Publications by authors named "Alessandro Fichera"

113 Publications

Upregulation of polycistronic microRNA-143 and microRNA-145 in colonocytes suppresses colitis and inflammation-associated colon cancer.

Epigenetics 2020 Dec 28:1-18. Epub 2020 Dec 28.

Department of Medicine, University of Chicago , Chicago IL, USA.

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3'UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, -148a or -152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3'UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an model of colonic tumorigenesis.
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http://dx.doi.org/10.1080/15592294.2020.1863117DOI Listing
December 2020

Clostridioides Difficile Infection.

Dis Colon Rectum 2021 Feb;64(2):151-155

Baylor University Medical Center, Dallas, Texas.

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http://dx.doi.org/10.1097/DCR.0000000000001900DOI Listing
February 2021

Surgical Treatment for Crohn's Disease: A Role of Kono-S Anastomosis in the West.

Clin Colon Rectal Surg 2020 Nov 14;33(6):335-343. Epub 2020 Sep 14.

Division of Colon and Rectal Surgery, Baylor University Medical Center, Dallas, Texas.

More than 80% of patients with Crohn's disease (CD) will require surgical intervention during their lifetime, with high rates of anastomotic recurrence and stenosis necessitating repeat surgery. Current data show that pharmacotherapy has not significantly improved the natural history of postoperative clinical and surgical recurrence of CD. In 2003, antimesenteric hand-sewn functional end-to-end (Kono-S) anastomosis was first performed in Japan. This technique has yielded very desirable outcomes in terms of reducing the incidence of anastomotic surgical recurrence. The most recent follow-up of these patients showed that very few had developed surgical recurrence. This new approach is superior to stapled functional end-to-end anastomosis because the stumps are sutured together to create a stabilizing structure (a "supporting column"), serving as a supportive backbone of the anastomosis to help prevent distortion of the anastomotic lumen due to disease recurrence and subsequent clinical symptoms. This technique requires careful mesenteric excision for optimal preservation of the blood supply and innervation. It also results in a very wide anastomotic lumen on the antimesenteric side. The Kono-S technique has shown efficacy in preventing surgical recurrence and the potential to become the new standard of care for intestinal CD.
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http://dx.doi.org/10.1055/s-0040-1714236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605911PMC
November 2020

Prophylaxis of Crohn's disease recurrence: A surgeon's perspective.

Ann Gastroenterol Surg 2020 Sep 24;4(5):514-520. Epub 2020 Jun 24.

Division of Colorectal Surgery Department of Surgery Baylor University Medical Center Dallas Texas USA.

Management of inflammatory bowel disease has evolved extensively in the last three decades. We have learnt a lot about the pathophysiology and natural history of the disease. New effective classes of drugs with the associated potential morbidity have been introduced. New surgical techniques have been popularized leading to a better understanding of the optimal timing of surgery. The result is a very complex subspecialty of gastroenterology and colorectal surgery called the "IBDologist." Only if we manage these complex patients in the context of a multi-disciplinary team will we be able to obtain outstanding outcomes, specifically with high and sustained remission rates for these patients.
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http://dx.doi.org/10.1002/ags3.12368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511563PMC
September 2020

ASO Author Reflections: Minimally Invasive Surgery for Colorectal Cancer: Where Do We Stand?

Ann Surg Oncol 2020 Oct 5;27(10):3716. Epub 2020 Aug 5.

Department of Surgery, Division of Colorectal Surgery, Baylor University Medical Center, Dallas, TX, USA.

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http://dx.doi.org/10.1245/s10434-020-08849-0DOI Listing
October 2020

Development and Validation of an Image-based Deep Learning Algorithm for Detection of Synchronous Peritoneal Carcinomatosis in Colorectal Cancer.

Ann Surg 2020 Jul 16. Epub 2020 Jul 16.

Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.

Objective: The aim of this study was to build a SVM classifier using ResNet-3D algorithm by artificial intelligence for prediction of synchronous PC.

Background: Adequate detection and staging of PC from CRC remain difficult.

