Publications by authors named "Jeffrey Marks"

223 Publications

Unmasking the immune microecology of ductal carcinoma in situ with deep learning.

NPJ Breast Cancer 2021 Mar 1;7(1):19. Epub 2021 Mar 1.

Centre for Evolution and Cancer, Institute of Cancer Research, London, UK.

Despite increasing evidence supporting the clinical relevance of tumour infiltrating lymphocytes (TILs) in invasive breast cancer, TIL spatial variability within ductal carcinoma in situ (DCIS) samples and its association with progression are not well understood. To characterise tissue spatial architecture and the microenvironment of DCIS, we designed and validated a new deep learning pipeline, UNMaSk. Following automated detection of individual DCIS ducts using a new method IM-Net, we applied spatial tessellation to create virtual boundaries for each duct. To study local TIL infiltration for each duct, DRDIN was developed for mapping the distribution of TILs. In a dataset comprising grade 2-3 pure DCIS and DCIS adjacent to invasive cancer (adjacent DCIS), we found that pure DCIS cases had more TILs compared to adjacent DCIS. However, the colocalisation of TILs with DCIS ducts was significantly lower in pure DCIS compared to adjacent DCIS, which may suggest a more inflamed tissue ecology local to DCIS ducts in adjacent DCIS cases. Our study demonstrates that technological developments in deep convolutional neural networks and digital pathology can enable an automated morphological and microenvironmental analysis of DCIS, providing a new way to study differential immune ecology for individual ducts and identify new markers of progression.
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http://dx.doi.org/10.1038/s41523-020-00205-5DOI Listing
March 2021

International Delphi Expert Consensus on Safe Return to Surgical and Endoscopic Practice: from the Coronavirus Global Surgical Collaborative.

Ann Surg 2020 Dec 29. Epub 2020 Dec 29.

*Hepatobiliary and Pancreas Surgery, Miami Cancer Institute, Miami, FL, USA †Department of Surgery, Istituto Fondazione Poliambulanza, Brescia, Italy ‡Department of Surgery, Southampton University Hospital., 1. Division of Hepatobiliary and Pancreas Surgery, Miami Cancer Institute, Miami, FL, USA §Department of Surgery, University of California San Francisco Fresno, Fresno, CA, USA ¶Department of Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands ||Department of Surgery, Trinity College Dublin, and St. Vincent's University Hospital, Dublin, Ireland **Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland ††Edward W. Archibald Professor and Chair, Department of Surgery McGill University Surgeon-in-chief, McGill University Health Centre Montreal, Quebec, Canada ‡‡University Hospital Virgen del Rocio, Sevilla, Spain §§Dipartimento di Scienze Clinico Chirurgiche, Diagnostiche e Pediatriche, Università Degli Studi Di Pavia, Pavia, Italy. Fondazione IRCCS Policlinico San Matteo, Pavia ¶¶Stony Brook University Department of Surgery, Stony Brook, NY, USA ||||Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, Canada ***Icahn School Medicine at Mount Sinai, New York, NY, USA †††Division of Colorectal Surgery, Department of Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain ‡‡‡Ministry of Health, Madrid, Spain §§§Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA ¶¶¶Department of Surgery, Mayo Clinic, Rochester, MN, USA ||||||Department of Anesthesia at Baptist Hospital of Miami, Miami, FL, USA. Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA ****General Management, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ††††BA Wake Forest University, Reno, NV, USA ‡‡‡‡Department of Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea. 16. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA §§§§Department of Anesthesiology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, USA ¶¶¶¶Communicable Diseases Division, Swiss Federal Office of Public Health, Bern, Switzerland ||||||||Department of Surgery, Massachusetts General Hospital, Boston, USA *****Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore †††††Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH, USA ‡‡‡‡‡Divisions of General and Gastrointestinal Surgery, Department of Surgery, Atrium Health Carolinas Medical Center, Charlotte, NC, USA §§§§§Southern Illinois University School of Medicine, Departments of Surgery and Medical Education, Springfield, IL, USA ¶¶¶¶¶Division of General Surgery, Department of Surgery, Montefiore Medical Center, New York, NY, USA ||||||||||Department of Surgery, ABC Medical Center, Mexico City, Mexico ******Servicio de Cirugía Endoscópica Hospital San Borja Arriarán de Santiago. Departamento de Cirugía, Clinica Santa Maria, Santiago, Chile ††††††Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA ‡‡‡‡‡‡Department of Digestive Surgery, Nouvel Hôpital Civil, Université de Strasbourg, IHU Institute of Image-Guided Surgery of Strasbourg and U1110 Inserm, Institute of Viral and Liver Disease, Strasbourg, France §§§§§§Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy. Department of Woman and Child Health and Public Health - Public Health Area Fondazione Policlinico Universitario A. Gemelli IRCCS Rome, Italy ¶¶¶¶¶¶Department of Surgery, University at Buffalo, Buffalo, NY, USA ||||||||||||Department of Surgery, NYU Langone Health, New York, NY, USA *******Department of Anesthesiology, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, IL, USA †††††††Departments of Surgery, State University of New York, Stony Brook, NY, USA ‡‡‡‡‡‡‡Departamento of Surgery, Hospital Escuela "José de San Martín", Corrientes, Argentina.**, 2. Department of Surgery, Istituto Fondazione Poliambulanza, Brescia, Italy §§§§§§§Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand ¶¶¶¶¶¶¶Fondazione Nadia Valsecchi Onlus, Palazzolo Sull'Oglio, Brescia, Italy ||||||||||||||Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA ********Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA ††††††††Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL, USA ‡‡‡‡‡‡‡‡Miami Cancer Institute, Miami, FL, USA §§§§§§§§Department of General Surgery, Yeovil District Hospital National Health Service Foundation Trust, Yeovil, England. Division of Surgery and Interventional Science, University College London. The Griffin Institute at Northwick Park Institute for Medical Research, Norwich Park London. Enhanced-Recovery After Surgery - UK (ERAS-UK).

