Abstract: Esophagectomy performed via thoracotomy is associated with a high rate of postoperative pulmonary complications. Video-assisted thoracoscopic surgery at the esophagus (VATS-E) can reduce the rate of postoperative pulmonary complications. VATS-E is being increasingly implemented owing to its benefits. This procedure makes early patient mobilization possible, because there is minimal thoracic wall invasion, and thus, less postoperative pain. This study aimed to identify the efficacy of early mobilization in patients undergoing VATS-E. We retrospectively reviewed the patients who underwent VATS-E between November 2008 and October 2016. All the patients underwent preoperative physiotherapy and postoperative early mobilization for standard perioperative management. We examined the relation between early mobilization and the factors affecting postoperative pulmonary complications and the duration of physiotherapy with regard to the surgical outcome of VATS-E. A total of 118 patients who underwent VATS-E were assessed. The incidence of postoperative pulmonary atelectasis decreased with early mobilization, and earlier mobilization was associated with a better decrease (P < 0.001). Multiple logistic regression analysis identified the percentage of volume capacity [odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93–0.99] and initial walking (OR 1.82; 95% CI 1.40–2.48) as independent risk factors for postoperative pulmonary atelectasis. In addition, the presence or absence of atelectasis was found to reduce the necessary period of physiotherapy (P < 0.001). Our results indicated that early mobilization reduces the incidence of postoperative pulmonary atelectasis, which may also contribute to early recovery in patients who undergo VATS-E.

Abstract: The p53 protein overexpression that usually results from genetic alterations reportedly induces serum antibodies against p53. However, little information is available about the prognostic significance of perioperative serum p53 antibody (s-p53-Abs) titers in patients with esophageal squamous cell carcinoma. In this study, we retrospectively evaluated the clinical significance of perioperative s-p53-Abs in 135 patients with esophageal squamous cell carcinoma. Of these, 58 patients received neoadjuvant chemotherapy comprising 5-FU and CDDP. While the cutoff level at 1.3 U/ml indicated seropositive patients, level of 13.4 U/ml was used to identify high-titer patients. We monitored serum titers seropositive patients after surgery and evaluated the prognostic significance by the univariate and multivariate analyses. In this study, 29 patients (21.5%) were positive for s-p53-Abs before treatment. The frequency of both seropositive patients and high-titer patients (> 13.4 U/ml) was not significantly associated with tumor progression. While seropositive patients did not demonstrate significant poor overall survival, high-titer patients demonstrated significant poor overall survival based on the multivariate analysis (P < 0.001). Moreover, the s-p53-Abs titer did not correlate with the response to neoadjuvant chemotherapy. Among seropositive patients, the negative conversion of s-p53-Abs more likely led to be long-term survival. This study determined that the high-titer of s-p53-Abs was an independent risk factor to reduce the overall survival of patients with esophageal cancer patients. The negative conversion of s-p53-Abs could be a good indicator of favorable prognosis.

Abstract: Oral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy. We performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system. Fourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade ≥ 2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p = 0.046). An ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study. The date of submission: Dec 08th, 2017.

Abstract: Immunotherapy has become a promising treatment strategy for cancer. Immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types including esophageal squamous cell carcinoma (ESCC). There are several clinical trials using anti-PD1 mAb for ESCC in early phases and the results are currently promising. In this review, recent advances in cancer immunotherapy for ESCC are discussed with particular focus on immune checkpoint inhibitors and cancer vaccine.

Abstract: Esophageal cancer has an aggressive behavior with rapid tumor mass growth and frequently poor prognosis; it is known as one of the most fatal types of cancer worldwide. The identification of potential molecular markers that can predict the response to treatment and the prognosis of this cancer has been subject of a vast investigation in the recent years. Among several molecules, various angiogenic factors that are linked to the tumor development, growth, and invasion, such as VEGF, HGF, angiopoietin-2, IL-6, and TGF-B1, were investigated. In this paper, the authors sought to review the role of these angiogenic factors in prognosis and hypothesize how they can be used as a treatment target.

Abstract: Gastric cancer is the second most common malignancy, overlapping with thoracic esophageal cancer (TEC). Among them, metachronous gastric tube cancers after TEC surgery have been increasing. The aims of this study were to examine the clinicopathological factors and treatment outcomes of gastric tube cancer (GTC) after TEC surgery. Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively. Most cases were males. The median interval from TEC surgery to GTC occurrence was 57 (6.5–107.5) months. Almost 2/3 lesions occurred in the lower third of the gastric tube (21/33); 29 lesions (in 26 cases) were superficial cancers, and 4 lesions were advanced cancers. Twenty-two lesions of superficial cancer were differentiated type, and the remaining seven lesions were undifferentiated type. Treatment for superficial cancer had previously been performed with partial gastric tube resection (10 lesions), and the number of cases undergoing endoscopic submucosal dissection (ESD) had increased recently (19 lesions). Most cases with superficial cancer survived without relapse. Four lesions of advanced cancer were found after a relatively long interval following TEC surgery. Most lesions of advanced cancer were scirrhous, undifferentiated type, and they died due to GTC. GTCs may occur late in the postoperative course following TEC surgery. If they are discovered at an early stage, these lesions can be cured with ESD. Long-term periodic endoscopic examinations after TEC surgery are important.

