Automated machine learning approach for developing a quantitative structure-activity relationship model for cardiac steroid inhibition of Na+/K+-ATPase.

BACKGROUND: Quantitative structure-activity relationship (QSAR) modeling is a method of characterizing the relationship between chemical structures and biological activity. Automated machine learning enables computers to learn from large datasets and can be used for chemoinformatics. Cardiac steroids (CSs) inhibit the activity of Na+/K+-ATPase (NKA) in several species, including humans, since the binding pocket in which NKA binds to CSs is highly conserved. CSs are used to treat heart disease and have been developed into anticancer drugs for use in clinical trials. Novel CSs are, therefore, frequently synthesized and their activities evaluated. The purpose of this study is to develop a QSAR model via automated machine learning to predict the potential inhibitory activity of compounds without performing experiments. METHODS: The chemical structures and inhibitory activities of 215 CS derivatives were obtained from the scientific literature. Predictive QSAR models were constructed using molecular descriptors, fingerprints, and biological activities. RESULTS: The best predictive QSAR models were selected based on the LogLoss value. Using these models, the Matthews correlation coefficient, F1 score, and area under the curve of the test dataset were 0.6729, 0.8813, and 0.8812, respectively. Next, we showed automated construction of the predictive models for CS derivatives, which may be useful for identifying novel CSs suitable for candidate drug development. CONCLUSION: The automated machine learning-based QSAR method developed here should be applicable for the time-efficient construction of predictive models using only a small number of compounds.

Interaction of Odoroside A, A Known Natural Cardiac Glycoside, with Na+/K+-ATPase.

The nature of odoroside A, a cardiac glycoside (CG) extracted from Nerium oleander, as well as its chemical structure is quite similar to a well-known CG, ouabain possessing a steroid skeleton, a five-membered unsaturated lactone ring, and a sugar moiety as a common structure. Like ouabain, odoroside A inhibits the activity of Na+/K+-ATPase (NKA) and shows significant anticancer activity, however its inhibitory mechanism remains unknown. CGs show various physiological activities, including cardiotonic and anticancer activities, through the inhibition of NKA by direct interaction. Additionally, X-ray crystallographic analysis revealed the inhibitory mechanism of ouabain and digoxin in relation to NKA. By using different molecular modeling techniques, docking simulation of odoroside A and NKA was conducted based on the results of these X-ray crystallographic analyses. Furthermore, a comparison of the results with the binding characteristics of three known CGs (ouabain, digoxin, and digitoxin) was also conducted. Odoroside A fitted into the CG binding pocket on the α-subunit of NKA revealed by X-ray crystallography. It had key interactions with Thr797 and Phe783. Also, three known CGs showed similar interactions with Thr797 and Phe783. Interaction modes of odoroside A were quite similar to those of ouabain, digoxin, and digitoxin. Docking simulations indicated that the sugar moiety enhanced the interaction between NKA and CGs, but did not show enhanced NKA inhibitory activity because the sugar moiety was placed outside the entrance of active site. Thus, these results suggest that the inhibitory mechanism of odoroside A to NKA is the same as the known CGs.

[A Case of De Novo Stage â £ Breast Cancer Successfully Treated with Surgery and Multiple Endocrine Therapies Over a Long Period of Time].

Here we present a case of de novo Stage Ⅳ breast cancer successfully treated with surgery and multiple endocrine therapies over a long period of time. A 75-year-old female presented with a breast tumor with skin invasion and multiple lung metastases. Diagnosed with infiltrating breast cancer of Luminal A-like subtype, endocrine therapy with anastrozole was initiated. Despite initial response to the treatment in both the primary site and lung metastases, the primary tumor regrew and surgery with lumpectomy was performed. After a 3-year-treatment of tamoxifen, axillary lymphadenopathy and bone metastases developed. The patient was treated with fulvestrant for 5 years, resulting in clinical complete response. The now 88-year-old patient has been free of disease without treatment for a year and a half. Generally, primary tumor resection of Stage Ⅳ breast cancer does not improve prognosis, but in this case it provided good local control and enabled long-term endocrine therapy, resulting in prolonged disease-free survival.

[A Case of Primary Gastric Lymphoma with Spontaneous Perforation].

