Nano-particulate Toll-like Receptor 9 Agonist Potentiates the Antitumor Activity of Anti-Glypican-1 Antibody.

BACKGROUND/AIM: Monoclonal antibodies (mAbs) that target tumor antigens have recently been developed. Their antitumor activity is mainly achieved through antibody-dependent cellular cytotoxicity (ADCC) via effector cells such as tumor-infiltrated macrophages and natural killer (NK) cells. CpG oligodeoxynucleotides (ODNs) have potent antitumor activity and are considered to increase the tumor infiltration of macrophages and NK cells; however, a completely solubilized novel CpG-schizophyllan (SPG) complex, K3-SPG, displays more potent antitumor activity. We recently reported the significant antitumor activity of anti-glypican-1 (GPC1) mAb against GPC1-positive esophageal squamous cell carcinoma (ESCC) via ADCC. The aim of this study was to evaluate the potential synergistic antitumor activity of anti-GPC1 mAb and K3-SPG and elucidate the underlying mechanisms using a xenograft model of GPC1-positive human ESCC cells. MATERIALS AND METHODS: The established human esophageal cancer cell line TE14 was subcutaneously injected into SCID mice. Xenograft mice were treated with anti-GPC1 mAb, K3-SPG, or their combination. Antitumor activity was evaluated by measuring the tumor volume. For FACS analysis, agents were administrated, and tumors were resected 1 day after the final treatment. RESULTS: Anti-GPC1 mAb or K3-SPG monotherapy showed dose-dependent antitumor activity, and combination therapy with anti-GPC1 mAb and K3-SPG showed antitumor activity (p=0.0859). Flow cytometry revealed significantly increased numbers of macrophages (p=0.0133) and of the ratio of activated NK cells/total NK cells (p=0.0058) following K3-SPG or combination therapy. CONCLUSION: Combination therapy with K3-SPG and anti-GPC1 mAb or another antitumor mAb may represent a new cancer treatment option acting via ADCC.

Plasma trough concentration of imatinib and its effect on therapeutic efficacy and adverse events in Japanese patients with GIST.

BACKGROUND: Imatinib mesylate (IM) is the standard chemotherapy for patients with gastrointestinal stromal tumors (GISTs) and has a favorable safety profile. Pharmacokinetics (PK), such as plasma trough concentration (Cmin), varies among patients, requiring the need for therapeutic drug monitoring (TDM) during IM administration. Despite some reports from overseas, the relationship between Cmin, adverse events (AEs), and treatment efficacy in Japanese patients with GIST has still been lacking. This study aimed to investigate the relationship between IM plasma concentration and AEs in Japanese patients with GISTs. METHODS: This retrospective study analyzed the data of 83 patients who underwent IM treatment for GISTs at our institution between May 2002 and September 2021. RESULTS: The IM Cmin was associated with any grade of AEs (with AEs vs. without AEs = 1294 (260-4075) vs. 857 (163-1886) ng/mL, P < 0.001), edema (with edema vs. without edema = 1278 (634-4075) vs. 1036 (163-4069) ng/mL, P = 0.017), and fatigue (with fatigue vs. without fatigue = 1373 (634-4069) vs. 1046 (163-4075) ng/mL, P = 0.044). Moreover, a Cmin ≥ 1283 ng/mL was a risk factor for severe AEs. The median progression-free survival (PFS) was 3.04 years in the lowest Cmin tertile (T1, < 917 ng/mL) compared with 5.90 years for T2 and T3 (P = 0.010). CONCLUSION: Edema and fatigue are potentially associated with IM plasma trough concentrations of ≥ 1283 ng/mL in Japanese patients with GISTs. Further, maintaining an IM plasma trough concentration above 917 ng/mL may improve PFS.

[A Case of Anal Canal Adenocarcinoma with Perianal Pagetoid Spread without a Macroscopic Finding].

We report a case of anal canal cancer with Pagetoid spread without a macroscopic skin lesion. A 54-year-old man was admitted to a hospital with complaints of bloody stools. Endoscopic examination revealed a polyp in the anal canal, and endoscopic mucosal resection was performed. Pathological examination revealed an adenocarcinoma accompanied by Pagetoid spread and the positive surgical margin. We additionally performed trans-anal resection twice, but the resected horizontal margin was positive. Mapping biopsy of rectal mucosa and perianal skin revealed adenocarcinoma in only rectal mucosa. Abdominoperineal resection was performed. Histopathological examination showed invasive adenocarcinoma with pagetoid spread and that the surgical margin was negative. Pagetoid spread of anal canal adenocarcinoma usually showed macroscopic abnormal findings, but in this case, there was no skin lesion. It suggests that preoperative mapping biopsy is helpful for determining the excision range. It is necessary to keep in mind that anal canal adenocarcinoma with no skin lesion may cause Pagetoid spread.

