Reovirus combined with a STING agonist enhances anti-tumor immunity in a mouse model of colorectal cancer.

Reovirus, a naturally occurring oncolytic virus, initiates the lysis of tumor cells while simultaneously releasing tumor antigens or proapoptotic cytokines in the tumor microenvironment to augment anticancer immunity. However, reovirus has developed a strategy to evade antiviral immunity via its inhibitory effect on interferon production, which negatively affects the induction of antitumor immune responses. The mammalian adaptor protein Stimulator of Interferon Genes (STING) was identified as a key regulator that orchestrates immune responses by sensing cytosolic DNA derived from pathogens or tumors, resulting in the production of type I interferon. Recent studies reported the role of STING in innate immune responses to RNA viruses leading to the restriction of RNA virus replication. In the current study, we found that reovirus had a reciprocal reaction with a STING agonist regarding type I interferon responses in vitro; however, we found that the combination of reovirus and STING agonist enhanced anti-tumor immunity by enhancing cytotoxic T cell trafficking into tumors, leading to significant tumor regression and survival benefit in a syngeneic colorectal cancer model. Our data indicate the combination of reovirus and a STING agonist to enhance inflammation in the tumor microenvironment might be a strategy to improve oncolytic reovirus immunotherapy.

Efficacy of minocycline hydrochloride aspiration sclerotherapy with additional monoethanolamine oleate aspiration sclerotherapy for symptomatic hepatic cysts.

AIM: Minocycline hydrochloride (MINO) aspiration sclerotherapy (AS) has been widely used for treating hepatic cysts (HC). However, cyst recurrence remains problematic. Information on monoethanolamine oleate (EO) AS, another effective HC treatment, is currently limited. We investigated the efficacy of EO on ineffective MINO treatments, and the relationship between MINO AS and cyst fluid pH. METHODS: A total of 22 cases with symptomatic HC underwent AS with 500 mg of MINO from January 2016 to June 2021. Cyst fluid pH was measured before and after MINO injection. Cyst volume ratio (CVR, %) after 2 weeks was calculated as follows:cyst volume 2 weeks after MINO injection / pre-treatment cyst volume × 100. Treatment was completed if CVR after 2 weeks was ≤35% (MINO-group). For patients with CVR >35%, 2 g of EO was added (MINO/EO-group). Cyst volume ratio was measured every 12 months thereafter. RESULTS: There were no recurrence symptoms in any of the patients during follow-up. Of the 22 cases, 21 had CVR ≤20% after 12 months. The MINO/EO-group (n = 8) tended to have smaller CVRs after 12 months than the MINO-group (n = 14). Cyst volume ratio after 2 weeks was correlated to pH change (p = 0.012) and was larger in patients whose pH decreased by <1.5 (p = 0.015). All adverse events were mild, including in elderly patients. CONCLUSION: Adding EO is an effective and safe treatment for symptomatic HC when MINO AS alone is insufficient. Patients with pH decreases of <1.5 should be considered for additional EO treatment.

[A case of gastric cancer showing a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse events].

The Japanese guidelines for the treatment of gastric cancer recommend nivolumab as third-line chemotherapy for metastatic gastric cancer. We report a case of gastric cancer exhibiting a durable response after the discontinuation of nivolumab due to the early onset of immune-related adverse event (irAE). A 64-year-old man with advanced HER2-positive gastric cancer and distant lymph node metastasis received nivolumab as fourth-line therapy. After two courses of nivolumab, the lymph nodes showed progression. However, the treatment was discontinued because of interstitial pneumonia as an irAE. Disease regression was sustained for approximately 11 months without the readministration of nivolumab.

Psychological burden on patients with cancer of unknown primary: from onset of symptoms to initial treatment.

