Protocol for a phase II study to evaluate the efficacy and safety of nivolumab as a postoperative adjuvant therapy for patients with esophageal cancer treated with preoperative docetaxel, cisplatin plus 5-fluorouracil treatment (PENTAGON trial).

BACKGROUND: In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. METHODS: This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. DISCUSSION: To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.

Impact of Tumor Size on Survival Outcome in Esophageal Squamous Cell Carcinoma After Esophagectomy Following Neoadjuvant Chemotherapy.

BACKGROUND: Large tumor size is a prognostic factor in esophageal squamous cell carcinoma (ESCC). However, the effect of tumor size on outcomes following neoadjuvant chemotherapy (NAC) has not been evaluated. This study aimed to assess the influence of tumor size on prognosis of patients undergoing esophagectomy after NAC. PATIENTS AND METHODS: This study was made up of 272 patients who underwent esophagectomy after NAC at Kobe University Hospital. We evaluated the pathological tumor size and determined the cutoff level for tumor size using receiver operating characteristics analysis to the survival status. Cox proportional hazards regression analyses were performed to identify prognostic factors. RESULTS: The patients were categorized into two groups: patients with tumor sizes ≥ 36 mm and < 36 mm. Deep pathological tumor invasion and worse histological response to NAC were associated with tumor size ≥ 36 mm. In patients with pT0-1, pT2, and pT4 ESCC, no significant differences in overall survival (OS) rates were observed between the two groups. In patients with pT3, OS of the tumor size ≥ 36 mm group was significantly worse than that of the tumor size < 36 mm group (p < 0.0001). Multivariate analysis in pT3 patients revealed tumor size ≥ 36 mm was an independent risk factor for OS. The 5-year OS rate was 10% in patients with tumor size ≥ 36 mm pT3 ESCC with pathological lymph node metastasis (p < 0.0001). CONCLUSIONS: Tumor size ≥ 36 mm is an independent risk factor for poorer survival in pT3 patients. Furthermore, tumor size ≥ 36 mm with pathological lymph node metastasis in pT3 patients was associated with very poor survival.

Effectiveness of long-term tube feeding intervention in preventing skeletal muscle loss after minimally invasive esophagectomy.

PURPOSE: Esophageal cancer is a lethal tumor typically treated by neoadjuvant chemotherapy and surgery. For patients undergoing esophagectomy, postoperative enteral nutrition is important in preventing complications. Sarcopenia is associated with poor postoperative outcomes in esophageal cancer. In this study, we evaluated the benefits of tube feeding intervention and compared its short- and long-term outcomes in patients who underwent esophagectomy. METHODS: Propensity score matching was performed in 303 patients who underwent esophagectomy at Kobe University Hospital between 2010 and 2020. Patients were divided into feeding and nonfeeding jejunostomy tube groups (n = 70 each). The feeding jejunostomy tube group was further divided into long-term (≥ 60 days) and short-term (< 60 days) subgroups. The groups were then retrospectively compared regarding postoperative albumin levels, body weight, and psoas muscle area and volume. RESULTS: In the long-term feeding jejunostomy tube group, anastomotic leakage (p = 0.013) and left laryngeal nerve palsy (p = 0.004) occurred frequently. There were no significant between-group differences in postoperative albumin levels, body weight, or psoas muscle area. However, significant psoas muscle volume recovery was confirmed in the long-term jejunostomy tube group at 6 months postoperatively (p = 0.041). CONCLUSIONS: Tube feeding intervention after minimally invasive esophagectomy may attenuate skeletal muscle mass loss and help prevent sarcopenia.

Oncological impact of unexpected horizontal tumor spread in gastric cancer that requires total gastrectomy.

