Masato Nishida

Caspase-3 is activated and rapidly released from human umbilical vein endothelial cells in response to lipopolysaccharide

Endothelial cell injury/dysfunction is considered to play a critical role in the pathogenesis of severe sepsis and septic shock. Although it is considered that endothelial cell apoptosis is involved in endothelial injury/dysfunction, physiological involvement remains ambiguous since the induction of apoptosis requires the inhibition of endogenous apoptosis inhibitors. Here we show that caspase-3 activation, a biological indicator of apoptosis, is observed in response to lipopolysaccharide (LPS) stimulation even under the influence of endogenous apoptosis inhibitors, and that activated caspase-3 is rapidly released from human umbilical vein endothelial cells (HUVEC). In the presence of cycloheximide (CHX), an increase in intracellular caspase-3/7 activity in response to LPS was not detected in HUVEC up to 24 h following stimulation even in the presence of LPS-binding protein (LBP), soluble CD14 and soluble MD-2, whereas the decrease in cell viability and increase in release of the cellular enzyme lactate dehydrogenase (LDH) were observed in a soluble CD14/LBP-dependent manner. On the other hand, even in the absence of CHX, a significant increase in caspase-3/7 activity and a cleaved caspase-3 fragment with a slight increase in LDH release was observed in culture supernatants in response to LPS. This increase in caspase-3/7 activity was observed even when LDH release was undetected. These results indicate that caspase-3 is activated by LPS under physiological conditions and suggest that HUVEC escape from cell death by rapidly releasing activated caspase-3 into extracellular space. Failure of this escape mechanism may result in endothelial injury/dysfunction.

Short-term outcomes of robotic radical esophagectomy for esophageal cancer by a nontransthoracic approach compared with conventional transthoracic surgery.

Summary Transthoracic esophagectomy (TTE) is believed to have advantages for mediastinal lymphadenectomy in the treatment of resectable esophageal cancer despite its association with a greater incidence of pulmonary complications and postoperative mortality. Transhiatal esophagectomy is regarded as less invasive, though insufficient in terms of lymph node dissection. With the aim of achieving lymph dissection equivalent to that of TTE, we have developed a nontransthoracic esophagectomy (NTTE) procedure combining a video‐assisted cervical approach for the upper mediastinum and a robot‐assisted transhiatal approach for the middle and lower mediastinum. We prospectively studied 22 accumulated cases of NTTE and verified feasibility by analyzing perioperative and histopathological outcomes. We compared this groups short‐term outcomes with outcomes of 139 equivalent esophageal cancer cases operated on at our institution by conventional TTE (TTE group). In the NTTE group, there were no procedure‐related events and no midway conversions to the conventional surgery; the mean operation time was longer (median, 524 vs. 428 minutes); estimated blood loss did not differ significantly between the two groups (median, 385 mL vs. 490 mL); in the NTTE group, the postoperative hospital stay was shorter (median, 18 days vs. 24 days). No postoperative pneumonia occurred in the NTTE group. The frequencies of other major postoperative complications did not differ significantly, nor were there differences in the numbers of harvested mediastinal lymph nodes (median, 30 vs. 29) or in other histopathology findings. NTTE offers a new radical procedure for resection of esophageal cancer combining a cervical video‐assisted approach and a transhiatal robotic approach. Although further accumulation of surgical cases is needed to corroborate these results, NTTE promises better prevention of pulmonary complications in the management of esophageal cancer.

Rapid and sensitive detection of early esophageal squamous cell carcinoma with fluorescence probe targeting dipeptidylpeptidase IV

Early detection of esophageal squamous cell carcinoma (ESCC) is an important prognosticator, but is difficult to achieve by conventional endoscopy. Conventional lugol chromoendoscopy and equipment-based image-enhanced endoscopy, such as narrow-band imaging (NBI), have various practical limitations. Since fluorescence-based visualization is considered a promising approach, we aimed to develop an activatable fluorescence probe to visualize ESCCs. First, based on the fact that various aminopeptidase activities are elevated in cancer, we screened freshly resected specimens from patients with a series of aminopeptidase-activatable fluorescence probes. The results indicated that dipeptidylpeptidase IV (DPP-IV) is specifically activated in ESCCs, and would be a suitable molecular target for detection of esophageal cancer. Therefore, we designed, synthesized and characterized a series of DPP-IV-activatable fluorescence probes. When the selected probe was topically sprayed onto endoscopic submucosal dissection (ESD) or surgical specimens, tumors were visualized within 5 min, and when the probe was sprayed on biopsy samples, the sensitivity, specificity and accuracy reached 96.9%, 85.7% and 90.5%. We believe that DPP-IV-targeted activatable fluorescence probes are practically translatable as convenient tools for clinical application to enable rapid and accurate diagnosis of early esophageal cancer during endoscopic or surgical procedures.