Abstract: This study aimed to compare the extent of lateral thermal spread of surrounding tissues after the use of advanced bipolar and ultrasonic coagulation and shearing devices. Association between recurrent laryngeal nerve paralysis (RLNP) and such devices was assessed in patients who underwent minimally invasive esophagectomy (MIE). LigaSure™ (LS) and Sonicision™ (SONIC) were used. In ex vivo experiments using the porcine muscle, blade temperature and tissue temperature were measured using a thermometer after the activation of both devices. For the clinical assessment, 46 consecutive patients who received MIE were retrospectively assessed. The temperature generated at the blade of both devices increased with the activation time. The blade temperature of LS was significantly lower than that of SONIC (P < 0.001). The blade temperature of SONIC exceeded 100 °C after 3-s activation. The temperature of surrounding tissues after a single activation of the devices decreased with the tissue distance from activation blade. The temperatures of tissues at 1 and 2 mm away from the blade side of LS were significantly lower than those of SONIC (P = 0.001 and P < 0.001, respectively). The temperature of tissue 2 mm away from the blade side of LS increased 6.4 °C from the baseline temperature. Furthermore, the incidence of RLNP in the LS group was lower than that in the SONIC group (P = 0.044). This study highlights the necessity of spatial and temporal recognition of the thermal spread of coagulation and shearing devices to reduce the thermal injuries following MIE.

Abstract: Recently, definitive chemoradiotherapy (dCRT) has become one of the essential treatment strategies for esophageal squamous cell carcinoma (ESCC) and has been especially gaining prevalence for cervical ESCC to preserve the larynx. Our department recently introduced dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for treating advanced cervical ESCC. This study aims to assess the safety and outcomes of DCF-R in patients with advanced cervical ESCC. We retrospectively assessed 11 patients with advanced cervical ESCC (clinical stage: II–IV, including T4b and/or M1 lymph node) who received DCF-R as the first-line treatment between December 2010 and February 2015. Our patient cohort comprised 8 males and 3 females (median age 68 years; range 54–76 years). The pretreatment clinical stage included stage II (1), stage III (7), and stage IV (3) cases [including 3 patients with T4b (2 trachea and 1 thyroid) and 3 patients with M1 lymph node]. We attained complete response (CR) in 10 patients and stable disease in 1 patient. Of 10 patients with CR, 5 experienced recurrence and 5 continued exhibiting CR. Furthermore, grade 3 or more adverse events included leucopenia (91%), neutropenia (91%), febrile neutropenia (45%), and pharyngeal pain (55%). While the 2-year overall survival rate was 72%, the 2-year recurrent-free survival rate was 64%, respectively. DCF-R treatment for advanced cervical esophageal cancer could be completed by the careful administration; although a strong blood toxicity might occur, this treatment may provide the chance to obtain favorable prognosis with larynx preservation.

Abstract: We determined the serum concentrations of Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) in patients with esophageal squamous cell carcinoma (ESCC) Blood samples were collected from 85 patients with histologically proved ESCC Serum levels of PD-1, PD-L1, and PD-L2 were measured using enzyme linked immunosorbent assays Correlations between serum PD-1, PD-L1, and PD-L2 concentration and tumor depth, number of lymph node metastases, organ metastasis status, or disease stage were assessed and five-year survival rates according to clinicopathological characteristics were calculated The concentration of PD-1 was not differed according to tumor progression On the other hand, the average concentration of PD-L1 in patients with T3/T4 disease was 156 (122–183) pg/mL (25–75%), and this was significantly higher than that in patients with Tis/T1/T2 disease (p = 0020) Similarly, PD-L1 levels were significantly higher in patients with positive lymph nodes than in cases with negative lymph node involvement (p = 0006) and were higher in patients with organ metastasis (p = 0123) and in more advanced stage (p = 0006) Similar tendency was observed regarding PD-L2 concentrations PD-L2 concentration was higher in T3, T4 cases (p = 0008), in LN positive cases (p = 0032), and in more advanced stage (p = 0024) Our data showed that a concentration of PD-L1 in peripheral blood was high in advanced cancer and high concentration of PD-L1 predicted disease progression and also poor survival in patients with ESCC

Abstract: Background Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility and microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients. Methods Forty patients for whom subtotal esophageal resection for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent was obtained: a TJ-100 (15 g/day)-treated group (n = 20) and a control group (n = 20). The primary efficacy end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary efficacy end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery. Results We examined 39 patients because one patient in the TJ-100 group was judged as having unresectable cancer after surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group patients.The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. the control group: 7.0%, p = 0.014), but the serum albumin level was not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group. There was no significant between-group difference in the length of hospital stay after surgery. The serum CRP level at postoperative day 3 was 4.9 mg/dl in the TJ-100 group and 6.9 mg/dl in the control group, showing a tendency of a suppressed serum CRP level in the TJ-100 group (p = 0.126). The rate of increase in adrenomedullin tended to be high postoperatively, but there was no significant difference between the two groups. Conclusions TJ-100 treatment after esophageal cancer resection has the effects of prompting the recovery of gastrointestinal motility and minimizing body weight loss, and it might suppress the excess inflammatory reaction related to surgery.