Comparison of Clinical Outcomes Between Laparoscopic and Open Extensive Resection for Complicated Appendicitis: Retrospective Observational Study.

BACKGROUND: The feasibility and safety of laparoscopic extensive resection (ER) for complicated appendicitis (CA) has not been clarified. We assessed the feasibility of laparoscopic ER versus open ER for CA. METHODS: We retrospectively enrolled consecutive 983 patients who underwent emergency surgery for appendicitis, including 91 patients who underwent ER for CA, between April 2007 and October 2019. RESULTS: Thirty-three patients underwent laparoscopic ER, and 58 patients underwent open ER. There were no significant differences in the reasons for performing ER between laparoscopic ER and open ER. The rates of suspicious for malignant tumor did not differ between laparoscopic and open ER [15.2% (5/33) vs. 17.2% (10/58)]. Blood loss was less in laparoscopic ER than in open ER (P=0.028). Superficial surgical site infection was less frequent in laparoscopic ER than in open ER (P=0.047). In addition, laparoscopic ER tended to be associated with a shorter hospital stay, lower rate of postoperative ileus, and higher rate of intra-abdominal abscess. CONCLUSION: Laparoscopic ER is feasible, and it is associated with less intraoperative blood loss and a lower frequency of postoperative superficial surgical site infection than open ER.

[A Case of Recurrent Hepatocellular Carcinoma Successfully Treated by Radiation Therapy].

We report a case of recurrent hepatocellular carcinoma(HCC)successfully treated by radiation therapy. A 79-year-old woman was diagnosed with HCC and underwent liver resection. Seven months after resection, CT and MRI detected a new HCC, and she had a surgery again. One year after the surgery, CT and MRI detected local recurrence, and she underwent the third operation. Three months after the operation, the third liver recurrence was treated by transcatheter arterial chemoembolization( TACE). Four months later, a new lesion was detected and treated by stereotactic body radiation therapy(SBRT) twice. She remains alive without recurrence 27 months after the last radiation therapy. Very few evidence is reported of radiation therapy for HCC, but this case suggests that radiation therapy provides a benefit for patients with HCC after other treatments.

Surgical technique for mesorectal division during robot-assisted laparoscopic tumor-specific mesorectal excision (TSME) for rectal cancer using da Vinci Si surgical system: the simple switching technique (SST).

In a narrow pelvic cavity, performing sufficient tumor-specific mesorectal excision (TSME) is difficult. Even in robot-assisted laparoscopic surgery (RALS), mesorectal division is difficult in a narrow pelvic cavity. To overcome this difficulty, we invented a novel method of mesorectal division. In this new approach, we switched the fenestrated bipolar forceps and the double-fenestrated forceps with each other so that both instruments were placed on the same (right) side of the patient. After the mesorectal fat and vessels were coagulated using the fenestrated bipolar forceps, coagulated tissues were divided using the monopolar scissors in the same direction. We named this technique the "simple switching technique (SST)". We retrospectively collected data and evaluated the usefulness of SST in 24 consecutive patients who underwent RALS TSME between July 2018 and January 2020. Twelve patients underwent SST, and 12 patients underwent other conventional surgical methods (non-SST). The median operation time for mesorectal division was 809.5 s (range 395-1491 s) in the SST group and 985.5 s (range 493-2353 s) in the non-SST group. The coefficient of variation for non-SST was 0.545, which was > 1.5 times the coefficient of 0.360 for SST. Although no significant differences were found for operation time for mesorectal division, the operation time for mesorectal division by SST tended to be shorter than by non-SST (P = 0.157). No significant differences were found regarding short-term outcomes between the groups. SST is feasible and can be an optional method of mesorectal division in RALS TSME.

Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer.

BACKGROUND: Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody-drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC. METHODS: We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo. RESULTS: GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice. CONCLUSIONS: GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.

[A Case of Advanced Gastric Cancer with Peritoneal Metastasis Achieved Pathological Complete Response by Chemotherapy(SOX Regimen)].

A 68-year-old woman was presented with anorexia. Upper gastrointestinal endoscopy revealed type 4 gastric cancer at corpus of the stomach. Peritoneal metastasis was detected by staging laparoscopy. After a diagnosis of cT4aN1M1, cStage ⅣB advanced gastric cancer, we performed chemotherapy(SOX regimen; S-1 100 mg/body on day 1-14, followed by 7 days of rest, oxaliplatin 130 mg/m2 on day 1). After the 3 courses of chemotherapy, the primary tumor had been reduced. Second staging laparoscopy revealed no peritoneal metastasis. Then, we performed total gastrectomy with D2 lymph node dissection. Histopathological examination revealed no residual cancer cells, indicating a pathological complete response (Grade 3). We report a case of advanced gastric cancer with peritoneal metastasis achieved pathological complete response by chemotherapy.

TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours.

BACKGROUND: Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. METHODS: We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/ß with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. RESULTS: TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. CONCLUSION: TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.

Long-term outcome after one-stage surgery without preoperative decompression for stage II/III malignant colorectal obstruction: a propensity score-matched analysis.

PURPOSE: Whether malignant colorectal obstruction (MCO) after one-stage curative surgery without preoperative decompression has a poor prognosis remains unclear. We assessed long-term outcomes of one-stage surgery without preoperative decompression for stage II/III MCO. METHODS: We retrospectively enrolled patients with stage II/III colorectal cancer (CRC) between April 2011 and December 2017. Propensity score-matched (PSM) analysis was used to reduce the possibility of selection bias. RESULTS: In total, 464 stage II/III CRC patients were identified, of which 145 (31%) had obstruction (MCO group) and 319 (69%) did not (non-MCO group). In the MCO group, 59 (40.7%) had emergency MCO (E-MCO) and 86 (59.3%) had semi-emergency MCO (SE-MCO). The median follow-up was 37.0 (range 0-86.5) months. The tumor was deeper and larger, and serum carcinoembryonic antigen level was higher (p < 0.001, respectively) in the MCO group (including E-MCO and SE-MCO). Venous invasion-positivity rate was significantly higher (MCO and SE-MCO only, p = 0.003 and 0.009, respectively) than that in the non-MCO group. Laparoscopic surgery rate was significantly lower (MCO and E-MCO only, p < 0.001) than that in the non-MCO group. Before PSM, disease-free survival (DFS) of the SE-MCO patients was worse than that of the non-MCO patients (p = 0.046). After PSM, DFS was not significantly different between the non-MCO and MCO, E-MCO, and SE-MCO groups (p = 0.619, 0.091, and 0.308, respectively). CONCLUSIONS: Long-term prognosis in patients with stage II/III MCO after one-stage surgery without preoperative decompression was similar to that in patients without MCO.

Robot-assisted laparoscopic surgery after placing a self-expanding metallic stent for malignant rectal obstruction: a case report.

BACKGROUND: Approximately 20% of colorectal cancer patients show complete or incomplete bowel obstruction as an early symptom. Preoperative nonsurgical decompression such as placing a self-expanding metallic stent for malignant colorectal obstruction has been shown to be effective for reducing perioperative morbidity and mortality. However, there is a lack of published studies reporting robot-assisted laparoscopic surgery (RALS) after self-expanding metallic stent (SEMS) placement for malignant rectal obstruction (MRO). To our knowledge, this is the first report to do so. CASE PRESENTATION: An 80-year-old man with incomplete paralysis of the lower limbs as well as bladder-rectal disorder due to a spine fracture sustained in a fall accident 26 years ago presented with lower abdominal pain and vomiting. Abdominal multi-detector computed tomography revealed an obstructive rectal tumor with distended bowel on the oral side. Emergency colonoscopy was performed, and an SEMS placed. The patency of SEMS and decompression of the distended bowel was confirmed, and elective RALS was performed 29 days after SEMS placement. To our knowledge, this is the first report of RALS after decompression with SEMS placement for MRO. CONCLUSIONS: RALS after SEMS placement is a safe and feasible therapeutic strategy for MRO.

Diagnostic effectiveness of preoperative water-soluble contrast enema in colorectal perforation.

OBJECTIVE: To evaluate the diagnostic usefulness of performing a preoperative water-soluble contrast enema (WSCE) before emergency surgery for colorectal perforation. METHODS: We retrospectively reviewed 68 consecutive patients who underwent a preoperative WSCE before emergency surgery for colorectal perforation during the period from January 2011 to December 2017. Clinical characteristics and inflammatory biomarkers were compared between patients with Hinchey I-II versus those with Hinchey III-IV. RESULTS: WSCE leakage occurred in 27 of 68 patients (39.7%). Univariate analysis showed that the two groups (Hinchey I-II and Hinchey III-IV) significantly differed regarding age, perforation site, cause of perforation, American Society of Anesthesiologists grade, presence or absence of WSCE leakage, and white blood cell count. Multivariable analysis revealed that WSCE leakage was a predictor of Hinchey III-IV, with an odds ratio of greater than 24 (P = 0.002). The sensitivity and specificity of WSCE leakage for differentiating those with Hinchey III-IV from those with Hinchey I-II were 76.5% and 97.1%, respectively. CONCLUSIONS: This retrospective study indicates that preoperative WSCE before emergency surgery is a useful tool for predicting the presence of Hinchey III-IV in patients with colorectal perforation.