Objective: The aim of this work is to formulate recommendations based on global expert consensus to guide the surgical community on the safe resumption of surgical and endoscopic activities.

Background: The COVID-19 pandemic has caused marked disruptions in the delivery of surgical care worldwide. A thoughtful, structured approach to resuming surgical services is necessary as the impact of COVID-19 becomes better controlled. The Coronavirus Global Surgical Collaborative (CVGSC) sought to formulate, through rigorous scientific methodology, a consensus-based recommendations in collaboration with a multidisciplinary group of international experts and policy makers.

Methods: Recommendations were developed following a Delphi process. Domain topics were formulated and subsequently subdivided into questions pertinent to different aspects of surgical care in the COVID-19 crisis. Forty-four experts from 15 countries across four continents drafted statements based on the specific questions. Anonymous Delphi voting on the statements was performed in two rounds, as well as in a telepresence meeting.

Results: One hundred statements were formulated across 10 domains. The statements addressed terminology, impact on procedural services, patient/staff safety, managing a backlog of surgeries, methods to restart and sustain surgical services, education, and research. Eightythree of the statements were approved during the first round of Delphi voting, and 11 during the second round. A final telepresence meeting and discussion yielded acceptance of five other statements.

Conclusions: The Delphi process resulted in 99 recommendations. These consensus statements provide expert guidance, based on scientific methodology, for the safe resumption of surgical activities during the COVID-19 pandemic.
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http://dx.doi.org/10.1097/SLA.0000000000004674DOI Listing
December 2020

SAGES guidelines for the use of peroral endoscopic myotomy (POEM) for the treatment of achalasia.

Surg Endosc 2021 Feb 9. Epub 2021 Feb 9.

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Peroral endoscopic myotomy (POEM) is increasingly used as primary treatment for esophageal achalasia, in place of the options such as Heller myotomy (HM) and pneumatic dilatation (PD) OBJECTIVE: These evidence-based guidelines from the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) intend to support clinicians, patients and others in decisions about the use of POEM for treatment of achalasia.

Results: The panel agreed on 4 recommendations for adults and children with achalasia.

Conclusions: Strong recommendation for the use of POEM over PD was issued unless the concern of continued postoperative PPI use remains a key decision-making concern to the patient. Conditional recommendations included the option of using either POEM or HM with fundoplication to treat achalasia, and favored POEM over HM for achalasia subtype III.
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http://dx.doi.org/10.1007/s00464-020-08282-0DOI Listing
February 2021

Revisional endoscopic sleeve gastroplasty: a new trick up our sleeves.

Gastrointest Endosc 2021 Jan;93(1):131-132

Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1016/j.gie.2020.07.002DOI Listing
January 2021

Management of patients after failed peroral endoscopic myotomy: a multicenter study.

Endoscopy 2020 Nov 16. Epub 2020 Nov 16.

Division of Gastroenterology and Hepatology, Johns Hopkins Medical Institution, Baltimore, Maryland, USA.

Background:  Although peroral endoscopic myotomy (POEM) is highly effective for the management of achalasia, clinical failures may occur. The optimal management of patients who fail POEM is not well known. This study aimed to compare the outcomes of different management strategies in patients who had failed POEM.

Methods:  This was an international multicenter retrospective study at 16 tertiary centers between January 2012 and November 2019. All patients who underwent POEM and experienced persistent or recurrent symptoms (Eckardt score > 3) were included. The primary outcome was to compare the rates of clinical success (Eckardt score ≤ 3) between different management strategies. RESULTS : 99 patients (50 men [50.5 %]; mean age 51.4 [standard deviation (SD) 16.2]) experienced clinical failure during the study period, with a mean (SD) Eckardt score of 5.4 (0.3). A total of 29 patients (32.2 %) were managed conservatively and 70 (71 %) underwent retreatment (repeat POEM 33 [33 %], pneumatic dilation 30 [30 %], and laparoscopic Heller myotomy (LHM) 7 [7.1 %]). During a median follow-up of 10 (interquartile range 3 - 20) months, clinical success was highest in patients who underwent repeat POEM (25 /33 [76 %]; mean [SD] Eckardt score 2.1 [2.1]), followed by pneumatic dilation (18/30 [60 %]; Eckardt score 2.8 [2.3]), and LHM (2/7 [29 %]; Eckardt score 4 [1.8];  = 0.12). A total of 11 patients in the conservative group (37.9 %; mean Eckardt score 4 [1.8]) achieved clinical success. CONCLUSION : This study comprehensively assessed an international cohort of patients who underwent management of failed POEM. Repeat POEM and pneumatic dilation achieved acceptable clinical success, with excellent safety profiles.
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http://dx.doi.org/10.1055/a-1312-0496DOI Listing
November 2020

Peroral Esophageal Myotomy.