Abstract: The aim of the study was to assess serum C-reactive protein (CRP) level immediately after minimally invasive esophagectomy (MIE) as a surrogate of surgical invasiveness in patients who underwent esophagectomy. In total, 104 patients were enrolled in the study: 37 patients underwent MIE in the left lateral decubitus position (MIE-LP) and 67 patients underwent MIE in the prone position (MIE-PP). Serum CRP levels were assessed on POD 1, 3, 5, and 7 after MIE, and were compared with surgical outcomes and duration of systemic inflammatory response syndrome (SIRS) to investigate less invasiveness of the MIE. Reduced serum CRP level on POD 1 was associated with PP during MIE (P < 0.001) and decreased blood loss (P = 0.03). MIE-PP was identified as a significant independent predictor of reduced CRP level on POD 1 (odds ratio 3.65, P = 0.042). CRP level on POD 7 was associated with gender (P = 0.02), position of MIE (P = 0.011), blood loss (P = 0.02), and respiratory complications and/or anastomotic leakage (P < 0.001). Postoperative respiratory and/or anastomotic complication was identified as a significant predictor of elevated serum CRP level on POD 7 (odds ratio 3.44, P = 0.048). Shorter duration of SIRS was shown in the patients with reduced serum CRP level on POD 1 and 7 (P = 0.03 and P < 0.001, respectively). Serial assessments of serum CRP level immediately after MIE may be a possible indicator that can reflect surgical invasiveness and postoperative complications.

Abstract: Esophagogastric anastomosis performed after esophagectomy is technically complex and often the source of postoperative complications. The best technique for this anastomosis remains a matter of debate. We describe a new all-stapled side-to-side anastomosis, which we refer to as triple-stapled quadrilateral anastomosis (TRIQ), that can be performed after minimally invasive surgery, and we report results of a retrospective evaluation of postoperative outcomes among the 60 patients in whom this anastomosis has been performed thus far. The anastomosis is created by apposition of the posterior walls of the esophagus and stomach. A linear stapler is applied to create a V-shaped posterior anastomotic wall. The anterior wall is closed in a gentle chevron-like shape with the use of 2 separate linear staplers, resulting in a wide quadrilateral anastomosis. The anastomosis is then wrapped with a greater omentum flap. The patient group comprised 48 men and 12 women with a mean age of 67.8 years. Neoadjuvant chemotherapy was performed in 43 of these patients. Neither the thoracoscopic or laparoscopic procedure was converted to open surgery in any patient. The median operation time was 474 min (range 680–320 min). The intraoperative blood loss volume was 104.4 mL (range 240–30 mL). There were no anastomosis-related complications above Clavien-Dindo grade II. TRIQ can be performed easily and safely, and good short-term outcome can be expected.

Abstract: Although most esophageal non-epithelial tumors are benign tumors, such as leiomyomas, they also include gastrointestinal tumors (GISTs); thus, a histopathological diagnosis is indispensable to determine the optimal treatment strategy. However, no consensus has been reached as to the diagnostic methods and treatments for esophageal non-epithelial tumors. The purpose of this study was to evaluate the reliability of the diagnostic methods and treatments for esophageal non-epithelial tumors in our hospital. All 28 cases of esophageal non-epithelial tumors at Kobe University Hospital from 2008 to 2016 were analyzed retrospectively with respect to the diagnostic methods, histopathological diagnosis, and treatments. Three diagnostic methods, endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA), endoscopic incisional biopsy, and endoscopic submucosal dissection (ESD)/endoscopic mucosal resection (EMR), were performed in our hospital. All GIST cases could be correctly diagnosed by EUS-FNA. Tumors less than approximately 20 mm in diameter and located in the superficial layer are good indications for ESD/EMR, which both play roles in diagnosis and treatment. The final diagnoses by these methods consisted of the following: 13 leiomyomas, 5 GISTs, 3 schwannomas, 2 liposarcomas, 3 cysts, 1 reactive lymphoid hyperplasia, and 1 granulosa cell tumor. Fifteen cases underwent surgery. Enucleation or partial resection was performed for leiomyomas, schwannomas and liposarcomas, while esophagectomy was performed for GISTs. Thus, sufficient management of non-epithelial tumors is achieved. Improved endoscopic procedures, including EUS-FNA and ESD/EMR, enabled the appropriate diagnosis and treatment of esophageal non-epithelial tumors.