OBJECTIVE: Supportive care is a critical issue especially for patients with cancer of unknown primary since they often face serious situations, continuing to seek for relevant diagnosis and treatment with the primary sites unknown. However, there are only few research reports on this subject. The aim of this study was to clarify the experience on patients with cancer of unknown primary until they have their initial treatment and to obtain suggestions of supportive care for them. METHODS: A qualitative study using semi-structured interviews regarding the experience on patients with cancer of unknown primary was conducted. RESULTS: Data of the experience of the nine patients with cancer of unknown primary until their initial treatment were collected by semi-structured interviews. Patients' speech at interviews recorded in verbatim reports was assigned with 545 codes, 102 subcategories and 38 categories. Experience of the patients with cancer of unknown primary was categorized into five phases: Phase 1: period of making self-judgment on symptoms; Phase 2: period of suspecting serious disease, and seeking for appropriate medical treatment; Phase 3: period of searching for cause of disease while having painful symptoms and anxiety; Phase 4: period of having fear for death, frustration with unknown cause and denial of unknown state; Phase 5: period of struggling but being determined to face disease. CONCLUSIONS: Experience of patients with cancer of unknown primary from onset of symptoms to their initial treatment was categorized into five phases, mainly manifesting their psychological burden. These findings will warrant for the future study of supportive care for patients with cancer of unknown primary.

Autonomic nervous responses in colorectal polypectomy: Randomized controlled trial comparing air and carbon dioxide insufflation.

BACKGROUND AND AIM: Carbon dioxide (CO2) insufflation devices are commonly used for endoscopic examination and treatment. In this prospective randomized controlled trial (RCT), we compared patient acceptance, cardiovascular tolerance,and autonomic nervous responses between patients receiving air insufflation and CO2 insufflation. METHODS: We initially enrolled 170 patients and, of these, 158 patients in total were analyzed (air group, 83; CO2 group, 75). Autonomic nervous responses were evaluated by analysis of heart rate variability (HRV). Primary end point was superiority in the effects of CO2 insufflation on the autonomic nervous system by HRV analysis. RESULTS: Visual analog scale disclosed significantly less abdominal pain and abdominal fullness with CO2. Percentage heart rate change rate at 1 h and 4 h after the procedure was also significantly lower in the CO2 group than in the air group (1 h after: P < 0.01, 4 h after: P < 0.05). Comparison based on age showed that % heart rate change was significantly lower in the younger CO2 patients (just after colonoscopy and 1 h after: P < 0.01, 4 h after: P < 0.05), but this difference was not apparent in an older group of patients. CONCLUSIONS: This is the first RCT showing that colorectal polypectomy using CO2 insufflation significantly decreases abdominal pain and abdominal fullness common in such patients with lowered stress to the autonomous nervous system. The effects using CO2 insufflation on the sympathetic nervous system also seemed to be more prominent among younger patients.

Establishment of a long-term three-dimensional primary culture of mouse glandular stomach epithelial cells within the stem cell niche.

Compared to the small intestine and colon, little is known about stem cells in the stomach because of a lack of specific stem cell markers and an in vitro system that allows long-term culture. Here we describe a long-term three-dimensional (3D) primary gastric culture system within the stem cell niche. Glandular stomach cells from neonatal mice cultured in collagen gel yielded expanding sphere-like structures for 3months. The wall of the gastrospheres consisted of a highly polarized epithelial monolayer with an outer lining of myofibroblasts. The epithelial cells showed a tall columnar cell shape, basal round nuclei, and mucus-filled cytoplasm as well as expression of MUC5AC, indicating differentiation into gastric surface mucous cells. These cells demonstrated the features of fully differentiated gastric surface mucous cells such as microvilli, junctional complexes, and glycogen and secretory granules. Fewer than 1% of cultured epithelial cells differentiated into enteroendocrine cells. Active proliferation of the epithelial cells and many apoptotic cells in the inner lumen revealed the rapid cell turnover in gastrospheres in vitro. This method enables us to investigate the role of signaling between cell-cell and epithelial-mesenchymal interactions in an environment that is extremely similar to the in vivo environment.

Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells.

BACKGROUND: Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. However, almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. Thus, new chemotherapeutic agents that can overcome the CDDP-resistant cancer cells will improve the survival of advanced cancer patients. METHODS: We synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl2 (L)] and [PdCl2 (L)]. CDDP-resistant gastric cancer cell lines were established by continuous exposure to CDDP, and gene expression in the CDDP-resistant gastric cancer cells was analyzed. The cytotoxicity and apoptosis induced by [PtCl2 (L)] and [PdCl2 (L)] in CDDP-sensitive and CDDP-resistant gastric cancer cells were evaluated. DNA double-strand breaks by drugs were assessed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established and antitumor effects were also examined in vivo. RESULTS: CDDP-resistant gastric cancer cells exhibit ABCB1 and CDKN2A gene up-regulation, as compared with CDDP-sensitive gastric cancer cells. In the analyses of CDDP-resistant gastric cancer cells, [PdCl2 (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl2 (L)] induced DNA double-strand breaks. CONCLUSION: These results indicate that [PdCl2 (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications.

Modulation of Reoviral Cytolysis (I): Combination Therapeutics.

Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To explore this issue, we used oncolytic reovirus in combination with currently used chemotherapeutic drugs (irinotecan, paclitaxel, and docetaxel) for the treatment of gastric and other gastrointestinal cancer cells in vitro and in a mouse model. Cell viability in vitro was quantified by WST-1 assays in human cancer cell lines treated with reovirus and/or chemotherapeutic agents. The expression of reovirus protein and caspase activity was determined by flow cytometry. For in vivo studies, athymic mice received intratumoral injections of reovirus in combination with irinotecan or paclitaxel, after which tumor size was monitored. In contrast to expectations, we found that reoviral oncolysis was only poorly correlated with Ras pathway activation. Even so, the combination of reovirus with chemotherapeutic agents showed synergistic cytopathic effects in vitro, plus enhanced reovirus replication and apoptosis. In vivo experiments showed that reovirus alone can reduce tumor size and that the combination of reovirus with chemotherapeutic agents enhances this effect. Thus, we find that oncolytic reovirus therapy is effective against gastric cancer. Moreover, the combination of reovirus and chemotherapeutic agents synergistically enhanced cytotoxicity in human gastric cancer cell lines in vitro and in vivo. Our data support the use of reovirus in combination with chemotherapy in further clinical trials, and highlight the need for better biomarkers for reoviral oncolytic responsiveness.

BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer: A Case Report.

Metastatic colorectal neuroendocrine carcinoma (NEC) is often treated using a chemotherapy protocol for small-cell lung cancer; however, the prognosis is extremely poor. A 55-year-old woman with BRAF V600E-mutated transverse colon NEC and liver metastases underwent colectomy followed by FOLFOXIRI plus bevacizumab. Consequently, the liver metastases markedly shrank. Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.

Phase II Prospective Study of Trastuzumab in Combination with S-1 and Oxaliplatin (SOX100) Therapy for HER2-Positive Advanced Gastric Cancer.

PURPOSE: The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m2) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC. METHODS: In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, oxaliplatin (100 mg/m2) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5-86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5-22.9) months, 7.6 (95% CI 5.0-10.9) months, and 75.0% (95% CI 53.3-90.2), respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%). CONCLUSION: SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC.

Role of ES cell-expressed Ras (ERas) in tumorigenicity of gastric cancer.

ERas, a unique member of the Ras family, was initially found only in embryonic stem (ES) cells, where it plays a crucial role in the transformation of transplanted ES cells to teratomas. ERas is involved in ES cell survival, and unlike other Ras family members, is constitutively active without any mutations. The aim of this study was to investigate the expression and role of ERas in human gastric cancer. To test whether ERas played a significant role in human cancer cells, we examined its expression and function in gastric cancer. ERas was expressed in gastric cancer cell lines at different levels. Induction of ERas expression activated the phosphatidylinositol 3 kinase (PI3K)/Akt axis and then enhanced anchorage-independent growth and ERas knockdown by siRNA suppressed cell invasion. Immunohistochemical analyses revealed that ERas was expressed in 38.7% (55/142) of human gastric carcinoma tissues, and its expression was significantly associated with metastasis to the liver (P < 0.0001) and lymph nodes (P < 0.05). ERas up-regulated transcription regulatory factors including ZFHX1A, ZFHX1B, and TCF3, which repress E-cadherin. These data suggest that ERas is activated in a significant population of gastric cancer, where it may play a crucial role in gastric cancer cell survival and metastases to liver via down-regulation of E-cadherin.

Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF-beta signal transduction.

