bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel therapeutic strategies and targets in advanced uveal melanoma
Authors: Chua Vivian , Aplin Andrew E. 
Published: December 2017

Purpose of review
Currently, there are no U.S. Food and Drug Administration-approved or effective treatment options for advanced-stage uveal melanoma. In this article, we focus on therapeutic targets in pathways/mechanisms associated with common mutations in uveal melanoma. We review the challenges associated with targeting of these pathways and novel treatment strategies.

Recent findings
Common mutations that promote uveal melanoma initiation and progression include alterations in G protein subunit alpha q/11 (GNAQ/GNA11) and breast cancer gene 1-associated protein 1 (BAP1). Mutant GNAQ/GNA11 induces constitutive activation of tumorigenic pathways such as extracellular signal-regulated kinase (ERK)1/2 and yes-associated protein. Inhibition of mitogen-activated protein kinase kinase (MEK) downstream of ERK1/2, however, was shown in trials to have limited clinical benefit. Recent reports suggested that combination therapies of MEK inhibition and modulators of mechanisms of drug resistance may improve tumor responses to MEK inhibitors. BAP1 has been shown to be involved in modulating chromatin dynamics and deubiquitination of proteins. Hence, epigenetic inhibitors are being investigated in BAP1 mutant uveal melanoma. However, other functions of BAP1, such as in DNA damage repair and cell cycle regulation, indicate additional targets for treatment of BAP1 mutant uveal melanoma. In addition, the frequent delayed development of uveal melanoma macrometastases is likely due to cellular dormancy mechanisms. Nuclear receptor subfamily 2, group F, member 1 and transforming growth factor beta 2 were among factors that have been shown in other cancers to induce dormant phenotypes.

Summary
Findings from studies in uveal melanoma and in other cancers provide evidence for potential strategies that may be tested preclinically and clinically in advanced-stage uveal melanoma to improve treatment outcome and overall survival of patients.
Patterns of Care and Outcomes of Hypofractionated Chemoradiation Versus Conventionally Fractionated Chemoradiation for Glioblastoma in the Elderly Population
Authors: Haque Waqar , Verma Vivek , Butler Edward B. , Teh Bin S. 
Published: December 2017

Purpose:
This study evaluated practice patterns, outcomes, and predictors of survival for elderly patients with glioblastoma (GBM) receiving definitive chemoradiotherapy (CRT) with either hypofractionated radiotherapy or conventionally fractionated radiotherapy.

Materials and Methods:
The National Cancer Data Base was queried for patients age 65 years and above diagnosed with GBM between 2006 and 2012 that received definitive CRT with either hypofractionated radiotherapy (hCRT) or conventionally fractionated radiotherapy (cCRT). Patient, tumor, and treatment parameters were extracted. Statistics included Kaplan-Meier analysis to evaluate overall survival (OS) as well as Cox proportional hazards modeling to determine variables associated with OS. Propensity score matching was performed in order to assess groups in a balanced manner while reducing indication biases.

Results:
Altogether, 5126 patients met inclusion criteria; 126 (2.5%) underwent hCRT, while 5000 (97.5%) received cCRT. Temporal trends revealed that the use of hCRT is rising, especially in more recent years. Patients undergoing hCRT were older, with worse performance status, treated with biopsy only, and more likely to receive treatment at an academic facility. cCRT was associated with improved median OS (10.7 vs. 6.2 mo, P<0.001). This persisted in both Cox multivariate analysis (hazard ratio, 0.59; 95% confidence interval, 0.49-0.72; P=<0.001) and on propensity-matched analysis (median OS 8.7 vs. 6.2 mo; hazard ratio, 0.69; 95% confidence intervcal, 0.53-0.89; P=0.005).

Conclusions:
This is the first study to directly evaluate hCRT versus cCRT for patients with GBM. The use of hCRT is rising over time; practice patterns of hCRT administration are evaluated. Delivery of hCRT independently predicted for poorer OS. Prospective data is recommended to validate the findings herein.
Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations
Authors: Kallenberg Frank G.J. , Latchford Andrew , Lips Nikki C. , Aalfs Cora M. , Bastiaansen Barbara A.J. , Clark Susan K. , Dekker Evelien 
Published: December 2017

BACKGROUND:
Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10–99) without a germline APC or MUTYH mutation.

