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Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2′-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention., We generated human ALDH2*2 (Glu504Lys) knock-in mice and showed the protective effects of Alda-1 (ALDH2 activator) on esophageal DNA damage in those mice with alcohol drinking. Our findings can be the basis for developing a novel prevention for alcohol-mediated esophageal carcinogenesis.

Background Talaporfin sodium photodynamic therapy (tPDT) is an effective salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Repeated tPDT could also be indicated for local recurrence or residue after the first salvage tPDT. However, the safety and efficacy of repeated tPDT have not been elucidated. Methods We reviewed 52 patients with esophageal cancer who were treated with the first tPDT at Kyoto University Hospital between October 2015 and April 2020. Results Among 52 patients, repeated tPDT after the first tPDT was indicated for 13 patients (25%), of which six had residual tumor, four had local recurrence after complete response (CR) after the first tPDT at the primary site, and six had metachronous lesion. The total session of repeated tPDT was 25; 16 were for primary sites and nine were for metachronous sites. Among them, six patients (46.2%) achieved local (L)-CR and nine lesions (56.3%) achieved lesion L-CR. By session, 10 sessions (40%) achieved L-CR. There were no severe adverse events except for one patient; this patient showed grade 3 esophageal stenosis and perforation after the third tPDT on the same lesion that was previously treated with porfimer sodium photodynamic therapy four times. Conclusion Repeated tPDT could be an effective and safe treatment for local failure even after salvage tPDT for esophageal cancer.

Endoscopic submucosal dissection (ESD) is a safe and minimally invasive method for the treatment of early gastric cancer (EGC). However, whether ESD for EGC is also safe and feasible in patients aged ≥85 years is unclear. The patients enrolled in this study were divided into three groups: age ≥85 years (44 patients, 49 lesions), age 65–84 years (624 patients, 687 lesions), and age ≤64 years (162 patients, 174 lesions). We evaluated the incidence of adverse events (AEs) and overall survival (OS) and disease-specific survival (DSS). We analyzed the factors that had a significant impact on the prognosis of patients aged ≥85 years. No significant differences were found in the incidence of AEs among the three groups (p = 0.612). The OS was significantly lower in patients aged ≥85 years (p < 0.001). Conversely, DSS was not significantly worse in patients aged ≥85 years (p = 0.100). The poor Geriatric Nutritional Risk Index correlated with poor prognosis in patients aged ≥85 years (p < 0.001). ESD is a safe and valid treatment for EGC in patients aged ≥85 years. However, the indications should be carefully decided because it is difficult to estimate the survival contribution of ESD for EGC in patients aged ≥85 years, especially in those with poor nutritional status.

Comprehensive genomic profiling (CGP) testing by next‐generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first‐line chemotherapy could be clinically useful is not clear. We conducted this single‐center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy‐naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne® companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular‐based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10‐329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular‐based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first‐line chemotherapy., Comprehensive genomic profiling (CGP) testing by next‐generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies; however, whether CGP testing at the time of first‐line chemotherapy could be clinically useful is not clear. We conducted this single‐center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy‐naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne® companion diagnostic assay. We found that CGP testing could be feasible in Japanese clinical practice for chemotherapy‐naïve patients with these cancers, and that CGP testing might be a useful tool to identify a potentially effective first‐line treatment, which will lead to the establishment of precision cancer medicine.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2), which is a homotetramer assembled by two equivalent dimers, is an important enzyme that metabolizes ethanol-derived acetaldehyde to acetate in a coenzyme-dependent manner. The highly reactive acetaldehyde exhibits a toxic effect, indicating that the proper functioning of ALDH2 is essential to counteract aldehyde-associated diseases. It is known that the catalytic activity of ALDH2 is drastically impaired by a frequently observed mutation, E487K, in a dominant fashion. However, the molecular basis of the inactivation mechanism is elusive because of the complex nature of the dynamic behavior. Here, we performed microsecond-timescale molecular dynamics simulations of the proteins complexed with coenzymes. The E487K mutation elevated the conformational heterogeneity of the dimer interfaces, which are relatively distal from the substituted residue. Dynamic network analyses showed that Glu487 and the dimer interface were dynamically communicated, and the dynamic community further spanned throughout all of the subunits in the wild-type; however, this network was completely rearranged by the E487K mutation. The perturbation of the dynamic properties led to alterations of the global conformational motions and destabilization of the coenzyme binding required for receiving a proton from the catalytic nucleophile. The insights into the dynamic behavior of the dominant negative mutant in this work will provide clues to restore its function.

