Ryota Nakanishi

Prognostic Significance of Postoperative Complications After Curative Resection for Patients With Esophageal Squamous Cell Carcinoma.

Objective: The objective of this study was to elucidate the impact of postoperative complications on long-term survival after curative resection for esophageal squamous cell carcinoma. Background: The relation between postoperative complications and long-term survival after curative surgery for esophageal squamous cell carcinoma is controversial; thus, this issue should be resolved with a large-scale, well-designed study. Methods: Clinicopathological features and survival of 580 consecutive patients who received curative resection for esophageal squamous cell carcinoma were investigated according to the development of postoperative pulmonary complications and anastomotic leakage. Results: The 5-year survival rates of patients with pStage 0, I, and II disease with postoperative complications (n = 116) were significantly poorer than those of patients without postoperative complications (n = 288) (overall 69.6% vs 46.9%, P < 0.0001; disease-specific; 76.7% vs 58.9%, P < 0.0022), whereas no differences were found in patients with pStage III and IV disease (n = 176). In the univariate and multivariate analyses for disease-specific survival, pT3, pT4, pN positivity, and development of postoperative complications were significant prognostic factors in all patients. Also, when the analysis was limited to the pStage 0, I, and II patients, development of postoperative complications, and pT3, pT4, and pN positivity, were found to be independent poor prognostic factors in multivariate analyses (hazard ratio: 1.56, 95% confidence interval, 1.01–2.41, P = 0.0476). Conclusions: The development of postoperative complications is an independent disease-specific poor prognostic factor after curative resection for patients with less-advanced esophageal squamous cell carcinoma.OBJECTIVE The objective of this study was to elucidate the impact of postoperative complications on long-term survival after curative resection for esophageal squamous cell carcinoma. BACKGROUND The relation between postoperative complications and long-term survival after curative surgery for esophageal squamous cell carcinoma is controversial; thus, this issue should be resolved with a large-scale, well-designed study. METHODS Clinicopathological features and survival of 580 consecutive patients who received curative resection for esophageal squamous cell carcinoma were investigated according to the development of postoperative pulmonary complications and anastomotic leakage. RESULTS The 5-year survival rates of patients with pStage 0, I, and II disease with postoperative complications (n = 116) were significantly poorer than those of patients without postoperative complications (n = 288) (overall 69.6% vs 46.9%, P < 0.0001; disease-specific; 76.7% vs 58.9%, P = 0.0022), whereas no differences were found in patients with pStage III and IV disease (n = 176). In the univariate and multivariate analyses for disease-specific survival, pT3, pT4, pN positivity, and development of postoperative complications were significant prognostic factors in all patients. Also, when the analysis was limited to the pStage 0, I, and II patients, development of postoperative complications, and pT3, pT4, and pN positivity, were found to be independent poor prognostic factors in multivariate analyses (hazard ratio: 1.56, 95% confidence interval, 1.01-2.41, P = 0.0476). CONCLUSIONS The development of postoperative complications is an independent disease-specific poor prognostic factor after curative resection for patients with less-advanced esophageal squamous cell carcinoma.

Assessment of Sarcopenia as a Predictor of Poor Outcomes after Esophagectomy in Elderly Patients with Esophageal Cancer

Objective:The objective of the study was to elucidate the impact of sarcopenia in elderly patients with esophageal cancer on postoperative complications and long-term survival after surgery for esophageal cancer. Summary Background Data:Sarcopenia, defined as loss of skeletal muscle mass with age, has been identified as a poor prognostic factor for malignancies. This retrospective study investigated the effect of sarcopenia on surgical outcomes among young and elderly patients with esophageal cancer. Methods:Data were collected for 341 consecutive patients who underwent esophagectomy for esophageal cancer. Patients were assigned to 2 groups according to age (younger than 65 years and 65 years or older) and the presence of sarcopenia. Results:Sarcopenia was present in 170 of 341 patients (49.9%) with esophageal cancer and in 74 of 166 elderly patients (44.6%). The incidence of anastomotic leak and in-hospital death was significantly higher in the elderly sarcopenia group than in the elderly nonsarcopenia group (31.5% vs 15.2%, P = 0.015, 6.8 vs 0.0%, P = 0.037, respectively), and the overall survival rate in patients with sarcopenia correlated with a significantly poor prognosis in the elderly group (P < 0.001). Multivariate analysis revealed that sarcopenia was a risk factor for an anastomotic leak (P = 0.034) and was an unfavorable prognostic factor for survival (P < 0.001). Those correlations between sarcopenia and surgical outcomes were not observed in the young group. Conclusions:Sarcopenia and worse surgical outcomes were significantly associated patients with in esophageal cancer aged 65 years and older but not in those younger than 65 years.

Contribution of Aurora-A and -B expression to DNA aneuploidy in gastric cancers

PurposeDNA aneuploidy, which is characterized by cells containing an abnormal number of chromosomes, is closely associated with carcinogenesis and malignant progression. Aneuploidy occurs during cell division when the chromosomes do not separate properly. Aurora kinases (Aurora-A, -B, and -C) contribute to accurate cell division, and are candidate molecular targets for mitosis-specific anticancer drugs.MethodsWe determined the expression of Aurora-A and -B in 110 gastric cancer specimens by performing an immunohistochemical analysis. We also determined the DNA content, TP53 gene mutations, and microsatellite instability in the same samples.ResultsWe found the nuclear expression of Aurora-A and -B to increase in tumor tissue in comparison to that in normal epithelial tissue. A high Aurora-B expression significantly correlated with aneuploidy and TP53 mutations, but not with microsatellite instability. In contrast, the Aurora-A expression did not correlate with either aneuploidy or microsatellite instability. In addition, the expression of Aurora-A or -B was not significantly associated with the clinical outcomes or prognosis.ConclusionsOur results suggest that an overexpression of Aurora-B, but not of Aurora-A, might contribute to DNA aneuploidy in gastric cancers by promoting chromosomal instability.

