Field experiment of a telesurgery system using a surgical robot with haptic feedback.

PURPOSE: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. METHODS: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. RESULTS: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. CONCLUSION: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

Telesurgery and telesurgical support using a double-surgeon cockpit system allowing manipulation from two locations.

BACKGROUND: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. METHODS: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. RESULTS: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. CONCLUSION: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

Artificial Intelligence-Based Prediction of Recurrence after Curative Resection for Colorectal Cancer from Digital Pathological Images.

BACKGROUND: To develop an artificial intelligence-based model to predict recurrence after curative resection for stage I-III colorectal cancer from digitized pathological slides. PATIENTS AND METHODS: In this retrospective study, 471 consecutive patients who underwent curative resection for stage I-III colorectal cancer at our institution from 2004 to 2015 were enrolled, and 512 randomly selected tiles from digitally scanned images of hematoxylin and eosin-stained tumor tissue sections were used to train a convolutional neural network. Five-fold cross-validation was used to validate the model. The association between recurrence and the model's output scores were analyzed in the test cohorts. RESULTS: The area under the receiver operating characteristic curve of the cross-validation was 0.7245 [95% confidence interval (CI) 0.6707-0.7783; P < 0.0001]. The score successfully classified patients into those with better and worse recurrence free survival (P < 0.0001). Multivariate analysis revealed that a high score was significantly associated with worse recurrence free survival [odds ratio (OR) 1.857; 95% CI 1.248-2.805; P = 0.0021], which was independent from other predictive factors: male sex (P = 0.0238), rectal cancer (P = 0.0396), preoperative abnormal carcinoembryonic antigen (CEA) level (P = 0.0216), pathological T3/T4 stage (P = 0.0162), and pathological positive lymph node metastasis (P < 0.0001). CONCLUSIONS: The artificial intelligence-based prediction model discriminated patients with a high risk of recurrence. This approach could help decision-makers consider the benefits of adjuvant chemotherapy.

RAD51 Expression as a Biomarker to Predict Efficacy of Preoperative Therapy and Survival for Esophageal Squamous Cell Carcinoma: A Large-cohort Observational Study (KSCC1307).

OBJECTIVE: The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC). BACKGROUND: It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study. METHODS: A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry. RESULTS: In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT. CONCLUSIONS: In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression.

Correction to: Recurrence with pagetoid spread arising 17 years after surgery for intramucosal rectal cancer: a case report.

After publication of the original article [1] the authors noted that the following errors had occurred.

Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability.

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.

Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma.

OBJECTIVES: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer. MATERIALS AND METHODS: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45. RESULTS: Overexpression of PD-L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells. CONCLUSIONS: PD-L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1.

Recurrence with pagetoid spread arising 17 years after surgery for intramucosal rectal cancer: a case report.

BACKGROUND: Perianal Paget's disease (pPD) is uncommon, with only about 180 cases documented in the literature. Anorectal carcinoma with pagetoid spread is even rarer. CASE PRESENTATION: An 81-year-old woman underwent rectal cancer extirpation with a transanal approach 17 years prior. She has since undergone two reoperations for local rectal cancer recurrence. Then, warts frequently appeared on the vulva on several occasions. Warts appeared on the vulva 1 year ago, which were diagnosed as pPD by biopsy. She underwent perineal tumor resection, and the final histological diagnosis was rectal cancer recurrence with pagetoid spread. The resected stump was positive for cancer cells, and tumor progression was rapid. She underwent additional abdominoperineal resection (Miles' operation) with lymph node dissection. However, disease progression was rapid and she died 7 months after the Miles' operation. CONCLUSIONS: There are some case reports describing anorectal carcinoma with pagetoid spread, however, almost of all those cases were synchronous primary anorectal cancer. Here, we report the first case of metachronous recurrence rectal cancer with pagetoid spread arising 17 years after surgery.

High ubiquitin-specific protease 44 expression induces DNA aneuploidy and provides independent prognostic information in gastric cancer.

Chromosomal instability (CIN), characterized by aneuploidy, is a major molecular subtype of gastric cancer. The deubiquitinase USP44 is an important regulator of APC activation in the spindle checkpoint and leads to proper chromosome separation to prevent aneuploidy. Aberrant expression of USP44 leads CIN in cells; however, the correlation between USP44 and DNA aneuploidy in gastric cancer is largely unknown. We analyzed USP44 expression in 207 patients with gastric cancer by immunohistochemistry and found that the proportion of USP44 expression was higher in gastric cancer tumors (mean, 39.6%) than in gastric normal mucosa (mean, 14.6%) (P < 0.0001). DNA aneuploidy was observed in 124 gastric cancer cases and high USP44 expression in cancer strongly correlated with DNA aneuploidy (P = 0.0005). The overall survival was significantly poorer in the high USP44 expression group compared with the low USP44 group (P = 0.033). Notably, USP44 expression had no prognostic impact in the diploid subgroup; however, high USP44 expression was a strong poor prognostic factor for progression-free survival (P = 0.018) and overall survival (P = 0.036) in the aneuploid subgroup. We also confirmed that stable overexpression of USP44 induced somatic copy-number aberrations in hTERT-RPE-1 cells (50.6%) in comparison with controls (6.6%) (P < 0.0001). Collectively, our data show USP44 has clinical impact on the induction of DNA aneuploidy and poor prognosis in the CIN gastric cancer subtype.

Anal metastasis of rectal cancer-adenocarcinoma of squamous cells: a case report and literature review.

Anal metastasis of colorectal cancer is very rare and is usually associated with a history of anal disease, including anal fistula, fissure, hemorrhoidectomy, and anastomotic injury. We report a case of rectal cancer with a synchronous anal metastasis consisting of adenocarcinoma of squamous cells without a history of anal disease. A 60-year-old woman had a chief complaint of melena. She had a 1.5-cm anal tumor on the perianal skin, and a Bollman type 2 rectal tumor on the Ra portion was found on colonoscopy. Biopsy of both tumors revealed a similar histology of well- to moderately differentiated adenocarcinoma. There was no sign of metastases in lymph nodes or other organs. For the purpose of diagnosis and treatment, transperineal local resection of the anal tumor was performed, and it was histologically identified as adenocarcinoma of squamous cells with no invasion to muscles, lymph ducts, or microvessels. The pathological margin was free. Then, to achieve radical cure, laparoscopic low anterior resection (LAR) with D3 lymphadenectomy was performed. The histological diagnosis of the anal tumor was adenocarcinoma of squamous cells without invasion to muscles, lymph ducts, or vessels. The surgical margin was completely free. Immunohistochemical analysis of both tumors revealed similar staining patterns, and the final diagnosis was rectal cancer with metastasis to the anal skin. The patient received no postoperative therapy, and no recurrences have been observed 12 months after surgery. We expect that our sphincter-preserving surgical strategy provided a good prognosis for the synchronous rectal cancer and anal metastasis. This is a rare report of a case with an anal metastasis of colorectal cancer on perianal squamous cells without a history of anal disease that was resected while preserving anal function.

Successful surgical intervention for rectal perforation due to polyarteritis nodosa: report of a case.

BACKGROUND: Polyarteritis nodosa (PAN) is a primary systemic necrotizing vasculitis with diffuse organ involvements, resulting in a high mortality rate due to multiple organ failure. Although the small bowel is the frequently targeted organ of PAN-associated vasculitis, rectal involvement is very rare, and only one case of rectal bleeding has been previously reported. The mortality rate of PAN with gastrointestinal (GI) perforation is reportedly much higher than that of without severe GI involvement. We herein report the first case of rectal perforation due to PAN, successfully managed with an adequate surgical intervention. CASE PRESENTATION: A 66-year-old woman with PAN had abdominal pain and melena with guarding. Computed tomography scan showed abdominal free air and bubbles in the rectal hematoma. We diagnosed it acute peritonitis, and emergency surgery was performed. After removing rectal hematoma and necrotic tissue, a huge lack of rectal wall spreading to the pelvirectal space was observed. In order to totally remove the necrotic tissue, abdominoperineal resection was needed. Together with histopathological examinations which showed neutrophils and fibrinous necrosis, we finally diagnosed rectal perforation due to PAN. At 19-month follow-up after surgery, she was still healthy with a stable disease of PAN. CONCLUSIONS: We herein reported the first case of successfully managed rectal perforation due to PAN. Early adequate surgical resection may be important for the case with rectal perforation.

Prognostic Significance of Sarcopenia in Patients with Esophagogastric Junction Cancer or Upper Gastric Cancer.

BACKGROUND: The association between sarcopenia and postoperative outcomes for patients with gastrointestinal malignancies remains controversial. This study aimed to assess the impact of sarcopenia on short- and long-term outcomes after surgery for esophagogastric junction cancer (EGJC) or upper gastric cancer (UGC). METHODS: The study reviewed 148 patients with EGJC or UGC who underwent surgical resection. The patients were categorized into the sarcopenia group or the non-sarcopenia group according to their skeletal muscle index calculated using abdominal computed tomography images. The study compared clinicopathologic factors, postoperative complications, and prognosis between the two groups. RESULTS: Sarcopenia was present in 19 patients (32.2%) with EGJC and 23 patients (25.8%) with UGC. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were significantly poorer in the sarcopenia group than in the non-sarcopenia group (OS 85.5 vs 54.8%, P = 0.0010; RFS 78.7 vs 51.7%, P = 0.0054). The development of postoperative complications did not differ significantly between the two groups. Both the uni- and multivariate analyses showed that N stage (P < 0.0001) and sarcopenia (P = 0.0024 and 0.0293, respectively) were independent poor prognostic factors for OS. CONCLUSIONS: Sarcopenia was strongly associated with a poor long-term prognosis for patients with EGJC or UGC who underwent surgery. The results suggest that special attention might be needed during the development of treatment strategies for patients with sarcopenia who intend to undergo operations for EGJC and UGC.

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.

Clinicopathological Features of Cervical Esophageal Cancer: Retrospective Analysis of 63 Consecutive Patients Who Underwent Surgical Resection.

OBJECTIVE: The objectives of this retrospective study were to elucidate the clinicopathological features and recent surgical results of cervical esophageal cancer. SUMMARY BACKGROUND DATA: Cervical esophageal cancer has been reported to have a dismal prognosis. Accurate knowledge of the clinical characteristics of cervical esophageal cancer is warranted to establish appropriate therapeutic strategies. METHODS: The clinicopathological features and treatment results of 63 consecutive patients with cervical esophageal cancer (Ce group) who underwent surgical resection from 1980 to 2013 were analyzed and compared with 977 patients with thoracic or abdominal esophageal cancer (T/A group) who underwent surgical resection during that time. RESULTS: Among the patients who received curative resection, the 5-year overall and disease-specific survival rates of the Ce patients were significantly better than those of the T/A patients (overall: 77.3% vs 46.5%, respectively, P = 0.0067; disease-specific: 81.9% vs 55.8%, respectively, P = 0.0135). Although total pharyngo-laryngo-esophagectomy procedures were less frequently performed in the recent period, the rate of curative surgical procedures was markedly higher in the recent period (2000-1013) than that in the early period (1980-1999) (44.4% vs 88.9%, P = 0.0001). The 5-year overall survival rate in the recent period (71.5%) was significantly better than that in the early period (40.7%, P = 0.0342). CONCLUSIONS: Curative resection for cervical esophageal cancer contributes to favorable outcomes compared with other esophageal cancers. Recent surgical results for cervical esophageal cancer have improved, and include an increased rate of curative resection and decreased rate of extensive surgery.

Prognostic value of BRAF V600E mutation and microsatellite instability in Japanese patients with sporadic colorectal cancer.

PURPOSE: In colorectal cancer (CRC), the BRAF V600E mutation is an important biomarker for poor prognosis, while high microsatellite instability (MSI-H) indicates good prognosis. Using a commercial BRAF V600E-specific antibody, we investigated the BRAF V600E mutation according to immunohistochemistry (IHC) and the MSI status in Japanese patients with CRC. METHODS: In this retrospective study, tissue samples from 472 Japanese patients with CRC, stratified for MSI, were analyzed to determine the prognostic value of BRAF V600E, as assessed using IHC. Mutations in 254 patients were evaluated using the direct sequencing method to check for concordance. RESULTS: The frequency of MSI-H was 9.3 % (44/472), and BRAF V600E mutation was detected immunohistochemically in 8.7 % patients (41/472). The sensitivity and specificity for detection of BRAF V600E mutations by IHC were 100 % (17/17) and 98.7 % (234/237), respectively. BRAF V600E mutations were significantly correlated with the anatomical tumor site (P = 0.0035), histological type (P < 0.0001), and MSI status (P < 0.0001). Consistent with other published series, patients with BRAF V600E mutation exhibited a significantly shorter overall survival (hazard ratio = 1.500, P = 0.0432). In particular, the microsatellite stable/BRAF mutation group had inferior prognosis compared with the MSI-H/BRAF wild-type group (hazard ratio = 2.621, P = 0.0004). CONCLUSIONS: IHC using a BRAF V600E-specific antibody was useful for diagnosis and concurred with direct sequencing results. CRC cases could be stratified by combining BRAF V600E mutation and MSI status as a prognostic factor in Japanese patients.

Distant lymph node metastases caused by esophageal cancer invasion to the lamina propria: a case report.

BACKGROUND: Pathological examination after endoscopic submucosal dissection revealed that a 62-year-old male had esophageal squamous cell carcinoma with lamina propria mucosal invasion and lymphatic permeation. CASE PRESENTATION: The patient underwent subtotal esophagectomy and reconstruction as an additional therapy. At 3 years and 4 months after esophagectomy, enlargement of abdominal para-aortic lymph nodes metastases was detected by computed tomography scanning. A total of 50.4 Gy of radiation and two cycles of 5-fluorouracil plus cisplatin were administered. The lymph node metastases were markedly reduced by chemoradiotherapy; however, at 1 year and 1 month later (4 years and 5 months after esophagectomy), left adrenal gland recurrence was found. Although resection was performed, the patient died from cancer progression at 5 years and 4 months after esophagectomy. CONCLUSIONS: This case demonstrates that esophageal squamous cell carcinoma with invasion to the lamina propria and lymphatic permeation has the potential to cause distant metastases.

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.

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.

Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. PATIENTS AND METHODS: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. RESULTS: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. CONCLUSIONS: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.