Conversion surgery for microsatellite instability-high gastric cancer with a complete pathological response to pembrolizumab: a case report.

BACKGROUND: Immune checkpoint inhibitors are reportedly effective in treating microsatellite instability (MSI)-high gastric cancer. There are a few case reports of conversion surgery (CS) with nivolumab but none with pembrolizumab. Herein, we describe a patient with MSI-high gastric cancer who was successfully treated with pembrolizumab and underwent CS with a pathological complete response. CASE PRESENTATION: A 69-year-old man was diagnosed with stage III gastric cancer (T3N2M0) based on contrast-enhanced computed tomography, which revealed a neoplastic lesion and enlarged perigastric lymph nodes in the gastric lesser curvature. The anterior superior lymph node of the common hepatic artery (CHA) was determined to be unresectable due to invasion of the pancreatic head and CHA. Histopathologically, the biopsied tissue showed moderately differentiated adenocarcinoma, then determined to be MSI-high. After three courses of mFOLFOX6 therapy, the patient was diagnosed with progressive disease. Since one course of paclitaxel plus ramucirumab therapy caused grade 3 fatigue, his second-line therapy was switched to pembrolizumab monotherapy. After three courses, the primary tumor and perigastric lymph nodes had shrunk, and it was determined as a partial response. The anterior superior lymph node of the CHA became resectable based on the improvement of infiltration of the pancreatic head and CHA due to shrinkage of the lymph node. Tumor markers remained low; hence, distal gastrectomy plus D2 lymphadenectomy was performed at the end of six courses. Anterior superior lymph node of the CHA was confirmed by intraoperative ultrasonography, and the resection was completed safely. The gross examination of the resected specimen revealed an ulcer scar at the primary tumor site. The histopathological examination showed no viable tumor cell remnants in the primary tumor, which had a grade 3 histological response, and resection margins were negative. The lymph nodes showed mucus retention only in the anterior superior lymph node of the CHA, indicating the presence of metastasis, but no viable tumor cells remained. The patient commenced 6 months of adjuvant pembrolizumab monotherapy 3 months after surgery. Twenty months after surgery, there was no evidence of recurrence. CONCLUSIONS: Conversion surgery following pembrolizumab monotherapy has a potential utility for the treatment of MSI-high gastric cancer.

Clinical Outcomes of Fully Covered Self-expanding Metallic Stent Placement for Palliation of Incurable Esophageal Cancer With or Without Radiotherapy.

BACKGROUND/AIM: A combination therapy of esophageal stent and chemoradiotherapy (CRT) is currently considered risky for severe complications. The aim of this study was to assess the safety and efficacy of a fully covered self-expandable metallic stent (FCSEMS) placement in palliating incurable esophageal cancer before and/or after CRT. PATIENTS AND METHODS: We retrospectively reviewed clinical outcomes of 64 incurable advanced esophageal cancer patients with FCSEMS placement. Forty-two of 64 patients had FCSEMS placement with RT. RESULTS: The rate of all of stent-related complications tended to be higher in patients who had RT, although no significant difference was observed. The stent-related deaths occurred in one patient due to hemorrhage after FCSEMS placement in the RT-negative group. CONCLUSION: Palliation of dysphagia or fistulas with FCSEMS in patients with incurable esophageal cancer before and/or after RT is not associated with an increased risk of life-threatening complications.

Neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) for locally advanced esophageal squamous cell carcinoma.