Actionable gene-based classification toward precision medicine in gastric cancer

BackgroundIntertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.MethodsA total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.ResultsComprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.ConclusionsThis actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

Postoperative development of sarcopenia is a strong predictor of a poor prognosis in patients with adenocarcinoma of the esophagogastric junction and upper gastric cancer

BACKGROUND There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC). METHODS Patients with AEG and UGC who were judged as non-sarcopenic before surgery were reassessed the presence of postoperative development of sarcopenia 6 months after surgery. Patients were divided into the development group or non-development group, and clinicopathological factors and prognosis between these two groups were analyzed. RESULTS The 5-year overall survival rates were significantly poorer in the development group than non-development group (68.0% vs. 92.6%, P = 0.0118). Multivariate analyses showed that postoperative development of sarcopenia was an independent prognostic factor for poor overall survival (P = 0.0237). CONCLUSIONS Postoperative development of sarcopenia was associated with a poor prognosis in patients with AEG and UGC.

Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent-induced mitotic arrest

Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood. Here, we found that HeLa and breast cancer cells treated with the different types of TBAs, such as paclitaxel and eribulin (MT-stabilizing and MT-destabilizing agents, respectively), exhibited distinct behaviors of mitotic slippage on inhibition of Aurora B. In such conditions, the cell fates after postmitotic slippage vastly differed with respect to cell morphology, cell proliferation, and cytotoxicity in short-term culture; that is, the effects of inhibition of Aurora B were beneficial for cytotoxicity enhancement in eribulin treatment but not in paclitaxel. However, in long-term culture, the cells that survived after mitotic slippage underwent endoreduplication and became giant cells in both cases, resulting in cellular senescence. We propose that MT-destabilizing agents may be more appropriate than MT-stabilizing agents for treating cancer cells with a weakened Aurora B kinase activity.

Development of fistula between esophagogastric anastomotic site and cartilage portion of trachea after subtotal esophagectomy for cervical esophageal cancer: a case report

A 65-year-old man with cT3N2M0 stage III cervical esophageal cancer underwent subtotal esophagectomy and gastric tube reconstruction through the retrosternal route after neoadjuvant chemoradiotherapy. The anastomosis was located adjacent to the left side of the trachea, and a circular stapler was used for anastomosis. Postoperative anastomotic leakage occurred, and an esophagotracheal fistula between the esophagogastric anastomotic site and cartilage portion of the trachea was observed on postoperative day 44. The patient underwent division of the fistula, direct suturing of the anastomotic leakage site, left pectoralis major muscle flap placement, and tracheotomy. He was discharged home on postoperative day 120 on an oral diet. All previous reports of tracheobronchial fistula describe the occurrence of the fistula at the membranous portion of the trachea. The formation of a fistula between the esophagogastric anastomotic site and cartilage portion of the trachea is considered a possible complication when a high esophagogastric anastomosis is created.

Blood Flow Assessment with Indocyanine Green Fluorescence Angiography for Pedicled Omental Flap on Cervical Esophagogastric Anastomosis after Esophagectomy

Esophagectomy is an invasive surgical procedure with several serious postoperative complications including anastomotic leak. To reduce the incidence of anastomotic leak, it is necessary to establish more reliable techniques for anastomosis.

High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer

The importance of Notch signaling in colorectal cancer (CRC) carcinogenesis and progression has previously been presented. Increased expression of Jagged‐1 (JAG1), a Notch ligand, in CRC has been revealed, but the detailed prognostic significance of JAG1 in CRC has not been determined. Protein expression of JAG1 was examined using immunohistochemistry in 158 CRC specimens. Expression of JAG1 and E‐cadherin and their associations with clinicopathologic characteristics, overall survival (OS) and relapse‐free survival (RFS) were evaluated. In vitro studies using compounds to regulate intracellular signaling and small interfering RNA to silence JAG1 were performed in a colon cancer cell line. JAG1 expression in cancerous tissues was weak, moderate or strong in 32%, 36% and 32% of specimens, respectively, and correlated with histologic type and T stage. In multivariate analysis, JAG1 expression, histologic type and lymphatic invasion independently correlated with OS and RFS. The combination of high JAG1 expression and low E‐cadherin expression had an additive effect toward poorer OS and RFS compared with the low JAG1/high E‐cadherin expression subtype. A significant correlation between JAG1 expression and KRAS status was detected in groups stratified as high E‐cadherin expression. In vitro studies suggested that RAS‐MEK‐MAP kinase and the Wnt pathways positively regulated JAG1 expression. Gene silencing with siJAG1 indicated that JAG1 promotes the transition from epithelial to mesenchymal characteristics and cell growth. High expression of JAG1 is regulated by various pathways and is associated with poor prognosis through promoting the epithelial to mesenchymal transition and cell proliferation or maintaining cell survival in CRC.

Impact of Concurrent Genomic Alterations Detected by Comprehensive Genomic Sequencing on Clinical Outcomes in East-Asian Patients with EGFR-Mutated Lung Adenocarcinoma

Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease.