The Present Status and Future of Barrett's Esophageal Adenocarcinoma in Japan.

BACKGROUND: The incidence of esophageal adenocarcinoma in Europe and the United States rapidly increased from the latter half of the 1970s and exceeded that of esophageal squamous cell carcinoma in the latter half of the 1990s, currently accounting for approximately 60% of all esophageal carcinomas. Recently, its incidence has also increased in Japan, raising concerns that it will follow a course similar to that in Europe and the United States. SUMMARY: The incidence of esophageal adenocarcinoma in Japan was about 2% until the 1990s, but in recent years, it has risen to 6.5-7.1%. Causes include the increase in the incidence of obesity due to changes in eating habits with resultant increases in the incidence of hiatal hernia and reflux esophagitis, a decrease in the rate of Helicobacter pylori infection, and the increased interest of physicians in the gastroesophageal junction. The number of gastroesophageal reflux disease patients in Japan rapidly increased from the 1990s, which accordingly increased the number of Barrett's esophageal adenocarcinoma patients from the latter half of the 1990s. Tabulation and analysis of 1,794 reported cases of Barrett's esophageal adenocarcinoma in Japan showed that superficial cancers accounted for 77.6%, and that the concomitant rates of hiatal hernia and reflux esophagitis were high at 87 and 70% respectively. Key Message: The future trend in the incidence of Barrett's esophageal adenocarcinoma in Japan will depend on the increase in the incidence of reflux esophagitis, which is essential for the development of Barrett's esophagus and Barrett's esophageal carcinoma. The obesity rate is lower in Japan than that in Europe and the United States, and the incidence and severity of reflux esophagitis are low. We expect that the incidence of Barrett's esophageal adenocarcinoma in Japan will not rise as high as in Europe and the United States, and will remain below 10%.

Thoracoscopic esophagectomy while in a prone position for esophageal cancer: a preceding anterior approach method.

BACKGROUND: In 2009, the rate of thoracoscopic esophagectomy for esophageal cancer was about 20% in Japan. This low rate may be due to the difficulty in maintaining a good surgical field and the meticulous procedures that are required. The purpose of this study was to establish and evaluate a new procedure for performing a thoracoscopic esophagectomy while the patient is in a prone position using a preceding anterior approach to make the esophagectomy easier to perform. METHODS: We have performed thoracoscopic esophagectomy using our new procedure in 60 patients with esophageal cancer. Each patient was placed in a prone position and five trocars were inserted; only the left lung was ventilated and a pneumothorax was maintained. The esophagus was mobilized from the anterior structure during the first step and from the posterior structure during the second step. The lymph nodes around the esophagus were also dissected anteriorly and posteriorly. The patients were sequentially divided into two groups and their clinical outcomes were evaluated. RESULTS: The mean operative time for the thoracoscopic procedure for the latter 30 cases (203 min) was shorter than that for the former 30 cases (260 min) (P = 0.001). Among the 52 cases without pleural adhesion, the mean blood loss in the latter 26 cases (18 mL) was also less than that in the former 26 cases (40 mL) (P = 0.027). There were no conversions to a thoracotomy and no operative deaths in this series. Postoperative complications related to the thoracoscopic procedure occurred in 8 cases (27%) in the former group and in 4 cases (13%) in the latter group. CONCLUSIONS: Thoracoscopic esophagectomy with the patient in the prone position using a preceding anterior approach is a safe and feasible procedure. As experience performing the procedure increases, the performance of the procedure stabilizes. This method seems to make the esophagectomy easier to perform.

[Recent advances in endoscopic resection for esophageal cancer].

