Optimal definition of coagulation syndrome after colorectal endoscopic submucosal dissection: a post hoc analysis of randomized controlled trial.

PURPOSE: Endoscopic clipping closure after colorectal endoscopic submucosal dissection (ESD) did not reduce the incidence of post-ESD coagulation syndrome (PECS) in our recent randomized controlled trial (RCT); however, the definition of PECS is still controversial. The aim of this study is to establish optimal definition of PECS with additional analysis of RCT based on another definition. METHODS: In this multicenter, single-blind RCT, individuals were randomly assigned to colorectal ESD followed by endoscopic clipping closure or non-closure. In this post hoc analysis, the definition of PECS was modified as both localized abdominal pain on visual analogue scale and inflammatory response (fever or leukocytosis), from either localized abdominal pain or inflammatory response in the original study. All participants underwent a computed tomography after ESD, and PECS was classified into type I, conventional PECS without extra-luminal air, and type II, PECS with peri-luminal air. RESULTS: A total of 155 patients (84 in the non-closure group and 71 in the closure group) were analyzed. As a result of criteria modification, 21 type I PECS and four type II PECS cases in the original study, which included patients with clear pain and inflammatory response, were downgraded to no adverse event and simple peri-luminal air, respectively. The frequency of PECS showed no significant difference between non-closure and closure groups. CONCLUSION: Clipping closure after colorectal ESD does not reduce the incidence of PECS regardless of the diagnostic criteria. Either localized abdominal pain or inflammatory response might be optimal criteria of PECS (UMIN000027031). TRIAL REGISTRATION NUMBER: UMIN000027031 DATE OF REGISTRATION: April 18, 2017.

A multicenter, single-blind randomized controlled trial of endoscopic clipping closure for preventing coagulation syndrome after colorectal endoscopic submucosal dissection.

BACKGROUND AND AIMS: Post endoscopic submucosal dissection coagulation syndrome (PECS) occasionally occurs after colorectal endoscopic submucosal dissection (ESD), presenting with localized abdominal pain and inflammation. We conducted a randomized controlled trial (RCT) to assess the usefulness of endoscopic clipping closure to prevent PECS and delayed perforation (DP). METHODS: This is a multicenter, single-blind RCT. Prospectively enrolled patients undergoing colorectal ESD were randomly allocated to endoscopic clipping closure and nonclosure after ESD, stratifying by institution and tumor size. All participants underwent a computed tomography scan after ESD. PECS was defined as visual analog scale (VAS) ≥30 mm, an increase in VAS ≥20 mm from baseline, body temperature ≥37.5°C or white blood cells ≥10,000/µL after colorectal ESD. DP was defined as PECS accompanied by extraluminal air. The preplanned sample size was 320 patients, and the primary endpoint was the rate of PECS/DP. RESULTS: At the planned interim analysis, this trial was terminated by recommendation of the independent data and safety monitoring committee because conditional power with superiority was lower than the preplanned futility limit. Finally, 155 patients were analyzed. The rate of PECS/DP was 16% (95% confidence interval [CI], 8%-23%) in the nonclosure group and 24% (95% CI, 14%-34%) in the closure group (P = .184). All cases of DP were within minor criteria, and all PECS/DP patients were managed conservatively without surgical treatment. Simple periluminal air without PECS was observed in 16% (95% CI, 8%-23%) in the nonclosure group and 10% (95% CI, 3%-17%) in the closure group. CONCLUSION: Endoscopic clipping closure could not reduce the high incidence of PECS/DP after colorectal ESD. (University Hospital Medical Network Clinical Trials Registry number: UMIN000027031.).

Pathological impact of transanal colorectal tube for obstructive colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) with acute colorectal obstruction (ACO) is an emergency. Transanal colorectal tube (TCT) use can be a safe single-stage surgery with laparoscopy-assisted colectomy; it offers long-term outcomes equivalent to emergency surgery for stage-II/III CRC with ACO. Self-expanding metallic stent use, another alternative, may have detrimental pathological and molecular effects, whereas the pathological impact of TCT placement remains unclear. We hypothesized that TCT placement might exert little damage on primary tumor. Hence, the current study analyzed the pathological impact of TCT placement for CRC with ACO compared to emergency surgery. METHODS: Data from consecutive patients with stage-II/III distal CRC with ACO who underwent surgery between January 2007 and December 2015 were retrospectively reviewed at two Japanese affiliate hospitals. Inflammatory and malignant potential-related parameters were analyzed by a single blinded pathologist. We extracted mRNA from tumor tissues to analyze inflammatory cytokines. RESULTS: Sixty-eight patients with stage-II/III distal CRC with ACO were identified (surgery: 25 patients; TCT: 43 patients). Baseline characteristics were well balanced between the two groups. TCT showed a significantly lower frequency of abscess (surgery vs TCT, 36.0% vs 11.6%; P = 0.017) and a lower tendency of pathological perforation (surgery vs TCT, 20.0% vs 4.7%, respectively; P = 0.091), compared to the surgery group. There were no significant intergroup differences in oncological factors, including perineural invasion (surgery vs TCT, 52.0% vs 62.8%; P = 0.383), microlymphatic involvement (surgery vs TCT, 52.0% vs 58.1%; P = 0.623), and microvascular involvement (surgery vs TCT, 32.0% vs 25.6%; P = 0.570). No significant intergroup differences were found in interleukin (IL)-6, IL-8, or IL-1ß gene expression levels (P = 0.580, 0.250, 0.941). CONCLUSIONS: TCT placement had no pathologically detrimental effects on the tumor or surrounding tissues and might be an attractive non-invasive strategy for cases of curative distal CRC with ACO.

Correction to: Pathological impact of transanal colorectal tube for obstructive colorectal cancer.

In Methods of Abstract, the word "2015" should be changed to "2011".

Colorectal obstruction is a potential prognostic factor for stage II colorectal cancer.

BACKGROUND: Obstructive colorectal cancer (CRC) is an emergency situation with high morbidity and mortality, but long-term outcomes of stage II/III obstructive CRC remain unclear. The aim of this study was to evaluate prognostic factors, including colorectal obstruction. METHODS: Data were retrospectively reviewed from consecutive patients with stage II/III CRC who underwent curative surgery between January 2007 and December 2011 at two Japanese institutions. We analyzed overall survival (OS) and relapse-free survival (RFS), according to various prognostic factors including colorectal obstruction. RESULTS: In total, 979 patients with stage II/III CRC were identified for this study. Among these 979 patients, 94 patients showed colorectal obstruction (9.6%). In both stage II and stage III CRCs, colorectal obstruction showed significantly poorer OS and RFS compared to non-obstruction (5-year OS, obstruction vs. non-obstruction, stage II: 65.9 vs. 86.5%, P = 0.002; stage III: 55.9 vs. 73.6%, P = 0.007) (5-year RFS, obstruction vs. non-obstruction, stage II: 59.2 vs. 77.8%, P = 0.008; stage III 31.3 vs. 56.3%, P = 0.001). Multivariate analysis demonstrated colorectal obstruction as a significant independent and poor prognostic factor in terms of both OS (hazard ratio (HR) 2.469; 95% CI 1.339-4.545; P = 0.004) and RFS (HR 1.992; 95% CI 1.160-3.425; P = 0.012) for stage II CRC, as well as pT4 stage. On multivariate analysis for stage III CRC, colorectal obstruction was a significant predictor of poor RFS (HR 1.626; 95% CI 1.070-2.469; P = 0.023), but not poor OS. CONCLUSIONS: Colorectal obstruction is an independent poor prognostic factor for stage II CRC. Adjuvant chemotherapy might be feasible for stage II CRC with colorectal obstruction.

Autonomic nervous responses in colorectal polypectomy: Randomized controlled trial comparing air and carbon dioxide insufflation.

