Bispecific CAR-T cells targeting FAP and GPC3 have the potential to treat hepatocellular carcinoma.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated robust efficacy against hematological malignancies, but there are still some challenges regarding treating solid tumors, including tumor heterogeneity, antigen escape, and an immunosuppressive microenvironment. Here, we found that SNU398, a hepatocellular carcinoma (HCC) cell line, exhibited high expression levels of fibroblast activation protein (FAP) and Glypican 3 (GPC3), which were negatively correlated with patient prognosis. The HepG2 HCC cell line highly expressed GPC3, while the SNU387 cell line exhibited high expression of FAP. Thus, we developed bispecific CAR-T cells to simultaneously target FAP and GPC3 to address tumor heterogeneity in HCC. The anti-FAP-GPC3 bispecific CAR-T cells could recognize and be activated by FAP or GPC3 expressed by tumor cells. Compared with anti-FAP CAR-T cells or anti-GPC3 CAR-T cells, bispecific CAR-T cells achieved more robust activity against tumor cells expressing FAP and GPC3 in vitro. The anti-FAP-GPC3 bispecific CAR-T cells also exhibited superior antitumor efficacy and significantly prolonged the survival of mice compared with single-target CAR-T cells in vivo. Overall, the use of anti-FAP-GPC3 bispecific CAR-T cells is a promising treatment approach to reduce tumor recurrence caused by tumor antigen heterogeneity.

Photokeratitis in Outdoor Event Participants Exposed to UV Radiation Display.

Importance: While UV radiation displays may be used for recreational purposes at outdoor events, unprotected eyes have been reported to have symptoms consistent with photokeratitis. Such symptoms warrant documentation and evaluation in ophthalmic peer reviewed literature. Objective: To describe a case series of photokeratitis associated with a single ultraviolet radiation display at an outdoor event. Design, Setting, and Participants: This case series involved a retrospective record review of 8 patients who presented in public and private health sectors in November 2023 after developing photokeratitis following UV radiation exposure at an outdoor event in Hong Kong on the night of November 4, 2023. Main Outcomes and Measures: Clinical symptoms, signs, and clinical course of patients who were diagnosed acute photokeratitis following exposure to UV radiation. Results: The mean time of UV display exposure for the 8 patients (mean [SD] age, 33.12 [5.19] years; 4 [50%] female) was 3.00 (1.41) hours, and symptoms presented at a mean (SD) 8.88 (8.24) hours after the exposure. None of the patients were wearing spectacles during the exposed period. All patients were affected bilaterally. All patients experienced eye pain, 6 experienced red eye, and 5 experienced tearing and photophobia. Mean (SD) presenting visual acuity was logMAR 0.10 (0.14) (approximate Snellen equivalent, 20/25) for right eyes and 0.06 (0.89) (approximate Snellen equivalent, 20/25) for left eyes. On examination, there were findings of cornea and conjunctival involvement with punctate epithelial erosions and ciliary vasodilation, but none of the patients presented with anterior chamber reaction. Corticosteroids, lubricants, and antibiotics, all provided topically, were prescribed. Five patients were not scheduled for a review, and 3 had follow-up visits, with the length of follow-up ranging from 7 to 10 days. All patients had undergone a complete recovery. Conclusions and Relevance: These findings provide evidence of an association between UV radiation used for recreational purposes and photokeratitis, which may help guide evaluation and management of future cases.

Comparison of adenoma miss rate and adenoma detection rate between conventional colonoscopy and colonoscopy with second generation distal attachment cuff: a multicenter, randomized, back-to-back trial.