BACKGROUND: Gastric cancer often exhibits discrepancies between the gross and pathological tumor boundaries, and the degree of discrepancy may be a tumor characteristic. However, whether these discrepancies influence oncological outcomes remains unclear. METHODS: The data of patients who underwent total gastrectomy for gastric cancer from 2005 to 2018 were collected. A new parameter, ΔPM, which corresponds to the length of the discrepancy between the gross and pathological proximal boundaries, was calculated and the patients were divided into two groups: patients with long ΔPM and those with short ΔPM. Oncological outcomes were compared between the two groups. RESULTS: A length of 8 mm was determined as the cutoff value for long or short ΔPM. Tumor size, growth pattern, pathological type, depth, and esophageal invasion were associated with ΔPM > 8 mm. Overall survival of the ΔPM > 8 mm group was significantly worse than that of the ΔPM ≤ 8 mm group (5-year overall survival: 58% vs 78%; p < 0.0001). Multivariate analysis revealed that ΔPM > 8 mm was an independent risk factor for poor survival and peritoneal metastasis. The likelihood ratio test revealed a significant interaction between pT status and ΔPM (p = 0.0007). Circumferential involvement and gross esophageal invasion were poorer survival factors in the ΔPM > 8 mm group. CONCLUSIONS: ΔPM > 8 mm is related to several clinicopathological characteristics and is an independent risk factor for poorer survival and peritoneal metastasis but not local recurrence. ΔPM > 8 mm combined with circumferential involvement or esophageal invasion is associated with relatively poor survival outcomes.

Required esophageal resection length beyond the tumor boundary to ensure a negative proximal margin for gastric cancer with gross esophageal invasion or esophagogastric junction cancer.

BACKGROUND: To obtain a pathologically negative proximal margin (PM) for gastric cancer with gross esophageal invasion (EI) or esophagogastric junction (EGJ) cancer, we should transect the esophagus beyond the proximal boundary of gross EI with a safety margin because of a discrepancy between the gross and pathological boundaries of cancer. However, recommendations regarding the esophageal resection length for these cancers have not been established. METHODS: Patients who underwent proximal or total gastrectomy for gastric cancer with gross EI or EGJ cancer were enrolled. A parameter ΔPM, which corresponded to the length of a discrepancy between the gross and pathological proximal boundary of the tumor, was evaluated. The maximum ΔPM, which corresponded to the minimum length ensuring a pathologically negative PM, was first determined in all patients. Then subgroup analyses according to factors associated with ΔPM ≥ 10 mm were performed to identify alternative maximum ΔPMs. RESULTS: A total of 289 patients with gastric cancer with gross EI or EGJ cancer were eligible and analyzed in this study. The maximum ΔPM was 25 mm. Clinical tumor (cTumor) size and growth and pathological types were independently associated with ΔPM ≥ 10 mm. In subgroup analyses, the maximum ΔPM was 15 mm for cTumor size ≤ 40 mm and superficial growth type. Furthermore, the maximum ΔPM was 20 mm in the expansive growth type. CONCLUSIONS: Required esophageal resection lengths to ensure a pathologically negative PM for gastric cancer with gross EI or EGJ cancer are proposed.

Minimum resection length to ensure a pathologically negative distal margin and the preservation of a larger remnant stomach in proximal gastrectomy for early upper gastric cancer.

BACKGROUND: In proximal gastrectomy (PG), a longer distal margin (DM) length should be maintained to obtain a pathologically negative DM. However, a shorter DM length is preferred to preserve a large remnant stomach for favorable postoperative outcomes. Evidence regarding the minimum DM length to ensure a pathologically negative DM is useful. METHODS: Patients who underwent PG or total gastrectomy for cT1N0M0 gastric cancer limited to the upper third were enrolled. A new parameter, ΔDM, which corresponded to the pathological extension distal to the gross tumor boundary towards the resection stump, was evaluated. The maximum ΔDM, which is the length ensuring a pathologically negative DM, was first determined. Furthermore, the possible incidences of pathologically positive DM were calculated for each pathological type and clinical tumor (cTumor) size. RESULTS: Of 361 patients eligible for this study, 190 and 171 were assigned to differentiated (Dif) and undifferentiated types (Und), respectively. The maximum ΔDM was 30 and 40 mm in Dif and Und, respectively. Considering a correlation between cTumor size and ΔDM, and possible incidences of pathologically positive DM, 10, 20, and 30 mm were the minimal gross DM lengths in Dif when cTumor size was ≤ 15 mm, > 15 and ≤ 50 mm, and > 50 mm, respectively. In Und, the incidences of pathologically positive DM were 0.59% and 2.3% for gross DM lengths of 30 and 20 mm, respectively. CONCLUSION: The minimum DM lengths to ensure a pathologically negative DM in PG are proposed according to the pathological type of early upper gastric cancer.

