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.

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.

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.

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.

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.

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.

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.

The Successful Treatment of Metastatic Extraosseous Ewing Sarcoma with Pazopanib.

The clinical efficacy and outcomes of pazopanib treatment for metastatic extraosseous Ewing sarcoma remain unclear. We herein report a case of heavily pre-treated metastatic extraosseous Ewing sarcoma in which pazopanib treatment achieved a significant improvement. A 17-year-old girl was referred to our hospital due to metastatic extraosseous Ewing sarcoma. The initial cytotoxic chemotherapy was temporarily effective, however, her disease eventually progressed, and she was subsequently treated with pazopanib. The recurrent tumor showed a marked response to pazopanib therapy; the therapeutic effect has lasted for more than 26 months. The present case suggests that pazopanib may be a therapeutic option for extraosseous Ewing sarcoma.

Urinary kallikrein 10 predicts the incurability of gastric cancer.

The current imaging modalities are not sufficient to identify inoperable tumor factors, including distant metastasis and local invasion. Hence, we conducted this study using urine samples to discover non-invasive biomarkers for the incurability of gastric cancer (GC). Urine samples from 111 GC patients were analyzed in this study. The GC cohort was categorized and analyzed according to disease stage and operability. In the discovery phase, protease protein array analysis identified 3 potential candidate proteins that were elevated in the urine of advanced GC patients compared to early GC patients. Among them, urinary kallikrein 10 (KLK10) was positively associated with tumor stage progression. Moreover, the urinary level of KLK10 (uKLK10) was significantly elevated in the urine of patients with inoperable GC compared to operable GC patients (median, 118 vs. 229; P=0.014). The combination of uKLK10, tumor location and tumor size distinguished operability of GC with an area under the curve of 0.859, 82.4% sensitivity and 86.2% specificity. Disease-free survival (DFS) was significantly shorter in GC patients with high uKLK10 compared to those with low uKLK10 (hazard ratio: 3.30 [95% confidence interval, 1.58-6.90] P<0.001). Immunohistochemical analyses also demonstrated a positive correlation between tumor stage and KLK10 expression in GC tissues (r=0.426, P<0.001). In addition, GC patients with high expression of pathological KLK10 (pKLK10) showed a significantly shorter DFS compared to those with low pKLK10 (hazard ratio: 3.79 [95% confidence interval, 1.27-11.24] P=0.010). uKLK10 is a promising non-invasive biomarker for the inoperability and incurability of GC.

Adalimumab therapy in a patient with Crohn's disease with a giant pelvic paraganglioma after chemotherapy.

A 23-year-old man was diagnosed with a giant pelvic paraganglioma in September 2013, and a 6-month chemotherapy course was performed. The chemotherapy resulted in stable disease of the tumor for about 1 year. However, in April 2015, the patient complained of fever and diarrhea of more than ten times a day. Endoscopy showed serpiginous (snake-like) ulcers in the cecum, ascending, descending, and sigmoid colons, with granulomas without caseation histologically. The patient was diagnosed with the active stage of Crohn's disease (CD) in June 2015. Oral mesalazine (3000 mg/day) and an elemental diet (900 kcal/day) led to temporary clinical remission. At the beginning of January in 2016, an abdominal abscess and fistula were detected by computed tomography, which needed surgical treatment. Adalimumab administration was started at the beginning of February, since active lesions were detected endoscopically. A second endoscopy showed improvement of the inflammatory lesions 3 months after induction therapy with adalimumab. Clinical remission has been maintained with adalimumab administration, with stable disease of the tumor and no adverse events. To the best of our knowledge, this is the first report of a patient with a paraganglioma who developed CD after chemotherapy. The patient was successfully treated with adalimumab after surgery for his CD.

Ectopic Gastric and Intestinal Phenotypes, Neuroendocrine Cell Differentiation, and SOX2 Expression Correlated With Early Tumor Progression in Colorectal Laterally Spreading Tumors.

INTRODUCTION: The significance of the ectopic gastric phenotype remains unclear in patients with colorectal laterally spreading tumors (LSTs). We investigated clinicopathologic differences among LST subtypes, aiming to identify factors indicative of malignant transformation and invasion that are linked to ectopic gastric phenotype and tumor progression. MATERIALS AND METHODS: We analyzed the morphologic characteristics of 105 colorectal LSTs resected by endoscopic submucosal dissection. LSTs were classified into 2 subtypes: granular (G-LST) and nongranular (NG-LST). Resected LSTs were analyzed histologically and were immunohistochemically stained for MUC5AC, MUC6, chromogranin A, CD10, and SOX2. RESULTS: The 105 LSTs included 60 G-LSTs and 45 NG-LSTs. By histology, G-LSTs comprised 5 adenomas with low-grade dysplasia (LAs), 45 adenomas with high-grade dysplasia (HAs), and 10 adenocarcinomas invading the submucosa (SMs). NG-LSTs comprised 8 LAs, 25 HAs, and 12 SMs. MUC5AC positivity was significantly higher in G-LSTs compared to NG-LSTs (P = .002), and MUC5AC positivity in HA lesions was significantly higher than in LA lesions (P = .01). MUC6 and SOX2 positivity in SM G-LSTs, and chromogranin A positivity in SM NG-LSTs were significantly higher than in HAs (P = .01, .01, and .03, respectively). CD10 positivity in SM NG-LSTs was significantly higher than in HAs and LAs (P = .02 and .01, respectively). CONCLUSION: Ectopic gastric and intestinal phenotypes, neuroendocrine cell differentiation, and SOX2 expression differ according to tumor grade in colorectal LSTs, and these markers are correlated with early tumor progression in each LST subtype.

Anti-tumor efficacy of oncolytic reovirus against gastrointestinal stromal tumor cells.

Imatinib, a multitargeted receptor tyrosine kinase inhibitor, is used as the standard initial therapy against inoperable gastrointestinal stromal tumor (GIST). However, GIST can acquire resistance to imatinib within several years of therapy. The development of oncolytic reovirus as an anticancer agent has expanded to many clinical trials for various tumors. Here, we investigated whether reovirus has antitumor activity against GIST cells in the setting of imatinib sensitivity in vitro and in vivo. Cell proliferation and apoptosis assays were performed using a human GIST cell line, GIST-T1, and imatinib-resistant GIST (GIST-IR) cells that we established. The molecular pathways responsible for cell damage by reovirus were explored using PCR-arrays and Western blots. Reovirus significantly induced apoptotic cell death in GIST-T1 and GIST-IR cells in vitro, despite differences in the activation of receptor tyrosine kinase pathways between GIST-T1 and GIST-IR. Molecular assays indicated the possibility that reovirus induces apoptotic cell death via Fas signaling. Furthermore, in vivo mouse tumor xenograft models demonstrated a significant anti-tumor effect of reovirus on both GIST-T1 and GIST-IR cells. Our results demonstrate the therapeutic potential of reovirus against GIST.

Anticancer Effects of a New Aminosugar-conjugated Platinum Complex Agent Against Cisplatin-resistant Gastric Cancer.

BACKGROUND/AIM: Resistance against cisplatin is a problem for the success of gastric cancer chemotherapy. Herein, we evaluated the antitumor effect of a new aminosugar-conjugated, mono-functional platinum complex (Pt-Oqn), which forms a single covalent bond with DNA. MATERIALS AND METHODS: We compared the cytotoxicity of Pt-Oqn to that of cisplatin (CDDP), oxaliplatin (L-OHP) and carboplatin (CBDCA). We also compared Pt-Oqn and cisplatin for DNA double-strand breaks based on phosphorylated histone H2AX levels in cancer cells and antitumor effects in xenograft models. RESULTS: The resistance factor (RF) for Pt-Oqn was low among the four drugs, indicating the potential of Pt-Oqn for overcoming CDDP-induced resistance. In MKN45-R cells, γ-H2AX protein increased following treatment with Pt-Oqn, but not with cisplatin. Finally, Pt-Oqn, but not cisplatin, showed significant antitumor effects in MKN45-R xenografts. CONCLUSION: This new aminosugar-conjugated platinum complex is a promising candidate agent for overcoming the drug resistance of cisplatin-resistant stomach cancer.

Long-Term Clinical Remission in Biologically Naïve Crohn's Disease Patients with Adalimumab Therapy, Including Analyses of Switch from Adalimumab to Infliximab.

