Neoadjuvant Triplet Chemotherapy with Docetaxel, Cisplatin plus 5-Fluorouracil versus Docetaxel, Cisplatin plus S-1 for Advanced Esophageal Squamous cell Carcinoma: Propensity Score Matched Analysis.

INTRODUCTION: This study examines whether neoadjuvant docetaxel, cisplatin plus S-1 (DCS) therapy is superior to docetaxel, cisplatin plus 5-fluorouracil (DCF) therapy for resectable advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients diagnosed with resectable advanced ESCC at our hospital between January 2010 and December 2019 underwent either neoadjuvant DCF therapy or DCS therapy, followed by radical esophagectomy. Prior to August 2014, we usually used neoadjuvant DCF therapy; we then completely transitioned to using neoadjuvant DCS therapy. RESULTS: A total of 144 patients received one of these triplet regimens as neoadjuvant chemotherapy: DCF therapy to 67 patients and DCS therapy to 77 patients. After propensity score matching, 55 patients in each group were selected as matched cohorts. There was no significant difference between the groups in complete response (DCF = 7.3%, DCS = 9.1%) or in partial response (DCF = 45.4%, DCS = 52.7%). The pathological response rate was 23.8% for grade 2 and 18.2% for grade 3 in the DCF group, compared with 30.9% and 14.5% in the DCS group. Independent predictive factors for recurrence-free survival were poor clinical response and pathological response ≤1b. Independent prognostic factors for overall survival were poor clinical response, anastomotic leakage, and pathological response ≤1b. Duration of hospital stays in the DCS group was significantly shorter than those of the DCF group (6.0 vs. 15.0 days, p < 0.001). Expenses of drug and hospitalization for the neoadjuvant chemotherapy in the DCS group were also significantly lower than those of the DCF group (265.7 vs. 550.3 USD, p < 0.001). CONCLUSIONS: Neoadjuvant DCS therapy for resectable advanced ESCC did not result in significantly higher clinical and pathological response than neoadjuvant DCF therapy. However, neoadjuvant DCS therapy for resectable ESCC required comparatively shorter hospital stays and incurred lower costs, making it an attractive therapeutic option.

Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system.

We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.

Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.

BACKGROUND: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking. METHODS: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer. DISCUSSION: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer. TRIAL REGISTRATION: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.

Impact of zero anastomotic leakage after esophagectomy followed by whole stomach reconstruction for esophageal cancer: prospective cohort study.

PURPOSE: The stomach is the most common organ which is used for reconstruction after esophagectomy for esophageal cancer. It is controversial which is better narrow gastric tube reconstruction or whole stomach reconstruction to prevent anastomotic leakage. METHODS: From August 2022 to March 2023, we started a prospective cohort study of whole stomach reconstruction after esophagectomy. Until then (from January 2018 to July 2022), narrow gastric tube reconstruction was performed as a standard reconstruction. RESULTS: Narrow gastric tube reconstruction and whole stomach reconstruction were performed in 183 patients and 20 patients, respectively. The patient's characteristics were not significantly different between the narrow gastric tube group and the whole stomach group. In particular, for all patients in the whole stomach reconstruction group, retrosternal route and esophagogastrostomy by hand sewn were applied. There were no occurrences of AL through the continuous 20 cases in the whole stomach group, otherwise 42 (22.9%) patients in the narrow gastric group (P = 0.016). Postoperative hospital stays were significantly shorter in the whole stomach group than in the narrow gastric group (21 days vs. 28 days, P < .001). Blood perfusions were evaluated by indocyanine green for all cases, which had very good blood perfusion in all cases. Additionally, quantitative blood perfusion was examined by SPY-QP (Stryker, USA) for one case. Even the edge of the fornix showed more than 90% blood perfusion levels when the antrum was fixed as the reference point. CONCLUSION: Whole stomach reconstruction with excellent blood perfusion is considered to be safe and has the possibility to prevent from occurring AL after esophagectomy for esophageal cancer patients.

Laparoscopic reconstruction in McKeown esophagectomy is a risk factor for postoperative diaphragmatic hernia.