OBJECTIVE:
We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation.

DESIGN:
This was an historical cohort study.

SETTINGS:
This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark’s Hospital in the United Kingdom.

PATIENTS:
We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy.

MAIN OUTCOME MEASURES:
The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas.

RESULTS:
Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45–75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas.

LIMITATIONS:
This study was limited by its retrospective design, selection bias, and small sample size.

CONCLUSIONS:
Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357.
Clinical Outcomes of Self-Expandable Metal Stents for Malignant Rectal Obstruction
Authors: Lee Hyun Jung , Hong Sung Pil , Cheon Jae Hee , Kim Tae Il , Kim Won Ho , Park Soo Jung 
Published: December 2017

BACKGROUND:
Self-expandable metal stents are widely used to treat malignant colorectal obstruction. However, data on clinical outcomes of stent placement for rectal obstruction specifically are lacking.

OBJECTIVE:
We aimed to investigate the clinical outcomes of self-expandable metal stents in malignant rectal obstruction in comparison with those in left colonic obstruction and to identify factors associated with clinical failure and complication.

DESIGN:
This was a retrospective study.

SETTINGS:
The study was conducted at a tertiary care center.

PATIENTS:
Between January 2005 and December 2013, medical charts of patients who underwent stent placement for malignant rectal or left colonic obstruction were reviewed retrospectively.

INTERVENTION:
Study intervention included self-expandable metal stent placement.

MAIN OUTCOME MEASURES:
Technical success, clinical success, and complications were measured.

RESULTS:
Technical success rates for the 2 study groups (rectum vs left colon, 93.5% vs 93.1%; p = 0.86) did not differ significantly; however, the clinical success rate was lower in patients with rectal obstruction (85.4% vs 92.1%; p = 0.02). In addition, the complication rate was higher in patients with rectal obstruction (37.4% vs 25.1%; p = 0.01). Patients with rectal obstruction showed higher rates of obstruction because of extracolonic malignancy (33.8% vs 15.8%; p < 0.001) and stent use for palliation (78.6% vs 56.3%; p < 0.001). Multivariate analysis indicated obstruction attributed to extracolonic malignancy and covered stent usage to be independent risk factors for clinical failure. Factors predictive of complications in the palliative group were total obstruction, obstruction because of extracolonic malignancy, and covered stent usage.

LIMITATIONS:
This was a retrospective, single-center study.

CONCLUSIONS:
The efficacy and safety of stent placement for malignant rectal obstruction were comparable with those for left colonic obstruction. However, obstruction attributed to extracolonic malignancy, use of covered stents, and total obstruction negatively impacted clinical outcomes of self-expandable metal stent placement and must be considered by endoscopists. See Video Abstract at http://links.lww.com/DCR/A417.
An Effective Bundled Approach Reduces Surgical Site Infections in a High-Outlier Colorectal Unit
Authors: Gorgun Emre , Rencuzogullari Ahmet , Ozben Volkan , Stocchi Luca , Fraser Thomas , Benlice Cigdem , Hull Tracy 
Published: December 2017

BACKGROUND:
Surgical site infections are the most common hospital-acquired infection after colorectal surgery, increasing morbidity, mortality, and hospital costs.

OBJECTIVE:
The purpose of this study was to investigate the impact of preventive measures on colorectal surgical site infection rates in a high-volume institution that performs inherent high-risk procedures.

DESIGN:
This was a prospective cohort study.

SETTINGS:
The study was conducted at a high-volume, specialized colorectal surgery department.

PATIENTS:
The Prospective Surgical Site Infection Prevention Bundle Project included 14 preoperative, intraoperative, and postoperative measures to reduce surgical site infection occurrence after colorectal surgery. Surgical site infections within 30 days of the index operation were examined for patients during the 1-year period after the surgical site infection prevention bundle was implemented. The data collection and outcomes for this period were compared with the year immediately before the implementation of bundle elements. All of the patients who underwent elective colorectal surgery by a total of 17 surgeons were included. The following procedures were excluded from the analysis to obtain a homogeneous patient population: ileostomy closure and anorectal and enterocutaneous fistula repair.

