Eijiro Harada

Long-term survival of xenogeneic heart grafts achieved by costimulatory blockade and transient mixed chimerism.

Background. Xenotransplantation holds great promise in clinical medicine, but is limited by the vigorous rejection response elicited against solid organs transplanted across species barriers. In this study, we investigated the role of anti-CD40L monoclonal antibody (mAb) in inducing xenogeneic mixed chimerism and donor-specific heart transplantation tolerance. Methods. One day before heart transplantation, mice were injected intraperitoneally with anti-mouse CD8/NK1.1/Thy1.2 mAbs. On day 0, the mice received 3 Gy total body irradiation (TBI), an intravenous injection of unseparated bone marrow (BM) harvested from F344 rats, and an intraperitoneal injection of hamster antimouse CD40L mAb, MR1. Heart grafts from F344 rats were heterotopically transplanted into the abdomen of B6 mouse recipients. Using flow cytometric analysis of peripheral white blood cells, we assessed donor hematopoiesis at various times after bone marrow transplantation (BMT). Results. Chimerism subsided gradually and disappeared completely 18 weeks after BMT. The cardiac graft survived permanently, even after the mixed chimerism disappeared. To determine if the mice acquired donor-specific tolerance, second rat heart grafts were transplanted 120 days after the first heart transplantation. The second transplanted hearts were also accepted over 60 days. Histological analysis revealed no remarkable vasculopathy in the coronary vessels at any stage. Conclusions. These findings clearly show that costimulatory blockade plays an important role in inducing xenochimerism, and that transient mixed chimerism can induce permanent acceptance of rat to mouse cardiac xenografts. Transplantation of xenogeneic bone marrow cells under costimulatory blockade at the time of heart transplantation may induce transplantation tolerance.

Single-incision laparoscopic splenectomy and splenic autotransplantation for an enlarged wandering spleen with torsion.

A wandering spleen is a rare condition in which the spleen is not located in the left upper quadrant, but instead is found in the lower abdomen or in the pelvic region because of the laxity of the peritoneal attachments. The unusually long pedicle is susceptible to twisting, which can lead to ischemia, and eventually to necrosis. We herein report a case of an enlarged wandering spleen with torsion, successfully treated by single-incision laparoscopic splenectomy and autotransplantation. The transplanted splenic tissues could be identified on a spleen scintigram obtained 3 months after the surgery. Howell-Jolly bodies were not observed in blood specimens. This procedure is able to prevent an overwhelming postsplenectomy infection, and leads to satisfactory cosmetic results.

Loss of skeletal muscle mass after curative gastrectomy is a poor prognostic factor

Sarcopenia has been reported to relate to poor prognosis in various malignant cancer types. The present study aimed to clarify the prognostic impact of skeletal muscle mass (SMM) loss after curative gastrectomy in patients with gastric cancer. A total of 119 patients who underwent curative gastrectomy for gastric cancer between 2009 and 2016 were analyzed. The SMM loss at 6 months postoperatively compared with the SMM prior to surgery was calculated using the hospital records. The median loss of SMM was 3.8%. Multivariate logistic regression analysis demonstrated that total gastrectomy was a significant and independent risk factor for SMM loss of ≥5% (odds ratio=2.58; P=0.02). Results from multivariate analysis using stepwise Cox proportional hazards regression indicated that the following factors were significantly associated with shorter overall survival after curative gastrectomy: Age [>70 years; hazard ratio (HR)=2.46, P=0.04], TNM stage (≥2; HR=2.65, P=0.04) and loss of SMM (≥5%; HR=2.57, P=0.03). The present findings suggested that loss of SMM after curative gastrectomy for gastric cancer is an independent predictive factor for poor prognosis.

JAB1‑STAT3 activation loop is associated with recurrence following 5‑fluorouracil‑based adjuvant chemotherapy in human colorectal cancer

Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia-inducible factor-1α. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5-FU-based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5-FU-based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5-FU-based adjuvant chemotherapy.

Tips for laparoscopic pancreaticoduodenectomy

Laparoscopic pancreaticoduodenectomy (LPD) is one of the most complex procedures performed in laparoscopic abdominal surgery, and its practice is still limited to only a few selected centers. Surgeons need to be proficient in advanced laparoscopic techniques and have a thorough understanding of the advantages and disadvantages inherent to the laparoscopic approach. LPD can be divided into the following steps: division of the omentum and colon mobilization; division of the proximal bowel and gastroduodenal artery, and transection of the common bile duct; making a retropancreatic window; dissection of ligament of Treitz and division of the distal bowel; dissection of the uncinate process and superior mesenteric vessels; and reconstruction. In this article, we describe our conventional technique for LPD.

Laparoscopic low anterior resection for rectal cancer after Whitehead's hemorrhoidectomy: A case report

A 65‐year‐old man presented with bloody stool. Colonoscopy revealed a raised tumor in the rectum, above the peritoneal reflection. He underwent endoscopic mucosal resection, but the pathological findings suggested the possibility of residual cancer. We performed laparoscopic low anterior resection using a circular stapling instrument for additional curative surgery. However, we could not insert the shaft of the endoscopic circular stapler from the anus because of anal stenosis due to Whiteheads hemorrhoidectomy the patient had undergone 20 years earlier. Therefore, we planned to use a linear stapler to insert an anvil into the rectum. The cartridge‐carrying instrument was inserted from the sigmoidal side, and we performed a side‐to‐end anastomosis. The patient was discharged without anastomotic leakage or defecation disorder. We present this case because laparoscopic low anterior resection for rectal cancer with anal stenosis has not been previously reported.