Minimum Esophageal Resection Length to Ensure Negative Proximal Margin in Total Gastrectomy for Gastric Cancer: A Retrospective Study.

Objective: To identify the minimum length of esophageal resection to ensure a pathologically negative proximal margin (PM) in total gastrectomy for gastric cancer. Background: In total gastrectomy, a certain esophageal length is resected to obtain a pathologically negative PM because of the possibility of unexpected pathological esophageal invasion. However, a recommendation regarding the esophageal transection site in total gastrectomy has not been established. Methods: The data of patients who underwent total gastrectomy for gastric cancer from 2005 to 2018 were collected. We evaluated the length of unexpected pathological esophageal invasion (esophageal ΔPM) in each type of disease and each location of the gross proximal tumor boundary (PB) using the length between the PB and the esophagogastric junction (PB-EGJ length). Results: Of the 1005 patients eligible for this study, 277, 196, and 532 had cT1, cT2-4 expansive (Exp), and cT2-4 infiltrative (Inf) growth patterns, respectively. In cT1 and Exp, no unexpected pathological esophageal invasion occurred when the PB-EGJ length was >1 cm, whereas pathological esophageal invasion occurred in 20.0% of cT1 and 32.7% of Exp when the PB-EGJ length was ≤1 cm. The esophageal ΔPM was <1 cm. In Inf, no unexpected pathological esophageal invasion occurred when the PB-EGJ length was >3 cm, whereas pathological esophageal invasion occurred in 17.4% of patients when the PB-EGJ length was ≤3 cm. The esophageal ΔPM was <2 cm. Conclusions: New recommendations regarding the esophageal resection length required to ensure a pathologically negative PM in total gastrectomy are herein proposed.

Severe weight loss after minimally invasive oesophagectomy is associated with poor survival in patients with oesophageal cancer at 5 years.

BACKGROUND: Patients often experience severe weight loss after oesophagectomy. Enteral nutrition via a feeding jejunostomy tube (FT) is commonly practised. This study aimed to assess the effect of severe weight loss postoperatively and enteral nutrition via an FT on long-term prognosis after oesophagectomy. METHODS: This study analysed 317 patients who underwent minimally invasive oesophagectomy at Kobe University Hospital and Hyogo Cancer Center from 2010 to 2015. The patients' body weight was evaluated at 3 months postoperatively. They were organised into the severe weight loss (n = 65) and moderate weight loss (n = 252) groups. Furthermore, they were categorised into the FT group (184 patients who had an FT placed during oesophagectomy) and no-FT group (133 patients without FT). Patients (119 per group) matched for the FT and no-FT groups were identified via propensity score matching. RESULTS: The 5-year overall survival (OS) rate in the severe weight loss group was significantly lower (p = 0.024). In the multivariate analysis, tumour invasion depth (pT3-4), preoperative therapy and severe weight loss had a worse OS (hazard ratio = 1.89; 95% confidence interval = 1.12-3.17, hazard ratio = 2.11; 95% confidence interval = 1.25-3.54, hazard ratio = 1.82; 95% confidence interval = 1.02-3.524, respectively). No significant differences in the number of severe weight loss patients and OS were found between the FT and no-FT groups. CONCLUSION: Severe weight loss is significantly associated with poor OS. In addition, enteral nutrition via an FT did not improve the severe weight loss and OS.

Acquisition of cancer stem cell properties in osteosarcoma cells by defined factors.

BACKGROUND: Cancer stem cells (CSCs) are considered to be responsible for tumor initiation, formation, and poor prognosis of cancer patients. However, the rarity of CSCs in clinical samples makes it difficult to elucidate characteristics of CSCs, especially in osteosarcoma (OS). The aim of this study is to verify whether it is possible to generate CSC-like cells by transducing defined factors into an OS cell line. METHODS: We retrovirally transduced the Octamer-binding transcription factor 3/4 (OCT3/4), Kruppel-like factor 4 (KLF4), and SRY-box transcription factor 2 (SOX2) genes into the MG-63 human OS cell line (MG-OKS). Parental and GFP-transduced MG-63 cells were used as negative control. We assessed the properties of the generated cells in vitro and in vivo. Multiple comparisons among groups were made using a one-way analysis of variance (ANOVA) followed by post hoc testing with Tukey's procedure. RESULTS: MG-OKS cells in vitro exhibited the significantly increased mRNA expression levels of CSC markers (CD24, CD26, and CD133), decreased cell growth, increased chemoresistance and cell migration, and enhanced sphere formation. Notably, MG-OKS cells cultured under osteogenic differentiation conditions showed strongly positive staining for both Alizarin Red S and alkaline phosphatase, indicating osteogenesis of the cells. Gene ontology analysis of microarray data revealed significant upregulation of epidermal-related genes. Tumors derived from MG-OKS cells in vivo were significantly larger than those from other cells in µCT analysis, and immunohistochemical staining showed that Ki-67, osteocalcin, and HIF-1α-positive cells were more frequently detected in the MG-OKS-derived tumors. CONCLUSIONS: In this study, we successfully generated OS CSC-like cells with significantly enhanced CSC properties following transduction of defined factors.

Correction to: Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium.

In the original publication of the article, the following errors were noted and corrected in this correction.

Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium.

BACKGROUND: The esophagus is known to be derived from the foregut. However, the mechanisms regulating this process remain unclear. In particular, the details of the human esophagus itself have been poorly researched. In this decade, studies using human induced pluripotent stem cells (hiPSCs) have proven powerful tools for clarifying the developmental biology of various human organs. Several studies using hiPSCs have demonstrated that retinoic acid (RA) signaling promotes the differentiation of foregut into tissues such as lung and pancreas. However, the effect of RA signaling on the differentiation of foregut into esophagus remains unclear. METHODS: We established a novel stepwise protocol with transwell culture and an air-liquid interface system for esophageal epithelial cell (EEC) differentiation from hiPSCs. We then evaluated the effect of all-trans retinoic acid (ATRA), which is a retinoic acid receptor (RAR)α, RARß and RARγ agonist, on the differentiation from the hiPSC-derived foregut. Finally, to identify which RAR subtype was involved in the differentiation, we used synthetic agonists and antagonists of RARα and RARγ, which are known to be expressed in esophagus. RESULTS: We successfully generated stratified layers of cells expressing EEC marker genes that were positive for lugol staining. The enhancing effect of ATRA on EEC differentiation was clearly demonstrated with quantitative reverse transcription polymerase chain reaction, immunohistology, lugol-staining and RNA sequencing analyses. RARγ agonist and antagonist enhanced and suppressed EEC differentiation, respectively. RARα agonist had no effect on the differentiation. CONCLUSION: We revealed that RARγ activation promotes the differentiation of hiPSCs-derived foregut into EECs.

Thoracoscopic retrosternal gastric conduit resection in the supine position for gastric tube cancer.

INTRODUCTION: Recent advances in the treatment for esophageal cancer have improved the prognosis after esophagectomy, but they have led to an increased incidence of gastric tube cancer. In most patients who underwent retrosternal reconstruction, median sternotomy is performed; it is associated with a risk of postoperative bleeding and osteomyelitis, and pain often negatively affects respiration. Here, we report the first case of thoracoscopic retrosternal gastric conduit resection in the supine position (TRGR-S). MATERIALS AND SURGICAL TECHNIQUE: A 75-year-old male patient was placed in the supine position. Four ports were placed in the left chest wall. The gastric tube was separated from the epicardium, sternum, and left brachiocephalic vein. Because of adhesions between the gastric tube and the right pleura, combined resection of the right pleura was performed. The dorsal side of the gastric tube was dissected before the ventral side, enabling the gastric tube to be suspended from the back of the sternum and, thus, making it easier to expose the surgical field. Next, pedicled jejunal reconstruction via the presternal route was performed. There were no postoperative complications. The pathological diagnosis was signet ring cell carcinoma (pT1b, pN0, M0, pStage I), indicating R0 resection. DISCUSSION: TRGR-S does not require sternotomy, reducing the risk of postoperative bleeding and osteomyelitis. In the presence of adhesions, TRGR-S is safe and provides a good surgical view. It is also reliable procedure for resection of retrosternal gastric tube cancer, and it is ergonomic for surgeons.

Routine placement of feeding jejunostomy tube during esophagectomy increases postoperative complications and does not improve postoperative malnutrition.

