Gastrointestinal Discontinuity After Emergency Laparotomy.

During laparotomy, patients requiring intestinal resection may be temporarily left in gastrointestinal discontinuity (GID). We performed this study to determine predictors of futility for patients initially left in GID after emergency bowel resection. We divided the patients into 3 groups: never restored continuity and died (group 1), restored continuity and died (group 2), and restored continuity and survived (group 3). We compared the 3 groups for differences in demographics, acuity at presentation, hospital course, laboratory data, comorbidities, and outcomes. From a total of 120 patients, 58 patients died and 62 survived. We identified 31 patients in group 1, 27 patients in group 2, and 62 patients in group 3. On multivariate logistic regression, only lactate (P = .002) and use of vasopressors (P = .014) remained significant to predict survival. The results of this study can be used to identify futile situations which can direct end-of-life decisions.

A Case of Trisomy 13 Mosaicism With Aortic Root Dilatation.

We present a 6-year-old female child, with prenatal diagnosis of trisomy 13 mosaicism and nondisjunction, a bicuspid aortic valve, and severe aortic root dilatation. This patient is only the third reported case of aortic dilatation in the setting of trisomy 13 mosaicism. (Level of Difficulty: Intermediate.).

Proteins inform survival-based differences in patients with glioblastoma.

BACKGROUND: Improving the care of patients with glioblastoma (GB) requires accurate and reliable predictors of patient prognosis. Unfortunately, while protein markers are an effective readout of cellular function, proteomics has been underutilized in GB prognostic marker discovery. METHODS: For this study, GB patients were prospectively recruited and proteomics discovery using liquid chromatography-mass spectrometry analysis (LC-MS/MS) was performed for 27 patients including 13 short-term survivors (STS) (≤10 months) and 14 long-term survivors (LTS) (≥18 months). RESULTS: Proteomics discovery identified 11 941 peptides in 2495 unique proteins, with 469 proteins exhibiting significant dysregulation when comparing STS to LTS. We verified the differential abundance of 67 out of these 469 proteins in a small previously published independent dataset. Proteins involved in axon guidance were upregulated in STS compared to LTS, while those involved in p53 signaling were upregulated in LTS. We also assessed the correlation between LS MS/MS data with RNAseq data from the same discovery patients and found a low correlation between protein abundance and mRNA expression. Finally, using LC-MS/MS on a set of 18 samples from 6 patients, we quantified the intratumoral heterogeneity of more than 2256 proteins in the multisample dataset. CONCLUSIONS: These proteomic datasets and noted protein variations present a beneficial resource for better predicting patient outcome and investigating potential therapeutic targets.

Sex-specific gene and pathway modeling of inherited glioma risk.

Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence.

Background: Models of epigenetic aging (epigenetic clocks) have been implicated as potentially useful markers for cancer risk and prognosis. Using 2 previously published methods for modeling epigenetic age, Horvath's clock and epiTOC, we investigated epigenetic aging patterns related to World Health Organization grade and molecular subtype as well as associations of epigenetic aging with glioma survival and recurrence. Methods: Epigenetic ages were calculated using Horvath's clock and epiTOC on 516 lower-grade glioma and 141 glioblastoma cases along with 136 nontumor (normal) brain samples. Associations of tumor epigenetic age with patient chronological age at diagnosis were assessed with correlation and linear regression, and associations were validated in an independent cohort of 203 gliomas. Contribution of epigenetic age to survival prediction was assessed using Cox proportional hazards modeling. Sixty-three samples from 18 patients with primary-recurrent glioma pairs were also analyzed and epigenetic age difference and rate of epigenetic aging of primary-recurrent tumors were correlated to time to recurrence. Results: Epigenetic ages of gliomas were near-universally accelerated using both Horvath's clock and epiTOC compared with normal tissue. The 2 independent models of epigenetic aging were highly associated with each other and exhibited distinct aging patterns reflective of molecular subtype. EpiTOC was found to be a significant independent predictor of survival. Epigenetic aging of gliomas between primary and recurrent tumors was found to be highly variable and not significantly associated with time to recurrence. Conclusions: We demonstrate that epigenetic aging reflects coherent modifications of the epigenome and can potentially provide additional prognostic power for gliomas.

