Hisashi Ishikura

Frequent microsatellite instability in lung cancer from chromate‐exposed workers

Although chromium has been the most extensively investigated metal with respect to mutagenicity and carcinogenicity, its genetic effects in humans are only partly understood. Our previous study demonstrated that lung cancer from chromate‐exposed workers infrequently (20%) displayed p53 gene mutations as well as a particular mutation pattern. In the present study, we examined the replication error (RER) and loss of heterozygosity (LOH) in 38 lung cancers from 28 chromate‐exposed workers (chromate lung cancer group) and in 26 lung cancer patients without chromate exposure (non‐chromate lung cancer group), using six microsatellite markers containing CA repeats: D3S647 (3p23), D3S966 (3p21.3), D3S1289 (3p21.1), D5S346 (5q21–q22), D9S161 (9p21), and TP53 (17p13.1). The RER phenotype was defined as the presence of microsatellite instability (MSI) at two or more loci. Thirty (78.9%) of 38 tumors in the chromate lung cancer group exhibited RER. In contrast, only four (15.4%) of 26 tumors in the non‐chromate lung cancer group exhibited RER. The frequency of RER in the chromate lung cancer group was significantly higher than that in the non‐chromate lung cancer group (P < 0.0001). By contrast, the frequency of LOH at 3p, 5q, 9p, and 17p loci in tumors with chromate exposure was not significantly different from that in tumors without chromate exposure. In the chromate lung cancer group, the period of chromate exposure in workers with RER (24.5 ± 6.7 yr) was significantly longer than that in workers without RER (17.0 ± 3.5 yr) (P = 0.0046). In addition, a longer period of chromate exposure was associated with a tendency toward a higher frequency of MSI. This finding suggests that MSI may play a role in chromium‐induced carcinogenesis. In addition to our previous study of p53 mutations, the present findings suggest that the carcinogenic mechanism of chromate lung cancer may differ from that of non‐chromate lung cancer.

Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

Matrix metalloproteinases (MMP) are considered to be critically involved in tumor invasion and the metastasis of various cancers. MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP-2, MMP-9, and MMP-14). The purpose of this study was to evaluate the effects of MMI-166 on both the growth of the implanted tumor and the lymph node metastasis of the mediastinum and prolonging the life span, using an orthotopic implantation model of the Ma44-3 cancer cell line. We examined the anti-invasive effect of MMI-166 in lung cancer cell lines using an in vitro invasion assay. Next, we examined the anticancer effect of MMI-166 in vivo. MMI-166 (200 mg/kg body weight) or a vehicle was administered orally to the orthotopically implanted lung cancer model. MMI-166 dose-dependently inhibited the invasion of cancer cell lines with expressions of MMP-2 and/or MMP-9 in vitro. In vivo, MMI-166 significantly inhibited mediastinal lymph node metastasis in this orthotopic model (weight of the mediastinum: control, 0.089 ± 0.009 versus MMI-166, 0.069 ± 0.008 mg; P = 0.005; metastatic area: control, 93,495 ± 55,747 versus MMI-166, 22,747 ± 17,478 pixels; P = 0.045). MMI-166 prolonged the life span by 6 days in median survival time in the orthotopically implanted model (P = 0.039). These results showed that MMI-166 could possibly inhibit lymph node metastasis and prolong the life span in lung cancer patients.

Artificial lymphogenous metastatic model using orthotopic implantation of human lung cancer

BACKGROUND AND METHODS We established a new, patientlike orthotopic model of lung cancer metastasis with human non-small cell lung cancer cell lines. In this report, we describe the progressive stages of development of lymphogenous mediastinal metastasis in the Ma44-3 cell line from day 3 to day 15 after implantation in severe combined immunodeficiency mice and the process of lymphogenous metastasis. RESULTS All mice killed after day 12 had perivascular and peribronchial tumor growth. Micrometastasis to the mediastinum was first observed on day 5. On days 5 through 9, 10 of 13 mice had metastasis to the mediastinum, and all mice had one by day 12. When perivascular and peribronchial tumor growth was present by day 5, metastasis to the mediastinum developed in all mice. CONCLUSIONS This study demonstrates the lymphogenous spread of human lung cancer in severe combined immunodeficiency mouse using an orthotopic implantation model. Our model was thought to be an artificial lymphogenous metastasis model, owing to forced tumor inoculation into lymphatic vessels.

Hepatobiliary cystadenoma exhibiting morphologic changes from simple hepatic cyst shown by 11-year follow up imagings.

BackgroundA long-term follow up case of hepatobiliary cystadenoma originating from simple hepatic cyst is rare.Case presentationWe report a case of progressive morphologic changes from simple hepatic cyst to hepatobiliary cystadenoma by 11 – year follow up imaging. A 25-year-old man visited our hospital in 1993 for a simple hepatic cyst. The cyst was located in the left lobe of the liver, was 6 cm in diameter, and did not exhibit calcification, septa or papillary projections. No surgical treatment was performed, although the cyst was observed to gradually enlarge upon subsequent examination. The patient was admitted to our hospital in 2004 due to epigastralgia. Re-examination of the simple hepatic cyst revealed mounting calcification and septa. Abdominal CT on admission revealed a hepatic cyst over 10 cm in diameter and a high-density area within the thickened wall. MRI revealed a mass of low intensity and partly high intensity on a T1-weighted image. Abdominal angiography revealed hypovascular tumor. The serum levels of AST and ALT were elevated slightly, but tumor markers were within normal ranges. Left lobectomy of the liver was performed with diagnosis of hepatobiliary cystadenoma or hepatobiliary cystadenocarcinoma. The resected specimen had a solid component with papillary projections and the cyst was filled with liquid-like muddy bile. Histologically, the inner layer of the cyst was lined with columnar epithelium showing mild grade dysplasia. On the basis of these findings, hepatobiliary cystadenoma was diagnosed.ConclusionWe believe this case provides evidence of a simple hepatic cyst gradually changing into hepatobiliary cystadenoma.

Resection of an azygos vein aneurysm with thrombosis.

Aneurysm of the azygos vein is rare. We describe the case of a 51-year-old nonsmoking woman with a posterior mediastinal mass caused by a giant azygos vein aneurysm with subtotal thrombosis. Surgical resection of the azygos vein was offered to our patient as a treatment option owing to theoretical risks of rupture and pulmonary embolism. After taping the azygos vein proximally and distally, the aneurysm was resected with video-assisted thoracoscopy. Approximately 30 cases have been reported in the literature to date. Dynamic computed tomography and a videoassisted approach were useful for the diagnosis and treatment for this abnormality.

Lymphoepithelial cyst of the pancreas that was difficult to distinguish from branch duct-type intraductal papillary mucinous neoplasm: Report of a case

A 58-year-old woman was admitted to our hospital to optimize the management of her diabetes mellitus. A computed tomography (CT) scan showed a 30-mmdiameter, multilocular cyst in the head of the pancreas. The tumor markers, including DUPAN 2, SPAN-1, and carbohydrate antigen 19-9, were within the normal ranges. A contrast-enhanced CT scan showed a nonenhanced, multilocular cyst. Abdominal magnetic resonance imaging showed a multilocular cyst. Endoscopic retrograde cholangiopancreatography showed that the main pancreatic duct was normal. Based on these findings, we suspected a branch duct type intraductal papillary mucinous neoplasm. A distal pancreatectomy with a splenectomy was performed, since more of the mass was located on the dorsolateral side, inconsistent with the preoperative imaging results. On the resected specimen, a 4-cm-diameter, multilocular cyst containing serous fluid was found. Pathologically, the cyst wall was lined with squamous epithelium surrounded by abundant lymphoid tissue with follicles, consistent with a lymphoepithelial cyst of the pancreas, which is an unusual benign cyst.

A feasibility study of postoperative adjuvant chemotherapy with fluoropyrimidine S‐1 in patients with stage II‐IIIA non‐small cell lung cancer

BACKGROUND Adjuvant chemotherapy with uracil tegafur (UFT) improved survival among patients with completely resected stage I lung adenocarcinoma. S-1, an oral dihydropyrimidine dehydrogenase (DPD)-inhibitory 5-fluorouracil, is a more potent DPD inhibitor than UFT;therefore, we hypothesized that postoperative adjuvant chemotherapy with S-1 would be effective for advanced non-small cell lung cancer (NSCLC). We conducted a feasibility study of S-1 as postoperative adjuvant chemotherapy in patients with curatively resected pathological stage bold I back 10 bold I and bold I back 10 bold I back 20 bold I A NSCLC. METHODS Adjuvant chemotherapy consisted of 9 courses (4-week administration, 2-week withdrawal) of S-1 at 80-120 mg/body per day. Twenty-four patients with completely resected NSCLC were enrolled in this study from November 2007 through December 2010. The primary endpoint was the rate of completion of the scheduled adjuvant chemotherapy. The secondary endpoints were safety, overall survival, and relapse-free survival. RESULTS Five patients were censored because of disease recurrence. The planned 9 courses of S-1 were administered to completion in 8 patients. Twelve patients completed more than 70% of the planned courses. Grade 3 adverse reactions, such as elevated total bilirubin (4.2%) and pneumonitis (4.2%), were observed, but there were no Grade 4 adverse reactions. Patients who completed more than 70% of the 9 courses demonstrated better overall survival than those who completed less than 70%. CONCLUSION Postoperative administration of S-1 may be possible with few severe adverse events as adjuvant chemotherapy for patients with curatively resected pathological stage bold I back 10 bold I -bold I back 10 bold I back 20 bold I A NSCLC. J. Med. Invest. 65:90-95, February, 2018.

A CASE OF HYPER BILIRUBINEMIA AFTER CHOLEDOCHOTOMY

We successfully saved a patients life who developed severe hyperbilirubinemia after choledochotomy by treating according to hepatic failure and by closing an external fistula. A 53-year-old man was pointed out having gallstone when he was treated for hepatitis type C on an ambulant basis. HCV antibody was positive. On and after 4th hospital day, an increase in direct type dominant T-Bilirubin and increased and diluted exudate from a T-tube were observed. According to the treatment for postoperative hepatic failure. G.I. treatment was started, the T-tube was clamped, and eventually T-Bilirubin gradually decreased. We sometimes experience that a large quantity of diluted bile juice is exuded from an external fistula in cases of impaired liver function or cirrhosis, but we are not able to find courage to perform the internal fistulization at present. It is thought that internal fistulization of external biliary fistula with make bile acid increase, an increase in endotoxin inhibit, the hepatic blood flow increase, and the relief of obstructive jaundice stimulate. When a case of hyperbillirubinemia exuding a large quantity of diluted bile juice from an enternal fistula is encountered, we can expect to accelerate the relief of obstructive jaundice by clamping of the T-tube. This procedure appears to be worth to try before plasma exchange.

Indications for Thoracoscopic Surgery in place of Open Lung Biopsy.

胸腔鏡下手術は, Video-Assisted Thoracic Surgery (VATS) として, 最近急速に普及しつつある. 適応疾患は, 自然気胸や嚢胞性疾患, 肺腫瘍, 胸膜及び胸壁病変, 縦隔病変など, 広範囲にわたっている. しかし, 個々の症例の適応決定には慎重であらねばならない.そこで我々は, 当科において, 最近10年間に行った呼吸器外科手術症例を検討し, 現在であればVATSが可能であったと考えられる症例が, どの程度存在したかについて考察を行った. その結果, 画像診断上, VATSの適応症例は, 開胸肺生検例の73%に存在し, VATSのみでその目的を完遂し得たであろう症例は, そのうちの約半数であった. 現在までに施行したVATS症例と比較検討し, 報告する.