Diaphragmatic hernia is a very rare but high-risk complication after esophagectomy. Although there are many studies on the Ivor Lewis esophagectomy procedure for diaphragmatic hernia, there are fewer studies on the McKeown procedure. The present study aimed to estimate the incidence of diaphragmatic hernia after esophagectomy, describing its presentation and management with the McKeown procedure. We retrospectively evaluated the 622 patients who underwent radical esophagectomy between January 2002 and December 2020 at the Wakayama Medical University Hospital. Statistical analyses were performed to evaluate risk factors for diaphragmatic hernia. Emergency surgery for postoperative diaphragmatic hernia was performed in nine of 622 patients (1.45%). Of these nine patients, one developed prolapse of the small intestine into the mediastinum (11.1%). The other eight patients underwent posterior mediastinal route reconstructions (88.9%), one of whom developed prolapse of the gastric conduit, and seven of whom developed transverse colon via the diaphragmatic hiatus. Laparoscopic surgery was identified in multivariate analysis as the only independent risk factor for diaphragmatic hernia (odd's ratio [OR] = 9.802, p = 0.034). In all seven cases of transverse colon prolapse into the thoracic cavity, the prolapsed organ had herniated from the left anterior part of gastric conduit. Laparoscopic surgery for esophageal cancer is a risk factor for diaphragmatic hernia. The left anterior surface of gastric conduit and diaphragmatic hiatus should be fixed firmly without compromising blood flow to the gastric conduit.

Impact of pulmonary vein anatomy and left atrial size on postoperative atrial fibrillation after esophagectomy for esophageal cancer.

BACKGROUND: This study aimed to investigate the relationship between postoperative atrial fibrillation (POAF) after esophagectomy and pre-existing cardiac substrate. METHODS: We retrospectively analyzed 212 consecutive patients from between July 2010 and December 2022 who were scheduled to undergo esophagectomy for esophageal cancer without previous history of atrial fibrillation. All the patients underwent both echocardiography and contrast-enhanced multi-detector computed tomography (MDCT). RESULTS: POAF occurred in 49 patients (23.1%). Multivariable logistic analysis demonstrated that independent predictors for POAF were age [OR; 1.06 (1.01-1.10), P < 0.01), three-field lymph node dissection [OR; 2.55 (1.25-5.23), P < 0.01), left atrial dilatation (> 35 mm) assessment by echocardiography [OR; 3.05 (1.49-6.25), P < 0.01) and common left pulmonary vein [OR; 3.03 (1.44-6.39), P < 0.01). The correlation coefficient was high for left atrial dimensions assessed by echocardiography and MDCT (r = 0.91, P < 0.01). Combination of left atrial dilatation by echocardiography and common left pulmonary vein had high odds ratio [OR; 8.10 (2.62-25.96), P < 0.01). Instead of echocardiographic assessment, combination of left atrial enlargement (> 35 mm) assessed by MDCT and common left pulmonary vein also showed high odds ratio for POAF [OR; 11.23 [2.19-57.63], P < 0.01). CONCLUSION: Incidence of POAF after esophagectomy was related to both left atrial enlargement and common left pulmonary vein assessed by preoperative MDCT. Additional analysis of atrial size and pulmonary vein variation would facilitate preoperative assessment of the risk of POAF, but future studies must ascertain therapeutic strategy.

Risk Factors of Postoperative Intra-Abdominal Infectious Complications after Robotic Gastrectomy for Gastric Cancer.

INTRODUCTION: Robotic surgery is regarded as an evolved type of laparoscopic surgery. Few studies have undertaken detailed analysis of complications following robotic gastrectomy for gastric cancer. METHODS: This is a single-center retrospective study of 149 consecutive patients with gastric cancer who underwent robotic gastrectomy. It examines in detail the postoperative complications in robotic gastrectomy for gastric cancer, focusing on intra-abdominal infectious complications including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess. We also aim to identify the related risk factors. RESULTS: The median operation time was 299 min and the median bleeding was 25 mL. The incidence of overall complications higher than grade II was 8.7%. Clinically serious complications higher than grade IIIa occurred in 6.7% of cases. The incidence of intra-abdominal infectious complications that were higher than grade II was 4.0%. Mortality in our consecutive series was zero. Multivariate logistic regression analysis indicated that postoperative intra-abdominal infectious complications were significantly associated with history of abdominal surgery (p = 0.043), with odds ratios of 17.890 (95% confidence interval 1.092-293.150) and with non-curative resection (p = 0.025), with odds ratios of 58.629 (95% confidence interval 1.687-2,037.450). DISCUSSION/CONCLUSION: Robotic gastrectomy was shown to be a safe and effective treatment for gastric cancer when performed by experienced surgeons. Attention should be paid to the risk of developing postoperative complications when performing robotic gastrectomy in gastric cancer patients with a history of abdominal surgery and in patients with advanced gastric cancer in whom there is expected to be difficulty in curative resection.