The indications for endoscopic resection (ER) in esophageal cancer are limited to cases without lymph node metastasis because it is a local therapy. The relationship between cancer depth and lymph node metastasis has been clarified according to the pathologic analysis of lymph nodes removed during esophagectomy for early esophageal cancer. Cancer invasion remaining in the lamina propria mucosa rarely metastasizes to the lymph nodes, and ER is thus indicated. ER allows the esophagus to be preserved and is less invasive, enabling the specimen to be examined pathologically. Lesions extending to a large area can be resected by repeated endoscopic mucosal resection (EMR), but have recently been resected en bloc in the endoscopic submucosal dissection (ESD) procedure, which is also indicated for the treatment of gastric cancer. The selection of EMR or ESD depends on the size of the lesion, the technique of the surgeon, the time the patient can safely spend under anesthesia, and economic management. ER is now employed in T1a-MM, SM1 cases without lymph node metastasis, although some require additional treatment including surgery after pathologic examination of the resected lesions.

Distal gastric tube resection with preservation of the right gastroepiploic artery for gastric tube cancer: a case report.

BACKGROUND: The incidence of gastric tube cancer is increasing because of improved survival rates in patients with esophageal cancer treated by esophagectomy. Total resection of the gastric tube is expected to be highly curative, but it is associated with a higher risk of severe postoperative complications. Herein we report a case of early gastric tube cancer that was successfully treated by distal gastric tube resection with preservation of the right gastroepiploic artery (RGEA). CASE PRESENTATION: An 82-year-old man was diagnosed as having gastric tube cancer, B-12-O, Type 0-IIc, T1b, N0, M0, cStage IA (Japanese Classification of Gastric Carcinoma). Upper gastrointestinal endoscopy showed a Type 0-IIc lesion measuring 30 mm in length in the lower part of the gastric tube, and histopathological examination of biopsy specimens revealed the features of poorly differentiated adenocarcinoma. The primary lesion could not be identified by computed tomography, and there was no obvious lymph node metastasis or distant metastasis. Considering that total resection of the gastric tube would have been highly invasive and that the gastric tube cancer was at a relatively early stage, we performed distal gastric tube resection with preservation of the RGEA. The postoperative course was uneventful, and the patient was discharged on postoperative day 12. There has been no recurrence during the 17 months of follow-up. CONCLUSION: We successfully treated a patient with gastric tube cancer by distal gastric tube resection with preservation of the RGEA. This treatment strategy may be acceptable for patients with early gastric tube cancer without lymph node metastasis, considering the balance between the surgical invasiveness and curability of the tumor.

Spatially restricted substrate-binding site of cortisol-synthesizing CYP11B1 limits multiple hydroxylations and hinders aldosterone synthesis.

Human cytochromes P45011ß (CYP11B1) and P450aldo (CYP11B2) are monooxygenases that synthesize cortisol through steroid 11ß-hydroxylation and aldosterone through a three-step process comprising 11ß-hydroxylation and two 18-hydroxylations, respectively. CYP11B1 also catalyzes 18-monohydroxylation and 11ß,18-dihydroxylation. To study the molecular basis of such catalytic divergence of the two enzymes, we examined a CYP11B1 mutant (Mt-CYP11B1) with amino acid replacements on the distal surface by determining the catalytic activities and crystal structure in the metyrapone-bound form at 1.4-Å resolution. Mt-CY11B1 retained both 11ß-hydroxylase and 18-hydroxylase activities of the wild type (Wt-CYP11B1) but lacked 11ß,18-dihydroxylase activity. Comparisons of the crystal structure of Mt-CYP11B1 to those of Wt-CYP11B1 and CYP11B2 that were already reported show that the mutation reduced the innermost space putatively surrounding the C3 side of substrate 11-deoxycorticosterone (DOC) bound to Wt-CYP11B1, while the corresponding space in CYP11B2 is enlarged markedly and accessible to bulk water through a channel. Molecular dynamics simulations of their DOC-bound forms supported the above findings and revealed that the enlarged space of CYP11B2 had a hydrogen bonding network involving water molecules that position DOC. Thus, upon positioning 11ß-hydroxysteroid for 18-hydroxylation in their substrate-binding sites, steric hindrance could occur more strongly in Mt-CYP11B1 than in Wt-CYP11B1 but less in CYP11B2. Our investigation employing Mt-CYP11B1 sheds light on the divergence in structure and function between CYP11B1 and CYP11B2 and suggests that CYP11B1 with spatially-restricted substrate-binding site serves as 11ß-hydroxylase, while CYP11B2 with spatially-extended substrate-binding site successively processes additional 18-hydroxylations to produce aldosterone.

