Hiromitsu Iwamoto

Antitumor immune response of dendritic cells (DCs) expressing tumor‐associated antigens derived from induced pluripotent stem cells: In comparison to bone marrow‐derived DCs

It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC‐based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell‐derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow‐derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (+) cytotoxic T lymphocytes (CTLs) was assayed using a 51Cr‐release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100‐specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor‐associated antigen‐specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.

Literature review of the energy sources for performing laparoscopic colorectal surgery.

Laparoscopic surgery for colorectal disease has become widespread as a minimally invasive treatment. This is important because the increasing availability of new devices allows us to perform procedures with a reduced length of surgery and decreased blood loss. We herein report the results of a literature review of energy sources for laparoscopic colorectal surgery, focused especially on 6 studies comparing ultrasonic coagulating shears (UCS) and other instruments. We also describe our laparoscopic dissection techniques using UCS for colorectal cancer. The short-term outcomes of surgeries using UCS and Ligasure for laparoscopic colorectal surgery were superior to conventional electrosurgery. Some authors have reported that the length of surgery or blood loss when Ligasure was used for laparoscopic colorectal surgery is less than when UCS was used. On the other hand, a recent study demonstrated that there were no significant differences between the short-term outcomes of UCS and Ligasure for laparoscopic colorectal surgery. It is therefore suggested that the choice of technique used should be made according to the surgeons preference. We also describe our laparoscopic dissection techniques using UCS (Harmonic ACE) for colorectal cancer with regard to the retroperitoneum dissection, dissection technique, dissection technique around the feeding artery, and various other dissection techniques. We therefore review the outcomes of using various energy sources for laparoscopic colorectal surgery and describe our laparoscopic dissection techniques with UCS (Harmonic ACE) for colorectal cancer.

Oncological Outcomes following Rectal Cancer Surgery with High or Low Ligation of the Inferior Mesenteric Artery

Background: The level of inferior mesenteric artery (IMA) ligation for anterior resection of rectal cancer has several considerations concerning oncological outcomes. The primary endpoint of this randomized controlled trial (RCT) was to assess bowel function between high and low ligation. This study was intended to clarify oncological outcome as the secondary endpoint. Objective: The aim of this study was to assess in a prospective RCT whether the ligation level of the IMA in rectal cancer influences oncological outcomes. Methods: Between February 2008 and December 2011, 100 patients who underwent anterior resection for rectal cancer were randomized to perform either high or low ligation of the IMA. Oncological outcomes was the secondary endpoint of this RCT, whereas assessing bowel function was the primary endpoint. This RCT was registered at clinicaltrials.gov (NCT00701012). Results: There were no differences between the groups in terms of clinical data except for tumor stage. There were more advanced-stage patients in the high ligation group (p = 0.046). There were no lymph node (LN) metastases in the root of the IMA in the high ligation group. The average number of harvested LNs for the high and low ligation groups was 16.7 and 14.9, respectively. There was no difference in disease-free survival (DFS), site of first recurrence, and overall survival (OS). When patients were in stage III, there was also no difference in DFS and OS. Conclusions: The ligation level of the IMA in rectal cancer may not influence oncological outcomes. However, further large-scale RCTs are needed to conclude this issue.

Successful laparoscopic resection for cap polyposis: case report, literature review

BackgroundCap polyposis is a rare gastrointestinal disease with endoscopically and pathologically distinctive features. Its exact etiology has not been fully elucidated. In a few cases, there was recurrence after inadequate treatment. Efficacy of Helicobacter pylori eradication therapy, however, has been shown in some published research.Case presentationA 70-year-old female patient developed intermittent mucous diarrhea with loss of body weight and visited a physician. Total colonoscopy showed multiple sessile polyps which were partially coadunated from the rectum to the sigmoid colon. Histopathological finding was tubular adenoma with mild atypia. The patient stayed for observation. Worsening symptoms following protein-losing enteropathy demanded surgical treatment because malignancy could not be ruled out. Laparoscopic resection was performed, and the surgical specimens revealed that the polypoid lesion mainly consisted of mild adenomatous glands which were covered with purulent granulation tissues. We made final diagnosis of cap polyposis and saw rapid improvement of her symptoms. Long-term observation is required after surgery.ConclusionsWe reported a case of successful laparoscopic resection of cap polyposis with protein-losing enteropathy (170 words).

Cancer Vaccine Therapy Using Carcinoembryonic Antigen - expressing Dendritic Cells generated from Induced Pluripotent Stem Cells

Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model. We differentiated hiPSDCs from iPSCs of three healthy donors and transduced CEA cDNA into the hiPSDCs. The surface marker expression, cytokine secretion and migratory capacity of the hiPSDCs were equivalent to those of human monocyte-derived DCs (hMoDCs). Cytotoxic T cells activated by hiPSDCs-CEA exhibited CEA-specific cytotoxic activity against the target cells expressing CEA. Furthermore, in the CEA transgenic mouse model, cytotoxic T cells activated in mice immunized with miPSDCs-CEA displayed CEA-specific cytotoxic activity against MC38-CEA. In the subcutaneous tumour model, vaccination with miPSDCs-CEA achieved a significant growth inhibitory effect on MC38-CEA. No adverse events caused by the administration of miPSDCs were observed. Genetic modification of iPSDCs, inducing the expression of CEA, is a promising tool for clinical applications of vaccine therapy for treating gastrointestinal cancer patients.

Using indocyanine green fluorescent imaging to successfully resect metachronous regional lymph node recurrence of rectosigmoid cancer

A 39‐year‐old female patient underwent anterior resection with locoregional lymph node dissection for rectosigmoid cancer at another hospital. The procedure involved transection of the superior rectal artery just below the origin of the left colic artery. Postoperative diagnosis was stage III B. The patient received adjuvant chemotherapy with oxaliplatin plus capecitabine for 6 months. Sixteen months after the operation, PET‐CT scans revealed regional lymph node metastases around the root of the inferior mesenteric artery. The patient was referred to our hospital with a recurrence of rectosigmoid cancer. We performed laparoscopic lymph node dissection with real‐time indocyanine green fluorescent images superimposed on color images to prevent intraoperative vascular insufficiency. We were able to successfully observe the sufficient blood flow in the descending colon. Postoperative pathological findings showed lymph node recurrence after initial surgery. She was discharged 7 days after the operation. In the 8 months since the second operation, the patient has not had any indication of further recurrence.

Horizontal rectal transection using an endolinear stapler for laparoscopic low anterior resection

Multiple firings with multiple cartridges for rectal transection have been reported as potential causes of anastomotic leakage in laparoscopic low anterior resection with the double-stapling technique [1]. Here we demonstrate an effective new method for horizontal transection of the rectum that we have used for laparoscopic low anterior resection, using a large endovascular clip for rectal alignment. The patient is placed in the head-down lithotomy position with the right side tilted down and the surgeon on the patient’s right. Five-port trocars including two 12-mm ports, two 5-mm ports, and a blunt port were introduced (Fig. 1). Pneumoperitoneum is created using carbon dioxide, and laparoscopic exploration is performed. After complete mobilization of the rectum to the levators, the surgeon inserts the linear stapler through the right lower quadrant port (Fig. 2a, b). The assistant through the left upper quadrant port pulls the rectum forward and cranially rolling it in a counterclockwise direction. The surgeon through the right upper quadrant port also rolls the rectum in a counterclockwise direction to align the horizontal line of the rectum with the linear staple insertion line (Fig. 2c, d). A 70-mm endovascular clip (B. Braun Aesculap Co., Tokyo, Japan) is introduced through the right lower quadrant port aligning, and the rectal wall is clamped below the tumor (Figs. 2e, 3a). Figure 3b shows the 70-mm endovascular clip. A distal rectal washout is performed using 1000 ml of 5% povidone-iodine solution. An endolinear stapler (Echelon FLEX 60 ; Ethicon EndoSurgery, Cincinnati, OH, USA) is inserted through the right lower quadrant port and then applied at the rectal wall parallel and caudal to the 70-mm endovascular clip (Fig. 3c). The assistant forceps in the left lower quadrant port pushes the distal rectum to the right, and the endolinear stapler with opened jaws is simultaneously pushed deeper into the left side space. The jaws are then closed at a position that enabled transection of the rectum with one firing using a single cartridge (Fig. 3d). Figure 3e shows Fig. 1 Port sites