Laparoscopic sleeve gastrectomy for morbid obesity improves gut microbiota balance, increases colonic mucosal-associated invariant T cells and decreases circulating regulatory T cells.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) for morbid obesity may improve gut microbiota balance and decrease chronic inflammation. This study examines the changes in gut microbiota and immune environment, including mucosal-associated invariant T cells (MAIT cells) and regulatory T cells (Treg cells) caused by LSG. METHODS: Ten morbidly obese patients underwent LSG at our institution between December 2018 and March 2020. Flow cytometry for Th1/Th2/Th17 cells, Treg cells and MAIT cells in peripheral blood and colonic mucosa and 16S rRNA analysis of gut microbiota were performed preoperatively and then 12 months postoperatively. RESULTS: Twelve months after LSG, the median percent total weight loss was 30.3% and the median percent excess weight loss was 66.9%. According to laboratory data, adiponectin increased, leptin decreased, and chronic inflammation improved after LSG. In the gut microbiota, Bacteroidetes and Fusobacteria increased after LSG, and indices of alpha diversity increased after LSG. In colonic mucosa, the frequency of MAIT cells increased after LSG. In peripheral blood, the frequency of Th1 cells and effector Treg cells decreased after LSG. CONCLUSIONS: After LSG for morbid obesity, improvement in chronic inflammation in obesity is suggested by change in the constituent bacterial species, increase in the diversity of gut microbiota, increase in MAIT cells in the colonic mucosa, and decrease in effector Treg cells in the peripheral blood.

Nutritional benefit of remnant gastric preservation in patients with esophageal cancer undergoing radical esophagectomy and ileo-colon interposition.

BACKGROUND: This retrospective study aimed to investigate the short-term surgical outcomes and nutritional status of ileo-colon interposition in patients with esophageal cancer who could not undergo gastric tube reconstruction. METHODS: Sixty-four patients underwent subtotal esophagectomy with reconstruction using ileo-colon interposition for esophageal cancer at the Wakayama Medical University Hospital between January 2001 and July 2020. Using propensity scores to strictly balance the significant variables, we compared treatment outcomes. RESULTS: Before matching, 18 patients had cologastrostomy and 46 patients had colojejunostomy. After matching, we enrolled 34 patients (n = 17 in cologastrostomy group, n = 17 in colojejunostomy group). Median operation time in the cologastrostomy group was significantly shorter than that in the colojejunostomy group (499 min vs. 586 min; P = 0.013). Perforation of the colon graft was observed in three patients (7%) and colon graft necrosis was observed in one patient (2%) in the gastrojejunostomy group. Median body weight change 1 year after surgery in the cologastrostomy group was significantly less than that of the colojejunostomy group (92.9% vs. 88.5%; P = 0.038). Further, median serum total protein level 1 year after surgery in the cologastrostomy group was significantly higher than that of the colojejunostomy group (7.0 g/dL vs. 6.6 g/dL, P = 0.030). CONCLUSIONS: Subtotal esophagectomy with reconstruction using ileo-colon interposition is a safe and feasible procedure for the patients with esophageal cancer in whom gastric tubes cannot be used. Cologastrostomy with preservation of the remnant stomach had benefits in the surgical outcomes and the postoperative nutritional status.

Phase 1 Study of Combined Chemotherapy of Nab-Paclitaxel, S-1, and Oxaliplatin for Gastric Cancer with Peritoneal Metastasis (NSOX Study).

OBJECTIVES: A regimen of S-1 combined with oxaliplatin (SOX) has been widely used as the first-line regimen for advanced gastric cancer. To further improve the antitumor efficacy for gastric cancer patients with peritoneal metastasis, we added nab-paclitaxel to the established SOX regimen (NSOX). Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) has effective transferability to tumor tissues and strong antitumor effects for peritoneal metastasis. We performed a phase 1 study of this regimen to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in patients with gastric cancer with peritoneal metastasis. METHODS: The NSOX regimen involved 21-day cycles with escalated doses of nab-paclitaxel (50 [level 1] to 80 [level 4] mg/m2 on days 1 and 8) and fixed doses of oxaliplatin (100 mg/m2 on day 1) and S-1 (80 mg/m2/day for 2 weeks). RESULTS: Six patients with gastric cancer with peritoneal metastasis were enrolled. The MTD was determined to be dose level 2, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 non-hematological toxicities. One patient experienced acute myocardial infarction, and the other patient developed jejunal perforation. There were no treatment-related deaths. No patients experienced DLTs, so the RD was determined to be dose level 1. CONCLUSIONS: The NSOX regimen was shown to be a tolerable regimen and may be a promising triplet therapy for patients with gastric cancer with peritoneal metastasis.

