Kae Okoshi

Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis.

BackgroundIt has been determined that the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1) regulate several key processes in a wide variety of cancers. However, the function and mechanism of the SDF-1/CXCR4 system in the metastasis of colorectal cancer remain controversial.MethodsImmunohistochemistry was performed to examine quantitatively the expression of CXCR4 in 40 human samples of colorectal cancer and liver metastasis. The functions of SDF-1 on HCT116 colon cancer cells were investigated in vitro. We subcutaneously inoculated HCT116 cells with hepatic stellate cells (HSCs) expressing SDF-1. The CXCR4 inhibitor AMD3100 was tested in vitro and in vivo.ResultsBy quantitatively counting the number of cells, it was shown that there are more CXCR4-positive cells at the metastatic site in the liver compared with the primary sites. We demonstrated the effect of SDF-1 on the invasion and antiapoptosis of HCT116 cells in vitro. In mouse experiment of liver metastasis, intraperitoneal administration of AMD3100 blocked the metastatic potential of HCT116 cells. Furthermore, we found that α-smooth muscle actin (α-SMA)-positive myofibroblasts derived from HSCs, surrounding the liver metastasis foci, secreted SDF-1. The subcutaneous inoculation of HCT116 cells with HSCs promoted the tumor initiation in nude mice, indicating the importance of the direct interaction between these cells in vivo.ConclusionThese results suggest that HSCs play important role in liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis and provide preclinical evidence that blockade of the axis is a target for antimetastasis therapy.

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.

Molecular mechanisms of liver metastasis

Colorectal cancer is the second most common cancer, and is the third leading cause of cancer-related death in Japan. The majority of these deaths is attributable to liver metastasis. Recent studies have provided increasing evidence that the chemokine–chemokine receptor system is a potential mechanism of tumor metastasis via multiple complementary actions: (a) by promoting cancer cell migration, invasion, survival and angiogenesis; and (b) by recruiting distal stromal cells (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor invasion and metastasis. Here, we discuss recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer.

Overcoming the Challenges of Primary Tumor Management in Patients with Metastatic Colorectal Cancer Unresectable for Cure and an Asymptomatic Primary Tumor

BACKGROUND: The management of asymptomatic primary tumor in patients with unresectable metastatic colorectal cancer remains inconsistent. OBJECTIVE: This study aimed to determine the rate of symptom-directed surgery after systemic chemotherapy and to estimate the impact of initial primary tumor resection on survival in patients with unresectable metastatic colorectal cancer and an asymptomatic primary tumor. DESIGN: This was a single-institution, retrospective observational study. SETTINGS: The study was conducted in a tertiary referral hospital. PATIENTS: Between 2005 and 2011, 191 consecutive patients with newly diagnosed stage IV colorectal cancer were identified. Of the 191, we analyzed 94 patients with unresectable, asymptomatic colorectal cancer. MAIN OUTCOME MEASURES: We measured symptom-directed surgery and overall survival. RESULTS: Forty-seven patients with an intact primary tumor received systemic chemotherapy (upfront chemotherapy group), 41 underwent primary tumor resection (upfront primary tumor resection group), and 6 underwent diversion enterostomy as first-line therapy. After excluding the 6 patients undergoing diversion enterostomy before systemic chemotherapy, this left 88 patients for final analysis. Twelve upfront chemotherapy patients required symptom-directed late surgery. Overall, 1-year and 2-year rates of symptom-directed surgery were 19.1% and 26.1%. In patients with nontraversable lesions by colonoscope at diagnosis, 64.3% required late intervention within 1 year. Competing risk regression analysis revealed that only colonoscopic traversability at diagnosis was significantly associated with symptom-directed late surgery (subhazard ratio, 7.9; p = 0.004). Median overall survival time was comparable between the 2 groups at 23.9 months for the upfront primary tumor resection group and 22.6 months for the upfront chemotherapy group (HR, 0.84; 95% CI: 0.51–1.39). LIMITATIONS: This study was limited by its retrospective nature and small sample size. CONCLUSIONS: Approximately 75% of upfront chemotherapy patients with unresectable, asymptomatic stage IV colorectal cancer can be spared initial resection of the primary tumor. Colonoscopic findings of nontraversable lesions at diagnosis may predict the need for late surgical intervention.

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.

Health risks associated with exposure to surgical smoke for surgeons and operation room personnel

Although surgical smoke contains potentially hazardous substances, such as cellular material, blood fragments, microorganisms, toxic gases and vapors, many operating rooms (ORs) do not provide protection from exposure to it. This article reviews the hazards of surgical smoke and the means of protecting OR personnel. Our objectives are to promote surgeons’ acceptance to adopt measures to minimize the hazards. Depending on its components, surgical smoke can increase the risk of acute and chronic pulmonary conditions, cause acute headaches; irritation and soreness of the eyes, nose and throat; dermatitis and colic. Transmission of infectious disease may occur if bacterial or viral fragments present in the smoke are inhaled. The presence of carcinogens in surgical smoke and their mutagenic effects are also of concern. This review summarizes previously published reports and data regarding the toxic components of surgical smoke, the possible adverse effects on the health of operating room personnel and measures that can be used to minimize exposure to prevent respiratory problems. To reduce the hazards, surgical smoke should be removed by an evacuation system. Surgeons should assess the potential dangers of surgical smoke and encourage the use of evacuation devices to minimize potential health hazards to both themselves and other OR personnel.

Efficacy of transanal drainage for anastomotic leakage after laparoscopic low anterior resection of the rectum.

Anastomotic leakage remains a devastating complication following low anterior resection of the rectum. Our aim was to retrospectively assess the efficacy of transanal drainage.

Laparoscopic right hemicolectomy for metachronous ascending colon cancer with preservation of an ileal conduit constructed after previous radical cystectomy for bladder cancer.

A 79‐year‐old woman who had undergone laparoscopic radical cystectomy and ileal conduit construction for bladder cancer 4 years earlier presented to our hospital with anemia. We diagnosed advanced ascending colon cancer (cT4bN2M1) and documented tumor regression after six courses of folinic acid, 5‐fluorouracil, and oxaliplatin therapy. We then performed laparoscopic right hemicolectomy. Intraoperatively, we found that the right colic artery was the feeding artery of the tumor, whereas the ileocolic artery, which was the main feeder of the conduit, was not. We performed lymph node dissection along the surgical trunk with central vascular ligation of the right colic artery and the right branch of the middle colic artery while preserving the ileal conduit and its blood supply (ileocolic artery and ileal branches). The postoperative course was uneventful, and the patient remains well and cancer‐free 2 years after colonic surgery. We believe that this is the first report of laparoscopic right colectomy in a patient with an ileal conduit.

A case report of pathologically complete response of a huge rectal cancer after systemic chemotherapy with mFOLFOX6

A 54-year-old man was referred to our hospital because of a huge, unresectable rectal cancer occupying his entire pelvic space with a solitary liver metastasis. He had undergone a laparotomy for surgical resection, but ended up with a sigmoid colostomy due to possible invasion into the urinary bladder and pelvic wall. At the completion of seven cycles of FOLFOX regimen, radiographic examination revealed remarkable reduction of the primary rectal tumor and regional lymph nodes, and also a complete response (CR) of the liver metastasis. The tumor was extirpated without any macroscopic residues by a low anterior resection of the rectum, along with a partial resection of the urinary bladder and seminal vesicles. Since pathological and immunohistochemical examinations showed no viable cancer cells in any parts of the resected specimens, the lesion was regarded as a pathologically CR. Analysis for single-nucleotide polymorphisms in the genes involved in nucleotide excision repair, excision repair cross-complementing group 1 and xeroderma pigmentosum group D, showed a genotypic pattern sensitive to oxaliplatin. To our knowledge, this is a rare case of an initially unresectable primary rectal cancer, which was down-staged to a pathologically CR by FOLFOX chemotherapy instead of chemoradiotherapy.

Musical Instrument-Associated Health Issues and Their Management

Playing musical instruments can bring joy to people, but can also cause a wide variety of health issues that range from mild disorders to potentially fatal conditions. Although sports medicine is an established medical subspecialty, relatively few studies have investigated the health issues associated with musical instruments. Here we present an overview of these health issues. These include infections due to microorganisms, allergic reactions, as well as mechanical injuries from sustained high pressures within the oral, mediastinal, thoracic, and abdominal cavities. For example, wind instruments can potentially harbor thousands of pathogenic organisms. If several players share the same instrument, these instruments present potential hazards in the spread of infections. A fatal case of hypersensitivity pneumonitis in a bagpiper is particularly noteworthy. Similarly, a case of gastrointestinal anthrax in an animal-hide drummer is a reminder of this rare but highly fatal disease. Although not fatal, hearing-related disorders, neuromuscular issues, musculoskeletal problems, and contact dermatitis are also very common among instrumentalists. This review aims to illuminate these under-recognized health issues by highlighting both the common conditions and the rare but fatal cases.