Publications by authors named "Grace E Kim"

103 Publications

Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.

Pancreatology 2021 Oct 28. Epub 2021 Oct 28.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN.

Methods: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups.

Results: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively).

Conclusions: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.
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http://dx.doi.org/10.1016/j.pan.2021.10.005DOI Listing
October 2021

Dysphagia in MEN.

Gastroenterology 2021 Oct 21. Epub 2021 Oct 21.

Center for Endoscopic Research and Therapeutics, Section of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, University of Chicago, Chicago, IL.

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http://dx.doi.org/10.1053/j.gastro.2021.10.021DOI Listing
October 2021

Durable virological response and functional cure of chronic hepatitis D after long-term peginterferon therapy.

Aliment Pharmacol Ther 2021 07 28;54(2):176-182. Epub 2021 May 28.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Hepatitis delta virus (HDV) infection is the most aggressive form of chronic viral hepatitis. Response rates to therapy with 1- to 2-year courses of pegylated interferon alpha (peginterferon) treatment are suboptimal.

Aims: To evaluate the long-term outcomes of patients with chronic hepatitis D after an extended course of peginterferon.

Methods: Patients were followed after completion of trial NCT00023322 and classified based on virological response defined as loss of detectable serum HDV RNA at last follow-up. During extended follow-up, survival and liver-related events were recorded.

Results: All 12 patients who received more than 6 months of peginterferon in the original study were included in this analysis. The cohort was mostly white (83%) and male (92%) and ranged in age from 18 to 58 years (mean = 42.6). Most patients had advanced but compensated liver disease at baseline, a median HBV DNA level of 536 IU per mL and median HDV RNA level of 6.86 log genome equivalents per mL. The treatment duration averaged 6.1 years (range 0.8-14.3) with a total follow-up of 8.8 years (range 1.7-17.6). At last follow-up, seven (58%) patients had durable undetectable HDV RNA in serum, and four (33%) cleared HBsAg. Overall, one of seven (14%) responders died or had a liver-related event vs four of five (80%) non-responders.

Conclusions: With further follow-up, an extended course of peginterferon therapy was found to result in sustained clearance of HDV RNA and favourable clinical outcomes in more than half of patients and loss of HBsAg in a third.
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http://dx.doi.org/10.1111/apt.16408DOI Listing
July 2021

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis.

J Pediatr Gastroenterol Nutr 2021 08;73(2):169-177

Texas Children's Hospital, Baylor College of Medicine, Houston, TX.

Objectives: To advance our understanding of monogenic forms of intrahepatic cholestasis.

Methods: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.

Results: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.

Conclusions: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.
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http://dx.doi.org/10.1097/MPG.0000000000003153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373673PMC
August 2021

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree.

Elife 2021 05 19;10. Epub 2021 May 19.

Diabetes Center, University of California, San Francisco, San Francisco, United States.

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
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http://dx.doi.org/10.7554/eLife.67776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184217PMC
May 2021

Towards a More Standardized Approach to Pathologic Reporting of Pancreatoduodenectomy Specimens for Pancreatic Ductal Adenocarcinoma: Cross-continental and Cross-specialty Survey From the Pancreatobiliary Pathology Society Grossing Working Group.

Am J Surg Pathol 2021 10;45(10):1364-1373

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

In recent literature and international meetings held, it has become clear that there are significant differences regarding the definition of what constitutes as margins and how best to document the pathologic findings in pancreatic ductal adenocarcinoma. To capture the current practice, Pancreatobiliary Pathology Society (PBPS) Grossing Working Group conducted an international multispecialty survey encompassing 25 statements, regarding pathologic examination and reporting of pancreatic ductal adenocarcinoma, particularly in pancreatoduodenectomy specimens. The survey results highlighted several discordances; however, consensus/high concordance was reached for the following: (1) the pancreatic neck margin should be entirely submitted en face, and if tumor on the slide, then it is considered equivalent to R1; (2) uncinate margin should be submitted entirely and perpendicularly sectioned, and tumor distance from the uncinate margin should be reported; (3) all other surfaces (including vascular groove, posterior surface, and anterior surface) should be examined and documented; (4) carcinoma involving separately submitted celiac axis specimen should be staged as pT4. Although no consensus was achieved regarding what constitutes R1 versus R0, most participants agreed that ink on tumor or at and within 1 mm to the tumor is equivalent to R1 only in areas designated as a margin, not surface. In conclusion, this survey raises the awareness of the discordances and serves as a starting point towards further standardization of the pancreatoduodenectomy grossing and reporting protocols.
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http://dx.doi.org/10.1097/PAS.0000000000001723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446290PMC
October 2021

New-Onset of Inflammatory Bowel Disease in a Patient Treated With Teprotumumab for Thyroid Associated Ophthalmopathy.

Ophthalmic Plast Reconstr Surg 2021 Sep-Oct 01;37(5):e160-e164

Department of Ophthalmology, University of California, San Francisco, San Francisco.

A patient with thyroid-associated ophthalmopathy was treated with teprotumumab and developed symptoms concerning for inflammatory bowel disease after her sixth infusion. Colonoscopy was performed, and mucosal biopsies identified evidence of active colitis consistent with a diagnosis of ulcerative colitis. Despite treatment with budesonide and mesalamine, the patient continued to be symptomatic one and a half months after cessation of teprotumumab and required infliximab to achieve good control of her inflammatory bowel disease. This case represents the first report of new-onset inflammatory bowel disease arising during treatment with teprotumumab.
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http://dx.doi.org/10.1097/IOP.0000000000001943DOI Listing
October 2021

Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth.

Nat Cell Biol 2021 03 8;23(3):232-242. Epub 2021 Mar 8.

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.
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http://dx.doi.org/10.1038/s41556-021-00644-7DOI Listing
March 2021

Dialogs in the assessment of neonatal cholestatic liver disease.

Hum Pathol 2021 06 25;112:102-115. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA. Electronic address:

Neonatal cholestatic liver disease is rarely encountered by pathologists outside of specialized pediatric centers and navigating the long list of potential diseases can be daunting. However, the differential diagnosis can be rapidly narrowed through open conversations between the pathologist and pediatric gastroenterologist. The dialog should ideally begin before obtaining the liver biopsy and continue through the rendering of the final pathologic diagnosis. Such dialogs are necessary to first ensure the proper handling of the precious sample and then to allow for synthesis of the clinical, laboratory, imaging, and genetic data in the context of the histologic features seen in the liver biopsy. In this review, we aim to provide a broad template on which such dialogs may be based and pitfalls that may be encountered on both the clinical and pathologic sides. This review will focus on non-biliary atresia etiologies of neonatal cholestasis, including select infectious, genetic, and metabolic entities.
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http://dx.doi.org/10.1016/j.humpath.2020.12.007DOI Listing
June 2021

Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated.

Cancer 2020 11 28;126(21):4788-4799. Epub 2020 Aug 28.

Department of Pathology, Koç University School of Medicine, Istanbul, Turkey.

Background: The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established.

Methods: In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically.

Results: MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method.

Conclusions: In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.
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http://dx.doi.org/10.1002/cncr.33135DOI Listing
November 2020

A Case of Lysosomal Acid Lipase Deficiency Confirmed by Response to Sebelipase Alfa Therapy.

J Pediatr Gastroenterol Nutr 2020 12;71(6):726-730

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

Lysosomal acid lipase (LAL) deficiency, or cholesterol ester storage disease, is a disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. Clinical findings include hepatomegaly, hepatic dysfunction, and dyslipidemia with a wide range of phenotypic variability and age of onset. The available clinical and molecular information of the patient presented herein was consistent with a diagnosis of LAL deficiency, but her LAL activity assay repeatedly showed normal or borderline low results. Her response to enzyme replacement therapy and demonstrable deficiency on a newer specific enzymatic assay ultimately confirmed her diagnosis of LAL deficiency.
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http://dx.doi.org/10.1097/MPG.0000000000002870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045466PMC
December 2020

Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.