Curative para-Aortic lymph node dissection Via INfra-mesocolonic approach in laparoscopic Gastrectomy (CAVING approach).

PURPOSE: Para-aortic lymph node (PAN) metastasis for gastric cancer is considered a distant lymph node metastasis. Meanwhile, multidisciplinary treatments have improved survival of patients with PAN metastases. We developed a novel technique of curative para-aortic lymph node dissection via infra-mesocolonic approach in laparoscopic gastrectomy (CAVING approach). This method minimizes the mobilization of the pancreas and the spleen and maximizes the view from the caudal side resembling cave exploration. METHODS: After laparoscopic gastrectomy, PAN dissection is performed using the same ports setup. The retroperitoneum is widely exposed to ease anatomical cognition and for troubleshooting. The inferior vena cava, the left gonadal vein, the left renal vein, and the aorta are recognized under Gerota's fascia. The retroperitoneum is then divided into four sections. We perform PAN dissection in the order of 16blat, 16b1int, 16a2lat, and then 16a2int. Using the CAVING approach, the caudal side of the root of the superior mesenteric artery can then be dissected below the pancreas, and only the cranial side of the SMA root requires a suprapancreatic approach. RESULTS: In three cases, preoperative chemotherapy and laparoscopic gastrectomy plus D2 with PAN dissection were performed for gastric cancer and esophagogastric junction cancer. The median operation totaled 484 min, 142 min for the PAN dissection. The median whole blood loss was 130 ml. The median harvested number of PAN was 25. CONCLUSIONS: The minimal mobilization of pancreas and the wide surgical fields by CAVING approach may facilitate safe and reliable PAN dissection.

Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade.

BACKGROUND: Cancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1+ DCs), with high ability to support CD8+ T-cell responses. METHODS: We have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice. RESULTS: The fusion protein was delivered to XCR1+ DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8+ T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab. CONCLUSIONS: Cancer Ag targeting to XCR1+ DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.

Treatment option of endoscopic stent insertion or gastrojejunostomy for gastric outlet obstruction due to gastric cancer: a propensity score-matched analysis.

BACKGROUND: There are currently two treatment options for gastric outlet obstruction (GOO) due to gastric cancer, endoscopic stenting and surgical gastrojejunostomy. However, their therapeutic effects have not yet been established. Therefore, the present study was undertaken to examine these effects. METHODS: The Japanese Gastric Cancer Association invited its delegates to participate in a retrospective multicenter cohort study on patients with GOO due to gastric cancer who underwent stent therapy or gastrojejunostomy in 2015. RESULTS: We obtained data from 85 patients undergoing stent therapy and 94 undergoing gastrojejunostomy from 42 hospitals. Baseline data revealed that stent patients had lower food intake, poorer performance status, and worse prognostic indices than gastrojejunostomy patients. Postoperative food intake and survival times were worse in stent patients than in gastrojejunostomy patients. We performed propensity score matching to select pairs of patients with similar baseline characteristics in the two treatment groups. After matching, the frequency of postoperative complications was significantly less in stent patients (3%, 1/33) than in gastrojejunostomy patients (21%, 7/34; p = 0.03). A low residue or full diet was achieved by 97% of stent patients (32/33) and 97% of gastrojejunostomy patients (33/34) (p = 0.98). Median survival times were 7.8 months in stent patients and 4.0 months in gastrojejunostomy patients (p = 0.38). CONCLUSIONS: Propensity score matching demonstrated that endoscopic stent placement resulted in less postoperative morbidity than and a similar food intake and equivalent survival times to gastrojejunostomy. These results suggest the utility of stent therapy.

