Yoshio Kadokawa

Thalidomide Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice

Pulmonary fibrosis in humans can occur as a result of a large number of conditions. In idiopathic pulmonary fibrosis (IPF), pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-β1 plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid (ATRA) prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide (Thal) has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced pulmonary fibrosis in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-β1, collagen type Iα1 (COL1A1), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-β1, VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1) production of IL-6, TGF-β1, VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-β1-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis. These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis.

All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production.

Background/Aims: Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all‐trans‐retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation‐ or bleomycin‐induced lung fibrosis.

All-trans-Retinoic Acid Attenuates Radiation-Induced Intestinal Fibrosis in Mice

BACKGROUND Intestinal fibrosis leading to severe bowel dysmobility or obstruction is a troublesome adverse effect of abdominal or pelvic radiation therapy. We have recently reported that all-trans-retinoic acid (ATRA) prevents radiation- or bleomycin-induced lung fibrosis. Here, we examined the impact of ATRA on the mouse model of radiation-induced intestinal fibrosis. MATERIALS AND METHODS We evaluated the histology of late radiation fibrosis in surgical samples. We then performed histological examinations and quantitative measurements of mRNA of interleukin-6 and transforming growth factor-beta(1) in intestinal tissues of irradiated mice with or without intraperitoneal administration of ATRA and investigated the effect of ATRA on the transdifferentiation and the production of collagen of irradiated human intestinal fibroblasts. RESULTS Human samples of late radiation enteritis showed thickened submucosa and serosa, consistent with mouse model. Administration of ATRA attenuated irradiation-induced intestinal fibrosis and reduced mRNA of interleukin-6 and transforming growth factor-beta(1). In vitro studies disclosed that ATRA suppressed the transdifferentiation of irradiated intestinal fibroblasts and diminished the production of collagen from the cells. CONCLUSIONS Our findings indicate that ATRA ameliorates irradiation-induced intestinal fibrosis. ATRA could be a novel approach in the treatment of fibrosis associated with chronic radiation enteritis.

Feasibility of thoracoscopic esophagectomy after neoadjuvant chemotherapy

Minimally invasive esophagectomy has been increasingly accepted to treat esophageal cancer. In Japan, neoadjuvant chemotherapy followed by surgery has become the standard procedure for advanced esophageal cancer. A randomized control study has shown neoadjuvant chemotherapys survival benefits, but it is unknown whether minimally invasive esophagectomy after chemotherapy is viable. This study investigated the feasibility of thoracoscopic esophagectomy after neoadjuvant chemotherapy.

Impact of stepwise introduction of esophagojejunostomy during laparoscopic total gastrectomy: a single-center experience in Japan

Background The number of laparoscopic gastrectomies performed in Japan is increasing with the development of laparoscopic and surgical instruments. However, laparoscopic total gastrectomy is developing relatively slowly because of technical difficulties, particularly in esophagojejunostomy. Methods We retrospectively reviewed 83 patients with early gastric cancer in the upper portion of the stomach who underwent laparoscopic total gastrectomy between April 2007 and March 2016. We classified the patients into three periods, mainly on the basis of the esophagojejunostomy procedures performed: first period, various conventional procedures based on the physicians’ choice (n=14); second period, transoral method (n=51); and third period, fully intracorporeal technique (n=18). We evaluated the clinical impact of a stepwise introduction of unfamiliar new methods during laparoscopic total gastrectomy. Results Between the first and second periods, there were significant differences in the blood loss volume, number of harvested lymph nodes, frequency of conversion to open surgery, and postoperative hospital stay. The number of harvested lymph nodes was significantly higher in the third than in the second period, with no detriment to other intraoperative or postoperative factors. Conclusion The use of a unified surgical method for esophagojejunostomy seems to be the key to a successful and advantageous laparoscopic total gastrectomy. Stepwise introduction of a well-established technique of esophagojejunostomy during laparoscopic total gastrectomy will benefit patients, as shown, for example, by the higher number of dissected lymph nodes in the present study. However, a protracted learning curve is required.

Safety and feasibility of laparoscopic gastrectomy accompanied by D1+ lymph node dissection for early gastric cancer in elderly patients: LG for EGC in elderly patients

The age of patients with gastric cancer has increased worldwide. The aim of this study was to investigate the safety and feasibility of laparoscopic gastrectomy (LG) for early gastric cancer in elderly patients.

Laparoscopic appendectomy for acute appendicitis: How to discourage surgeons using inadequate therapy

Acute appendicitis (AA) develops in a progressive and irreversible manner, even if the clinical course of AA can be temporarily modified by intentional medications. Reliable and real-time diagnosis of AA can be made based on findings of the white blood cell count and enhanced computed tomography. Emergent laparoscopic appendectomy (LA) is considered as the first therapeutic choice for AA. Interval/delayed appendectomy at 6-12 wk after disease onset is considered as unsafe with a high recurrent rate during the waiting time. However, this technique may have some advantages for avoiding unnecessary extended resection in patients with an appendiceal mass. Non-operative management of AA may be tolerated only in children. Postoperative complications increase according to the patient’s factors, and temporal avoidance of emergent general anesthesia may be beneficial for high-risk patients. The surgeon’s skill and cooperation of the hospital are important for successful LA. Delaying appendectomy for less than 24 h from diagnosis is safe. Additionally, a semi-elective manner (i.e., LA within 24 h after onset of symptoms) may be paradoxically acceptable, according to the factors of the patient, physician, and institution. Prompt LA is mandatory for AA. Fortunately, the Japanese government uses a universal health insurance system, which covers LA.