODS: A total of 804 patients undergoing curative resection (R0) were enrolled prospectively. The APR and LAR groups (n = 402, respectively) were matched for gender, age, and stage, for a retrospectively comparative analysis. RESULTS: In a multivariate analysis with potential variables, APR itself was not a risk factor for increased local recurrence (LR) or reduced survival (P = 0.243-0.994). Circumferential resection margin (CRM) involvement as an operation-related risk was 1.6-fold more frequent in the APR group and was significantly associated with LR and systemic recurrence (OR, 2.487-4.017; P < 0.01). Circumferential margin positivity (CRM+) was concurrently correlated with advanced stage, larger tumor (long diameter, >4 cm), and longer sagittal midpelvic diameter (>10 cm) in a multivariate analysis (P < 0.001-0.05). The site of metastasis did not differ between the two groups, with the exception of lung metastasis which was more frequent in the APR group (APR vs. LAR: 15.9 vs. 10 %, P = 0.015). In the APR group, CRM+ and the presence of an infiltrating tumor were correlated with disease-free survival (hazard ratio (HR), 1.644 and 1.654, respectively), whereas elevated serum carcinoembryonic antigen and LVI+ were correlated with overall survival (HR, 1.57 and 1.671, respectively), in a multivariate analysis with potential variables (P < 0.05). CONCLUSIONS: When performed with appropriate skill to achieve R0 resection, APR can be used safely without impairing oncological outcome, although sphincter-preserving surgery should remain the preferred option.

Washout times of desflurane, sevoflurane and isoflurane from the GE Healthcare Aisys® and Avance®, Carestation®, and Aestiva® anesthesia system.

BACKGROUND/AIM: Malignant hyperthermia susceptible patients may experience a fatal reaction to volatile anesthetic gases. This study sought to determine the washout characteristics of desflurane, sevoflurane, and isoflurane from the Aisys® , Avance® , and Aestiva® anesthesia machines. (GE Healthcare, Madison, WI, USA). METHODS: All machines were inspected by a GE Healthcare engineer prior to testing. The machines were primed with desflurane 7 vol%, sevoflurane 2.5 vol%, and isoflurane 1.2 vol% on three separate occasions for 2 h each with each gas. The Aisys® and Avance® were tested with and without an Advanced Breathing System (ABS™ , GE Healthcare, Madison, WI, USA). The Aestiva® was tested without modification to its breathing system. Additionally, the Aisys was evaluated with desflurane 1.2 vol% and the Avance with a preflushed fresh gas line was tested with an autoclaved ABS. After priming, disposable components of the patient breathing system were replaced. The fresh gas flow was increased to 15 lpm. Gas measurements were recorded until the concentration was 4 parts per million (p.p.m). RESULTS: The fastest median washout time was achieved by the Avance in 3 min or less without an ABS or with an autoclaved ABS. The longest median time was 35 min for the Aestiva® . Clearance of desflurane was the most time consuming for all machines. CONCLUSION: This study demonstrates that saturated vapor pressure and priming concentration exert a greater effect on washout times than gas solubility. The Aisys utilizes an electronic vaporizer system that may expose the breathing system to retained saturated vapor. The breathing systems for all machines may hinder washout of gases.

Reliability and accuracy in radiographic measurements of musculoskeletal tumors.

Tumor size and growth are important parameters when evaluating bone and soft tissue neoplasms. There are no reports comparing the intra- and interobserver reliability among physicians in their evaluation of musculoskeletal (MSK) tumor imaging. This study investigates the accuracy and precision of measurements made by orthopedic and radiology physicians in different stages of training. Blinded magnetic resonance imaging (MRI) scans from six patients, three soft tissue, and three bone tumors were selected: each case included an "old" and "new" scan that was performed at least 3 months apart. Fourteen participants were selected, representing varying levels of education and experience, including two of each of the following: medical students, orthopedic and radiology residents, oncology and nononcologic orthopedic attendings, and MSK and non-MSK radiology attendings. Participants compared the old and new studies, recording tumor size in the transverse, cranial-caudal, and anterior-posterior dimensions, and determined if the tumor was stable or unstable. The MRI's official report served as the "gold standard." Average intraobserver variability (|Trial 1 - Trial 2|/[(Trial 1 + Trial 2)/2])) in size measurements was 11.08% (0.00%-68.62%). The lowest variability was recorded by the MSK radiologist 1 (6.16%), and the greatest variability by Orthopedic Surgery Resident 1 (16.70%). Participants correctly determined stability 82% of the time (71%-100%). Only MSK radiologists correctly determined stability in over 90% of cases. There is considerable variability and inaccuracy in MRI-based measurements of MSK tumors. These findings motivate opportunities for improving MSK imaging education of radiology and orthopedic residents. Physicians ordering MRI scans should evaluate them themselves, instead of relying on the radiology report alone, to inform clinical decision-making.

Clinical Practice Guideline: Tympanostomy Tubes in Children (Update).

OBJECTIVE: Insertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ear fluid, frequent ear infections, or ear infections that persist after antibiotic therapy. All these conditions are encompassed by the term otitis media (middle ear inflammation). This guideline update provides evidence-based recommendations for patient selection and surgical indications for managing tympanostomy tubes in children. The guideline is intended for any clinician involved in managing children aged 6 months to 12 years with tympanostomy tubes or children being considered for tympanostomy tubes in any care setting as an intervention for otitis media of any type. The target audience includes specialists, primary care clinicians, and allied health professionals. PURPOSE: The purpose of this clinical practice guideline update is to reassess and update recommendations in the prior guideline from 2013 and to provide clinicians with trustworthy, evidence-based recommendations on patient selection and surgical indications for managing tympanostomy tubes in children. In planning the content of the updated guideline, the guideline update group (GUG) affirmed and included all the original key action statements (KASs), based on external review and GUG assessment of the original recommendations. The guideline update was supplemented with new research evidence and expanded profiles that addressed quality improvement and implementation issues. The group also discussed and prioritized the need for new recommendations based on gaps in the initial guideline or new evidence that would warrant and support KASs. The GUG further sought to bring greater coherence to the guideline recommendations by displaying relationships in a new flowchart to facilitate clinical decision making. Last, knowledge gaps were identified to guide future research. METHODS: In developing this update, the methods outlined in the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition: A Quality-Driven Approach for Translating Evidence Into Action" were followed explicitly. The GUG was convened with representation from the disciplines of otolaryngology-head and neck surgery, otology, pediatrics, audiology, anesthesiology, family medicine, advanced practice nursing, speech-language pathology, and consumer advocacy. ACTION STATEMENTS: The GUG made strong recommendations for the following KASs: (14) clinicians should prescribe topical antibiotic ear drops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea; (16) the surgeon or designee should examine the ears of a child within 3 months of tympanostomy tube insertion AND should educate families regarding the need for routine, periodic follow-up to examine the ears until the tubes extrude.The GUG made recommendations for the following KASs: (1) clinicians should not perform tympanostomy tube insertion in children with a single episode of otitis media with effusion (OME) of less than 3 months' duration, from the date of onset (if known) or from the date of diagnosis (if onset is unknown); (2) clinicians should obtain a hearing evaluation if OME persists for 3 months or longer OR prior to surgery when a child becomes a candidate for tympanostomy tube insertion; (3) clinicians should offer bilateral tympanostomy tube insertion to children with bilateral OME for 3 months or longer AND documented hearing difficulties; (5) clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who do not receive tympanostomy tubes, until the effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are suspected; (6) clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media who do not have middle ear effusion in either ear at the time of assessment for tube candidacy; (7) clinicians should offer bilateral tympanostomy tube insertion in children with recurrent acute otitis media who have unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy; (8) clinicians should determine if a child with recurrent acute otitis media or with OME of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors; (10) the clinician should not place long-term tubes as initial surgery for children who meet criteria for tube insertion unless there is a specific reason based on an anticipated need for prolonged middle ear ventilation beyond that of a short-term tube; (12) in the perioperative period, clinicians should educate caregivers of children with tympanostomy tubes regarding the expected duration of tube function, recommended follow-up schedule, and detection of complications; (13) clinicians should not routinely prescribe postoperative antibiotic ear drops after tympanostomy tube placement; (15) clinicians should not encourage routine, prophylactic water precautions (use of earplugs or headbands, avoidance of swimming or water sports) for children with tympanostomy tubes.The GUG offered the following KASs as options: (4) clinicians may perform tympanostomy tube insertion in children with unilateral or bilateral OME for 3 months or longer (chronic OME) AND symptoms that are likely attributable, all or in part, to OME that include, but are not limited to, balance (vestibular) problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life; (9) clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is likely to persist as reflected by a type B (flat) tympanogram or a documented effusion for 3 months or longer; (11) clinicians may perform adenoidectomy as an adjunct to tympanostomy tube insertion for children with symptoms directly related to the adenoids (adenoid infection or nasal obstruction) OR in children aged 4 years or older to potentially reduce future incidence of recurrent otitis media or the need for repeat tube insertion.

Executive Summary of Clinical Practice Guideline on Tympanostomy Tubes in Children (Update).

OBJECTIVE: This executive summary of the guideline update provides evidence-based recommendations for patient selection and surgical indications for managing tympanostomy tubes in children. The summary and guideline are intended for any clinician involved in managing children aged 6 months to 12 years with tympanostomy tubes or children being considered for tympanostomy tubes in any care setting as an intervention for otitis media of any type. The target audience includes specialists, primary care clinicians, and allied health professionals. PURPOSE: The purpose of this executive summary is to provide a succinct overview for clinicians of the key action statements (recommendations), summary tables, and patient decision aids from the update of the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline: Tympanostomy Tubes in Children (Update)." The new guideline updates recommendations in the prior guideline from 2013 and provides clinicians with trustworthy, evidence-based recommendations on patient selection and surgical indications for managing tympanostomy tubes in children. This summary is not intended to substitute for the full guideline, and clinicians are encouraged to read the full guideline before implementing the recommended actions. METHODS: The guideline on which this summary is based was developed using methods outlined in the American Academy of Otolaryngology-Head and Neck Surgery Foundation's "Clinical Practice Guideline Development Manual, Third Edition: A Quality-Driven Approach for Translating Evidence Into Action," which were followed explicitly. The guideline update group represented the disciplines of otolaryngology-head and neck surgery, otology, pediatrics, audiology, anesthesiology, family medicine, advanced practice nursing, speech-language pathology, and consumer advocacy. ACTION STATEMENTS: Strong recommendations were made for the following key action statements: (14) Clinicians should prescribe topical antibiotic ear drops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea. (16) The surgeon or designee should examine the ears of a child within 3 months of tympanostomy tube insertion AND should educate families regarding the need for routine, periodic follow-up to examine the ears until the tubes extrude.Recommendations were made for the following key action statements: (1) Clinicians should not perform tympanostomy tube insertion in children with a single episode of otitis media with effusion (OME) of less than 3 months' duration, from the date of onset (if known) or from the date of diagnosis (if onset is unknown). (2) Clinicians should obtain a hearing evaluation if OME persists for 3 months or longer OR prior to surgery when a child becomes a candidate for tympanostomy tube insertion. (3) Clinicians should offer bilateral tympanostomy tube insertion to children with bilateral OME for 3 months or longer AND documented hearing difficulties. (5) Clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who do not receive tympanostomy tubes, until the effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are suspected. (6) Clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media (AOM) who do not have middle ear effusion (MEE) in either ear at the time of assessment for tube candidacy. (7) Clinicians should offer bilateral tympanostomy tube insertion in children with recurrent AOM who have unilateral or bilateral MEE at the time of assessment for tube candidacy. (8) Clinicians should determine if a child with recurrent AOM or with OME of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors. (10) The clinician should not place long-term tubes as initial surgery for children who meet criteria for tube insertion unless there is a specific reason based on an anticipated need for prolonged middle ear ventilation beyond that of a short-term tube. (12) In the perioperative period, clinicians should educate caregivers of children with tympanostomy tubes regarding the expected duration of tube function, recommended follow-up schedule, and detection of complications. (13) Clinicians should not routinely prescribe postoperative antibiotic ear drops after tympanostomy tube placement. (15) Clinicians should not encourage routine, prophylactic water precautions (use of earplugs or headbands, avoidance of swimming or water sports) for children with tympanostomy tubes.Options were offered from the following key action statements: (4) Clinicians may perform tympanostomy tube insertion in children with unilateral or bilateral OME for 3 months or longer (chronic OME) AND symptoms that are likely attributable, all or in part, to OME that include, but are not limited to, balance (vestibular) problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life. (9) Clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is likely to persist as reflected by a type B (flat) tympanogram or a documented effusion for 3 months or longer. (11) Clinicians may perform adenoidectomy as an adjunct to tympanostomy tube insertion for children with symptoms directly related to the adenoids (adenoid infection or nasal obstruction) OR in children aged 4 years or older to potentially reduce future incidence of recurrent otitis media or the need for repeat tube insertion.

Preparation of modern anesthesia workstations for malignant hyperthermia-susceptible patients: a review of past and present practice.

Patients with malignant hyperthermia experience an exaggerated metabolic response when exposed to volatile anesthetic gases and succinylcholine. The minimum concentration of anesthetic gas needed to trigger a malignant hyperthermia crisis in humans is unknown and may remain so because of the inherent risks associated with studying the complex nature of this rare and lethal genetic disorder. The Malignant Hyperthermia Association of the United States provides specific instructions on purging anesthesia machines of volatile agents to reduce the risk of exposure. However, these recommendations were developed from studies of older generation machines. Modern anesthesia workstations are more complex and contain more gas absorbing materials. A review of the literature found the current guidelines inadequate to prepare newer generation workstations, which require more time for purging anesthetic gases, autoclaving or replacement of parts, and modifications to the gas delivery system. Protocols must be developed to prepare newer generation anesthesia machines.

Nerve Blocks for Postoperative Pain Management in Children Receiving Subcutaneous Implantable Cardioverter-Defibrillators: A Case Series.

Subcutaneous implantable cardioverter-defibrillator (S-ICD) placement may cause significant postoperative pain. Limited research exists on regional anesthesia for pediatric S-ICD placement. This case series examined transversus thoracic plane blocks (TTPBs), pectointercostal fascial plane blocks (PIFBs), pectoralis nerve I and II blocks, paravertebral, serratus anterior plane, and erector spinae plane blocks (ESPBs) in 10 children receiving S-ICDs. Parasternal nerve blocks consisting of TTPB or PIFB and left ESPB appeared to provide adequate pain control. These children had reduced opioid consumption, lower mean pain scores, longer delay in first postoperative analgesic, and no complications. Regional anesthesia may reduce pain after pediatric S-ICD implantation.

Genome-wide identification of chemosensitive single nucleotide polymorphism markers in colorectal cancers.

Improved methods for predicting chemoresponsiveness involving the identification of polymorphic markers is highly desirable, considering narrow therapeutic index and frequent resistance to anti-cancer regimens. The genome-wide screening of chemosensitive single nucleotide polymorphisms (SNPs) was undertaken in association with in vitro chemosensitivity assays in 104 colorectal cancer patients for the initial screening step. Allele frequency, linkage disequilibrium, potential function, and Hardy-Weinberg equilibrium of the candidate SNPs were then determined for the identifying step. Finally, clinical association analysis in the other 260 evaluable patients or cell viability assays of transfected RKO cells was used to verify candidate SNPs for the validation step. In total, 12 SNPs to six regimens were initially chosen during the screening and identifying steps. In patients receiving fluoropyrimidine-based adjuvant chemotherapy, the substitution alleles of GPC5 rs553717 (AA) correlated significantly with tumor recurrence and shorter disease-free survival (P = 0.019 and 0.023, respectively). Interestingly, RKO cells expressing mutant GPC5 showed enhanced cell death in response to 5-FU in cytotoxicity assays. Patients that were homozygous for the reference alleles SSTR4 rs2567608 (AA) and EPHA7 rs2278107 (TT) showed lower disease control rates in response to irinotecan and oxaliplatin regimens, respectively, than those with substitution alleles (P = 0.022 and 0.014, respectively). Thus, we identified chemosensitive SNP markers using a novel three step process of genome-wide analysis consisting of in vitro screening, identification, and validation. The candidate chemosensitive SNP markers identified in our study, including those identified in vitro, can now be further verified in a large cohort study.

Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas.

BACKGROUND: Promoter methylation of colorectal cancer-related genes were examined with respect to phenotype and tumor progression. MATERIALS AND METHODS: We assayed promoter methylation of 11 genes including established CpG island methylator phenotype (CIMP) markers (MLH1, MINT1, MINT2, MINT31, p16 ( INK4a ), p14 ( ARF ), and CACNA1G) and four genes (COX2, DAPK, MGMT, and APC) frequently methylated in colorectal cancer in 285 patients with sporadic colorectal cancer. RESULTS: CIMP+ tumors were more than two times more frequent among high-frequency microsatellite instability tumors (MSI-H) than in tumors without MSI (P < or = .0001-.002). COX2 and DAPK methylation were significantly associated with CIMP+ and MSI. KRAS showed tendency toward more frequent codon 12-13 mutations identified in tumors with APC and p16 ( INK4a ) methylation than in those with unmethylation (P = .033 and .05, respectively). Additionally, tumors with synchronous adenoma were associated with p16 ( INK4a ) methylation (P = .004). The p16 ( INK4a ) methylation was significantly associated with poor overall and disease-free survival in 131 rectal cancer patients who underwent curative operation, according to multivariate analyses (relative risk [RR] = 0.317 and 0.349; P = .033 and .024, respectively). Specifically, in 175 stage II and III patients receiving adjuvant-based fluoropyrimidine chemotherapy, p16 ( INK4a ) methylation and MINT31 unmethylation showed a significant or tendency toward an association with recurrence and DFS (P = .007-.032). CONCLUSIONS: The study suggests that specific CIMP markers, such as p16 ( INK4a ) and MINT31, should be further verified as potential epigenetic targets for the design of efficient chemotherapy regimens. We also identified a subset of colorectal cancer, possibly comprising APC methylation-KRAS mutation-p16 ( INK4a ) methylation.

Nerve Blocks for Postoperative Pain Management in Children Receiving a Subcutaneous Implantable Cardioverter-Defibrillator: A Case Series.

Subcutaneous implantable cardioverter-defibrillator (S-ICD) placement causes significant postoperative pain. Limited research exists on nerve blocks for treating pediatric S-ICD pain. This case series presents pain outcomes in 10 children receiving nerve blocks for S-ICD placement. Nerve blocks performed include bilateral parasternal with left erector spinae plane (ESP), pectoralis with left ESP, fascial plane, and paravertebral blocks. The predominant combination of bilateral parasternal blocks with a left ESP block seemed to contribute toward adequate pain control. These children appeared to have low pain scores, low opioid consumption, and no block complications. Nerve blocks may benefit pediatric patients after S-ICD implantation.

Evaluation of novel histone deacetylase inhibitors as therapeutic agents for colorectal adenocarcinomas compared to established regimens with the histoculture drug response assay.