Background: The chick chorioallantoic membrane (CAM) tumor model is an in vivo three-dimensional culture model that is easy to use and inexpensive, has no ethical issues, and has been used in cancer research, although the success rate of generating CAM tumors varies among reports. We analyzed the success rate of CAM tumors from patient-derived xenograft (PDX) of esophageal squamous cell carcinoma (ESCC) and many cell line-derived xenograft (CDX) tumors of different cancer types, and we sought to determine which factors affected the success rate of generating CAM tumors. Method: We used patient cancer tissue (ESCC) and/or commercially available 12 tumorigenic cancer cell lines (esophageal cancer [TE-11 and HCE4], pancreatic cancer [CFPA-1, MIA PaCa2, and PANC-1], lung cancer [A549 and H358], skin cancer [A431 and B16F10], and biliary tract cancer [HuCCT-1, TFK-1, and MzchA2]) to generate xenograft tumors. Small (1- to 2-mm) pieces of xenograft tumors were grafted onto the CAMs of fertilized eggs. After incubating for an additional 7 to 9 days at 37.5°C and 65% humidity, nodules were observed on the assigned locations of each CAM. On the basis of hematoxylin and eosin (H&E) staining, we calculated the success rate of the CAM tumor engraftment. H&E staining was also performed with parental PDX or CDX tumors as well as parental ESCC tissues, to compare them with CAM tumors. Results: A total of 29 xenograft tumors were transplanted onto CAMs. The overall success rate in generating CAM tumors was 19/29 (66%). The CAM tumors were histologically quite similar to those of their parental CDX or PDX tumors, and the CAM tumors from PDX ESCC were also histologically similar to their parent ESCC tumors. Tumor pieces from poorly-differentiated xenograft tumors (including PDX ESCC) generated CAM tumors with a 90% success rate (19/21), in comparison with well-differentiated xenograft tumors, whose success rate was 0% (0/8). Conclusion: The overall success rate in generating CAM tumors, especially from poorly differentiated tumors, seems acceptable. The histological similarity between CAM tumors and both parent xenograft and parent tumors from humans indicates that the CAM tumor model is a promising in vivo model for the study of poorly differentiated tumors. As for well-differentiated tumors, this model has to be further optimized to increase the success rate of engraftment. Citation Format: Tomoki Saito, Shinya Ohashi, Ayaka Mizumoto, Osamu Kikuchi, Kotaro Matsumoto, Aoi Komatsu, Seiji Naganuma, Yoshihiro Yamamoto, Kenshiro Hirohashi, Masahiro Yoshioka, Masashi Tamaoki, Makiko Funakoshi, Fuyuhiko Tamanoi, Manabu Muto. Characterization of the chick chorioallantoic membrane tumor model in comparison with various xenograft mouse tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1670.

Background Esophageal squamous cell carcinoma (ESCC) is one of the most intractable cancers, so the development of novel therapeutics has been required to improve patient outcomes. Curcumin, a polyphenol from Curcuma longa, exhibits various health benefits including antitumor effects, but its clinical utility is limited because of low bioavailability. Theracurmin® (THC) is a highly bioavailable curcumin dispersed with colloidal submicron particles. Methods We examined antitumor effects of THC on ESCC cells by cell viability assay, colony and spheroid formation assay, and xenograft models. To reveal its mechanisms, we investigated the levels of reactive oxygen species (ROS) and performed microarray gene expression analysis. According to those analyses, we focused on NQO1, which involved in the removal of ROS, and examined the effects of NQO1-knockdown or overexpression on THC treatment. Moreover, the therapeutic effect of THC and NQO1 inhibitor on ESCC patient-derived xenografts (PDX) was investigated. Results THC caused cytotoxicity in ESCC cells, and suppressed the growth of xenografted tumors more efficiently than curcumin. THC increased ROS levels and activated the NRF2–NMRAL2P–NQO1 expressions. Inhibition of NQO1 in ESCC cells by shRNA or NQO1 inhibitor resulted in an increased sensitivity of cells to THC, whereas overexpression of NQO1 antagonized it. Notably, NQO1 inhibitor significantly enhanced the antitumor effects of THC in ESCC PDX tumors. Conclusions These findings suggest the potential usefulness of THC and its combination with NQO1 inhibitor as a therapeutic option for ESCC. Electronic supplementary material The online version of this article (10.1007/s00535-019-01549-x) contains supplementary material, which is available to authorized users.

Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA-DNA cross-links. Among these, DNA adducts such as N²-ethylidene-2'-deoxyguanosine, N²-ethyl-2'-deoxyguanosine, N²-propano-2'-deoxyguanosine, and N²-etheno-2'-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA-DNA cross-links, DSBs, and SCEs. Acetaldehyde is produced endogenously by alcohol metabolism and is catalyzed by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract. Based on extensive epidemiological evidence, the International Agency for Research on Cancer defined acetaldehyde associated with the consumption of alcoholic beverages as a "group 1 carcinogen" (definite carcinogen) for the esophagus and/or head and neck. In this article, we review recent advances from studies of acetaldehyde-mediated carcinogenesis in the squamous epithelium, focusing especially on acetaldehyde-mediated DNA adducts. We also give attention to research on acetaldehyde-mediated DNA repair pathways such as the Fanconi anemia pathway and refer to our studies on the prevention of acetaldehyde-mediated DNA damage.

Objectives: Acetaldehyde, the first metabolite of ethanol, is a definite carcinogen for the esophagus, head, and neck; and aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that catalyzes the metabolism of acetaldehyde. The ALDH2 genotype exists as ALDH2*1/*1 (active ALDH2), ALDH2*1/*2 (heterozygous inactive ALDH2), and ALDH2*2/*2 (homozygous inactive ALDH2). Many epidemiological studies have reported that ALDH2*2 carriers are at high risk for esophageal or head and neck squamous cell carcinomas by habitual drinking. Therefore, identification of ALDH2*2 carriers would be helpful for the prevention of those cancers, but there have been no methods suitable for mass screening to identify these individuals. Methods: One hundred and eleven healthy volunteers (ALDH2*1/*1 carriers: 53; ALDH2*1/*2 carriers: 48; and ALDH2*2/*2 carriers: 10) were recruited. Breath samples were collected after drinking 100 ml of 0.5% ethanol using specially designed gas bags, and breath ethanol and acetaldehyde levels were measured by semiconductor gas chromatography. Results: The median (range) breath acetaldehyde levels at 1 min after alcohol ingestion were 96.1 (18.1–399.0) parts per billion (p.p.b.) for the ALDH2*1/*1 genotype, 333.5 (78.4–1218.4) p.p.b. for the ALDH2*1/*2 genotype, and 537.1 (213.2–1353.8) p.p.b. for the ALDH2*2/*2 genotype. The breath acetaldehyde levels in ALDH2*2 carriers were significantly higher than for the ALDH2*1/*1 genotype. Notably, the ratio of breath acetaldehyde level-to-breath ethanol level could identify carriers of the ALDH2*2 allele very accurately (whole accuracy; 96.4%). Conclusions: Our novel breath test is a useful tool for identifying ALDH2*2 carriers, who are at high risk for esophageal and head and neck cancers.

The efficacy of ERCP for histologic diagnosis of malignant biliary strictures is disappointingly low. The aim of this study was to investigate the diagnostic performance of a newly developed endoscopic device with scraping loops in combination with conventional biopsy forceps.We performed a multicenter single-arm prospective study. Between February 2013 and December 2014, 123 patients with suspected malignant biliary strictures were enrolled in the study. The new device and conventional biopsy forceps were applied for histologic diagnosis by ERCP. The primary outcome was to evaluate cancer detectability by biopsy forceps, the new device, and their combined use.Of the 123 patients, 119 were diagnosed with a malignant stricture. Sufficient samples were collected in 83.7% (103/123), 93.5% (115/123), and 95.9% (118/123) of patients using biopsy forceps, the new device, and their combination, respectively. Cancer detectability of forceps biopsy, the new device, and their combination were 51.3% (61/119), 64.7% (77/119), and 74.8% (89/119), respectively. The new device had a significantly higher sample yield and cancer detectability than biopsy forceps (P .01 and P = .018, respectively, McNemar test). Complementary use of the new device with biopsy forceps demonstrated a significantly additive effect in both sample yield and cancer detection (P .01 each, McNemar test). The new device detected 48.3% (28/58) of cancers that were not diagnosed as malignant by biopsy forceps.The new endoscopic scraper demonstrated a large sample yield and high cancer detectability. It could be a first-line tissue-sampling device for biliary strictures. (University Hospital Medical Information Network Clinical Trial Registry [UMIN-CTR] (http://www.umin.ac.jp/ctr/index.htm) registration number: UMIN000009895.).