PURPOSE: To further improve the prognosis of esophageal cancer patients, it is necessary to investigate new treatment strategies. The purposes of this study were to retrospectively assess the safety and efficacy of neoadjuvant chemoradiotherapy (CRT) with docetaxel/cisplatin/5-fluorouracil (DCF) (DCF-RT) in patients with thoracic esophageal squamous cell carcinoma (ESCC). METHODS: We reviewed 30 thoracic ESCC patients who underwent neoadjuvant DCF-RT followed by esophagectomy, and evaluated the safety and efficacy of DCF-RT. DCF-RT consisted of 40 Gy radiation with two courses of intravenous DCF (docetaxel, 30 mg/m2/day, day 1; cisplatin, 7 mg/m2/day, day 1; 5-FU, 350 mg/m2/day, days 1-5 and days 8-12) repeated every 2 weeks. Esophagectomy was scheduled 8-10 weeks after completion of DCF-RT. RESULTS: Twenty-nine of thirty patients completed radiotherapy; however, 27 of 30 patients required dose reduction of the second cycle of DCF. Complete response (CR), partial response, and stable disease were observed in 7, 11, and 10 patients, respectively. The number of lymph node metastases after DCF-RT was significantly lower than that before DCF-RT (P < 0.0001). Among the 30 patients, pathological CR (pCR) in the primary tumor was observed in 17 patients, and pCRs in both the primary tumor and lymph nodes were observed in 14 patients. The 3-year overall survival rate was 62.2%, and that of patients who experienced pCR was 84%. CONCLUSIONS: Neoadjuvant DCF-RT was tolerable and yielded a high pCR rate in ESCC. Therefore, neoadjuvant DCF-RT may confer a survival benefit and may be a candidate neoadjuvant therapy regimen for patients with locally advanced thoracic ESCC.

Antitumor miR-150-5p and miR-150-3p inhibit cancer cell aggressiveness by targeting SPOCK1 in head and neck squamous cell carcinoma.

OBJECTIVE: Our recent studies have revealed that both strands of pre-miRNAs, the guide strand and the passenger strand, are involved in cancer pathogenesis. Analyses of miRNA expression signatures by RNA sequencing in head and neck squamous cell carcinoma (HNSCC) showed that both of the strands of pre-miR-150 (miR-150-5p and miR-150-3p) were significantly downregulated, and that these miRNAs acted as antitumor miRNAs in HNSCC cells. The aim of this study was to identify oncogenic genes in HNSCC cells that were regulated by miR-150-5p and miR-150-3p. METHODS: Genome-wide gene expression studies, in silico analyses and dual-luciferase reporter assays were carried out to predict miR-150-5p and miR-150-3p regulation in HNSCC cells. Knockdown assay was applied to investigate the functional significance of the target gene. Overall patient survival as a function of target gene expression was estimated by The Cancer Genome Atlas (TCGA) database. RESULTS: A total of 19 genes were putative targets of both miR-150-5p and miR-150-3p regulation. Among them, SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was directly regulated by both miRNAs in HNSCC cells. Knockdown studies using si-SPOCK1 showed that expression of SPOCK1 enhanced HNSCC cell aggressiveness. Overexpression of SPOCK1/SPOCK1 was confirmed in HNSCC clinical specimens. Interestingly, analysis of a large number of patients in the TCGA database (n=248) demonstrated that patients with high SPOCK1 expression had significantly shorter survival than did those with low SPOCK1 expression (P=0.0003). Moreover, 15 pathways were identified as SPOCK1-mediated downstream pathways. CONCLUSION: Downregulation of both strands of pre-miR-150 (miR-150-5p and miR-150-3p) and overexpression of SPOCK1 contribute to the aggressive nature of HNSCC. The involvement of passenger strand miRNA in the regulation of HNSCC pathogenesis is a novel concept in RNA research.

The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster.

We analysed the RNA sequence-based microRNA (miRNA) signature of pancreatic ductal adenocarcinoma (PDAC). Aberrantly expressed miRNAs were successfully identified in this signature. Using the PDAC signature, we focused on 4 clustered miRNAs, miR-216a-5p, miR-216a-3p, miR-216b-5p and miR-216b-3p on human chromosome 2p16.1. All members of the miR-216 cluster were significantly reduced in PDAC specimens. Ectopic expression of these miRNAs suppressed cancer cell aggressiveness, suggesting miR-216 cluster as anti-tumour miRNAs in PDAC cells. The impact of miR-216b-3p (passenger strand of pre-miR-216b) on cancer cells is still ambiguous. Forkhead box Q1 (FOXQ1) was directly regulated by miR-216b-3p and overexpression of FOXQ1 was confirmed in clinical specimens. High expression of FOXQ1 predicted a shorter survival of patients with PDAC by Kaplan-Meier analysis. Loss-of-function assays showed that cancer cell migration and invasion activities were significantly reduced by siFOXQ1 transfectants. We investigated pathways downstream from FOXQ1 by using genome-wide gene expression analysis. Identification of the miR-216-3p/FOXQ1-mediated network in PDAC should enhance understanding of PDAC aggressiveness at the molecular level.

