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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.

OBJECTIVES Photodynamic therapy (PDT) is an effective salvage endoscopic treatment for local failure at the primary site after chemoradiotherapy (CRT) in esophageal cancer patients. However, the contribution of local control by salvage PDT to the prognosis is unclear. We investigated whether complete response at primary site by salvage PDT could improve the prognosis. METHODS Between January 2008 and March 2016, 34 patients received salvage PDT for local failure of esophageal cancer limited to stage T1-2 after definitive CRT or radiotherapy. Local complete response (L-CR) rate, adverse events, overall survival (OS), and progression-free survival (PFS) were assessed retrospectively. RESULTS Local complete response rates after PDT were 68% (23/34; 95% CI, 50-83%) in all patients: 81% (17/21; 95% CI, 58-95%) for stage T1 and 46% (6/13; 95% CI, 19-75%) for stage T2 patients. Grade 3 esophageal stricture occurred in one patient. The median follow-up was 26.0 months (range, 3.7-93.6 months); 21 patients died. The median survival times were 54.3 months in patients who achieved L-CR after PDT (L-CR group) and 19.8 months in those who did not (non-CR group). The 2-year OS rates were 79% (95% CI, 54-92%) in the L-CR group and 40% (95% CI, 11-68%) in the non-CR group (P = 0.0389; log-rank test). The median PFS was 21.2 months in the L-CR group and 1.9 months in the non-CR group (P

Advanced gastric cancer with bone metastasis has a very poor prognosis with short median survival. To the best of our knowledge, no reports in literature have described extensive recovery of paralysis with multimodality treatment without surgery in these cases. This report describes the case of a 52-year-old severely paralyzed female patient with spinal metastasis from advanced gastric cancer. She was inoperable, owing to a large thrombus in the inferior vena cava; alternative multimodality treatments, including chemotherapy and radiotherapy, were administered. The paralysis and the bladder and rectal dysfunction improved considerably. In addition, the performance status (PS) and Frankel grade also improved dramatically, from 4 to 1 and grade B to D, respectively. At 1 year after initiation of treatment, she is ambulatory. Patients with poor PS are often offered palliative therapy. However, this case demonstrates that poor PS solely due to paralysis from spinal metastasis may necessitate multimodality treatment instead of palliative care.

4525 Background: Addition of an anti-PD-1 antibody to trastuzumab (Tmab) reportedly enhances ADCC activity of Tmab, leading to an additive antitumor effect. We investigated the safety and tolerability of nivolumab (Nivo) plus Tmab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for pts with HER2-positive (+) advanced gastric cancer (AGC). Here, we report the safety evaluation results. Methods: This open-label, phase 1b study was conducted at four centers in Japan. The study consisted of safety (n = 12) and expansion (n = 24–30) parts. Chemotherapy-naïve pts aged ≥ 20 years with histopathologically confirmed HER2+ AGC and measurable lesions were eligible. In the safety evaluation, pts were assigned to cohort 1 or 2 in sequence. Pts received Nivo (360 mg, day 1), Tmab (course 1: 8 mg/kg; course 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) and either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. The primary purpose of the safety evaluation was to determine the toxicity and tolerability of this combination therapy. An independent data and safety monitoring committee assessed the tolerability of the study treatments before starting the second treatment course. A preliminary evaluation of tumor response on the cut-off date (December 16, 2019) was also performed. Results: From November 2018 to August 2019, 12 pts with HER2+ AGC were enrolled in the safety part (six pts each in cohorts 1 and 2). During the 1st course, all 12 pts experienced at least one adverse event (AE). The most common AEs were peripheral sensory neuropathy (PSN) (n = 4) and leukocytopenia (n = 3) in cohort 1 and PSN (n = 5) and anorexia (n = 4) in cohort 2. AEs of grade ≥ 3 were observed in only one pt in cohort 1 (grade 3 neutropenia). No pt suspended or discontinued study treatments due to AEs. One pt in cohort 1 reduced dose of S-1 due to grade 2 erythema and continued the subsequent courses with the dose. After a median follow-up of 6.1 (range, 3.1–13.3) months, one pt from cohort 1 achieved a complete response, eight pts (four in each cohort) achieved a partial response, and three pts (one in cohort 1 and two in cohort 2) showed stable disease. No progressive disease was observed. Conclusions: Both Nivo plus Tmab and either S-1 or Cape plus Ox are tolerable in pts with HER2+ AGC. Both cohorts 1 and 2 have progressed to the expansion part of the study. Clinical trial information: 000034222 .

377 Background: Nivolumab has demonstrated a survival benefit for advanced gastric cancer (AGC). However, hyperprogressive disease (HPD) has been reported in various cancers. Methods: The subjects of this retrospective study were AGC patients with measurable disease who received nivolumab, and their tumors were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. Tumor growth rates (TGR) during nivolumab were compared to those during prior therapy as reported (Champiat S, 2017). HPD was defined as an increase in TGR > 2-fold. Results: 218 patients were identified as the subjects. While 33 (15.1%) partial response (PR) were achieved, 130 patients (59.6%) showed progression disease (PD), 38 of whom were classified as HPD (17.4%) and 2 patients showed pseudo progression (1.0%). The median progression-free survival (PFS) was 1.9 months (95% CI: 1.9–2.4) and the median overall survival (OS) was 8.5 months (95% CI: 7.1–9.6) in all patients. While patients with PD showed shorter prognosis compared with non-PD patients (median PFS: 1.5 months vs 6.4 months, hazard ratio; 6.0 [95% CI: 4.3–8.4]; p < 0.0001; median OS: 4.7 months vs not reached, hazard ratio; 4.1 [95% CI: 2.8–6.3]; p < 0.0001), there were no differences either in PFS or OS between patients with HPD and those with PD other than HPD (median PFS: 1.5 months vs 1.6 months, hazard ratio; 1.3 [95% CI: 0.9–2.0]; p = 0.1194; median OS: 5.0 months vs 4.6 months, hazard ratio; 1.0 [95% CI: 0.6–1.5]; p = 0.8695). Histological type, liver metastases, carbohydrate antigen 19-9 (CA19-9) level were associated with HPD. Conclusions: HPD was observed 17.4% in AGC patients treated with nivolumab. There were no differences either in PFS or OS between patients with HPD and those with PD other than HPD. Clinicopathological characteristics might be a predict factor for HPD.

Background The 7th edition of the Union for International Cancer Control (UICC) TNM staging system is based on pathologic data from esophageal cancers treated by surgery alone. In the 8th edition of UICC-TNM staging system, there is no information available for treatment modality (surgery alone or neoadjuvant therapy [NAC] followed by surgery [NAC-S]), although clinical stage, neoadjuvant pathologic stage, and pathologic stage were analyzed and identified. The objective of this study was to evaluate the prognostic impact of the new staging system on esophageal squamous cell cancer (ESCC) patients treated by NAC-S. Methods Database of 140 consecutive ESCC patients in our hospital was retrospectively restaged in 7th and 8th UICC-TNM system. The prognostic impacts of pathologic stage after NAC according to the both staging systems were compared. Results The median follow-up period was 4.8 years (range 0.2–9.7), with 49 patients dead at the time of analysis. In 7th edition, the 3-year overall survival rates (3y-OS) of ypStages 0, I, II, III, and IV were 100%, 93.5%, 93.5%, 43.9%, and 0.0%, respectively. In 8th edition, the 3y-OS of ypStages 0, I, II, III, and IV were 100%, 96.5%, 90.2%, 51.7%, and 29.6%, respectively. There were no marked differences between 7th and 8th edition in the prognoses. The both editions poorly distinguish the prognoses of ypStages 0, I, and II. For pathological prognostic group in 7th edition, the 3y-OS of Groups 0, I, II, III, and IV were 100%, 97.0%, 90.6%, 43.9%, and 0.0%, respectively. For pathological prognostic group in 8th edition, the 3y-OS of Groups 0, I, II, III, and IV were 100%, 96.7%, 89.8%, 51.7%, and 29.6%, respectively. For patients with ypStages 0-II, pretreatment higher CEA was poor prognostic factor (HR 7.1, 95% confidence interval 1.9–25.9). Conclusion Our study indicates the problem that the ypStage in the 8th TNM staging system poorly distinguish the prognoses of ypStages 0, I, and II in patients undergoing NAC-S. Additional study is needed to evaluate the role of ypStage 0-II incorporation of new prognostic factors. Disclosure All authors have declared no conflicts of interest.