Methods: The primary tumors in synchronous PC were delineated on preoperative contrast-enhanced computed tomography (CT) images. The features of adjacent peritoneum were extracted to build a ResNet3D + SVM classifier. The performance of ResNet3D + SVM classifier was evaluated in the test set and was compared to routine CT which was evaluated by radiologists.

Results: The training set consisted of 19,814 images from 54 patients with PC and 76 patients without PC. The test set consisted of 7837 images from 40 test patients. The ResNet-3D spent only 34 seconds to analyze the test images. To increase the accuracy of PC detection, we have built a SVM classifier by integrating ResNet-3D features with twelve PC-specific features (P < 0.05). The ResNet3D + SVM classifier showed accuracy of 94.11% with AUC of 0.922 (0.912-0.944), sensitivity of 93.75%, specificity of 94.44%, PPV of 93.75%, and NPV of 94.44% in the test set. The performance was superior to routine contrast-enhanced CT (AUC: 0.791).

Conclusions: The ResNet3D + SVM classifier based on deep learning algorithm using ResNet-3D framework has shown great potential in prediction of synchronous PC in CRC.
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http://dx.doi.org/10.1097/SLA.0000000000004229DOI Listing
July 2020

Surgical Prophylaxis of Crohn Disease Recurrence: "Light at the End of The Tunnel".

Ann Surg 2020 08;272(2):218-219

Division Chief, Colon and Rectal Surgery, Baylor University Medical Center, Dallas, TX.

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http://dx.doi.org/10.1097/SLA.0000000000003936DOI Listing
August 2020

The Landmark Series: Minimally Invasive (Laparoscopic and Robotic) Colorectal Cancer Surgery.

Ann Surg Oncol 2020 Oct 9;27(10):3704-3715. Epub 2020 Jul 9.

Department of Surgery, Division of Colorectal Surgery, Baylor University Medical Center, 3409 Worth Street. Worth Tower, Suite 640, Dallas, TX, 75246, USA.

Current high-quality evidence supports the routine use of the laparoscopic approach for patients with colon cancer. Laparoscopic colectomy is associated with earlier resumption of gastrointestinal function and shorter hospital stay, with no increased morbidity or mortality. Pathology and long-term oncologic outcomes are similar to those achieved with open surgery. The absolute benefits of laparoscopic resection for rectal cancer are still under evaluation. While its safety in terms of early postoperative clinical outcomes has been confirmed, two recent randomized controlled trial (RCTs) have questioned its routine use even in expert hands, since its non-inferiority has not been demonstrated when compared with the gold standard of open surgery. Furthermore, the impact of robotic technology is still unclear, since the only RCT available so far failed to demonstrate any benefits compared with standard laparoscopic rectal resection.
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http://dx.doi.org/10.1245/s10434-020-08833-8DOI Listing
October 2020

Diverting colostomy is an effective and reversible option for severe hemorrhagic radiation proctopathy.

World J Gastroenterol 2020 Feb;26(8):850-864

Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, Guangdong Province, China.

Background: Severe chronic radiation proctopathy (CRP) is difficult to treat.

Aim: To evaluate the efficacy of colostomy and stoma reversal for CRP.

Methods: To assess the efficacy of colostomy in CRP, patients with severe hemorrhagic CRP who underwent colostomy or conservative treatment were enrolled. Patients with tumor recurrence, rectal-vaginal fistula or other types of rectal fistulas, or who were lost to follow-up were excluded. Rectal bleeding, hemoglobin (Hb), endoscopic features, endo-ultrasound, rectal manometry, and magnetic resonance imaging findings were recorded. Quality of life before stoma and after closure reversal was scored with questionnaires. Anorectal functions were assessed using the CRP symptom scale, which contains the following items: Watery stool, urgency, perianal pain, tenesmus, rectal bleeding, and fecal/gas incontinence.

