Clinical Outcomes of Comprehensive Genomic Profiling Tests for Gastrointestinal Cancers: Experience from Tokushima University Hospital.

In Japan, cancer genome profiling (CGP) for cancer patients without standard treatment has been covered by public insurance since June 2019. This study analyzed data of 122 patients with gastrointestinal tumors who underwent CGP to clarify cancer genome medicine's current status and possible problems at the Tokushima University Hospital. The major types of cancer included pancreatic (n=30), colorectal (n=25), biliary tract (n=15), gastric (n=11), and hepatocellular carcinoma (n=8). CGP tests included F1CDx in 70 patients (57%), F1LCDx in 36 (30%), TSO500 in 14 (11%), and NCC Oncopanel in 2 (2%). Actionable gene alterations were identified in 72 patients (59%), but only 5 patients (4%) were treated for pancreatic (n=1), colorectal (n=3), and small bowel cancers (n=1). The main reasons for not receiving genotype-matched therapy included the lack of appropriate drugs or clinical trials that matched the actionable gene alterations (n=40) and the inability to participate in clinical trials (n=10). There is still not a sufficient number of patients receiving genotype-matched treatment for gastrointestinal cancers. To promote cancer genome medicine in regional areas, attempts to improve access to genotype-matched therapies are required, as well as to promote the development of new molecular-targeted drugs and clinical trials for these drugs. J. Med. Invest. 70 : 154-159, February, 2023.

[Gastric cancer genome profiling reveals HER2 false-negative status and informs a successful trastuzumab treatment strategy].

Intratumoral HER2 heterogeneity is a well-described gastric cancer feature and may explain many false-negative results related to this oncogene. An 81-year-old man was diagnosed at our hospital with stage IV gastric cancer with multiple lymph node metastases. Immunohistochemistry (IHC) analysis indicated that the primary tumor was HER2-negative. After a chemotherapy course, we submitted a pretreatment biopsy specimen for comprehensive cancer genome profiling (CGP) to determine the last-line therapy. This revealed HER2 amplification. The specimen was reevaluated using fluorescence in situ hybridization and IHC with deeper-cut specimens, which confirmed that the tumor was indeed HER2-positive. Therefore, the patient was treated with chemotherapy plus trastuzumab, which elicited tumor shrinkage and conferred long-term survival. Our current data underscore the CGP importance, which can provide more accurate tumor profilings and inform subsequent treatment decisions.

Colorectal carcinoma occurring via the adenoma-carcinoma pathway in patients with serrated polyposis syndrome.

BACKGROUND: Although serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, the carcinogenic mechanisms remain unknown. We investigated clinicopathological characteristics and genetic abnormalities in colorectal polyps and CRC to elucidate carcinogenic mechanisms in SPS. METHODS: We retrospectively analyzed clinicopathological features of colorectal polyps in 44 SPS patients, and examined mutations of genes including APC, RAS, BRAF, and TP53, and microsatellite instability (MSI) in CRC tissues. RESULTS: Of the 44 patients, 25 (56%) fulfilled WHO criterion 1, 11 (25%) fulfilled criterion 2, and 8 (18%) fulfilled both. A total of 956 polyps were observed; 642 (67%) hyperplastic polyps (HP), 204 (21%) sessile serrated lesions (SSL), 10 (1%) traditional serrated adenoma (TSA), and 100 (11%) adenomas. The median numbers of polyps (/patient) were 10.5 (IQR 2.75-23) HPs, 4.0 (2.0-6.0) SSLs, 0 (0-0) TSA, and 1 (0-3.3) adenoma. SSL and HP located preferentially in the proximal and distal colon, respectively. Twenty-two CRCs were found in 18 patients. Based on the histological coexistence of SSL/TSA, BRAF mutation and MSI, 5 CRCs (26%) were classified as serrated-neoplasia pathway. Conversely, based on the coexistence of adenoma, APC/RAS and TP53 mutations, 11 CRCs (58%) were classified as adenoma-carcinoma pathway. The remaining three were unclassifiable. Most CRCs through adenoma-carcinoma pathway were located in the left-side colorectum and patients bearing those met criterion 2, characterized by many HP and advanced adenomas. Adenoma was a significant risk factor for CRC. CONCLUSIONS: Our results suggest that more than half of the CRCs, particularly those in the left-side colorectum, developed through the adenoma-carcinoma pathway in SPS patients. Adenoma was a risk factor for CRCs, suggesting its importance in colorectal carcinogenesis.

Long-Term Survival due to Chemotherapy including Paclitaxel in a Patient with Metastatic Primary Splenic Angiosarcoma.

A primary splenic angiosarcoma is a rare type of soft tissue sarcoma and is associated with an extremely poor prognosis. In this study, we describe the case of a patient who was diagnosed with metastatic primary splenic angiosarcoma and survived for about 2 years. A 62-year-old female was referred to us for the treatment of splenic angiosarcoma with disseminated intravascular coagulation (DIC) and multiple liver and bone metastases. Paclitaxel therapy resulted in recovery from DIC and enabled her to continue sequential treatment through to sixth-line chemotherapy. We reviewed all splenic angiosarcoma case reports which were described as stage IV to date and compared with our case. From these data, we found that the median overall survival was 105 days, and the prognosis of splenic angiosarcoma of stage IV was worse than conventional case series. Splenectomy was performed in more patients than chemotherapy as a treatment. Moreover, various chemotherapeutic regimens were used. These data suggest that administering chemotherapy including paclitaxel to patients with splenic angiosarcoma might improve their prognosis.

S100P Expression via DNA Hypomethylation Promotes Cell Growth in the Sessile Serrated Adenoma/Polyp-Cancer Sequence.

BACKGROUND/AIMS: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. METHODS: We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. RESULTS: The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5'-flanking promoter region. CONCLUSION: These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.

Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and in vitro assessment via protein phosphorylation array.

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group (p < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC50 of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.

Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma.

BACKGROUND: The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC. METHODS: Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy. RESULTS: DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI < 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients. CONCLUSIONS: Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC.

Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression.

Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer-adipocyte interaction. We first investigated the ability of adipocytes to de-differentiate to cancer-associated adipocytes (CAAs) by co-culturing with pancreatic cancer cells. We then examined the effects of CAA-conditioned medium (CAA-CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3-L1 adipocytes were co-cultured with pancreatic cancer cells (PANC-1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast-like cells (CAA). Adipocyte-specific marker mRNA levels significantly decreased but those of fibroblast-specific markers appeared, characteristic findings of CAA, as revealed by real-time PCR. When PANC-1 cells were cultured with CAA-CM, significantly higher migration/invasion capability, chemoresistance, and epithelial-mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC-1 cells cultured with CAA-CM and found a 78.5-fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC-1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1-positive group was significantly shorter than in the SAA1-negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de-differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.

MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer.

BACKGROUND/AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive invasion, early metastasis, and resistance to chemotherapy, leading to a poor prognosis. To clarify the molecular mechanism of these malignant characteristics, we performed a genome-wide microRNA (miRNA) array analysis utilizing micro-cancer tissues from patients with unresectable PDAC (stage IV), obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA). METHODS: The expression profiles of 2,042 miRNAs were determined using micro-cancer tissues from 13 patients with unresectable PDAC obtained by EUS-FNA. The relationship between individual miRNA levels and overall survival (OS) was analyzed. Possible target genes for miRNAs were bioinformatically analyzed using the online database miRDB. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and PK-8 were transfected with miRNA mimic or small interfering RNA, and cell invasion, epithelial-mesenchymal transition (EMT), and apoptosis markers were examined. miRNA and mRNA expressions were examined by quantitative polymerase chain reaction. RESULTS: Of 2,042 miRNAs, the 10 that exhibited the lowest correlation coefficient (p ≤ 0.005) between miRNA expression level and OS among the patients were identified. The miRDB and expression analysis in cancer cell lines for the 10 miRNAs identified miR-296-5p and miR-1207-5p as biomarkers predictive of shorter survival (p < 0.0005). Bioinformative target gene analysis and transfection experiments with miRNA mimics showed that Bcl2-related ovarian killer (BOK), a pro-apoptotic gene, is a target for miR296-5p in pancreatic cancer cells; transfection of miR-296-5p mimic into PANC-1, MIA PaCa-2, and PK-8 cells resulted in significant suppression of BOK mRNA and protein expression. These transfectants showed significantly higher invasion capability compared with control cells, and knock down of BOK in pancreatic cancer cells similarly enhanced invasion capability. Transfectants of miR-296-5p mimic also exhibited aberrant expression of EMT markers, including vimentin and N-cadherin. Moreover, these transfectants showed a significantly lower apoptosis rate in response to 5-fluorouracil and gemcitabine with a decrease of BOK expression, suggesting a role of miR-296-5p in drug resistance. CONCLUSION: These results suggest that miR-296-5p is a useful biomarker for a poor prognosis in patients with PDAC, and that the miR-296-5p/BOK signaling axis plays an important role in cell invasion, drug resistance, and EMT in PDACs.

JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8.

BACKGROUND: Jumonji domain-containing protein 2A (JMJD2A) of the JMJD2 family of histone lysine demethylases has been implicated in tumorigenesis. However, its expression and role in gastric cancer (GC) drug resistance remain unknown. Here, we investigated the role of JMJD2A in GC chemotherapeutic susceptibility and its clinical relevance in GC. METHODS: We selected 12 relevant genes from previously identified gene signatures that can predict GC susceptibility to docetaxel, cisplatin, and S-1 (DCS) therapy. Each gene was knocked down using siRNA in GC cell lines, and cell viability assays were performed. JMJD2A expression in GC cell lines and tissues was assessed using qRT-PCR and immunohistochemistry, respectively. A JMJD2A downstream target related to drug susceptibility was examined using whole-gene expression array and immunoprecipitation. RESULTS: Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the IC50 values for 5-FU, cisplatin, and docetaxel 15.3-, 2.7-, and 4.0-fold, respectively. JMJD2A was universally expressed in 12 GC cell lines, and its overexpression in GC tissue was positively correlated with tumor regression in 34 DCS-treated patients. A whole-gene expression array of JMJD2A-knockdown GC cells demonstrated a significant decrease in the expression of pro-apoptotic coiled-coil domain containing 8 (CCDC8), a downstream target of JMJD2A. Direct interaction between CCDC8 and JMJD2A was verified using immunoprecipitation. CCDC8 inhibition restored drug resistance to docetaxel, cisplatin, and S-1. CONCLUSIONS: Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target.

The influence of various distractions prior to upper gastrointestinal endoscopy: a prospective randomized controlled study.

BACKGROUND: Although many patients still have anxiety about upper gastrointestinal (GI) endoscopy, there have been few reports on the influence of distractions for a person who is going to undergo upper GI endoscopy soon. This study was a prospective randomized controlled study investigating the influence of distractions, such as auditive and visual distractions using subjective and objective assessments including autonomic nervous function prior to upper GI endoscopy. METHODS: 206 subjects who underwent upper GI endoscopy as regular health check-ups were divided randomly into 4 groups prior to upper GI endoscopy; group 1 (control group), group 2 (auditive group), group 3 (visual group), and group 4 (combination group). We measured vital signs, autonomic nervous function, profile of mood state (POMS), and the impression for upper GI endoscopy pre- and post-distraction in the 4 groups. RESULTS: There was no significant difference in vital signs between 5 and 15 min after sitting in group 1, however, several vital signs in all distraction groups improved significantly after distraction (Pulse rate (P): p <  0.001 in group 4; blood pressure: p <  0.05 in group 2, 3, 4) and the rate of decrease in P and diastolic blood pressure was highest in group 4 (p <  0.001). Several scores of POMS and the impression for upper GI endoscopy post-distraction improved significantly compared to pre-distraction between distraction groups and the satisfaction for distraction was highest in group 4 (p <  0.01). Regarding autonomic nerve function, the low- frequency power/ high- frequency power ratio post-distraction was significantly lower than that pre-distraction in all distraction groups (p <  0.001). CONCLUSIONS: Although auditive distraction alone and visual distraction alone were effective, a combination distraction was more effective than any other distraction by subjective and objective assessments. These distractions, which were simple and safe, may play an assistive role in the stability of physical and psychological conditions prior to upper GI endoscopy. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000022801 . Registered on 10 July 2016.