Regulation of actin-binding protein ANLN by antitumor miR-217 inhibits cancer cell aggressiveness in pancreatic ductal adenocarcinoma.

Analysis of our microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC) revealed that microRNA-217 (miR-217) was significantly reduced in cancer tissues. The aim of this study was to investigate the antitumor roles of miR-217 in PDAC cells and to identify miR-217-mediated molecular pathways involved in PDAC aggressiveness. The expression levels of miR-217 were significantly reduced in PDAC clinical specimens. Ectopic expression of miR-217 significantly suppressed cancer cell migration and invasion. Transcription of actin-binding protein Anillin (coded by ANLN) was detected by our in silico and gene expression analyses. Moreover, luciferase reporter assays showed that ANLN was a direct target of miR-217 in PDAC cells. Overexpression of ANLN was detected in PDAC clinical specimens by real-time PCR methods and immunohistochemistry. Interestingly, Kaplan-Meier survival curves showed that high expression of ANLN predicted shorter survival in patients with PDAC by TCGA database analysis. Silencing ANLN expression markedly inhibited cancer cell migration and invasion capabilities of PDAC cell lines. We further investigated ANLN-mediated downstream pathways in PDAC cells. "Focal adhesion" and "Regulation of actin binding protein" were identified as ANLN-modulated downstream pathways in PDAC cells. Identification of antitumor miR-217/ANLN-mediated PDAC pathways will provide new insights into the potential mechanisms underlying the aggressive course of PDAC.

Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma.

Analysis of our microRNA (miRNA) expression signatures of human cancers based on RNA sequencing have shown that both strands of pre-miR-150, miR-150-5p (the guide strand) and miR-150-3p (the passenger strand), are significantly reduced in cancer tissues. We have investigated the functional significance of both strands of pre-miR-150 in cancer cells. The aim of this study was to investigate the antitumor function of these miRNAs and how these miRNAs regulated oncogenic targets in esophageal squamous cell carcinoma (ESCC). Ectopic expression studies demonstrated that both strands of pre-miR-150 miRNA inhibited ESCC cancer cell migration and invasion, indicating that both miR-150-5p and miR-150-3p acted as antitumor miRNAs. A combination of genome-wide gene expression analyses and in silico database searches showed that SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was a candidate target of miR-150-5p and miR-150-3p in ESCC cells. Luciferase reporter assays showed that SPOCK1 was directly regulated by these miRNAs. Silencing of SPOCK1 by small interfering RNA inhibited cancer cell migration and invasion. Overexpression of SPOCK1/SPOCK1 was confirmed by real-time PCR methods and immunohistochemistry. Taken together, downregulation of both strands of pre-miR-150 and overexpression of SPOCK1 are involved in ESCC pathogenesis. The involvement of passenger strand miRNAs in the regulation of cancer cell aggressiveness is a novel concept in RNA research.

Dual strands of pre-miR­150 (miR­150­5p and miR­150­3p) act as antitumor miRNAs targeting SPOCK1 in naïve and castration-resistant prostate cancer.

Analysis of our microRNA (miRNA) expression signature in human cancers has shown that guide and passenger strands of pre-miR­150, i.e., miR­150­5p and miR­150­3p, are significantly downregulated in cancer tissues. In miRNA biogenesis, the passenger strand of miRNA is degraded and is thought to have no functions. Thus, the aim of this study was to investigate the functional significance of miR­150­5p and miR­150­3p in naïve prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Ectopic expression assays showed that both strands of miRNAs significantly suppressed cancer cell migration and invasion. Our strategies of miRNA target searching demonstrated that SPOCK1 (SPARC/osteonectin, cwcv and kazal like domains proteoglycan 1) was directly regulated by miR­150­5p and miR­150­3p. Knockdown of SPOCK1 by siRNA inhibited cancer cell aggressiveness. Moreover, overexpression of SPOCK1 was observed in naïve PCa and CRPC tissues. Taken together, dual strands of pre-miR­150 (miR­150­5p and miR­150­3p) acted as antitumor miRNAs in naïve PCa and CRPC cells. Expression of oncogenic SPOCK1 was involved in naïve PCa and CRPC pathogenesis. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in cancer cells may provide new insights into the pathogenic mechanisms of naïve PCa and CRPC.

