Citations

Background: Adjacent segment pathology is a known complication after spinal fusion, but little has been reported on junctional failure. A series of adolescent patients presented with acute distal junctional failure (DJF). We sought to determine any common features of these patients to develop a prevention strategy. Methods: A retrospective review was conducted of pediatric patients who developed DJF after instrumented spinal fusion performed at 2 institutions from 1999 to 2013. Patients with proximal junctional failure or junctional kyphosis without failure were excluded. Results: Fifteen subjects were identified with mean follow-up of 38 months. Distal failure occurred a mean of 60 days after index surgery, with history of minor trauma in 4 patients. Failures included 3-column Chance fracture (11) or instrumentation failure (4). Thirteen patients presented with back pain and/or acute kyphosis, whereas 2 asymptomatic patients presented with healed fractures. Two patients also developed new onset of severe lower extremity neurological deficit after fracture, which improved but never resolved after revision. A total of 13/15 subjects required revision surgery, typically within 1 week. Complications associated with revision surgery were encountered in 8 patients (62%). Major complications that required return to the operating room included 2 deep infections, 2 instrumentation failures, and dense lower extremity paralysis that improved after medial screw revision and decompression. At final follow-up, 10 patients are asymptomatic, 2 have persistent neurological deficit, 2 have chronic pain, and 1 has altered gait with gait aid requirement. Conclusions: This study analyzes a heterogenous cohort of spinal fusion patients who developed DJF from 3-column Chance fracture or instrumentation failure. Revision surgery is typically required, but has a high complication rate and can result in severe neurological deficit, highlighting the morbidity of this complication. It is unclear whether level of the lowest instrumented vertebra contributes to DJF. Increased awareness of junctional failure in children may prompt additional studies to further characterize risk factors and preventative strategies. Level of Evidence: Level IV—study-type case series.

The ruthenium(II) polypyridyl complexes (RPCs), [(phen)2Ru(tatpp)]Cl2 (3Cl2) and [(phen)2Ru (tatpp)Ru(phen)2]Cl4 (4Cl4), containing the large planar and redox‐active tetraazatetrapyrido‐pentacene (tatpp) ligand, cleave DNA in the presence of reducing agents in cell‐free assays and show significant tumor regression in mouse tumor models with human non‐small cell lung carcinoma xenografts. ITC, CD, and ESI‐MS techniques were used to study the thermodynamics of RPC·DNA complex formation and the complex structure for binding three different RPCs to duplex DNA. The specific RPCs were [Ru(phen)3]2+ (12+), [Ru(phen)2(dppz)]2+ (22+), and [Ru(phen)2(tatpp)]2+ (32+). We examined the enatiomerically pure Δ‐RPC and Λ‐RPC isomers as well as the racemic mixture in terms of their binding to B‐DNA. B‐DNA binding of the three RPCs is characterized by a combination of groove binding (including electrostatic effects) and intercalation, with the thermodynamics being very similar for binding both the enantiomerically pure compounds and the racemic mixture. 12+ is the weakest DNA binder, exhibiting a Ka = 1.3 × 104 m–1 while 22+ binds with significantly higher affinity, Ka,1 = 1.4 × 106 m–1, and 32+ exhibits the tightest binding, Ka = 4.7 × 106 m–1. The trend is to increase the affinity as longer bridging ligands engage in additional π‐bonding with the DNA base pairs via an intercalative binding mode. A second binding mode, two orders of magnitude weaker was also seen for 22+. The ITC values for binding the racemic mixtures exhibit ΔGs ranging from –5.6 to –9.1 kcal mol–1 (12+·DNA and 32+·DNA respectively), while the ITC values for ΔH range from +4.9 to –5.0 kcal mol–1 (32+·DNA and mode 2 binding for 22+·DNA respectively). All of the primary complexes exhibit very negative values for –TΔS ranging from –7.3 to –14.0 kcal mol–1 (mode 1 binding for 22+·DNA and 32+·DNA respectively). To further understand the intercalation vs. groove binding contributions to the overall binding energy we compared the thermodynamics for formation of the 12+·DNA, 22+·DNA, and 32+·DNA complexes to the thermodynamics for formation of the 44+·DNA complex. The RPC binding affinities to duplex DNA follow the trend: 12+ < 44+ < 22+ < 32+. Differences in the affinity for binding 12+ vs. 22+ or 32+ are almost entirely due to the size of the intercalating moiety, e.g. phen which can only be partially intercalated in comparison to dppz and tatpp which can be completely intercalated. The lower affinity for the dinuclear ruthenium 44+ is due to the solvation penalty for the second Ru core complex that extends out from the major groove. Comparing these results, we have begun to develop the structure function relationships for the interaction of RPCs with B‐DNA.

Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed “RASopathies,” which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS -encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of MRAS in a cohort of 109 unrelated patients with phenotype-positive/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene.