An 85-year-old female patient presented to the emergency department with the chief complaint of sudden upper abdominal pain. The patient suffered from anorexia and epigastric pain for a month, and a local physician suspected a diagnosis of gastric ulcer. An abdominal computed tomography(CT)scan showed intraperitoneal free air as well as irregular thickening and thinning of the gastric wall. Gastric ulcer perforation was suspected, and an emergency operation was performed. Surgical findings showed thickening of the gastric wall in the pylorus and gastric corpus but partial thinning of areas of the anterior wall of the gastric corpus with a perforation measuring 5 mm. A distal gastrectomy and reconstruction were performed using the Billroth Ⅱ method. The histopathological diagnosis was malignant gastric lymphoma(diffuse large B- cell lymphoma). Considering the patient's age and general condition, chemotherapy was not administered after surgery. The patient was alive without recurrence 8 months after the operation.

[Resectable Pancreatic Cancer Successfully Treated with Neoadjuvant Chemotherapy Regimen Change to Modified FOLFIRINOX-A Case Report].

A 72-year-old woman presented with obstructive jaundice. Computed tomography revealed a 12-mm low-density mass in the head of the pancreas. She was diagnosed as having pancreatic cancer by endoscopic ultrasound-guided fine-needle aspiration. She received gemcitabine plus nab-paclitaxel as preoperative chemotherapy. After 2 courses, hepatoduodenal lymph node metastasis appeared and was accompanied by increased tumor marker levels. The regimen was changed to modified FOLFIRINOX. After 5 courses, the lymph node metastasis was reduced in size and the tumor marker levels were decreased, so subtotal stomach-preserving pancreaticoduodenectomy was performed. Adjuvant chemotherapy was administered postoperatively. The patient was alive and well without recurrence 2 years and 9 months after the surgery, but died of sepsis. Nevertheless, this case highlights that when preoperative chemotherapy for resectable pancreatic cancer appears to be ineffective, a change in regimen may be useful.

Location, morphology and invasiveness of lateral spreading tumors in the colorectum differ between two large cohorts from an eastern and western country.

BACKGROUND AND STUDY AIMS: Data from Japanese series show that surface morphology of laterally spreading tumors (LST) in the colon identifies lesions with different incidence and pattern of submucosal invasion. Such data from western countries are scarce. We compared clinical and histological features of LST in a western country and an eastern country, with special interest on mucosal invasiveness of LST, and investigated the effect of clinical factors on invasiveness in both countries. PATIENTS AND METHODS: Patients with LST lesions ≥20mm were included from a multicenter prospective registry in Spain and from a retrospective registry from the National Cancer Center Hospital East, Japan. The primary outcome was the presence of submucosal invasion in LST. The secondary outcome was the presence of high-risk histology, defined as high-grade dysplasia or submucosal invasion. RESULTS: We evaluated 1102 patients in Spain and 663 in Japan. Morphological and histological characteristics differed. The prevalence of submucosal invasion in Japan was six-fold the prevalence in Spain (Prevalence Ratio PR=5.66; 95%CI: 3.96, 8.08), and the prevalence of high-risk histology was 1.5 higher (PR=1.44; 95%CI: 1.31, 1.58). Compared to the granular homogeneous type and adjusted by clinical features, granular mixed, flat elevated, and pseudo-depressed types were associated with higher odds of submucosal invasion in Japan, whereas only the pseudo-depressed type showed higher risk in Spain. Regarding high-risk histology, both granular mixed and pseudo-depressed were associated with higher odds in Japan, compared with only the granular mixed type in Spain. CONCLUSION: This study reveals differences in location, morphology and invasiveness of LST in an eastern and a western cohort.

[Locally Advanced HER2-Positive Breast Cancer Successfully Treated with Trastuzumab Emtansine].

Although the prognosis of HER2-positive breast cancer(BC)has been improving than before, that of locally advanced cases is not satisfactory. A 41-year-old female presented with a huge breast lump and massive lymphadenopathy, which was diagnosed as HER2-positive, unresectable, locally advanced BC. The first treatment, consisting of docetaxel, trastuzumab and pertuzumab, had only a limited and temporary effect, with subsequent mass regrowth. After initiation of the second treatment, trastuzumab emtansine(TDM1), the mass gradually shrank, and mastectomy and axillary lymphadenectomy were performed successfully. Histologically, several tiny invasive foci were observed in the mammary gland. No lymph node metastases were observed. The patient subsequently underwent radiation therapy and a 1-year course of TDM1 treatment. The patient has been in remission for 5 years. HER2-positive, locally advanced BC can be successfully treated with multimodal therapy, including anti-HER2 therapy, timely surgery and radiation therapy.

[A Case of Pancreatic Invasive Micropapillary Carcinoma That Survived Seven Years after Resection and Chemotherapy].

We present the case of a 47-year-old man who underwent a subtotal stomach-preserving pancreaticoduodenectomy for pancreatic head cancer. Histopathological diagnosis revealed that the majority of the cancer was an invasive micropapillary carcinoma(IMPC). Postoperative adjuvant chemotherapy using S-1 was continued for 4 years, at the end of which, multiple lymph node metastases were identified. Therefore, gemcitabine plus S-1 therapy was initiated. The treatment reduced the lymph node in size and resulted in the maintenance of a partial response for a year and a half. However, increased lymph node metastases recurred, and multiple lung metastases were noted. The patient died 7 years and 2 months after the resection of the primary lesion. Although pancreatic IMPC has a poor prognosis, long-term survival may be achieved by resection of the primary region, the administration of adjuvant chemotherapy and management of recurrent lesions by chemotherapy.

[Total Pancreatectomy for Remnant Pancreatic Cancer with Positive Washing Cytology after Conversion to Negative Cytology Following Gemcitabine plus Nab-Paclitaxel Therapy-A Case Report].

A 53-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy(SSPPD)for resectable pancreatic cancer after neoadjuvant chemotherapy. Postoperatively, she received hepatic arterial infusion of 5-FU and S-1 chemotherapy. Two years after SSPPD, abdominal computed tomography showed a 2-cm mass in the remnant pancreas, which was diagnosed as recurrence of cancer by endoscopic ultrasound-guided fine-needle aspiration. Staging laparoscopy was performed and peritoneal washing cytology(CY)was positive. She then received gemcitabine plus nab-paclitaxel chemotherapy for 8 months. After that, staging laparoscopy was performed again and negative CY was confirmed. A total remnant pancreatectomy with splenectomy was performed. She received chemotherapy after pancreatectomy and is now alive and well without recurrence 2 years and 1 month after the second surgery. Although positive CY is a poor prognostic factor, surgery combined with perioperative chemotherapy may contribute to prolonged survival for some patients who have recurrence in the remnant pancreas with positive CY.

[Breast Cancer Metastasis to the Mesentery Diagnosed Via Laparoscopic Biopsy-A Case Report].

Breast cancer can metastasize to organs all over the body, but isolated mesenteric metastases are rare. A 72-year-old female, with a history of invasive lobular carcinoma of the breast treated with breast-conserving therapy and axillary lymphadenectomy 7 years previously and 5 years of endocrine therapy, presented with asymptomatic elevated serum carcino- embryonic antigen. Computed tomography(CT)revealed no obvious distant metastasis, but showed increased adipose tissue density around the pancreas suggestive of acute pancreatitis. During follow-up, in addition to the abnormality around the pancreas, mild thickening of the mesentery was observed on CT. Definitive diagnosis of mesenteric metastasis of invasive lobular carcinoma was confirmed via laparoscopic biopsy. It was supposed that the breast cancer had first metastasized to the retroperitoneum via the hematogenous route, and had then directly infiltrated the mesentery. Laparoscopic biopsy is effective for diagnosis of intra-peritoneal metastases.

[A Case of Surgical Resection of Anaplastic Carcinoma of the Pancreas(Pleomorphic Cell Type)with Poor Response to Neoadjuvant Chemotherapy].

A 62-year-old man was incidentally found to have a pancreatic tumor by CT. He was diagnosed with pancreatic cancer by EUS-FNAB. Gemcitabine(GEM)plus nab-paclitaxel(PTX)was started as neoadjuvant chemotherapy(NAC)for resectable pancreatic cancer. However, after the end of the second course, the tumor grew rapidly and invaded the stomach, so NAC was discontinued, and surgery was performed. The pathological diagnosis was anaplastic ductal carcinoma of the pleomorphic cell type, and the histological response was Grade 1a. Multiple liver metastases appeared during adjuvant chemotherapy with S-1, so GEM plus nab-PTX and modified FOLFIRINOX were administered, but the therapeutic response was poor, the patient died 9 months after surgery. Anaplastic carcinoma has a poor response to chemotherapy and may be included with cancers showing treatment resistance to NAC, as seen in our case. It is necessary to pay attention to anaplastic carcinoma during the course of NAC for pancreatic cancer.

Complications and outcomes in diffuse large B-cell lymphoma with gastric lesions treated with R-CHOP.

Standard therapy for gastric diffuse large B-cell lymphoma (DLBCL) is considered to be chemotherapy with or without involved-field radiation therapy. Although R-CHOP therapy alone is widely used for DLBCL with gastric lesions (DLBCL-GL), the outcome and incidence of treatment-related gastric complications following R-CHOP are not well known. This study aimed to evaluate the outcome after R-CHOP therapy in patients with gastric DLBCL including gastric complications and to identify risk factors for the complications. Consecutive patients with newly diagnosed DLBCL-GL treated with R-CHOP between 2003 and 2014 were retrospectively evaluated. DLBCL-GL was defined only when pathologically confirmed in the stomach. Of the 96 patients with DLBCL-GL, 63 patients were diagnosed with gastric symptoms. Eighty-eight patients (92%) completed six to eight cycles of R-CHOP. The complete remission (CR) rate was 86%, and 3-year and 5-year overall survival rates were 80% and 73%, respectively. Patients were well stratified according to the Revised International Prognostic Index (R-IPI). Complication rate was 8% (8/96); seven patients had bleeding and three had stenosis. No patients had gastric perforation. Bleeding occurred during the first cycle of R-CHOP in five patients (5/7, 71%). Patients with gastric complications had a lower R-CHOP completion rate (50%, P = 0.001) and a lower CR rate (25%, P < 0.001) than those without complications. A low serum albumin level at diagnosis was the only risk factor identified for gastric complications (P = 0.001) and six of the eight patients with complications were shown to be at stage IV. Further studies of DLBCL-GL are warranted to identify patients at high risk for gastric complications and to provide better treatment strategies.

Mechanism for Decreased Gene Expression of ß4-Galactosyltransferase 5 upon Differentiation of 3T3-L1 Mouse Preadipocytes to Adipocytes.

Upon differentiation of cells, remarkable changes in the structures of glycans linked to lipids on cell surface have been observed. Lactosylceramide (Lac-Cer) serves as a common precursor for a series of glycosphingolipids with diverse structures. In the present study, we examined the underlying mechanism for the biosynthesis of Lac-Cer upon differentiation of 3T3-L1 mouse preadipocytes to adipocytes. TLC analysis showed that the amounts of Lac-Cer decrease in 3T3-L1 adipocytes compared to 3T3-L1 preadipocytes. In accordance with this change, the gene expression level of ß4-galactosyltransferase (ß4GalT) 5, which was identified as Lac-Cer synthase, decreased drastically upon differentiation of 3T3-L1 preadipocytes. The analysis of the transcriptional mechanism of the ß4GalT5 gene demonstrated that the core promoter region is identified between nucleotides -299 and -1 relative to the translational start site. During adipocyte differentiation, the expression levels and promoter activities of the ß4GalT5 gene decreased dramatically. Since the Specificity protein 1 (Sp1)-binding sites in the promoter region were critical for the promoter activity, it is suggested that Sp1 plays an important role for the expression of the ß4GalT5 gene in 3T3-L1 cells. The gene and protein expression of Sp1 decreased significantly upon differentiation of 3T3-L1 preadipocytes. Taken together, the present study suggest that the expression of the ß4GalT5 gene decreases through reduced expression of the Sp1 gene and protein upon differentiation of 3T3-L1 peradipocytes to adipocytes, which may lead to the decreased amounts of Lac-Cer in 3T3-L1 adipocytes.

Correction: The different pathogenesis of sporadic adenoma and adenocarcinoma in non-ampullary lesions of the proximal and distal duodenum.

[This corrects the article DOI: 10.18632/oncotarget.17051.].

Multiple convex demarcation line for prediction of benign depressed gastric lesions in magnifying narrow-band imaging.

BACKGROUND AND STUDY AIMS: With magnifying narrow-band imaging (M-NBI) of the gastric mucosa, a characteristic demarcation line (DL) is occasionally found in non-cancerous depressed lesions. This DL forms multiple convex shapes along the edge of the epithelia of surrounding mucosa. We have termed this novel finding a multiple convex DL (MCDL). In this study, we clarified the prevalence of an MCDL in depressed gastric lesions detected in patients at high risk for gastric cancer and determined the diagnostic yield necessary to distinguish between cancer and non-cancer. PATIENTS AND METHODS: This was a post hoc analysis of a multicenter prospective trial. In total, 362 small (≤ 10 mm) depressed lesions were detected in 1353 patients. Presence or absence of a DL in target lesions was evaluated on M-NBI images. The proportion of MCDLs among lesions with a DL was evaluated. RESULTS: Images of 347 lesions (39 cancerous and 308 non-cancerous) were evaluable. A DL was present in 252/347 lesions (73 %). When the cutoff value for the proportion of MCDLs needed to distinguish non-cancer from cancer was set at two-thirds, an MCDL was observed in 86/252 lesions (34 %). In 86 lesions with an MCDL, 83 (97 %) were non-cancerous. The sensitivity, specificity, positive predictive value, and negative predictive value of an MCDL for non-cancerous lesions were 38 %, 91 %, 97 %, and 19 %, respectively. CONCLUSIONS: Presence of an MCDL had high specificity and positive predictive value for non-cancerous lesions. Evaluating the shape of the DL is useful for differentiation between cancer and non-cancerous lesions.

A non-randomized confirmatory trial of an expanded indication for endoscopic submucosal dissection for intestinal-type gastric cancer (cT1a): the Japan Clinical Oncology Group study (JCOG0607).

BACKGROUND: Endoscopic resection has been limited to intestinal-type gastric cancer (cT1a) with a low risk of lymph node metastasis (T1a ≤2 cm, without ulcers). This single-arm confirmatory trial evaluated the efficacy and safety of endoscopic submucosal dissection (ESD) for >2 cm ulcer-negative and ≤3 cm ulcer-positive intestinal-type gastric cancer (cT1a). METHODS: The eligibility criteria included endoscopically diagnosed cT1a, a single primary intestinal-type gastric adenocarcinoma, an ulcer-negative lesion of any size or a ≤3 cm ulcer-positive lesion, cN0M0, and no prior treatment. If ESD resulted in noncurative resection, surgical resection was added. The primary endpoint was the 5-year overall survival (OS) (planned sample size was 470, with a one-sided alpha level of 2.5%). The threshold 5-year OS was 86.1%. RESULTS: We enrolled 470 early gastric cancer patients [median tumor size, 25 (5-130) mm] from 29 institutions between June 2007 and October 2010. These patients had 152 ulcer-negative lesions (>2 and ≤3 cm), 111 ulcer-negative lesions (>3 cm), and 207 ulcer-positive lesions (≤3 cm). The success rate for en block resection was 99.1% (466/470). Additional gastrectomy was conducted in 131 patients (28%) who did not fulfill the curative resection criteria. The 5-year OS of all patients was 97.0% (95% confidence interval, 95.0-98.2%), which was higher than the threshold 5-year OS (86.1%). The 317 patients who satisfied the curative resection criteria had no recurrence. There were no ESD-related grade 4 adverse events. CONCLUSION: ESD for early gastric cancers that met the expanded criteria for intestinal-type gastric cancer (cT1a) was acceptable and should be the standard treatment instead of gastrectomy.

Progress in a selective method for the determination of the acetaldehyde-derived DNA adducts by using HILIC-ESI-MS/MS.

Acetaldehyde (AA), which is present in tobacco smoke, automobile exhaust gases and alcohol beverage, is a mutagen and carcinogen. AA reacts with 2'-deoxyguanosine (dG) in DNA to form N2-ethyl-dG (EtdG) and cyclic, 1, N2-propano-dG (CPrdG), which are considered to have a critical role in carcinogenesis induced by AA. In this study, we have developed a highly sensitive method for the quantitation of the two AA-derived DNA adducts by using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) in which hydrophilic interaction chromatography (HILIC) employing mobile phases of high organic solvent concentration was selected to improve the ionization efficiency in the ESI process. Fourteen times and 11 times larger peak areas for EtdG and CPrdG, respectively, in HILIC-ESI-MS/MS were obtained compared with those in reversed phase (RP)-LC-ESI-MS/MS. Furthermore, 6.9 times (for EtdG) and 2.4 times (for CPrdG) larger peak areas were also obtained as additional enhancement by varying additive compounds in the HILIC mobile phases from ammonium acetate to ammonium bicarbonate. In total, the enhancements in detected MS signal intensities by exchanging from the RP-LC system to the HILIC system are 97 times for EtdG and 26 times for CPrdG, respectively. Three commercially available HILIC columns with different polar functional groups were examined and sufficient separation between normal 2'-deoxynucleosides and the AA-derived DNA adducts was achieved by a carbamoyl-bonded HILIC column. Finally, we applied the established method to quantify EtdG and CPrdG in the damaged calf thymus DNA.

Lead substances selection using GHS approach for the classification of mixtures: Case study of painting in the work environment.

We developed a lead substances selection approach based on the concept of mixture classification of UN GHS for the purpose of efficient risk assessment of mixtures consisting of multiple components. Lead substances selection methods are being actively developed in Europe, but these methods are predicated on the regulations and information sources available within Europe and are therefore not readily applicable to countries outside Europe. In this study, the features of the GHS-based approach and the risk assessment results for outdoor painting work as a specific utilization example of the GHS-based approach were described. Comparison with the DPD + method and the CCA method proposed in Europe revealed that the GHS-based approach resulted in the selection of the safest lead substances. The GHS method, like the DPD + method, is a classification-based approach. We believe that a classification-based approach based on the GHS method can be an appropriate tool to efficiently implement risk assessment of mixtures for countries outside Europe. Some tools for business operators to conduct the management of chemicals using the GHS classification have been established in Japan. We plan to propose the GHS-based approach as a standardized assessment tool.

Evaluation of an e-learning system for diagnosis of gastric lesions using magnifying narrow-band imaging: a multicenter randomized controlled study.

Background and study aim Magnifying narrow-band imaging (M-NBI) is useful for the accurate diagnosis of early gastric cancer (EGC). However, acquiring skill at M-NBI diagnosis takes substantial effort. An Internet-based e-learning system to teach endoscopic diagnosis of EGC using M-NBI has been developed. This study evaluated its effectiveness. Participants and methods This study was designed as a multicenter randomized controlled trial. We recruited endoscopists as participants from all over Japan. After completing Test 1, which consisted of M-NBI images of 40 gastric lesions, participants were randomly assigned to the e-learning or non-e-learning groups. Only the e-learning group was allowed to access the e-learning system. After the e-learning period, both groups received Test 2. The analysis set was participants who scored < 80 % accuracy on Test 1. The primary end point was the difference in accuracy between Test 1 and Test 2 for the two groups. Results A total of 395 participants from 77 institutions completed Test 1 (198 in the e-learning group and 197 in the non-e-learning group). After the e-learning period, all 395 completed Test 2. The analysis sets were e-learning group: n = 184; and non-e-learning group: n = 184. The mean Test 1 score was 59.9 % for the e-learning group and 61.7 % for the non-e-learning group. The change in accuracy in Test 2 was significantly higher in the e-learning group than in the non-e-learning group (7.4 points vs. 0.14 points, respectively; P < 0.001). Conclusion This study clearly demonstrated the efficacy of the e-learning system in improving practitioners' capabilities to diagnose EGC using M-NBI.Trial registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000008569).

The different pathogeneses of sporadic adenoma and adenocarcinoma in non-ampullary lesions of the proximal and distal duodenum.

Non-ampullary duodenal adenoma with activation of Wnt/ß-catenin signalling is common in familial adenomatous polyposis (FAP) patients, whereas sporadic non-ampullary adenoma is uncommon. The adenoma-carcinoma sequence similar to colon cancer is associated with duodenal tumors in FAP, but not always in sporadic tumors. We obtained 37 non-ampullary duodenal tumors, including 25 adenomas and 12 adenocarcinomas, were obtained from biopsies and endoscopic resections. We performed immunohistochemistry for ß-catenin, the hallmark of Wnt activation, and aldehyde dehydrogenase 1 (ALDH1), a putative cancer stem cell marker. In non-ampullary lesions, abnormal nuclear localization of ß-catenin was observed in 21 (84.0%) of 25 adenomas and 4 (33.3%) of 12 adenocarcinomas. In the proximal duodenum, nuclear ß-catenin was less frequent in both adenomas and adenocarcinomas. Gastric duodenal metaplasia (GDM) was observed only in the proximal duodenum. All adenomas with GDM were the gastric foveolar and pyloric gland types, and showed only membranous ß-catenin. The intestinal-type adenomas had nuclear ß-catenin in the proximal and distal duodenum. ALDH1-positive cells were more frequent in adenocarcinomas than adenomas. Nuclear ß-catenin accumulation frequently occurred in ALDH1-positive cells in adenoma, but not in adenocarcinoma. In the non-ampullary proximal duodenum, Wnt/ß-catenin pathway activation was more closely associated with adenomas than adenocarcinomas, and while it might cooperate with ALDH1 in adenoma, it does not in adenocarcinoma. The pathogenesis thus may differ between sporadic adenoma and adenocarcinoma of non-ampullary duodenal lesions, especially in the proximal and distal duodenum.