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XVI) Small Bowel Lymphoma
Symposium (XVI)
SMALL BOWEL LYMPHOMA
Hsu-Heng Yen Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
Although gastrointestinal (GI) tract is the most common extranodal site involved in nonHodgkin lymphoma (NHL), primary small intestinal lymphoma is a rare problem. Lymphoid neoplasms may consist of T or B cell lymphomas and less commonly extranodal NK/T cells. The presentation of these patient may be varied. With the introduction of deep enteroscopy, there has been an improvement in the diagnosis, or management of small bowel lymphomas instead of surgery alone. In this session, we present clinical, endoscopic, and radiological features of endoscopically diagnosed small bowel lymphomas from the TASSID multicenter registry study.
Symposium (XVI)
SMALL BOWEL LYMPHOMA
Chen-Shuan Chung Division of Gastroenterology and Hepatology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan Ultrasound and Endoscopy Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
Small intestinal cancers are rare malignancies compared with other parts of gastrointestinal tract. Among malignancies of small intestine, lymphoma is always ranking top 5 histology. The gold standard of diagnosis for small intestinal lymphoma is pathological immunohistochemical stain of malignant tissues. In this lecture, I will introduce the data from Taiwan Association for the Study of Small Intestinal Diseases (TASSID) about the endoscopic diagnosis of small bowel lymphoma.
Symposium (XVI)
SMALL BOWEL LYMPHOMA
Wei-Pin Lin Department of Gastroenterology and Hepatology, LinKuo Chang Gung Memorial Hospital, Taoyuan, Taiwan
Traditionally, chemotherapy has been important for management of GI lymphoma, with surgical resection being recommended only under specific circumstances; however, many authors have advocated a combination of surgery and chemotherapy to improve overall survival. Base on TASSID data, after the era of enteroscopy, since the enteroscopy has the ability for tissue sampling, most cases (45/67) received chemotherapy after diagnosis; less cases (15/67) received surgery and the main reason is tumor related complications: obstruction and bleeding. Age more than 65, advanced stage disease (stage III/IV) and chemotherapy alone are associated with poor prognosis; the 5-year overall survival (44%) is similar, but not superior to previous study.
Large study randomising patients to chemotherapy or surgery plus chemotherapy should be undertaken, for the best strategy of treating small bowel lymphoma.
Symposium (XVI)
SMALL BOWEL LYMPHOMA
GASTROINTESTINAL LYMPHOMA: THE NEW MIMIC
Zhi-Hua Ran Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Primary gastrointestinal lymphoma (PGIL) is a type of malignant tumor that originates from the lamina propria and submucosal lymphoid tissues of the gastrointestinal mucosa. It accounts for 1% to 8% of gastrointestinal malignant tumors. It is the most common extranodal lymphoma, which accounts for 30% to 40% of extranodal lymphoma. With the increase of microbial infections, autoimmune diseases and secondary immune dysfunction diseases, the incidence of PGIL has increased. It lacks specific clinical manifestations in the early stage and has a high rate of misdiagnosis. In Western countries, the main site of gastrointestinal lymphoma is the stomach, followed by the small intestine. A study in China have reported that PGIL sites are most common in the stomach, followed by ileocecal, ileum, colon, jejunum, rectum, and duodenum. About 1/4 of the patients have lesions involving multiple parts of the gastrointestinal tract. Macroscopically, lymphomas appear in various types, such as small lesions, large masses, polyplike features, submucosal tumor, ulcers, necrosis or perforations. Some features are similar to inflammatory bowel disease or other tumors of the digestive system, and it is often difficult to differentially diagnose. Diagnosis usually requires a combination of general morphology, microscopic features and immunophenotyping. Gastrointestinal lymphoma is dominated by B-cell non-Hodgkin lymphoma, accounting for approximately 90% of all pathological types. The most common pathological types are mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBL). T/NK cell nonHodgkin’s lymphoma accounts for approximately 10% of all gastrointestinal lymphomas, and Hodgkin’s lymphoma is rare. For early stage MALT lymphoma, remission can usually be achieved by eradicating Helicobacter pylori. For DLBL, a chemotherapy regimen combined with rituximab is usually used. The prognosis of T/NK cell lymphoma is relatively poor.
Young Investigator Award (YIA)
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SUPERIORITY OF EUS-GUIDED GASTROENTEROSTOMY OVER ENDOSCOPIC STENTING FOR PALLIATION OF MALIGNANT GASTRIC OUTLET OBSTRUCTION
Yu-Ting Kuo1,2, Weng-Fai Wong1,2 , Ming-Lun Han1,2, Chieh-Chang Chen1 , Wei-Chih Liao1, Hsiu-Po Wang1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan1 Division of Endoscopy, Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan2 針對惡性胃出口阻塞接受內視鏡超音 波指引胃腸造口術與內視鏡腸道金屬 支架置放術的長期預後比較
郭雨庭1,2 黃永輝1,2 韓明倫1,2 陳介章1 廖偉智1 王秀伯1 台大醫院消化內科1 台大醫院綜合診療部內視鏡科2
Background: Gastric outlet obstruction (GOO) in patients with malignancies causes nausea, vomiting, abdominal pain, malnutrition, and dehydration. EUS-guided gastroenterostomy (EUS-GE) is a novel procedure for palliation of malignant GOO; however, data comparing EUSGE to endoscopic placement of self-expandable metallic stent (SEMS) are limited. Aims: We aimed to compare clinical outcomes between EUS-GE and endoscopic SEMS placement in the palliation of malignant GOO. Methods: We performed a retrospective analysis of patients with malignant GOO who underwent endoscopic SEMS placement (n = 48) or EUSGE (n = 19) from January 2019 through July 2021 at National Taiwan University Hospital. Primary outcome was the rate of stent failure requiring repeat intervention. Secondary outcomes included technical and clinical success, time to repeat intervention, length of hospital stay, and adverse events. We performed multivariable analyses to identify factors associated with survival. Results: Rate of stent failure requiring repeat intervention was higher in the endoscopic SEMS group than the EUS-GE group (37.5% vs. 5.3%, p = 0.047). Proportions of patients with clinical success did not differ significantly between the SMES group (97.9%) and the gastrojejunostomy group (100%) (P = 1). The median length of hospital stay following stent placement was higher in the endoscopic SEMS group than the EUSGE group (11.5 days vs. 5 days, p = 0.014). The endoscopic SEMS group significantly increased adverse events (39.6% vs. 5.3%, p = 0.044). Poor performance status, presence of ascites, low albumin and distal metastasis were independent risk factors for mortality. Conclusions: Compared to endoscopic SEMS placement, EUS-GE has a higher rate of initial clinical success and lower rate of stent failure requiring repeat intervention. EUS-GE should therefore be considered the alternative treatment option for patients with good performance status and reasonable survival expectancy.
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MACROSCOPIC ON-SITE EVALUATION NO LONGER NEEDED IN FINE NEEDLE BIOPSY ERA
Meng-Ying Lin1, Chun-Te Lee1 , Wei-Lun Chang1, Bor-Shyang Sheu1,2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nation Cheng Kung University Hospital, Tainan, Taiwan1 Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan2 在內視鏡超音波導引胰臟腫瘤組織取 樣中使用切片針具時，及時宏觀分析法 將不再被需要
林孟穎1 李俊德1 張維倫1 許博翔1,2 國立成功大學醫學院附設醫院內科部胃腸肝膽科1 高雄醫學大學醫學系臨床醫學研究所2
Background: EUS-guided fine needle biopsy is standard procedure in diagnosing pancreatic mass. Macroscopic on-site evaluation (MOSE) significantly improved diagnostic efficacy and replaced microscopic on-site evaluation in area without on-site cytopathologist. Biopsy needle had been designed with better tissue quality recently. Aims: We aim to test if MOSE is no longer needed while applying biopsy needles in EUS pancreatic tissue acquisition. Methods: Patients received EUS tissue acquisition of pancreatic mass from January 2020 to May 2021 in National Cheng Kung University Hospital were included. Every patient had 2 needle passes and the acquired tissue was sent to histology review separately. In MOSE group, white tissue was picked up from red tissue then put into different formalin bottles and sent for histology diagnosis separately. In no MOSE group, specimen was not separated and sent for diagnosis together. The baseline character and diagnostic performance in each group was recorded and analysis. Results: A total 100 patients were finally enrolled. The first 50 patients were included into No MOSE group and the other 50 patients were included into MOSE group. The baseline character was similar between groups except tumor size. (33.3 mm v.s 38.4 mm, p = 0.03) In MOSE group, 100 % specimen had adequate white tissue length and the diagnostic consistency rate between white tissue and red tissue was 80 %. The overall diagnostic sensitivity and accuracy within 2 needle passes were the same while compare between MOSE group to no MOSE group. (85.4% v.s 93.6%, p = 0.317 & 86.0% v.s 94.0%, p = 0.318) Conclusions: Using biopsy needle in EUS tissue acquisition, all specimens had enough white tissue length and high diagnostic consistency. The diagnostic performance was also similar no matter applied MOSE or not.
③
Ming-Tsung Hsieh1, Chung-Tai Wu1 , Wei-Lun Chang1, Hsin-Yu Kuo1 , Meng-Ying Lin1, Yu-Chin Tsai1 , Bor-Shyang Sheu1,2 Division of Gastroenterology and Hepatobiliary, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan1 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan2 針對多重抗藥性幽門桿菌感染的抗生 素救援療法，採用下修後 Amoxicillin 和 Tetracycline 最小有效濃度有效提 升救援療法療效
謝名宗1 吳忠泰1 張維倫1 郭欣瑜1 林孟穎1 蔡郁清1 許博翔1,2 國立成功大學醫學院附設醫院肝膽胃腸科1 高雄醫學大學醫學院臨床醫學研究所2
Background: H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. Amoxicillin and tetracycline have the first priority because their low resistance rate. Two bismuth quadruple therapy including ATBP (amoxicillin, tetracycline, bismuth, PPI) and MTBP (metronidazole, tetracycline, bismuth, PPI) were the commonly used in the rescue therapy. Revised amoxicillin and tetracycline MIC breakpoint (0.032 mg/L and 0.094 mg/L) better predicted the outcome of bismuth quadruple therapy. Aims: To evaluate the efficacy of susceptibilityguided treatment for triple-drug resistant H. pylori according to revised amoxicillin and tetracycline MIC breakpoint. Methods: During January 2020 to December 2020, 13 patients with triple-drug resistant H. pylori were enrolled for susceptibility- guided treatment according to revised amoxicillin and tetracycline MIC breakpoint. ATBP, MTBP, AMBP (amoxicillin, metronidazole, bismuth, PPI), and MRBP (metronidazole, rifabutin, bismuth, PPI) regimens were assigned based on the MIC of amoxicillin and tetracycline (Figure 1). Each regimen was given for 14 days. Eradication was determined by 14C-urea breath test after the rescue therapy. Results: Five patients with H. pylori susceptible to amoxicillin and tetracycline had 100% eradication rate with ATBP therapy. One patient susceptible to tetracycline but resistant to amoxicillin was successfully treated with AMBP. Five of the seven patients (71.4%) susceptible to amoxicillin but resistant to tetracycline were successfully treated with MTBP. Overall eradication rate was 85% which was better than the historical cohort (59.4%). Conclusions: Susceptibility-guided treatment for triple-drug resistant H. pylori according to revised amoxicillin and tetracycline MIC breakpoint showed better eradication efficacy than the historical record. A larger case number is needed to strengthen the evidence.
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THE POLYGENIC RISK SCORES DERIVED FROM WESTERN COHORT FOR FATTY LIVER PREDICTION IS NOT VALID IN TAIWANESE POPULATION
Chien-Wei Peng1,2, Wen-Juei Jeng1,2 , Yi-Chung Hsieh1,2, Mei-Hung Pan3 , Chih-Jen Huang3, Hwai-I Yang3 Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan1 College of medicine, Chang Gung University, Taoyuan, Taiwan2 Genomics Research Center, Academia Sinica, Taipei, Taiwan3 西方世代研究發展之預測脂肪肝風險 之多基因風險分數無法於台灣族群中 驗證
彭建維1,2 鄭文睿1,2 謝彝中1,2 潘眉虹3 黃志仁3 楊懷壹3 林口長庚紀念醫院胃腸肝膽科系1 長庚大學醫學院2 中央研究院基因體研究中心3
Background: Polygenic risk scores (PRS) have been developed to predict hepatic steatosis and hepatocellular carcinoma in western cohorts, which were based on five single-nucleotide polymorphisms, including PNPLA3 (rs738409), GCKR (rs1260326), MBOAT7 (rs641738), TM6SF2 (rs641738) and HSD17B13 (rs72613567). However, information about their utility in detecting hepatitis steatosis in Asian patients is limited. Aims: We validated the association of the existing PRS and hepatic steatosis in a population-based Taiwanese cohort. Methods: This study included 555 subjects who had available information on next-generation sequencing and liver sonography in Taiwan biobank. Subjects with seropositivity of HBsAg and/ or anti-HCV antibody were excluded. The hepatic steatosis was diagnosed by liver sonography. Baseline age, sex, body mass index, body fat rate, use of alcohol, history of hypertension, and serum biochemistry tests including glycohemoglobin, triglyceride (TG), low density cholesterol (LDL), and alanine transaminase (ALT) level were analyzed. PRS-HFC (Bianco et al., 2020) and simplified PRS (Liu et al., 2021) were validated in this study. PRS-HFC was the sum of each risk allele multiply its effect size to hepatic steatosis. The simplified PRS was the sum of each risk allele multiply one, while the minor allele of HSD17B13, as a protective factor, multiply minus one. Logistic regression analysis was performed to identify the predictors of fatty liver. Results: Among the 555 subjects, 242 (43.6%) was diagnosed with fatty liver using abdominal ultrasonography. By multivariate logistic regression analysis, higher body fat rate (adjusted odds ratio (OR): 1.062, P < 0.001), higher levels of TG (adjusted OR: 1.005, P =0.007), LDL (adjusted OR: 1.007, P =0.0259), and ALT (adjusted OR: 1.035, P = 0.0123), and carrier of homozygous minor allele of PNPLA3 (adjusted OR: 1,905, P = 0.0124) were at increased risk of hepatic steatosis, while GCKR, MBOAT7, TMS6SF2, and HSD17B13 were not associated with hepatic steatosis. Neither PRS-HFC (crude OR: 5.09, P = 0.1232) nor simplified PRS (crude OR: 1.149, P = 0.1548) was associated with fatty liver. Conclusions: PNPLA3 was associated with elevated risk of hepatic steatosis, while HSD17B13 was not a protective factor in our Taiwanese cohort. The PRS derived from western cohorts may not be useful for detecting hepatic steatosis in Taiwanese. Therefore, different PRS should be developed according to different ethnicity.
⑤
SURVIVAL OF PATIENTS WITH HEPATOCELLULAR CARCINOMA IN RENAL INSUFFICIENCY: PROGNOSTIC ROLE OF ALBUMINBILIRUBIN GRADE
Shu-Yein Ho1, Chih-Chieh Ko2, Chien-Wei Su2 , Ming-Chih Hou2, Yi-Hsiang Huang2 , Teh-Ia Huo3,4
Division of Gastroenterology and Hepatology, Min-Sheng General Hospital, Taoyuan, Taiwan1 Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan2 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan3 Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan4 利用白蛋白 - 膽紅素等級預後模型用於 預測肝細胞癌合併腎功能不全患者的 預後
何樹仁1 柯智傑2 蘇建維2 侯明志2 黃怡翔2 霍德義3,4 敏盛綜合醫院胃腸肝膽科1 臺北榮民總醫院胃腸肝膽科2 臺北榮民總醫院醫學研究部3 國立陽明交通大學藥理研究所4
Background: Renal insufficiency (RI), defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2, is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade, a marker of liver dysfunction, in this special setting is unclear. Aims: We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. Methods: A prospective cohort of 3690 HCC patients between 2002 and 2016 were retrospectively analyzed. The Kaplan-Meier method and multivariate Cox proportional hazards model were used to determine survival and independent prognostic predictors. Results: Of all patients, RI was an independent predictor associated with decreased survival (hazard ratio [HR]: 1.234, p<0.001). In multivariate Cox analysis for patients with RI, -fetoprotein level ≥ 20 ng/mL (HR:1.727, p<0.001), multiple tumors (HR: 1.178, p=0.036), tumor size >3 cm (HR: 2.293, p<0.001), vascular invasion or metastasis (HR: 1.289, p=0.004), presence of ascites (HR: 1.288, p=0.045), performance status 1-2 (HR: 1.143, p<0.001), performance status 3-4 (HR: 1.985, p<0.001), ALBI grade 2 (HR: 1.695, p<0.001) and grade 3 (HR: 2.878, p<0.001) were independent predictors of decreased survival. In subgroup analysis of patients with RI undergoing curative and non-curative treatments, the ALBI grade remained a significant prognostic predictor associated with decreased survival in the multivariate Cox analysis (p<0.001). Conclusions: HCC patients with RI have decreased survival compared to those without RI. The ALBI grade can discriminate the survival in patients with RI independent of treatment strategy and is a feasible prognostic tool in this special patient population.
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LONG-TERM EFFECTIVENESS OF POPULATION-WIDE MULTIFACETED INTERVENTIONS FOR HEPATOCELLULAR CARCINOMA IN TAIWAN
Sih-Han Liao1,2,3, Chi-Ling Chen3,4,5 , Chen-Yang Hsu3, Kuo-Liong Chien3,6 , Jia-Horng Kao2,4, Pei-Jer Chen2,4 , Hsiu-Hsi Chen3, Chien-Hung Chen2,7,8 Section of Gastroenterology, Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan2 Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan3 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan4 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan5 Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan6 Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan7 College of Medicine, National Taiwan University, Taipei, Taiwan8 台灣全國性肝癌防治介入的長期有效性
廖思涵1,2,3 陳祈玲3,4,5 許辰陽3 簡國龍3,6 高嘉宏2,4 陳培哲2,4 陳秀熙3 陳健弘2,7,8 台大癌醫分院綜合內科部消化科1 台大醫院內科部胃腸肝膽科2 台大公衛學院流行病學與預防醫學研究所3 台大醫學院臨床醫學研究所4 台大醫院外科部5 台大醫院內科部心臟科6 台大雲林分院內科部7 台大醫學院8
Background: Taiwan has launched a series of population-wide interventions to prevent hepatocellular carcinoma (HCC) related to hepatitis B and C virus infection since 1984. Aims: We took this opportunity to investigate the impact of each intervention on the incidence and case-fatality rate of HCC, and assessed their relative contributions to the overall reduction in mortality during this period. Methods: Population-based registry data on HCC mortality and incidence from individuals aged 0 to 84 years between 1979 and 2016 were collected before (Period 1) and after universal hepatitis B vaccination from 1984 (Period 2), universal health care from 1995 (Period 3), and viral hepatitis therapy from 2003 (Period 4). A Bayesian Poisson regression model was used for mortality decomposition analysis to estimate the respective contributions of these interventions to the reduction in age-specific incidence and casefatality rates. Results: Mortality declined substantially in children, young- and middle-aged groups, but only slightly decreased in the elderly group. The declining trends in mortality were in part explained by incidence reduction and in part by a remarkable decline in case-fatality rate attributed to universal health care. Hepatitis B vaccination led to a 35.9% (26.8% to 44.4%) reduction in incidence for individuals aged 30 years or below, whereas antiviral therapy reduced the incidence of HCC by 14.9% (11.8% to 17.9%) and 15.4% (14.1% to 16.6%) for individuals aged 30–49 years and 50–69 years, respectively. Conclusions: Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups.
