Observation of the Pharynx to the Cervical Esophagus Using Transnasal Endoscopy with Blue Laser Imaging

Background In 2014, the new transnasal endoscopy with Blue laser Imaging (BLI) has been developed. Aim We present the usefulness of the observation of from the pharynx to the cervical esophagus using transnasal endoscopy with BLI. Patients and Methods This study was conducted between June 2014 and October 2014. During this period, 70 consecutive patients (60 men, 10 women; mean age 67.9 years old) with esophageal or head and neck cancer underwent endoscopic screening at the oropharynx and hypopharynx by transnasal endoscopy with BLI system We performed this endoscopic observation from oral cavity to pharynx before inserting into the cervical esophagus.The visibility of subsites of the hypopharynx and the orifice of the esophagus was evaluated. The extent of the view of hypopharyngeal opening was classified into 3 categories (excellent, good, poor). Then, the diagnostic accuracy of transnasal endoscopy with BLI system was estimated. Our screening is as follows. First, the patient is asked to bow their head deeply in the left lateral position. We put a hand on the back of the patient’s head and push it forward. The patient is then asked to lift the chin as far as possible. In order to inspect the oral cavity, we insert an endoscope without a mouthpiece. After observation of the oral cavity, the endoscope was inserted through the nose. When the tip of the endoscope reached caudal to the uvula, the patient opened his mouth wide, stuck his tongue forward as much as possible and made a vocal sound like “ayyy”. The endoscopist caused the endoscope to U-turn and observed the oropharynx, in particular the radix linguae (Intra-oropharyngeal U-turn method). For examination of the hypopharynx and the orifice of the esophagus, the patient is asked to blow hard and puff their cheeks while the mouth remains closed (Trumpet maneuver). Results 8 elderly cases were excluded because they could not perform the adequate ballooning. Finally, 62 cases were investigated. The ballooning the pyriform sinus and posterior wall not only allows accurate assessment of the stretched pharyngeal mucosa but also gives a view of postcricoid subsite and the orifice of the esophagus. The wide endoscopic view of the pharynx was obtained in a series of the procedures (excellent=53/62, 85.4%; good=7/52, 4.5%; and poor=2/62, 7.6%). Among 70 patients, 6 superficial lesions (8.6%) at the oropharynx(n=1) and hypopharynx (n=5) were discovered with BLI system. Mucosal redness, a pale thickened mucosa, white deposits or loss of a normal vascular pattern, well demarcated areas covered with scattered dots are important characteristics to diagnose superficial carcinoma. Conclusion The more progress achieved in transnasal endoscopy rapidly in the last few years, it can improve for observing the blind area using trans-oral endoscopy, therefore the trans-nasal endoscope will be a standard tool for the screening of the upper gastrointestinal tract in the near future

CHAC1 overexpression in human gastric parietal cells with Helicobacter pylori infection in the secretory canaliculi

Background Cation transport regulator 1 (CHAC1), a newly discovered enzyme that degrades glutathione, is induced in Helicobacter pylori (H. pylori)‐infected gastric epithelial cells in culture. The CHAC1‐induced decrease in glutathione leads to an accumulation of reactive oxygen species and somatic mutations in TP53. We evaluated the possible correlation between H. pylori infection and CHAC1 expression in human gastric mucosa. Materials and Methods Both fresh‐frozen and formalin‐fixed paraffin‐embedded tissue samples of gastric mucosa with or without H. pylori infection were obtained from 41 esophageal cancer patients that underwent esophago‐gastrectomy. Fresh samples were used for real‐time polymerase chain reaction for H. pylori DNA and CHAC1 mRNA, and formalin‐fixed samples were used for immunohistochemistry with anti‐CHAC1 and anti‐H. pylori monoclonal antibodies. Double‐enzyme or fluorescence immunohistochemistry and immuno‐electron microscopy were used for further analysis. Results Significant CHAC1 overexpression was detected in H. pylori‐infected parietal cells that expressed the human proton pump/H,K‐ATPase α subunit, whereas a constitutively low level of CHAC1 mRNA expression was observed in the other samples regardless of the H. pylori infection status, reflecting the weak CHAC1 expression detected by immunohistochemistry in the fundic‐gland areas. Immuno‐electron microscopy revealed intact H. pylori cells in the secretory canaliculi of infected parietal cells. Some parietal cells exhibited positive nuclear signals for Ki67 in the neck zone of the gastric fundic‐gland mucosa with H. pylori infection. Conclusion Cation transport regulator 1 overexpression in H. pylori‐infected parietal cells may cause the H. pylori‐induced somatic mutations that contribute to the development of gastric cancer.This work was supported by the Japan Society for the Promotion of Science KAKENHI (16K19077), and by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development, AMED

Interaction of Mlh1 deficiency with radiation and/or mild inflammation in colon carcinogenesis in mice

Both genetic and environmental factors play critical roles in colon carcinogenesis. The mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, is a main causal gene of hereditary nonpolyposis colorectal cancer (HNPCC). Ionizing radiation and colitis are also known risk factors for colorectal cancer. However, little is known about the interaction of these factors. Hence, we examined the combined effects of radiation and inflammation on colon carcinogenesis using Mlh1-deficient mice. Male and female 2- and 7-week-old Mlh1-/-, Mlh1+/- and Mlh1+/+ mice were irradiated with X-rays at a dose of 2 Gy. Then, they were treated with 1% dextran sodium sulfate (DSS) or vehicle in drinking water for 7 days at 10 weeks of age to induce inflammatory colitis. Colons were examined for tumors at the 14th week after the end of DSS treatment. We found more colon tumors after combined exposure of radiation with DSS, compared with single or no treatment in Mlh1-/- mice. But the effect was much less in Mlh1+/- or Mlh1+/+ mice. In conclusion, combined exposure of radiation with mild inflammation enhances colon carcinogenesis in homozygous Mlh1 mice.第72回日本癌学会学術総

Radiation carcinogenesis in Mlh1 knock-out mice

DNA mismatch repair (MMR) system is one of the important mechanisms to suppress cancer development. MMR deficiency is a cause of hereditary non-polyposis colorectal cancer (HNPCC) as well as mammary, gastric, pancreatic cancers and leukemia. Colon cancers in HNPCC patients and the lymphomas in Msh2-deficient mice have shown frequent frame shift mutations in TgfbrII. It has not yet examined whether MMR deficiency is involved in the susceptibility to radiation carcinogenesis. The aims of the current study are both to elucidate the susceptibility of Mlh1-/- mice to radiation induced tumors and to determine the mutation of TgfbrII in the tumors. Eleven-day- and 10-week-old Mlh1-/- mice were exposed to 2 Gy of X-rays. The mice were sacrificed at moribund and autopsied. Mutation of TgfbrII was analyzed in the DNA from pathological samples after microdissection or fresh samples. Thymic lymphomas (TL) after irradiation at 11-days and 10-weeks developed much earlier than spontaneous ones with the incidence of 87% (13/15) and 87%(13/15), respectively, which was significantly higher than that of spontaneous ones (61%, 11/18). Gastrointestinal tumors (GIT) also developed earlier when irradiated at 10-weeks, but not 11-days, old. The mutation of TgfbrII was not found in any tumors. We conclude that Mlh1 deficiency accelerates radiation-induced TL and GIT development. TgfbrII mutation, however, was not involved in cancer induction of Mlh1-/- mice.第48回日本放射線影響学会／第1回アジア放射線研究会

Mammary tumorigenesis in ApcMin/+ mice is enhanced by X irradiation with a characteristic age dependence

The ApcMin/+ (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7-10 weeks of age developed mammary tumors with squamous metaplasia, whereas their wild-type littermates did not. Interestingly, irradiation of Min mice at 2-5 weeks did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases with age in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling

Mediastinoscopic esophagectomy with lymph node dissection using a bilateral transcervical and transhiatal pneumomediastinal approach

We developed a method for mediastinoscopic esophagectomy via a bilateral transcervical and transhiatal approach under pneumomediastinum as a less-invasive radical operation. The right recurrent nerve is first identified using an open approach, and the right cervical paraesophageal lymph nodes and part of the right recurrent nerve lymph nodes are dissected, after which pneumomediastinum is initiated. The upper thoracic paraesophageal lymph nodes and right recurrent nerve lymph nodes are dissected along the right vagus nerve. The dorsal side of the esophagus is dissected along the visceral sheath taking care to avoid thoracic duct injury and is then dissected along the vascular sheath in front of the descending aorta. The esophagus is dissected from the trachea at the caudal side of the aortic arch, and then dissected along the ventral side of the left main bronchus, reaching the pulmonary artery. Finally, the right recurrent nerve lymph nodes around the right subclavian artery are completely retrieved. The left cervical approach is almost the same as that via the right side. The dorsal side of the esophagus is almost dissected along the visceral sheath with a right transcervical approach. The subaortic arch to the left tracheobronchial lymph nodes are dissected using the crossover technique. These lymph nodes are easily dissected by cutting the left and ventral side of the lymph nodes because the caudal side is already dissected in the right transcervical approach. A bilateral (especially right trans-cervico-pneumomediastinal) approach is useful for bilateral upper mediastinal lymph node dissection and esophagectomy

Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice

Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor suppressor genes or oncogenes, and cause hereditary nonpolyposis colorectal cancer (HNPCC). Hematological malignancy with microsatellite instability is also associated with defective MMR, but little is known about the target genes for MMR. Here we identified Ikaros, a master transcription factor of lymphoid lineage commitment and differentiation, as a mutational target in spontaneous and radiation-induced T-cell lymphomas in Mlh1-deficient mice. Three quaters of lymphomas lacked Ikaros protein expression, which resulted from a frameshift mutation that created a stop codon. Mononucleotide repeat sequences at 1029-1034(C)6 and 1567-1572(G)6 in Ikaros were mutational hot spots with a one-base deletion occurring with a frequency of 45% and 50%, respectively. Point mutations and splicing alterations were also observed. In total, 85% of the lymphomas showed aberrations in Ikaros. The characteristics of Mlh1-deficient lymphomas is harboring of multiple mutations simultaneously in the same tumor, displaying a combination of two frameshift mutations at different repeats, frameshift and point mutations, and/or deletion mutations. This is the first report of Ikaros mutations coupled with Mlh1 deficiency in lymphomagenesis