Fumihiko Fujita

The risk factors and predictive factors for anastomotic leakage after resection for colorectal cancer: reappraisal of the literature

Anastomotic leakage is a serious complication that can occur after colorectal surgery. Several risk factors for anastomotic leakage have been reported based on the findings of prospective and retrospective studies, including patient characteristics, the use of neoadjuvant therapy, the tumor location, intraoperative events, etc. However, as these risk factors affect each other, the statistical results have differed in each study. In addition, differences in surgical methods, including laparoscopy versus laparotomy or stapling anastomosis versus handsewn anastomosis, may influence the incidence of anastomotic leakage. This mini-review summarizes the results of reported papers to clarify the current evidence of risk factors for anastomotic leakage.

Inactivation of porcine endogenous retrovirus by human serum as a function of complement activated through the classical pathway

BACKGROUND: The clinical use of organs and cells of pig donors as a source of tissue for xenotransplantation and extracorporeal therapies has been problematic due to the risk for zoonotic infection of porcine endogenous retroviruses (PERV). METHODS: The effect of human serum on PERV was evaluated using an infectivity assay and virolysis assay. Cell-free PERV infection to human 293 cells was determined by the presence of proviruses 5 days post-infection by a highly sensitive nested PCR, and the lysis of PERV virions was determined by the reverse transcriptase activities released into the supernatant. RESULTS: Treatment of PERV-PK, the culture supernatant of a pig kidney cell line containing the virus titer of 10(2.8) TCID(50) units/ml, with a quarter volume of human serum completely inactivated the infectivity. This activity was heat-labile and sensitive to an anti-complement agent, nafamostat mesilate, and a Ca(2+)-chelator, EGTA, indicating the crucial involvement of complement activated through the classical pathway. Since a synthetic galactosyl alpha1-3 galalactose (Galalpha1-3Gal) largely absorbed the activity from the serum, natural antibodies to the Galalpha1-3Gal epitopes are likely to trigger the complement activation. CONCLUSION: Cell-free PERV seems no longer be infectious in human serum. This greatly encourages the clinical application of pig tissues in particular for extracorporeal therapies such as a bioartificial liver, in which pig cells do not come in direct contact with a recipient.

Efficacy of Multilayered Hepatocyte Sheet Transplantation for Radiation-Induced Liver Damage and Partial Hepatectomy in a Rat Model

Although cell sheet technology has recently been developed for use in both animal experiments and in the clinical setting, it remains unclear whether transplanted hepatocyte sheets improve the liver function in vivo. Radiation-induced liver damage (RILD) combined with partial hepatectomy (PH) has been reported to suppress the proliferation of host hepatocytes and induce critical liver failure. The aim of this study was to improve the liver function in the above-mentioned diseased rat model (RILD + PH) using multilayered hepatocyte sheet transplantation. In this study, we used Fischer rats as a donor for primary hepatocytes and dermal fibroblast isolation. Cocultured multilayered hepatocyte sheets were generated by disseminating hepatocytes onto fibroblasts cultured beforehand on temperature-responsive culture dishes. Four cell sheets were transplanted into the recipient rats subcutaneously. Prior to transplantation, RILD (50 Gy) with 2/3PH was induced in the recipients. The same model was applied in the control group without transplantation. The serum was collected each week. The rats in both groups were sacrificed at 2 months after transplantation for the histological analysis. Consequently, the serum albumin concentrations were significantly higher in the transplant group than in the control group (54.3 ± 9.6 vs. 32.7 ± 5.7 mg/ml; p < 0.01) after 2 months and comparable to the serum albumin levels in the normal rats (58.1 ± 6.4 mg/ml). In addition, treatment with the transplanted sheets significantly improved the survival rate (57% vs. 22%, p < 0.05), and the hepatocyte sheets showed the storage of albumin, glycogen, and bile canaliculus structures. Some hepatocytes and fibroblasts were positive for Ki-67, and vascularization was observed around the cell sheets. Transplanted multilayered hepatocyte sheets can survive with additional proliferative activity, thereby maintaining the liver function in vivo for at least 2 months, providing metabolic support for rats with RILD.

Immune complexome analysis reveals the specific and frequent presence of immune complex antigens in lung cancer patients: A pilot study.

Cancer immunotherapies such as antibodies targeting T cell checkpoints, or adaptive tumor‐infiltrating lymphocyte (TIL) transfer, have been developed to boost the endogenous immune response against human malignancies. However, activation of T cells by such antibodies can lead to the risk of autoimmune diseases. Also, the selection of tumor‐reactive T cells for TIL relies on information regarding mutated antigens in tumors and does not reflect other factors involved in protein antigenicity. It is therefore essential to engineer therapeutic interventions by which T cell reactivity against tumor cells is selectively enhanced (i.e., “focused cancer immunotherapy”) based on tumor antigens that are specifically expressed in the tumor of a certain cancer and in many patients with this cancer. Immune complexes (ICs) are the direct and stable products of immunological recognition by humoral immunity. Here, we searched for tumor‐specific IC antigens in each of five cancers (lung (n = 28), colon (n = 20), bladder (n = 20), renal cell (n = 15) and malignant lymphoma (n = 9)), by using immune complexome analysis that comprehensively identifies and profiles the constituent antigens in ICs. This analysis indicated that gelsolin and inter‐alpha‐trypsin inhibitor heavy chains were specifically and frequently detected (at a frequency higher than 80%), and that phosphoproteins (VENTX, VCIP135) were also specifically present in the ICs of lung cancer patients. Immune complexome analysis successfully identified several tumor‐specific IC antigens with high detection frequency in lung cancer patients. These specific antigens are required to validate the clinical benefit by further analysis using a large number of patients.

A novel animal model of long-term sustainable anal sphincter dysfunction

BACKGROUND Although intersphincteric resection can avoid the need for permanent colostomy in patients with lower rectal cancer, it sometimes causes anal sphincter dysfunction, thus resulting in a lifelong, debilitating disorder due to incontinence of solid and liquid stool. The development of regenerative medicine could improve this condition by regenerating impaired anal muscle. In order to prove this hypothesis, preliminary experiments in animals will be indispensable; however, an adequate animal model is currently lacking. The purpose of this study was to establish a novel animal model with long-term sustainable anal sphincter dysfunction. MATERIALS AND METHODS Twenty male Sprague-Dawley rats were allocated into sham operation (n = 10) and anal sphincter resection (ASR) (n = 10) groups. The ASR group underwent removal of the left half of both the internal and external anal sphincters. Both groups were evaluated for anal function by measuring their resting pressure before surgery and on postoperative day (POD) 1, 7, 14, and 28. RESULTS The rats in the sham operation group recovered their anal pressure up to baseline on POD 7. The rats in the ASR group showed a significant decrease in anal pressure on POD 1 (P < 0.0001) compared with the baseline, and kept this low pressure until POD 28 (P < 0.0001). The defect of the anal sphincter muscle was confirmed histologically in the ASR group on POD 28. CONCLUSIONS The present novel model exhibits continuous anal sphincter dysfunction for at least 1 mo and may contribute to further studies evaluating the efficacy of therapies such as regenerative medicine.

Suppression of reactive oxygen species develops lymph node metastasis in colorectal cancer.

BACKGROUND/AIMS Recent evidence indicates that reactive oxygen species (ROS) can induce a wide type of cellular responses from proliferation to senescence and cell death. ROS may not be an absolute carcinogenic factor or cancer suppressor. The aim of this study was to assess the biological paradox of ROS in colorectal cancer cells. METHODOLOGY Blood specimens were obtained from the drainage vein of the tumor during operation in 135 patients with colorectal cancer. Serum ROS levels were measured using the derivatives of reactive oxygen metabolites (d-ROM) test. RESULTS Serum ROS levels increased significantly in tumor size larger than 40mm (p<0.01). On the other hand, serum ROS levels decreased significantly in patients with lymph node metastasis (p<0.01). Multiple linear regression models showed a significant association of serum ROS levels with serum carcinoembryonic antigen (CEA) levels (p<0.01) and lymph node metastasis (p=0.026). CONCLUSIONS In colorectal cancer cells, the increase of intracellular ROS is first associated with cell growth and invasion. However, a further increase inhibits cancer cell proliferation, whereas any decrease in ROS concentration needs to stimulate lymph node metastasis. Thus, a precise understanding how ROS are generated and involved in lymph node metastasis will help us to design better therapeutic strategies.

Epiploic appendagitis in a 27-year-old man.

Summary Background Epiploic appendagitis is an ischemic infarction of an epiploic appendage caused by torsion or spontaneous thrombosis of the central draining vein. Epiploic appendagitis is self-limited without surgery, and it is imperative for clinicians to be familiar with this entity. Case Report A healthy 27-year-old man was admitted due to acute right lower quadrant abdominal pain. Physical examination showed focal abdominal tenderness with slight rebound tenderness. Laboratory tests showed leukocytosis and an increased serum C-reactive protein level. Computed tomography (CT) showed a fatty ovoid pericolonic mass measuring 12 mm in diameter, with a circumferential hyperdense ring that abutted on the ascending colon and was surrounded by ill-defined fat stranding with a hyperdense ring. These findings were diagnostic of primary epiploic appendagitis. The patient was given high-dose antibiotics due to the secondary inflammation involving the parietal peritoneum. Conclusions Epiploic appendagitis presents with an abrupt onset of focal abdominal pain and tenderness without significant guarding or rigidity; it is an uncommon and difficult diagnosis. With awareness of this condition, however, evaluation by CT can provide an accurate diagnosis of epiploic appendagitis, distinguishing it from conditions with clinically overlapping manifestations.

Prediction and management of a low-lying costal arch which restricts the operative working space during laparoscopic cholecystectomy.

Background/purposeLaparoscopic cholecystectomy is difficult to perform in patients with a low-lying costal arch that entirely covers the liver. We conducted this study to clarify the factors related to a low-lying costal arch and establish countermeasures to circumvent this characteristic.MethodsThe study included 103 consecutive patients who underwent a laparoscopic cholecystectomy. The possible clinical factors associated with a low-lying costal arch restricting the operative working space were analyzed. The position of the liver against the costal arch and the presumed surgical visual angle for laparoscopic cholecystectomy, comprising the hepatic porta, umbilicus, and costal arch, were estimated with abdominal multidetector computed tomography (MDCT).ResultsSeven (7%) patients had a low-lying costal arch presenting an inadequate exposure of Calot’s triangle and restricted instrument mobility during laparoscopic cholecystectomy, and three patients required conversion to a laparotomy. A low-lying costal arch was significantly associated with advanced age, shorter stature, lighter body weight, coexisting kyphoscoliosis, gallbladder pathology, laparotomy conversion, and most of all, the liver edge lying above the costal arch and a narrow surgical visual angle upon MDCT. Of the seven patients with a critical low-lying costal arch, four underwent a successful laparoscopic cholecystectomy, this being done by lifting the right costal arch to create a workable surgical field; the rib-lifting procedure was planned as part of the scheduled procedure in the other three patients because the preoperative MDCT examination indicated a poor working space for a laparoscopic cholecystectomy.ConclusionsA low-lying costal arch is a substantial risk factor for conversion to a laparotomy when performing a laparoscopic cholecystectomy. However, the operative difficulty related to a low-lying costal arch can be predicted by using preoperative MDCT images and can be managed with proper planning and the appropriate use of the rib-lifting technique.

Hand-assisted laparoscopic subtotal colectomy with cecorectal anastomosis for chronic idiopathic colonic pseudo-obstruction: report of a case

Chronic idiopathic colonic pseudo-obstruction (CICP) is characterized by the chronic disturbance of colonic motility without mechanical obstruction, any underlying disease or medication. Currently, there are no established medical treatments for CICP. A 62-year-old female who had undergone right hemicolectomy for splenic flexure syndrome caused by idiopathic megacolon was referred to our hospital with relapse, experiencing palpitation and abdominal fullness. She was diagnosed with CICP according to findings of marked dilation of the colon without mechanical obstruction, dilation of other parts of the gastrointestinal tract, or underlying disease. The dilated colon was surgically removed by hand-assisted laparoscopic subtotal colectomy, followed by cecorectal anastomosis. Histopathologically, there was no degeneration or lack of ganglion cells in Auerbach’s plexus. The patient has experienced no severe symptoms after undergoing the present operation.

The serum level of carcinoembryonic antigen in drainage venous blood is not a sensitive predictor of metachronous hepatic metastasis for patients with colorectal cancer

PurposeTo establish whether the serum levels of carcinoembryonic antigen (CEA) in drainage venous blood (d-CEA) is a better predictor of prognosis or survival than the preoperative CEA level in peripheral venous blood (p-CEA), and how these two CEA levels compare as predictive factors for metachronous hepatic metastasis.MethodsWe examined specimens of peripheral and drainage venous blood from 119 patients with colorectal cancer.ResultsThere was a strong positive correlation between p-CEA and d-CEA levels. The 5-year survival rates were 81.5% and 80.2% for patients with normal p-CEA and d-CEA levels (≤5 ng/ml), respectively, and 68.4% and 71.1% for those with abnormal p-CEA and d-CEA levels (>5 ng/ml). The p-CEA and d-CEA levels were both normal in seven of ten patients with metachronous hepatic metastasis. The CEA gradient between the d-CEA and p-CEA levels (d-p CEA gradient) was not a significant predictive factor for hepatic metastases.ConclusionsThere was virtually no change between preoperative p-CEA and d-CEA levels. These findings suggest that the d-CEA level is not a predictor for metachronous hepatic metastasis and that measuring p-CEA levels is sufficient in the surveillance of colorectal cancer.