Anti-Tumor Effect in Human Lung Cancer by a Combination Treatment of Novel Histone Deacetylase Inhibitors: SL142 or SL325 and Retinoic Acids

Histone deacetylase (HDAC) inhibitors arrest cancer cell growth and cause apoptosis with low toxicity thereby constituting a promising treatment for cancer. In this study, we investigated the anti-tumor activity in lung cancer cells of the novel cyclic amide-bearing hydroxamic acid based HDAC inhibitors SL142 and SL325. In A549 and H441 lung cancer cells both SL142 and SL325 induced more cell growth inhibition and cell death than the hydroxamic acid-based HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Moreover, the combination treatment using retinoid drugs ATRA or 9-cis RA along with SL142 or SL325 significantly induced more apoptosis and suppressed colony formation than the single use of either. The expression of the retinoic acid receptors RARα, RARβ, RXRα and RXRβ were unchanged with the treatment. However a luciferase reporter construct (pGL4. RARE 7x) containing seven tandem repeats of the retinoic acid responsible element (RARE) generated significant transcriptional activity after the combination treatment of retinoic acids and SL142 or SL325 in H441 lung cancer cells. Moreover, apoptosis-promoting Bax expression and caspase-3 activity was increased after the combination treatment. These results suggest that the combination treatment of SL142 or SL325 with retinoic acids exerts significant anti-tumor activity and is a promising therapeutic candidate to treat human lung cancer

A case of gastrointestinal stromal tumor (GIST) with peritoneal dissemination : Imatinib re-challenged case

Unresectable, metastatic, recurrent gastrointestinal stromal tumor (GIST) is primarily treated with a molecular-targeted therapeutic agent, imatinib. However, after an initial response, a secondary resistance to the drug often occurs after a few years. We report here a case of a resected giant GIST of the jejunum that disseminated following treatment with imatinib. A 59-year-old male presented with a giant tumor in the abdominal cavity, which was diagnosed as GIST by needle biopsy; he was administered 400 mg/day imatinib. Eight months later, the tumor had considerably decreased, but multiple tumors in small intestine and mesenterium, indicating dissemination, appeared. Administration of imatinib was continued for 36 months from the initial treatment and the dissemination gradually reduced and almost disappeared except for a tumor in the right upper abdomen. Three years later, follow-up computed tomography revealed that the disseminated lesions had enlarged; a part of the intrapelvic tumor was suspected to be viable. We deduced that the tumor developed partial resistance to imatinib: therefore, we surgically removed as many disseminated tumors as possible. Pathologically, resected tumors appeared to have no viable tumor cells except for a small part of the primary tumor in which mitosis was 0-1/50 high-power fields. Genetic analysis of surgically resected specimen for c-kit mutation revealed an exon 11 c554-559 deletion. 17 months after operation, another disseminated tumor was detected. Imaninib therapy was re-introduced. The dissemination was diminished after three months re-challenged imatinib and continues to be recurrence-free for two years. When partial resistance to imatinib is observed, combined modality therapy that involves chemotherapy with surgical intervention at early stages is expected to improve the outcome

Obesity and Perioperative management – Review –

　Obesity is a contributing factor to life-style related diseases such as diabetes, hypertension and dyslipidemia, as well as being a cause of metabolic syndromes. It has been predicted that more than half of the adult population in the world might be obese within the next twenty years. Once a person is diagnosed with metabolic syndrome, conditions such as diabetes, hypertension and dyslipidemia may remain mild even while visceral fat obesity slowly advances arterial sclerosis. Eventually, severe clinical conditions such as heart diseases and stroke can result. In recent years, there are more and more patients diagnosed with morbid obesity both inside and outside of Japan. This case report will discuss some concerns and tasks in treating patients with obesity and morbid obesity

A surgical case of mitral valve replacement for a patient with Fabry disease complicated with hemodialysis

　Fabry disease is a rare genetic disease, and surgical reports for the patients with Fabry disease are also rarer.　A 58-year-old man presented with chest pain. At the age of 40, he commenced dialysis due to chronic renal failure and at the age of 50, he developed shortness of breath on exertion, and echocardiography showed mitral regurgitation and left ventricular hypertrophy. He was then diagnosed with Fabry disease due to decreased alpha-galactosidase activity. This diagnosis led to enzyme replacement therapy (ERT). The ERT was effective as he had not never experienced further exacerbation of congestive heart failure. While the CHF was put under control, his mitral stenosis gradually worsened, and the patient began to have more chest pain and became hypotensive. He then referred to our section for mitral valve replacement. His mitral annulus was severely calcified and we removed mitral annulus calcification (MAC) at minimum so that we could stich needles and implanted mechanical valve. Paroxysmal atrial fibrillation and bradycardia made his hemodynamics unstable against ERT, which also caused low dialysis efficiency. It took longer than usual to wean him off catecholamines. His hemodynamics became more stable and dialysis efficiency generally improved, so he moved from ICU to ward on postoperative day 11. On day 32, he was transferred back to the referring hospital for his rehabilitation.　We have reported a surgical case of Fabry disease, that are not only rare but have high perioperative risk due to Fabry disease’s specific complications

Case report on a coronary artery bypass graft for a patient with antiphospholipid antibody syndrome associated with systemic lupus erythematosus

　Antiphospholipid antibody syndrome (APS) is an immune disease in which antiphospholipid antibodies cause hypercoagulability and thromboembolic complications. We experienced APS cases associated with systemic lupus erythematosus with three-vessel lesions of the coronary artery. After a below knee amputation on a 60-year-old woman with APS, she complained of chest pain at rest. An electrocardiogram showed an ST depression and a coronary angiography showed complicated three-vessel disease, as a result she was referred to the cardiac surgery department. A coronary artery bypass with arterial grafts was performed along with postoperative anticoagulant and antiplatelet therapy, and the short-term graft patency was good. Case reports of coronary artery bypass grafts for secondary APS are rare, so we report here on our case and our strategy to treat thromboembolic complications

Retroperitoneal liposarcoma presenting a indirect inguinal hernia

A 60-year-old man was admitted to our hospital with a right inguinal swelling that had been growing in size without any pain for 7 months. We diagnosed the growth as a right inguinal hernia and operated on him. The growth, however, was found to be a tumor it situated along the spermatic cord and testicular vessels. We diagnosed it as a lipoma. The tumor was resected near part of the internal inguinal ring. Histopathological diagnosis showed well-differentiated liposarcoma of the sclerosing type. Postoperative computed tomography (CT) revealed a large residual tumor in the retroperitoneum. We believed that the tumor was a retroperitoneal liposarcoma and that it developed in the inguinal region. The residue of the liposarcoma was resected onto the right inguinal tract. A periodic follow up has been performed and no evidence of recurrence or metastasis has been seen in the 4 years and 9 months since the second surgery. No adjuvant therapy was performed. Inguinal liposarcomas are relatively rare and in most cases these tumors are thought to originate in the spermatic cord. The origin of the tumor is believed to be the retroperitoneum</p

SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma.

Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A

Jejunal interposition reconstruction with a stomach preserving esophagectomy improves postoperative weight loss and reflux symptoms for esophageal cancer patients

Background: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed. Materials and methods: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings. Results: The SPE group had a longer operation time (SPE: 560 +/- 121 min, control 414 +/- 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 +/- 5.4% versus 87.5 +/- 4.7% at 3 mo, P = 0.017; 97.2 +/- 7.5% versus 85.0 +/- 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01). Conclusions: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss