Urinary dipeptidase 1 and trefoil factor 1 are promising biomarkers for early diagnosis of colorectal cancer.

BACKGROUND: Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs). METHODS: Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0-III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts. RESULTS: Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825-0.956 for stage 0-III CRC and 0.792-0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively. CONCLUSIONS: This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity.

Laparoscopic pancreas-preserving duodenectomy: Minimally invasive surgery for superficial nonampullary duodenal epithelial tumors.

No consensus exists regarding the optimal treatment for superficial nonampullary duodenal epithelial tumors. Herein, we describe a laparoscopic pancreas-preserving duodenectomy for the treatment of a 30-mm adenoma located in the third portion of the duodenum. The adenoma was located on the pancreatic side, further hindering safe endoscopic resection. Via laparoscopy, the jejunum was transected first. After releasing the third portion of the duodenum from the retroperitoneal space, the jejunum was pulled to the right side of the superior mesenteric artery and separated from the pancreas. Under endoscopic guidance, the duodenum was then transected and duodenojejunostomy performed intracorporeally. Laparoscopic pancreas-preserving duodenectomy can be considered minimally invasive, achieving tumor radicality while preserving organs and causing minimal destruction to the abdominal wall. In conclusion, although technically demanding, laparoscopic pancreas-preserving duodenectomy is a valuable treatment option for superficial nonampullary duodenal epithelial tumors.

Osteopontin secreted from obese adipocytes enhances angiogenesis and promotes progression of pancreatic ductal adenocarcinoma in obesity.

PURPOSE: Obesity is a risk factor and poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms remain unclear. METHODS: PDAC cells and obese visceral adipocytes (O-Ad) derived from mice and humans were used to analyze interactions between the two cell types, and human microvascular endothelial cells were used for angiogenesis assay. A xenograft mouse model with subcutaneously injected PDAC cells was used for animal studies. The relationship between visceral fat and prognosis was analyzed using resected tissues from PDAC patients with and without obesity. RESULTS: Conditioned media (CM) from O-Ad significantly increased PDAC cell growth and migration and angiogenic capacity in both human and mice cells, and blocking osteopontin (OPN) in O-Ad canceled O-Ad-induced effects in both mouse and human cells. In addition, O-Ad directly increased the migratory and tube-forming capacities of endothelial cells, while blocking OPN canceled these effects. O-Ad increased AKT phosphorylation and VEGFA expression in both PDAC and endothelial cells, and OPN inhibition in O-Ad canceled those O-Ad-induced effects. In the xenograft model, PDAC tumor volume was significantly increased in obese mice compared with lean mice, whereas blocking OPN significantly inhibited obesity-accelerated tumor growth. OPN expression in adipose tissues adjacent to human PDAC tumor was significantly higher in obese patients than in non-obese patients. In PDAC patients with obesity, high OPN expression in adipose tissues was significantly associated with poor prognosis. CONCLUSION: Obese adipocytes trigger aggressive transformation in PDAC cells to induce PDAC progression and accelerate angiogenesis via OPN secretion.

A prospective cohort study of a new electrosurgical unit for preventing colorectal post-endoscopic submucosal dissection coagulation syndrome.

BACKGROUND AND AIM: Post-endoscopic submucosal dissection coagulation syndrome (PECS) is a recognized complication of colorectal endoscopic submucosal dissection (ESD); however, there is a lack of interventions for preventing PECS. We therefore conducted a prospective study to evaluate the utility of maXium, a novel electrosurgical unit, for preventing PECS. METHODS: This single-center, prospective cohort study prospectively enrolled patients undergoing colorectal ESD. The voltage and power of the electrosurgical units were measured. PECS was defined as a visual analog scale (VAS) ≥ 30 mm, an increase of VAS ≥ 20 mm from baseline, body temperature ≥ 37.5°C, or white blood cell count ≥ 10 000/µL after ESD. PECS was classified into type I (without extra-luminal air) and type II (with peri-luminal air). The primary endpoint was the incidence of PECS. A sample size of 92 patients was required to ensure the upper limit of the 90% CI for the incidence of PECS was less than 15%. RESULTS: At resistances greater than 400 Ω, the maXium unit allowed submucosal dissection with lower power than with the VIO300D unit. Ninety-one patients meeting the inclusion criteria were included in the final study analysis. The incidence of PECS was 16% (90% CI, 10-23%), comprising type I (11%) and type II (5%) PECS. Simple extra-luminal air without PECS was observed in 7% of patients. CONCLUSION: Use of the maXium electrosurgical unit did not reduce the incidence of PECS after colorectal ESD; however, the maXium unit had equivalent performance to a conventional electrosurgical unit used for colorectal ESD.

