[Rectal cancer with multiple metastases complicated by Crohn's disease 5 years after surgery:a case report].

In recent years, with the rising incidence of patients having long-term Crohn's disease, there has been an increase in the number of reports of carcinogenesis from dysplasia with chronic inflammation as the primary pathogenic factor. We hereby report a case of multiple metastases that appeared 5 years after surgery, in a patient with rectal cancer who had Crohn's disease. A man in his 50s was diagnosed with Crohn's disease which affected his small and large intestines 21 years back. The patient was being treated with oral steroids, 5-aminosalicylic acid, and modified nutrition. Infliximab was added to the treatment after it was introduced 11 years ago. He also had a history of rectal cancer and had undergone surgery for the same 5 years back. He was diagnosed with stage II cancer, and had not received any adjuvant chemotherapy. However, 5 years after surgery, multiple metastases recurred, and chemotherapy with mFOLFOX6 was administered. Additionally, for treating his Crohn's disease, which was also active, infliximab was changed to vedolizumab;however, the patient died a year later. Colorectal cancer accompanied with Crohn's disease has a higher risk of developing metastasis and is associated with poorer prognosis as compared to the noncomplicated colorectal cancer. Regarding treatment modalities, while searching for multidisciplinary treatment methods centered on surgical treatment in collaboration with medical oncologists and radiologists, the safety of treatment for Crohn's disease in patients with cancer must be borne in mind. The rising prevalence of cases of colorectal cancer with Crohn's disease is expected to lead to the formulation of specialized diagnostic and treatment strategies for these patients.

Potential for replacing warfarin with a direct oral anticoagulant for endoscopic mucosal resection in the colorectum: A multicenter, open-label, randomized controlled trial.

Objectives: This study aimed to evaluate the efficacy and safety of apixaban replacement (AR) as an alternative to heparin bridging (HB) in patients taking warfarin and scheduled for endoscopic mucosal resection (EMR) in the colorectum. Methods: This trial was conducted at seven institutes in Japan between May 2016 and May 2018. Enrolled patients had been taking oral warfarin and were diagnosed within 3 months with colorectal polyps for which EMR was indicated. Patients were randomly assigned to receive HB or AR. The primary endpoint was the incidence of postoperative bleeding. Secondary endpoints were the length of hospital stay, therapeutic endoscopy outcomes, and adverse events. Results: The planned sample size was 160 patients, but due to a decrease in the number of patients taking warfarin, the target number of cases could not be achieved within the case enrollment period, 44 cases were enrolled. They were divided into HB and AR groups. The incidence of postoperative bleeding was 15% (3/20) in HB and 0% in AR (P = 0.199). The total number of postoperative bleeding events was five in HB and none in AR. The length of hospital stay was significantly shorter in AR than in HB (median: 3.0 vs. 13.5 days, p < 0.001). There were no serious adverse events and no cerebral infarction/systemic embolism events. Conclusion: AR for colorectal EMR may prove safe and has the potential to shorten hospital stay and reduce medical costs, though we were unable to evaluate the primary endpoint due to insufficient sample size.

Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

A study for every second day administration of vonoprazan for maintenance treatment of erosive GERD (ESD von GERD): a multicenter randomized cross-over study.

BACKGROUND: Vonoprazan is a potassium competitive acid blocker used to treat erosive gastroesophageal reflux disease (GERD) with stronger, more stable acid-suppressing effects than proton pump inhibitors (PPIs). This study clarified the usefulness and superiority of vonoprazan administered every second day over PPIs in the maintenance therapy of erosive GERD. METHODS: This is a prospective, multicenter, open-label, two-period randomized cross-over study. Patients were randomized to either the vonoprazan-lansoprazole (VP-LZ) group, who were given vonoprazan 10 mg for the first 4 weeks and then lansoprazole 15 mg for the next 4 weeks both administered once every second day, or the lansoprazole-vonoprazan (LZ-VP) group, who were treated in reverse. GERD symptoms were compared using symptom diaries, the frequency scale for symptoms of GERD (FSSG), and the gastrointestinal symptom rating scale (GSRS). RESULTS: We enrolled 122 patients between December 2017 and May 2019. Symptoms were well controlled in vonoprazan administration and lansoprazole administration were 93.6% and 82.1%, respectively, with a significant difference on McNemar's test (P = 0.003). During the second 4 weeks, 94.4% and 76.7% of patients in the VP-LZ and LZ-VP groups, respectively, were well controlled following for ≥ 6 consecutive days a week (P = 0.009). During the first 4 weeks, 96.7% and 80.0% of patients were well controlled with < 1 weekly in the VP-LZ and LZ-VP groups, respectively, during the first 4 weeks (P = 0.007). GERD symptoms, assessed via FSSG and GSRS, significantly decreased with vonoprazan administration once every second day. CONCLUSIONS: Vonoprazan administered once every second day could be an effective alternative to PPIs in the maintenance treatment of erosive GERD (UMIN000030393).

[A case of severe colitis induced by the administration of pembrolizumab for pulmonary adenocarcinoma in a patient with ulcerative colitis].

Pembrolizumab is an immunoglobulin G4 isotype antibody that targets the programmed cell death protein 1 (PD-1) receptor of lymphocytes. It is used in the treatment of advanced non-small cell lung cancer (NSCLC). The safety and efficacy of immunotherapy for autoimmune disease are currently unknown;immune-related adverse events induced by immune checkpoint inhibitors (ICIs) have been reported. We report a case of severe colitis induced by the administration of pembrolizumab for pulmonary adenocarcinoma in a patient with ulcerative colitis. A 72-year-old man with a 3-year history of ulcerative colitis maintained clinical remission with mesalazine. The recurrence of lung adenocarcinoma was diagnosed and treated with pembrolizumab as second-line treatment. Diarrhea and bloody stool recurred 5 months after the first administration of pembrolizumab. The colitis did not respond to corticosteroids and infliximab. Because of the recurrence of ulcerative colitis, treatment of the lung adenocarcinoma was discontinued, and the patient died 1 year after the first administration of pembrolizumab. Few cases of severe colitis induced by the administration of pembrolizumab in patients with ulcerative colitis have been reported. This case suggests that the clinical stratification of autoimmune disease and typical standards of effectiveness of treatment are needed for patients with autoimmune disease who are treated with ICIs.

Formal proof of the requirement of MESP1 and MESP2 in mesoderm specification and their transcriptional control via specific enhancers in mice.

MESP1 and MESP2 are transcriptional factors involved in mesoderm specification, somite boundary formation and somite polarity regulation. However, Mesp quadruple mutant zebrafish displayed only abnormal somite polarity without mesoderm specification defects. In order to re-evaluate Mesp1/Mesp2 mutants in mice, Mesp1 and Mesp2 single knockouts (KOs), and a Mesp1/Mesp2 double KO were established using genome-editing techniques without introducing selection markers commonly used before. The Mesp1/Mesp2 double KO embryos exhibited markedly severe mesoderm formation defects that were similar to the previously reported Mesp1/Mesp2 double KO embryos, indicating species differences in the function of MESP family proteins. However, the Mesp1 KO did not display any phenotype, including heart formation defects, which have been reported previously. We noted upregulation of Mesp2 in the Mesp1 KO embryos, suggesting that MESP2 rescues the loss of MESP1 in mesoderm specification. We also found that Mesp1 and Mesp2 expression in the early mesoderm is regulated by the cooperation of two independent enhancers containing T-box- and TCF/Lef-binding sites. Deletion of both enhancers caused the downregulation of both genes, resulting in heart formation defects. This study suggests dose-dependent roles of MESP1 and MESP2 in early mesoderm formation.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Risk Factors for Delayed Bleeding after Therapeutic Gastrointestinal Endoscopy in Patients Receiving Oral Anticoagulants: A Multicenter Retrospective Study.

BACKGROUND/AIMS: Delayed bleeding is among the adverse events associated with therapeutic gastrointestinal endoscopy. The aim of this study was to evaluate risk factors for delayed bleeding after gastrointestinal endoscopic resection in patients receiving oral anticoagulants as well as to compare the rates of occurrence of delayed bleeding between the oral anticoagulants used. METHODS: We retrospectively analyzed a total of 772 patients receiving anticoagulants. Of these, 389 and 383 patients were receiving direct oral anticoagulants (DOACs) and warfarin, respectively. Therapeutic endoscopic procedures performed included endoscopic submucosal dissection (ESD), endoscopic mucosal resection, polypectomy, and cold polypectomy. RESULTS: Delayed bleeding occurred in 90 patients (11.7%) with no significant difference between the DOAC and warfarin groups (9.5 and 13.8%, respectively). Delayed bleeding occurred significantly more frequently with apixaban than with rivaroxaban (13.5 vs. 6.4%; p < 0.05). A multivariate analysis identified continued anticoagulant therapy (OR 2.29), anticoagulant withdrawal with heparin bridging therapy (HBT; OR 2.18), anticoagulant therapy combined with 1 antiplatelet drug (OR 1.72), and ESD (OR 3.87) as risk factors for delayed bleeding. CONCLUSION: This study identified continued anticoagulant therapy, anticoagulant withdrawal with HBT, anticoagulant therapy combined with 1 antiplatelet drug, and ESD as risk factors for delayed bleeding after therapeutic endoscopy in patients receiving oral anticoagulants. Delayed bleeding rates were not significantly different between those receiving DOACs and warfarin. It was also suggested that the occurrence of delayed bleeding may vary between different DOACs and that oral anticoagulant withdrawal should be minimized during therapeutic gastrointestinal endoscopy, given the thromboembolic risk involved.

[A case of idiopathic thrombocytopenic purpura development after total colectomy for ulcerative colitis].

Ulcerative colitis (UC) is known to be associated with extraintestinal manifestations. However, idiopathic thrombocytopenic purpura (ITP) has rarely been reported as one of the extraintestinal manifestations in UC. In most cases, ITP develops as an extraintestinal manifestation during the treatment for UC. After treatment with medications or colectomy, there is often a remission of UC and ITP. However, we experienced a case of ITP development after total colectomy for UC. An 83-year-old man was diagnosed as having UC and started treatment with medications. After 3 years, total colectomy and ileostomy were performed to prevent UC remission. Subsequently, no further treatment was provided. Two years later, he presented to the hematology department in our hospital with the chief complaint of thrombocytopenia and was diagnosed as having ITP. ITP was treated with steroids, and his platelet count increased to within the normal range. Immunological abnormalities may be involved in the development of extraintestinal manifestation, including UC-associated ITP. In previous reports, ITP was cured by colectomy for UC. In contrast, peripheral arthritis is a common extraintestinal manifestation of UC, and it is known that 75% of these patients develop or continue to experience such symptoms after colectomy. Some extraintestinal manifestations may equally persist after colectomy. However, the underlying mechanisms are poorly understood. Ileitis and small intestinal and duodenal inflammation are all known bowel complications associated with colectomy, and some immunological mechanisms have been suggested to be involved. Therefore, careful monitoring in these patients is necessary to detect any possibility of developing extraintestinal manifestations after colectomy. Further studies to examine the mechanisms underlying the immunological abnormality between UC and extraintestinal manifestations such as ITP are needed.

Application of artificial intelligence using convolutional neural networks in determining the invasion depth of esophageal squamous cell carcinoma.

OBJECTIVES: In Japan, endoscopic resection (ER) is often used to treat esophageal squamous cell carcinoma (ESCC) when invasion depths are diagnosed as EP-SM1, whereas ESCC cases deeper than SM2 are treated by surgical operation or chemoradiotherapy. Therefore, it is crucial to determine the invasion depth of ESCC via preoperative endoscopic examination. Recently, rapid progress in the utilization of artificial intelligence (AI) with deep learning in medical fields has been achieved. In this study, we demonstrate the diagnostic ability of AI to measure ESCC invasion depth. METHODS: We retrospectively collected 1751 training images of ESCC at the Cancer Institute Hospital, Japan. We developed an AI-diagnostic system of convolutional neural networks using deep learning techniques with these images. Subsequently, 291 test images were prepared and reviewed by the AI-diagnostic system and 13 board-certified endoscopists to evaluate the diagnostic accuracy. RESULTS: The AI-diagnostic system detected 95.5% (279/291) of the ESCC in test images in 10 s, analyzed the 279 images and correctly estimated the invasion depth of ESCC with a sensitivity of 84.1% and accuracy of 80.9% in 6 s. The accuracy score of this system exceeded those of 12 out of 13 board-certified endoscopists, and its area under the curve (AUC) was greater than the AUCs of all endoscopists. CONCLUSIONS: The AI-diagnostic system demonstrated a higher diagnostic accuracy for ESCC invasion depth than those of endoscopists and, therefore, can be potentially used in ESCC diagnostics.

Breast metastasis from rectal cancer with BRAF V600E mutation: a case report with a review of the literature.

Metastasis of rectal cancer to the breast is an extremely rare clinical event. We report the case of a 67-year-old woman with a metastatic breast tumor derived from a BRAF V600E mutant rectal carcinoma that was diagnosed and resected curatively 1 year previously. Computed tomography showed a left breast mass and multiple lung nodules suspected to be indicative of recurrent rectal cancer. The ultrasonography examination demonstrated a 10 × 10-mm hypoechoic solid lesion in the left breast with an elevation in the serum carcinoembryonic antigen level and serum carbohydrate antigen 19-9 level. Core needle biopsy was performed, and histopathologic examination showed Cytokeratin 20 and CDX-2 positivity, compatible with rectal cancer. To our knowledge, this is the first case of a metastatic breast tumor arising from rectal carcinoma with BRAF mutation. Although breast metastasis is very rare event, the possibility of breast metastasis from extra mammary sites should be considered when the breast tumor is found in cancer treatment.

Endoscopic alterations in Peyer's patches in patients with ulcerative colitis: A prospective, multicenter study.

BACKGROUND AND AIM: Peyer's patches (PPs) play a major role in intestinal mucosal immunity; however, their role in ulcerative colitis (UC) is not well investigated. We evaluated endoscopic features of PPs on narrow-band imaging with magnifying endoscopy (NBI-ME) and investigated their association with clinical factors. METHODS: We prospectively recruited 105 patients with UC, 18 with Crohn's disease, 16 with disease control, and 33 healthy control subjects at three institutions from 2014 to 2017. NBI-ME images of the villi of PPs were evaluated according to the Villi Index, and patients were divided into the Villi Index low (L) and high (H) types. The 1-year sustained clinical remission rate was evaluated between L-type and H-type PPs in patients with UC. RESULTS: The proportions of patients with H-type PPs were significantly higher among UC, Crohn's disease, and disease control patients than among healthy control patients (P = 0.0125, 0.018, 0.0007). In UC, age, gender, endoscopic score, and extent of disease involvement were not significantly different between L-type and H-type PPs, whereas the sustained clinical remission rate was significantly higher in L-type PPs than in H-type PPs (88% [57/65] vs 65% [17/26], P = 0.019). Multivariate analysis revealed that the L type of PPs was a significant factor for sustained clinical remission (odds ratio 3.8, 95% confidence interval 1.1-12.9, P = 0.033). CONCLUSIONS: Patients with UC showed endoscopic alterations in PPs on NBI-ME, and highly altered appearance of PPs can be associated with a high risk of clinical relapse in patients with UC.

[A case of refractory pouchitis following surgery for ulcerative colitis successfully treated with adalimumab].

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is widely accepted as the operation of choice for refractory ulcerative colitis (UC), UC with dysplasia or cancer, or familial adenomatous polyposis. Pouchitis is the most frequent complication after IPAA for UC. Although the pathogenesis of pouchitis remains unclear, current evidence suggests that dysbiosis and mucosal immune response are important mechanisms. Antibiotics are the first-line treatment for the condition, but some patients develop chronic refractory pouchitis. Such cases can be treated with regimens such as longer courses of antibiotic combinations, mesalazine, corticosteroids, probiotics, or biologics. But if pouch inflammation is not ameliorated, a permanent ileostomy may be required. A 40-year-old man had undergone IPAA for UC and was diagnosed with pouchitis according to the Pouchitis Disease Activity Index. Antibiotics, mesalazine, and corticosteroids were given, but the inflammation was difficult to control. He developed chronic refractory pouchitis associated with perianal abscesses and anal fistulae. Following a seton procedure for fistulae, adalimumab (ADA) was administered. After 42 weeks, the ulcers in the pouch became scarred, and the anal fistulae were closed endoscopically. After remission was induced, it has been maintained. ADA is a fully human anti-tumor necrosis factor-α (TNF-α) monoclonal antibody that has been successfully used to treat refractory Crohn disease of the ileoanal pouch. Although some studies report that infliximab, a chimeric anti-TNF-α monoclonal antibody, is efficacious in patients with refractory pouchitis, clinical evidence for the use of ADA is limited. This case illustrates achievement of induction and maintenance of remission of refractory pouchitis with ADA. It is possible that patients with this condition can avoid a permanent ileostomy with anti-TNF-α therapy. In the near future, further study of long-term clinical outcomes of anti-TNF-α therapy is expected.

Continuous Anticoagulation and Cold Snare Polypectomy Versus Heparin Bridging and Hot Snare Polypectomy in Patients on Anticoagulants With Subcentimeter Polyps: A Randomized Controlled Trial.

Background: Management of anticoagulants for patients undergoing polypectomy is still controversial. Cold snare polypectomy (CSP) is reported to cause less bleeding than hot snare polypectomy (HSP). Objective: To compare outcomes between continuous administration of anticoagulants (CA) with CSP (CA+CSP) and periprocedural heparin bridging (HB) with HSP (HB+HSP) for subcentimeter colorectal polyps. Design: Multicenter, parallel, noninferiority randomized controlled trial. (University Hospital Medical Information Network Clinical Trials Registry: UMIN000019355). Setting: 30 Japanese institutions. Patients: Patients receiving anticoagulant therapy (warfarin or direct oral anticoagulants) who had at least 1 nonpedunculated subcentimeter colorectal polyp. Intervention: Patients were randomly assigned to undergo HB+HSP or CA+CSP and followed up 28 days after polypectomy. Measurements: The primary end point was incidence of polypectomy-related major bleeding (based on the incidence of poorly controlled intraprocedural bleeding or postpolypectomy bleeding requiring endoscopic hemostasis). The prespecified inferiority margin was -5% (CA+CSP vs. HB+HSP). Results: A total of 184 patients were enrolled: 90 in the HB+HSP group, 92 in the CA+CSP group, and 2 who declined to participate after enrollment. The incidence of polypectomy-related major bleeding in the HB+HSP and CA+CSP groups was 12.0% (95% CI, 5.0% to 19.1%) and 4.7% (CI, 0.2% to 9.2%), respectively. The intergroup difference for the primary end point was +7.3% (CI, -1.0% to 15.7%), with a 0.4% lower limit of 2-sided 90% CI, demonstrating the noninferiority of CA+CSP. The mean procedure time for each polyp and the hospitalization period were longer in the HB+HSP than in the CA+CSP group. Limitation: An open-label trial assessing 2 factors (anticoagulation approach and polypectomy procedure type) simultaneously. Conclusion: Patients having CA+CSP for subcentimeter colorectal polyps who were receiving oral anticoagulants did not have an increased incidence of polypectomy-related major bleeding, and procedure time and hospitalization were shorter than in those having HB+HSP. Primary Funding Source: Japanese Gastroenterological Association.

Favorable outcome with direct-acting antiviral treatment in hepatitis C patients coinfected with HIV.

AIM: To investigate the efficacy and safety of all-oral direct-acting antiviral treatments in patients coinfected with hepatitis C virus (HCV) and HIV. METHODS: In all, 35 patients with HCV/HIV coinfection (22 patients with HCV genotype 1 infection, 6 with genotype 2, and 7 with genotype 3) were treated with sofosbuvir and ledipasvir (for genotype 1 patients) or sofosbuvir and ribavirin (for genotypes 2 and 3). Sustained virological response (SVR) at 24 weeks after end of treatment and adverse events were assessed. RESULTS: The overall SVR rate was 91.4% (32/35). One patient with genotype 1 infection discontinued treatment on day 2 due to severe headache, which subsided after the cessation of medication; all other patients completed their treatment without severe adverse events. Two patients who had a relapse of HCV were infected with a genotype 3 strain. We observed hyperbilirubinemia in a patient with genotype 3, who was under antiretroviral therapy including atazanavir. He completed the treatment and achieved SVR. CONCLUSION: Direct-acting antiviral treatment for patients coinfected with HCV/HIV is as effective as in patients infected only with HCV. It was generally well tolerated, except in one patient who discontinued the treatment due to severe headache.

Comparison of the developmental/reproductive toxicity and hepatotoxicity of phthalate esters in rats using an open toxicity data source.

Phthalate esters (PEs) are widely used as plasticizers in various kinds of plastic products. Some PEs have been known to induce developmental and reproductive toxicity (DART) as well as hepatotoxicity in laboratory animals. In some cases of DART, the strength of toxicity of PEs depends on the side chain lengths, while the relationship between hepatotoxicity and side chain length is unknown. Therefore, in this study, we compared DART and hepatotoxicity in rats, focusing on 6 PEs with different side chains. We collected toxicity data of 6 PEs, namely, n-butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), di-isodecyl phthalate (DIDP), di-isononyl phthalate (DINP), and di-n-octyl phthalate (DNOP), from open data source, then, we constructed the toxicity database to comprehensively and efficiently compare the toxicity effects. When we compared DART using the toxicity database, we found that BBP, DBP, and DEHP with short side chains showed strong toxicities against the reproductive organs of male offspring, and the No-Observed-Adverse-Effect Levels (NOAELs) of BBP, DBP, and DEHP were lower than DIDP, DINP, and DNOP with long side chains. Comparing hepatotoxicities, the lowest NOAEL was shown 14 mg/kg/day for DEHP, based on liver weight gain with histopathological changes. However, as BBP and DBP showed higher NOAEL than the other 3 PEs (DIDP, DINP, and DNOP), we conclude that hepatotoxicity does not depend on the length of side chain. Concerning side chain length of PEs, we effectively utilized our constructed database and found that DART and hepatotoxicity in rats showed different modes of toxicities.