Surg Clin North Am 2020 Dec 10;100(6):1183-1192. Epub 2020 Oct 10.

Department of Surgery, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106-5047, USA.

Achalasia is a neurodegenerative disorder of the lower esophagus characterized by high lower esophageal pressures and aperistalsis of the esophageal body. It remains a difficult to treat disease with significant burden on patients due to difficulty swallowing leading to malnutrition. Peroral endoscopic myotomy (POEM) is a newer endoscopic treatment of achalasia. It involves dividing the muscular layer of the esophagus through a submucosal tunnel. Ten-year data show POEM is a safe and effective treatment of achalasia. However, postoperative gastroesophageal reflux disease remains an important consideration.
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http://dx.doi.org/10.1016/j.suc.2020.08.004DOI Listing
December 2020

Unbundling General Surgery: Have We Taken Specialization Too Far?

Am Surg 2020 Oct 29:3134820940626. Epub 2020 Oct 29.

173812 Department of Hepatopancreaticobiliary Surgery, Methodist Richardson Medical Center, Richardson, TX, USA.

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http://dx.doi.org/10.1177/0003134820940626DOI Listing
October 2020

An evaluation of the complication risks following peroral endoscopic myotomy in patients on antithrombotic therapy.

Surg Endosc 2020 Oct 8. Epub 2020 Oct 8.

Department of Surgery, University Hospitals Cleveland Medical Center/Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH, 44106, USA.

Background: Per oral endoscopic myotomy (POEM) is used to treat a variety of esophageal motility disorders and is associated with relatively few complications. However, complications in patients on antithrombotic therapy (AT) is not well-studied. We hypothesize AT patients have a higher risk of post-operative bleeding and 30-day complication rate compared to all other patients, even when these medications are held peri-operatively.

Methods: A single-institution retrospective review of a prospectively collected database of patients who underwent POEM procedures January 2011-July 2019 was performed. All 30-day complications were recorded, as well as management of AT medications peri-operatively. Demographic and clinical characteristics were compared using t test, Chi-Square, and Fisher's exact test as appropriate. Multivariate logistic regression was performed to examine factors associated with post-operative complications.

Results: A total of 219 POEM procedures were performed. 50.2% of patients were male, and AT patients tended to be older (66.9 vs. 55.4, p = 0.01). The major complication rate was higher among AT patients (36.8% vs. 9.0%, p = 0.01), as was the rate of post-operative bleeding (10.5% vs. 1.0%, p = 0.04). After adjusting for gender and age, the use of antithrombotic therapy was significantly associated with 30-day complications (OR 6.03, p = 0.001).

Conclusions: Patients on AT who undergo POEM are significantly more likely to experience complications, including bleeding, within 30 days of surgery. Safe timing of post-operative resumption of antithrombotic medications remains a difficult decision that must be carefully considered by the endoscopist.
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http://dx.doi.org/10.1007/s00464-020-08065-7DOI Listing
October 2020

Fact or Fiction? Practice on a Simulator is Not Required to Pass the Fundamentals of Endoscopic Surgery (FES) Skills Exam.

J Surg Educ 2020 Nov - Dec;77(6):e229-e236. Epub 2020 Jun 10.

University Hospitals, Cleveland Medical Center, Cleveland, Ohio.

Purpose: Initial work on the validity evidence used to support the Fundamentals of Endoscopic Surgery (FES) performance exam as a measure of technical competency showed a strong relationship to clinical experience. Despite this evidence, there is a perception among some program directors that the exam cannot be successfully passed without practice on a simulator. We assess the validity of this perception.

Methods: Deidentified data from the initial FES skills examination (prior to the 2014 FEC requirement) was reviewed, and 335 unique participants with reported simulation experience demographics were identified. Self reported data analyzed included gender, total clinical endoscopy procedure experience (1-150, 151-300, >300), and endoscopy simulator training hours (0, 1-5, 6-10, 11-20, >20). Final FES skills exam scores, and pass/fail designations for each participant were reported by the FES program staff. Continuous variables were compared between groups using one-way analysis of variance with post-hoc analysis where appropriate. Categorical variables were compared using Pearson Chi-Squared. The effect of variables on pass rate was assessed using univariate and multivariate logistic regression.

Results: Simulation training experience (SE) was categorically reported in hours(n,%): 0 (98, 29%), 1-5 (135, 40%), 6-10 (52, 16%), 11-20 (24, 7%), and >20 (26, 8%). Clinical endoscopy experience (CE), reported categorically as total cases performed (n,%), was available for 323 of 355 identified participants: 1-150 (126, 39%), 151-300 (99, 31%), >300 (98, 30%). There was no statistically discernible differences in mean FES total or task scores across the SE groups (total score 0:72 ± 15, 1-5:72 ± 13, 6-10:71 ± 14, 11-20:71 ± 16, 20:78 ± 13; p = 0.28), while both total score and task scores were discernibly higher in the more experienced CE groups (>151) compared to the least experienced group (total score; <150:67 ± 15, 151-300:75 ± 1, >300:77 ± 14; p < 0.01). Similarly, there was no statistically discernible difference in FES skills exam pass rates between SE groups (0: 80%, 1-5: 82%, 6-10: 79%, 11-20: 75%, >20: 85%; x2 = 2.5, p = 0.6), but there was a strong relationship between clinical experience and pass rate (<150: 70%, 151-300: 87%, >300: 89%; x2 = 15.8, p < 0.001). Finally, on both univariate and multivariate logistic regression, CE remained a discernible predictor of passing, even when controlling for SE (odds ratio = 2, 95% confidence interval 1.4-2.9, p < 0.001).

Conclusions: FES skills examination data collected on participants completing the examination before the FEC requirement shows no demonstrable relationship with self-reported training experience on a simulator but confirms a strong relationship with clinical endoscopy experience. This lends further evidence to the validity of the FES exam as a marker of clinical endoscopic skill.
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http://dx.doi.org/10.1016/j.jsurg.2020.05.019DOI Listing
June 2020

Commentary on Lineberry et al., The Fundamentals of Endoscopic Surgery (FES) skills test: factors associated with first-attempt scores and pass rate.

Surg Endosc 2020 Aug;34(8):3289-3291

University Hospitals Case Medical Center, Cleveland, OH, USA.

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http://dx.doi.org/10.1007/s00464-020-07692-4DOI Listing
August 2020

Minimal barriers to invasion during human colorectal tumor growth.

Nat Commun 2020 03 9;11(1):1280. Epub 2020 Mar 9.

Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.

Intra-tumoral heterogeneity (ITH) could represent clonal evolution where subclones with greater fitness confer more malignant phenotypes and invasion constitutes an evolutionary bottleneck. Alternatively, ITH could represent branching evolution with invasion of multiple subclones. The two models respectively predict a hierarchy of subclones arranged by phenotype, or multiple subclones with shared phenotypes. We delineate these modes of invasion by merging ancestral, topographic, and phenotypic information from 12 human colorectal tumors (11 carcinomas, 1 adenoma) obtained through saturation microdissection of 325 small tumor regions. The majority of subclones (29/46, 60%) share superficial and invasive phenotypes. Of 11 carcinomas, 9 show evidence of multiclonal invasion, and invasive and metastatic subclones arise early along the ancestral trees. Early multiclonal invasion in the majority of these tumors indicates the expansion of co-evolving subclones with similar malignant potential in absence of late bottlenecks and suggests that barriers to invasion are minimal during colorectal cancer growth.
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http://dx.doi.org/10.1038/s41467-020-14908-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062901PMC
March 2020

Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor-Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903 (Alliance).

J Clin Oncol 2020 04 3;38(12):1284-1292. Epub 2020 Mar 3.

University of California, San Francisco, San Francisco, CA.

Purpose: Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)-positive DCIS.

Patients And Methods: A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline.

Results: Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm. Median reductions from baseline MRI volume (1.4 cm) were 0.6 cm (61.0%) at 3 months ( < .001) and 0.8 cm (71.7%) at 6 months ( < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; = .005), progesterone receptor H-score (15; median reduction, 85.0; < .001), and Ki67 score (12%; median reduction, 6.3%; = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%).

Conclusions: In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.
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http://dx.doi.org/10.1200/JCO.19.00510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164489PMC
April 2020

DNA methylation markers predict recurrence-free interval in triple-negative breast cancer.

NPJ Breast Cancer 2020 31;6. Epub 2020 Jan 31.

1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.

We lack tools to risk-stratify triple-negative breast cancer (TNBC). Our goal was to develop molecular tools to predict disease recurrence. Methylation array analysis was performed on 110 samples treated by locoregional therapy obtained from institutional cohorts. Discovered marker sets were then tested by Kaplan-Meier analyses in a prospectively collected TNBC cohort of 49 samples from the no-chemotherapy arms of IBCSG trials VIII and IX, and by logistic regression in a chemotherapy-treated cohort of 121 TNBCs from combined IBCSG trials and institutional repositories. High methylation was associated with shorter recurrence-free interval in the no-chemotherapy arm of the IBCSG studies, as well as in the chemotherapy-treated patients within the combined institutional and IBCSG chemotherapy cohorts (100 marker panel,  = 0.002; 30 marker panel,  = 0.05). Chromosome 19 sites were enriched among these loci. In conclusion, our hypermethylation signatures identify increased recurrence risk independent of whether patients receive chemotherapy.
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http://dx.doi.org/10.1038/s41523-020-0145-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994477PMC
January 2020

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence.

Cell Death Differ 2020 07 27;27(7):2234-2247. Epub 2020 Jan 27.

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27710, USA.

The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically reexpressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo necroptosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.
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http://dx.doi.org/10.1038/s41418-020-0499-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308288PMC
July 2020

Gastric Per Oral Pyloromyotomy for Post-Vagotomy-Induced Gastroparesis Following Esophagectomy.

J Gastrointest Surg 2020 03 2;24(3):715-719. Epub 2019 Dec 2.

Department of Surgery, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH, 44106, USA.