Abstract: Most elderly patients poorly tolerate the standard treatment for esophageal cancer; however, little information is available regarding the appropriateness of non-standard esophageal cancer treatments for those patients. This study aims to analyze the treatment costs and completion rates of patients undergoing a real-world treatment for esophageal cancer to elucidate the treatment selection and its quality. We analyzed treatment costs and completion rates for patients with esophageal cancer and analyzed these data relative to patient age and center volumes. Patients with esophageal cancer [UICC, TMN, Clinical stage II/III (excluding T4)] who were diagnosed in 2013 were analyzed. Patients were classified into five groups defined as follows: surgical therapy, chemotherapy, concurrent chemoradiotherapy (CCRT), modified concurrent chemoradiotherapy (mCRT), and radiotherapy (RT). Mean and median age of patients who received surgery and CCRT were comparable; however, patients who underwent mCRT and RT tended to be older. Medical costs associated with surgery were higher than costs associated with other non-surgical treatments. Cost and completion rate of chemoradiotherapy did not differ between CCRT and mCRT; however, both had higher completion rates compared to that of RT. Surgical expenses tended to be the highest in low-volume centers and the lowest in high-volume centers. Treatment of esophageal cancer at high-volume centers seems well balanced compared with medium- to low-volume centers. mCRT was widely performed and comparable in medical cost to CCRT, although additional clinical impacts were unclear.

Abstract: High-resolution manometry (HRM), which is breakthrough testing equipment to evaluate esophageal motor function, was developed in Europe and United State and has garnered attention. Moreover, multichannel intraluminal impedance pH (MII-pH) testing has allowed us to grasp all liquid/gas reflux including not only acid but also non-acid reflux. We examined the impact of the presence of reflux esophagitis (RE) on esophageal motor function before and after laparoscopic fundoplication. The subjects included 100 patients (male: 63 patients, mean age: 54.1 ± 15.8) among 145 patients who underwent laparoscopic fundoplication for GERD associated diseases during a 4-year period from October 2012 to September 2016, excluding 6 patients who underwent further surgery, 32 patients on whom HRM was not performed, 3 patients who had technical errors during testing, and 4 patients for whom the status of RE was unknown. Regarding HRM, Mano Scan from Given Imaging Ltd. was used, and for the analysis, Mano View version 3.0 from the same company was used, after which data was calculated based on the Chicago Classification advocated by Pandolfino et al. Moreover, for the MII-pH testing, Sleuth manufactured by Sandhill Scientific. Inc. was used and automatic analysis was conducted by a computer. Postoperative assessments were conducted 3 months following surgery for all. Data was described in the median value and inter-quartile range, with a statistically significant difference defined as p < 0.05 by Chi square, Mann–Whitney, and Wilcoxon tests. RE+ group (Los Angeles classification A:B:C:D = 7:9:16:12 patients) included 44 patients (44%), of older age compared to the RE− group (62 vs. 50 years, p = 0.012) and a higher Body Mass Index value (24.0 vs. 22.5, p = 0.045); however, no differences were observed in terms of gender and duration of symptoms. In the preoperative findings on MII-pH, the RE+ group demonstrated significantly longer acid reflux time (4.7 vs. 1.3%, p = 0.005), while in the HRM findings, the RE− group demonstrated a significantly longer abdominal esophagus (0 vs. 0.4 cm, p = 0.049) and maintained esophageal body motor function (DCI: 1054 vs. 1407 mmHg s cm, p = 0.021, Intact peristalsis ratio: 90 vs. 100%, p = 0.037). As to the comparison of the treatment effect before and after laparoscopic fundoplication (Toupet fundoplication for all), significant improvements were observed in both groups in various parameters regarding reflux including acid reflux time, total number of liquid reflux episodes and total number of reflux episodes. Moreover, for both groups, the total length of the lower esophageal sphincter (LES) (RE+ group: 2.7 vs. 3.2 cm, p = 0.001, RE− group: 3.0 vs. 3.4 cm, p = 0.003) and the total length of the abdominal esophagus (RE+ group: 0 vs. 1.6 cm, p < 0.001, RE− group: 0 vs. 1.8 cm, p = 0.001) were significantly extended following surgery; however, no change was observed in DCI before and after surgery. Regardless of the presence of RE, cardiac function and LES function were improved following laparoscopic Toupet fundoplication, but no changes were observed in esophageal body motor function.

Abstract: Little is known about hyponatremia in patients with esophageal cancer treated with cisplatin-based chemotherapy. The aim of this study was to analyze the risk factors for hyponatremia and its effect on outcomes in patients with esophageal cancer treated with chemotherapy including cisplatin. We retrospectively analyzed the records of 137 patients with esophageal cancer who received chemotherapy including cisplatin for the first time between January 2011 and December 2014. Hyponatremia (Na < 135 mEq/L) was seen in 77 patients (59%), of whom 29 had Grade 3 (120 ≤ Na < 130 mEq/L) or Grade 4 (Na < 120 mEq/L) hyponatremia. We divided patients into the hyponatremia group (patients with Na < 130 mEq/L) and the control group (patients with Na ≥ 130 mEq/L), and compared the results between the two groups. Three patients (2%) were diagnosed with the syndrome of inappropriate secretion of antidiuretic hormone. The serum sodium level before starting chemotherapy was significantly lower and white blood cell count was significantly higher in the hyponatremia group. Appetite loss was seen significantly more often in the hyponatremia group as the chemotherapy-related adverse effect. There was no significant difference in overall survival between the two groups. Hyponatremia is a common adverse effect induced by cisplatin. Caution should be exercised with patients with a low sodium level before starting chemotherapy. Hyponatremia can be associated with other chemotherapy-related adverse effects, and it should therefore be treated correctly.