BACKGROUND AND AIMS: AT motif binding factor 1 (ATBF1), a homeotic transcription factor, was identified as a tumor suppressor, and loss of heterozygosity at ATBF1 locus occurs frequently in gastric cancers. We previously showed that ATBF1 expression inversely correlated with the malignant character of gastric cancer and that ATBF1 enhanced the promoter activity of p21Waf1/Cip1. We also found that ATBF1 moves between cytoplasm and nucleus, but the precise mechanism of translocation is unknown. In this study, we investigated the mechanism of ATBF1 translocation to the nucleus with the runt domain transcription factor 3 (RUNX3) in cooperation with TGF-beta signal transduction. MATERIALS AND METHODS: To analyze the expression of ATBF1 and RUNX3 in gastric cancer cells, we performed immunohistochemistry on 98 resected gastric cancer tissue samples and scored the nuclear staining intensity as grade 0 to grade 5. Co-immunoprecipitation (co-IP) of ATBF1 and RUNX3 was performed. Dual luciferase assays were performed by transfecting ATBF1 and RUNX3 with a p21Waf1/Cip1 reporter vector. To investigate the nuclear translocation of endogenous ATBF1 and RUNX3 in response to TGF-beta signal, we examined the subcellular localization of ATBF1 and RUNX3 in gastric cancer cells treated with recombinant TGF-beta1 using confocal laser scanning microscopy. RESULTS: Strong immunohistochemical nuclear staining of ATBF1 was observed in 37 (37.8%) of the gastric cancer tissue samples, and RUNX3 nuclear staining was observed in 15 (15.3%). There was a statistically significant correlation between ATBF1 and RUNX3 nuclear localization (rs=0.433, p<0.001). Co-IP revealed a physical association between ATBF1 and RUNX3. ATBF1 and RUNX3 up-regulated p21Waf1/Cip1 promoter activity synergistically. In SNU16 gastric cancer cells, ATBF1 and RUNX3 were cytoplasmic before TGF-beta1 stimulation, but after 24h of TGF-beta1 stimulation, endogenous ATBF1 and RUNX3 translocated to the nucleus. CONCLUSION: ATBF1 associates with RUNX3 and translocates to the nucleus in response to TGF-beta signal transduction and might function in the nucleus as tumor suppressor and transcriptional regulator.

Tumor Location Is Associated With the Prevalence of Braf And Pik3ca Mutations in Patients with Wild-Type Ras Colorectal Cancer: A Prospective Multi-Center Cohort Study in Japan.

BACKGROUND: Primary tumor location is a critical prognostic factor that also impacts the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in wild-type RAS (KRAS/NRAS) metastatic colorectal cancer (CRC). However, the association between the incidence of BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations and primary tumor location remains unclear. METHODS: We prospectively collected tumor samples and clinical data of patients from 15 hospitals between August 2014 and April 2016 to investigate RAS, BRAF, and PIK3CA mutations using a polymerase chain reaction-based assay. According to the primary tumor location, patients were classified to right-sided (from cecum to splenic flexure) and left-sided (from descending colon to rectum) tumor groups. RESULTS: In total, 577 patients with CRC were investigated, 331 patients (57%) had CRC with wild-type RAS; of these 331 patients, 10.5%, 4.8%, and 5.9% patients harbored BRAFV600E, BRAFnon-V600E, and PIK3CA mutations, respectively. BRAF/PIK3CA mutations were more frequent in females, patients with right-sided tumors, and patients with peritoneal metastasis cases and less frequent in patients with liver metastases. The prevalence rates of BRAFV600E and PIK3CA mutations were higher in patients with right-sided tumors than in those with left-sided tumors (32.3% vs. 4.8% and 17.2% vs. 3.6%, respectively). CONCLUSIONS: More than half of the patients with right-sided CRC and wild-type RAS harbored BRAF/PIK3CA mutations, including BRAFnon-V600E, which may contribute to the difference in the anti-EGFR efficacy between the right- and left-sided CRC.

Gastric-and-intestinal mixed endocrine cell phenotypic expression of carcinoid tumors in the rectum.