Background: Following the success of per-oral endoscopic myotomy (POEM) for achalasia, application of this minimally invasive skillset has broadened to other disease processes. Since 2013, gastric per-oral pyloromyotomy (GPOP) has become an increasingly accepted therapy for refractory gastroparesis. Although it does not treat the underlying etiology of the disease, pyloromyotomy has demonstrated measurable improvements in gastric emptying scintigraphy, nausea, and quality of life. Gastroparesis is a common complication of esophagectomy due to the inherent vagotomy that occurs during creation of the gastric conduit. Fifteen to 30% of post-esophagectomy patients develop gastroparesis with a large portion of them reporting symptoms refractory to medical therapy, botox injection, and endoscopic dilation. Therefore, GPOP may have the potential to offer symptomatic relief to a significant population of debilitated post-esophagectomy patients.

Materials And Methods: The procedure was recorded using standard operating room equipment. Materials utilized included high-definition single-channel gastroscope, therapeutic overtube, clear endoscopic cap, triangle tip (TT) knife, ERBE energy source, endoscopic clips, sclerotherapy needle, methylene blue with epinephrine, and CO insufflator.

Results: We present a video of GPOP for a 71-year-old male with post-vagotomy-induced gastroparesis after esophagectomy. His pre-operative course was significant for persistent nausea and vomiting, diet intolerance, 20 lb weight loss, and frequent hospitalizations for aspiration pneumonia. Post-operatively, the patient recovered well and was discharged home on post-operative day 1 on a liquid diet. At 3-week follow-up, his nausea, vomiting, and PO intolerance had improved. At 6-month follow-up, he had no recent admissions for aspiration pneumonia and his pylorus remained widely patent on EGD.

Conclusions: GPOP status post-esophagectomy presented multiple challenges: difficulty maintaining field of view and insufflation, establishing tension and counter tension for the mucosotomy, and a limited working space. With care and patience, endoscopists trained to perform POEM may apply their skillset to help a large population of patients suffering with post-esophagectomy gastroparesis.
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http://dx.doi.org/10.1007/s11605-019-04418-3DOI Listing
March 2020

Utilization of a Novel Program-Specific Evaluation Tool Results in a Decidedly Different Interview Pool Than Traditional Application Review.

J Surg Educ 2019 Nov - Dec;76(6):e110-e117. Epub 2019 Oct 23.

University Hospitals Cleveland Medical Center, Cleveland, Ohio. Electronic address:

Background: There are almost twice as many applicants as there are general surgery internships, each utilizing a common application with standard components. These elements are frequently not useful in determining affinity for a program or overall ability, and resultant poor fit may be partially responsible for program attrition. Alternative evaluation instruments would be beneficial to both programs and applicants.

Methods: An application review committee comprised of resident representatives, faculty representing all program-affiliated institutions, and program leadership completed a written evaluation developed by a third party (SurgWise Consulting) that specializes in industrial and organizational psychology. The responses were compiled to create a standardized assessment tool. This assessment was sent to applicants who were subsequently ranked according to fit with our program. The pool of applicants was separately evaluated using our traditional application review. Two residents independently graded each applicant on a 5-point Likert scale to evaluate common application elements; applicants were subsequently assigned an overall score.

Results: The assessment was completed by 507 (99%) of 512 qualifying applicants. Separately, 378 applications were reviewed by the traditional method for a total of 756 reviews. Of the 96 applicants identified by the assessment tool to invite for interviews, 22 (23%) qualified for interview invitations according to the traditional review method. The assessment produced 74 applicants that otherwise would not have been interviewed.

Conclusion: Traditional application review strategies have many shortcomings. A competency-based assessment tool in the residency application selection process identifies a pool of applicants not identified by traditional review methods.
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http://dx.doi.org/10.1016/j.jsurg.2019.10.007DOI Listing
December 2020

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Cell Rep 2019 10;29(4):889-903.e10

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address:

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.
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http://dx.doi.org/10.1016/j.celrep.2019.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874102PMC
October 2019

Post-POEM reflux: who's at risk?

Surg Endosc 2020 Jul 18;34(7):3163-3168. Epub 2019 Oct 18.

Department of Surgery, Case Western Reserve University/University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Lakeside Building, 7th Floor, Cleveland, OH, 44106, USA.

Introduction: Per-Oral Endoscopic Myotomy (POEM) is a less invasive alternative to laparoscopic Heller myotomy for patients with achalasia. While a partial fundoplication is often performed concurrently with laparoscopic myotomy, an endoscopic approach does not offer this and leaves patients prone to post-operative reflux. The objectives of this study were to (1) identify patients with post-POEM reflux using BRAVO pH and endoscopic evaluations, and (2) investigate risk factors associated with post-POEM reflux and esophagitis to optimize patient selection for POEM and identify those who will benefit from a proactive approach to post-operative reflux management.

Methods: A retrospective review of a prospectively collected database of patients who underwent POEM between January 2011 and July 2017 at a single institution was performed. Demographics along with pre-POEM and post-POEM variables were obtained. Univariate and multivariate analyses were performed, using p values ≤ 0.05 for statistical significance.