Linked color imaging enhances endoscopic detection of sessile serrated adenoma/polyps.

BACKGROUND AND STUDY AIMS: Although new image-enhanced endoscopy (IEE) technologies such as blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI) have been developed, their utility for the detection of sessile serrated adenoma/polyps (SSA/Ps) is still unclear. This study aimed to evaluate the utility of BLI, BLI-bright, and LCI for SSA/P detection in still image examinations and in a prospective randomized controlled trial (RCT). PATIENTS AND METHODS: A group of 6 expert and non-expert endoscopists read 200 endoscopic still images containing SSA/P lesions using white light image (WLI), BLI, BLI-bright, and LCI. Color differences were calculated using the color space method. A prospective RCT of tandem colonoscopy with WLI and LCI was performed. Patients with SSA/P and those with a history of SSA/P that had been endoscopically removed were enrolled and randomly allocated to WLI-LCI or LCI-WLI groups. Additional endoscopic detection rates for SSA/P were compared between the 2 groups. RESULTS: LCI showed the highest SSA/P detection rate among the 4 modes for both expert and non-expert endoscopists. The detection rate with LCI for the 6 expert endoscopists (mean 98.3 ±â€Šstandard deviation 2.0 %) was significantly higher than that with WLI (86.7 ±â€Š6.0 %, P  < 0.01). Likewise, the detection rate with LCI for the 6 non-expert endoscopists (92.3 ±â€Š2.9 %) was significantly higher than that with WLI (72.7 ±â€Š11.5 %, P  < 0.01). The color difference of SSA/P with LCI was the highest among the 4 modes, and was significantly higher than with WLI (median 15.9, (interquartile range 13.7 - 20.6) vs. 10.2, (7.6 - 14.2); P  < 0.0001). In the RCT, a total of 44 patients (WLI-LCI 22 vs. LCI-WLI 22) underwent colonoscopy. The additional detection rate for SSA/P in the second inspection in the WLI-LCI group (21.6 %, 8/37) was significantly higher than in the LCI-WLI group (3.2 %, 1/31; P  = 0.02). The small, flat, non-mucus and isochromatic SSA/Ps in the transverse colon were detected more frequently in the second inspection with LCI. CONCLUSIONS: LCI was the most sensitive mode for SSA/P detection among WLI, BLI, BLI-bright, and LCI in the still image examinations. Our RCT strongly suggests that LCI is superior to conventional WLI for SSA/P detection during colonoscopy. UMIN000017599.

Downregulation of microRNA-100/microRNA-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion.

A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion.

Localized amyloidosis of the stomach mimicking a superficial gastric cancer.

A 73-year-old man was referred to our hospital for further examination of a depressed lesion in the stomach found by cancer screening gastroscopy. A barium upper gastrointestinal series showed an area of irregular mucosa measuring 15 mm on the anterior wall of the gastric body. Esophagogastroduodenoscopy revealed a 15 mm depressed lesion on the anterior wall of the lower gastric body. We suspected an undifferentiated adenocarcinoma from the appearance and took some biopsies. However, histology of the specimens revealed amyloidal deposits in the submucosal layer without malignant findings. Congo red staining was positive for amyloidal protein and green birefringence was observed under polarized light microscopy. Congo red staining with prior potassium permanganate incubation confirmed the light chain (AL) amyloid type. There were no amyloid deposits in the colon or duodenum. Computed tomography of the chest, abdomen, and pelvis showed no remarkable findings. Thus, this case was diagnosed as a localized gastric amyloidosis characterized by AL type amyloid deposition in the mucosal or submucosal layer. As the clinical outcome of gastric AL amyloidosis seems favorable, this case is scheduled for periodic examination to recognize potential disease progression and has been stable for 2 years.

A phase I/II study of fixed-dose-rate gemcitabine and S-1 with concurrent radiotherapy for locally advanced pancreatic cancer.

PURPOSE: This study was conducted to identify the maximum-tolerated dose (MTD) of fixed-dose-rate gemcitabine (FDR-gem) administered concurrently with S-1 and radical radiation for locally advanced pancreatic cancer (LAPC) and to provide efficacy and safety data. METHODS: Patients with unrespectable pancreatic cancer confined to the pancreatic region were treated with FDR-gem (300-400 mg/m(2), 5 mg/m(2)/min) on days 1, 8, 22, and 29 and 60 mg/m(2) of S-1 orally on days 1-14, 22-35. A total radiation dose of 50.4 Gy (1.8 Gy/day, 28 fractions) was delivered concurrently. RESULTS: Twenty-five patients were enrolled; all were evaluable for toxicity assessment. In phase I, eight patients were treated in sequential cohorts of three to five patients per dose level. The MTD was reached at level 2, and dose-limiting toxicities were neutropenia and thrombocytopenia. The recommended doses were 300 mg/m(2) of gemcitabine and 60 mg/m(2) of S-1 daily. The overall response rate was 25% and disease control rate (partial response plus stable disease) was 92%. The progression-free survival was 11.0 months. The median overall survival and 1-year survival rates were 16.0 months and 73%, respectively. CONCLUSION: The combination of FDR-gem and S-1 with radiation is a feasible regimen that shows favorable antitumor activity with an acceptable safety profile in patients with LAPC.

Investigation of Gastroduodenal Mucosal Injury in Japanese Asymptomatic Antiplatelet Drug Users.

Antiplatelet drugs are widely used for the prevention of cardiovascular disease and cerebral vascular disorders. Although there have been several studies on gastroduodenal mucosal injury with gastrointestinal (GI) symptoms such as GI bleeding, in antiplatelet drug users (including low-dose aspirin (LDA)), there have been few reports on the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users. This study was a cross-sectional study elucidating the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Subjects were 186 asymptomatic Japanese antiplatelet drug users who underwent a regular health checkup. Subjects were divided into those with and without gastroduodenal mucosal injury endoscopically, and the association between gastroduodenal mucosal injury and other data in asymptomatic antiplatelet drug users was investigated.The prevalence of males and drinkers were significantly higher in subjects with gastroduodenal mucosal injury than in those without. In addition, the prevalence of proton pump inhibitor (PPI) users was significantly lower in subjects with gastroduodenal mucosal injury than in subjects without gastroduodenal mucosal injury. Logistic regression analysis showed PPI (odds ratios: 0.116; 95% confidence intervals: 0.021-0.638; P < 0.05) was a significant predictor of a decreased prevalence of gastroduodenal mucosal injury and closed-type (C-type) atrophy (3.172; 1.322-7.609; P < 0.01) was a significant predictor of an increased prevalence of severe gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Gender and lifestyle, such as drinking, may have an impact on risk of gastroduodenal mucosal injury in asymptomatic subjects taking antiplatelet drugs. Although PPI is a significant predictor of a decreased prevalence of gastroduodenal mucosal injury, including in asymptomatic antiplatelet drug users, status of gastric atrophy should also be considered against severe gastroduodenal mucosal injury.

Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy.