Endoscopic submucosal tunnel dissection versus conventional endoscopic submucosal dissection for early gastric cancers: outcomes of 799 consecutive cases in a single institution.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a standard treatment for early gastric cancers (EGCs), but because of the obscured view and difficulty in submucosal lifting it is time consuming and poses high risk of perforation and bleeding in large lesions. In endoscopic submucosal tunnel dissection (ESTD) technique, good visualization of the submucosal layer can be achieved in the tunnel, it is, therefore, easy to discern the muscularis propria and visualize the vessels in the submucosal area. This study aims to evaluate the technical feasibility, efficacy, and safety of ESTD in comparison with conventional ESD (cESD) technique for treatment of EGCs. METHODS: This is a single-center retrospective study of 799 consecutive patients with EGCs who underwent ESD. ESTD (n = 141) were performed between 2015 and 2018 and cESD (n = 658) were performed between 2003 and 2015. Using propensity scores to strictly balance the significant variables, we compared treatment outcomes. RESULTS: After matching, we enrolled 444 patients (n = 111 in ESTD group, n = 333 in cESD group). The resection speeds for lesions of the ESTD were faster than those of cESD (19.3 mm2/min versus 17.7 mm2/min, P = 0.009). There was no need to use additional countertraction by clip-with-line technique or snare for the submucosal dissection in the ESTD procedure. The incidence of perforation was significantly higher in the cESD group (6.0%) than in the ESTD group (0.9%) (P = 0.035). Among 799 patients, four patients who received non-curative ESD had recurrence of gastric cancer. CONCLUSION: ESTD technique is a safe and feasible treatment procedure for EGCs. It presents many theoretical advantages and may have definite benefits over cESD. ESTD may, therefore, be considered as the standard endoscopic treatment for EGCs.

Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment.

Although a role of PD-L1 in the suppression of anti-tumor immunity and its value as a predictive biomarker has been suggested by various preclinical and clinical studies, the precise mechanisms how PD-L1 and PD-L2, another ligand of PD-1, regulate anti-tumor immunity in the tumor microenvironment are yet to be fully explored. Here, we address this issue using PD-L1-deficient tumor cells, PD-L1-knockout (KO) mice, anti-PD-L1 monoclonal antibody (mAb), and anti-PD-L2 mAb. Firstly, PD-L1-deficient or competent tumor cells were inoculated into wild-type or PD-L1-KO mice. Results of tumor growth and mouse survival indicated that both tumor- and host-derived PD-L1 are functional to suppress anti-tumor immunity, while the former contributes predominantly than the latter. Experiments using bone marrow (BM) chimeric mice, generated by transferring PD-L1-KO BM cells into wild-type mice or vice versa, further suggested that PD-L1 expressed on BM-derived hematopoietic cells mediates the suppressive effects on anti-tumor immunity. Secondly, anti-PD-L2 mAb treatment demonstrated a profound synergy with anti-PD-L1 mAb therapy, whereas anti-PD-L2 mAb alone hardly induced any anti-tumor effects, suggesting that PD-L2's function becomes evident when the effects of PD-L1 are abrogated by anti-PD-L1 mAb. Consistent with this notion, PD-L2 expression was upregulated on tumor-associated macrophages (TAM) when mice were treated with anti-PD-L1 mAb. Taken together, our study elucidated the importance of PD-L1 associated with tumor cells and non-tumor host cells, particularly BM-derived hematopoietic cells, as well as PD-L2 inducibly expressed on TAM in the suppression of anti-tumor immunity in the tumor microenvironment.

Phase I/II Trial of Chemotherapy with Docetaxel, Cisplatin, and S-1 for Unresectable Advanced Squamous Cell Carcinoma of the Esophagus.

Our previous trial with a docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen showed high response rates in metastatic squamous cell carcinoma of the esophagus (SCCE). The observed increased toxicity of the DCF regimen, however, was clinically harmful. S-1, an oral anticancer drug, has been approved as a combination therapy for SCCE, and alternate-day regimen with S-1 has shown lower levels of toxicity. This prospective single-center phase I/II trial examines the efficacy and toxicity of a combination of docetaxel, cisplatin, and an alternate-day regimen of S-1 (modified DCS) for patients with metastatic SCCE. We use a two-stage design. Phase I is undertaken to determine the maximum tolerated dose and the recommended dose. The phase I trial adopts a three-patient cohort with escalating dose study design. In the phase II trial, the primary endpoint is the assessment of the overall response rate (Response Evaluation Criteria in Solid Tumors 1.1). The secondary endpoints are the evaluation of drug-related toxicity (National Cancer Institute Common Toxicity Criteria 4.0), overall survival, and progression-free survival. Fifty patients with metastatic SCCE participate in the phase II section. This study protocol is the first to test the effects of the modified DCS regimen for metastatic SCCE.

Laparoscopic and endoscopic cooperative surgery is a feasible treatment procedure for intraluminal gastric gastrointestinal stromal tumors compared to endoscopic intragastric surgery.