Nature 2020 05 22;581(7806):100-105. Epub 2020 Apr 22.

Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB, mutations that cause loss of MHC-I are rarely found despite the frequent downregulation of MHC-I expression. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8 T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
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http://dx.doi.org/10.1038/s41586-020-2229-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296553PMC
May 2020

Patterns of chromosome 18 loss of heterozygosity in multifocal ileal neuroendocrine tumors.

Genes Chromosomes Cancer 2020 09 27;59(9):535-539. Epub 2020 Apr 27.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Ileal neuroendocrine tumors (NETs) represent the most common neoplasm of the small intestine. Although up to 50% of patients with ileal NETs are diagnosed with multifocal disease, the mechanisms by which multifocal ileal NETs arise are not yet understood. In this study, we analyzed genome-wide sequencing data to examine patterns of copy number variation in 40 synchronous primary ileal NETs derived from three patients. Chromosome (chr) 18 loss of heterozygosity (LOH) was the most frequent copy number alteration identified; however, not all primary tumors from the same patient had evidence of this LOH. Our data revealed three distinct patterns of chr18 allelic loss, indicating that primary tumors from the same patient can present different LOH patterns including retention of either parental allele. In conclusion, our results are consistent with the model that multifocal ileal NETs originate independently. In addition, they suggest that there is no specific germline allele on chr18 that is the target of somatic LOH.
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http://dx.doi.org/10.1002/gcc.22850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384092PMC
September 2020

A novel stratification of mesenteric mass involvement as a predictor of challenging mesenteric lymph node dissection by minimally invasive approach for ileal neuroendocrine tumors.

J Surg Oncol 2020 Aug 14;122(2):204-211. Epub 2020 Apr 14.

Department of Surgery, University of California, San Francisco, San Francisco, California.

Background And Objectives: We classified the extent of mesenteric mass (MM) involvement that predicts challenging mesenteric lymph node dissection (mLND) by minimally invasive surgery (MIS) for ileal neuroendocrine tumors (i-NETs).

Methods: Patients who underwent surgery for i-NETs were retrospectively reviewed. MM involvement was classified as region-0: no MM; region-1: >2 cm from the origins of the ileocolic artery/vein; region-2: ≤2 cm from the origins; and region-3: more proximal superior mesenteric artery/vein. Logistic regression analysis was used to evaluate the predictive value of MM regions for gross positive mesenteric margin (mR2) and/or conversion among the MIS cohort. The open surgery cohort was used as a reference for mR2 rates.

Results: Of 108 patients, 83 patients (77%) underwent MIS. MMs in region-2 and region-3 were independent risk factors for mR2 and/or conversion (odds ratio [95% confidence interval]: 4.25 [1.17-16.4] and 8.51 × 10 [11.0-], respectively, against regions-0 and 1]. mR2 rates of MIS and open surgery cohorts per region did not differ significantly (4% and 7% for regions-0 and 1; 17% and 25% for region-2; and 100% and 83% for region-3).

Conclusions: The novel stratification of MM regions was predictive of challenging mLND by MIS. Surgeons should have a low threshold for conversion for MMs in proximal regions.
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http://dx.doi.org/10.1002/jso.25930DOI Listing
August 2020

A Rare Presentation of Pancreatic Lymphoepithelial Cyst: A Case Report and Review.

Case Rep Med 2020 13;2020:4590758. Epub 2020 Feb 13.

University of Maryland School of Medicine, Division of Gastroenterology and Hepatology, Baltimore, Maryland, USA.