PURPOSE: We previously reported that a triplet combination of docetaxel, cisplatin, and S-1 (DCS) is active against metastatic gastric cancer with a very high response rate of 87.1 % in a phase II study. Recently, the efficacy of trastuzumab (T-mab) for the treatment of HER2-positive gastric cancer has been reported. Therefore, we investigated the feasibility and preliminary efficacy of DCS + T-mab (DCS-T) for unresectable HER2-positive metastatic gastric cancer. METHODS: Patients received oral S-1 (40 mg/m(2) b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m(2)), docetaxel (50 mg/m(2)), and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. RESULTS: The study included 16 patients: median age, 60 (34-76) years; males/females, 11:5; intestinal-type/diffuse-type histology, 11:5; and HER2 3+/2+(FISH+), 13:3. The completion rate until the third cycle was 87.5 % (14/16) (95 %CI 71.3-103.7 %). Adverse events of grade 3/4 severity during the first 3 cycles were: leukopenia/neutropenia, 50.0:75.0 %; febrile neutropenia, 12.5 %; diarrhea, 12.5 %; and stomatitis, 12.5 %. All of these side effects were manageable and well controlled. There were no treatment-related deaths. The overall response rate was 93.8 % (15/16), and the response rate in patients with measurable lesions was 100 % (15/15). The median cycle to response was only 1 (1-3 cycles). Non-curative factors disappeared in 56.3 % (9/16) of patients, and conversion surgery (R0 resection) was performed in all these cases. Pathological response rates in primary and metastatic lesions were 88.9 % (8/9) and 100 % (9/9), respectively. The median PFS and OS were not reached during the median follow-up time of 18.3 months ranged from 11.0 to 34.3 months. CONCLUSIONS: DCS-T was feasible in patients with unresectable HER2-positive metastatic gastric cancer. The observed response was very promising and warrants further investigation. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005603.

Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs.

BACKGROUND AND AIM: Objective evaluation of intestinal mucosal damage due to anticancer drugs is generally difficult. Serum diamine oxidase (DAO) activity is reported to reflect the integrity and maturity of the small intestinal mucosa. Therefore, we investigated whether serum DAO activity is an indicator of gastrointestinal toxicity or nutritional status in patients receiving chemotherapy. METHODS: We prospectively enrolled 20 patients with unresectable metastatic gastric cancer who received oral S-1 (80 mg/m(2) ) on days 1-14, and intravenous cisplatin (60 mg/m(2) ) and docetaxel (50 mg/m(2) ) on day 8 every 3 weeks. Serum DAO activity was measured by colorimetry. Gastrointestinal toxicity was evaluated by Common Toxicity Criteria for Adverse Events version 4.0. Endoscopic examination and biopsy of duodenal mucosa assessed mucosal damage. Malnutrition was evaluated by measuring serum total protein and albumin levels. RESULTS: Serum DAO activity decreased step-by-step significantly during anticancer drug treatment and recovered after drug holidays. In all 14 patients who experienced diarrhea, serum DAO activity significantly decreased prior to diarrhea onset. Percent decrease in DAO activity was significantly correlated with severity of diarrhea. Significant correlation was observed between percent decrease in DAO activity and percent decrease in duodenal villus height or surface area from baseline. There were also significant correlations between percent decrease in serum DAO activity at day 14 and percent decrease in serum total protein or albumin levels at day 21 from baseline. CONCLUSION: Serum DAO activity sensitively indicates gastrointestinal damage prior to symptom onset and can be a useful predictor of intestinal mucosal damage and nutritional status in patients receiving chemotherapy.

Perineurioma in the sigmoid colon diagnosed and treated by endoscopic resection.

Perineuriomas are rare benign peripheral nerve sheath tumors in the gastrointestinal tract. We recently encountered a submucosal lesion in the sigmoid colon that was resected by endoscopic mucosal resection and was then diagnosed as perineurioma by immunohistochemistry. A 51-year-old female with a positive test for fecal occult blood was referred to our hospital for screening colonoscopy. Colonoscopy identified a submucosal lesion, approximately 15 mm in diameter, in the sigmoid colon. Endoscopic ultrasound showed a 15-mm tumor with a strong acoustic shadow. Endoscopic mucosal resection was performed in order to make a precise diagnosis as well as removal. The specimen revealed spindle cell proliferation without atypia, and immunostaining revealed that the spindle cells were positive for collagen type IV and glut-1, and the lesion was diagnosed as a colonic perineurioma with no malignancy. Gastroenterologists as well as pathologists should be aware of this type of submucosal lesion, and immunohistochemical evaluation is highly recommended when an unusual mesenchymal tumor is found.