MAIN OUTCOME MEASURES:
Surgical site infection occurring within 30 days of the index operation was measured. Surgical site infection–related outcomes after implementation of the bundle (bundle February 2014 to February 2015) were compared with same period a year before the implementation of bundle elements (prebundle February 2013 to February 2014).

RESULTS:
Between 2013 and 2015, 2250 abdominal colorectal surgical procedures were performed, including 986 (43.8%) during the prebundle period and 1264 (56.2%) after the bundle project. Patient characteristics and comorbidities were similar in both periods. Compliance with preventive measures ranged between 75% and 99% during the bundle period. The overall surgical site infection rate decreased from 11.8% prebundle to 6.6% at the bundle period (P < 0.001). Although a decrease for all types of surgical site infections was observed after the bundle implementation, a significant reduction was achieved in the organ-space subgroup (5.5%–1.7%; P < 0.001).

LIMITATION:
We were unable to predict the specific contributions the constituent bundle interventions made to the surgical site infection reduction.

CONCLUSIONS:
The prospective Surgical Site Infection Prevention Bundle Project resulted in a substantial decline in surgical site infection rates in our department. Collaborative and enduring efforts among multiple providers are critical to achieve a sustained reduction See Video Abstract at http://links.lww.com/DCR/A438.
Comparison of the ARK Immunoassay With High-Performance Liquid Chromatography With Ultraviolet Detection for Therapeutic Drug Monitoring of Linezolid
Authors: Castoldi Simone , Cozzi Valeria , Baldelli Sara , Fucile Serena , Clementi Emilio , Cattaneo Dario 
Published: December 2017

Background:
An enzymatic immunoassay is under development by ARK Diagnostics, Inc for the quantification of plasma concentrations of linezolid (LZD). In this study, the authors aimed to assess the performance of this immunoassay using a validated high-performance liquid chromatography (HPLC) ultraviolet method as reference.

Methods:
Within- and between-day in vitro inaccuracy and imprecision of the ARK LZD assay were firstly tested using spiked quality controls (QC) provided by the kit manufacturer. Subsequently, the performance of the immunoassay was verified in vivo by analyzing 170 trough LZD plasma samples from patients on antibiotic therapy.

Results:
Imprecision of the spiked QCs resulted in every instance less than 7.0% and the inaccuracy ranged from −1.5% to 6.6%. The linear correlation between the 2 methods was documented by the Pearson analysis of plasma samples from patients on LZD therapy (coefficient = 0.9619). By Bland–Altman comparison, 8.2% of the patient samples resulted out of the limits ranging from −27.0% to +33.5%, with most of them having LZD concentrations exceeding 10 mg/L.

Conclusions:
Acceptable analytical performance of the ARK LZD immunoassay has been demonstrated both with spiked QC and patients' samples, making it a viable alternative to HPLC for the therapeutic drug monitoring of LZD in clinical practice in laboratory hospitals that do not have HPLC equipment.
Ultra–High Performance Liquid Chromatography Tandem Mass Spectrometry for Cyclosporine Analysis in Human Whole Blood and Comparison With an Antibody-Conjugated Magnetic Immunoassay
Authors: Mei Shenghui , Wang Jiaqing , Chen Di , Zhu Leting , Zhao Ming , Hu Xin , Yang Li , Zhao Zhigang 
Published: December 2017

Background:
Various immunoassays have been used for cyclosporine A (CsA) analysis in human whole blood; however, they could not fully satisfy the requirements of criteria for accuracy and specificity in CsA measurement. The liquid chromatography tandem mass spectrometry is a gold method for CsA analysis. The aim of the study was to develop and validate an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for CsA analysis and establish its agreement with an antibody-conjugated magnetic immunoassay (ACMIA) in clinical sample analysis.

Methods:
An UHPLC-MS/MS method for CsA analysis in human whole blood was developed, validated, and applied in 85 samples, which were also tested by ACMIA. The agreement between UHPLC-MS/MS and ACMIA was evaluated by Bland–Altman plot.

Results:
The calibration range was 5–2000 ng/mL. The inaccuracy and imprecision were −4.60% to 5.56% and less than 8.57%, respectively. The internal standard-normalized recovery and matrix factor were 100.4%–110.5% and 93.5%–107.6%, respectively. The measurements of ACMIA and UHPLC-MS/MS were strongly correlated (r > 0.98). Evaluated by Bland–Altman plot, the 95% limit of agreement of the ACMIA:UHPLC-MS/MS ratio was 88.7%–165.6%, and the mean bias of the ratio was 21.1%.

Conclusions:
A rapid, simple, accurate, and reliable UHPLC-MS/MS method for CsA analysis in human whole blood was developed, validated, and applied in 85 samples. On average, 21.1% overestimation was observed in ACMIA compared with that in the UHPLC-MS/MS. Further and larger studies are required to identify whether this degree of variance could be accepted by clinicians.
The Impact of Clostridium difficile Infection on Mortality in Patients With Inflammatory Bowel Disease
Authors: Tariq Raseen , Law Cindy C.Y. , Khanna Sahil , Murthy Sanjay , McCurdy Jeffrey D. 
Published: December 2017

Background and Aims:

Clostridium difficile infection (CDI) has been associated with an increased mortality risk among patients with inflammatory bowel disease (IBD) in multiple observational studies. We performed a systematic review and meta-analysis to help clearly define the magnitude of risk in IBD patients with and without CDI, and to assess the risk in individual IBD subtypes.

Methods:
A systematic search of multiple electronic databases was conducted for observational studies reporting the risk of mortality in IBD, stratified by the presence of CDI. Weighted summary estimates were calculated using generalized inverse variance with random-effects model. Study quality was assessed using the Newcastle-Ottawa scale.

Results:
Ten observational studies were identified (8 from North America and 2 from Europe) and included 40,700 IBD patients with CDI and 1,320,764 IBD controls without CDI. Overall, IBD patients with CDI had a higher risk of mortality compared with IBD patients without CDI [odds ratios (OR), 4.39; 95% confidence interval (CI), 3.56-5.42; I
2=93%]. The results were stable in high-quality studies and in hospitalized patients. When patients were stratified by IBD type, CDI was associated with increased mortality in patients with ulcerative colitis (7 studies) (OR, 4.39; 95% CI, 3.44-5.61; I
2), but not in patients with Crohn’s disease (4 studies) (OR, 2.21; 95% CI, 0.84-5.77; I
2). Individual studies were limited by an inability to control for IBD disease activity and therapeutic interventions.

Conclusions:
On the basis of 10 observational studies with at least moderate quality, CDI seems to increase mortality risk in IBD, particularly in ulcerative colitis. These findings are a cause for concern and suggest that CDI should be managed aggressively in patients with IBD.
Noninvasive fibrosis markers and chronic kidney disease among adults with nonalcoholic fatty liver in USA
Authors: Wijarnpreecha Karn , Thongprayoon Charat , Scribani Melissa , Ungprasert Patompong , Cheungpasitporn Wisit 
Published: December 2017

Background/Aims
Studies have shown that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of chronic kidney disease (CKD). However, it is unknown whether severe liver fibrosis is associated with a higher prevalence of CKD among NAFLD. We examined the diagnostic performance of noninvasive fibrosis markers in identifying prevalent CKD among NAFLD.

Methods
This study represents an analysis of the National Health and Nutrition Examination Survey conducted in the USA between 1988 and 1994. NAFLD was defined by ultrasonographic evidence of hepatic steatosis without other liver diseases. CKD was defined by estimated glomerular filtration rate less than 60 ml/min/1.73 m2. The presence and severity of hepatic fibrosis were determined by the NAFLD fibrosis score (NFS), FIB-4 score, APRI score, and BARD score. Multiple logistic regression was performed to generate odds ratios (ORs) and receiver operating characteristic curves were used to assess the predictive values of each marker.