Pancreatic lymphoepithelial cyst (LEC) is a rare, benign collection of keratinizing squamous epithelial cells encapsulated by lymphoid tissue. Because of its limited data and nonspecific features that can mimic malignant lesions, LECs can lead to unnecessary operations. A 62-year-old male with a known pancreatic mass presented with abdominal pain. CT scan showed an increased mass in the pancreatic head, and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed "rare fragments of benign-appearing squamous epithelium in a background of keratin debris, cyst contents, and scattered lymphocytes," consistent with a lymphoepithelial cyst. Pancreatic LEC is an extremely rare lesion that comprises of only 0.5% of all pancreatic cysts. EUS-FNA has become the mainstay for diagnosing pancreatic LECs. Given the slow growing and benign nature, conservative management and observation is adequate for pancreatic LECs with excellent long-term outcome. With increasing number of imaging ordered by clinicians, it is anticipated that there will be a greater number of incidental pancreatic LECs detected. Thus, EUS-FNA should be utilized more frequently to help distinguish benign pancreatic LECs from premalignant or malignant lesions to avoid surgery.
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http://dx.doi.org/10.1155/2020/4590758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040412PMC
February 2020

Spontaneous lymphocele presenting with obstructive jaundice.

Gastrointest Endosc 2020 05 19;91(5):1209-1210. Epub 2019 Dec 19.

Ohio Gastroenterology Group, Inc, Columbus, Ohio, USA; Riverside Methodist Hospital, Columbus, Ohio, USA; The Ohio State University College of Medicine, Columbus, Ohio, USA.

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http://dx.doi.org/10.1016/j.gie.2019.12.014DOI Listing
May 2020

Residual tumor volume discriminates prognosis after surgery for neuroendocrine liver metastasis.

J Surg Oncol 2019 Dec 11. Epub 2019 Dec 11.

Department of Surgery, University of California, San Francisco, San Francisco, California.

Background And Objectives: We developed objective measurements of preoperative and residual tumor volume, and debulking rate, to evaluate their prognostic value for neuroendocrine liver metastasis (NELM).

Methods: Seventy-three patients who underwent surgery for NELM were analyzed retrospectively. Indices of preoperative and postoperative residual tumor volume (pre-volume index [VI] and post-VI) were calculated as the sum of the cubes of individual tumor diameters on preoperative and postoperative imaging, respectively. The debulking rate (%) was calculated as 100 - 100 × post-VI/pre-VI. The classification and regression trees method was used to classify pre-VI and post-VI.

Results: Overall survival (OS) was discriminated by preoperative tumor volume (5-year OS rates, 87.8% for low pre-VI and 60.1% for high pre-VI; P = .037) and residual tumor volume (5-year OS rates, 88.1% for low post-VI and 24.8% for high post-VI; P < .001). In contrast, debulking rates of 100%, ≥90%, and <90% did not discriminate OS (5-year OS rates, 88.0%, 61.9%, and 58.9%, respectively, not significant). In multivariate analysis, residual tumor volume (high post-VI, hazard ratio, 6.40; 95% confidence interval, 1.45-32.3) was an independent prognostic factor for OS.

Conclusions: Objective measurement of tumor volume demonstrates that residual tumor volume is prognostic after surgery for NELM.
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http://dx.doi.org/10.1002/jso.25811DOI Listing
December 2019

Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival.

Cancer Res 2019 12 31;79(24):6190-6203. Epub 2019 Oct 31.

Department of Pathology, University of California, San Francisco, San Francisco, California.

Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress. SIGNIFICANCE: The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911642PMC
December 2019

Prognostic impact of a large mesenteric mass >2 cm in ileal neuroendocrine tumors.

J Surg Oncol 2019 Dec 15;120(8):1311-1317. Epub 2019 Oct 15.

Department of Surgery, University of California, San Francisco, California.

Background And Objectives: Ileal neuroendocrine tumors (i-NETs) frequently metastasize to mesenteric lymph nodes and the liver. Regional lymphadenopathy is associated with desmoplasia of the mesentery forming a large mesenteric mass (LMM). Although the latest American Joint Committee on Cancer TNM staging (8th edition) defined LMM >2 cm as N2, the prognostic impact of LMM is ill-defined. We evaluated whether LMM is prognostic for patients with i-NETs.

Methods: This single-institution, retrospective cohort study included 106 patients who underwent resection of i-NETs between 2007 and 2018. Overall survival (OS) and liver progression-free survival (LPFS) were compared between patients with and without LMM.