We have previously demonstrated that gastric and intestinal endocrine cell (End-cell) marker expression is important for assessment of the histogenesis of endocrine cell tumors. However, the End-cell phenotypes of carcinoid tumors in the rectum remain largely unclear. We therefore examined marker expression of rectal carcinoid tumors. We evaluated 20 rectal carcinoid tumors (as well as 8 from the stomach for comparison) phenotypically, using gastrin, gastric inhibitory polypeptide (GIP) and glucagons-like peptide-1 (GLP-1) as End-cell markers. Rectal carcinoid tumors were divided into 3 endocrine-gastric (e-G), 16 endocrine-gastric-and-intestinal mixed (e-GI), 1 endocrine-intestinal (e-I), and 0 endocrine-null (e-N) types, thus 19 (e-G+ e-GI types, 95%) had gastric phenotypic expression, while 17 (e-GI+ e-I types, 85%) harbored intestinal elements. Stomach carcinoid tumors were classified as 6 e-G and 2 e-N types, respectively. In conclusion, most rectal carcinoid tumors exhibited the e-GI type, suggesting the importance of gastric End-cell marker expression for histogenesis of the rectal carcinoid tumors. Further studies of pathological and biological analyses are needed to clarify the histogenesis of the carcinoid tumors.

Sarcoptes scabiei var. hominis: three-dimensional structure of a female imago and crusted scabies lesions by X-ray micro-CT.

The three-dimensional structure of scabies mites (Sarcoptes scabiei var. hominis) and keratin layers affected by crusted scabies lesions were obtained using X-ray computed tomography at sub-micrometer and micrometer resolution, respectively (X-ray micro-CT). Clear three-dimensional images including internal structure of scabies mites were obtained. Utilizing reconstructed micro-CT data, the sections of the capitulum (head part), digestive organs, and legs are shown. The reconstructed capitulum shows a jaw-like structure capable of penetrating the keratin layer of the skin. The tip of the forelegs of female scabies mites has a flat disk structure that may be used to grasp the skin surface. The keratin layer of a crusted scabies lesion spontaneously exfoliated from a patient was also reconstructed by the X-ray micro-CT technique. Extracted sections from CT data revealed a network structure of tunnels made by scabies mites with numerous larvae and eggs inside the tunnels.

Advanced stomach and pancreas cancer successfully treated with combination chemotherapy with S-1/paclitaxel/lentinan.

We report a case of stomach and pancreas cancers that showed marked responses to combination chemotherapy consisting of S-1, paclitaxel (PTX), and lentinan (LNT). A 67-year-old Japanese man was referred to our hospital in July 2005, diagnosed with advanced gastric cancer. Subsequent examination revealed the existence of cancers in the stomach and pancreas, with lymph nodes and peritoneal metastasis and ascites. The patient received combined chemotherapy (one course comprised 3 weeks) with S-1 (100 mg/body, day 1-14 followed by withdrawal for 1 week), PTX (50 mg/m2, day 1 and day 8), and LNT (2 mg/m2, day 1, day 8 and day 15). After completion of 4 courses, the patient achieved partial response (PR), with complete disappearance of the primary gastric tumor and ascites. He maintained in PR for 17 months. We analyzed Th1/ Th2 ratio and LNT binding rate to monocytes by flow cytometry. Combination chemotherapy with S-1/PTX/LNT can be an effective treatment for unresectable advanced gastric carcinoma.

Gastric phenotypic expression and histogenesis of metachronous gastric cancers endoscopically resected.

BACKGROUND/AIMS: Endoscopic Resection (ER) has been performed for early gastric cancers, and metachronous gastric cancers (MGCs) were occasionally observed. Most MGCs were classified histologically as the differentiated type. However, there have been no data on the gastric and intestinal phenotypic classification of MGCs. In our previous study, Hp-infection in MG may trigger intestinalization of gastric cancers. We therefore speculate the phenotype shift in MGC lesions under Hp-chronic-infection. METHODOLOGY: We examined the 17 MGC lesions phenotypically and histologically by using several gastric and intestinal epithelial cell markers, MUC5AC, MUC6, MUC2 and villin. RESULTS: Most lesions (16/17) exhibited the differentiated type. In 8 first cancers, the lesions were divided phenotypically into 2 G, 4 GI, 1 I, and 1 N types. In 9 second/third cancers, the lesions were divided phenotypically into 3 G, 1 GI, 4 I, and 1 N types. The first lesions (6/8) had more gastric phenotypic expression compared with the second/third ones (4/9) in the MGCs, although there was no significant difference between two groups (P = 0.28). CONCLUSION: Our present data suggest the possibility that the cancer retaining G type is detected endoscopically earlier than that obtaining the intestinal phenotypic expression by the phenotypic shift, which may partially explain the MGC occurrence.