Esophagectomy for esophageal cancer is a highly invasive procedure, and a feeding jejunostomy tube (FJT) is routinely placed to ensure adequate enteral nutrition. However, the effect of perioperative short-term FJT placement remains controversial, and the aim of this study was to assess risks and benefits of routine FJT placement during esophagectomy and to determine parameters that can identify patients needing long-term FJT. This retrospective study included 393 patients who had undergone esophagectomy with gastric tube reconstruction via the posterior mediastinal route at the Kobe University Hospital and the Hyogo Cancer Center between April 2010 and December 2017. Propensity score matching was used to identify matched patients (139 per group) in the FJT and no-FJT groups. The incidence of postoperative complications and weight loss (3 months post-procedure) was compared in the matched cohort and significant risk factors predicting the need for long-term FJT placement in the whole cohort were identified. In the matched cohort, while weight loss was not different between the FJT and no-FJT groups (11% vs. 10%), the incidence of small bowel obstruction in the FJT group (11.5%) was significantly higher than that in the no-FJT group (0%). Multivariate analysis revealed that age (≥75 years), preoperative therapy, anastomosis leakage, and pulmonary complications were independent risk factors for long-term FJT placement. Routine placement of an FJT during esophagectomy increases small bowel obstruction and does not result in better nutritional status, suggesting that selective long-term FJT placement in high-risk patients should be considered.

Prophylactic Cervical Lymph Node Dissection in Thoracoscopic Esophagectomy for Esophageal Cancer Increases Postoperative Complications and Does Not Improve Survival.

BACKGROUND: Esophagectomy with three-field lymph node dissection is common, but the effects of cervical lymph node dissection on overall survival in patients with thoracic esophageal cancer remain controversial. Recently, we performed thoracoscopic esophagectomy and superior mediastinum and paracervical esophageal lymph nodes could have been effectively dissected from the thoracic cavity. This study assessed the risks and benefits of prophylactic supraclavicular lymph node dissection in patients who underwent thoracoscopic esophagectomy. METHODS: This retrospective study included 294 patients who underwent thoracoscopic esophagectomy at Kobe University Hospital and Hyogo Cancer Center between April 2010 and December 2015. Patients in the two-field (paracervical esophageal lymph nodes were dissected from the thoracic cavity) and three-field lymph node dissection groups were matched using propensity score matching. We compared overall survival and the incidence of postoperative complications in the matched cohort and assessed the estimated efficacy of additional lymphadenectomy for supraclavicular lymph node recurrence in the entire cohort. RESULTS: In the matched cohort, overall survival was not significantly different between the two groups, but the incidence of recurrent laryngeal nerve palsy was significantly higher in the 3FL group than in the 2FL group. In the entire cohort, 162 patients underwent a two-field lymph node dissection; 11 experienced supraclavicular nodal recurrence. We performed additional supraclavicular lymph node dissection in three patients without systemic metastasis, all of whom are alive without any other recurrence. CONCLUSIONS: Prophylactic cervical lymph nodes dissection in thoracoscopic esophagectomy does not improve long-term survival but does increase the risk of postoperative complications.

A comparison of the clinical outcomes of esophagectomy and chemoradiotherapy after noncurative endoscopic submucosal dissection for esophageal squamous cell carcinoma.

PURPOSE: Endoscopic submucosal dissection (ESD) is widely used to treat esophageal cancer, but some patients require additional treatment due to the possibility of lymph node metastasis. The aim of this study was to elucidate the clinical outcomes of these additional treatments. METHODS: The study included 59 patients who developed superficial esophageal squamous cell carcinoma after noncurative ESD treated between 2005 and 2016, of whom 28 underwent esophagectomy and 31 received chemoradiotherapy (CRT). RESULTS: The median follow-up periods were 45 months in the esophagectomy group and 41 months in the CRT group. The overall survival did not differ significantly between the groups (P = 0.46). However, there were no recurrences in the esophagectomy group, and the disease-specific survival rate was significantly higher in this group (P = 0.042). Among the patients at high risk for recurrence due to massive tumor invasion (≥ SM2) with lymphovascular invasion (esophagectomy group, six patients; CRT group, ten patients), none in the esophagectomy group had recurrence, whereas four in the CRT group died of esophageal cancer (P = 0.031). CONCLUSION: The overall survival did not differ significantly between the groups. However, compared with CRT, esophagectomy provided more favorable disease control for patients with massive tumor invasion (≥ SM2) with lymphovascular invasion.