Exploratory open-label clinical study to determine the S-588410 cancer peptide vaccine-induced tumor-infiltrating lymphocytes and changes in the tumor microenvironment in esophageal cancer patients.

Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy.Trial registration UMIN-CTR registration identifier: UMIN000023324.

An anatomical hypothesis: a "concentric-structured model" for the theoretical understanding of the surgical anatomy in the upper mediastinum required for esophagectomy with radical mediastinal lymph node dissection.

Understanding the surgical anatomy is the key to reducing surgical invasiveness especially in the upper mediastinal dissection for esophageal cancer, which is supposed to have a significant impact on curability and morbidity. However, there is no theoretical recognition regarding the surgical anatomy required for esophagectomy, although the surgical anatomy in abdominal digestive surgery has been developed on the basis of embryological findings of intestinal rotation and fusion fascia. Therefore, we developed a hypothesis of a 'concentric-structured model' of the surgical anatomy in the upper mediastinum based on human embryonic development. This model was characterized by three factors: (1) a concentric and symmetric three-layer structure, (2) bilateral vascular distribution, and (3) an 'inter-layer potential space' composed of loose connective tissue. The concentric three-layer structure consists of the 'visceral layer', the 'vascular layer', and the 'parietal layer': the visceral layer containing the esophagus, trachea, and recurrent laryngeal nerves as the central core, the vascular layer of major blood vessels surrounding the visceral core to maintain the circulation, and the parietal layer as the outer frame of the body. The bilateral vascular distribution consists of the inferior thyroid arteries and bronchial arteries originating from the bilateral dorsal aortae in an embryo. This bilateral vascular distribution may be related to the formation of the proper mesentery of the esophagus and frequent lymph node metastasis observed in the visceral layer around recurrent laryngeal nerves. The three concentric layers are bordered by loose connective tissue called the 'inter-layer potential space'. This inter-layer potential space is the fundamental factor of our concentric-structured model as the appropriate surgical plane of dissection. The peripheral blood vessels, nerves, and lymphatics transition between each layer, thereby penetrating this loose connective tissue forming the inter-layer potential space. Recurrent laryngeal nerves also transition from the vascular layer after branching off from the vagal nerves and then ascend consistently in the visceral layer. We investigated the validity of this concentric-structured model, confirming the intraoperative images and the surgical outcomes of thoracoscopic esophagectomy in a prone position (TSEP) before and after the introduction of this hypothetical anatomy model. A total of 226 patients with esophageal cancer underwent TSEP from January 2015 to December 2016. After the introduction of this model, the surgical outcomes in 105 patients clearly improved for the operation time of the thoracoscopic procedure (160 min vs. 182 min, P = 0.01) and the incidence of recurrent laryngeal nerve palsy (19.0% vs. 36.4%, P = 0.004). Moreover, we were able to identify the concentric and symmetric layer structure through surgical dissection along the inter-layer potential space between the visceral and vascular layers ('viscero-vascular space') in all 105 cases after introduction of the hypothetical model. The concentric-structured model based on embryonic development is clinically beneficial for achieving less-invasive esophagectomy by ensuring a theoretical understanding of the surgical anatomy in the upper mediastinum.

Thermogenesis induced by amino acid administration prevents intraoperative hypothermia and reduces postoperative infectious complications after thoracoscopic esophagectomy.

Minimally invasive thoracoscopic esophagectomy has potential advantages in minimizing the impairment of respiratory function and reducing surgical stress. However, thoracoscopic esophagectomy occasionally results in anesthesia-induced hypothermia, particularly in cases involving artificial pneumothorax with CO2. Thermogenesis induced by amino acid administration has been reported during anesthesia. Here, we tested the efficacy of amino acid treatment for the prevention of hypothermia, and we investigated the potential of this treatment to reduce postoperative infectious complications after thoracoscopic esophagectomy. We conducted a randomized trial in patients with esophageal cancer who underwent thoracoscopic esophagectomy in the prone position in two groups and analyzed the incidences of hypothermia and surgical complications. One-hundred and thirty patients were randomized. Administration of amino acids resulted in a significant increase in core body temperature. In the saline (n = 60) and amino acid (n = 70) administration groups, 30% and 14.2% of patients, respectively, experienced infectious surgical complications (P = 0.029), and 21.6% and 22.8% of patients, respectively, experienced noninfectious surgical complications (P = 0.86). Univariate analysis revealed that blood loss and amino acid administration were significant factors for infectious surgical complications. Multivariate analysis revealed that amino acid administration was an independent factor reducing infectious surgical complications (P = 0.025, 95% confidence interval: 0.105-0.864). Administration of amino acids prevents hypothermia and reduces postoperative infectious complications after thoracoscopic esophagectomy.