BACKGROUND AND AIM: Carbon dioxide (CO2) insufflation devices are commonly used for endoscopic examination and treatment. In this prospective randomized controlled trial (RCT), we compared patient acceptance, cardiovascular tolerance,and autonomic nervous responses between patients receiving air insufflation and CO2 insufflation. METHODS: We initially enrolled 170 patients and, of these, 158 patients in total were analyzed (air group, 83; CO2 group, 75). Autonomic nervous responses were evaluated by analysis of heart rate variability (HRV). Primary end point was superiority in the effects of CO2 insufflation on the autonomic nervous system by HRV analysis. RESULTS: Visual analog scale disclosed significantly less abdominal pain and abdominal fullness with CO2. Percentage heart rate change rate at 1 h and 4 h after the procedure was also significantly lower in the CO2 group than in the air group (1 h after: P < 0.01, 4 h after: P < 0.05). Comparison based on age showed that % heart rate change was significantly lower in the younger CO2 patients (just after colonoscopy and 1 h after: P < 0.01, 4 h after: P < 0.05), but this difference was not apparent in an older group of patients. CONCLUSIONS: This is the first RCT showing that colorectal polypectomy using CO2 insufflation significantly decreases abdominal pain and abdominal fullness common in such patients with lowered stress to the autonomous nervous system. The effects using CO2 insufflation on the sympathetic nervous system also seemed to be more prominent among younger patients.

Multicenter, prospective trial of white-light imaging alone versus white-light imaging followed by magnifying endoscopy with narrow-band imaging for the real-time imaging and diagnosis of invasion depth in superficial esophageal squamous cell carcinoma.

BACKGROUND: Magnifying endoscopy with narrow-band imaging (ME-NBI) has been used to estimate the invasion depth of superficial esophageal squamous cell carcinoma (SESCC), but the real diagnostic power of ME-NBI remains unclear because of few prospective studies. OBJECTIVES: To evaluate whether ME-NBI adds additional information to white-light imaging (WLI) for the diagnosis of invasion depth of SESCC. DESIGN: Multicenter, prospective trial using real-time imaging and diagnosis. SETTING: Seven Japanese institutions. PATIENTS: Fifty-five patients with SESCC were enrolled from June 2011 to October 2013, and the results for 49 lesions were analyzed. INTERVENTIONS: Patients underwent primary WLI followed by ME-NBI, and reports of primary WLI (WLI alone) were completed before secondary ME-NBI (WLI followed by ME-NBI). To standardize diagnosis among examiners, this trial was started after achievement of a mean κ value≥.6 among 11 participating endoscopists. MAIN OUTCOME MEASUREMENTS: Diagnosis of invasion depth by each tool was divided into cancer limited to the epithelium and the lamina propria mucosa and cancer invading beyond the muscularis mucosae (≥T1a-MM) and then collated with the final pathologic diagnosis by an independent pathologist blinded to the clinical data. RESULTS: The accuracy of invasion depth in WLI alone and WLI followed by ME-NBI was 71.4% and 65.3% (P=.375), respectively. Sensitivity for ≥T1a-MM was 61.1% for both groups (P=1.000), and specificity for ≥T1a-MM was 77.4% for WLI alone and 67.7% for WLI followed by ME-NBI (P=.375). LIMITATION: Open-label trial. CONCLUSIONS: ME-NBI showed no additional benefit to WLI for diagnosis of invasion depth of SESCC. (University Hospital Network Clinical Trials Registry number: UMIN000005632.).

Correlation between long-term outcome and steroid therapy in type 1 autoimmune pancreatitis: relapse, malignancy and side effect of steroid.

OBJECTIVES: Autoimmune pancreatitis (AIP) responds well to corticosteroid therapy (CST), and CST is essential to induce remission. However, the correlation between long-term outcome and CST has not been evaluated. We aimed to clarify the correlation between long-term outcome of AIP and CST. MATERIAL AND METHODS: We retrospectively evaluated relapse, risk of malignancy and side effects of CST by focusing on the correlation with CST in 84 patients with type 1 AIP. RESULTS: The incidence of relapse was 23.8%. The frequency of relapse after CST administration was significantly lower in patients taking CST for >6 months than in those who did not (22% versus 67%; p = 0.036). The incidence of malignancy was 10.7%. The standardized incidence ratio of malignancy was 2.14 [95% confidence interval 0.74-3.54]. There were no significant correlations between development of malignancy and CST. The incidences of total and serious side effects due to CST were 75% and 19.1%, respectively. Relapse was the only significant independent predictive risk factor for serious side effects in a multivariate analysis (odds ratio 4.065; 95% confidence interval 1.125-14.706; p = 0.032). The cumulative dose of corticosteroid was significantly higher in patients with serious side effects than in those without (12,645 mg versus 7322 mg; p = 0.041). CONCLUSIONS: CST reduces relapse of AIP. However, CST causes serious side effects, particularly in relapsing patients. Alternative maintenance therapy to prevent relapse is needed.

Magnifying chromoendoscopy and endoscopic ultrasonography measure invasion depth of early stage colorectal cancer with equal accuracy on the basis of a prospective trial.

BACKGROUND & AIMS: Magnifying chromoendoscopy (MC) and endoscopic ultrasonography (EUS) are used to estimate the depth of colorectal cancer (CRC) invasion, but it is not clear which procedure is more accurate. We performed a prospective study to compare MC and EUS. METHODS: A total of 70 patients with an early stage flat CRC lesion were enrolled at 6 institutions in Japan and randomly assigned to groups assessed by MC followed by EUS or EUS followed by MC. Results from MC and EUS measurements of 66 lesions were included in the final analysis. The invasion depth of each lesion was measured by each procedure and categorized as mucosal to slight submucosal (depth <1000 µm) or deep submucosal (depth ≥ 1000 µm); measurements were compared with the final diagnosis on the basis of the pathology analysis. All participating examiners achieved a mean κ value ≥ 0.6 for both MC and EUS before this trial. RESULTS: MC and EUS each measured the depth of lesion invasion with 71.2% accuracy (correctly for 47 of 66 lesions). MC identified lesions with deep submucosal invasion with 74.2% sensitivity and 68.6% specificity, whereas EUS identified them with 67.7% sensitivity and 74.3% specificity. The differences between MC and EUS measurements did not differ significantly. However, MC required significantly shorter observation time than EUS (361.7 ± 164.5 seconds vs 451.2 ± 209.4 seconds, P = .002). CONCLUSIONS: MC and EUS are equally accurate in estimating the invasion depth of early stage CRC lesions. However, neither procedure has sufficient diagnostic accuracy to be used as the standard. University Hospital Medical Network Clinical Trials Registry, Number: UMIN 000005085.

Urgent colonoscopy is not necessary in case of colonic diverticular bleeding without extravasation on contrast-enhanced computed tomography.

BACKGROUND AND AIMS: Acute lower gastrointestinal bleeding (ALGIB) increase with age and the administration of antiplatelet drugs. Colonic diverticular bleeding (CDB) is the most common cause of ALGIB, and endoscopic hemostasis is an effective treatment for massive CDB. But in patients without extravasation on contrast-enhanced computed tomography (CECT), the efficacy of urgent colonoscopy (UCS) is controversial from the point of the clinical course, including rebleeding rate. We aimed to establish a potential strategy including UCS for CDB patients without extravasation on CECT. PATIENTS AND METHODS: Patients from two centers treated for CDB without extravasation on CECT between July 2014 and July 2019 were retrospectively identified (n = 282). Seventy-four underwent UCS, and 208 received conservative management. We conducted two analyses. The first analysis investigates the risk factors of rebleeding rate within 5 days after administration (very early rebleeding), and no UCS (NUCS) was not the independent factor of the very early rebleeding. The second analysis is whether UCS positively influenced the clinical course after hospitalization. RESULTS: The prevalence of very early rebleeding and early rebleeding (6-30 days from admission), patients requiring blood transfusion within 0-5 days and 6-30 days post-admission, and duration of hospitalization were examined as clinical course factors between UCS and NUCS group. There was no significant difference between the UCS and non-UCS groups in the clinical course factors. UCS for the CDB patients without extravasation was not improved rebleeding rate and clinical course. CONCLUSIONS: UCS is not necessary in case ofCDB patient without extravasation on CECT.

A Case of Adult-onset Still's Disease (AOSD) with Gastrointestinal Lesions.

A 51-year-old woman with fever was admitted to our hospital. A computed tomography (CT) scan showed thickened colonic walls. Colonoscopy revealed erosion in the ileum and colon. Adult-onset Still's disease (AOSD) was diagnosed due to a subsequent sore throat and skin rash. Following AOSD treatment, methylprednisolone pulse therapy, followed by prednisolone and cyclosporine, was initiated. Despite achieving a temporary improvement, relapse occurred with fever, abdominal pain, with worsening CT and endoscopic findings. The reappearance of a skin rash confirmed an exacerbation of AOSD. Tocilizumab treatment alleviated the symptoms and improved the endoscopic findings. Considering their correlation with the symptoms and endoscopic findings, the observed gastrointestinal lesions may be linked to AOSD.

Antimicrobial usage surveys using electronic medical records in cattle practice in Gifu Prefecture.

As the majority of antimicrobial treatments for cattle in Japan are prescribed by veterinarians, medical record information can be useful in clarifying the amount and purpose of antimicrobial use. In this study, we examined their amount and purpose in cattle practices in Gifu Prefecture. In cattle, approximately 85% of the antimicrobials are used for the treatment of gastrointestinal (50.4%) and respiratory diseases (34.4%). The main antimicrobials were sulfonamides (27.1 kg, 49.2%), followed by amphenicols (11.9 kg, 21.7%). As for second-line antimicrobials for veterinary treatment, fluoroquinolones, a third-generation cephalosporins, and 15 membered-ring macrolides, accounted for 5.6%, 0.1%, and 0.9% of all antimicrobials, respectively. Thus, medical record information may represent the actual situation of not only antimicrobial use, but also the significance of the disease in local regions.

Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion.

BACKGROUND: Membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear. METHODS: We investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay. RESULTS: Of the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P < 0.01). The growth of wt-HB-EGF- and HB-EGF-mC-expressing cells significantly increased compared with control cells, but the growth of HB-EGF-mC-expressing cells was significantly decreased compared with wt-HB-EGF-expressing cells. Gastric cancer cell invasion obviously increased in wt-HB-EGF-expressing cells, but invasion in HB-EGF-mC-expressing cells showed a slight increase compared with control cells. Moreover, wt-HB-EGF overexpression increased the effectiveness of wound healing, but had no significant effect in HB-EGF-mC-expressing cells. CONCLUSIONS: Both the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.

The impact of cross-resistance between paclitaxel and docetaxel for metastatic gastric cancer.

BACKGROUND: Paclitaxel and docetaxel show similar anticancer mechanisms, but cross-resistance for gastric cancer chemotherapy remains unclear. PATIENTS AND METHODS: Among 484 patients with metastatic gastric cancer, who had received chemotherapy in 4 Japanese hospitals, we identified 28 patients who had received either paclitaxel- or docetaxel-containing chemotherapy and who were refractory to the other taxane. RESULTS: The median age was 65 years, and target lesions were present in 20 patients and absent in 8. The first taxane was administered to 16 patients as first-line chemotherapy and to 12 patients as second-line chemotherapy, while the second taxane was administered to 5 patients as second-line, 13 as third-line, and 10 as fourth-line or beyond. The median survival time was 456 days (95% confidence interval (CI) 145-767 days), and the median survival time and median progression-free survival after the second taxane were 119 days (95% CI 85-153 days) and 50 days (95% CI 42-58 days), respectively. The second taxane chemotherapy achieved a response rate of 5% (1/20 patients) and an overall disease control rate of 17.9% (5/28 patients). CONCLUSIONS: Paclitaxel and docetaxel might show a large degree of cross-resistance for gastric cancer. Paclitaxel and docetaxel should not be routinely administered for metastatic gastric cancer after failure of the other taxane.

Efficacy of transcatheter arterial embolization for first-line treatment of colonic diverticular bleeding with extravasation on contrast-enhanced computed tomography.

Colonic diverticular bleeding (CDB) is the most frequent cause of acute lower gastrointestinal bleeding. The aim of this study was to evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for CDB as first-line treatment with extravasation on contrast-enhanced computed tomography (CECT), compared with endoscopic hemostasis. Three Japanese institutions participated in this retrospective cohort study. Data from consecutive patients admitted with a diagnosis of CDB with extravasation on CECT were reviewed. One hospital performed TAE and the others conducted urgent colonoscopy (CS) as the first-line treatment for CDB with extravasation on CECT. The primary outcome was rebleeding rate within 30 days after first-line treatment. In total, 165 CDB cases with extravasation on CECT (TAE group, n = 39; CS group, n = 126) were analyzed in this study. The rebleeding rate within 30 days was significantly lower in the TAE group (7.69%) than in the CS group (23.02%; P = .038). The bleeding point detection rate was significantly higher in the TAE group (89.74%, 35/39) than in the CS group (37.30%, 47/126; P < .0001). Even in those cases in which a bleeding point was detected, the rebleeding rate was significantly lower in the TAE group (0%) than in the endoscopic hemostasis-success group (23.91%; P = .005). No severe complications of Grade 3 or more were seen with TAE. We showed that TAE is an effective, safe hemostatic method, and a useful alternative to endoscopic hemostasis for first-line treatment of CDB.

Eosinophilic pancreatitis presenting as rupture of a pancreatic cystic lesion into the chest cavity.

A 71-year-old man was receiving follow-up examination because of a retention cyst in the pancreatic body that extended to the dorsal extrahepatic area, but presented to the Emergency Department at our hospital with dyspnea and cough. Chest X-ray showed a large amount of left-sided pleural effusion and abdominal computed tomography (CT) showed reduction in size of the cystic lesion. Biochemical testing of the pleural effusion revealed high levels of pancreatic enzymes. We, therefore, diagnosed rupture of the pancreatic cystic lesion into the chest cavity. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated stenosis of the pancreatic duct and leakage of contrast medium at the cystic lesion. CT after ERCP revealed leakage of contrast medium from the cystic lesion through the dorsal extrahepatic area into the chest cavity. Endoscopic naso-pancreatic drainage was performed, but the cystic lesion and pleural effusion remained unimproved. Distal pancreatectomy was, therefore, performed. Microscopic examination revealed eosinophilic infiltration of the pancreatic parenchyma, leading to a diagnosis of eosinophilic pancreatitis (EP). Pancreatic retention cyst secondary to chronic pancreatitis associated with eosinophilic infiltration was considered to have ruptured into the chest cavity. EP is a rare etiology of pancreatitis and few cases have been reported. This case was thus considered valuable.

Phase II Prospective Study of Trastuzumab in Combination with S-1 and Oxaliplatin (SOX100) Therapy for HER2-Positive Advanced Gastric Cancer.

PURPOSE: The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m2) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC. METHODS: In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, oxaliplatin (100 mg/m2) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5-86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5-22.9) months, 7.6 (95% CI 5.0-10.9) months, and 75.0% (95% CI 53.3-90.2), respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%). CONCLUSION: SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC.

Incidence of gastrointestinal bleeding in patients with cardiovascular disease: buffered aspirin versus enteric-coated aspirin.

OBJECTIVE: Aspirin-induced enteropathy is increasing, but whether the type of aspirin affects the gastrointestinal (GI) bleeding, especially small intestine, is unclear. The incidence of GI bleeding for buffered aspirin and enteric-coated aspirin was evaluated in patients receiving long-term low-dose aspirin (LDA) for cardiovascular (CV) diseases. METHODS: This retrospective cohort study assessed overt GI bleeding, decreased hemoglobin levels suspecting small bowel blood loss, and CV death in patients taking LDA for more than 1 year (LDA group) and in patients not taking LDA (control group). The LDA group was divided into two subgroups, patients taking either buffered aspirin (buffered subgroup) or enteric-coated aspirin (enteric subgroup), and their outcomes were compared. RESULTS: A total of 1402 patients (LDA group 701, control group 701; median follow-up duration 1778 ± 747 days) were assessed. The incidences of overt GI bleeding and decreased hemoglobin were 3.9% and 1.4% in LDA group, respectively, significantly higher than the control group (p < 0.01; p < 0.01). In the LDA group, 3% died during the follow-up period. Ten (3.7%) in the buffered subgroup (n = 267) and 17 (3.9%) in the enteric subgroup (n = 434) developed GI bleeding (p = 0.92). One (0.3%) in the buffered subgroup and nine (2%) in the enteric subgroup developed decreased hemoglobin (p = 0.06, log-rank test). CONCLUSIONS: The type of aspirin does not affect the incidence of overt GI bleeding and decreased hemoglobin, but enteric-coated aspirin may be associated with an increased incidence of decreased hemoglobin.

TGFß induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells.

BACKGROUND AND AIMS: Transforming growth factor-beta (TGFß) is known to potently inhibit cell growth. Loss of responsiveness to TGFß inhibition on cell growth is a hallmark of many types of cancer, yet its mechanism is not fully understood. Membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) ectodomain is cleaved by a disintegrin and metalloproteinase (ADAM) members and is implicated in epidermal growth factor receptor (EGFR) transactivation. Recently, nuclear translocation of the C-terminal fragment (CTF) of pro-HB-EGF was found to induce cell growth. We investigated the association between TGFß and HB-EGF signal transduction via ADAM activation. MATERIALS AND METHODS: The CCK-8 assay in two gastric cancer cell lines was used to determine the effect for cell growth by TGFß. The effect of two ADAM inhibitors was also evaluated. Induction of EGFR phosphorylation by TGFß was analyzed and the effect of the ADAM inhibitors was also examined. Nuclear translocation of HB-EGF-CTF by shedding through ADAM activated by TGFß was also analyzed. EGFR transactivation, HB-EGF-CTF nuclear translocation, and cell growth were examined under the condition of ADAM17 knockdown. RESULT: TGFß-induced EGFR phosphorylation of which ADAM inhibitors were able to inhibit. TGFß induced shedding of proHB-EGF allowing HB-EGF-CTF to translocate to the nucleus. ADAM inhibitors blocked this nuclear translocation. TGFß enhanced gastric cancer cell growth and ADAM inhibitors suppressed this effect. EGFR phosphorylation, HB-EGF-CTF nuclear translocation, and cell growth were suppressed in ADAM17 knockdown cells. CONCLUSION: HB-EGF-CTF nuclear translocation and EGFR transactivation from proHB-EGF shedding mediated by ADAM17 activated by TGFß might be an important pathway of gastric cancer cell proliferation by TGFß.

Efficacies of first and second tumor necrosis factor inhibitors in refractory ulcerative colitis patients in real-world practice.

BACKGROUND: Switching tumor necrosis factor-α inhibitors is an important treatment option for refractory ulcerative colitis (UC) patients who fail the first anti-tumor necrosis factor-α therapy, although many questions about this option remain unanswered. METHODS: The efficacy of the second anti-tumor necrosis factor-α therapy in refractory UC patients who failed the first anti-tumor necrosis factor-α therapy was examined using the Mayo score as a measure of disease activity at week 8. The efficacy of the first anti-tumor necrosis factor-α therapy before treatment and at weeks 8 and 52 was also evaluated in real-world practice. RESULTS: There were no significant differences in remission induction and maintenance between infliximab and adalimumab as the first anti-tumor necrosis factor-α therapy in UC patients. Of 123 UC patients, 21 (17.1%) switched tumor necrosis factor-α inhibitors. Eight (38.1%), 4 (19.0%), 7 (33.3%), and 2 (9.5%) patients switched from infliximab to adalimumab, infliximab to golimumab, adalimumab to infliximab, and adalimumab to golimumab, respectively. Three (100%) with intolerance to the first anti-tumor necrosis factor-α therapy, 5 (41.7%) with loss of response to the first anti-tumor necrosis factor-α therapy, and 1 (20.0%) with no improvement with the first anti-tumor necrosis factor-α therapy had clinical remission at week 8. CONCLUSIONS: Switching tumor necrosis factor-α inhibitors is more effective for refractory UC patients who are intolerant and lose response to the first anti-tumor necrosis factor-α therapy rather than for those showing no improvement with the first anti-tumor necrosis factor-α therapy. Patients with primary failure of anti-tumor necrosis factor-α therapy should be switched to another class of drug.