Results
A total of 4142 individuals with NAFLD were included; 200 (4.8%) had CKD. The area under the receiver operating characteristic curves was 0.77, 0.75, 0.62, and 0.51 for the multivariable equation with FIB-4, NFS, BARD, and APRI score, respectively. Compared with patients with a low probability of developing advanced liver fibrosis, individuals with a high probability of developing fibrosis showed significantly increased odds of CKD as estimated by NFS (adjusted OR: 4.92, 95% confidence interval: 2.96–8.15) and FIB-4 (adjusted OR: 2.27, 95% confidence interval: 1.05–4.52).

Conclusion
Advanced liver fibrosis, defined by NFS and FIB-4 scores, is associated independently with CKD among individuals with NAFLD. FIB-4 is the best predictor of an increased risk of prevalent CKD.
Pancreatic Insufficiency in Cystic Fibrosis
Authors: Marson Fernando Augusto Lima , Bertuzzo Carmen Sílvia , de Araujo Tânia Kawasaki , Hortencio Taís Daiene Russo , Ribeiro Antônio Fernando , Ribeiro José Dirceu 
Published: December 2017

Objective
Pancreatic insufficiency (PI) in cystic fibrosis (CF) patients is a crucial clinical marker for severity and disease progression. In our study, 125 modifier genes and their SNPs were associated between CF patients with PI or pancreatic sufficiency.

Methods
We prospectively evaluated 214 CF patients admitted at 1 hospital for a 2-year period. The PI status was associated with clinical variables and SNPs related with inflammatory response considering CFTR mutations. Open Array technique was used to perform the SNPs identification.

Results
For PI risk, after correction by multiple test, in CF patients and 2 CFTR mutations class I, II, and/or III, there were 6 SNPs with positive association (P < 0.005). The odds ratio amplitude was 0.087 (95% confidence interval [CI], 0.004–0.544) for rs9870255*CG (CTNNB1 gene) to 11.06 (95% CI, 1.746–252.3) for rs729302*AA (IRF5 gene). For all CF patients at the same time, 9 SNPs showed positive association. The odds ratio amplitude was 0.144 (95% CI, 0.028–0.602) for rs2348071*AA (PSMA3 gene) to 5.809 (95% CI, 1.536–37.54) for rs11702779*AA (RUNX1 gene). In our data, we observed the interaction between CFTR mutations, rs9870255*CTNNB1, rs9378805*IRF4, and rs7664617*KCNIP4 to PI status.

Conclusions
Multiple SNPs in inflammatory response genes showed association with PI considering the CFTR mutations screening.
The −251 A/T Polymorphism in the IL8 Promoter is a Risk Factor for Acute Pancreatitis
Authors: Bishu Shrinivas , Koutroumpakis Efstratios , Mounzer Rawad , Stello Kimberly , Pollock Nijole , Evans Anna , Whitcomb David C. , Papachristou Georgios I. 
Published: December 2017

Objectives
Inflammation in the setting of acute pancreatitis (AP) is partially driven by pathogen recognition receptors that recognize damage-associated molecular patterns. Interleukin (IL)-8 is a chemotactic factor produced by pathogen recognition receptor-expressing cells. A single-nucleotide polymorphism in IL8 promoter region (−251 A/T) has been implicated in inflammatory diseases. We examined whether this IL8 polymorphism confers susceptibility to AP.

Methods
Patients with AP (n = 357) were prospectively recruited. Clinical data and blood were collected in subjects and controls (n = 347). Severity was defined following the Revised Atlanta Classification. Genotypes were assessed by quantitative polymerase chain reaction using TaqMan probes.

Results
Patients and controls had similar demographics and had no difference in Hardy-Weinberg (patients, P = 0.29; controls, P = 0.66). Twenty-five percent of patients developed severe AP. Compared with controls, the A/A genotype was more common in AP (P = 0.041; odds ratio, 1.42; 95% confidence interval, 1–1.99). Obese patients with the A/A genotype were more likely to develop mild AP (P = 0.047).

Conclusions
The −251 polymorphism confers susceptibility to AP and disease severity in obese patients. However, its effect is moderate. One potential mechanism for this susceptibility is via increased IL8 production by innate cells, with subsequent enhanced neutrophil influx and pancreatic injury.