Results: Forty-six patients were included, with a mean follow-up of 358 days. Mean age was 58 (19.2); 61% were female. Thirty-six patients underwent 48-h BRAVO pH testing after POEM, which revealed abnormal esophageal acid exposure in 15 patients (41.7%). There was a correlation between positive BRAVO results and presence of preoperative esophagitis (p = 0.02). Only 13% of patients had symptom-related reflux episodes based on the Symptom Associated Probability of the BRAVO study. Post-operative endoscopy revealed 6 patients with esophagitis, compared to 4 patients who had esophagitis on preoperative endoscopy. Only higher preoperative Eckardt score was significantly associated with endoscopic evidence of esophagitis post-POEM.

Conclusions: Reflux is common after POEM. A majority of patients with a positive BRAVO study are asymptomatic, which is concerning. Objective follow-up is of paramount importance with upper endoscopy and ambulatory pH monitoring being the gold standard. Elevated preoperative Eckardt score and esophagitis are associated with post-POEM reflux. This population warrants close surveillance.
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http://dx.doi.org/10.1007/s00464-019-07086-1DOI Listing
July 2020

Prediction of Upstaged Ductal Carcinoma In Situ Using Forced Labeling and Domain Adaptation.

IEEE Trans Biomed Eng 2020 06 9;67(6):1565-1572. Epub 2019 Sep 9.

Objective: The goal of this study is to use adjunctive classes to improve a predictive model whose performance is limited by the common problems of small numbers of primary cases, high feature dimensionality, and poor class separability. Specifically, our clinical task is to use mammographic features to predict whether ductal carcinoma in situ (DCIS) identified at needle core biopsy will be later upstaged or shown to contain invasive breast cancer.

Methods: To improve the prediction of pure DCIS (negative) versus upstaged DCIS (positive) cases, this study considers the adjunctive roles of two related classes: atypical ductal hyperplasia (ADH), a non-cancer type of breast abnormity, and invasive ductal carcinoma (IDC), with 113 computer vision based mammographic features extracted from each case. To improve the baseline Model A's classification of pure vs. upstaged DCIS, we designed three different strategies (Models B, C, D) with different ways of embedding features or inputs.

Results: Based on ROC analysis, the baseline Model A performed with AUC of 0.614 (95% CI, 0.496-0.733). All three new models performed better than the baseline, with domain adaptation (Model D) performing the best with an AUC of 0.697 (95% CI, 0.595-0.797).

Conclusion: We improved the prediction performance of DCIS upstaging by embedding two related pathology classes in different training phases.

Significance: The three new strategies of embedding related class data all outperformed the baseline model, thus demonstrating not only feature similarities among these different classes, but also the potential for improving classification by using other related classes.
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http://dx.doi.org/10.1109/TBME.2019.2940195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757748PMC
June 2020

Benign Prostatic Hyperplasia and Lower Urinary Tract Symptoms: What Is the Role and Significance of Inflammation?

Curr Urol Rep 2019 Aug 3;20(9):54. Epub 2019 Aug 3.

Department of Urology, Wisconsin Institutes for Medical Research, University of Wisconsin, 1111 Highland Avenue, Madison, WI, 53705, USA.

Purpose Of Review: The purpose of this review is to summarize the role and significance of inflammation as a putative additional factor contributing to lower urinary tract symptoms and the progression of benign prostatic hyperplasia. We review (1) the histologic definition of prostatic inflammation and its prevalence, (2) the effects inflammation in the prostate including on risk of acute urinary retention, and (3) the effects of systemic inflammation on the prostate and on voiding.

Recent Findings: Inflammation is a highly prevalent finding in the prostate, both on a histological and biochemical level. Men with inflammation have higher IPSS scores and increased prostate size; however, these differences appear to be imperceptibly small. Men with inflammation do experience a significantly increased risk of developing acute urinary retention, an event that is associated with significant morbidity. Recently, attempts have been made to identify more specific biochemical markers of local inflammation, and to identify regional patterns of inflamed tissue within the prostate which may be associated with higher IPSS scores, accelerated progression, and AUR. The effects of systemic inflammatory states, most notably MetS, and their role in LUTS have also been examined. Inflammation is a common finding in prostates of aging men, but its contribution to lower urinary tract symptoms and benign prostatic hyperplasia progression appears to be small when considered as a clinically relevant entity. Advances in the understanding of different forms of inflammation, and their impact when experienced in different locations within the prostate, may refine this knowledge. Systemic inflammation affects voiding, including in the absence of a prostate, but again significant effects of systemic inflammation on the prostate itself are also difficult to demonstrate. Prostatic inflammation is associated with a significantly increased risk of acute urinary retention.
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http://dx.doi.org/10.1007/s11934-019-0917-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339114PMC
August 2019

Side by side or stent within stent: the beauty is in the eye of the beholder.

Gastrointest Endosc 2019 08;90(2):231-232

University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1016/j.gie.2019.05.020DOI Listing
August 2019

Multicenter Evaluation of Clinical Efficacy and Safety of Per-oral Endoscopic Myotomy in Children.

J Pediatr Gastroenterol Nutr 2019 11;69(5):523-527

Gastroenterology, Edouard Herriot Hospital, Hospices Civils de Lyon and Lyon University, Lyon, France.

Objectives: Per-oral endoscopic myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children.

Methods: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes, such as clinical response were assessed whenever available. Adverse events and factors associated with clinical failure were also investigated.