Results: A total of 738 continual CRP patients were screened. After exclusion, 14 patients in the colostomy group and 25 in the conservative group were included in the final analysis. Preoperative Hb was only 63 g/L ± 17.8 g/L in the colostomy group compared to 88.2 g/L ± 19.3 g/L ( < 0.001) in the conservative group. All 14 patients in the former group achieved complete remission of bleeding, and the colostomy was successfully reversed in 13 of 14 (93%), excepting one very old patient. The median duration of stoma was 16 (range: 9-53) mo. The Hb level increased gradually from 75 g/L at 3 mo, 99 g/L at 6 mo, and 107 g/L at 9 mo to 111 g/L at 1 year and 117 g/L at 2 years after the stoma, but no bleeding cessation or significant increase in Hb levels was observed in the conservative group. Endoscopic telangiectasia and bleeding were greatly improved. Endo-ultrasound showed decreased vascularity, and magnetic resonance imaging revealed an increasing presarcal space and thickened rectal wall. Anorectal functions and quality of life were significantly improved after stoma reversal, when compared to those before stoma creation.

Conclusion: Diverting colostomy is a very effective method in the remission of refractory hemorrhagic CRP. Stoma can be reversed, and anorectal functions can be recovered after reversal.
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http://dx.doi.org/10.3748/wjg.v26.i8.850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052535PMC
February 2020

Chronic Antibiotic Dependent Pouchitis Is Associated With Older Age at the Time of Ileal Pouch Anal Anastomosis (J-pouch) Surgery.

Crohns Colitis 360 2019 Oct 26;1(3):otz029. Epub 2019 Sep 26.

Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Background: Risk factors for the development of chronic antibiotic dependent pouchitis (CADP) are not well understood.

Methods: Using multivariable logistic regression, we compared clinical factors between 194 patients with acute antibiotic responsive pouchitis or CADP.

Results: Individuals with CADP were significantly older (40.9 vs 30.8 years, < 0.001) and demonstrated a longer disease duration before IPAA (10.3 vs 7.0 years, = 0.004). Age ≥55 years at the time of IPAA was significantly associated with CADP (adjusted odds ratio = 4.35, 95% confidence interval = 1.01-18.7).

Conclusions: Although older age should not represent a barrier to IPAA, further studies evaluating etiologies of this association are warranted.
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http://dx.doi.org/10.1093/crocol/otz029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798791PMC
October 2019

Lateral Lymph Nodes as the Achilles Heel of Low Rectal Cancer Surgery After Neoadjuvant Chemoradiation Therapy: Are We Close to Solving the Riddle?

JAMA Surg 2019 09 18;154(9):e192220. Epub 2019 Sep 18.

Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill.

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http://dx.doi.org/10.1001/jamasurg.2019.2220DOI Listing
September 2019

Challenges in IBD Research: Preclinical Human IBD Mechanisms.

Inflamm Bowel Dis 2019 05;25(Suppl 2):S5-S12

University of Chicago, Chicago, IL, USA.

Preclinical human IBD mechanisms is part of five focus areas of the Challenges in IBD research document, which also include environmental triggers, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the preclinical human IBD mechanisms manuscript is focused on highlighting the main research gaps in the pathophysiological understanding of human IBD. These research gap areas include: 1) triggers of immune responses; 2) intestinal epithelial homeostasis and wound repair; 3) age-specific pathophysiology; 4) disease complications; 5) heterogeneous response to treatments; and 6) determination of disease location. As an approach to address these research gaps, the prioritization of reverse translation studies is proposed in which clinical observations are the foundation for experimental IBD research in the lab, and for the identification of new therapeutic targets and biomarkers. The use of human samples in validating basic research findings and development of precision medicine solutions is also proposed. This prioritization aims to put emphasis on relevant biochemical pathways and humanized in vitro and in vivo models that extrapolate meaningfully to human IBD, to eventually yield first-in-class and effective therapies.
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http://dx.doi.org/10.1093/ibd/izz075DOI Listing
May 2019

SSAT State-of-the-Art Conference: Advances in the Management of Rectal Cancer.

J Gastrointest Surg 2019 02 13;23(2):433-442. Epub 2018 Sep 13.

Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1007/s11605-018-3965-9DOI Listing
February 2019

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

Dis Colon Rectum 2018 Oct;61(10):1146-1155

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response.

Objective: The purpose of this study was to analyze disease-free and overall survival.

Design: This was a nonrandomized phase II trial.

Settings: The study was conducted at multiple institutions.