Lentinan with S-1 and paclitaxel for gastric cancer chemotherapy improve patient quality of life.

BACKGROUND/AIMS: Lentinan (LNT), a purified beta-glucan, is a biological and immunological modifier and has been used as an anticancer drug in combination with 5-fluorouracil for gastric cancer in Japan. In this prospective randomized study, we evaluated the effects of LNT combination with regard to quality of life (QOL) and LNT binding ratio in monocytes. METHODOLOGY: Twenty patients were evaluated for 12 weeks. One cycle was 3 weeks and S-1 (day1-14) and Paclitaxel (days1 and 8) were administered. LNT was used once a week (days 1, 8 and 15) and it was used for all 12 weeks in the LNT 12-wk group and only for the last 6 weeks in the LNT 6-wk group. QOL was evaluated weekly by QOL-ACD, and binding of LNT to monocytes was measured by flow cytometry. RESULTS: There were individual variations in the binding ratio of LNT to monocytes from 0.16% to 11.95%. Toxicity with chemotherapy was not improved in the LNT 12-wk group, however, the total QOL score was significantly elevated in the LNT 12-wk group (p = 0.018) but not in the LNT 6-wk group. CONCLUSION: LNT combination from the beginning of the chemotherapy may be an important factor for the improvement of patient QOL.

An endocrine cell carcinoma with gastric-and-intestinal mixed phenotype adenocarcinoma component in the stomach.

A 77-year-old man complained of bodyweight loss, and a Borrmann 3 type lesion was observed endoscopically in the anterior wall of angular region of the stomach. The endocrine cell carcinoma (ECC) having the cytoplasmic staining of chromogranin A (CgA) was detected pathologically in the biopsy samples. The patient underwent distal gastrectomy plus systemic lymph node (LN) dissection (D2 LN dissection), and pathological examination revealed ECC invading the subserosa, and no LN metastasis (pT2N0M0). None of the gastric and intestinal endocrine cell marker expression was apparent in the ECC cells. The lesion also contained a moderately differentiated type tubular adenocarcinoma component, which was judged to be gastric-and-intestinal mixed (GI type) phenotype, using gastric and intestinal exocrine cell markers. After the surgery, he left the hospital and started oral doxifluridine (600 mg/day). The patient now (March 2008, about 19 months since the surgery) continues this chemotherapy with no recurrence. In conclusion, we experienced ECC with a GI type adenocarcinoma component. The ECC cases with the GI type adenocarcinoma component may have a relatively good prognosis, being similar to the results of advanced gastric cancers from the viewpoint of gastric and intestinal phenotypic expression.

Going (Reo)Viral: Factors Promoting Successful Reoviral Oncolytic Infection.

Oncolytic viruses show intriguing potential as cancer therapeutic agents. These viruses are capable of selectively targeting and killing cancerous cells while leaving healthy cells largely unaffected. The use of oncolytic viruses for cancer treatments in selected circumstances has recently been approved by the Food and Drug Administration (FDA) of the US and work is progressing on engineering viral vectors for enhanced selectivity, efficacy and safety. However, a better fundamental understanding of tumour and viral biology is essential for the continued advancement of the oncolytic field. This knowledge will not only help to engineer more potent and effective viruses but may also contribute to the identification of biomarkers that can determine which patients will benefit most from this treatment. A mechanistic understanding of the overlapping activity of viral and standard chemotherapeutics will enable the development of better combinational approaches to improve patient outcomes. In this review, we will examine each of the factors that contribute to productive viral infections in cancerous cells versus healthy cells. Special attention will be paid to reovirus as it is a well-studied virus and the only wild-type virus to have received orphan drug designation by the FDA. Although considerable insight into reoviral biology exists, there remain numerous deficiencies in our understanding of the factors regulating its successful oncolytic infection. Here we will discuss what is known to regulate infection as well as speculate about potential new mechanisms that may enhance successful replication. A joint appreciation of both tumour and viral biology will drive innovation for the next generation of reoviral mediated oncolytic therapy.