Clinical utility of KRAS and BRAF mutations in a cohort of patients with colorectal neoplasms submitted for microsatellite instability testing.

BACKGROUND: Molecular analysis has become important in colorectal carcinoma (CRC) evaluation. Alterations in KRAS, BRAF, or mismatch repair (MMR) genes may determine therapeutic response or define a hereditary cancer syndrome. Correlation of DNA studies with clinical findings will further clarify the clinical utility of these markers. PATIENTS AND METHODS: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted for microsatellite instability (MSI) testing based on clinical history or histologic examination, or both. DNA samples were screened for 7 KRAS mutations and the BRAF p.V600E mutation using fluorescent allele-specific polymerase-chain reaction (PCR) and capillary electrophoresis. Clinical data were collected through chart review. RESULTS: Fifty-eight male and 53 female patients were studied. The incidence of KRAS and BRAF mutations was 49.5% and 7.2%, respectively. Dideoxy sequencing verified KRAS mutation status in 46 of 49 specimens tested. There was a trend toward significance of individual KRAS mutations on survival (P = .003). Dually positive KRAS and MSI tumors exclusively demonstrated p.G12D and p.G13D mutations (G>A transitions). BRAF-mutated tumors were predominantly right-sided and associated with a borderline worse prognosis. Forty-eight percent of tumors with MSI were present in the left colon or rectum. CONCLUSION: Allele-specific PCR is an accurate and convenient method to assess KRAS and BRAF mutations and may detect mutations not identified by dideoxy sequencing. KRAS mutation status, in conjunction with morphologic or clinical parameters, may be useful in determining whether a tumor should be tested for MSI. MSI testing should not be considered exclusively in right-sided lesions. BRAF analysis may not be useful in rectal adenocarcinomas and should be evaluated in larger studies.

Radiographic outcomes of volar locked plating for distal radius fractures.

PURPOSE: To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures. METHODS: We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type. RESULTS: At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome. CONCLUSIONS: Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Operative intervention for complete pancreatic transection in children sustaining blunt abdominal trauma: revisiting an organ salvage technique.

Complete pancreatic transection (CPT) in children is managed commonly with distal pancreatectomy (DP). Alternatively, Roux-en-Y distal pancreaticojejunostomy (RYPJ) may be performed to preserve pancreatic tissue. The purpose of this study was to review our experience using either procedure in the management of children sustaining CPT after blunt abdominal trauma. We retrospectively reviewed the records of all children admitted to our institution during the last 15 years who were confirmed at operation to have CPT after blunt mechanisms. Summary statistics of demographic data were performed to describe children receiving either RYPJ or DP. CPT occurred in 28 children: 15 had DP, 10 had RYPJ, and three had cystogastrostomy. RYPJ children, compared with DP, were younger (7.5 vs. 12.3 years, P = 0.039) and sustained more grade IV pancreatic injuries (70% vs. 14%, P = 0.01). DP patients were 5.63 times more likely to tolerate full enteral feeds (P = 0.009). Nevertheless, when controlling for age, injury severity score, and pancreatic injury grade, procedure type did not statistically affect total and postoperative lengths of stay and postoperative complications. In the operative management algorithm of children sustaining CPT, DP may afford an earlier return to full enteral feeds. RYPJ seems otherwise equivalent to DP and preserves significant pancreatic glandular tissue and the spleen.

Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome.

OBJECTIVES: To determine whether prehospital statin use is associated with a lower risk of sepsis, acute lung injury/acute respiratory distress syndrome, and mortality in critically ill patients. We also investigated the effect of combined prehospital use of both statins and aspirin. DESIGN: Cross-sectional analysis of a prospective cohort. PATIENTS: A total of 575 critically ill patients admitted to the medical or surgical intensive care unit of an academic tertiary-care hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 575 patients, 149 (26%) were on statin therapy before hospitalization. A multivariable analysis including age, gender, current tobacco use, prehospital aspirin use, race, and Acute Physiology and Chronic Health Evaluation II score revealed that patients on statin therapy before hospitalization were less likely to have or develop severe sepsis (odds ratio 0.62, 95% confidence interval 0.40-0.96) or acute lung injury/acute respiratory distress syndrome (odds ratio 0.60, 95% confidence interval 0.36-0.99) during the first four intensive care unit days. In-hospital mortalities for patients with and without prehospital statin use (odds ratio 1.06, 95% confidence interval 0.62-1.83) were similar. Patients who had prehospital use of both statins and aspirin had the lowest rates of severe sepsis, acute lung injury/acute respiratory distress syndrome, and mortality. CONCLUSIONS: Prehospital use of statins may be protective against sepsis and acute lung injury. This effect may be potentiated by prehospital aspirin use.