A multicenter case-control study of self-expanding metallic stent versus trans-anal colorectal tube for stage II/III non-right-sided obstructive colon cancer.

BACKGROUND: Self-expanding metallic stent (SEMS) and trans-anal colorectal tube (TCT) are alternative treatments to conventional emergency surgery for non-right-sided obstructive colon cancer (NROCC). However, the one with better short- and long-term outcomes remains controversial. Thus, this multicenter case-control study aimed to analyze and compare SEMS and TCT for NROCC. METHODS: Patients with stage II/III NROCC who underwent surgery between January 2010 and December 2019 at either of the eight selected Japanese affiliate hospitals were, retrospectively, reviewed. Baseline characteristics between the SEMS and TCT groups were adjusted by propensity score (PS) matching. RESULTS: Among 239 reviewed patients (SEMS: 76, TCT: 163), 180 were finally included in two well-balanced cohorts through PS: SEMS group (65 patients) and TCT group (115 patients). Technical success, clinical success, morbidity, and short-term mortality were not significantly different between the two groups. SEMS placement achieved significantly higher rates for primary resection/anastomosis without stoma (SEMS: 90.8% vs. TCT: 77.4%, p < 0.001) and laparoscopic surgery (SEMS: 64.6% vs. TCT: 43.5%, p < 0.001) than TCT placement. However, 5-year overall survival (SEMS: 83.7% vs. TCT: 86.4%; p = 0.822) and 5-year relapse-free survival (SEMS: 64.7% vs. TCT: 66.4%; p = 0.854) showed no significant differences between these groups. CONCLUSIONS: Both SEMS and TCT revealed similar long-term outcomes, but SEMS placement was better in achieving primary resection/anastomosis and laparoscopic surgery in patients with stage II/III NROCC.

The Risk Analyses of Lymph Node Metastasis and Recurrence for Submucosal Invasive Colorectal Cancer: Novel Criteria to Skip Completion Surgery.

(1) Background: Additional surgical resection after endoscopic resection (ER) is recommended for patients with submucosal invasive colorectal cancer (pT1 CRC) who have risk factors for lymph node metastasis (LNM) (high-risk pT1 CRC). This study aimed to identify risk factors for LNM and metastatic recurrence and to determine the low-risk population for whom additional surgery can be omitted among high-risk pT1 CRCs. (2) Methods: We retrospectively identified 404 patients with pT1 CRC who underwent ER or surgery, and patients were divided into three groups: low-risk (n = 79); high-risk pT1 with ER (n = 40); and high-risk with surgery (n = 285). We also enrolled another 64 patients with high-risk pT1 CRC in an independent validation cohort. (3) Results: In the high-risk with surgery group, LNM was seen in 11.2%, and vascular and lymphatic invasions were significantly independent risk factors for LNM on multivariate analysis. No LNMs were observed in pT1 CRCs with a negative vertical margin and SM invasion depth ≤2000 µm that had no other risk factors except for budding. Five patients developed metastatic recurrence in the high-risk with surgery group, and rectal cancer and undifferentiated histology were significantly independent risk factors for poor relapse-free survival. No LNM or recurrent cases were seen in high-risk pT1 CRCs that met these criteria: differentiated adenocarcinoma, no lymphovascular invasion, colon cancer, SM invasion depth ≤2000 µm, and a negative vertical margin, which were validated in an independent validation cohort. (4) Conclusions: Completion surgery may be skipped for high-risk pT1 CRCs that meet our proposed criteria.

Successful diagnosis and endoscopic submucosal dissection of a gastric gastrointestinal stromal tumor originating from the submucosal layer.

Video 1Endoscopic submucosal dissection for a gastric GI stromal tumor originating from the submucosal layer.

A Novel Urinary miRNA Biomarker for Early Detection of Colorectal Cancer.

Since noninvasive biomarkers as an alternative to invasive colonoscopy to detect colorectal cancer (CRC) are desired, we conducted this study to determine the urinary biomarker consisting of microRNAs (miRNAs). In total, 415 age- and sex-matched participants, including 206 patients with CRC and 209 healthy controls (HCs), were randomly divided into three groups: (1) the discovery cohort (CRC, n = 3; HC, n = 6); (2) the training cohort (140 pairs); and (3) the validation cohort (63 pairs). Among 11 urinary miRNAs with aberrant expressions between the two groups, miR-129-1-3p and miR-566 were significantly independent biomarkers that detect CRC. The panel consisting of two miRNAs could distinguish patients with CRC from HC participants with an area under the curve (AUC) = 0.811 in the training cohort. This panel showed good efficacy with an AUC = 0.868 in the validation cohort. This urinary biomarker combining miR-129-1-3p and miR-566 could detect even stage 0/I CRC effectively with an AUC = 0.845. Moreover, the expression levels of both miR-129-1-3p and miR-566 were significantly higher in primary tumor tissues than in adjacent normal tissue. Our established novel biomarker consisting of urinary miR-129-1-3p and miR-566 enables noninvasive and early detection of CRC.

Relationship between gene mutations and clinicopathological features in nonampullary duodenal epithelial tumors.

BACKGROUND: Molecular features of nonampullary duodenal epithelial tumors (NADETs) remain unclear. AIM: The aim of this study is to determine the association between the genetic features and clinicopathological findings of NADETs. METHODS: In total, 75 NADETs were enrolled in this study, and was performed targeted DNA sequencing of the GNAS, KRAS, TP53, and APC genes. Histological grade was classified as category 3 or category 4/5 according to the Vienna classification, and the immunophenotype was categorized as the gastric phenotype (G type), gastrointestinal phenotype (GI type), or the intestinal phenotype (I type). RESULTS: The prevalence of GNAS and KRAS mutations was significantly higher in the G type than in the GI/I type (GNAS, P = 0.027; KRAS, P = 0.005). In contrast, the frequency of TP53 mutations was significantly higher in the GI/I type than in the G type (P = 0.049). Notably, APC mutations, excluding c.4479 G>A which was synonymous mutation, were more frequently identified in category 4/5 tumors than in category 3 tumors (50% vs. 24.5%; P = 0.039). CONCLUSION: G-type NADETs harbored frequent GNAS and KRAS mutations, whereas TP53 mutations are common in NADETs with intestinal features. APC mutations were significantly associated with high-grade neoplasia and invasive carcinoma.

Combination Therapy With Ustekinumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Refractory Ulcerative Colitis.

There are currently no reports on the efficacy and safety of combination therapy with ustekinumab (UST) plus intensive granulocyte and monocyte adsorptive apheresis (GMA) for the treatment of refractory ulcerative colitis (UC). We retrospectively evaluated the 10-week effectiveness of combination therapy with UST plus intensive GMA on refractory UC patients including two corticosteroid (CS)-dependent patients, two CS-refractory patients and one patient with loss of response to tacrolimus. Four patients were administered initial combination therapy of UST (6 mg/kg UST followed by subcutaneous injections of 90 mg UST every 8 weeks) plus intensive GMA. Of the four patients who received this combination therapy, two (50%) achieved clinical remission at 10 weeks. The rate of patients achieving endoscopic improvement (endoscopy subscore ≤ 1) at 10 weeks was 50%. In all cases, CSs were discontinued within 10 weeks. No adverse events were observed. Combination therapy with UST plus intensive GMA is helpful to reduce clinical disease activities in refractory UC patients and appears well tolerated.