Patients: Four sequential study groups with stage II or III rectal cancer were included.

Intervention: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6.

Main Outcome Measures: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study.

Results: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03).

Limitations: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients.

Conclusions: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.
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http://dx.doi.org/10.1097/DCR.0000000000001207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130918PMC
October 2018

Management of Acute Ulcerative Colitis.

Dis Colon Rectum 2018 09;61(9):1010-1013

Department of Surgery, University of North Carolina, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1097/DCR.0000000000001173DOI Listing
September 2018

Disease-free Survival and Local Recurrence for Laparoscopic Resection Compared With Open Resection of Stage II to III Rectal Cancer: Follow-up Results of the ACOSOG Z6051 Randomized Controlled Trial.

Ann Surg 2019 04;269(4):589-595

Mayo Clinic, Rochester, MN.

Objective: To determine the disease-free survival (DFS) and recurrence after the treatment of patients with rectal cancer with open (OPEN) or laparoscopic (LAP) resection.

Background: This randomized clinical trial (ACOSOG [Alliance] Z6051), performed between 2008 and 2013, compared LAP and OPEN resection of stage II/III rectal cancer, within 12 cm of the anal verge (T1-3, N0-2, M0) in patients who received neoadjuvant chemoradiotherapy. The rectum and mesorectum were resected using open instruments for rectal dissection (included hybrid hand-assisted laparoscopic) or with laparoscopic instruments under pneumoperitoneum. The 2-year DFS and recurrence were secondary endpoints of Z6051.

Methods: The DFS and recurrence were not powered, and are being assessed for superiority. Recurrence was determined at 3, 6, 9, 12, and every 6 months thereafter, using carcinoembryonic antigen, physical examination, computed tomography, and colonoscopy. In all, 486 patients were randomized to LAP (243) or OPEN (243), with 462 eligible for analysis (LAP = 240 and OPEN = 222). Median follow-up is 47.9 months.

Results: The 2-year DFS was LAP 79.5% (95% confidence interval [CI] 74.4-84.9) and OPEN 83.2% (95% CI 78.3-88.3). Local and regional recurrence was 4.6% LAP and 4.5% OPEN. Distant recurrence was 14.6% LAP and 16.7% OPEN.Disease-free survival was impacted by unsuccessful resection (hazard ratio [HR] 1.87, 95% CI 1.21-2.91): composite of incomplete specimen (HR 1.65, 95% CI 0.85-3.18); positive circumferential resection margins (HR 2.31, 95% CI 1.40-3.79); positive distal margin (HR 2.53, 95% CI 1.30-3.77).

Conclusion: Laparoscopic assisted resection of rectal cancer was not found to be significantly different to OPEN resection of rectal cancer based on the outcomes of DFS and recurrence.
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http://dx.doi.org/10.1097/SLA.0000000000003002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360134PMC
April 2019

Expert Commentary on Neoadjuvant Therapy for Rectal Cancer.

Dis Colon Rectum 2018 08;61(8):887

Department of Surgery, University of North Carolina, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1097/DCR.0000000000001140DOI Listing
August 2018

Less Is More in Colorectal Cancer Posttreatment Surveillance.

JAMA Surg 2018 10;153(10):877

Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1001/jamasurg.2018.2066DOI Listing
October 2018

Role of surgery in the management of Crohn's disease.

Curr Probl Surg 2018 May 15;55(5):162-187. Epub 2018 May 15.

Northwest Hospital, University of Washington, Seattle, WA.

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http://dx.doi.org/10.1067/j.cpsurg.2018.05.001DOI Listing
May 2018

Locally Advanced Rectal Cancer: Is It Time for a Paradigm Change?

JAMA Surg 2018 08 15;153(8):e181620. Epub 2018 Aug 15.

Department of Surgery, University of North Carolina, Chapel Hill, Chapel Hill.

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http://dx.doi.org/10.1001/jamasurg.2018.1620DOI Listing
August 2018

A historical perspective on rectal cancer treatment: from the prehistoric era to the future.

Minerva Chir 2018 12 13;73(6):525-527. Epub 2018 Apr 13.