BACKGROUND AND AIMS: Endocuff VisionTM has been designed to enhance mucosal visualization thereby improving detection of (pre-)malignant colorectal lesions. This multicenter, international, back-to-back, randomized colonoscopy trial compared adenoma detection rate (ADR) and adenoma miss rate (AMR) between Endocuff Vision-assisted colonoscopy (EVC) and conventional colonoscopy (CC). METHODS: Patients aged 40-75 years referred for non-immunochemical fecal occult blood test-based screening, surveillance, or diagnostic colonoscopy were included at ten hospitals and randomized into four groups: Group 1; 2xCC, Group 2; CC followed by EVC, Group 3; EVC followed CC and Group 4; 2xEVC. Primary outcomes included ADR and AMR. RESULTS: A total of 717 patients were randomized of which 661 patients (92.2%) had one and 646 (90.1%) patients had two completed back-to-back colonoscopies. EVC did not significantly improve ADR compared to CC (41.1% [95%-CI;36.1-46.3] versus 35.5% [95%-CI;30.7-40.6], respectively, P=0.125), but EVC did reduced AMR by 11.7% (29.6% [95%-CI;23.6-36.5] versus 17.9% [95%-CI;12.5-23.5], respectively, P=0.049). AMR of 2xCC compared to 2xEVC was also not significantly different (25.9% [95%-CI;19.3-33.9] versus 18.8% [95%-CI;13.9-24.8], respectively, P=0.172). Only 3.7% of the polyps missed during the first procedures had advanced pathologic features. Factors affecting risk of missing adenomas were age (P=0.002), Boston Bowel Preparation Scale (P=0.008) and region where colonoscopy was performed (P<0.001). CONCLUSIONS: Our trial shows that EVC reduces the risk of missing adenomas but does not lead to a significant improved ADR. Remarkably, 25% of adenomas are still missed during conventional colonoscopies, which is not different from miss rates reported 25 years ago; reassuringly, advanced features were only found in 3.7% of these missed lesions. TRAIL REGISTRATION NUMBER: NCT03418948.

A review of the American College of Surgeons accredited education institutes' assessment practices for learners, faculty, and continuous program improvement.

Purpose: Simulation is an instructional modality that offers opportunities for assessment across many domains. The American College of Surgeons created the Accredited Education Institutes (AEIs) to build a community of high-quality simulation centers focused around improving surgical education and training. The goals of this project were to identify assessment methods used by AEIs, discuss how these methods align with established assessment frameworks, identify best practices, and provide guidance on best practice implementation. Methods: The authors analyzed responses regarding learner assessment, faculty assessment, and continuous program improvement from AEI accreditations surveys using deductive qualitative analysis. Results: Data from ninety-six centers were reviewed. Codes for each category were organized into formal and informal themes. For learner assessment, examinations and checklists identified as the most common types of formal assessment used and oral feedback as the most common type of informal assessment. For faculty assessment, written evaluations were the most common formal type and debriefs were the most common informal type. For continuous program improvement, written evaluations were the most common formal type and oral feedback was the most frequent informal type. Discussion: The goal of assessment should be to encourage learning through feedback and to ensure the attainment of educational competencies. The data revealed a variety of assessment modalities used to accomplish this goal with AEIs frequently utilizing some of the most reliable forms of assessment. We discuss how these forms of assessment can be integrated with best practices to develop assessment portfolios for learners and faculty, performance improvement reports for faculty, and assessments of clinical impact. Supplementary Information: The online version contains supplementary material available at 10.1007/s44186-023-00132-6.

A sub-10-nm, folic acid-conjugated gold nanoparticle as self-therapeutic treatment of tubulointerstitial fibrosis.

Nanomedicines for treating chronic kidney disease (CKD) are on the horizon, yet their delivery to renal tubules where tubulointerstitial fibrosis occurs remains inefficient. We report a folic acid-conjugated gold nanoparticle that can transport into renal tubules and treat tubulointerstitial fibrosis in mice with unilateral ureteral obstruction. The 3-nm gold core allows for the dissection of bio-nano interactions in the fibrotic kidney, ensures the overall nanoparticle (~7 nm) to be small enough for glomerular filtration, and naturally inhibits the p38α mitogen-activated protein kinase in the absence of chemical or biological drugs. The folic acids support binding to selected tubule cells with overexpression of folate receptors and promote retention in the fibrotic kidney. Upon intravenous injection, this nanoparticle can selectively accumulate in the fibrotic kidney over the nonfibrotic contralateral kidney at ~3.6% of the injected dose. Delivery to the fibrotic kidney depends on nanoparticle size and disease stage. Notably, a single injection of this self-therapeutic nanoparticle reduces tissue degeneration, inhibits genes related to the extracellular matrix, and treats fibrosis more effectively than standard Captopril therapy. Our data underscore the importance of constructing CKD nanomedicines based on renal pathophysiology.

The use of magnet-controlled capsule endoscopy as the initial diagnostic tool in patients with acute upper gastrointestinal bleeding.