Noncoding RNA and colorectal cancer: its epigenetic role.

The use of novel sequencing and high-throughput techniques has become widespread, and are now readily available to obtain the comprehensive transcription profile of the human genome. Noncoding RNAs (ncRNAs) are transcripts that have no apparent protein-coding capacity, but they have important roles in human physiology. Most research in this area has focused on micro-RNAs. However, the role of long ncRNAs (lncRNAs) as drivers of tumor suppression and oncogenic functions has recently been examined in numerous cancer types. Epigenetic alterations can reportedly deregulate the expression of any type of transcript. However, the exact mechanisms of epigenetic regulation of lncRNA are still unknown. In this review, the authors primarily focus on the epigenetic effects modulating ncRNA in colorectal cancer (CRC). The authors specifically discuss examples of oncogenic ncRNA in CRC pathobiology, as well as its extended diagnosis, prognosis and therapy.

ZFP36L2 promotes cancer cell aggressiveness and is regulated by antitumor microRNA-375 in pancreatic ductal adenocarcinoma.

Due to its aggressive nature, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and hard-to-treat malignancies. Recently developed targeted molecular strategies have contributed to remarkable improvements in the treatment of several cancers. However, such therapies have not been applied to PDAC. Therefore, new treatment options are needed for PDAC based on current genomic approaches. Expression of microRNA-375 (miR-375) was significantly reduced in miRNA expression signatures of several types of cancers, including PDAC. The aim of the present study was to investigate the functional roles of miR-375 in PDAC cells and to identify miR-375-regulated molecular networks involved in PDAC aggressiveness. The expression levels of miR-375 were markedly downregulated in PDAC clinical specimens and cell lines (PANC-1 and SW1990). Ectopic expression of miR-375 significantly suppressed cancer cell proliferation, migration and invasion. Our in silico and gene expression analyses and luciferase reporter assay showed that zinc finger protein 36 ring finger protein-like 2 (ZFP36L2) was a direct target of miR-375 in PDAC cells. Silencing ZFP36L2 inhibited cancer cell aggressiveness in PDAC cell lines, and overexpression of ZFP36L2 was confirmed in PDAC clinical specimens. Interestingly, Kaplan-Meier survival curves showed that high expression of ZFP36L2 predicted shorter survival in patients with PDAC. Moreover, we investigated the downstream molecular networks of the miR-375/ZFP36L2 axis in PDAC cells. Elucidation of tumor-suppressive miR-375-mediated PDAC molecular networks may provide new insights into the potential mechanisms of PDAC pathogenesis.

Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Recently developed molecular targeted therapies are not available for patients with ESCC. After curative surgical resection, patients frequently suffer distant metastasis and recurrence. Exploration of novel ESCC metastatic pathways may lead to the development of new treatment protocols for this disease. Accordingly, we have sequentially identified microRNA (miRNA)-mediated metastatic pathways in several cancers. Our past studies of miRNA expression signatures have shown that microRNA-375 (miR-375) is frequently reduced in several types of cancers, including ESCC. In the present study, we aimed to investigate novel miR-375-mediated metastatic pathways in ESCC cells. The expression of miR-375 was downregulated in ESCC tissues, and ectopic expression of this miRNA markedly inhibited cancer cell migration and invasion, suggesting that miR-375 acted as an antimetastatic miRNA in ESCC cells. Our strategies for miRNA target searching demonstrated that matrix metalloproteinase 13 (MMP13) was directly regulated by miR-375 in ESCC cells. Overexpression of MMP13 was observed in ESCC clinical tissues, and the expression of MMP13 promoted cancer cell aggressiveness. Moreover, oncogenic genes, including CENPF, KIF14 and TOP2A, were shown to be regulated downstream of MMP13. Taken together, these findings demonstrated that the antitumor miR-375/oncogenic MMP13 axis had a pivotal role in ESCC aggressiveness. These results provide novel insights into the potential mechanisms of ESCC pathogenesis.