There is little evidence regarding the maintenance of long-term clinical remission by adalimumab (ADA) therapy in Crohn's disease (CD) patients naïve to anti-tumor necrosis factor treatment (naïve CD patients), since most CD patients are treated with ADA after infliximab (IFX) therapy. The long-term clinical response to ADA was retrospectively analyzed in 17 naïve CD patients for at least 24 months, and the serum trough IFX levels were evaluated in patients switching from ADA to IFX. Of the 17 naïve CD patients, 14 (82.4%) maintained long-term clinical remission with ADA therapy for at least 24 months, without serious adverse events. The clinical condition of 7 patients was observed for more than 36 months, and 3, 1, 1, and 2 cases maintained remission at months 42, 48, 54, and 60 after ADA therapy, respectively. Three patients (17.6%) switched from ADA to IFX less than 24 months after the start of ADA therapy, and they had remission, retaining trough levels of IFX higher than 1 µg/ml, occasionally by dose escalation. In conclusion, maintenance ADA therapy achieves long-term clinical remission in naïve CD patients. Switching from ADA to IFX is an important therapeutic option in CD patients showing loss of response to ADA, occasionally with dose escalation, based on the analysis of serum IFX trough levels.

Organizing Pneumonia in a Patient with Quiescent Crohn's Disease.

A 64-year-old man with Crohn's disease (CD) was admitted to our hospital due to moderate risk of pneumonia while receiving scheduled adalimumab maintenance therapy. Symptoms remained virtually unchanged following administration of antibiotics. A final diagnosis of organizing pneumonia (OP) was made based on findings of intra-alveolar buds of granulation tissue and fibrous thickening of the alveolar walls on pathological examination and patchy consolidations and ground glass opacities on computed tomography. Immediate administration of prednisolone provided rapid, sustained improvement. Although a rare complication, OP is a pulmonary manifestation that requires attention in CD patients.

Immunogenic cell death due to a new photodynamic therapy (PDT) with glycoconjugated chlorin (G-chlorin).

Both the pre-apoptotic exposure to calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death. Photodynamic therapy (PDT) uses non-toxic photosensitizers and visible light at a specific wavelength in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumor microvasculature, and stimulate the host immune system. We have previously shown that glycoconjugated chlorin (G-chlorin) has superior cancer cell selectivity and effectively suppresses the growth of xenograft tumors. In the present study, we evaluated the immunogenicity of PDT with G-chlorin treatment in colon cancer cells. PDT with G-chlorin suppressed CT26 (mouse colon cancer cells) tumor growth considerably more efficiently in immunocompetent mice (wild-type mice, allograft model) than in immune-deficient mice (nude mice, xenograft model), although control treatments were not different between the two. This treatment also induced CRT translocation and HMGB1 release in cells, as shown by western blot and immunofluorescence staining. To evaluate the use of PDT-treated cells as a tumor vaccine, we employed a syngeneic mouse tumor model (allograft model). Mice inoculated with PDT-treated CT26 cells were significantly protected against a subsequent challenge with live CT26 cells, and this protection was inhibited by siRNA for CRT or HMGB1. In conclusion, PDT with G-chlorin treatment induced immunogenic cell death in a mouse model, where the immunogenicity of this treatment was directed by CRT expression and HMGB1 release.

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.

A phase II prospective study of the trastuzumab combined with 5-weekly S-1 and CDDP therapy for HER2-positive advanced gastric cancer.

BACKGROUND: We evaluated the efficacy and safety of 5-weekly S-1 and cisplatin combined with trastuzumab, a monoclonal antibody against human epidermal growth factor receptor type 2 (HER2) for HER2-positive advanced gastric cancer (AGC). METHODS: This phase II study treatment consisted of S-1 (80-120 mg per day) orally on day 1-21, cisplatin (60 mg/m(2)) intravenously on day 8, 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, progression-free survival (PFS), response rate (RR), and safety. RESULTS: A total 22 patients from seven centers were enrolled. In the 20 patients evaluable for analysis, the 1-year survival rate was 70 % (95 % confidence interval (CI) 49.9-90.1 %), and median survival time, PFS, and RR were 15.3, 7.5 months and 41.2 %, respectively. Major grade 3/4 adverse events were neutropenia (30 %), anorexia (30 %), leukopenia (25 %), fatigue (20 %), and anemia (15 %). CONCLUSIONS: Five-weekly S-1 and cisplatin combined with trastuzumab showed effective with favorable safety profile in patients with HER2-positive AGC.

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.