Association of immune-related expression profile with sensitivity to chemotherapy in esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) followed by surgery is one of the standard therapeutic approaches in Japan for patients with locally advanced esophageal carcinoma. Recently, the JCOG1109 study revealed that NAC with docetaxel, cisplatin and 5-fluorouracil (5-FU) (DCF-NAC) is superior to NAC with cisplatin and 5-FU, and has now become the standard preoperative chemotherapy. Using a microarray system, we have previously investigated the expression profiles of endoscopic biopsy samples from patients with esophageal squamous cell carcinoma (ESCC) before DCF-NAC (preNAC) and identified 17 molecules as biomarkers predictive of a pathologically complete response to DCF-NAC. Here, we re-grouped our previous dataset based on the histopathological response grade with the addition of several microarray profiles and conducted a re-analysis using bioinformatic web tools including DAVID, GSEA, UALCAN, and CIBERSORTx. We identified 204 genes that were differentially expressed between the highly resistant and sensitive groups. Some of these differentially expressed genes (DEGs) were related to the immune response and showed higher expression in the sensitive group. UALCAN showed that high expression of 28 of the top 50 DEGs was associated with a favorable prognosis (p < 0.25), and that this reached a significant (p < 0.05) level for 18 of them, suggesting that patients with high expression of these genes might have benefited from chemotherapy and thus had a better outcome. In preNAC biopsy tissues from a DCF-sensitive case, we demonstrated the presence of cells expressing mRNA for CXCL9, one of the prognosis-related DEGs. Our results highlight the association of immune-related expression profile in preNAC ESCC with the DCF-NAC efficacy.

Phase II Adjuvant Cancer-specific Vaccine Therapy for Esophageal Cancer Patients Curatively Resected After Preoperative Therapy With Pathologically Positive Nodes; Possible Significance of Tumor Immune Microenvironment in its Clinical Effects.

OBJECTIVES: To elucidate the efficacy of adjuvant vaccine monotherapy using 3 Human Leukocyte Antigen (HLA)-A∗24-restricted tumor-specific peptide antigens for ESCC, upregulated lung cancer 10, cell division cycle associated 1, and KH domain-containing protein overexpressed in cancer 1. SUMMARY OF BACKGROUND DATA: ESCC patients with pathologically positive nodes (pN(+)) have a high risk for postoperative recurrence, despite curative resection after preoperative therapy. Subclinical micrometastases are an appropriate target for cancer vaccine. METHODS: This is a non-randomized prospective phase II clinical trial (UMIN000003557). ESCC patients curatively resected after preoperative therapy with pN(+) were allocated into the control and vaccine groups (CG and VG) according to the HLA-A status. One mg each of three epitope peptides was postoperatively injected 10 times weekly followed by 10 times biweekly to the VG. The primary and secondary endpoints were relapse-free survival (RFS) and esophageal cancer-specific survival (ECSS), respectively. RESULTS: Thirty were in the CG and 33 in the VG. No significant difference was observed in RFS between the CG and VG (5-year RFS: 32.5% vs 45.3%), but the recurrence rate significantly decreased with the number of peptides which induced antigen-specific cytotoxic T lymphocytes. The VG showed a significantly higher 5-year ECSS than the CG (60.0% vs 32.4%, P = 0.045) and this difference was more prominent in patients with CD8+ and programmed death-ligand 1 double negative tumor (68.0% vs 17.7%, P = 0.010). CONCLUSIONS: Our cancer peptide vaccine might improve the survival of ESCC patients, which is warranted to be verified in the phase III randomized controlled study.

Positron emission tomography complete metabolic response as a favorable prognostic predictor in esophageal cancer following neoadjuvant chemotherapy with docetaxel/cisplatin/5-fluorouracil.

BACKGROUND: 18F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography is useful in diagnosing lymph node and distant metastases of esophageal cancer. However, its value for predicting survival is controversial. AIM: To evaluate the value of PET complete metabolic response (CMR) as a prognostic predictor for esophageal cancer. METHODS: Between June 2013 and December 2017, 58 patients with squamous cell esophageal cancer who underwent neoadjuvant chemotherapy (NAC) in Oita University were enrolled in this retrospective cohort study. Tumors were clinically staged using fluorodeoxyglucose-PET/computed tomography before and after NAC. After NAC, maximal standardized uptake value ≤ 2.5 was defined as PET-CMR, and maximal standardized uptake value > 2.5 was defined as non-PET-CMR. We compared short-term outcomes between the PET-CMR group and non-PET-CMR group and evaluated prognostic factors by univariate and multivariate analyses. RESULTS: The PET-CMR group included 22 patients, and the non-PET-CMR group included 36 patients. There were no significant differences in intraoperative and postoperative complications between the two groups. Five-year relapse-free survival and overall survival in the PET-CMR group were significantly more favorable than those in the non-PET-CMR group (38.6 mo vs 20.8 mo, P = 0.021; 42.8 mo vs 25.1 mo, P = 0.011, respectively). PET-CMR was a significant prognostic factor in terms of relapse-free survival by univariate analysis (hazard ratio: 2.523; 95% confidence interval: 1.034-7.063; P < 0.041). Particularly, PET-computed tomography negative N was an independent prognostic factor of relapse-free survival and overall survival by multivariate analysis. CONCLUSION: PET-CMR after NAC is considered a favorable prognostic factor for esophageal cancer. Evaluation by PET-computed tomography could be useful in clinical decision making for esophageal cancer.