Portal and mesenteric vein resection during pancreaticoduodenectomy and total pancreatectomy

Background Portal vein invasion by a malignant pancreatic mass is currently not a contraindication to pancreatic resection with acceptable oncologic outcomes. Aim The aim of this paper was to identify the perioperative morbidity and long-term outcomes of venous resection (VR) during pancreaticoduodenectomy (PD) and total pancreatectomy (TP) operations. Materials and methods We carried out a retrospective study of patients undergoing PD or TP between March 1995 and December 2014 at Mayo Clinic in Jacksonville, Florida, using data collected from an institutional review board-approved prospective database. Preoperative, operative, and postoperative clinicopathological data were collected and analyzed. Results Out of 601 patients who underwent PD and TP in this study, 104 (17.3%) underwent VR. The types of VR and reconstruction were as follows: type I (lateral venorrhaphy) in 49 (47.1%) patients, type II (patch graft) in 10 (9.6%) patients, type III (primary anastomosis) in 27 (26%) patients, and type IV (interposition venous graft) in 16 (15.4%) patients. Two (1.9%) patients underwent no portomesenteric reconstruction. The 90-day major postoperative complications and mortality in patients with VR were 44.2 and 7.7%, respectively, versus 29.2 and 4.4%, respectively, in patients with standard resection. The 1-year, 3-year, 5-year, and 7-year survival rates in VR with periampullary adenocarcinoma (PAAC) were 55.1, 27, 21.9, and 15.4%, respectively, whereas in patients with PAAC without VR, the survival rates were 78.4, 45.6, 34.6, and 30.9%, respectively (P<0.01). Conclusion VR and reconstruction with PD can be performed safely with acceptable perioperative morbidity and long-term survival rates to achieve complete removal of the tumor.

Abstract 1072: Synergistic effect of gemcitabine and a Dclk1 inhibitor on pancreatic cancer cell survival

Pancreatic cancer has the highest mortality rate of all major cancers and is one of the most lethal malignancies. There is a constant upward trend in the number of patients diagnosed with pancreatic cancer and the number of deaths due to pancreatic cancer. Gemcitabine (GEM) is often used in the treatment of pancreatic cancer (PDAC), but has limited effects. Doublecortin-like kinase 1 (Dclk1) is important in the progression of early pancreatic neoplastic lesions and PDAC. However, the functional role of Dclk1 in PDAC is unknown. To identify the substrate protein phosphorylated by Dclk1, we performed a protein microarray analysis on Dclk1 knockdown cells. The results of this analysis directed our studies toward Chk1, which is known to be a potential regulator of the cell cycle and experiences upregulation of phosphorylation after GEM treatment. In general, GEM treatment results in DNA damage to pancreatic cancer cells, an increase in phosphorylated Chk1 (p-Chk1), and arrests the cell cycle progression to repair the damaged DNA. On the basis of the preliminary data, we hypothesized that the decrease in Chk1 phosphorylation by Dclk1 inhibition circumvents cell cycle arrest and impairs the subsequent DNA repair. The aim of this study was to evaluate the synergistic effect of Dclk1 inhibition and GEM treatment on pancreatic cancer cell survival. We used the human pancreatic cancer cell line MIA PaCa-2 and LRRK2-IN-1 (LRRK) as the Dclk1 inhibitor for this study. First, we examined the effects of GEM or the Dclk1 inhibitor or both on cancer cell proliferation and the expression of p-Chk1. Significantly decreased cell proliferation was observed on co-treatment of GEM and LRRK compared to GEM treatment alone. In addition, the expression of p-Chk1 significantly decreased on co-treatment compared to GEM treatment alone. Second, we used flow cytometry to analyze the cell cycle after treatment with GEM and/or LRRK. Almost all cancer cells treated with GEM alone were arrested in the S phase of the cell cycle. The addition of LRRK allows the cell cycle to proceed in the same manner as untreated control cancer cells do. We also evaluated DNA damage by measuring the intensity of gamma-H2AX. Cancer cells that were co-treated experienced more DNA damage than with GEM treatment alone. The co-treatment induced apoptosis without the repair of DNA damage in the cancer cells. In conclusion, the combined treatment with GEM and a Dclk1 inhibitor decreased the cell survival rate compared to treatment with GEM alone through the suppression of p-Chk1. Targeting Dclk1 in combination with GEM might offer an excellent opportunity for future pancreatic cancer treatments. Citation Format: Daichi Kawamura, Yoshihiro Takemoto, Arata Nishimoto, Toshiki Tanaka, Yukari Hironaka, Kumiko Yoshida, Junichi Murakami, Naruji Kugimiya, Eijiro Harada, Koji Ueno, Tohru Hosoyama, Kimikazu Hamano. Synergistic effect of gemcitabine and a Dclk1 inhibitor on pancreatic cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1072. doi:10.1158/1538-7445.AM2017-1072