Coexistence of gastric cancer and gastric GIST with intra-tumor bleeding: successful embolization with subsequent total gastrectomy.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare tumor, however, simultaneous development of gastric cancer and gastric GIST has been documented more frequently in recent years. Rupture of gastric GIST is even more rare and occurred in 7% of all GISTs. Although ruptured GIST might be occasionally difficult to be managed by endoscopy, transcatheter arterial embolization (TAE) was reported to control bleeding from GIST effectively. We report herein a case of coexistence of gastric cancer and gastric GIST with progressing intra-tumor bleeding managed successfully by TAE and review the clinicopathological characteristics of this rare condition reported previously in the Japanese literature. CASE PRESENTATION: A 75-year-old woman with dyspnea and systemic edema was diagnosed as simultaneous occurrence of gastric cancer (histopathologically detected tubular adenocarcinoma pT2N1M0 fStageIIA) and gastric GIST (65 × 92 mm in diameter at the anterior wall of the fornix) with intra-tumor hemorrhage. Perceiving the progress of bleeding from tumor growth and exacerbating anemia, TAE of left gastric artery was performed. Then remission of anemia has been obtained, the patient underwent an elective radical surgery. CONCLUSIONS: Simultaneous occurrence of gastric cancer and gastric GIST was speculated to be more common. TAE for ruptured GIST may be effective for hemostasis and reduction of tumor burden, which could facilitate minimal invasive surgery.

Cell-free synthesis of cytochrome c oxidase, a multicomponent membrane protein.

Cell-free protein synthesis is a useful technique that can site-specifically incorporate isotope-labeled amino acids into proteins. This incorporation is essential for infrared analyses of the electronic state of a specific amino acid residue used to elucidate protein function. Although 17 membrane proteins have been synthesized in their active state by cell-free systems, to date no hetero-subunit protein has been synthesized with this technique, suggesting that there are serious technical limitations. Here we report the cell-free synthesis of Paracoccus denitrificans cytochrome c oxidase, a membrane protein complex composed of three distinct subunits that contain two heme A molecules and two redox-active copper centers. The synthesized protein exhibited normal Soret/vis absorption spectra and ferrocytochrome c oxidation activity.

A role of the heme-7-propionate side chain in cytochrome P450cam as a gate for regulating the access of water molecules to the substrate-binding site.

Cytochrome P450cam is a heme-containing enzyme which catalyzes hydroxylation of d-camphor. The heme is bound in the heme pocket via noncovalent interactions, where two heme-propionate side chains interact with Arg, His, and/or Asp residues. To understand the role of the heme-7-propionate side chain, we prepared reconstituted P450cam with an artificial one-legged heme which has a methyl group at the position of the 7-propionate. Removal of 7-propionate dramatically decreases the d-camphor affinity by 3 orders of magnitude relative to that of the wild-type enzyme, and spectroscopic data indicate that 74% of the ferric P450cam exhibits a low-spin state owing to water molecule occupancy in the substrate-binding site under the normal assay conditions. Thus, the monooxygenase activity of the reconstituted protein is remarkably low due to the decrease in the rate of the first electron transfer from reduced putidaredoxin, whereas 87% of oxidized NADH was utilized to produce 5-hydroxy-d-camphor without any significant uncoupling reactions. X-ray structural analysis of the reconstituted enzyme reveals a novel water array extending from the substrate-binding site to bulk solvent through the position occupied by 7-propionate. This water array appears without causing any major changes in the protein structure with the notable exception of conformational changes occurring at Asp297 and Gln322 residues. We propose that the 7-propionate forms a barrier against entry of bulk water molecules and therefore in combination with Asp297, Arg299, and Gln322 plays an essential role in the process of elimination of the substrate-binding site water cluster which occurs upon d-camphor binding.