Background Photodynamic therapy (PDT) is an effective salvage treatment for local failure after chemoradiotherapy in patients with esophageal cancers. However, the treatment strategy for local failure after initial PDT has not been established, and the safety and efficacy of repetitive PDT for such lesions are also unknown. Methods We retrospectively investigated 33 esophageal cancer patients who received initial salvage PDT at Kyoto University Hospital between May 2012 and November 2017. Additionally, we examined the treatment outcomes of those patients who received repetitive PDT. Results Twenty-one patients (64%) achieved local complete response (CR) by initial PDT, and local recurrence did not occur in those patients. Eleven patients (33%) had residual lesions after initial PDT. Among these, 7 patients were treated with repetitive PDT, 2 patients selected best supportive care, 1 patient was treated with surgery, and 1 patient was treated with chemotherapy. Five of the 7 patients who received repetitive PDT were treated with talaporfin sodium, and 2 patients were treated with porfimer sodium. The median age of the patients who received repetitive PDT was 70 years old, and all patients were men. Regarding histology, 6 patients were squamous cell carcinoma and 1 patient was adenocarcinoma. The median period from initial PDT to repetitive PDT was 3 months (range 1–4). Lesion depth before initial PDT was T1 in 3 patients and T2 in 4 patients. Lesion depth before repetitive PDT was T1 in 5 patients, and T2 in 2 patients. Local CR rate in 7 patients treated with repetitive PDT was 42.9% (3/7). Additionally, local CR rate in T1 cases was 60% and 0% in T2 cases. Adverse events of grade 3 or higher were not observed in any patient. Conclusion Repetitive salvage PDT was considered to be an effective and safe treatment option in residual T1 lesions after initial PDT for local failure of esophageal cancer treated with chemoradiotherapy. Disclosure All authors have declared no conflicts of interest.

Although chemoradiotherapy (CRT) is one curative treatment option for patients with esophageal squamous cell carcinoma (ESCC), local failure after CRT remains a major problem for patients’ curability. The aim of this study was to evaluate the efficacy and safety of photodynamic therapy (PDT) as a salvage treatment for local failure. From August 2007 to March 2012, 193 consecutive ESCC patients were treated with definitive CRT in Kyoto University Hospital. Eighteen of the patients with T2 or earlier T-stage local failure after CRT underwent salvage PDT. After the salvage PDT, 11 patients (61.1%) achieved a complete response at the primary site. Over a median follow-up period of 28.3 months, the 1-year survival and progression-free survival rates were 77.8% and 38.9%, respectively; and the 2-year survival and progression-free survival rates were 60.6% and 33.3%, respectively. Adverse events were mild esophageal stricture in seven (38.9%), esophageal obstruction because of necrotic tissue in nine (50.0%), and photosensitivity in three (16.7%) patients. There were no severe complications or treatment-related deaths. Salvage PDT may be a promising treatment option for the patients with a local residual or recurrent tumor after CRT for ESCC when the lesion is suspected to be in T2 or earlier.

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.

Background Dysplastic squamous epithelium is a precancerous lesion for squamous cell carcinoma. It is often present in the esophagus and head and neck region, and can be visualized as a Lugol-voiding lesion (LVL) by iodine chromoendoscopy. However, effective treatment for such dysplastic epithelia has not yet been developed.

Background We previously conducted an investigator-initiated trial of photodynamic therapy (PDT) using talaporfin sodium (talaporfin-PDT) and laser irradiation (PD-laser) against local failure after chemoradiotherapy (CRT) in patients with esophageal cancer (EC) and reported a high local complete response rate (L-CR) (88.5%) (Yano et al., Oncotarget 2017). Thereafter, talaporfin-PDT has been applied clinically as a salvage treatment for local failure after CRT in Japan since October 2015. The current study retrospectively reviewed the efficacy and safety of talaporfin-PDT in patients who underwent this treatment in our clinical practice. Methods This study was a single-center retrospective observational study. Patients who received salvage talaporfin-PDT for local failure of EC limited to T1–2 after definitive CRT or radiotherapy from May 2011 to July 2017 in our hospital were included. PDT was applied with an intravenous administration of talaporfin sodium (40 mg/kg) followed 4 h later by diode laser irradiation at 100 J/cm2. The primary and secondary endpoints were the rate of L-CR and the safety of PDT, respectively. The criteria for L-CR were as follows: 1) no residual tumor, 2) disappearance of post-PDT ulcer and scar formation, and 3) disappearance of cancer cells as assessed histologically. Results Thirty-one patients were analyzed in this study (26 men, 5 women, median age: 68 years). Histological types were squamous cell carcinoma and adenocarcinoma (30 and 1 patients, respectively). The failure patterns of lesions after CRT were recurrence after achieving a CR and residual lesion just after CRT (25 and 6 patients, respectively). The recurrent T stages were T1a, T1b, and T2 (1, 18, and 12 patients, respectively). The median total laser exposure dose was 500 J (range: 200–900). The L-CR rates were 84.2% (16/19), 41.7% (5/12), and 61.3% (19/31) in patients with T1, T2, and all stages, respectively. No severe adverse events greater than grade 3 related to PDT were observed. Although four patients had grade 2 esophageal stenosis after PDT, the stenosis was controlled by endoscopic balloon dilation. Conclusion Salvage talaporfin-PDT is a safe and curative treatment for local failure, especially stage T1, after CRT in patients with EC. Disclosure All authors have declared no conflicts of interest.

4023Background: For clinical stage I submucosal (cT1b-SM) ESCC, surgery is the standard treatment and CRT is optional. We conducted a single-arm confirmatory study of diagnostic ER plus selective C...

Background & AimsSome patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking.MethodsWe examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1–9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking.ResultsOver the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25–0.91; P = .025), whereas smoking abstinence did not.ConclusionsMultiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466.

Purpose: Circulating microRNAs (miRNA) are emerging as promising diagnostic biomarkers for colorectal cancer, but their usefulness for detecting early colorectal neoplasms remains unclear. This study aimed to identify serum miRNA biomarkers for the identification of patients with early colorectal neoplasms. Experimental Design: A cohort of 237 serum samples from 160 patients with early colorectal neoplasms (148 precancerous lesions and 12 cancers) and 77 healthy subjects was analyzed in a three-step approach that included a comprehensive literature review for published biomarkers, a screening phase, and a validation phase. RNA was extracted from sera, and levels of miRNAs were examined by real-time RT-PCR. Results: Nine miRNAs (miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-24, miR-29a, miR-92, and miR-125b) were selected as candidate biomarkers for initial analysis. In the screening phase, serum levels of miR-21, miR-29a, and miR-125b were significantly higher in patients with early colorectal neoplasm than in healthy controls. Elevated levels of miR-21, miR-29a, and miR-125b were confirmed in the validation phase using an independent set of subjects. Area under the curve (AUC) values for serum miR-21, miR-29a, miR-125b, and their combined score in discriminating patients with early colorectal neoplasm from healthy controls were 0.706, 0.741, 0.806, and 0.827, respectively. Serum levels of miR-29a and miR-125b were significantly higher in patients who had only small colorectal neoplasms (≤5 mm) than in healthy subjects. Conclusions: Because serum levels of miR-21, miR-29a, and miR-125b discriminated patients with early colorectal neoplasm from healthy controls, our data highlight the potential clinical use of these molecular signatures for noninvasive screening of patients with colorectal neoplasia. Clin Cancer Res; 21(18); 4234–42. ©2015 AACR.

