Early detection of pancreatic cancer by comprehensive serum miRNA sequencing with automated machine learning.

BACKGROUND: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers. METHODS: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort. RESULTS: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%). CONCLUSIONS: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer.

Identification of an Anti-Integrin αvß6 Autoantibody in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis is the most frequent type of inflammatory bowel disease and is characterized by colonic epithelial cell damage. Although involvement of autoimmunity has been suggested in ulcerative colitis, specific autoantigens/antibodies have yet to be elucidated. METHODS: Using 23 recombinant integrin proteins, we performed enzyme-linked immunosorbent assays on sera from patients with ulcerative colitis and controls. Integrin expression and IgG binding in the colon tissues of patients with ulcerative colitis and controls were examined using immunofluorescence and coimmunoprecipitation, respectively. The blocking activity of autoantibodies was examined using solid-phase binding and cell adhesion assays. RESULTS: Screening revealed that patients with ulcerative colitis had IgG antibodies against integrin αvß6. In the training and validation groups, 103 of 112 (92.0%) patients with ulcerative colitis and only 8 of 155 (5.2%) controls had anti-integrin αvß6 antibodies (P < .001), resulting in a sensitivity of 92.0% and a specificity of 94.8% for diagnosing ulcerative colitis. Anti-integrin αvß6 antibody titers coincided with ulcerative colitis disease activity, and IgG1 was the major subclass. Patient IgG bound to the integrin αvß6 expressed on colonic epithelial cells. Moreover, IgG of patients with ulcerative colitis blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif and inhibited cell adhesion. CONCLUSIONS: A significant majority of patients with ulcerative colitis had autoantibodies against integrin αvß6, which may serve as a potential diagnostic biomarker with high sensitivity and specificity.

Pathogenicity of IgG in patients with IgG4-related disease.

OBJECTIVE: IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. DESIGN: We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). RESULTS: Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. CONCLUSIONS: IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.

CRAFITY score as a predictive marker for refractoriness to atezolizumab plus bevacizumab therapy in hepatocellular carcinoma: a multicenter retrospective study.

BACKGROUND: Although atezolizumab plus bevacizumab (Atezo/Bev) therapy has been used as the preferred first-line treatment for advanced hepatocellular carcinoma (HCC), up to 26% of patients do not achieve disease control, suggesting alternative treatments might be more beneficial for such patients. We investigated key predictors for refractoriness to Atezo/Bev therapy, particularly in the first-line setting. METHODS: We retrospectively analyzed 302 patients with HCC who received Atezo/Bev therapy between October 2020 and September 2022 across nine hospitals in Japan. Refractoriness was defined as best overall response (BOR) of progressive disease or stable disease and a progression-free survival (PFS) of < 180 days (RECIST v1.1). Clinical benefit was defined as BOR of partial/complete response or stable disease with PFS of ≥ 180 days. Baseline characteristics and potential predictors, identified through literature review, were compared between these groups. Stratifications of overall survival (OS), and PFS were also assessed. RESULTS: Refractoriness was observed in 126 (41.7%) patients, while 154 (51.0%) achieved clinical benefit. Due to a significant association between the treatment line and refractory rate, the subsequent analysis focused on the first-line cohort (n = 214; 72 [33.6%] patients showed refractoriness). Among 13 potential predictors, the CRP and AFP in immunotherapy (CRAFITY) score had the best predictive performance, with refractory rates of 24.6%, 44.6%, and 57.9% in CRAFITY-0, 1, and 2 patients, respectively (p < 0.001). OS and PFS were also well-stratified by this scoring system. CONCLUSIONS: Approximately one-third of patients were refractory to first-line Atezo/Bev therapy. The CRAFITY score demonstrated superior performance in predicting refractoriness.

A case of dedifferentiated liposarcoma of the descending colon.

A 54-year-old man referred to our hospital for abdominal distension. He had no medical history. On physical examination, he complained lower abdominal distention, and had no spontaneous pain or tenderness. The blood tests showed that CEA and CA19-9 levels were within normal limits. Colonoscopy revealed a submucosal tumor with irregularities and mucosal defects in the descending colon. Computed tomography (CT) showed a 3-cm-diameter mass in the descending colon and ascites. Due to the presence of ascites, laparoscopic examination was performed, which revealed multiple peritoneal seeding of the tumor. Given the presence of peritoneal dissemination, the tumor was determined to be unresectable, and a histological examination was performed from the disseminated nodule. Pathologically, atypical spindle cells were observed and infiltrated into adipose tissue. Additional immunohistochemistry revealed positive expression for Murine double minute 2 (MDM2) and Cyclin-dependent kinase 4 (CDK4), and fluorescence in situ hybridization showed amplification of MDM2. Thus, the tumor was diagnosed with a dedifferentiated liposarcoma of the descending colon. Liposarcoma is a type of soft-tissue sarcoma that arises from soft tissues such as the extremities or retroperitoneum. Here, we report an extremely rare case of a dedifferentiated liposarcoma of the colon.

Application and usefulness of a new eight-wire basket catheter for endoscopic extraction of small common bile duct stones: A retrospective multicenter study.

Objectives: Distally located small common bile duct stones are often difficult to treat or grasp endoscopically. Therefore, multiple devices, such as baskets or balloon catheters, are frequently used in such cases. However, it is desirable to use a single device for stone extraction from the perspective of cost-effectiveness. In this multicenter study, we evaluated the efficacy of a new eight-wire basket catheter for extracting small (≤10 mm) common bile duct stones. Methods: We retrospectively analyzed the records of 144 patients who underwent stone extraction using the eight-wire basket catheter for common bile duct stones ≤10 mm. The success rate of complete stone extraction and the risk factors for the difficulty in stone extraction with the eight-wire catheter alone were mainly evaluated. Results: The success rate of stone extraction with the eight-wire catheter alone was 86.1%. The final rate of complete stone extraction was 98.0%. The mean of the maximum diameter of the common bile duct and the largest stone dimension were 10.5 ± 3.5, and 5.1 ± 2.1 mm, respectively. Common bile duct diameter ≥12 mm and stone diameter ≥6 mm were identified as independent risk factors for the difficulty in stone extraction with the eight-wire catheter alone. Conclusions: The success rate of the new eight-wire basket for small common bile duct stone extraction was acceptable. The device is beneficial and could be used from the start for the extraction of small stones < 6 mm.

[Large serous cystic adenoma at the pancreas tail mimicking mucinous cystic neoplasm].

A 62-year-old woman presented with left abdominal pain. A large and multi-cystic lesion at the pancreas tail was recognized on imaging examinations. MRI revealed low and high signal intensity on T1- and T2-weighted imaging, with focal and bright components in the nodule adjacent to the septum on T2-weighted imaging. Distal pancreatectomy was performed, and the cystic lesion was diagnosed as serous cystic adenoma with hemorrhage. The characters of serous cystic components on imaging examinations could help to distinguish the lesion from mucinous cystic neoplasm.

Therapeutic endoscopy for stenotic pancreatodigestive tract anastomosis after pancreatoduodenectomy (with videos).

BACKGROUND: Pancreatodigestive tract anastomotic site stenosis is a problematic complication after pancreatoduodenectomy. OBJECTIVE: We evaluated the feasibility and efficacy of endoscopic treatments for a stenotic pancreatodigestive tract anastomosis. DESIGN: Retrospective study. SETTING: Endoscopic units of a university-affiliated hospital and a general hospital. PATIENTS: Fourteen patients with recurrent pancreatitis (n=10) and pancreatic fluid fistula (n=4) after anatomy-altering surgery with pancreatodigestive tract anastomosis. INTERVENTIONS: The initial ERCP included obtaining a pancreatogram, introducing a 0.025-inch guidewire through the anastomosis, along which a 5F plastic stent or nasopancreatic drain was inserted. If initial ERCP failed, we attempted EUS-guided rendezvous, with a guidewire passed antegrade from the main pancreatic duct across the stenotic anastomosis. MAIN OUTCOME MEASUREMENTS: Rates of successful intervention and clinical relief. RESULTS: The initial intervention was successfully achieved in 6 of 14 patients (38%). Of the 6 patients with successful therapeutic endoscopies, 4 (66.7%) and 2 (25.0%) had undergone a previous pancreatogastrostomy or pancreatojejunostomy, respectively. Eight patients with an initial unsuccessful intervention successfully underwent a second intervention using an EUS-guided or US-guided rendezvous method. Finally, stenosis was relieved in all patients with either the retrograde placement of a pancreatic duct stent across the stenosis of an anastomotic site or antegrade percutaneous bougienage of the stenotic anastomosis. LIMITATIONS: Small sample size and lack of control patients. CONCLUSIONS: Endoscopic treatment of stenotic pancreatodigestive tract anastomosis for transanastomotic pancreatic juice drainage is safe and feasible.

Mucinous Cystic Adenoma of the Liver: A Thought-Provoking Case of an Uncommon Hepatic Neoplasm.

BACKGROUND Mucinous cystic neoplasm (MCN) of the liver is a rare hepatic neoplasm: a cystic, mucus-producing tumor. Histopathologic examination reveals ovarian-like stroma. The origin of MCN of the liver is still unknown, although ectopic ovarian-like stroma in the liver has been suggested as a possibility. We document a thought-provoking case of MCN of the liver, and intratumoral fatty tissue may support the opinion that ectopic ovarian-like stroma in the liver is a possible origin for both MCN and ovarian teratoma. CASE REPORT An expansive 10.5-cm cystic tumor was incidentally detected in a 71-year-old woman. Imaging studies revealed that the tumor was multiloculated, with cyst contents comprising mucus, muddy-looking fluid (inspissated bile), and hematoma. Imaging studies revealed fatty tissue and calcifications in the cyst walls. The diagnosis of MCN of the liver was made, although MCNs have never been reported to include fatty tissue. Extended left lobectomy was performed, and the tumor was curatively removed without any rupture. A multilocular cyst, mucus, calcifications, and fatty tissue were clearly observed on gross inspection. Histopathological examination revealed ovarian-like stroma. Evidence of malignancy was not detected. Her postoperative course was uneventful. To the best of our knowledge, our patient is the first case of MCN of the liver with intratumoral fatty tissue. This case may support the hypothesis that MCN originates from ectopic ovarian-like stroma in the liver. CONCLUSIONS We documented a thought-provoking case of MCN of the liver in detail, and this MCN accompanied with fatty tissue might originate from ectopic ovarian-like stroma.

Reducing the risk of developing walled-off necrosis in patients with acute necrotic collection using recombinant human soluble thrombomodulin.

BACKGROUND/PURPOSE: The purpose of the present study was to investigate the possibility of reducing clinical impacts of acute necrotic collection (ANC) on patients with acute pancreatitis (AP) using recombinant human soluble thrombomodulin (rTM). METHODS: In this retrospective multicenter study, 233 consecutive AP patients with ANC and acute peripancreatic fluid collection (APFC) from 2012 to 2016 were enrolled. To assess clinical impacts of ANC, severity on admission (JPN score, JPN CT grade, and Modified CT severity index), development of walled-off necrosis (WON), imaging costs for follow-up, and mortality were recorded. Finally, we investigated whether rTM could reduce the clinical impacts, adjusting the severity using propensity analysis with Inverse probability of treatment weighting. RESULTS: Patients with ANC developed WON with higher ratio than APFC (58/98 [59.2%] vs 20/135 [14.8%], OR = 8.3, P < .01]. Severity on admission and imaging costs for follow-up in ANC patients were significantly higher than those in APFC (P < .01). However, regarding mortality, there was no significant difference between patients with ANC and APFC (P = .41). Adjusting severity, it was revealed that rTM administration significantly reduced the risk of ANC developed WON (OR = 0.23, P = .01). CONCLUSIONS: While ANC had a higher clinical impact than that of APFC, we found that early administration of rTM may reduce the impact.

Impact of continuous local lavage on pancreatic juice-related postoperative complications: Three case reports.

BACKGROUND: Postoperative pancreatic leakage readily results in intractable pancreatic fistula and subsequent intraperitoneal abscess. This refractory complication can be fatal; therefore, intensive treatment is important. Continuous local lavage (CLL) has recently been reevaluated as effective treatment for severe infected pancreatitis, and we report three patients with postoperative intractable pancreatic fistula successfully treated by CLL. We also discuss our institutional protocol for CLL for postoperative pancreatic fistula. CASE SUMMARY: The first patient underwent subtotal stomach-preserving pancreaticoduodenectomy, and pancreatic leakage was observed postoperatively. Intractable pancreatic fistula led to intraperitoneal abscess, and CLL near the pancreaticojejunostomy site was instituted from postoperative day (POD) 8. The abscess resolved after 7 d of CLL. The second patient underwent distal pancreatectomy. Pancreatic leakage was observed, and intractable pancreatic fistula led to intraperitoneal abscess near the pancreatic stump. CLL was instituted from POD 9, and the abscess resolved after 4 d of CLL. The third patient underwent aneurysmectomy and splenectomy with wide exposure of the pancreatic parenchyma. Endoscopic retrograde pancreatic drainage was performed on POD 15 to treat pancreatic fistula; however, intraperitoneal abscess was detected on POD 59. We performed CLL endoscopically via the transgastric route because the percutaneous approach was difficult. CLL was instituted from POD 63, and the abscess resolved after 1 wk of CLL. CONCLUSION: CLL has therapeutic potential for postoperative pancreatic fistula.

Hypocalcemia secondary to hypomagnesemia in a patient with Crohn's disease.