Urinary microRNA biomarkers for detecting the presence of esophageal cancer.

Esophageal cancer (EC) including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) generally exhibits poor prognosis; hence, a noninvasive biomarker enabling early detection is necessary. Age- and sex-matched 150 healthy controls (HCs) and 43 patients with ESCC were randomly divided into two groups: 9 individuals in the discovery cohort for microarray analysis and 184 individuals in the training/test cohort with cross-validation for qRT-PCR analysis. Using 152 urine samples (144 HCs and 8 EACs), we validated the urinary miRNA biomarkers for EAC diagnosis. Among eight miRNAs selected in the discovery cohort, urinary levels of five miRNAs (miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b) were significantly higher in the ESCC group than in the HC group, in the training/test cohort. Consistently, these five urinary miRNAs were significantly different between HC and ESCC in both training and test sets. Especially, urinary miR-1273f and miR-619-5p showed excellent values of area under the curve (AUC) ≥ 0.80 for diagnosing stage I ESCC. Similarly, the EAC group had significantly higher urinary levels of these five miRNAs than the HC group, with AUC values of approximately 0.80. The present study established novel urinary miRNA biomarkers that can early detect ESCC and EAC.

Relationship between Immunophenotype and Clinicopathological Findings for Superficial Nonampullary Duodenal Epithelial Tumor.

INTRODUCTION: The natural history and prognosis of superficial nonampullary duodenal epithelial tumors (SNADETs) remain uncertain. We elucidated the relationship between immunophenotype and clinicopathological features. MATERIALS AND METHODS: A total of 98 SNADETs were divided into 3 groups according to immunohistochemical findings: gastric phenotype (G type), gastrointestinal phenotype (GI type), and intestinal phenotype (I type). Cellular dysplasia was divided into low-grade dysplasia and high-grade dysplasia/adenocarcinoma (≥HGD). White opaque substance (WOS) deposition was categorized into diffuse WOS, partial WOS, and no WOS, based on endoscopic findings. RESULTS: Of the 98 SNADETs, 4 lesions (4.1%) were G type, 32 lesions (32.7%) were GI type, and 62 lesions (63.2%) were I type. All G-type SNADETs were located in the oral side of the papilla including the bulb, and the rate of bulbar lesions was significantly higher in the G type than in the GI and I types (p = 0.004). The most frequent type of WOS was no WOS (4/4, 100%) for G type, partial WOS (19/32, 59.4%) for GI type, and diffuse WOS (34/62, 54.8%) for I type (p < 0.001), and loss of intestinal character was significantly correlated with WOS deficiency. GI/I-type SNADETs with partial or no WOS and G-type SNADETs were associated with ≥HGD. Additionally, the frequency of ≥HGD lesion was significantly higher in the CD10-negative group than in the CD10-positive group (57.1 vs. 19.8%, p = 0.043). CONCLUSION: Pathological intestinal character was correlated with the presence of WOS, and CD10 loss was associated with malignant potential of SNADETs.

Novel and Simple Criteria for Predicting Mortality of Peptic Ulcer Disease.