BACKGROUND: Laparoscopic wedge resection of the stomach is an ideal procedure if the gastric gastrointestinal stromal tumors (GISTs) are located in the extraluminal stomach. When the tumor is located in the intraluminal stomach, two minimally invasive surgical procedures involving laparoscopic and endoscopic cooperative surgery (LECS) or endoscopic intragastric surgery (EIGS) are frequently performed. To date, there have been no comparative studies of LECS and EIGS in patients with intraluminal gastric GISTs regarding short-term and long-term outcomes. The aim of this study was to compare the safety and feasibility of LECS and EIGS in patients with intraluminal gastric GISTs. METHODS: This was a single-center retrospective study of 46 consecutive patients with intraluminal gastric GISTs who underwent minimally invasive surgery. LECS (n = 21) was performed between 2013 and 2015 and EIGS (n = 26) was performed between 2001 and 2013. RESULTS: The overall incidence of perioperative complications was significantly higher in the EIGS group than in the LECS group (40 vs 4.8%; P = 0.006). In the EIGS group, three patients with intraoperative gastric mucosal injury were followed-up throughout surgical repair (12%). An esophageal tear was found in one patient during oral removal of tumor (4%). Postoperative gastric hemorrhage occurred in three patients (12%) and superficial surgical site infection was observed in three patients (12%). In the LECS group, anastomotic leakage requiring additional drainage was observed in one patient (4.8%). EIGS had less favorable results regarding median time to resumption of first oral intake (2 vs 1 days; P = 0.005). Two of 46 patients (4.3%), including one patient who underwent LECS and one patient who underwent EIGS developed recurrence. No cause-specific deaths were observed. CONCLUSION: LECS is a feasible and safe procedure for intraluminal gastric GISTs with regard to both short-term surgical and long-term oncological outcomes. Registration number: UMIN000026631.

[In Vivo Antigen Delivery to Dendritic Cells-A Novel Peptide Vaccine for Cancer Therapy].

Tumor-derived peptides can induce antitumor cytotoxic T lymphocyte(CTL)response. However, the effects are limited. We aimed to overcome this limitation by selectively delivering antigen peptides to an XC chemokine receptor 1-expressing dendritic cell subset(XCR1+DC)that is notable for its exceptional ability to generate CTL response. To do that, we designed a vaccine(mXCL1-OVA peptide vaccine)that consisted of a murine XCR1 ligand(XCL1)and an ovalbumin(OVA)-derived MHC class I-restricted antigen. When co-injected with the immune adjuvant polyinosinic-polycytidylic acid(poly[I: C]), mXCL1-OVA peptide vaccine showed much greater antigen-specific cytotoxic T cell(CTL)response than either OVA protein plus poly(I: C)or OVA peptide plus poly(I: C). Furthermore, mXCL1-OVA peptide vaccine plus poly(I: C)showed more prominent antitumor effects against OVA-expressing melanoma(B16-OVA)than other vaccines with regard to growth inhibition. Thus, our results suggest that chemokine-directed antigen delivery to DC subsets with high CTL-inducing ability is a promising method for generating effective antitumor immunity.

Expression of BRCA1, a factor closely associated with relapse-free survival, in patients who underwent neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil for squamous cell carcinoma of the esophagus.

PURPOSE: The aim of this study was to identify the biomarkers associated with chemotherapeutic efficacy and long-term survival for patients with advanced squamous cell carcinoma of the esophagus (SCCE) who had received neoadjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil (NAC-DCF). METHODS: This study included 45 patients with advanced SCCE who received NAC-DCF between 2008 and 2012. The NAC-DCF was conducted as a phase II study (UMIN000007408). The expressions of excision repair cross-complementing-1 (ERCC1), class III beta-tubulin, breast cancer susceptibility gene I (BRCA1), and thymidylate synthase were investigated simultaneously in the pre-treatment endoscopic tumor biopsy samples. RESULTS: A multivariate logistic regression analysis indicated that pathological responses were significantly associated with tumors with low ERCC1 expression (P = 0.016) and with tumors with high BRCA1 expression (P = 0.030). The multivariate Cox proportional hazard model analysis for relapse-free survival revealed high BRCA1 expression (P = 0.031, hazards ratio 4.39) as the factor associated with survival. CONCLUSIONS: Low ERCC1 expression and high BRCA1 expression in patients with SCCE were associative biomarkers for chemotherapeutic efficacy. High BRCA1 expression was considered the factor associated with survival. These findings may be helpful for tailoring chemotherapy.