Perineural Invasion Is Associated with Poor Survival after Preoperative Chemoradiation Therapy for Advanced Lower Rectal Cancer

Background: Preoperative chemoradiation therapy (pCRT) is a standard procedure for patients with advanced lower rectal cancer. It has been reported that pCRT cannot prolong the survival of patients with advanced lower rectal cancer. The aim of this study is to address the controllable and uncontrollable pathological factors of pCRT in predicting local and distant recurrences. Methods: One hundred two patients with stages 2 and 3 cancer were consecutively enrolled to the study. The first 51 patients (October 2008-August 2010) underwent curative resection without pCRT. The latter 51 patients (September 2010-May 2015) underwent curative resection after pCRT. Pathological factors of patients were evaluated to assess the association between local and distant recurrences. Results: Multivariate analyses for local and distant recurrences of patients without pCRT revealed that the independent risk factors were tumor deposit and perineural invasion respectively. pCRT was able to diminish circumferential resection margin, tumor deposit, venous invasion, and lymphatic permeation but not neural invasion and lymph node involvement. Kaplan-Meier curve of local and distant recurrence-free survival of patients with pCRT illustrated that tumor deposit is controllable, whereas perineural invasion is uncontrollable by pCRT. Conclusion: pCRT-uncontrollable perineural invasion may be a factor for distant recurrence of advanced rectal cancer patients, leading to poor survival.

Expression of P4H9-detecting molecule on spindle-shaped fibroblasts to indicate malignant phenotype of colorectal cancer.

539 Background: Cancer cells and fibroblasts are coordinated for cancer progression. Our previous study has shown that P4H9, produced by epitope for b2 integrin, detected a molecule on fibroblasts in mammary fat pad mouse model in response to Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressing cancer cells. P4H9 detecting molecule (PDM) expression appeared to be associated with myofibroblast differentiation. The aim of the present study is to investigate whether PDM express on fibroblast and cancer cells in clinical tissue samples, and whether PDM expressing cells in colorectal cancer tissue are correlated with clinicopathological features of patients with colorectal cancer. Methods: Immunohistochemistry were conducted with P4H9 on clinical tissue samples from 156 patients with colorectal cancer. The risk factors for metastases and survival were calculated for clinical implication of PDM expressing spindle shaped fibroblasts. Immunofluorescence with P4H9 were performed on CCD-18...

Laparoscopic abdominoperineal resection with lateral lymph node dissection for anorectal melanoma: A case report.

Because anorectal melanoma, a rare cancer with a poor outcome, does not respond well to local radiation therapy or systemic chemotherapy, surgery is the primary treatment. Herein, we present a case of anorectal melanoma with lateral and inguinal lymph node metastases. A 61‐year‐old woman presented with rectal bleeding. Colonoscopy revealed a black tumor with ulceration in the anorectum. A CT scan revealed an anorectal tumor with left lateral lymph node swelling and right inguinal lymph node swelling. We performed a laparoscopic abdominoperineal resection with lateral lymph node dissection and right inguinal lymph node dissection. One year after the initial operation, pulmonary metastases were observed, and pulmonary resection was performed. After the pulmonary resection, brain metastases developed, and surgical resection was performed. Despite the recurrence of disease, the patient has survived for 52 months since the initial surgery and continues to receive systemic chemotherapy.