Results: LMM was present in 66 patients (62%) and was not associated with the presence or absence of liver metastasis (P = .969) or the extent of liver involvement (P = .938). OS and LPFS differed significantly between patients with and without LMM (5-year OS rates of 64.8% and 92.9%, respectively, P = .011; 3-year LPFS rates of 45.3% and 67.5%, respectively, P = .025). In multivariate analysis, LMM was an independent prognostic factor for both OS (hazard ratio: 4.69, 95% confidence interval: 1.63-17.6) and LPFS (1.99, 1.08-3.88).

Conclusion: LMM >2 cm is prognostic for OS and LPFS and represents aggressive tumor biology.
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http://dx.doi.org/10.1002/jso.25727DOI Listing
December 2019

Poorly Cohesive (Signet Ring Cell) Carcinoma of the Ampulla of Vater.

Int J Surg Pathol 2020 May 15;28(3):236-244. Epub 2019 Oct 15.

Koç University, Istanbul, Turkey.

In the ampulla of Vater, carcinomas with "diffuse-infiltrative"/"signet ring cell" morphology, designated as "poorly cohesive carcinoma" (PCC) in the WHO classification, are very rare and poorly characterized. Nine cases with a classical PCC morphology constituting >50% of the tumor were identified. Mean age was 64.8 years (vs 64.6 in ampullary carcinomas [ACs]) and 6 were males, 3 females. The mean invasive tumor size was 2.5 cm (vs 1.9 in ACs). Other morphologic patterns displayed included cord-like infiltration (n=2), plasmacytoid cells (n=2), and microglandular component (n=4), including goblet cell adenocarcinoma-like foci. None of the cases were associated with dysplasia. By immunohistochemistry, the carcinomas did not show intestinal differentiation (CDX2 0/9, CK20 1/9, MUC2 3/9), MUC1 was positive in 4/9, MUC5AC was positive in 7/8. E-cadherin loss was noted in 4/9. All cases were advanced stage (6/9-pT3, 3/9-pT4) (vs 43% in ACs). Lymph node metastases were identified in 44% (vs 45% in AC). Six patients (67%) died of disease at a median of 25 months, 3 were alive at 13, 15, and 60 months. Overall median survival was significantly worse than that of intestinal-type ACs (26 vs 122 months, = .006) and trended toward worse than pancreatobiliary type (26 vs 42 months, = .1). In conclusion, PCCs constitute 2.45% of all ACs. These present as advanced tumors and express upper-gastrointestinal immunoprofile with frequent MUC5AC labeling, which may be helpful in identifying subtle infiltration in the surface mucosa since MUC5AC is not expressed in the ampullary mucosa. Patients have poor prognosis.
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http://dx.doi.org/10.1177/1066896919880968DOI Listing
May 2020

A practical approach to the pathology of neonatal cholestatic liver disease.

Semin Diagn Pathol 2019 Nov 26;36(6):375-388. Epub 2019 Jul 26.

Department of Pathology, University of California San Francisco, San Francisco, CA United States. Electronic address:

Navigating the complexities of interpreting a liver biopsy performed on a neonate with conjugated/direct hyperbilirubinemia can be an arduous task given these biopsies are infrequently encountered. The list of entities is long and yet there are only a few histologic patterns of liver injury. The first step for the pathologist is to determine the histologic pattern, which will guide further inquiry into the useful clinical information to have while evaluating the biopsy. Ultimately, the goal is to identify those conditions that will benefit from early intervention. We begin with a review of biliary development to help understand what findings may be physiologic versus pathologic, particularly in premature infants. Then we review eight cases that cover the three most common histologic patterns of injury in patients with neonatal cholestasis: biliary obstructive, neonatal hepatitis, and paucity of intrahepatic bile ducts. The entities that serve as prototypes for these histologic patterns are covered, including biliary atresia, idiopathic neonatal hepatitis, and Alagille syndrome, along with rarer entities that have histologic overlap. The cases with accompanying tables and algorithms are intended to help place the histologic findings in the context of the overall clinical work-up, including genetic testing.
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http://dx.doi.org/10.1053/j.semdp.2019.07.004DOI Listing
November 2019

Recognizing intrapancreatic accessory spleen via EUS: Interobserver variability.