Laparoscopic transhiatal surgery for an epiphrenic esophageal diverticulum derived from a jackhammer esophagus: a case report.

BACKGROUND: An esophageal diverticulum is rare and is frequently associated with esophageal motility disorders. Jackhammer esophagus is also rare, is characterized by esophageal hypercontraction, and comprises 4.1% of esophageal motility disorders. Here, we report a case of a patient successfully treated by laparoscopic transhiatal surgery for an epiphrenic esophageal diverticulum derived from a jackhammer esophagus diagnosed with high-resolution manometry (HRM). CASE PRESENTATION: The patient was a 78-year-old man who presented to the hospital with dysphagia. A diverticulum was detected in the lower part of his esophagus by upper gastrointestinal endoscopy. HRM was performed to investigate esophageal motility disorders. His integrated relaxation pressure was normal at 25.9 (< 26) mmHg, but his distal contractile integral (DCI) was very high at 21,464 (1500-13,000) mmHg s cm. Esophageal peristalsis was preserved. Therefore, the patient was diagnosed as having an epiphrenic esophageal diverticulum derived from a jackhammer esophagus for which laparoscopic transhiatal diverticulectomy and Heller-Dor procedure were performed. The postoperative course was uneventful. His symptoms improved, and the level of DCI also returned to a normal level of 3867 mmHg s cm at 2 months after the operation. CONCLUSION: Laparoscopic transhiatal diverticulectomy and esophagomyotomy can be useful procedures for an epiphrenic esophageal diverticulum derived from a jackhammer esophagus due to their lower invasiveness.

A 17-molecule set as a predictor of complete response to neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer.

BACKGROUND: Recently, neoadjuvant chemotherapy with docetaxel/cisplatin/5-fluorouracil (NAC-DCF) was identified as a novel strong regimen with a high rate of pathological complete response (pCR) in advanced esophageal cancer in Japan. Predicting pCR will contribute to the therapeutic strategy and the prevention of surgical invasion. However, a predictor of pCR after NAC-DCF has not yet been developed. The aim of this study was to identify a novel predictor of pCR in locally advanced esophageal cancer treated with NAC-DCF. PATIENTS AND METHODS: A total of 32 patients who received NAC-DCF followed by esophagectomy between June 2013 and March 2016 were enrolled in this study. We divided the patients into the following 2 groups: pCR group (9 cases) and non-pCR group (23 cases), and compared gene expressions between these groups using DNA microarray data and KeyMolnet. Subsequently, a validation study of candidate molecular expression was performed in 7 additional cases. RESULTS: Seventeen molecules, including transcription factor E2F, T-cell-specific transcription factor, Src (known as "proto-oncogene tyrosine-protein kinase of sarcoma"), interferon regulatory factor 1, thymidylate synthase, cyclin B, cyclin-dependent kinase (CDK) 4, CDK, caspase-1, vitamin D receptor, histone deacetylase, MAPK/ERK kinase, bcl-2-associated X protein, runt-related transcription factor 1, PR domain zinc finger protein 1, platelet-derived growth factor receptor, and interleukin 1, were identified as candidate molecules. The molecules were mainly associated with pathways, such as transcriptional regulation by SMAD, RB/E2F, and STAT. The validation study indicated that 12 of the 17 molecules (71%) matched the trends of molecular expression. CONCLUSIONS: A 17-molecule set that predicts pCR after NAC-DCF for locally advanced esophageal cancer was identified.

Randomized study of the clinical effects of ω-3 fatty acid-containing enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer.

OBJECTIVES: Omega-3 (ω-3) fatty acids have potential positive effects during chemotherapy, such as body weight maintenance and muscle mass preservation. However, little is known about the effect this supplement might have on reducing chemotherapy-induced toxicities. The aim of this study was to determine the usefulness of ω-3 fatty acid supplementation in the reduction of chemotherapy-related toxicities. METHODS: Sixty-one patients undergoing neoadjuvant chemotherapy for esophageal cancer randomly received ω-3-rich enteral nutrition (EN; n = 31) or ω-3-poor EN support (n = 30) for 15 d during chemotherapy. The daily dosage of ω-3 fatty acids was 900 mg in the ω-3-rich group and 250 mg in the ω-3-poor group. The primary endpoint was the frequency of grade 3/4 neutropenia, and secondary endpoints included other chemotherapy-related adverse events, body weight, and inflammatory markers. RESULTS: The total and dietary intake calories during chemotherapy were equal in both groups. There was no significant difference in the body weight change after chemotherapy between the two groups. There was no significant difference in the incidence of grade 3/4 leukopenia and neutropenia (P > 0.05). However, stomatitis was significantly less frequent in the ω-3-rich group, than in the ω-3-poor group (P = 0.018). Grade 3/4 diarrhea occurred relatively less frequently in the ω-3-rich group than in the ω-3-poor group; however, this difference was not significant (16.1% versus 36.7%, respectively, P = 0.068). Increases in the aspartate aminotransferase and alanine aminotransferase levels were seen significantly less frequently in the ω-3-rich group than in the ω-3-poor group (P = 0.012 and P = 0.015, respectively). CONCLUSIONS: ω-3-rich EN support decreased the frequency of chemotherapy-induced mucosal toxicities, such as stomatitis and diarrhea, and exhibited a hepatoprotective effect during chemotherapy, compared with the ω-3-poor EN support.

[A Patient Who Underwent Surgery after CR to Chemotherapy for Scirrhous Gastric Cancer Suspected because of Lymphangitis Carcinomatosa].

A 58-year-old woman was diagnosed with scirrhous gastric cancer suspected because of lymphangitis carcinomatosa. She was treated with 10 courses of S-1+CDDP chemotherapy. After 3 years and 6 months, CR was obtained and she underwent curative total gastrectomy with D2 lymph node dissection plus resection of the spleen and transverse colon. The pathological results of the resected specimen were tub2>por, pT1a, N1 (No.7), M0, CY0, P0, and HER2 (3+). After surgical treatment, supraclavicular lymph node metastasis occurred, and the patient underwent trastuzumab+capecitabine therapy, which resulted in CR for 1 year and 6 months. Thus, for unresectable scirrhous gastric cancer, multidisciplinary therapy such as longterm chemotherapy including trastuzumab and surgery is useful.

A newly modified esophagogastrostomy with a reliable angle of His by placing a gastric tube in the lower mediastinum in laparoscopy-assisted proximal gastrectomy.

BACKGROUND: An optimal reconstruction method for proximal gastrectomy (PG) remains elusive. Esophagogastrostomy (EG) is technically simple but suffers from the disadvantage of gastroesophageal reflux. Jejunal interposition (JI) has a low rate of gastroesophageal reflux, but the procedure is more complicated, and delayed gastric emptying is a problem. METHODS: We created a modified EG and have used the modified technique for PG since 2006. The procedure involves shaping the remnant stomach into a gastric conduit. The EG is performed high on the anterior wall, and the conduit is kept straight by applying a circular stapler inserted from the anterior wall of the antrum. The tip of the gastric conduit is then inserted into the lower mediastinum, creating a sharp angle of His. In this retrospective cohort study, the clinical and physiological outcomes were compared between 25 patients who underwent this procedure and 21 patients who underwent JI from 2001 to 2005. RESULTS: Laparoscopic procedures were performed more frequently, and residual food and bile reflux were less common in the EG group than in the JI group. No significant differences in remnant gastritis or reflux esophagitis were observed between the two groups. However, the late complication of intestinal obstruction occurred only in the JI group. CONCLUSIONS: The modified EG technique has advantages over the JI technique because of its simplicity and low incidence of residual food and bile reflux. The next step would be to explore this technique further by a prospective multi-institutional study to confirm the reproducibility of its benefits. Miniabstract: The modified EG technique has advantages over the JI technique because of its simplicity, high rate of laparoscopy use, and low incidence of gastroesophageal reflux.

High expression of epithelial cellular adhesion molecule in peritoneal metastasis of gastric cancer.

Intraperitoneally administrated epithelial cellular adhesion molecule (EpCAM) monoclonal antibody is a therapeutic agent in patients with malignant effusion in several types of carcinoma. However, the role of EpCAM in peritoneal metastasis (PM) lesions and primary lesions of gastric cancer (GC) is still unclear. Therefore, in this study, we investigated EpCAM expression in GC patients with PM. We investigated the expression of EpCAM in 35PM lesions and 104 biopsy samples as primary lesions. Immunohistochemical staining was performed using the Ventana Benchmark XT (Roche Diagnostics) system. EpCAM expression was evaluated by calculating the total immunostaining score, which is the product of the proportion score and the intensity score. Overexpression was defined as a total score greater than 4. All PM specimens showed overexpression of EpCAM, and GC cells in both the surface layer and the deep layer of the PM showed a high expression of EpCAM. Meanwhile, in the biopsy sample, the expression of EpCAM ranged from none to strong. The EpCAM score results for PM specimens and biopsy samples were 11.0 ± 2.0 and 6.9 ± 3.9, respectively. The difference between the scores was statistically significant (P < 0.05). The intraperitoneally administrated EpCAM antibody might have a anti-cancer effect in PM lesions of GC. Additionally, it can be assumed that only GC cells which express a high level of EpCAM might metastasize to the peritoneum.

Single-incision surgery with SILS port for anterior mediastinal lesions: initial experience.

Infrasternal mediastinoscopic single-incision surgery is a minimally invasive surgical option for patients with anterior mediastinal lesions. The main drawback of the procedure is difficult when handling the endoscopic instruments through the small infrasternal incision. Herein, we report our initial experience with use of the procedure in 2 patients with bronchogenic cysts in the anterior mediastinum. We found that use of an SILS Port, now widely available for single-incision laparoscopic surgery, can decrease the difficulty of this approach.