Abstract: The aim of this study is to evaluate the anti-inflammatory and anti-fibrotic effects of halofuginone in caustic esophageal burn injury in rats. Corrosive esophageal injury (CEI) was produced in male Wistar albino rats by instilling NaOH solution (1 ml, 37.5%) into the distal esophagus. Rats were decapitated on the 3rd day (early group) or 28th day (late group), and treated daily with either saline or halofuginone (100 µg/kg/day; i.p.), continued on alternate days after the third day. Histopathological evaluation and measurement of nitric oxide (NO), peroxynitrite (ONOO-) and oxygen-derived radicals by chemiluminescence (CL) were made in the distal 2 cm of the esophagus. Non-irrigated proximal esophageal samples were assessed for the levels of nuclear factor (NF)-κB, caspase-3, glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) activity. GSH, MDA, NF-κB and caspase-3 levels, and MPO activity in the proximal esophagus were not different among groups. Increased number of TUNEL (+) cells in the irrigated esophagus of the early and late caustic injury groups was reduced by halofuginone treatment. High microscopic damage scores in both early and late CEI groups were decreased with halofuginone treatment. NO, ONOO- and CL levels, which were elevated in the saline-treated early CEI group, were reduced by halofuginone treatment, but reduced NO and ONOO- levels in the late period of saline-treated group were increased by halofuginone. In addition to its anti-fibrotic effects, current findings demonstrate that halofuginone exerts antioxidant and anti-apoptotic actions and supports therapeutic potential for halofuginone in CEI-induced oxidative stress.

Abstract: The relationship between thymidine phosphorylase (TP) and angiogenesis at the early stage of esophageal squamous cell carcinoma has been unclear. Using 14 samples of normal squamous epithelium, 11 samples of low-grade intraepithelial neoplasia, and 64 samples of superficial esophageal cancer, microvessel density (MVD) was estimated using immunostaining for CD34 and CD105. TP expression was also evaluated in both cancer cells and stromal monocytic cells (SMCs). We then investigated the correlation between MVD and TP expression in both cancer cells and SMCs. On the basis of the above parameters, MVD was significantly higher in cancerous lesions than in normal squamous epithelium. In terms of CD34 and CD105 expression, MVD showed a gradual increase from normal squamous epithelium, to low-grade intraepithelial neoplasia, and then to M1 and M2 cancer, and M3 or deeper cancer. M1 and M2 cancer showed overexpression of TP in both cancer cells and SMCs. There was no significant correlation between TP expression in cancer cells and MVD estimated from CD34 (rS = 0.16, P = 0.21) or CD105 (rS = 0.05, P = 0.68) expression. Significant correlations were found between TP expression in SMCs and CD34-related (rS = 0.46, P < 0.001) and CD105-related (rS = 0.34, P < 0.01) MVD. In M3 or deeper cancers, there were no significant correlations between TP expression in cancer cells or SMCs and venous invasion, lymphatic invasion, and lymph node metastasis. TP expression is activated in both cancer cells and stromal monocytic cells at the very early stage of ESCC progression. TP expression in SMCs, rather than in cancer cells, is significantly correlated with angiogenesis.

Abstract: Balloon dilatation is reportedly less effective for young patients with esophageal achalasia than for older patients. However, there is no consensus on the impact of prior balloon dilatation on outcomes of surgical treatment. This study investigated the significance of preoperative balloon dilatation on surgical outcomes in young patients with esophageal achalasia. Of patients aged less than 40 years who had undergone a laparoscopic Heller–Dor operation for esophageal achalasia, 201 with a postoperative follow-up period of at least 1 year were included. They were divided into two groups with and without a history of balloon dilatation, and compared preoperative pathological conditions and surgical outcomes. This study included 100 men and 101 women with a median age of 31 years, of whom 158 patients without a history of pneumatic dilatation (79%, non-PD group) and 43 with a history of pneumatic dilatation (21%, PD group) The preoperative symptom scores for dysphagia and regurgitation were significantly higher in the non-PD group. Although no differences were observed in surgical outcomes or postoperative course, the esophageal clearance rates calculated on preoperative and postoperative timed barium esophagograms were lower in terms of both height and width of the barium column in the PD group than in the non-PD group. Subjectively, both groups expressed equally high satisfaction. In patients aged less than 40 years with esophageal achalasia, although preoperative balloon dilatation did not affect subjective levels of satisfaction with surgery, postoperative improvement in esophageal clearance in the lower esophagus was inhibited.