Endosc Ultrasound 2019 Nov-Dec;8(6):392-397

Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA.

Background And Objective: Accessory spleen (AS) may be encountered as an intrapancreatic lesion on EUS. This can look similar to other pancreatic pathologies and may lead to unnecessary interventions. The goal of this study was to evaluate the accuracy of EUS in distinguishing intrapancreatic AS (IPAS) from other pancreatic lesions.

Materials And Methods: Twelve sets of endoscopic images of the spleen and various pancreatic lesions confirmed on histology or cytology were gathered. Ten endosonographers were asked to characterize and identify the lesions. The responses were analyzed via Excel and the interobserver agreement was analyzed using Gwet's agreement coefficient statistic via Stata I/C v15.

Results: In our sample, the interobserver agreement was 0.37 (-+1-1; 0-0.2 poor, 0.2-0.4 fair, 0.4-0.6 moderate, 0.6-0.8 substantial, and 0.8-1.0 almost perfect) for determining whether or not the pancreatic lesion is IPAS. The reviewers were able to correctly determine IPAS endosonographically with a sensitivity of 77%, specificity of 74%, and positive and negative predictive values of 50% and 92%, respectively.

Conclusion: There is a moderate-to-substantial interobserver agreement in describing the sonographic characteristics of the pancreatic lesions, such as the shape, echogenicity compared to spleen, echotexture, and border of the lesions. However, the interobserver agreement is only fair when deciding if the pancreatic lesion is an IPAS. The similar profile of IPAS and pancreatic neuroendocrine tumor could confound the diagnosis of IPAS, thus contributing to the decreased interobserver agreement. This study demonstrates that EUS criteria alone are not accurate for IPAS diagnosis. Fine-needle aspiration (FNA) may be required for a confirmatory diagnosis.
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http://dx.doi.org/10.4103/eus.eus_35_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927143PMC
August 2019

Pancreatic Non-Hodgkin Lymphoma Presenting as Pancreatitis and Duodenal Polyps in a Pediatric Patient.

J Pediatr Gastroenterol Nutr 2019 11;69(5):e146-e147

The Ohio State University College of Medicine.

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http://dx.doi.org/10.1097/MPG.0000000000002463DOI Listing
November 2019

DNA flow cytometric and interobserver study of crypt cell atypia in inflammatory bowel disease.

Histopathology 2019 Oct 13;75(4):578-588. Epub 2019 Aug 13.

Department of Pathology, University of California at San Francisco, San Francisco, CA, USA.

Aims: The pathological features and diagnostic reliability of crypt cell atypia (CCA) arising in inflammatory bowel disease (IBD) and its clinical significance are unknown.

Methods And Results: DNA flow cytometry (FCM) was performed on 14 colon biopsies of CCA from seven IBD patients (male-to-female ratio, 5:2; mean age, 53 years; mean IBD duration, 15 years) using paraffin-embedded tissue. Seven gastrointestinal pathologists were asked to diagnose each biopsy as negative for dysplasia (NEG), indefinite for dysplasia (IND), low-grade dysplasia (LGD) or high-grade dysplasia (HGD) by morphology alone, then again with knowledge of FCM results. Aneuploidy was detected in all 14 biopsies, and five of eight biopsies (63%) also showed strong and diffuse nuclear staining for p53 in the areas of CCA. Six (86%) patients developed HGD (n = 5) or adenocarcinoma (n = 1) in the same colonic segment where CCA had been diagnosed within a mean follow-up time of 27 months. No follow-up information was available in the remaining one patient. When diagnoses were grouped as NEG or 'atypical' (including IND, LGD or HGD), the overall agreement rate of 76% (kappa = 0.51) based on morphology alone improved to 90% (kappa = 0.81) with knowledge of FCM results. Even when categorised as NEG or dysplasia (LGD or HGD) with each of the IND diagnoses reclassified into three categories (NEG, LGD or HGD) based on the degree of suspicion for dysplasia, the overall agreement rate of 63% (kappa = 0.25) based on morphology alone improved to 73% (kappa = 0.46) with knowledge of FCM results. However, when grouped as NEG, LGD or HGD, the overall agreement rate was less than 40% (kappa < 0.09) regardless of knowledge of FCM results.