BACKGROUND: We have shown that Notch3 plays an important role in the regulation of esophageal squamous cell differentiation. However, it remains unclear how Notch3-mediated squamous cell differentiation influences the tumorigenicity of esophageal squamous cell carcinoma (ESCC) or its sensitivity to anti-cancer agents, including 5-Fluorouracil (5-FU). METHODS: We used 5-FU-resistant human ESCC cells, TE-11R, established by the step-wise continuous exposure of parental TE-11 cells to 5-FU. The TE-11R cells were stably transduced with intracellular domain of Notch3 (ICN3), an active form of Notch3, in a regulatable manner (Tet-On system). The anti-tumor effect of Notch3-overexpression was evaluated by implanting those cells into NOD SCID mice. 5-FU resistance was determined by calculating the 50% inhibitory concentration (IC50) of 5-FU using the WST-1 assay. Gene expression of squamous differentiation markers such as involucrin and cytokeratin 13 (CK13) as well as proliferative activity were determined. RESULTS: TE-11R cells formed bulky tumors in NOD SCID mice, and the tumor formation rate of TE-11R cells (6/6: 100%) was higher than that of TE-11 cells (1/8: 12.5%). TE-11R-derived tumors showed a less differentiated and more proliferative phenotype represented by fewer ‘keratin pearl’ formations with lower involucrin and Notch3 expressions as well as higher Ki67 expression in comparison with TE-11-derived tumors. Consistent with this, TE-11R cells showed lower gene expressions of Notch3, involucrin, and CK13, and exhibited approximately 1.4-fold higher proliferative activity than parental TE-11 cells in vitro. Notch3 overexpression resulted in the promotion of cell differentiation accompanied by increased expressions of involucrin and CK13, and suppressed cell growth in vitro as well as tumorigenicity in vivo. Finally, it clearly reduced the 5-FU resistance of TE-11R cells in vitro. IC50 values of TE-11R-ICN3 (DOX-) and TE-11R-ICN3 (DOX+) were 96.0 ± 19.7 and 21.6 ± 10.4 μM (P < 0.01), respectively. CONCLUSION: Our study showed that Notch3-mediated squamous cell differentiation reduced both the tumorigenicity and 5-FU resistance of ESCC cells. We suggest that a strategy to promote squamous cell differentiation may ameliorate the outcome associated with 5-FU-resistant ESCC. Citation Format: Osamu Kikuchi, Shinya Ohashi, Yukie Nakai, Yusuke Amanuma, Masahiro Yoshioka, Shin'ichi Miyamoto, Mitsuteru Natsuizaka, Hiroshi Nakagawa, Tsutomu Chiba, Manabu Muto. Notch3-mediated squamous cell differentiation shows anti-tumor effect on esophageal squamous cell carcinoma as well as reduces its resistance to 5-Fluorouracil. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5346. doi:10.1158/1538-7445.AM2015-5346

Objectives: Early detection of precancerous lesions and early-stage cancers are essential to reduce mortality from colorectal cancer (CRC). Serum/plasma microRNAs (miRs) have been reported as diagnostic and prognostic biomarkers of CRC, but their utility in detecting patients with early lesions has not been fully explored. The aim of this study is to identify serum miRs which are potentially useful as diagnostic biomarkers for early colorectal neoplasms, and potential confounders in a blood test. Methods: Candidate biomarker miRs were selected from previously published studies. Serum samples were collected from patients with low-grade intraepithelial neoplasias (LGINs) including tubular adenomas and tubulovillous adenomas, high-grade intraepithelial neoplasias (HGINs), early cancers, and healthy volunteers, and divided into discovery and validation sets. Total RNA was extracted from serum samples and levels of candidate miRs were measured by real-time RT-PCR. To evaluate the impact of hemolysis on serum miR levels, serially diluted hemolysed controls were prepared from stock solution made by hemolysing the red blood cells in distilled water. Levels of candidate miRs in hemolysed controls were also examined by real-time RT-PCR. Absorbance of serum samples at 560 nm, 576 nm, and 592 nm was measured by spectrophotometry and hemoglobin levels were estimated from a standard curve. Results: Fourteen miRs were selected as candidate diagnostic biomarkers of early colorectal neoplasms from a review of the literature. Serum levels of five miRs were too low to be accurately quantified by real-time RT-PCR, and excluded from further evaluation. Sera from 12 patients with LGINs, 8 patients with HGINs, 4 patients with cancers, and 25 healthy volunteers were included in the discovery phase. Of 9 miRs examined, miR21 (p = 0.0007), miR29a (p < 0.0001) and miR125b (p = 0.0198) showed significantly higher levels in sera from early colorectal neoplasms compared to those from healthy volunteers. Higher levels of miR29a and miR125b in sera from early colorectal neoplasms were confirmed in the validation phase using independent set of samples. Levels of miR21, 29a, and miR125b in sera significantly correlated with the degree of hemolysis. Conclusions: Serum miRs may be useful biomarkers to detect patients with early colorectal neoplasia, including adenomas. Hemolysis affects serum miR levels, and will confound measurement. Since hemolysis occurs frequently during blood collection, its impact on serum miRs should be further investigated. Citation Format: Atsushi Yamada, Takahiro Horimatsu, Yoshinaga Okugawa, Naoshi Nishida, Tadayuki Kou, Toshihiro Kusaka, Hajime Honjo, Yusuke Amanuma, Osamu Kikuchi, Manabu Muto, Ajay Goel, C. Richard Boland. Serum microRNAs as diagnostic biomarkers for early colorectal neoplasms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2014-867