BACKGROUND: The latest magnet-controlled capsule endoscopy (MCCE) system can examine the water-distended stomach, duodenum, and the small bowel. We assessed the use of MCCE as the first diagnostic tool in patients with acute upper gastrointestinal bleeding (AUGIB). METHODS: This was a prospective cohort study that enrolled patients admitted with AUGIB from two teaching hospitals. Patients underwent MCCE as the initial diagnostic modality. Our primary endpoint was the diagnostic yield of MCCE. The subsequent care of these patients was guided by MCCE findings. RESULTS: Of 100 enrolled patients, 99 (mean age 54 years, 70.7% men) with a median Glasgow-Blatchford score of 6 (IQR 3-9) underwent MCCE. In three patients, MCCE found active bleeding (two duodenal ulcers and Dieulafoy's lesion). The overall diagnostic yield of MCCE was 95.8% (92 lesions in 96 patients); five in the esophagus (Mallory Weiss tears 2, varices 1, and esophagitis 2), 51 in the stomach (gastric erosions 26, gastric ulcers 14, cancer 3, GIST 3, gastric polyps 3, antral vascular ectasia 1,angiodysplasia 1), 32 in the duodenum (ulcers 28, erosions 3, polyp 1), and four in the small bowel (ulcers 2, an erosion with a nonbleeding vessel 1, Meckel's diverticulum 1). Fifty-two (52.5%) patients were discharged without endoscopy. Forty-five (45.5%) patients underwent inpatient esophagogastroduodenoscopy (EGD), which found an antral ulcer and six duodenal ulcers in addition. CONCLUSIONS: In stable patients with AUGIB, MCCE can be used as a diagnostic tool. EGD should follow in patients with an inadequate view of the duodenum.

Global prospective case series of ERCPs using a single-use duodenoscope.

BACKGROUND: The first commercialized single-use duodenoscope was cleared by the US Food and Drug Administration in December 2019. Data regarding endoscopic retrograde cholangiopancreatography (ERCP) using a single-use duodenoscope are needed on a broader range of cases conducted by endoscopists with varying levels of experience in a wide range of geographic areas. METHODS: 61 endoscopists at 22 academic centers in 11 countries performed ERCP procedures in adult patients aged ≥ 18. Outcomes included ERCP completion for the intended indication, rate of crossover to a reusable endoscope, device performance ratings, and serious adverse events (SAEs). RESULTS: Among 551 patients, 236 (42.8 %) were aged > 65, 281 (51.0 %) were men, and 256 (46.5 %) had their procedure as an inpatient. ERCPs included 196 (35.6 %) with American Society for Gastrointestinal Endoscopy complexity of grades 3-4. A total of 529 ERCPs (96.0 %) were completed: 503 (91.3 %) using only the single-use duodenoscope, and 26 (4.7 %) with crossover to a reusable endoscope. There were 22 ERCPs (4.0 %) that were not completed, of which 11 (2.0 %) included a crossover and 11 (2.0 %) were aborted cases (no crossover). Median ERCP completion time was 24.0 minutes. Median overall satisfaction with the single-use duodenoscope was 8.0 (scale of 1 to 10 [best]). SAEs were reported in 43 patients (7.8 %), including 17 (3.1 %) who developed post-ERCP pancreatitis. CONCLUSIONS: In academic medical centers over a wide geographic distribution, endoscopists with varying levels of experience using the first marketed single-use duodenoscope had good ERCP procedural success and reported high performance ratings for this device.

Comparison of Over-the-Scope Clips to Standard Endoscopic Treatment as the Initial Treatment in Patients With Bleeding From a Nonvariceal Upper Gastrointestinal Cause : A Randomized Controlled Trial.

BACKGROUND: Current endoscopic methods in the control of acute nonvariceal bleeding have a small but clinically significant failure rate. The role of over-the-scope clips (OTSCs) as the first treatment has not been defined. OBJECTIVE: To compare OTSCs with standard endoscopic hemostatic treatments in the control of bleeding from nonvariceal upper gastrointestinal causes. DESIGN: A multicenter, randomized controlled trial. (ClinicalTrials.gov: NCT03216395). SETTING: University teaching hospitals in Hong Kong, China, and Australia. PATIENTS: 190 adult patients with active bleeding or a nonbleeding visible vessel from a nonvariceal cause on upper gastrointestinal endoscopy. INTERVENTION: Standard hemostatic treatment (n = 97) or OTSC (n = 93). MEASUREMENTS: The primary outcome was 30-day probability of further bleeds. Other outcomes included failure to control bleeding after assigned endoscopic treatment, recurrent bleeding after initial hemostasis, further intervention, blood transfusion, and hospitalization. RESULTS: The 30-day probability of further bleeding in the standard treatment and OTSC groups was 14.6% (14 of 97) and 3.2% (3 of 93), respectively (risk difference, 11.4 percentage points [95% CI, 3.3 to 20.0 percentage points]; P = 0.006). Failure to control bleeding after assigned endoscopic treatment in the standard treatment and OTSC groups was 6 versus 1 (risk difference, 5.1 percentage points [CI, 0.7 to 11.8 percentage points]), respectively, and 30-day recurrent bleeding was 8 versus 2 (risk difference, 6.6 percentage points [CI, -0.3 to 14.4 percentage points]), respectively. The need for further interventions was 8 versus 2, respectively. Thirty-day mortality was 4 versus 2, respectively. In a post hoc analysis with a composite end point of failure to successfully apply assigned treatment and further bleeds, the event rate was 15 of 97 (15.6%) and 6 of 93 (6.5%) in the standard and OTSC groups, respectively (risk difference, 9.1 percentage points [CI, 0.004 to 18.3 percentage points]). LIMITATION: Clinicians were not blinded to treatment and the option of crossover treatment. CONCLUSION: Over-the-scope clips, as an initial treatment, may be better than standard treatment in reducing the risk for further bleeding from nonvariceal upper gastrointestinal causes that are amenable to OTSC placement. PRIMARY FUNDING SOURCE: General Research Fund to the University Grant Committee, Hong Kong SAR Government.

Management of iron-deficiency anemia following acute gastrointestinal hemorrhage: A narrative analysis and review.

Many patients experiencing acute gastrointestinal bleeding (GIB) require iron supplementation to treat subsequent iron deficiency (ID) or iron-deficiency anemia (IDA). Guidelines regarding management of these patients are lacking. We aimed to identify areas of unmet need in patients with ID/IDA following acute GIB in terms of patient management and physician guidance. We formed an international working group of gastroenterologists to conduct a narrative review based on PubMed and EMBASE database searches (from January 2000 to February 2021), integrated with observations from our own clinical experience. Published data on this subject are limited and disparate, and those relating to post-discharge outcomes, such as persistent anemia and re-hospitalization, are particularly lacking. Often, there is no post-discharge follow-up of these patients by a gastroenterologist. Acute GIB-related ID/IDA, however, is a prevalent condition both at the time of hospital admission and at hospital discharge and is likely underdiagnosed and undertreated. Despite limited data, there appears to be notable variation in the prescribing of intravenous (IV)/oral iron regimens. There is also some evidence suggesting that, compared with oral iron, IV iron may restore iron levels faster following acute GIB, have a better tolerability profile, and be more beneficial in terms of quality of life. Gaps in patient care exist in the management of acute GIB-related ID/IDA, yet further data from large population-based studies are needed to confirm this. We advocate the formulation of evidence-based guidance on the use of iron therapies in these patients, aiding a more standardized best-practice approach to patient care.

Artificial Intelligence-Assisted Colonoscopy for Colorectal Cancer Screening: A Multicenter Randomized Controlled Trial.

BACKGROUND AND AIMS: Artificial intelligence (AI)-assisted colonoscopy improves polyp detection and characterization in colonoscopy. However, data from large-scale multicenter randomized controlled trials (RCT) in an asymptomatic population are lacking. METHODS: This multicenter RCT aimed to compare AI-assisted colonoscopy with conventional colonoscopy for adenoma detection in an asymptomatic population. Asymptomatic subjects 45-75 years of age undergoing colorectal cancer screening by direct colonoscopy or fecal immunochemical test were recruited in 6 referral centers in Hong Kong, Jilin, Inner Mongolia, Xiamen, and Beijing. In the AI-assisted colonoscopy, an AI polyp detection system (Eagle-Eye) with real-time notification on the same monitor of the endoscopy system was used. The primary outcome was overall adenoma detection rate (ADR). Secondary outcomes were mean number of adenomas per colonoscopy, ADR according to endoscopist's experience, and colonoscopy withdrawal time. This study received Institutional Review Board approval (CRE-2019.393). RESULTS: From November 2019 to August 2021, 3059 subjects were randomized to AI-assisted colonoscopy (n = 1519) and conventional colonoscopy (n = 1540). Baseline characteristics and bowel preparation quality between the 2 groups were similar. The overall ADR (39.9% vs 32.4%; P < .001), advanced ADR (6.6% vs 4.9%; P = .041), ADR of expert (42.3% vs 32.8%; P < .001) and nonexpert endoscopists (37.5% vs 32.1%; P = .023), and adenomas per colonoscopy (0.59 ± 0.97 vs 0.45 ± 0.81; P < .001) were all significantly higher in the AI-assisted colonoscopy. The median withdrawal time (8.3 minutes vs 7.8 minutes; P = .004) was slightly longer in the AI-assisted colonoscopy group. CONCLUSIONS: In this multicenter RCT in asymptomatic patients, AI-assisted colonoscopy improved overall ADR, advanced ADR, and ADR of both expert and nonexpert attending endoscopists. (ClinicalTrials.gov, Number: NCT04422548).

Importance of Physical Medicine and Rehabilitation in a Patient With Bilateral Lumbosacral Plexopathy Following the Course of Ladiratuzumab Vedotin for Breast Cancer: A Case Report.

A 74-year-old female with metastatic triple-negative breast cancer was admitted to the acute care hospital after several ground-level falls and a two-week history of bilateral lower extremity weakness with foot drop, numbness, and tingling. She was on ladiratuzumab vedotin (SGN-LIV1A) and pembrolizumab for four months prior to cancer treatment. Lumbar and sacral imaging studies did not identify neoplastic invasion into the bone or lumbosacral plexus. Electrodiagnostic findings suggested bilateral lumbosacral plexopathy (L3-S1). In the setting of rapid functional decline, medications were reviewed, and SGN-LIV1A was held. On initial evaluation, she required significant assistance with ambulation, transfers, and activities of daily living (ADLs). She remained off SGN-LIV1A and was discharged to acute inpatient rehabilitation. One month following discharge from acute inpatient rehabilitation, she exhibited improvements in right lower extremity strength and foot drop and progressed to modified-independent with ADLs, ambulating with a walker. In a discussion between cancer rehabilitation and oncology with consideration of the timing of presentation, distribution of symptoms, nerve conduction study and electromyography (NCS/EMG) findings, and improvement after SGN-LIV1A discontinuation, the patient was diagnosed with lumbosacral plexopathy from SGN-LIV1A administration. This is the only reported case of lumbosacral plexopathy secondary to SGN-LIV1A and addresses the importance of early consultation with cancer rehabilitation to address sequelae stemming from cancer therapy.

Identification of Tissue Types and Gene Mutations From Histopathology Images for Advancing Colorectal Cancer Biology.

Objective: Colorectal cancer (CRC) patients respond differently to treatments and are sub-classified by different approaches. We evaluated a deep learning model, which adopted endoscopic knowledge learnt from AI-doscopist, to characterise CRC patients by histopathological features. Results: Data of 461 patients were collected from TCGA-COAD database. The proposed framework was able to 1) differentiate tumour from normal tissues with an Area Under Receiver Operating Characteristic curve (AUROC) of 0.97; 2) identify certain gene mutations (MYH9, TP53) with an AUROC > 0.75; 3) classify CMS2 and CMS4 better than the other subtypes; and 4) demonstrate the generalizability of predicting KRAS mutants in an external cohort. Conclusions: Artificial intelligent can be used for on-site patient classification. Although KRAS mutants were commonly associated with therapeutic resistance and poor prognosis, subjects with predicted KRAS mutants in this study have a higher survival rate in 30 months after diagnoses.

Nurse-led reinforced education by mobile messenger improves the quality of bowel preparation of colonoscopy in a population-based colorectal cancer screening program: A randomized controlled trial.

BACKGROUND: Adequate bowel preparation is an important colonoscopy quality indicator. Reinforced education is effective in improving bowel preparation quality of colonoscopy with mixed indications. However, it remains unclear whether such improvement can be consistently observed in pre- and post-irrigation during colonoscopy in screening population. OBJECTIVE: We aimed to study the effectiveness of nurse-led reinforced education delivered via mobile messenger (WhatsApp Messenger) on pre- and post-irrigation bowel preparation adequacy in colonoscopies for positive fecal immunochemical test in a population-based colorectal cancer screening program. DESIGN: Randomized controlled trial. SETTING: A hospital-based endoscopy centre in Hong Kong, China. PARTICIPANTS: Patients undergoing colonoscopy for positive fecal immunochemical test in a population-based colorectal cancer screening program. METHODS: The recruited patients were randomized to receive either WhatsApp Reinforced Education (WRE) or No Reinforced Education (NRE) (1:1). Patients in WRE group received one-off reinforced education of bowel preparation in text and video formats via WhatsApp Messenger four days prior to colonoscopy sent by investigator while NRE group received standard-of-care only. Primary outcome was the bowel preparation adequacy rate as evaluated by Aronchick Scale. Secondary outcomes included bowel preparation adequacy rate as evaluated by Boston Bowel Preparation Scale, adenoma detection rate and risk factors of bowel preparation inadequacy. Continuous variables were described as means with standard deviation (SD) and analyzed with Student's t-test. The Pearson Chi Square Test or Fisher Exact Test was used to assess categorical variables when appropriate. Risk factors were determined by logistic regression. RESULTS: From July 2017 to April 2019, 685 eligible patients were randomized to WRE (n = 343) and NRE (n = 342) groups. Patients in WRE group had higher bowel preparation adequacy rate as evaluated by Aronchik Scale (83.4% vs 75.4%, p = 0.010) and Boston Bowel Preparation Scale (94.2% vs 88.9%, p = 0.013). Adenoma detection rate was higher in WRE group but without statistical significance (71.4% vs 67.5%, p = 0.27). In logistic regression, WhatsApp Reinforced Education reduced the inadequate bowel preparation risk (Adjusted odds ratio: 0.564; 95% confidence interval: 0.371-0.856, p = 0.007). Male gender (Adjusted odds ratio [AOR]: 1.638; 95% confidence interval [CI]: 1.054-2.546, p = 0.028) and diabetes (AOR: 2.062; 95% CI: 1.215-3.497, p = 0.007) were risk factors of bowel preparation inadequacy. CONCLUSIONS: Nurse-led mobile messenger-initiated reinforced education improves both pre- and post-irrigation bowel preparation quality of screening colonoscopy following positive fecal immunochemical test. It is readily incorporable in clinical practice because of its low setup cost. REGISTRATION NUMBER: Registered on 4 July 2017 on https://clinicaltrials.gov/ (NCT03209739).

Use of topical mineral powder as monotherapy for treatment of active peptic ulcer bleeding.

BACKGROUND AND AIMS: The aim of this study was to evaluate the safety and effectiveness of Hemospray (Cook Medical, Winston-Salem, NC, USA), a hemostatic powder, as monotherapy for active peptic ulcer bleeding. METHODS: In this prospective, multicenter, single-arm study, patients with Forrest Ia or Ib peptic ulcers underwent endoscopic application of Hemospray as treatment of first intent. Effectiveness endpoints were successful hemostasis at the end of the index endoscopy, recurrent bleeding within 72 hours and from 72 hours to 30 days, adverse events requiring reintervention or resulting in morbidity or mortality, and 30-day mortality. RESULTS: Hemospray was successfully administered in 98.5% of patients (66/67). Hemostasis was achieved at the index endoscopy in 90.9% of patients (60/66) with Hemospray alone and in an additional 4 patients treated with additional modalities, yielding an overall hemostasis rate of 97.0% (64/66). Rebleeding occurred in 13.3% of patients (8/60), 5 within 72 hours and 3 between 72 hours and 30 days. Two cases of perforation and 2 patient deaths occurred during the study, but none of these cases or any other adverse events were attributed to the use of Hemospray. The rate of early rebleeding was significantly higher in patients with Forrest Ia ulcers compared with patients with Forrest Ib ulcers. Higher rates of early bleeding in patients with Forrest Ia ulcers is consistent with results from studies where Hemospray was used as rescue after failure of conventional methods. CONCLUSIONS: Hemospray is an effective initial treatment for patients with active peptic ulcer bleeding, but care should be taken to monitor for recurrent bleeding. (Clinical trial registration number: NCT01306864.).

Scheduled second look endoscopy after endoscopic hemostasis to patients with high risk bleeding peptic ulcers: a Randomized Controlled Trial.

BACKGROUND: The recommendation of second look endoscopy (SLOGD) in selected patients at high risk for rebleeding has been inconclusive. This study aimed to evaluate the benefit of SLOGD in selected patients predicted at high risk of recurrent bleeding. METHODS: From a cohort of 939 patients with bleeding peptic ulcers who underwent endoscopic hemostasis, we derived a 9-point risk score (age > 60, Male, ulcer ≥ 2 cm in size, posterior bulbar or lesser curve gastric ulcer, Forrest I bleeding, haemoglobin < 8 g/dl) to predict recurrent bleeding. We then validated the score in another cohort of 1334 patients (AUROC 0.77). To test the hypothesis that SLOGD in high-risk patients would improve outcomes, we did a randomized controlled trial to compare scheduled SLOGD with observation alone in those predicted at high risk of rebleeding (a score of ≥ 5). The primary outcome was clinical bleeding within 30 days of the index bleed. RESULTS: Of 314 required, we enrolled 157 (50%) patients (SLOGD n = 78, observation n = 79). Nine (11.8%) in SLOGD group and 14 (18.2%) in observation group reached primary outcome (absolute difference 6.4%, 95% CI - 5.0% to 17.8%). Twenty-one of 69 (30.4%) patients who underwent SLOGD needed further endoscopic treatment. No surgery for bleeding control was needed. There were 6 vs. 3 of 30-day deaths in either group (p = 0.285, log rank). No difference was observed regarding blood transfusion and hospitalization. CONCLUSIONS: In this aborted trial that enrolled patients with bleeding peptic ulcers at high-risk of recurrent bleeding, scheduled SLOGD did not significantly improve outcomes. CLINICALTRIALS: gov:NCT02352155.

Development of CD44E/s dual-targeting DNA aptamer as nanoprobe to deliver treatment in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer with an extraordinary high mortality. Resistance to systemic therapy is a major cause of inferior clinical outcome in most patients with HCC. CD44 is a transmembrane cell-surface glycoprotein that is characterized by its variants displaying differential overexpression in human cancers. Aptamers, also known as chemical antibodies, can target cell-surface molecules with high affinity and specificity via structural recognition. Aptamer-mediated drug delivery hence is of high potentials in guiding therapy to improve efficacy. Methods: Variants CD44E and CD44s were studied for HCC relevance by investigating their expressions in primary HCC tumors, adjacent cirrhotic/fibrotic livers and normal livers using junction specific primers in qPCR assay. CD44E/s dual-targeted aptamers were uncovered by integrating loss-gain cell-SELEX and next generation sequencing. Selected aptamers were characterized for binding affinity and specificity, biostability, in vivo and in vitro cytotoxicity, in vivo homing and biodistribution, and ability to deliver 5-FU into targeted cells in vitro. Results: Both CD44E and CD44s isoforms showed significant upregulations in HCC tumors with CD44E/s activities promoting cell proliferation and migration. Loss-gain cell-SELEX uncover a CD44E/s dual-targeting aptamer, termed CD44-Apt1. Strong binding of CD44-Apt1 to cell-surface CD44 positive cells but not CD44-negative cells was demonstrated by flow-cytometry. CD44-Apt1 displayed strong affinity to CD44E and CD44s with KD as low as 1 nM but not the hyaluronic acid binding domain of CD44. Confocal imaging of CD44-positive cells stained with fluorescent-labeled CD44-Apt1 showed profound cytoplasmic localization, suggesting efficient cell-penetrating ability. Meanwhile, no apparent staining was observed in CD44-negative cells. CD44-Apt1 when conjugated with inhibitor 5-FU showed efficient guidance of 5-FU into HCC cells that significantly enhanced drug toxicity by more than thousands-fold. Both in vitro cell treatment and in vivo animal biodistribution indicated that CD44-Apt1 is non-toxic. In HCC xenograft model, CD44-Apt1 efficiently homed to tumor xenografts in a CD44 expression-dependent manner. Conclusion: Novel discovery of aptamer CD44-Apt1 that can bind both CD44E and CD44s illustrates high potential as nanoprobe to deliver anti-cancer therapeutics.