Division of Gastrointestinal Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA -

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http://dx.doi.org/10.23736/S0026-4733.18.07708-8DOI Listing
December 2018

Dynamic plasma microRNAs are biomarkers for prognosis and early detection of recurrence in colorectal cancer.

Br J Cancer 2017 Oct 15;117(8):1202-1210. Epub 2017 Aug 15.

Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D4-100, Seattle, WA 98109, USA.

Background: Plasma microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC) prognosis. However, the published studies to date have yielded conflicting and inconsistent results for specific plasma miRNAs.

Methods: We have conducted a study using robust assays to assess a panel of nine miRNAs for CRC prognosis and early detection of recurrence. Plasma samples from 144 patients in a prospective CRC cohort study were collected at diagnosis, 6, 12, and 24 months after diagnosis. miRNAs were assayed by Taqman qRT-PCR to generate miRNA normalised copy numbers.

Results: Preoperative high plasma miRNA levels were associated with increased recurrence risk for miR-200b (HR [95% CI]=2.04 [1.00, 4.16], P=0.05), miR-203 (HR=4.2 [1.48, 11.93], P=0.007), miR-29a (HR=2.61 [1.34,5.07], P=0.005), and miR-31 (HR=4.03 [1.76, 9.24], P=0.001). Both plasma miR-31 (AUC: 0.717) and miR-29a (AUC: 0.703) could discriminate recurrence from these patients without recurrence. In addition, high levels of miR-31 during surveillance was associated with a three-fold increased risk of recurrence across all time points. Dynamic postoperative plasma miR-141 and 16 levels correlated with recurrence in the surveillance samples.

Conclusions: Pre-operative plasma miR-29a, 200b, 203, and 31 are potential CRC prognosis biomarkers. In addition, dynamic postoperative miR-31, 141 and 16 levels are potential biomarkers for the early detection of recurrence during CRC surveillance.
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http://dx.doi.org/10.1038/bjc.2017.266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674097PMC
October 2017

miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling.

Inflamm Bowel Dis 2017 08;23(8):1328-1337

*Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago, Illinois; †Department of Chemistry, University of Chicago, Chicago, Illinois; ‡Section of Gastroenterology, Northwestern University, Chicago, Illinois; §Department of Surgery, University of Chicago, Chicago, Illinois; ‖Department of Surgery, University of Washington, Seattle, Washington; and ¶Department of Pathology, University of Chicago, Chicago, Illinois.

Background: As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population.

Methods: MicroRNA (miRNA) and mRNA expression was examined in nondysplastic rectosigmoid mucosa from UC patients with (n = 19) or without remote colon neoplasia (n = 23). We developed a method to identify miRNA-regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling was further evaluated in vitro and through examination of expression in UC-cancers.

Results: There were 101 significantly up-regulated and 98 down-regulated miRNAs (adjusted P < 0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down-regulation of miR-4728-3p in nondysplastic tissue remote from UC-neoplasia and in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3' untranslated region compared with a mutant 3' untranslated region for all 3 genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes.

Conclusions: Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in nondysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor suppressor in UC-associated colon carcinogenesis.
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http://dx.doi.org/10.1097/MIB.0000000000001104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535754PMC
August 2017

Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2017 03;15(3):370-398

This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy have included treatment history, extent of disease, goals of treatment, the efficacy and toxicity profiles of the regimens, mutational status, and patient comorbidities and preferences. Location of the primary tumor, the mutation status, and tumor microsatellite stability should also be considered in treatment decisions.
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http://dx.doi.org/10.6004/jnccn.2017.0036DOI Listing
March 2017

Orthopaedic Aspects of Marfan Syndrome: The Experience of a Referral Center for Diagnosis of Rare Diseases.

Adv Orthop 2016 5;2016:8275391. Epub 2016 Dec 5.

Department of Orthopaedics and Traumatology, University of Rome "Tor Vergata", Viale Oxford 81, 00133 Rome, Italy.