Laparoscopic colectomy after self-expanding metallic stent placement through the ileocecal valve for right-sided malignant colonic obstruction: A case report.

A 78-year-old man with a history of open sigmoidectomy for sigmoid cancer presented with abdominal pain and vomiting. Abdominal multi-detector CT revealed an obstructive ileocecal tumor with distended small bowel on the oral side. We performed emergency drainage using a transnasal decompression tube, and 2 days later, we conducted a colonoscopic examination, which lead to a provisional diagnosis of obstruction with a malignant tumor invading the ileocecal valve. We then placed a self-expanding metallic stent (SEMS) through the ileocecal valve. We confirmed patency of the ileocecal valve and removed the transnasal decompression tube 2 days after SEMS placement. We then performed elective laparoscopic colectomy 8 days after SEMS placement. To the best of our knowledge, there has been only one previous report of laparoscopic colectomy after decompression with SEMS placement through the ileocecal valve for right-sided malignant colonic obstruction.

An analysis of the risk factors of anastomotic stricture after esophagectomy.

PURPOSE: Anastomotic stricture after esophagectomy is a major cause of long-term morbidity and a poor quality of life. The aim of this study was to identify the risk factors for the development of anastomotic stricture after esophagectomy. METHODS: The study subjects were 213 patients who underwent esophagectomy for squamous cell carcinoma of the esophagus between 2012 and 2014. Anastomotic stricture was defined as stenosis at the site of anastomosis that required endoscopic dilation. Refractory stricture was defined as that requiring more than four sessions of dilations. Univariate and multivariate logistic regression analyses were used to identify the potential risk factors for the development of anastomotic stricture. RESULTS: In this retrospective study, 29 patients (13.6%) developed anastomotic stricture within a median period of 108 postoperative days and required a median of 2 dilations. Tumors located in the upper part of the esophagus (p = 0.004), the presence of cardiovascular disease (p = 0.024) and anastomotic leakage (p = 0.002) were identified as independent risk factors for the development of anastomotic stricture. The time to the diagnosis of refractory stricture (85 ± 33 days) was significantly shorter than that of non-refractory stricture (171 ± 22 days, p = 0.038). CONCLUSIONS: Patients with squamous cell carcinoma in the upper esophagus with cardiovascular disease who develop postoperative anastomotic leakage should be carefully monitored to prevent the development of benign anastomotic stricture.

Broad ligament hernia successfully repaired by single-incision laparoscopy: A case report.

A 52-year-old woman with a history of two parturitions presented with lower abdominal pain. Multi-detector CT of the abdomen showed discontinuity of the sigmoid colon near the broad ligament on the left side. We assigned a provisional diagnosis of an internal hernia progressing through a defect in the broad ligament. SILS revealed a total broad ligament defect on the left side but no signs of ischemic, necrotic bowel. We successfully repaired the broad ligament defect with suturing. At the 2-month follow-up, the patient remained well with no signs of recurrence. This case appears to be the first report of a broad ligament hernia successfully diagnosed and repaired by SILS.

Glypican-1 targeted antibody-based therapy induces preclinical antitumor activity against esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite the development of multimodal therapy. Expression of glypican-1 (GPC1) has been reported to be elevated in a subset of patients with ESCC and associated with chemoresistance. This study aimed to determine the association of GPC1 with ESCC growth and potential usefulness of the GPC1 targeted therapy by monoclonal antibody (mAb) in ESCC. Expression of GPC1 was higher in ESCC tumor tissues than in adjacent non-tumoral tissues and normal tissues. Knockdown of GPC1 decreased growth of ESCC cells and induced apoptosis via inhibition of EGFR, AKT and p44/42-MAPK signaling pathways in vitro. Anti-GPC1 mAb strongly inhibited tumor growth via antibody-dependent cellular cytotoxicity dependent and independent manner in GPC1-positive ESCC xenograft models. Anti-GPC1 mAb also inhibited tumor growth of GPC1 positive ESCC patients derived tumor xenograft models. Furthermore, anti-GPC1 mAb showed a significant tumor growth inhibition with decreased angiogenesis compared with IgG treated controls in ESCC xenografted mice. Treatment with anti-GPC1 mAb was not toxic in mice. Anti-GPC1 mAb may have a potent anti-tumor effect and represent a novel treatment option for patients with GPC1-positive ESCC.

Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice.

Chronic inflammation is involved in cancer growth in esophageal squamous cell carcinoma (ESCC), which is a highly refractory cancer with poor prognosis. This study investigated the antitumor effect and mechanisms of SOCS1 gene therapy for ESCC. Patients with ESCC showed epigenetics silencing of SOCS1 gene by methylation in the CpG islands. We infected 10 ESCC cells with an adenovirus-expressing SOCS1 (AdSOCS1) to examine the antitumor effect and mechanism of SOCS1 overexpression. SOCS1 overexpression markedly decreased the proliferation of all ESCC cell lines and induced apoptosis. Also, SOCS1 inhibited the proliferation of ESCC cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). Additionally, we established two xenograft mouse models in which TE14 ESCC cells or ESCC patient-derived tissues (PDX) were subcutaneously implanted. Mice were intra-tumorally injected with AdSOCS1 or control adenovirus vector (AdLacZ). In mice, tumor volumes and tumor weights were significantly lower in mice treated with AdSOCS1 than that with AdLacZ as similar mechanism to the in vitro findings. The Ki-67 index of tumors treated with AdSOCS1 was significantly lower than that with AdLacZ, and SOCS1 gene therapy induced apoptosis. These findings demonstrated that overexpression of SOCS1 has a potent antitumor effect against ESCC both in vitro and in vivo including PDX mice. SOCS1 gene therapy may be a promising approach for the treatment of ESCC.

Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib-resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single-nucleotide variants and copy-number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin-dependent kinase activity. Some variants in the resistant samples were traced back to the drug-sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre-existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. © 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.

Overexpression of glypican-1 implicates poor prognosis and their chemoresistance in oesophageal squamous cell carcinoma.

BACKGROUND: Despite the recent improvements in multimodal therapies for oesophageal squamous cell carcinoma (ESCC), the prognosis remains poor. The identification of suitable biomarkers for predicting the prognosis and chemo-sensitivity is required to develop targeted treatments and improve treatment results. METHODS: Proteins highly expressed in ESCC cell lines compared with normal oesophageal cell lines were screened by isobaric tag for relative and absolute quantitation (iTRAQ). We identified glypican-1 (GPC1) as a novel molecule. The clinicopathological characteristics of GPC1 were evaluated by immunohistochemistry using ESCC specimens, and clinical parameters were assessed. The correlation between GPC1 expression levels and chemo-sensitivity were analysed in vitro. RESULTS: In the immunohistochemical assessment of 175 ESCC patients, 98.8% expressed GPC1. These patients demonstrated significantly poorer prognosis compared with patients with low-GPC1 expression by survival assay (P<0.001). Higher chemoresistance was observed in the GPC1 high-expression group. GPC1 expression levels positively correlated with chemo-sensitivity against cis-Diammineplatinum (II) dichloride (CDDP), and are potentially associated with anti-apoptotic function based on alterations in the MAPK downstream signalling pathway and Bcl-2 family member proteins. CONCLUSIONS: GPC1 is an independent prognostic factor in ESCC and is a critical molecule for altering the threshold of chemoresistance to CDDP.

Gene therapy with SOCS1 for gastric cancer induces G2/M arrest and has an antitumour effect on peritoneal carcinomatosis.

BACKGROUND: Suppressor of cytokine signaling1 (SOCS1) is a negative regulator of various cytokines. Recently, it was investigated as a therapeutic target in various cancers. However, the observed antitumour effects of SOCS1 cannot not be fully explained without taking inhibition of proliferation signalling into account. Our aim was to discover a new mechanism of antitumour effects of SOCS1 for gastric cancer (GC). METHODS: We analysed the mechanism of antitumour effect of SOCS1 in vitro. In addition, we evaluated antitumour effect for GC using a xenograft peritoneal carcinomatosis mouse model in preclinical setting. RESULTS: We confirmed that SOCS1 suppressed proliferation in four out of five GC cell lines. SOCS1 appeared to block proliferation by a new mechanism that involves cell cycle regulation at the G2/M checkpoint. We showed that SOCS1 influenced cell cycle-associated molecules through its interaction with ataxia telangiectasia and Rad3-related protein. The significant difference in therapeutic effects was noted in terms of the post-treatment weight and total photon count of the intra-abdominal tumours. CONCLUSION: Forced expression of SOCS1 revealed a heretofore-unknown mechanism for regulating the cell cycle and may represent a novel therapeutic approach for the treatment of peritoneal carcinomatosis of GC.