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

Aims Haemophagocytic lymphohistiocytosis (HLH) is divided into paediatric (primary) and adult (secondary) types. While paediatric-HLH has been extensively characterised, similar studies in adults are limited. This study aims to evaluate the significance of the HLH diagnostic criteria as well as other clinical parameters in adults with bone marrow evidence of haemophagocytosis. Methods We conducted a 10-year retrospective search of the pathology archives of two institutions for cases with bone marrow haemophagocytosis. We included those cases that fulfilled the currently established HLH diagnostic criteria. For the 29 cases that met inclusion criteria, we assessed clinical features, co-morbidities, therapy and clinical outcome. The effect of 19 clinical variables on mortality outcomes was assessed using logistic and hazard regression analyses. Results Of cases for which an aetiology could be identified, infectious diseases were the most common association (14 of 19, 74%). Fever and elevated ferritin were the most frequently available criteria used to establish HLH. The overall mortality rate was 61% despite HLH-specific therapy, which had been initiated in 48% of the cases. The remaining cases were treated with supportive therapy and antibiotics. The most statistically significant marker of mortality was an elevated absolute neutrophil count (ANC), a feature not typical of HLH. Conclusions Since elevated ANC correlates with poor outcomes in sepsis, and not HLH, we postulate that many of the patients fulfilling HLH diagnostic criteria in this study likely had sepsis/systemic inflammatory response syndrome rather than HLH. Our results highlight the need to define HLH diagnostic criteria specific to the adult population.

BACKGROUNDWomen with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.METHODSAll samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). The BC risk was stratified for the number of AH foci within AH subtypes.RESULTSThe study included 708 Mayo AH subjects and 466 Nashville AH subjects. In the Mayo cohort, an increasing number of foci of AH was associated with a significant increase in the risk of BC both for ADH (relative risks of 2.61, 5.21, and 6.36 for 1, 2, and ≥3 foci, respectively; P for linear trend = .006) and for ALH (relative risks of 2.56, 3.50, and 6.79 for 1, 2, and ≥3 foci, respectively; P for linear trend = .001). In the Nashville cohort, the relative risks of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2, and ≥3 foci, respectively (P for linear trend < .001); for ALH, the relative risks also increased but not significantly (2.61, 3.48, and 4.02, respectively; P = .148). When the Mayo and Nashville samples were combined, the risk increased significantly for 1, 2, and ≥3 foci: the relative risks were 2.65, 5.19, and 8.94, respectively, for ADH (P < .001) and 2.58, 3.49, and 4.97, respectively, for ALH (P = .001).CONCLUSIONSIn 2 independent cohort studies of benign breast disease, the extent of atypia stratified the long‐term BC risk for ADH and ALH. Cancer 2016;122:2971‐2978. © 2016 American Cancer Society.

AbstractIntroductionPatients at risk for microaspiration during elective intubation often receive cricoid pressure in the hopes of mitigating such risk. However, there is scarce evidence to either support or reject this practice. The objective of this investigation was to assess the effect of cricoid pressure on microaspiration and to inform the potential feasibility of conducting a larger, more definitive clinical trial.MethodsThis was a pilot randomized clinical trial set in the operating rooms of a tertiary referral hospital between August and October of 2014. Patients with risk factors for microaspiration (obesity, gastroesophageal reflux disease, or diabetes) were enrolled. The patients were randomized to either cricoid pressure or no cricoid pressure during induction of anesthesia with endotracheal intubation. Immediately after intubation, a sample of lower airway secretions was collected and analyzed for pepsin A.Main ResultsA total of 95 patients were evaluated, randomized and completed the study protocol. 46 were randomized to cricoid pressure and 49 to no cricoid pressure. Seven patients crossed‐over treatment arms. A total of 18 (19.6%) patients met the pre‐defined criteria for microaspiration. In both the intention‐to‐treat and per‐protocol analyses, there were no statistically significant differences in the rate of microaspiration [OR (95% CI)] = 1.39 (0.49–3.92) and 1.30 (0.44–3.86), respectively.ConclusionsUtilizing pepsin A as a biomarker of aspiration, this pilot clinical trial did not find evidence for a reduced rate of aspiration or adverse clinical events with the administration of cricoid pressure during elective endotracheal intubation of patients with risk factors for microaspiration.

Background: Intraoperative computed tomography and image-guided navigation improve the accuracy of screw placement. Radiation exposure to the patient remains a primary drawback. The objective of the present study was to compare the total intraoperative radiation dose and assess the resultant image quality for O-arm-assisted pedicle screw insertion, among 3 protocols: default (manufacturer recommended), institutional (reduced dose utilized in our institution), and pediatric (new protocol with lowest dose). Methods: Thirty-seven consecutive patients under the age of 18 years underwent posterior instrumentation of the spine and underwent an intraoperative O-arm scan. Techniques (kV and mAs) for default and institutional dose settings were manually adjusted based on spinal level and body weight. Pediatric dose techniques were 80 kV/80 mAs with no adjustment for level or weight. The number of scans repeated because of inadequate imaging was assessed, and the mean estimated effective dose between the 3 protocols was compared. Results: Sixty-eight scans were performed in 37 consecutive patients with mean age of 14 years and mean weight of 55 kg. For reference, the effective radiation dose of a chest x-ray is approximately 0.10 mSv. Use of the default protocol resulted in higher mean effective dose per scan of 4.65 mSv, whereas institutional protocol resulted in 2.37 mSv. The pediatric protocol reduced the mean dose to 0.65 mSv. The total effective dose per surgery was: 1.17 mSv (pediatric), 3.83 mSv (institutional), and 12.79 mSv (default) (P<0.0001 each). All scans lead to satisfactory image quality except in 1 patient >100 kg with stainless steel implants. There were no neurological or other implant-related complications. The pediatric protocol resulted in satisfactory image quality with the lowest total radiation dose, only 1/10 of that of the default protocol. Conclusions: We successfully switched to a pediatric low-dose O-arm protocol in clinical practice, reducing the dose to <1/4 of the mean annual natural background radiation. This may allow use of intraoperative computed tomography and navigation for pedicle screw placement without excessive radiation exposure to young patients. Level of Evidence: Level III—retrospective comparative study.