Marfan syndrome is caused by mutations in the fibrillin-1 gene (). The most important features affect the cardiovascular system, eyes, and skeleton. The aim of this study was to report the most frequent musculoskeletal alterations observed in 146 patients affected by Marfan syndrome. Fifty-four patients (37%) underwent cardiac surgery and 11 of them received emergent surgery for acute aortic dissection. Ectopia lentis was found in 68 patients (47%) whereas myopia above 3D occurred in 46 patients (32%). Musculoskeletal anomalies were observed in all patients with Marfan syndrome. In 88 patients (60.2%), the associated "wrist and thumb sign" was present; in 58 patients (39.7%), pectus carinatum deformity; in 44 patients (30.1%), pectus excavatum; in 49 patients (33.5%), severe flatfoot; in 31 patients (21.2%), hindfoot deformity; in 54 patients (36.9%), reduced US/LS ratio or increased arm span-height ratio; in 37 patients (25.3%), scoliosis or thoracolumbar kyphosis; in 22 patients (15%), reduced elbow extension (170° or less). Acetabular protrusion was ascertained on radiographs in 27 patients (18.4%). Orthopaedic aspects of the disease are very important for an early diagnosis; however, we have not observed definite correlations between the extent of orthopaedic involvement and aortic complications.
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http://dx.doi.org/10.1155/2016/8275391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165130PMC
December 2016

Preoperative Immunonutrition and Elective Colorectal Resection Outcomes.

Dis Colon Rectum 2017 Jan;60(1):68-75

1 Department of Surgery, University of Washington, Seattle, Washington 2 Department of Surgery, University of Utah, Salt Lake City, Utah 3 Department of Biostatistics, University of Washington, Seattle, Washington 4 Department of Surgery, Madigan Army Medical Center, Tacoma, Washington 5 Colon and Rectal Surgery, Swedish Medical Center, Seattle, Washington 6 General Surgery, Virginia Mason Medical Center, Seattle, Washington.

Background: Randomized controlled trials demonstrate the efficacy of arginine-enriched nutritional supplements (immunonutrition) in reducing complications after surgery. The effectiveness of preoperative immunonutrition has not been evaluated in a community setting.

Objective: This study aims to determine whether immunonutrition before elective colorectal surgery improves outcomes in the community at large.

Design: This is a prospective cohort study with a propensity score-matched comparative effectiveness evaluation.

Settings: This study was conducted in Washington State hospitals in the Surgical Care Outcomes Assessment Program from 2012 to 2015.

Patients: Adults undergoing elective colorectal surgery were selected.

Interventions: Surgeons used a preoperative checklist that recommended that patients take oral immunonutrition (237 mL, 3 times daily) for 5 days before elective colorectal resection.

Main Outcome Measures: Serious adverse events (infection, anastomotic leak, reoperation, and death) and prolonged length of stay were the primary outcomes measured.

Results: Three thousand three hundred seventy-five patients (mean age 59.9 ± 15.2 years, 56% female) underwent elective colorectal surgery. Patients receiving immunonutrition more commonly were in a higher ASA class (III-V, 44% vs 38%; p = 0.01) or required an ostomy (18% vs 14%; p = 0.02). The rate of serious adverse events was 6.8% vs 8.3% (p = 0.25) and the rate of prolonged length of stay was 13.8% vs 17.3% (p = 0.04) in those who did and did not receive immunonutrition. After propensity score matching, covariates were similar among 960 patients. Although differences in serious adverse events were nonsignificant (relative risk, 0.76; 95% CI, 0.49-1.16), prolonged length of stay (relative risk, 0.77; 95% CI, 0.58-1.01 p = 0.05) was lower in those receiving immunonutrition.

Limitations: Patient compliance with the intervention was not measured. Residual confounding, including surgeon-level heterogeneity, may influence estimates of the effect of immunonutrition.

Conclusions: Reductions in prolonged length of stay, likely related to fewer complications, support the use of immunonutrition in quality improvement initiatives related to elective colorectal surgery. This population-based study supports previous trials of immunonutrition, but shows a lower magnitude of benefit, perhaps related to compliance or a lower rate of adverse events, highlighting the value of community-based assessments of comparative effectiveness.
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http://dx.doi.org/10.1097/DCR.0000000000000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147426PMC
January 2017

ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer.

Clin Cancer Res 2017 Jan 3;23(2):549-561. Epub 2016 Aug 3.

Department of Medicine, University of Chicago, Chicago IL 60637.

Purpose: Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein-coupled receptors, including CXCR4. Here we investigated CXCR4-ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis.

Experimental Design: We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4-ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa.

Results: CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes.

Conclusions: ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet→CXCL12→CXCR4→ADAM17→TGFα→EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549-61. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-3140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241244PMC
January 2017

Inflammatory bowel disease surgery in the biologic era.

World J Gastrointest Surg 2016 May;8(5):363-70

Linda Ferrari, Mukta K Krane, Alessandro Fichera, University of Washington Medical Center, Seattle, WA 98195-6410, United States.

Anti-tumour necrosis factor (TNF)-α therapy has revolutionized inflammatory bowel disease (IBD) treatment. Infliximab and adalimumab either as monotherapy or in combination with an immunomodulator are able to induce clinical and biological remission in patients with moderate and severe Crohn's disease (CD) and ulcerative colitis (UC). These new therapies have led to a shift in the goals of IBD management from just controlling clinical symptoms to preventing disease progression. However, despite these advances in medical therapy, surgery is still required in 30%-40% of patients with CD and 20%-30% of patients with UC at some point during their lifetime. While biologics certainly play a major role in the medical treatment of IBD, there is concern about the effects of these anti-TNF-α agents on postoperative complications and morbidity. The purpose of this article is to review the role of surgery in the treatment of IBD in the age of biologics and the impact of these medications on per-operative outcomes. In this manuscript we review the relationship between biologic agents and surgery in the treatment of IBD. We also discuss in detail the periopetative risks and complications.
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http://dx.doi.org/10.4240/wjgs.v8.i5.363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872064PMC
May 2016

Postoperative Medical Management of Crohn's Disease: Prevention and Surveillance Strategies.

J Gastrointest Surg 2016 08 26;20(8):1415-20. Epub 2016 May 26.

Department of Surgery, University of Washington Medical Center, 1959 NE Pacific St, Box 356410, Seattle, WA, 98195, USA.

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http://dx.doi.org/10.1007/s11605-016-3172-5DOI Listing
August 2016

Alvimopan Use, Outcomes, and Costs: A Report from the Surgical Care and Outcomes Assessment Program Comparative Effectiveness Research Translation Network Collaborative.

J Am Coll Surg 2016 05 5;222(5):870-7. Epub 2016 Feb 5.

Department of Surgery, University of Washington, Seattle, WA.

Background: Randomized trials have found that alvimopan hastens return of bowel function and reduces length of stay (LOS) by 1 day among patients undergoing colorectal surgery. However, its effectiveness in routine clinical practice and its impact on hospital costs remain uncertain.

Study Design: We performed a retrospective cohort study of patients undergoing elective colorectal surgery in Washington state (2009 to 2013) using data from a clinical registry (Surgical Care and Outcomes Assessment Program) linked to a statewide hospital discharge database (Comprehensive Hospital Abstract Reporting System). We used generalized estimating equations to evaluate the relationship between alvimopan and outcomes, and adjusted for patient, operative, and management characteristics. Hospital charges were converted to costs using hospital-specific charge to cost ratios, and were adjusted for inflation to 2013 US dollars.

Results: Among 14,781 patients undergoing elective colorectal surgery at 51 hospitals, 1,615 (11%) received alvimopan. Patients who received alvimopan had a LOS that was 1.8 days shorter (p < 0.01) and costs that were $2,017 lower (p < 0.01) compared with those who did not receive alvimopan. After adjustment, LOS was 0.9 days shorter (p < 0.01), and hospital costs were $636 lower (p = 0.02) among those receiving alvimopan compared with those who did not.

Conclusions: When used in routine clinical practice, alvimopan was associated with a shorter LOS and limited but significant hospital cost savings. Both efficacy and effectiveness data support the use of alvimopan in routine clinical practice, and its use could be measured as a marker of higher quality care.
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http://dx.doi.org/10.1016/j.jamcollsurg.2016.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848460PMC
May 2016