Results: A total of 117 patients (mean ± SD age: 14.2 ± 3.7 years) underwent POEM for achalasia (type I, n = 36; type II n=66; type III, n=8). Among these, 30 (26%) were pretreated (botulinum injection and/or pneumatic dilatation). Mean ± SD baseline Eckardt score was 7.5 ± 2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean ± SD Eckardt score post-POEM was 0.9 ± 1.2 (P < 0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% vs 8%, P = 0.069).

Conclusions: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.
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http://dx.doi.org/10.1097/MPG.0000000000002432DOI Listing
November 2019

Decline of open surgical experience for general surgery residents.

Surg Endosc 2020 02 10;34(2):967-972. Epub 2019 Jun 10.

Department of Surgery, University Hospitals, Cleveland Medical Center, Cleveland, OH, USA.

Background: Minimally invasive surgery is now preferred to open in many surgical procedures. This has led to changes in training to ensure skills acquisition and education in minimally invasive technique. There have been limited data regarding the effect of the number of open procedures being performed in training. The aim of this paper is to examine the relationship in trends for open and laparoscopic procedures performed by general surgery residents.

Methods: A retrospective review of the Accreditation Council for Graduate Medical Education publicly available resident case log statistical reports for the academic years from 1999-2000 to 2017-2018 was performed for laparoscopic and open anti-reflux surgery, appendectomy, colectomy, splenectomy, and inguinal hernia repair. The data were grouped by time period and compared to evaluate changes in operative patterns.

Results: The mean number for all (open and MIS) of the selected procedures increased from 159.1 in 2000 to 223.8 in 2018 (40.7%). The mean number of laparoscopic cases increased from 23.6 to 135.6 (462%), and open decreased from 135.5 to 88.2 (- 34.9%). There was a significant decrease in the average number of open procedures performed in each period among anti-reflux operations (3.4, 1.8, 1.5, 0.7, p < 0.01), appendectomy (30.7, 23.4, 13.6, 6.8, p < 0.01), and splenectomy (3.0, 2.0, 1.6, 1.4, p < 0.05); the number of open colectomies decreased significantly from Period 2 to Period 4 (46.1, 38.5, 33.4, p < 0.02). There was a significant increase in the number of laparoscopic procedures performed in each period among appendectomy (13.1, 28.3, 48.9, 58.4, all p < 0.02), colectomy (2.9, 10.1, 19.1, 23.4, all p < 0.01), and inguinal hernia repair (9.7, 14.9, 25.6, 34.1, all p < 0.01).

Conclusion: The number of open procedures performed by general surgery residents continues to decline despite an increase in total cases reported. The reduction in open surgical experience may result in surgeons who lack technical skills to safely complete open procedures.
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http://dx.doi.org/10.1007/s00464-019-06881-0DOI Listing
February 2020

Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

Nat Immunol 2019 07 3;20(7):835-851. Epub 2019 Jun 3.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
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http://dx.doi.org/10.1038/s41590-019-0400-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619502PMC
July 2019

ASGE EndoVators Summit: simulators and the future of endoscopic training.

Gastrointest Endosc 2019 07 20;90(1):13-26. Epub 2019 May 20.

Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, Ohio.

Interest in the use of simulation for acquiring, maintaining, and assessing skills in GI endoscopy has grown over the past decade, as evidenced by recent American Society for Gastrointestinal Endoscopy (ASGE) guidelines encouraging the use of endoscopy simulation training and its incorporation into training standards by a key accreditation organization. An EndoVators Summit, partially supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, (NIH) was held at the ASGE Institute for Training and Technology from November 19 to 20, 2017. The summit brought together over 70 thought leaders in simulation research and simulator development and key decision makers from industry. Proceedings opened with a historical review of the role of simulation in medicine and an outline of priority areas related to the emerging role of simulation training within medicine broadly. Subsequent sessions addressed the summit's purposes: to review the current state of endoscopy simulation and the role it could play in endoscopic training, to define the role and value of simulators in the future of endoscopic training and to reach consensus regarding priority areas for simulation-related education and research and simulator development. This white paper provides an overview of the central points raised by presenters, synthesizes the discussions on the key issues under consideration, and outlines actionable items and/or areas of consensus reached by summit participants and society leadership pertinent to each session. The goal was to provide a working roadmap for the developers of simulators, the investigators who strive to define the optimal use of endoscopy-related simulation and assess its impact on educational outcomes and health care quality, and the educators who seek to enhance integration of simulation into training and practice.
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http://dx.doi.org/10.1016/j.gie.2018.10.031DOI Listing
July 2019

Cyclodextrin Polymer Preserves Sirolimus Activity and Local Persistence for Antifibrotic Delivery over the Time Course of Wound Healing.

Mol Pharm 2019 04 26;16(4):1766-1774. Epub 2019 Feb 26.

Department of Biomedical Engineering , Case Western Reserve University , 10900 Euclid Avenue , Cleveland , Ohio 44106 , United States.

Fibrosis and dysphagic stricture of the esophagus is a major unaddressed problem often accompanying endoscopic removal of esophageal cancers and precancerous lesions. While weekly injections of antiproliferative agents show potential for improved healing, repeated injections are unlikely clinically and may alternatively be replaced by creating an esophageal drug delivery system. Affinity-based polymers have previously shown success for continuous delivery of small molecules for weeks to months. Herein, we explored the potential of an affinity-based microparticle to provide long-term release of an antiproliferative drug, sirolimus. In molecular docking simulations and surface plasmon resonance experiments, sirolimus was found to have suitable affinity for beta-cyclodextrin, while dextran, as a low affinity control, was validated. Polymerized beta-cyclodextrin microparticles exhibited 30 consecutive days of delivery of sirolimus during in vitro release studies. In total, the polymerized beta-cyclodextrin microparticles released 36.9 mg of sirolimus per milligram of polymer after one month of incubation in vitro. Taking daily drug release aliquots and applying them to PT-K75 porcine mucosal fibroblasts, we observed that cyclodextrin microparticle delivery preserved bioactivity of sirolimus inhibiting proliferation by 27-67% and migration of fibroblasts by 28-100% of buffer treated controls in vitro. Testing for esophageal injection site losses, no significant loss was incurred under simulated saliva flow for 10 min, and 16.7% of fluorescently labeled polymerized cyclodextrin microparticle signal was retained at 28 days after submucosal injection in esophageal tissue ex vivo versus only 4% of the initial amount remaining for free dye molecules injected alone. By combining affinity-based drug delivery for continuous long-term release with a microparticle platform that is injectable yet remains localized in tissue interstitium, this combination platform demonstrates promise for preventing esophageal fibrosis and stricture.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00144DOI Listing
April 2019

BCG Renal Granuloma.

Urology 2019 May 8;127:e10. Epub 2019 Feb 8.

Denver Veterans Affairs Medical Center, Aurora, CO.

A 66-year-old man with a history of recurrent urothelial carcinoma in situ treated with endoscopic resection and induction Bacillus Calmette-Guerin (BCG) developed a new renal mass on surveillance computerized tomography and was referred to our institution for surgery. Biopsy was performed and pathology showed BCG granuloma. The patient was clinically asymptomatic. No surgical intervention was required. This is a rare entity in those undergoing intravesical BCG therapy. To avoid unnecessary surgery, a careful patient history and judicious use of renal mass biopsy is critical.
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http://dx.doi.org/10.1016/j.urology.2019.01.026DOI Listing
May 2019

Association of distant recurrence-free survival with algorithmically extracted MRI characteristics in breast cancer.

J Magn Reson Imaging 2019 06 22;49(7):e231-e240. Epub 2019 Jan 22.

Department of Radiology, Duke University School of Medicine, Durham, North Carolina, USA.

Background: While important in diagnosis of breast cancer, the scientific assessment of the role of imaging in prognosis of outcomes and treatment planning is limited.

Purpose: To evaluate the potential of using quantitative imaging variables for stratifying risk of distant recurrence in breast cancer patients.

Study Type: Retrospective.

Population: In all, 892 female invasive breast cancer patients.

Sequence: Dynamic contrast-enhanced MRI with field strength 1.5 T and 3 T.

Assessment: Computer vision algorithms were applied to extract a comprehensive set of 529 imaging features quantifying size, shape, enhancement patterns, and heterogeneity of the tumors and the surrounding tissue. Using a development set with 446 cases, we selected 20 imaging features with high prognostic value.

Statistical Tests: We evaluated the imaging features using an independent test set with 446 cases. The principal statistical measure was a concordance index between individual imaging features and patient distant recurrence-free survival (DRFS).

Results: The strongest association with DRFS that persisted after controlling for known prognostic clinical and pathology variables was found for signal enhancement ratio (SER) partial tumor volume (concordance index [C] = 0.768, 95% confidence interval [CI]: 0.679-0.856), tumor major axis length (C = 0.742, 95% CI: 0.650-0.834), kurtosis of the SER map within tumor (C = 0.640, 95% CI: 0.521-0.760), tumor cluster shade (C = 0.313, 95% CI: 0.216-0.410), and washin rate information measure of correlation (C = 0.702, 95% CI: 0.601-0.803).

Data Conclusion: Quantitative assessment of breast cancer features seen in a routine breast MRI might be able to be used for assessment of risk of distant recurrence.

Level Of Evidence: 4 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2019.
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http://dx.doi.org/10.1002/jmri.26648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551277PMC
June 2019

LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition.

Cell Res 2019 04 10;29(4):286-304. Epub 2019 Jan 10.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Despite the structural conservation of PTEN with dual-specificity phosphatases, there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase activity. Here, we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase activity. Mechanistically, high glucose, TGF-β, CTGF, SHH, and IL-6 induce the expression of a long non-coding RNA, GAEA (Glucose Aroused for EMT Activation), which associates with an RNA-binding E3 ligase, MEX3C, and enhances its enzymatic activity, leading to the K27-linked polyubiquitination of PTEN. The MEX3C-catalyzed PTEN activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity. With this altered enzymatic activity, PTEN dephosphorylates the phosphoserine/threonine residues of TWIST1, SNAI1, and YAP1, leading to accumulation of these master regulators of EMT. Animals with genetic inhibition of PTEN, by a single nucleotide mutation generated using CRISPR/Cas9 (Pten), exhibit inhibition of EMT markers during mammary gland morphogenesis in pregnancy/lactation and during cutaneous wound healing processes. Our findings illustrate an unexpected paradigm in which the lncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development.
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http://dx.doi.org/10.1038/s41422-018-0134-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461864PMC
April 2019