Abstract: Besides stricture formation, diminished esophageal motility after caustic esophageal burns also plays a role in the deterioration of the clinical course. In this study, we aimed to investigate the effect of caustic burn on the esophageal contractions and the effect of platelet-rich plasma (PRP) on these changes. Twenty-one Wistar albino rats were divided into three groups [Sham operation (n = 8), caustic esophageal burn with NaOH (n = 6), PRP treatment after caustic burn (n = 7)]. After 3 weeks, esophagectomy was performed and contractions and EFS responses were evaluated in the organ bath. KCl- and acetylcholine-induced responses were reduced in the Burn group, but increased in Sham and PRP groups (p < 0.05). EFS responses were higher in Burn group compared to the other groups. Response with l-arginine was increased in Burn group, but decreased in PRP group. There was more decrease in the contraction in Sham and PRP groups compared to the Burn group after SNP (sodium nitroprusside) incubation (p < 0.05). L-NAME (Nω-Nitro-l-arginine methyl ester) did not change the EFS responses in the Burn group, but EFS responses were decreased significantly in Sham and PRP groups (p < 0.05). EFS responses were decreased in all groups, but more in the Sham and PRP groups after Y-27632 (Rho-kinase inhibitor) incubation (p < 0.05). For the first time, we demonstrated that both cholinergic and non-adrenergic non-cholinergic mechanisms are responsible for the altered motility in corrosive esophageal injury. Our results suggest that PRP treatment may be helpful in regulating the esophageal motility and decreasing altered contractions in corrosive burns. This effect may also contribute to the reduction of stricture formation, especially by reducing inappropriate contractions of the esophageal wall during the post-burn healing phase.

Abstract: For patients with postoperative lymph node (LN) recurrent esophageal cancer, the appropriate irradiation field in chemoradiotherapy (CRT) remains controversial. We assessed the clinical outcomes and prognostic factors related to involved-field CRT for postoperative solitary LN recurrence of esophageal squamous cell carcinoma (ESCC). We retrospectively evaluated 21 patients who had received curative resection, with LN recurrence of ESCC. Patients received CRT using 5-fluorouracil plus cisplatin or docetaxel, prescribed at 60 Gy in 30 fractions. We evaluated the pattern of failure, toxicities, survivals, and prognostic factors. We defined elective nodal failure (ENF) as recurrence in a regional LN without involved-field failure. The median follow-up duration was 32 months (range, 4–106 months). Nine patients experienced failure—4 (19%) within involved-field and 5 (24%) with distant metastasis. No patients had ENF. We observed no severe toxicities. The 2-year overall survival (OS) rate was 78%. In the univariate analysis of OS, two factors, the maximal diameter of the metastatic LN < 25 mm and the absence of serum p53 antibodies (s-p53-Abs), were associated with a significantly better prognosis (p = 0.025 and p = 0.01, respectively). Involved-field CRT for postoperative solitary LN recurrence of ESCC did not cause ENF and was without severe toxicities. Two factors, a length of the metastatic LN < 25 mm and the absence of s-p53-Abs may improve the treatment outcome. Involved-field CRT is a treatment option worthy of consideration for postoperative solitary LN recurrence of ESCC.

Abstract: Cricopharyngeal myotomy with flexible endoscope is a well-known and safe treatment for Zenker’s diverticulum. We describe hereafter how we perform this flexible endotherapy. From January 2011 to January 2017, we treated 28 patients with this endotherapy. Our technique is described step-by-step in the paper: the main principle is to perform an endoscopic cut of the diverticular septum and cricopharyngeal muscle’s fibers (see the video). We describe an objective measurement of the cutting length and depth of the myotomy. Technical success was achieved in all the patients. As to clinical success, 76.2% of patients showed a significant improvement and relevant disappearance of preoperative dysphagia. The present follow-up ranges from 6 months to 5 years. This flexible endoscopic technique can overcome some limitations of rigid endoscopic technique (i.e., upper teeth protrusion, inadequate jaw opening, or limited neck mobility). The main indication was based on clinical presentation and referred to the diverticular dimensions between 2 and 5 cm. Tips for the technique are described in the paper. This variant of cricopharyngeal myotomy with flexible endoscopy is feasible and effective for the treatment of Zenker’s diverticulum in selected patients.

Abstract: The purpose of this study was to investigate modifiable predisposing factors associated with anastomotic leak in the anterior mediastinal (AM) reconstruction route. We reviewed the data on 154 patients who underwent esophagectomy and gastric tube reconstruction using the AM route between 2008 and 2016. The data included computed tomography (CT) scans with sagittal reconstruction of the thoracic section. The level of the esophagogastric anastomosis (LEA) and pretracheal distance (PTD) was measured from sagittal reconstructed CT images. Vascularization of the gastric tube was evaluated by postoperative endoscopy. Variables associated with anastomotic leak were determined using univariate and multivariate analyses. Anastomotic leak developed in 13 patients (8%). The cut-off level at which the anastomosis was less likely to develop a leak, as determined by Chi-square tests, was 1.5 cm for LEA and 1.3 cm for PTD. On univariate analysis, the factors that were significantly associated with the risk of anastomotic leak included diabetes, hand-sewn anastomosis, the LEA ≥ 1.5 cm, and severe mucosal degeneration. On multivariate analysis, diabetes (OR 4.7, 95% CI 1.29–17.2), LEA ≥ 1.5 cm (OR 20.1, 95% CI 3.15–128), and severe mucosal degeneration (OR 7.2, 95% CI 1.42–36.8) were found to be statistically significant independent risk factors. Use of the AM route to place the cervical anastomosis within 1.5 cm above the suprasternal notch might avoid excessive pressure on the gastric tube from the surrounding structures, resulting in a reduction in the risk of an anastomotic leak.

Abstract: We have routinely performed three-dimensional computed tomography (3-D CT) prior to video-assisted transmediastinal esophagectomy to evaluate the small arteries in the mediastinal operative field. This evaluation would be helpful in performing mediastinoscopic esophagectomy. Thirty-one patients who underwent transmediastinal esophagectomy with preoperative evaluations by 3-D CT were the study subject. The bronchial arteries depicted by the 3-D CT were classified by their origin and laterality. In 18 of the 31 cases, the surgical video was available and the identification rate in the video was reviewed for each of the categorized bronchial arteries. The detection rates of each classified artery were as follows (abbreviations, detection rate); the intercostal-bronchial trunk (IBT, 22/31), the direct left bronchial artery (LBA, 17/31), the common trunk of bronchial arteries (CTB, 7/31), the direct right bronchial artery (RBA, 2/31), and the ectopic arteries (16/31). The ectopic arteries arose from the aortic arch (11 cases), the right subclavian artery (6 cases) or the left subclavian artery (1 case). The identification rates of IBT, LBA, CTB, RBA and any of the ectopic arteries in the video review were 12/13, 4/8, 3/4, 1/1 and 2/10, respectively. Preoperative 3-D CT was a highly sensitive evaluation for the bronchial arteries encountered during transmediastinal esophagectomy. Orthotopic arteries except for LBA were frequently identified at the predicted sites. Although RBA and CTB were present infrequently, they often flowed into regional nodes at the bilateral bronchi or the tracheal bifurcation and, therefore, should be preoperatively evaluated.

Abstract: Surgical results of GERD have mainly been reported from the Western countries, with a few reports found in Japan. We examined the surgical results of laparoscopic Toupet fundoplication and clarify the characteristics of recurrent cases. The subjects included 375 patients who underwent laparoscopic Toupet fundoplication from June 1997 to December 2016 as the initial surgery. Patient characteristics, pathophysiology, and surgical results were examined. In addition, we compared the patient characteristics and pathophysiology of recurrent cases in comparison with non-recurrent cases. Age 59 (43–70) and male 211 (56.3%). The operation time was 141 min (113–180) and intraoperative complications were found to have onset in 13 subjects (3.5%). Dysphagia after surgery was found in 18 cases (4.8%). The A factor (the degree of hiatal hernia), P factor (the degree of esophagitis), and pH < 4 holding time significantly improved after surgery compared with prior to surgery (p < 0.001 for all), while the LES lengths and abdominal LES lengths were extended (p < 0.001 for each). Recurrence was found in 48 patients (15.1%) among the 318 patients for whom we could confirm the presence or absence of recurrence. The A factor, P factor, and pH < 4 holding time prior to surgery were, respectively, higher in the recurrence group (p = 0.031, p < 0.001, p < 0.001). Laparoscopic Toupet fundoplication for GERD could be performed safely, with a response rate as good as 85%. Compared with non-recurrent cases, preoperative clinical conditions such as esophageal hiatal hernia, reflux esophagitis, and acid reflux time were all advanced in recurrent cases.

Abstract: We aimed to analyze the clinical and histological effects of chemotherapy in superficial esophageal squamous cell carcinoma (SESCC). We analyzed tumor samples from five patients with cT1bN1M0 who underwent subtotal esophagectomy following two courses of a new triplet chemotherapy regimen including docetaxel, cisplatin, and 5-fluorouracil (DCF). To assess the histological effects of chemotherapy, resected specimens were analyzed by macroscopic examination, hematoxylin & eosin (HE) staining, immunohistochemical (IHC) staining (p53, Ki-67 and cytokeratin) and periodic acid-Schiff (PAS) staining. All five patients had a pathological T stage of T0/1a-LPM/1a-MM/1b (1/2/1/1) and histological grade of grade1a/1b/2/3 (1/1/2/1). Endoscopic examination revealed substantial shrinkage of lugol-voiding lesions (LVLs) in all cases. One case showed complete LVL disappearance, and resected specimen examination confirmed pathological complete response (pCR). IHC and PAS staining revealed that most initial LVLs were PAS-negative. Obvious viable cells were confirmed in two cases. The other three cases exhibited nuclear atypia and strong expression of p53 and Ki-67 in the basal layer of mucosa or lamina propria mucosae, even though the superficial layer of mucosa showed no obvious LVLs with PAS-positive. p53-positive lesions were also observed in Ki-67-positive. This indicated discordance between the endoscopic findings and histopathological evaluation. DCF chemotherapy alone had a substantial therapeutic effect on SESCC in all cases. However, despite the normal appearance of the mucosal surface, viable cancer cells remained below the basal layer of mucosa. Careful attention should be paid when diagnosing clinical CR, or securing a resection margin of SESCC after DCF chemotherapy.