A 42-year-old female with Crohn's disease who had previously undergone multiple surgical interventions developed marked hypocalcemia, which could not be resolved with calcium administration. Markedly reduced serum magnesium levels were also observed. After intravenous magnesium administration, serum calcium levels rapidly normalized. In addition, the plasma levels of intact parathyroid hormone increased immediately after magnesium administration. These data strongly suggest that hypocalcemia resulted from disturbance of appropriate parathyroid hormone secretion caused by hypomagnesemia. After introduction of infliximab therapy, her abdominal symptoms and endoscopic findings improved, and serum calcium and magnesium levels stabilized within the normal range without magnesium administration.

Mucosal addressin cell adhesion molecule 1 plays an unexpected role in the development of mouse guard hair.

The first wave of coat hair development is initiated around embryonic day 14 in the mouse. Whereas ectodysplasin and ectodermal dysplasia receptor, tumor necrosis factor and tumor necrosis factor receptor family molecules, respectively, were identified to be signals triggering this process, not much was known regarding their downstream molecular targets. In this report, we show that mucosal addressin cell adhesion molecule 1 and intercellular adhesion molecule 1 are induced in the keratinocytes of the hair placode as a direct consequence of ectodermal dysplasia receptor signal, and tumor-necrosis-factor-receptor-associated factor 6 is involved in this mucosal addressin cell adhesion molecule 1 expression. Experiments using an in vitro culture of skin fragments demonstrated that ectodermal-dysplasia-receptor-induced mucosal addressin cell adhesion molecule 1 expression occurs at the initial phase of follicle development before involvement of Sonic hedgehog signal. Follicle development in this culture was also suppressed to some extent, though not completely, by addition of soluble mucosal addressin cell adhesion molecule 1/IgG-Fc chimeric protein, whereas monoclonal antibody that can inhibit mucosal addressin cell adhesion molecule 1 interaction with integrin alpha4beta7 had no effect on this process. These results demonstrated for the first time that the structural proteins, mucosal addressin cell adhesion molecule 1 and intercellular adhesion molecule 1, are induced by ectodermal dysplasia receptor signal and suggested the potential involvement of mucosal addressin cell adhesion molecule 1 in the morphogenesis of follicular keratinocytes.

Assessment of [(18)F]-fluoroacetate PET/CT as a tumor-imaging modality: preclinical study in healthy volunteers and clinical evaluation in patients with liver tumor.

OBJECTIVE: Although [(18)F]-FDG is a useful oncologic PET tracer, FDG uptake is known to be low in a certain type of hepatocellular carcinoma (HCC). [(18)F]-fluoroacetate ((18)F-FACE) is an [(18)F] fluorinated acetate, which is known to be converted into fatty acids, incorporated in membrane and is expected to be a promising oncologic PET tracer. The aim of this study was to evaluate the usefulness of (18)F-FACE as an oncologic PET tracer in preclinical study in healthy volunteers and in patients with liver tumors. METHODS: Twenty-four healthy volunteers (age 48.2 ± 12.9 years old; 15 male and 9 female) and ten patients with liver tumor (age 72.1 ± 7.0 years old; 6 male and 4 female) were included. We performed whole-body static PET/CT scan using (18)F-FACE (n = 34) and (18)F-FDG (n = 5 for volunteers, n = 8 for patients) on each day, respectively. Qualitative analysis and quantitative analysis of tumors (5 HCCs, 1 cholangiocellular carcinoma, 4 metastatic tumors from colon cancer and P-NET) were performed using SUVmax and tumor-to-normal liver ratio (TNR). RESULTS: In healthy volunteers, (18)F-FACE was metabolically stable in vivo and its biodistribution was almost similar to blood pool, basically uniformly independent of age and gender during PET scan time (up to 3 h). Normal physiological uptake of (18)F-FACE at each organ including liver (SUVmean 1.8 ± 0.2) was lower than that of blood pool (SUVmean 2.3 ± 0.3) at 1 h after injection. Chronic inflammatory uptake around femur of post-operative state of femoral osteotomy and faint uptake of benign hemangioma were observed in a case of healthy volunteer. (18)F-FACE (SUVmax 2.7 ± 0.6, TNR 1.5 ± 0.4) of liver tumors was significantly lower than those of (18)F-FDG uptake (6.5 ± 4.2, 2.6 ± 1.7, respectively). In qualitative analysis, (18)F-FDG was positive in 4 tumors (3 HCCs, 1 CCC) and negative in the other 6 tumors, while (18)F-FACE was also positive in 4 tumors which were the same tumors with positive (18)F-FDG uptake. CONCLUSIONS: Biodistribution of (18)F-FACE was appropriate for oncologic imaging. Tumor (18)F-FACE uptake was positive in four patients with HCC and CCC, but the uptake pattern was similar to (18)F-FDG. Further evaluation was needed.