Conclusions: The presence of aneuploidy, p53 positivity and development of HGD or adenocarcinoma on follow-up indicate that CCA likely represents a dysplastic lesion (at least LGD) and is a histological marker of neoplastic progression. Although the grading of CCA, largely based on cytological abnormalities, is subject to significant interobserver variability, CCA can be histologically identified and should lead to a recommendation of increased endoscopic surveillance, especially if aneuploidy is detected.
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http://dx.doi.org/10.1111/his.13923DOI Listing
October 2019

CholedochoClip: A Case of Obstructive Jaundice 14 Years after Cholecystectomy.

Case Rep Gastrointest Med 2019 19;2019:8038469. Epub 2019 Mar 19.

Department of Internal Medicine, University of Maryland Medical Center, Baltimore, MD 21201, USA.

Gallstone disease is a common gastrointestinal pathology that may result in surgical intervention. While cholecystectomy has relatively minimal risks, surgical clip migration is a rare complication that can cause severe morbidity and mortality. This report describes a rare phenomenon of a biliary stone forming onto a migrated surgical clip 14 years after cholecystectomy causing an obstructive jaundice. This case illustrates the importance of keeping a migrated surgical clip on the differential when encountering patients with symptoms of cholangitis after cholecystectomy.
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http://dx.doi.org/10.1155/2019/8038469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444230PMC
March 2019

Diagnosis, risk stratification, and management of ampullary dysplasia by DNA flow cytometric analysis of paraffin-embedded tissue.

Mod Pathol 2019 09 11;32(9):1291-1302. Epub 2019 Apr 11.

Department of Pathology, University of California at San Francisco, San Francisco, CA, 94143, USA.

The limited accuracy of endoscopic biopsy in detecting high-grade dysplasia or adenocarcinoma within ampullary adenoma or dysplasia has been reported. The natural history of ampullary dysplasia is also unclear, and there are no established guidelines to determine which patients with ampullary dysplasia require resection versus surveillance endoscopy. DNA flow cytometry was performed on 47 ampullary biopsies with low-grade dysplasia, 18 high-grade dysplasia, and 23 negative for dysplasia, as well as 11 cases of ampullary adenocarcinoma. Abnormal DNA content (aneuploidy or elevated 4N fraction > 6%) was identified in 9 (82%) of adenocarcinoma, 13 (72%) of high-grade dysplasia, 7 (15%) of low-grade dysplasia, and none (0%) of non-dysplastic mucosa. One-, 2-, and 7-year detection rates of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with abnormal DNA content were 57%, 86%, and 88%, respectively, whereas low-grade dysplasia patients in the setting of normal DNA content had 1-, 2-, and 7-year detection rates of 10%, 10%, and 10%, respectively. The univariate and multivariate hazard ratios (HRs) for subsequent detection of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with DNA content abnormality were 16.8 (p = <0.01) and 9.8 (p = <0.01), respectively. Among the 13 high-grade dysplasia patients with DNA content abnormality, 5 patients (38%) were subsequently found to have adenocarcinoma within a mean follow-up time of 3 months, whereas only 1 (20%) of the remaining 5 patients in the setting of normal DNA content developed adenocarcinoma in a month (HR = 2.6, p = 0.39). The overall 1- and 2-year detection rates of adenocarcinoma in all high-grade dysplasia patients (regardless of flow cytometric results) were 34% (95% confidence interval = 16-63%) and 47% (95% confidence interval = 23-79%), respectively. In conclusion, the majority of low-grade dysplasia patients (86%) in the setting of abnormal DNA content developed high-grade dysplasia or adenocarcinoma within 2 years and thus may benefit from resection, whereas those with normal DNA content may be followed with surveillance endoscopy. The presence of DNA content abnormality can also confirm a morphologic suspicion of high-grade dysplasia, which should be managed with resection, as nearly 50% of the high-grade dysplasia patients were found to have adenocarcinoma within 2 years.
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http://dx.doi.org/10.1038/s41379-019-0272-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549479PMC
September 2019

Implementation and evaluation of Stanford Health Care store-and-forward teledermatology consultation workflow built within an existing electronic health record system.