AIM: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed worldwide and known to induce gastric injury from multiple mechanisms. Aloe vera is known to effectively decrease inflammation and promote ulcer healing but there are still limited data. Therefore, this study performs to evaluate the protective effects of Aloe vera on gastric injury in rats with indomethacin-induced gastropathy. METHODS: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control group, n = 6) were given orally distilled water (DW) at 0 and 4 hours. Group 2 [indomethacin (IMN) group, n = 6] were given orally IMN (150 mg/kg) dissolved in 5% NaHCO3at time 0 and 4 hours. Group 3 (Aloe vera-treated group, n = 6) were given orally Aloe vera (150 mg/kg) dissolved in DW and IMN at 0 and 4 hours. At 8 hours after the first dose, the rat's stomach was removed to determine gastric malondialdehyde (MDA), the number of interleukin-18 (IL-18) positive stained cells (%) by immunohistochemistry method, and histopathological examination. Serum was collected to determine the level of tumor necrosis factorα (TNFα) and Cytokine-induced neutrophil chemoattractant-1 (CINC-1) (by ELISA method). RESULTS: In the IMN group, serum TNF-α, CINC-1and gastric MDA significantly increased when compared to the control group (27.8±1.5 vs. 85.1±49.1 pg/mL, 104.5 ± 45.8 vs. 1054.7 ± 20.4 pg/mL and 1.7±0.2 vs. 9.4±1.1 nmol/mg protein, p

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive squamous cell carcinomas and is highly prevalent in Asia. Alcohol and its metabolite, acetaldehyde, are considered definite carcinogens for the esophagus. Polymorphisms in the aldehyde dehydrogenase 2 gene, which encodes an enzyme that eliminates acetaldehyde, have been associated with esophageal carcinogenesis. Studies of the mutagenic and carcinogenic effects of acetaldehyde support this observation. Several recent large-scale comprehensive analyses of the genomic alterations in ESCC have shown a high frequency of mutations in genes such as TP53 and others that regulate the cell cycle or cell differentiation. Moreover, whole genome and whole exome sequencing studies have frequently detected somatic mutations, such as G:C→A:T transitions or G:C→C:G transversions, in ESCC tissues. Genomic instability, caused by abnormalities in the Fanconi anemia DNA repair pathway, is also considered a pathogenic mechanism of ESCC. Advances in diagnostic techniques such as magnifying endoscopy with narrow band imaging or positron emission tomography have increased the accuracy of diagnosis of ESCC. Updated guidelines from the National Comprehensive Cancer Network standardize the practice for the diagnosis and treatment of esophageal cancer. Patients with ESCC are treated endoscopically or with surgery, chemotherapy, or radiotherapy, based on tumor stage. Minimally invasive treatments help improve the quality of life of patients who undergo such treatments. We review recent developments in the diagnosis and treatment of ESCC and advances gained from basic and clinical research.