Substrate binding induces structural changes in cytochrome P450cam.

The binding of (+)-camphor to cytochrome P450cam (P450cam) expels a cluster of waters at the active site, raising the redox potential of the haem to an extent that allows reduction by the electron-transfer system. This binding was reported to involve no significant structural changes in the protein. Here, two ferric P450cam structures partially complexed with (+)-camphor were determined by X-ray crystallography at 1.30-1.35 A resolution, revealing the structures of the substrate-free and substrate-bound forms. (+)-Camphor binding induces rotation of Thr101 to form a hydrogen bond that acts as a hydrogen donor to a peripheral haem propionate. This bonding contributes to the redox-potential change.

Red-excitation resonance Raman analysis of the nu(Fe=O) mode of ferryl-oxo hemoproteins.

The Raman excitation profile of the nuFe O mode of horseradish peroxidase compound II exhibits a maximum at 580 nm. This maximum is located within an absorption band with a shoulder assignable to an oxygen-to-iron charge transfer band on the longer wavelength side of the alpha-band. Resonance Raman bands of the nuFe O mode of various ferryl-oxo type hemoproteins measured at 590 nm excitation indicate that many hemoproteins in the ferryl-oxo state have an oxygen-to-iron charge transfer band in the visible region. Since this red-excited resonance Raman technique causes much less photochemical damage in the proteins relative to blue-excited resonance Raman spectroscopy, it produces a higher signal-to-noise ratio and thus represents a powerful tool for investigations of ferryl-oxo intermediates of hemoproteins.

[Recent advances of endoscopic treatment for esophageal cancer].

The indications for endoscopic treatment are limited to cases without lymph node metastasis, because it is only a local therapy. The relationship between cancer depth and lymph node metastasis has been clarified based on the pathologic analysis of lymph nodes removed during esophagectomy for early esophageal cancer. Cancer confined to the lamina propria mucosa rarely undergoes lymph node metastasis and complete endoscopic resection (ER) is indicated. ER allows the esophagus to be preserved and is less invasive, enabling specimens to be pathologically examined. Lesions extending over large area can be resected by repeating endoscopic mucosal resection (EMR), but have recently been resected using endoscopic submucosal dissection (ESD), as indicated for gastric cancer. Which of the two procedures, EMR or ESD, to be chosen depends on the difficulty, skill of the surgeon, time to be spared, and economic management. ER is now performed in SM1 without lymph node metastasis, although some patients require additional treatment after pathologic examination of resected lesions.

Single-center analysis of appendiceal neoplasms.

The purpose of the present study was to evaluate the recent trend of diagnosing appendiceal diseases through the analysis of appendectomy materials, stressing the importance of their pathological examination. A clinicopathological assessment of patients undergoing an appendectomy was conducted, based on the pathological examination of resected appendiceal lesions. Using a pathological database of surgical specimens from patients who underwent an appendectomy between March 2002 and September 2014, a retrospective, single-center analysis was performed. Among the 803 patients identified, 752 with appendiceal disease were selected for clinicopathological analysis. The diagnosis was inflammation (i.e. appendicitis) in 97.7% (n=735) and appendiceal neoplasm in 2.3% (n=17) of the patients. The most frequent type of appendiceal neoplasm was an intramucosal neoplasm (23.5%, n=4). In conclusion, the incidence of appendiceal neoplasms has increased in recent years, potentially due to increased and earlier detection by newer imaging modalities.

Perforated gastrointestinal stromal tumor in the small intestine: A rare case of Torricelli-Bernoulli sign.