Brain tumor biobanking in the precision medicine era: building a high-quality resource for translational research in neuro-oncology.

The growth of precision medicine has made access to biobanks with high-quality, well-annotated neuro-oncology biospecimens critical. Developing and maintaining neuro-oncology biobanks is best accomplished through multidisciplinary collaboration between clinicians and researchers. Balancing the needs and leveraging the skills of all stakeholders in this multidisciplinary effort is of utmost importance. Collaboration with a multidisciplinary team of clinicians, health care team members, and institutions, as well as patients and their families, is essential for access to participants in order to obtain informed consent, collect samples under strict standard operating procedures, and accurate and relevant clinical annotation. Once a neuro-oncology biobank is established, development and implementation of policies related to governance and distribution of biospecimens (both within and outside the institution) is of critical importance for sustainability. Proper implementation of a governance process helps to ensure that the biospecimens and data can be utilized in research with the largest potential benefit. New NIH and peer-reviewed journal policies related to public sharing of 'omic' data generated from stored biospecimens create new ethical challenges that must be addressed in developing informed consents, protocols, and standard operating procedures. In addition, diversification of sources of funding for the biobanks is needed for long-term sustainability.

Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011.

The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007­2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0­14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0­14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.

Integrins protect cardiomyocytes from ischemia/reperfusion injury.

Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7ß1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of ß1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7ß1D exposed to I/R had a substantial reduction in infarct size compared with that of α5ß1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7ß1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that ß1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7ß1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.

Novel role for vinculin in ventricular myocyte mechanics and dysfunction.

Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.

ß1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses.

How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which ß1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of ß1 integrin was reduced to 35% of control levels, but function remained normal at baseline. With aortic constriction, the knockout mice survived but had a blunted hypertrophic response. Integrin knockout myocytes, in contrast to controls, showed reduced integrin-linked kinase expression both at baseline and after hemodynamic stress; focal adhesion kinase expression was reduced after stress. Alterations in multiple signaling pathways were detected in the integrin knockout group after acute and chronic hemodynamic stress. Most remarkably, when we challenged the knockout mice with short-term loading, the robust responses of several kinases (extracellular signal-regulated kinase 1/2, p38, and Akt) evident in control mice were essentially abolished in the knockout mice. We also found that reduction of myocyte ß1 integrin expression modified adrenergic-mediated signaling through extracellular signal-regulated kinase, p38, and Akt. Reduction of ß1 integrin expression in the mature cardiac myocyte leads to a varied response compared with when this protein is reduced during either the embryonic or perinatal period. These results show that ß1 integrin expression is required for proper mechanotransductive and adrenergic responses of the adult heart.

Association between support group attendance and weight loss after Roux-en-Y gastric bypass.

BACKGROUND: Attending support group meetings has been linked to increased weight loss after gastric bypass surgery. However, the degree to which support group attendance influences weight loss is still unclear. This study quantitatively described the association between support group attendance and weight loss after Roux-en-Y gastric bypass. METHODS: The weight loss data and support group attendance of 78 consecutive Roux-en-Y gastric bypass patients were studied retrospectively. The patients were analyzed in 2 groups: those who attended >5 monthly support group meetings (group A) compared with those who went to < or =5 support group meetings (group B). The data from the first 12 months after surgery were analyzed. RESULTS: Group A achieved a mean percentage of excess weight loss of 10.5% at 2 weeks after surgery, 21.4% at 6 weeks, 30.9% at 3 months, 45.4% at 6 months, 53.6% at 9 months, and 55.5% at 12 months. Group B achieved a mean percentage of excess weight loss of 11.3% at 2 weeks, 21.8% at 6 weeks, 31.8% at 3 months, 41.3% at 6 months, 45.2% at 9 months, and 47.1% at 12 months. The differences between the 2 groups were significant at P <0.05 at 9 and 12 months. The weight loss was nonlinear and slowed as patients approached 1 year after surgery. CONCLUSION: Support groups are important for maintaining weight loss throughout the first year after surgery, especially after 6 months when the rate of weight loss from surgery begins to naturally decline. The amount of postoperative weight loss was greater than, or comparable to, the published data. Implementing regular support groups within the postoperative follow-up care may provide patients with the best chances of achieving maximal weight loss.

Minimally invasive surgery via laparoscopy for intra-abdominal biopsy in obese rhesus macaques (Macaca mulatta).

PURPOSE: To determine the safety and effectiveness of laparoscopy for repeated intra-abdominal biopsy of liver and omental adipose tissue (AT) in obese rhesus monkeys (Macaca mulatta). METHODS: Nine obese rhesus monkeys were studied by use of 18 laparoscopic procedures (two procedures each, approx. six weeks apart). Time-sensitive liver and omental AT specimens were obtained from monkeys under general anesthesia, using a three-port approach with a roticulating endoscopic stapler/divider and a monopolar electrosurgery for hemostasis. RESULTS: All subjects tolerated the initial and repeat laparoscopic procedures well. Liver specimens weighed a mean +/- SEM of 3.8 +/- 0.5 g, and omental AT specimens weighed 16.6 +/- 0.8 g. Compared with previous studies of conventional laparotomy with liver wedge resection, the monkeys experienced faster postoperative recovery via laparoscopy, with rapid return to normal food intake and activity. Minimal to no adhesions were observed by use of the repeat procedure in all monkeys, with no major complications. CONCLUSIONS: Laparoscopy in obese rhesus monkey (ranging from young to older-aged), with repeated intra-abdominal liver and omental AT biopsy, was an excellent minimally invasive surgical method. In contrast to laparotomy with wedge resection, this approach greatly decreases operative time and stress, provides generous tissue specimens in a time-efficient manner, and facilitates rapid and full recovery of the nonhuman primate.

Laparoscopic donor nephrectomy: the University of Maryland 6-year experience.

PURPOSE: We determined whether the results of laparoscopic donor nephrectomy warranted expansion of the availability of the technique. MATERIALS AND METHODS: Donor and recipient charts for 738 consecutive laparoscopic living donor nephrectomies have been reviewed. RESULTS: Renal donors were 69% white race and 57% female. Age range was 18 to 74 years. Neither age nor obesity alone were exclusionary criteria. Nephrectomy was left sided in 96%. Donors with body mass index greater than 33 had longer operative times. The extraction site changed from umbilical to suprapubic during the series. Warm ischemia time was 169 seconds. Conversion to open nephrectomy occurred in 1.6% of cases and blood transfusion was required in 1.2%. Major intraoperative complications occurred in 6.8% and major postoperative complications occurred in 17.1% of cases. Hospitalization lasted 64.4 hours. Postoperative donor creatinine was 1.5 times the preoperative level. Recipient serum creatinine averaged 2.0 mg% at 1 week and 1.6 mg% at 1 year. Delayed graft function occurred in 2.6%. However, 9.1% of recipients did not achieve a serum creatinine less than 3.0 mg% within 7 days. The endovascular stapler also created 37 extra arteries for implantation. CONCLUSIONS: Risks of laparoscopic donor nephrectomy to the donor must not be minimized. Rapid conversion to open surgery to control bleeding may be necessary. Nonvascular intraoperative injuries require recognition. Slow bowel function recovery prolongs hospitalization and may indicate unrecognized pancreatitis or small bowel herniation. Surgical technique and complication management have improved. Laparoscopic donor nephrectomy is now routine but still requires an intense level of attention to prevention of complications.