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RECURRENCE OUTCOMES LESS FAVORABLE IN T1 RECTAL CANCER THAN IN T1 COLON CANCER
Jer-Wei Wu1, Li-Chun Chang1,2 , Chia-Tung Shun3, Been-Ren Lin4 , Ming-Shiang Wu1, Han-Mo Chiu1,2 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan1 Health Management Center, National Taiwan University Hospital, Taipei, Taiwan2 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan3 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan4 T1 直腸癌的復發率較 T1 結腸癌高
吳哲瑋1 張立群1,2 孫家棟3 林本仁4 吳明賢1 邱瀚模1,2 台大醫院內科部1 台大醫院健康管理中心2 台大醫院病理部3 台大醫院外科部4
Background: With the implementation of screening program worldwide, diagnosis of early-stage colorectal cancer steadily increased, including T1 cancer. Current T1 cancer treatment does not differ according to anatomic location. Aims: We therefore compared the disease-free survival of T1 cancer arising from rectum versus colon. Methods: The hospital-based study included subjects with T1 cancer at National Taiwan University Hospital from 2005 to 2014. Clinical, colonoscopy, and histopathology were reviewed for patients with a mean follow-up time of 7.1 (0.712.9) years. We conducted Kaplan-Meier analysis to compare the risk of recurrence by cancer location and Cox-regression analysis to identify risk factors for T1 cancer recurrence. Results: The final cohort included a total of 343 subjects with T1 cancer (mean age, 64.9 ± 11.7 years; 56.1% males), of whom 25 underwent endoscopic resection alone. Of the subjects who underwent surgery, 50 had lymph node metastasis and 268 did not. Kaplan-Meier analysis showed that the risk of recurrence was higher in T1 rectal cancer than T1 colon cancer (p = 0.022). Rectal location, and larger neoplasm size were independent risk factors for recurrence, with hazard ratios (95% confidence interval) of 4.84 (1.18-19.92), and 1.32 (1.06-1.65), respectively. The occurrence of advanced histology did not differ between T1 rectal and colon cancers (p = 0.58). Conclusions: T1 cancers arising from the rectum had less favorable recurrence outcomes than those arising from the colon. Further studies are needed to examine whether adjuvant radiotherapy or chemotherapy can reduce the risk of recurrence in T1 rectal cancer.
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PREDICTING OUTCOMES FOR CROHN’S DISEASE USING A MOLECULAR BIOMARKER: PROFILE TRIAL INTERIM UPDATE
Nurulamin M Noor1, Biljana Brezina2 , Juan De La Revilla Negro2, Francis Dowling3 , Leisha M O’Brien3, Sanjana Choudhury3 , Simon Bond3, Lynne Whitehead4 , Sara Upponi5, Paul A Lyons1,6,7 , Eoin F McKinney1,6,7, Kenneth GC Smith1,6,7 , James C Lee1,2,6, Miles Parkes1,2 , PROFILE Trial Investigators8 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom1 Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge, United Kingdom2 Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom3 Clinical Trials Pharmacy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom4 Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom5 Cambridge Institute for Therapeutic Immunology and Infectious Disease, Cambridge, United Kingdom6 PredictImmune Ltd, Babraham Research Campus, Cambridge, United Kingdom7 National Health Service, United Kingdom8 Background: The course of IBD varies substantially between individuals, but there are a lack of reliable prognostic markers to guide clinical practice. Previously, we have described a transcriptional signature detectable within peripheral blood CD8 T-cells at diagnosis, identifying two subgroups of patients, correlating with prognosis. Aims: We have sought to develop a biomarker that could re-capitulate the prognostic CD8 subgroups and then assess whether this can improve clinical outcomes by appropriately matching therapy to disease course. Methods: From a training cohort of 69 newlydiagnosed IBD patients, we simultaneously obtained a whole-blood PAXgene RNA tube and peripheral-blood CD8 T-cell sample. Gene expression in both samples was measured by microarray. Statistical modelling was used to identify a transcriptional classifier in whole-blood gene expression data re-capitulating the CD8 findings and optimised into a multi-gene qPCR assay with independent validation in a second, independent cohort of 123 newly-diagnosed patients. The PROFILE trial has incorporated this classifier to compare relative efficacy of ‘topdown’ and ‘accelerated step-up’ therapy between biomarker-defined subgroups of 400 patients with newly-diagnosed Crohn’s disease. Results: Following application of statistical learning methods described, a 17-gene qPCR assay was developed and optimised. In the validation cohort, 123 patients could be classified into two distinct subgroups, IBDhi (high risk) and IBDlo (lower risk). IBDhi patients experienced significantly more aggressive disease than IBDlo patients, with earlier need for treatment escalation (hazard ratio = 2.65 (CD), 3.12 (UC)). Subsequently this biomarker is being used to stratify therapy in the PROFILE trial, where at the time of writing over 300 participants have been randomised - with recruitment ongoing. Conclusion: We have developed, optimised and validated a whole-blood qPCR classifier that is able to predict disease course from diagnosis in patients with IBD. This classifier is currently being assessed for clinical utility in the PROFILE trial, which would represent a major step towards personalised therapy in IBD.