J Telemed Telecare 2020 04 9;26(3):125-131. Epub 2018 Oct 9.

Department of Dermatology, Stanford School of Medicine, Stanford, CA, USA.

Introduction: Teledermatology services that function separately from patients’ primary electronic health record (EHR) can lead to fragmented care, poor provider communication, privacy concerns and billing challenges. This study addresses these challenges by developing PhotoCareMD, a store-and-forward (SAF) teledermatology consultation workflow built entirely within an existing Epic-based EHR.

Methods: Thirty-six primary care physicians (PCPs) from eight outpatient clinics submitted 215 electronic consults (eConsults) for 211 patients to a Stanford Health Care dermatologist via PhotoCareMD. Comparisons were made with in-person referrals for this same dermatologist prior to initiation of PhotoCareMD.

Results: Compared to traditional in-person dermatology clinic visits, eConsults decreased the time to diagnosis and treatment from 23 days to 16 hours. The majority (73%) of eConsults were resolved electronically. In-person referrals from PhotoCareMD (27%) had a 50% lower cancellation rate compared with traditional referrals (11% versus 22%). The average in-person visit and documentation was 25 minutes compared with 8 minutes for an eConsult. PhotoCareMD saved 13 additional clinic hours to be made available to the dermatologist over the course of the pilot. At four patients per hour, this opens 52 dermatology clinic slots. Over 96% of patients had a favourable experience and 95% felt this service saved them time. Among PCPs, 100% would recommend PhotoCareMD to their colleagues and 95% said PhotoCareMD was a helpful educational tool.

Discussion: An internal SAF teledermatology workflow can be effectively implemented to increase access to and quality of dermatologic care. Our workflow can serve as a successful model for other hospitals and specialties.
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http://dx.doi.org/10.1177/1357633X18799805DOI Listing
April 2020

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy.

J Clin Invest 2018 11 8;128(11):4997-5007. Epub 2018 Oct 8.

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.
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http://dx.doi.org/10.1172/JCI93090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205380PMC
November 2018

Genome-Informed Targeted Therapy for Osteosarcoma.

Cancer Discov 2019 01 28;9(1):46-63. Epub 2018 Sep 28.

Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, California.

Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach..
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http://dx.doi.org/10.1158/2159-8290.CD-17-1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134333PMC
January 2019

A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors.

Mol Cancer Ther 2018 12 25;17(12):2702-2709. Epub 2018 Sep 25.

Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.

Patients with pancreatic neuroendocrine tumors (PNET) commonly develop advanced disease and require systemic therapy. However, treatment options remain limited, in part, because experimental models that reliably emulate PNET disease are lacking. We therefore developed a patient-derived xenograft model of PNET (PDX-PNET), which we then used to evaluate two mTOR inhibitor drugs: FDA-approved everolimus and the investigational new drug sapanisertib. PDX-PNETs maintained a PNET morphology and PNET-specific gene expression signature with serial passage. PDX-PNETs also harbored mutations in genes previously associated with PNETs (such as and ), displayed activation of the mTOR pathway, and could be detected by Gallium-68 DOTATATE PET-CT. Treatment of PDX-PNETs with either everolimus or sapanisertib strongly inhibited growth. As seen in patients, some PDX-PNETs developed resistance to everolimus. However, sapanisertib, a more potent inhibitor of the mTOR pathway, caused tumor shrinkage in most everolimus-resistant tumors. Our PDX-PNET model is the first available, validated PDX model for PNET, and preclinical data from the use of this model suggest that sapanisertib may be an effective new treatment option for patients with PNET or everolimus-resistant PNET.
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279485PMC
December 2018
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