Objective Conventional risk scores of peptic ulcer disease (PUD) are based on many parameters, and their application in clinical practice is therefore limited. The aim of this study was to establish simple and reliable criteria for predicting PUD-associated mortality. Methods A total of 499 patients with PUD were divided into 2 groups: the training cohort (n=333) and the validation cohort (n=166). To minimize selection bias due to missing values, we used imputed datasets generated by the multiple imputation method (training-cohort dataset, n=33,300; validation-cohort dataset, n=16,600). Results In the training-cohort dataset, the heart rate-to-systolic blood pressure ratio (HR/SBP) and serum albumin (s-Alb) level were significant independent predictive factors for mortality according to the multivariate analysis [HR/SBP, odds ratio (OR): 1.72; 95% confidence interval (CI), 1.06-2.80, p=0.028; s-Alb, OR: 0.23, 95% CI, 0.11-0.51, p<0.001]. The model comprising HR/SBP and s-Alb was able to detect mortality due to PUD with an area under the curve (AUC) of 0.855. In the validation-cohort dataset, this model also showed good efficacy with an AUC of 0.835. The novel criteria combining HR/SBP and s-Alb developed by a decision tree analysis showed 73.3% sensitivity and 87.6% specificity for predicting mortality in the total-cohort dataset. Our criteria were superior to the Glasgow Blatchford and Rockall scores and similar to the AIMS65 and Progetto Nazionale Emorragia Digestiva scores for predicting mortality. Conclusion The combination of the HR/SBP ratio and s-Alb level is a good predictor of mortality in patients with PUD.

Serum Exosomal Dicer Is a Useful Biomarker for Early Detection of Differentiated Gastric Adenocarcinoma.

BACKGROUND AND AIM: A recent basic study identified that Dicer is contained in exosomes derived from cancer cells and plays crucial roles in microRNA maturation and cancer development. Based on this novel basic concept, we analyzed the usefulness of serum exosomal Dicer as a diagnostic biomarker for gastrointestinal cancers. METHODS: Enrolled participants (691) were categorized into 3 groups: gastric cancer (GC) cohort, 183 patients (90 healthy controls (HCs) and 93 GC patients); esophageal cancer (EC) cohort, 115 patients (90 HCs and 25 EC patients); and colorectal cancer (CRC) cohort, 188 patients (92 HCs and 96 CRC patients) after age- and sex matching using the propensity score. The quality of isolated serum exosomes was validated with an electron microscope, particle size analyzer, and exosome marker, CD63. RESULTS: Serum exosomal Dicer was significantly higher in the GC group than in the HC group (p = 0.004), whereas no significant differences were found in both EC and CRC cohorts. Serum exosomal Dicer was significantly higher in only differentiated gastric adenocarcinoma and not in the undifferentiated type. Moreover, serum exosomal Dicer showed no significant differences regardless of Helicobacter pylori (H. pylori) status. The biomarker panel combining serum exosomal Dicer with H. pylori status distinguished between HC and differentiated GC patients with an area under the curve (AUC) of 0.762. As for early-stage diagnosis, this combination distinguished between HC and stage I differentiated GC with an AUC = 0.758. CONCLUSIONS: Serum exosomal Dicer is a potential noninvasive diagnostic biomarker for early detection of differentiated gastric adenocarcinoma.

Novel urinary protein biomarker panel for early diagnosis of gastric cancer.

BACKGROUND: With the goal of discovering non-invasive biomarkers for early diagnosis of GC, we conducted a case-control study utilising urine samples from individuals with predominantly early GC vs. healthy control (HC). METHODS: Among urine samples from 372 patients, age- and sex-matched 282 patients were randomly divided into three groups: 18 patients in a discovery cohort; 176 patients in a training cohort and 88 patients in a validation cohort. RESULTS: Among urinary proteins identified in the comprehensive quantitative proteomics analysis, urinary levels of TFF1 (uTFF1) and ADAM12 (uADAM12) were significantly independent diagnostic biomarkers for GC, in addition to Helicobacter pylori status. A urinary biomarker panel combining uTFF1, uADAM12 and H. pylori significantly distinguished between HC and GC patients in both training and validation cohorts. On the analysis for sex-specific biomarkers, this combination panel demonstrated a good AUC of 0.858 for male GC, whereas another combination panel of uTFF1, uBARD1 and H. pylori also provided a good AUC of 0.893 for female GC. Notably, each panel could distinguish even stage I GC patients from HC patients (AUC = 0.850 for males; AUC = 0.845 for females). CONCLUSIONS: Novel urinary protein biomarker panels represent promising non-invasive biomarkers for GC, including early-stage disease.