The Torricelli-Bernoulli sign is a computed tomography (CT) finding that occurs when ulceration/necrosis of a submucosal gastrointestinal tumor releases a stream of air bubbles into the intestinal lumen. A 75-year-old man developed acute abdominal pain at night and presented to a local doctor. Acute abdomen was diagnosed and he was referred to the Emergency Department at Tokai University Oiso Hospital. On CT scans, disseminated intestinal tumor-like lesions were seen in the right lower abdomen. The Torricelli-Bernoulli sign and free intraabdominal gas were observed, so perforation of an intestinal tumor was diagnosed and emergency surgery was performed. At operation, there was scanty opaque ascites in the right lower abdomen and an ileal tumor associated with nodules that suggested peritoneal dissemination. Partial resection of the ileum was performed and peritoneal lavage was conducted. The patient was discharged on postoperative day 11. Histopathological examination revealed a high risk gastrointestinal stromal tumor. The abdominal nodules were metastases, indicating that the tumor was Stage IV. The patient is currently on treatment with an oral tyrosine kinase inhibitor (imatinib).

Reaction mechanism of bovine heart cytochrome c oxidase.

The 1.9 A resolution X-ray structure of the O2 reduction site of bovine heart cytochrome c oxidase in the fully reduced state indicates trigonal planar coordination of CuB by three histidine residues. One of the three histidine residues has a covalent link to a tyrosine residue to ensure retention of the tyrosine at the O2 reduction site. These moieties facilitate a four electron reduction of O2, and prevent formation of active oxygen species. The combination of a redox-coupled conformational change of an aspartate residue (Asp51) located near the intermembrane surface of the enzyme molecule and the existence of a hydrogen bond network connecting Asp51 to the matrix surface suggest that the proton-pumping process is mediated at Asp51. Mutation analyses using a gene expression system of the Asp51-containing enzyme subunit yield results in support of the proposal that Asp51 plays a critical role in the proton pumping process.

Proton pumping mechanism of bovine heart cytochrome c oxidase.

X-ray structures of bovine heart cytochrome c oxidase at 1.8/1.9 A resolution in the oxidized/reduced states exhibit a redox coupled conformational change of an aspartate located near the intermembrane surface of the enzyme. The alteration of the microenvironment of the carboxyl group of this aspartate residue indicates the occurrence of deprotonation upon reduction of the enzyme. The residue is connected with the matrix surface of the enzyme by a hydrogen-bond network that includes heme a via its propionate and formyl groups. These X-ray structures provide evidence that proton pumping occurs through the hydrogen bond network and is driven by the low spin heme. The function of the aspartate is confirmed by mutation of the aspartate to asparagine. Although the amino acid residues of the hydrogen bond network and the structures of the low spin heme peripheral groups are not completely conserved amongst members of the heme-copper terminal oxidase superfamily, the existence of low spin heme and the hydrogen bond network suggests that the low spin heme provides the driving element of the proton-pumping process.

Clinical analysis of reflux esophagitis following esophagectomy with gastric tube reconstruction.

BACKGROUND: Recently, the rate of postoperative long-term survival has increased in cases of esophageal cancer. We report on our analysis of postoperative reflux esophagitis (RE) at Tokai University. METHODS: We enrolled 48 patients who underwent gastric tube reconstruction after esophagectomy. The diagnosis of RE was confirmed by endoscopy. RESULTS: Of the 48 patients, 28 (58.3%) were found to have RE. Among the 28 patients with RE, only four (14.3%) reported symptoms. The distribution of the severity of RE according to the Los Angeles classification in the patients was as follows: grade M, 1 (3.6%); grade A, 2 (7.1%); grade B, 6 (21.4%); grade C, 17 (60.7%); and grade D, 2 cases (7.1%). Barrett's epithelium was detected in 9 of the 28 patients (31%) with RE and in 3 of the 20 (15%) patients with no evidence of RE. CONCLUSIONS: To detect the presence of RE as well as monitor for recurrence and development of metachronous cancer, we consider it important to perform endoscopy regularly over the long term. As Barrett's epithelium is frequently encountered, care should be exercised to detect the specialized columnar epithelium showing dysplastic changes.

Pulmonary artery hypoplasia associated with posterior mediastinal hematoma accompanied by a ruptured pseudoaneurysm of the esophageal branch of the left gastric artery.

A 65-year-old woman with no significant medical history visited the emergency department complaining of epigastric discomfort. A computed tomography of the thorax and abdomen showed the attenuation of the pulmonary artery and a posterior mediastinal hematoma. Angiography showed a tortuous esophageal branch of the left gastric artery and a pseudoaneurysm, and during the later phase, the left lower lobe of the lung was enhanced, and finally, the left pulmonary vein was enhanced. We considered that the patient was exhibiting hypoperfusion of the left pulmonary artery arising from left pulmonary artery hypoplasia, since the left lung was supplying the systemic circulation. Transcatheter arterial embolization was performed. The patient has not experienced any recurrence of a ruptured pseudoaneurysm or epigastric discomfort. Here, we report the first documented case of pulmonary artery hypoplasia associated with posterior mediastinal hematoma accompanied by a ruptured aneurysm of the left gastric artery.

Expandable Metallic Stent for Endobronchial Metastasis from Colorectal Cancer: Reports of 2 Cases.

In recent years, there have been many reports about the efficacy of stenting for central bronchial stenosis. When central bronchial stenosis is due to metastasis of a malignant tumor to the trachea and/or bronchi (endobronchial metastasis: EM), it is classified as "narrow EM" and "broad EM." [1] We managed two patients in whom bilateral stent placement was required for narrow and broad EM arising from colorectal cancer. Case 1: In September 2011, a 66-year-old man underwent low anterior resection for advanced colorectal cancer associated with unresectable liver metastasis. The liver metastasis became resectable after chemotherapy, with two resection procedures and radiofrequency ablation (RFA) being performed. Thereafter, lung metastasis occurred and a tumor in the left lung was resected. In May 2015, he developed respiratory distress. CT identified multiple lesions protruding into the lumen of the trachea and the left and right main bronchi. There was no evidence of mediastinal relapse or local relapse at the resection margin, and tumors were only detected in the tracheobronchial walls. Accordingly, narrow EM was diagnosed. An expandable metallic stent (EMS) was placed on the right side where stenosis was more severe, and radiation therapy was conducted for the non-stented tumors. The patient died 8 months later. Case 2: A 69-year-old woman had undergone laparoscopic right hemicolectomy and adjuvant chemotherapy for Stage lllb cancer of the ascending colon. Due to subsequent elevation of tumor markers, PET-CT was conducted and abnormal uptake was seen in the apex of the right lung and right upper abdomen. Both lesions were resected, and omental and lung metastases were diagnosed. She received treatment with UFT / calcium folinate, but relapse occurred at the resection margin in the right lung. At 7 years and 5 months after initial surgery, she complained of respiratory distress at an outpatient visit. CT demonstrated displacement of the trachea and right main bronchus due to enlargement of upper mediastinal lymph nodes. There was also severe stenosis of the right main bronchus due to tumor infiltration. Because there was both infiltration from local recurrence after resection and upper mediastinal lymph node enlargement, broad EM was diagnosed. An EMS was placed at the site of severe stenosis in the right main bronchus. Similar to Case 1, radiation therapy was also conducted, but respiratory distress occurred after 3 months due to tumor re-growth at the stent margin. Accordingly, stent-in-stent placement was performed and her respiratory symptoms improved. However, superior vena cava syndrome occurred 1 month later and the patient died. We consider that placing an EMS is effective in patients with tracheal stenosis due to EM that is judged to be an oncological emergency.

[Endoscopic treatment for esophageal cancer].

Endoscopic therapy has now become the treatment of first choice of early esophageal cancer. We developed endoscopic esophageal mucosal resection (EEMR)-tube method employing a silicon rubber tube. The 4-step EEMR-tube method is our standard way to resect a wide lesion. In the 1st step, the lesion containing the deepest area is mostly resected. In the 2nd step, the residual lesion is resected, repeating a similar procedure. In the 3rd step, the surrounding residual area is resected bythe double channel method. In the 4th step, resected edge and tiny residual portions are treated by hot biopsy and argon plasma coagulation. In the patients treated by endoscopic mucosal resection (EMR), local recurrence rate was 3.6% and most of these cases were treated successfully again by endoscopic maneuver.