Early enteral nutrition reduces the rate of life-threatening complications after thoracic esophagectomy in patients with esophageal cancer.

BACKGROUND: Early postoperative enteral nutrition has been suggested to improve the nutritional status of patients after esophageal surgery. However, whether enteral nutrition decreases rates of surgical complications and increases the completion rate of the clinical management pathway is unclear. METHODS: We analyzed 154 patients who were randomly assigned to either an enteral or parenteral nutrition group after undergoing esophagectomy, compared the incidence of surgical complications, and evaluated the completion rate of the clinical pathway. In these 2 patient groups, perioperative management was performed through identical clinical pathways, except for nutrition. RESULTS: The overall rate of surgical complications of any type did not differ between patients who received early enteral nutrition and those who did not (p = 0.50); however, the rate of life-threatening surgical complications was significantly lower in patients who received early enteral nutrition (p = 0.02). The rate of non-life-threatening surgical complications did not differ between the groups (p = 0.98). In patients who received enteral nutrition, the completion rate of the clinical pathway was higher (p = 0.03), and the postoperative hospital stay was shorter (p = 0.04). CONCLUSIONS: Early enteral nutrition reduces the incidence of life-threatening surgical complications and improves the completion rate of the clinical pathway for thoracic esophagectomy.

Three-field lymph node dissection for esophageal cancer in elderly patients over 70 years of age.

BACKGROUND: The risk and benefit of esophagectomy with three-field lymph node dissection has not been well defined in elderly esophageal cancer patients. METHODS: A total of 441 patients underwent three-field lymph node dissection from 1986 to 1998. Patients were divided into two age groups: group 1 consisted of 79 patients aged 70 years or over, and group 2 consisted of 362 patients under 70 years of age. Patients' characteristics and surgical outcomes were compared between groups. Risk factors for morbidity, mortality, and survival of patients in group 1 were further studied by multivariate analysis. RESULTS: Significantly more patients had multiorgan dysfunction preoperatively in group 1 (24; 30.4%) than in group 2 (34; 9.4%, p < 0.001). The overall (65.8% vs 61.6%, p = 0.483) and surgically related complication rates (41.8% vs 52.2%, p = 0.093) were similar, but significantly more organ failure (11.4% vs 5.0%, p = 0.031) and infection (22.8% vs 13.8%, p = 0.045), defined as medical complications, occurred in group 1. There was no significant difference in 30-day (3.8% vs 0.8%, p = 0.074) or in-hospital mortality (7.6% vs 3.3%, p = 0.082) between groups. The overall (40.9% vs 48.1%, p = 0.235) and cause-specific 5-year survivals (55.4% vs 59.1%, p = 0.688) were comparably good in both groups, but the risk of death due to causes other than esophageal cancer was much higher in the elderly (p = 0.028). Multiorgan dysfunction was an independent predictive factor in elderly patients for overall and medical morbidity, overall survival, and risk of death from causes other than esophageal cancer. CONCLUSIONS: Esophagectomy with three-field lymph node dissection could be carried out safely in patients over 70 years of age with satisfactory long-term results. For elderly patients with multiorgan dysfunction, however, less invasive procedures might be more appropriate.

Clinicopathologic characteristics and survival of patients with clinical Stage I squamous cell carcinomas of the thoracic esophagus treated with three-field lymph node dissection.

OBJECTIVE: Clinicopathologic characteristics and survival rates of patients with clinical Stage I tumors treated with three-field lymph node dissection have not been well investigated. This report documents the results of a series of cases of clinical Stage I squamous cell carcinomas treated with this surgical procedure in our institute. METHODS: From January 1988 to March 1997, 326 patients with carcinomas of the thoracic esophagus underwent transthoracic esophagectomy with three-field lymph node dissection. Two hundred and ninety-seven (91%) of these had squamous cell carcinomas. Fifty-seven (18%) patients with clinical Stage I squamous cell carcinomas of the thoracic esophagus were retrospectively reviewed here. RESULTS: Among 57 clinical Stage I squamous cell carcinomas, ten (18%) were diagnosed as T1-mucosal and 47 (83%) as T1-submucosal. Seventy percent of the patients with clinical T1-mucosal tumors had additional primary esophageal lesions. The operative morbidity and in-hospital mortality rates were 63 and 0%, and the overall 1-, 3-, 5-, and 10-year survival rates were 95, 86, 78, and 70%, respectively. Of the 57 tumors assessed pathologically, 12 (21%) were T1-mucosal, 42 (74%) were T1-submucosal, and three (5%) were T2. Nineteen (33%) exhibited lymph node metastasis. The 1-, 3-, 5-, and 10-year survival rates for patients with lymph node metastasis were 90, 79, 73, and 58%, respectively, as compared with 97, 90, 80, and 76, respectively for patients without lymph node metastasis (P=0.24). The accuracy of preoperative staging, based on both wall penetration and the status regarding lymph node metastasis, was 63%. With reference to the 1997 UICC-TNM staging system, 36 (63%) were pStage I, two (4%) were pStage IIA, 18 (28%) were pStage IIB, and three (6%) were pStage IVB. The 1-, 3-, 5-, and 10-year survival rates for patients with pStage I disease were 97, 92, 85, and 81%, respectively. In those with pStage II or IV disease, the values were 91, 76, 65, and 52%, respectively. CONCLUSIONS: Three-field lymph node dissection may be indicated even for patients with clinical Stage I squamous cell carcinoma requiring surgical intervention because this surgical procedure provides for possible cure by removing unsuspected lymph node metastasis.

Prognostic evaluation for squamous cell carcinomas of the lower thoracic esophagus treated with three-field lymph node dissection.

OBJECTIVE: The efficacy of esophagectomy with three-field lymph node dissection in surgical treatment for patients with squamous cell carcinomas of the lower thoracic esophagus remains controversial. This report documents the outcomes of this surgical procedure for a large series. METHODS: From February 1986 to November 1998, 437 patients with squamous cell carcinomas of the thoracic esophagus underwent transthoracic esophagectomy with three-field lymph node dissection. One hundred and sixteen of these had cancer of the lower thoracic esophagus. To avoid the influence of adjuvant therapy on survival, 20 who also received radiation and/or chemotherapy were excluded, leaving 96 patients who were retrospectively analyzed. RESULTS: The operative morbidity, and 30-day and in-hospital mortality rates were 62, 0, and 3%, respectively. The overall 1-, 3-, and 5-year survival rates were 89, 65, and 59%, with a median survival of 76 months. In those with lymph node metastases (66% of cases), the values were 87, 56, and 48%, as compared with 94, 84, and 79%, respectively (P=0.005) for patients without lymph node metastasis. Factors significantly influencing the overall survival rates were patient age (> or = 65 vs. <65), clinical N status (cN1 vs. cN0), clinical M status (cM1 vs. cM0), longitudinal tumor length of resected specimen (> or =5 vs. <5 cm), pathologic T status (pT3 vs. pT1, 2), pathologic N status (pN1 vs. pN0), lymphatic invasion (positive vs. negative), vascular invasion (positive vs. negative) and intramural metastasis (present vs. absent). Independent prognostic factors for survival determined by multivariate analysis were pathologic T status (P=0.02), pathologic N status (P=0.03), and presence of intramural metastasis (P=0.04). Additional pathologic M1 status, cervical or celiac lymph node metastasis, was without significant influence. CONCLUSIONS: Patients with pathologic T3 tumors with both pathologic N1 status and the presence of intramural metastasis in the lower thoracic esophagus had a poor prognosis. Cervical or celiac lymph node metastasis in patients with carcinomas of the lower thoracic esophagus should be distinguished from pathologic M1 status in the UICC-TNM staging system.

A new approach for posterior mediastinal tumors: thoracoscopic resection in the prone position.

Video-assisted thoracoscopic surgery in the lateral position has been the standard surgical approach for posterior mediastinal tumors. Herein, we report the successful thoracoscopic resection of a posterior mediastinal tumor with the patient in the prone position. The patient was a 62-year-old man with a posterior mediastinal mass. We were able to completely extirpate the posterior mediastinal tumor by means of thoracoscopic resection, with the patient in the prone position, much in the manner of solo surgery. The prone position has the potential to become the standard thoracoscopic surgical approach for posterior mediastinal tumors because it provides excellent exposure of the posterior mediastinum.