Technical details of video-assisted transcervical mediastinal dissection for esophageal cancer and its perioperative outcome

To reduce pulmonary complications after esophagectomy, the transthoracic procedure should be shortened or totally avoided. Transcervical approach assisted by mediastinoscope for the upper mediastinum may be advantageous for this purpose. We carried out video‐assisted transcervical mediastinal dissection (VATCMD) as part of totally non‐transthoracic radical esophagectomy. A single‐port laparoscopy device was adopted to a small cervical incision and the mediastinum was inflated with a positive pressure of 6 to 10 mmHg. Without assistants retractor, the upper mediastinum and partially the middle mediastinum were dissected mainly by mediastinoscopic‐assisted surgery. Video of the operation is demonstrated with illustrations. We have carried out and reported 17 cases of esophagectomy including VATCMD and its perioperative outcome. Non‐transthoracic esophagectomy was completed without conversion to transthoracic procedure in all 17 cases. Procedure‐related adverse event was not observed and postoperative course was favorable with a zero occurrence (0%) of recurrent laryngeal nerve palsy, chyle leakage or pulmonary complications. Median number of harvested lymph nodes from the upper mediastinal stations was 10. VATCMD is suggested as a safe and feasible approach for the upper mediastinum in esophagectomy for malignancies. It enabled a totally non‐transthoracic radical esophagectomy in combination with a transhiatal approach.

Numeric pathologic lymph node classification shows prognostic superiority to topographic pN classification in esophageal squamous cell carcinoma

Background. The current eighth tumor node metastasis lymph node category pathologic lymph node staging system for esophageal squamous cell carcinoma is based solely on the number of metastatic nodes and does not consider anatomic distribution. We aimed to assess the prognostic capability of the eighth tumor node metastasis pathologic lymph node staging system (numeric‐based) compared with the 11th Japan Esophageal Society (topography‐based) pathologic lymph node staging system in patients with esophageal squamous cell carcinoma. Methods. We retrospectively reviewed the clinical records of 289 patients with esophageal squamous cell carcinoma who underwent esophagectomy with extended lymph node dissection during the period from January 2006 through June 2016. We compared discrimination abilities for overall survival, recurrence‐free survival, and cancer‐specific survival between these 2 staging systems using C‐statistics. Results. The median number of dissected and metastatic nodes was 61 (25% to 75% quartile range, 45 to 79) and 1 (25% to 75% quartile range, 0 to 3), respectively. The eighth tumor node metastasis pathologic lymph node staging system had a greater ability to accurately determine overall survival (C‐statistics: tumor node metastasis classification, 0.69, 95% confidence interval, 0.62–0.76; Japan Esophageal Society classification; 0.65, 95% confidence interval, 0.58–0.71; P = .014) and cancer‐specific survival (C‐statistics: tumor node metastasis classification, 0.78, 95% confidence interval, 0.70–0.87; Japan Esophageal Society classification; 0.72, 95% confidence interval, 0.64–0.80; P = .018). Rates of total recurrence rose as the eighth tumor node metastasis pathologic lymph node stage increased, while stratification of patients according to the topography‐based node classification system was not feasible. Conclusion. Numeric nodal staging is an essential tool for stratifying the oncologic outcomes of patients with esophageal squamous cell carcinoma even in the cohort in which adequate numbers of lymph nodes were harvested.

Quality of life after robot-assisted transmediastinal radical surgery for esophageal cancer