BACKGROUND AND AIMS: This study was to evaluate the efficacy of histone deacetylase (HDAC) inhibitors in colorectal cancer together with other established regimens. MATERIALS AND METHODS: Chemosensitivities of 114 colorectal cancer patients to established regimens (fluorouracil (5-FU with leucovorin (FL), capecitabine, FL with irinotecan (FLIRI), and FL with oxaliplatin (FLOX)) as well as five hydroxamic acid derivatives (suberoylanilide hydroxamic acid, PXD101, and three novel candidates of CG-1, CG-2, and CG-3) were comparatively evaluated using the histoculture drug response assay. RESULTS: The chemosensitivity with established regimens was between 34.2% and 52.6%, when the cutoff value of the inhibition ratio was set at 30%, and between 54.5% and 84.1% with HDAC inhibitors. All HDAC inhibitors displayed synergistic effects in combination with established regimens of FLOX and FLIRI (P < or = 0.0001-0.002). Advanced T- and N-category tumors and patients with synchronous adenoma displayed higher chemosensitivity to CG-3, CG-2, and CG-1, respectively, on a multivariate analysis (P = 0.023, 0.044, and 0.045, respectively). Tumors with mismatch repair defects were closely correlated with chemosensitivities to combined regimens of PDX101 with FLOX and FLIRI (P = 0.044 and 0.048, respectively). CONCLUSIONS: Our findings firstly demonstrated the chemo-responsiveness of colorectal cancers to HDAC inhibitors with therapeutic efficacy comparable to the established regimens. Additionally, tumor growth and heredity were significantly associated with specific regimens, supporting their possible role as chemosensitive predictors.

Clinical Utility of a Fully Automated Microsatellite Instability Test with Minimal Hands-on Time.

BACKGROUND: Microsatellite instability (MSI) analysis is becoming increasingly important in many types of tumor including colorectal cancer (CRC). The commonly used MSI tests are either time-consuming or labor-intensive. A fully automated MSI test, the Idylla MSI assay, has recently been introduced. However, its diagnostic performance has not been extensively validated in clinical CRC samples. METHODS: We evaluated 133 samples whose MSI status had been rigorously validated by standard polymerase chain reaction (PCR), clinical nextgeneration sequencing (NGS) cancer panel test, or both. We evaluated the diagnostic performance of the Idylla MSI assay in terms of sensitivity, specificity, and positive and negative predictive values, as well as various sample requirements, such as minimum tumor purity and the quality of paraffin blocks. RESULTS: Compared with the gold standard results confirmed through both PCR MSI test and NGS, the Idylla MSI assay showed 99.05% accuracy (104/105), 100% sensitivity (11/11), 98.94% specificity (93/94), 91.67% positive predictive value (11/12), and 100% negative predictive value (93/93). In addition, the Idylla MSI assay did not require macro-dissection in most samples and reliably detected MSI-high in samples with approximately 10% tumor purity. The total turnaround time was about 150 minutes and the hands-on time was less than 2 minutes. CONCLUSIONS: The Idylla MSI assay shows good diagnostic performance that is sufficient for its implementation in the clinic to determine the MSI status of at least the CRC samples. In addition, the fully automated procedure requires only a few slices of formalin-fixed paraffin-embedded tissue and might greatly save time and labor.

Efficacy and Cost Comparison of Case-based Learning to Simulation-based Learning for Teaching Malignant Hyperthermia Concepts to Anesthesiology Residents.

BACKGROUND: Case-based learning (CBL) is a distinct classroom-based teaching format. We compare learning and retention using a CBL teaching strategy vs simulation-based learning (SBL) on the topic of malignant hyperthermia. METHODS: In this study, 54 anesthesia residents were assigned to either a CBL or SBL experience. All residents had prior simulation experience, and both groups received a pretest and a lecture on rare diseases with emphasis on malignant hyperthermia followed by a CBL or SBL session. Test questions were validated for face and construct validity. Postsession testing occurred on the same day and at 4 months. RESULTS: Twenty-seven residents completed all components of the study. The CBL group had 10 residents, and the SBL group had 17 residents. Most residents (80%) had previous exposure to malignant hyperthermia education. ANOVA for repeated measures demonstrated superior learning and long-term retention in the CBL group. In addition, our cost analysis reveals the cost of SBL to be approximately 17 times more expensive per learner than CBL. CONCLUSIONS: We found that CBL promoted learning and long-term retention for the topic of malignant hyperthermia and it is a more affordable teaching method. Affordability and effectiveness evidence may guide some programs toward CBL, particularly if access to simulation is limited. The number of participants and full validation of the examination questions are limitations of the study. Further studies are required to validate the findings of this study.

Mutation Burden and I Index for Detection of Microsatellite Instability in Colorectal Cancer by Targeted Next-Generation Sequencing.

Next-generation sequencing (NGS) panels are widely used for defining tumor mutation profiles and determining treatment approaches. We performed targeted NGS with 382 colorectal cancer genes with known microsatellite instability (MSI). After exclusion of germline alterations, the load of somatic mutations and small insertion/deletion (indel) alterations were determined. In the test set, 79 patients with 41 microsatellite-stable (MSS) and 38 MSI tumors were included. There were 120 MSS and eight MSI-high tumors in the validation set. The number of somatic mutations of whole samples were distinguished into three groups: mutant functional polymerase epsilon catalytic subunit, MSI, and MSS tumors. The median numbers of somatic and indel mutations in MSI tumors were higher. The indel mutation to whole mutation ratio (I index) was higher in MSI tumors. Hypermutation and low I index of polymerase epsilon catalytic subunit mutant tumors, a somatic mutation load cut-off of ≥40, and an I index of ≥9% were selected as the criteria for detecting MSI tumors with high sensitivity and specificity. With the analysis of alteration patterns of homopolymer genes, a higher median number of homopolymer mutations in MSI tumors was observed. Mutated homopolymer ≥5 was selected as the criterion for detecting MSI tumors. MSI in colorectal cancer can be detected by targeted NGS panels with high sensitivity and specificity using somatic mutation load and I index.

Clinical Practice Guideline: Tonsillectomy in Children (Update)-Executive Summary.

OBJECTIVE: This update of a 2011 guideline developed by the American Academy of Otolaryngology-Head and Neck Surgery Foundation provides evidence-based recommendations on the pre-, intra-, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children <15 years of age, based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy. PURPOSE: The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology-head and neck surgery, pediatrics, and sleep medicine. KEY ACTION STATEMENTS: The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been <7 episodes in the past year, <5 episodes per year in the past 2 years, or <3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of >1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep-disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep-disordered breathing for polysomnography if they are <2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep-disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of obstructive sleep-disordered breathing. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep-disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are <3 years old or have severe obstructive sleep apnea (apnea-hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir <80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option: (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature >38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta-hemolytic streptococcus. DIFFERENCES FROM PRIOR GUIDELINE: Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. Inclusion of 2 consumer advocates on the guideline update group. Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep-disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). Addition of an algorithm outlining KASs. Enhanced emphasis on patient and/or caregiver education and shared decision making.

Clinical Practice Guideline: Tonsillectomy in Children (Update).

OBJECTIVE: This update of a 2011 guideline developed by the American Academy of Otolaryngology-Head and Neck Surgery Foundation provides evidence-based recommendations on the pre-, intra-, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children <15 years of age based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy. PURPOSE: The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology-head and neck surgery, pediatrics, and sleep medicine. KEY ACTION STATEMENTS: The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been <7 episodes in the past year, <5 episodes per year in the past 2 years, or <3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of >1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep-disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep-disordered breathing for polysomnography if they are <2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep-disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of oSDB. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep-disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are <3 years old or have severe obstructive sleep apnea (apnea-hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir <80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option: (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature >38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta-hemolytic streptococcus. DIFFERENCES FROM PRIOR GUIDELINE: (1) Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. (2) There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. (3) Inclusion of 2 consumer advocates on the guideline update group. (4) Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep-disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). (5) Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). (6) Addition of an algorithm outlining KASs. (7) Enhanced emphasis on patient and/or caregiver education and shared decision making.