Abstract: The aim of this study was to evaluate the differences in upper gastrointestinal symptoms between generations and genders in relatively healthy Japanese subjects. Altogether, 4086 healthy Japanese male and female (M/F) adults (M/F: 2244/1842) were analyzed. Among them, 3505 subjects (M/F: 1922/1583) were underwent a routine medical checkup at one of five hospitals in Saga, Japan from January 2013 to December 2013. The others were 581 (M/F: 322/259) healthy young volunteers at the Saga Medical School from April 2007 to March 2013. The participants were asked to complete the frequency scale for the symptoms of gastroesophageal reflex disease (FSSG) questionnaire, undergo upper gastrointestinal endoscopy, and submit to a rapid urease test to diagnose Helicobacter pylori infection. Among the 4086 subjects, the 2414 who had no H. pylori infection and no positive endoscopic findings were enrolled in the study. Subjects’ average age was 46.9 ± 12.2 years, with males’ and females’ ages being almost equivalent. The total FSSG score were high in females compared to males (P < 0.01) and decreased significantly with aging (P < 0.05). Among the generations, FSSG scores were the highest for those 20–29 years old, and they were significantly decreased with ageing in both males and females (P < 0.05). The FSSG score was significantly higher in healthy Japanese females than in males, and the scores decreased with aging.

Abstract: This study investigated the long-term risk factors for pneumonia after esophageal reconstruction using a gastric tube via the posterior mediastinal route following esophagectomy for esophageal cancer. The influence of columnar metaplasia in the remnant esophagus was specifically assessed. Among 225 patients who underwent esophagectomy between January 2004 and December 2010, the subjects were 54 patients who could be followed up for more than 5 years. Routine oncologic follow-up consisted of CT scanning of the abdomen and chest every 4–6 months and annual endoscopy. Data on the occurrence of pneumonia were collected by retrospective review of chest CT scans. Risk factors for pneumonia investigated by univariate and multivariate analyses included the age, gender, diameter of the stapler, length of the intrathoracic remnant esophagus, anastomotic stricture, and presence of columnar metaplasia in the remnant esophagus. The median age was 62.4 years (interquartile range: 55.8–68.0 years). Forty-three patients were men. Pneumonia was detected in 39 patients (72.2%). The incidence of columnar metaplasia in the remnant esophagus increases with time. Anastomotic stricture was significantly related to the absence of columnar metaplasia on endoscopy in the first year after esophagectomy (p = 0.013). Univariate analysis showed that the frequency of pneumonia was significantly related to the intrathoracic remnant esophagus length ≥4.4 cm (p = 0.014), age over 65 years (p = 0.014), and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy (p = 0.005). Among them, age over 65 years and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy were found to be independent indicators of the postoperative pneumonia by multivariate analysis. Pneumonia occurred in 72.2% (39/54) of patients after esophagectomy for esophageal cancer. The presence of columnar metaplasia after esophagectomy is an indicator for pneumonia over the long term.

Abstract: I read with interest the paper by Booka et al.: Postoperative delirium after pharyngolaryngectomy with esophagectomy: a role for ramelteon and suvorexant, which has been published in Esophagus. The authors investigated the relationships between sleeping medications and postoperative delirium after pharyngolaryngectomy with esophagectomy. Data from 65 patients were used for the analysis and multiple logistic regression analysis was applied. The number of events was 9 and adjusted odds ratio (95% confidence interval) of ramelteon with or without suvorexant for postoperative delirium was 0.060 (0.0066–0.55) [1]. I have some concerns about their study. First, Hatta et al. conducted a randomized placebo-controlled trial (RCT) on the preventive effects of ramelteon and suvorexant on delirium, respectively [2, 3]. They concluded that ramelteon and suvorexant were effective for the prevention of delirium in the elderly. As their study did not evaluate the combination effect of ramelteon and suvorexant for delirium, further randomized placebo-controlled trial is needed to confirm the causal association. On this point, I appreciate the study design by Booka et al. [1], and the increased number of samples would be needed to construct appropriate statistical model in multiple logistic regression analysis. Relating to the first query, the minimum number of events per independent variable by multiple logistic regression analysis has been considered as 10 to keep statistical power [4, 5]. Booka et al. used 2 independent variables and the minimum number of events should be kept at 20. Although goodness-of-fit of their statistical model was good from the result of Hosmer–Lemeshow’s test, the use of minor tranquilizer should be included into independent variables by summing-up the number of samples and events. Anyway, enough number of samples is required for conducting appropriate risk estimation in multivariate analysis. Second, Scholz et al. conducted a systematic review of risk factors for postoperative delirium among older patients undergoing gastrointestinal surgery [6]. Old age, American Society of Anesthesiologists (ASA) physical status grade at least III, body mass index (BMI), lower serum level of albumin, intraoperative hypotension, perioperative blood transfusion and history of alcohol excess were risk factors. I understand that Booka et al. assessed the relationship between delirium and conventional risk factors including age, BMI, ASA physical status and medical history by univariate analysis. To avoid long duration of hospital stay and death, prevention of postoperative delirium by the combination of ramelteon and suvorexant should be evaluated by RCT procedure.