BackgroundThe aim of this retrospective study was to assess postoperative quality of life (QOL) after robot-assisted radical transmediastinal esophagectomy, defined as a nontransthoracic esophagectomy with radical mediastinal lymphadenectomy combining a robotic transhiatal approach and a video-assisted cervical approach. The results were compared to those of transthoracic esophagectomy.MethodsIn this study, all consecutive patients who underwent robot-assisted radical transmediastinal esophagectomy or transthoracic esophagectomy for esophageal cancer at University of Tokyo between January 2010 and December 2014 were included. The European Organization for Research and Treatment of Cancer (EORTC)’s quality of life questionnaires QLQ-C30 and QLQ-OES18 were sent to all patients that were still living, had no recurrence or other malignancy, and had not undergone a reoperation because of complications after esophagectomy.ResultsWe were able to survey 63 (98.4%) of 64 eligible patients. We assessed and compared the QOL scores of both groups of patients. Compared to transthoracic esophagectomy, transmediastinal esophagectomy was associated with better QOL. Global health status and the physical, role, and cognitive function scale scores were significantly superior in the transmediastinal esophagectomy group (P = 0.004, < 0.0001, 0.007, 0.002, respectively). Fatigue, nausea and vomiting, pain, appetite loss, reflux, and taste scores were significant lower (superior) in the transmediastinal esophagectomy group (P = 0.003, 0.032, 0.025, 0.018, 0.001, 0.041, respectively).ConclusionsThis study indicates that robot-assisted radical transmediastinal esophagectomy is associated with better postoperative QOL compared to transthoracic esophagectomy. A larger study and prospective analyses are needed to confirm the current results.

Mediastinoscopic view of the bronchial arteries in a series of surgical cases evaluated with three-dimensional computed tomography

BackgroundWe 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.MethodsThirty-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.ResultsThe 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.ConclusionsPreoperative 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.

Giant Brunner's gland adenoma of the duodenum manifested by melena

A 41-year-old Japanese man without any remarkable medical history visited a clinic with a complaint of melena. Esophagogastroduodenoscopy demonstrated a large polypoid mass arising from the anterior wall of the duodenal bulb. He was referred to our hospital for further assessment and treatment. Laboratory tests indicated mild anaemia with a haemoglobin level of 12.7 g/dL. The duodenal mass was, on esophagogastroduodenoscopy, a bulky tumour with superficial ulceration (Fig. 1). Repetitive endoscopic biopsies failed to prove any tumourous components, only finding non-atypical hyperplastic epithelium with mild inflammation. Computed tomography and magnetic resonance imaging with intravenous contrast exhibited a large pedunculated tumour occupying the first part of the duodenum. Endoscopic excision seemed unfeasible considering the tumour volume and we thus opted surgical resection for pathological diagnosis and treatment of potential bleeding and obstruction. A longitudinal duodenotomy facilitated to identify the tumour after the duodenum was well-lifted medially by Kocher’s manoeuvre (Fig. 2), and it was successfully removed by local resection of the duodenum. The resected specimen, measured 40 × 31 × 23 mm, was histopathologically diagnosed as Brunner’s gland adenoma (BGA)/hyperplasia without malignant components (Fig. 3). The tumour was characterized by Brunner’s gland proliferation, ducts embedded in fibrous stroma with focal infiltration of mononuclear cells. The surgical margins were negative for the tumour. BGA is a benign tumour of the duodenum; its incidence was reportedly estimated to be 0.008% in an analysis of 215 000 autopsies. Endoscopic appearance of BGA is classically presented as being pedunculated and located in the duodenal bulb. BGA is generally asymptomatic, incidentally found on endoscopic screening, and rarely intended to be a surgical issue. We should keep in mind, however, that a large-sized BGA can cause haemorrhage, as well as gastric outlet obstruction, biliary obstruction and/or pancreatitis. Furthermore, even though extremely rare, malignant transformation of BGA has been documented previously in two case reports. Typical BGAs are located in the submucosal layer and endoscopic biopsies hence show negative findings in the vast majority as in our case. Fine-needle aspiration under guidance of endoscopic ultrasound is also controversial because BGA is often too small to conduct accurate puncture on: the majority of BGA measure less than 2 cm in diameter. Taken

Efficacy of trastuzumab beyond progression as second-line chemotherapy for HER2-positive advanced gastric cancer

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Case Report: Repetitive Surgical Resections for Intestinal Intussusception due to Multiple Ileal Lipomatosis

Adult intestinal intussusception is a rare disease known to be associated with intestinal tumors. We describe a case requiring partial ileal resection in 2 occasions due to intussusception from multiple lipomatosis. A 45-year-old Japanese man was referred to our hospital for detailed examination after positive fecal blood test results and intermittent abdominal pain. He was diagnosed with intussusception of the ileum due to multiple lipomatosis and underwent partial ileal resection. Three years after the first surgery, he again experienced intermittent abdominal pain and nausea, and was referred to our department. Contrast-enhanced computed tomography at this time also showed intussusception near the ileocecal valve, with several fat-density tumors. He underwent partial ileal resection as an emergency surgery, with the histologic diagnosis confirming ileal multiple lipomatosis. Repeated surgical resections are sometimes required for patients with intestinal intussusception due to lipomatosis, since lipoma...