Driving with an arm immobilized in a splint: a randomized higher-order crossover trial.

BACKGROUND: The aim of this study was to determine whether immobilization of an arm has detrimental effects on driving performance. METHODS: Thirty-six healthy officers-in-training were assigned a sequence of fiberglass splints (left and right-sided above-the-elbow thumb spica and below-the-elbow splints) with use of a randomized higher-order crossover design. Runs were scored on a cone-marked driving course used for officer certification with predetermined passing requirements. Driving time, the number of cones hit per course section, and the cone-adjusted total time (a five-second penalty per hit cone) were recorded. A linear mixed-effect model with random environmental and learning effects for cone-adjusted time analysis was used. Participants rated perceived driving difficulty and safety with each splint, and ratings were compared with the Wilcoxon signed-rank test. RESULTS: Thirty participants completed the entire set of runs. Analysis of total cone-adjusted time revealed a significant performance decrease with the left arm in an above-the-elbow thumb spica splint (average, 22.2 seconds; p < 0.001) and with the left arm in a below-the-elbow splint (average, 16.2; p = 0.007). Analysis of forward-only course sections revealed poorer performance trends with all splints, with the worst performance with the left arm in an above-the-elbow thumb spica splint. Driving with the left arm in an above-the-elbow thumb spica splint had the highest perceived difficulty (median, 8.0) and lowest perceived safety (median, 3.0). CONCLUSIONS: Driving performance as measured with a standardized track and scoring system was significantly degraded with splint immobilization of the left arm. Further studies are required to determine the effect of arm immobilization on normal driving conditions.

Dopamine and cAMP regulated phosphoprotein MW 32 kDa is overexpressed in early stages of gastric tumorigenesis.

BACKGROUND: Gastric adenocarcinoma is a leading cause of cancer mortality. The role of dopamine and cAMP regulated phosphoprotein MW 32 kDa (DARPP-32) overexpression in the gastric tumorigenesis cascade remains unclear. METHODS: The expression of DARPP-32 in the multistep carcinogenesis cascade was examined using immunohistochemistry analysis on 533 samples. The contribution of DARPP-32 in cellular transformation and molecular signaling was investigated using NIH3T3, AGS, and SNU16 cells. RESULTS: The composite expression score (CES), calculated from immunostaining patterns, increased significantly from normal or gastritis to metaplasia, dysplasia, and adenocarcinoma (P < .001). In patients with normal stomach or gastritis and tumor samples, a 76% and 77% chance, respectively, was found (P < .001) that CES was higher in the tumor. High median CES correlated with well- or moderately differentiated (P = .03) gastric adenocarcinomas. NIH3T3 cells transfected with DARPP-32 demonstrated increased levels of phospho-AKT and a 5-fold increase in the number of foci as compared with the control (P = .02). DARPP-32 expression in AGS cells led to increased protein levels of phospho-AKT and BCL-2. For validation, the knockdown of endogenous DARPP-32 expression in SNU16 cells using shRNA resulted in decreased levels of phospho-AKT phosphorylation and BCL-2. CONCLUSION: Our results suggest that DARPP-32 overexpression may participate in the transition to intestinal metaplasia and in the progression to neoplasia. The ability of DARPP-32 to transform NIH3T3 cells and to regulate AKT and BCL-2 underscores its possible oncogenic potential.

Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: who really benefits?

BACKGROUND: The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients. STUDY DESIGN: Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown. RESULTS: There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n=374) and those receiving adjuvant CRT (n=299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p=0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p=0.034). CONCLUSIONS: This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival.