Junko Kishikawa

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel‐incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX‐Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX‐Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX‐Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX‐Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX‐Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX‐Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX‐Cre group (24 100 ± 3560 vs 108 ± 25 ng/mL, respectively; P < 0.001), as was the area under the concentration–time curve from 0 to 48 h (191 000 ± 32 100 vs 1500 ± 108 ng·h/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation. (Cancer Sci 2012; 103: 1304–1310)

Pouchitis after ileal pouch-anal anastomosis in ulcerative colitis: diagnosis, management, risk factors, and incidence

Restorative proctocolectomy with ileal pouch‐anal anastomosis has been the surgical treatment of choice for patients with ulcerative colitis who require surgery. Quality of life after this procedure is satisfactory in most cases; however, pouchitis is a troublesome condition involving inflammation of the ileal pouch. When a patient presents with symptoms of pouchitis, such as increased bowel movements, mucous and/or bloody exudates, abdominal cramps, and fever, endoscopy is essential for a precise diagnosis. The proximal ileum and rectal cuff, as well as the ileal pouch, should be endoscopically observed. The reported incidence of pouchitis ranges from 14% to 59%, and antibiotic therapy is the primary treatment for acute pouchitis. Chronic pouchitis includes antibiotic‐dependent and refractory pouchitis. Intensive therapy including antitumor necrosis factor antibodies and steroids may be necessary for antibiotic‐refractory pouchitis, and pouch failure may occur despite such intensive treatment. Reported risk factors for the development of pouchitis include presence of extraintestinal manifestations, primary sclerosing cholangitis, non‐smoking, and postoperative non‐steroidal anti‐inflammatory drug usage. In the present review, we focus on the diagnosis, endoscopic features, management, incidence, and risk factors of pouchitis in patients with ulcerative colitis who underwent ileal pouch‐anal anastomosis.

Hereditary gastrointestinal cancer

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li–Fraumeni syndrome.

Temsirolimus and chloroquine cooperatively exhibit a potent antitumor effect against colorectal cancer cells.

PurposeTemsirolimus (TEM) is a novel, water-soluble mammalian target of rapamycin (mTOR) inhibitor that has shown activity against a wide range of cancers in preclinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored.MethodsWe evaluated the antitumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in vitro and in vivo. In vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Antitumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in vitro and in vivo.ResultsIn vitro, TEM was effective in inhibiting the growth of two CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1α and VEGF in all three cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. We also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the antitumor activity of TEM in vitro and in vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio.ConclusionsBased on these data, we propose TEM with or without chloroquine as a new treatment option for CRC.

Surveillance colonoscopy for colitis-associated dysplasia and cancer in ulcerative colitis patients

Long‐standing ulcerative colitis patients are known to be at high risk for the development of colorectal cancer. Therefore, surveillance colonoscopy has been recommended for these patients. Because colitis‐associated colorectal cancer may be difficult to identify even by colonoscopy, a random biopsy method has been recommended. However, the procedure of carrying out a random biopsy is tedious and its effectiveness has also not yet been demonstrated. Instead, targeted biopsy with chromoendoscopy has gained popularity in European and Asian countries. Chromoendoscopy is generally considered to be an effective tool for ulcerative colitis surveillance and is recommended in the guidelines of the British Society of Gastroenterology and the European Crohns and Colitis Organisation. Although image‐enhanced endoscopy, such as narrow‐band imaging and autofluorescence imaging, has been investigated as a potential ulcerative colitis surveillance tool, it is not routinely applied for ulcerative colitis surveillance in its present form. The appropriate intervals of surveillance colonoscopy have yet to be determined. Although the Japanese and American guidelines recommend annual or biannual colonoscopy, the British Society of Gastroenterology and the European Crohns and Colitis Organisation stratified their guidelines according to the risks of colorectal cancer. A randomized controlled trial comparing random and targeted biopsy methods has been conducted in Japan and although the final analysis is still ongoing, the results of this study should address this issue. In the present review, we focus on the current detection methods and characterization of dysplasia/cancer and discuss the appropriate intervals of colonoscopy according to the stratified risks.

Clinical pattern and progression of ulcerative proctitis in the Japanese population: a retrospective study of incidence and risk factors influencing progression

The rate of extension of proctitis in Western countries has been reported, but no data regarding long‐term follow‐up have been described for the Japanese population. Additionally, patients with long‐standing or extensive ulcerative colitis have an increased risk for developing colorectal cancer. This study evaluated both the rate of extension of the disease and the development of neoplasia among patients with an initial diagnosis of ulcerative proctitis.

Appendiceal orifice inflammation is associated with proximal extension of disease in patients with ulcerative colitis.

Ulcerative colitis (UC) is considered to be a disease of continuous mucosal inflammation extending proximally from the rectum. However, appendiceal orifice inflammation (AOI) is a skip lesion with segments of continuous involvement from the rectum. The aim of this study was to examine the clinical characteristics and clinical course, particularly focused on proximal extension, of UC in patients with AOI.

Tracheobronchitis with dyspnea in a patient with ulcerative colitis.

We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patients respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement.

Results of a 36‐year surveillance program for ulcerative colitis‐associated neoplasia in the Japanese population

Surveillance colonoscopy has been carried out for patients with long‐standing ulcerative colitis who have an increased risk for colorectal cancer. The aim of the present study was to determine the incidence of and the risk factors for neoplasia.

Ulcerative colitis with hepatitis B virus infection treated successfully by granulocyte monocyte apheresis.

Ulcerative colitis (UC) is a major type of idiopathic inflammatory bowel disease (IBD). Immunosuppressive therapies are used to treat IBD patients. Clinicians have strong concerns about using immunosuppressive therapies for IBD patients with hepatitis B virus (HBV) infection because aggressive immunosuppressive therapy can promote reactivation of HBV. For that reason, physicians hesitate to use steroids or other immunosuppressive drugs for IBD patients with HBV infection. Granulocyte monocyte apheresis (GMA) is a safe and effective therapy for UC patients. In Japan, a maximum of 11 sessions of GMA are allowed for moderate‐to‐severe, steroid‐resistant UC patients. However, the effects of GMA on HBV remain unclear. This case report describes a 39‐year‐old man with active UC complicated by HBV infection. Although his symptoms improved with steroid treatment while under entecavir therapy, clinical remission could not be maintained after the steroid dosage was decreased, so GMA was started. After GMA initiation, the frequency of diarrhea decreased and his symptoms improved, and the steroid dosage could be decreased. During the course of GMA, the patient did not experience deterioration in his hepatitis and the HBV DNA level gradually decreased, although GMA itself did not affect the HBV DNA level during each session of GMA. Results show that GMA is a safe and efficacious strategy against UC complicated by HBV without affecting hepatitis because GMA had no remarkable effect on HBV activity. J. Clin. Apheresis 31:584–586, 2016.