Yoshinori Ishikawa

Massachusetts General Hospital, Boston, MA, United States

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Publications (26)75.13 Total impact

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    ABSTRACT: Long-term tolerance of class I disparate renal allografts in miniature swine can be induced by a short course of cyclosporine and persists for 3 to 4 months after grafts are removed. Donor class I peptide immunization 6 weeks after graftectomy of tolerated kidneys leads to sensitization, but donor skin grafts do not. Here, we tested the hypothesis that skin grafts prevent rejection after simultaneous peptide administration and skin grafting. Miniature swine underwent bilateral nephrectomy and class I-mismatched renal transplantation with a 12-day course of cyclosporine A to induce long-term tolerance. Tolerated allografts were then replaced with recipient-matched kidneys, and animals were challenged with simultaneous donor-type skin grafts and peptide. Six weeks later, second donor-matched kidneys were transplanted without immunosuppression, and immune responses were characterized. Animals treated only with peptide (n=2) rejected subsequent renal transplants in 3 to 5 days with strong in vitro antidonor responses. Of five recipients of skin-plus-peptide regimen, two accepted kidneys long term, one demonstrated a modestly prolonged survival (11 days), and two rejected rapidly (5-7 days). The two long-term acceptors maintained donor-specific hyporesponsiveness in vitro. Sensitization by class I peptide in previously tolerant swine could be prevented by simultaneous class I skin grafts. These data suggest that skin grafts may actually augment rather than abrogate downregulation in some cases. A mechanistic hypothesis for this surprising result is that recognition of class I antigens through the direct rather than the indirect pathway of antigen presentation promotes tolerance by expanding regulatory T cells.
    Transplantation 12/2012; 94(12):1192-9. · 3.78 Impact Factor
  • Gastroenterology 05/2010; 138(5). · 12.82 Impact Factor
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    ABSTRACT: To investigate whether maximal sterile barrier precautions (MSBPs) during central venous catheter (CVC) insertion are truly effective in preventing catheter-related bloodstream infections (CRBSIs) in patients in general surgical units. The reported effectiveness of MSBPs was based on the results of a single-center randomized controlled trial by Raad et al and the majority of the patients (99%) in the study were chemotherapy outpatients. Between March 14, 2004 and December 28, 2006, the patients scheduled for CVC insertion in surgical units at 9 medical centers in Japan were randomly assigned to either an MSBP group (n = 211) or a standard sterile barrier precaution (SSBP) group (n = 213). This study was registered in the UMIN Clinical Trials Registry (registration ID number: UMIN000001400). The median (range) duration of catheterization was 14 days (0-92 days) in the MSBP group and 14 days (0-112 days) in the SSBP group. There were 5 cases (2.4%) of CRBSI in the MSBP group and 6 cases (2.8%) in the SSBP group (relative risk, 0.84; 95% confidence interval, 0.26-2.7; P = 0.77). The rate of CRBSIs per 1000 catheter days was 1.5 in the MSBP group and 1.6 in the SSBP group. There were 8 cases (3.8%) of catheter-related infections in the MSBP group and 7 cases (3.3%) in the SSBP group (relative risk, 1.2; 95% confidence interval, 0.43-3.1; P = 0.78). The rate of catheter-related infection per 1000 catheter days was 2.4 in the MSBP group and 1.9 in the SSBP group. This study is larger in sample size than the one performed by Raad et al and could not demonstrate better prevention of CRBSIs by MSBP compared with SSBP. A large randomized controlled trial or at least a meta-analysis of any other studies in the literature is necessary to reach to a conclusion on this issue.
    Annals of surgery 03/2010; 251(4):620-3. · 7.19 Impact Factor
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    ABSTRACT: Allogeneic skin is currently the best alternative to autologous skin as a temporary treatment for severe burns, but it has several drawbacks. As a potential alternative, we have evaluated GalT-KO swine skin, which lacks expression of the Gal epitope, to investigate the effect of eliminating this epitope on survival of pig-to-baboon skin grafts. Two adult baboons that had fully recovered from previous T cell depletion received simultaneous skin grafts from: (i) GalT-KO swine, (ii) Gal-positive swine, (iii) a third-party baboon, and (iv) self (control skin). Recipients were treated with cyclosporin for 12 days and the survival, gross appearance, and histology of the grafts were compared. In both baboons, the GalT-KO skin survived longer than either the Gal-positive swine skin or the allogeneic skin. Early rejection of the Gal-positive skin appeared to be mediated by cytotoxic preformed anti-Gal IgM antibodies, while the rejection of GalT-KO skin appeared to result from cellular mechanisms. GalT-KO skin may have potential clinical benefits as an alternative to allogeneic skin as a temporary treatment for severe skin injuries.
    Xenotransplantation 03/2010; 17(2):147-52. · 1.78 Impact Factor
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    ABSTRACT: Clinical intestinal transplantation (Int-Tx) is limited by high rates of rejection, infection, and graft versus host disease. To improve clinical outcomes and eliminate the comorbidities associated with chronic immunosuppression, the induction of donor-specific tolerance to intestinal grafts is desirable, especially in the pediatric population. This study determined the ability of intestinal grafts to facilitate tolerance induction in major histocompatibility complex (MHC)-inbred miniature swine. Seven MGH-miniature swine received heterotopic intestinal grafts, two across MHC-matched, minor-antigen disparities, three across a class I MHC disparity with 12 days of cyclosporine A, and two across a class I MHC disparity without an immunosuppressant. Chimerism was assessed by FACS analysis and immunohistochemistry. Cell-mediated lympholysis assays were used to assess antidonor responses. Two animals receiving intestinal grafts without an immunosuppressant developed antidonor IgG in 14 days and rejected these completely. All other grafts were accepted with 12 days of cyclosporine A across both MHC-matched and MHC class I barriers. Cell-mediated lympholysis assays showed donor-specific unresponsiveness by day 30 across MHC class I barriers. Greater than 15% peripheral donor cell chimerism persisted for more than 60 days after MHC-matched Int-Tx. Although less than 1.5% peripheral donor cell chimerism was seen during the maintenance period after class I-mismatched Int-Tx, 5% to 10% myeloid chimerism was found in the peripheral blood 14 to 90 days after Int-Tx. FACS analysis demonstrated that 1% to 2% of lymphocytes in the graft mesenteric lymph nodes were CD4/CD25(HIGH+)/Foxp3(+) cells. To our knowledge, this is the first demonstration of tolerance induction and persistence of chimerism in a large animal intestinal transplant model.
    Transplantation 02/2010; 89(4):417-26. · 3.78 Impact Factor
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    ABSTRACT: Early prospective randomized clinical trials demonstrated that perioperative parenteral nutrition (PN) with branched chain amino acids (BCAA) is beneficial in cirrhotic patients with hepatocellular carcinoma who undergo hepatectomy. However, PN support is expensive and requires a long hospital stay. Moreover, PN support has not been evaluated in patients with a normal liver who undergo hepatectomy. It was studied the benefits of perioperative oral nutrition (ON) with BCAA in patients who underwent hepatectomy, including those with a non-hepatitis liver. In this prospective, randomized, controlled trial, 38 patients were assessed for eligibility. Fourteen patients were excluded because they had received intraoperative blood transfusions or incomplete resections. The 24 eligible patients (20 with malignant liver tumors and 4 with benign liver tumors) were randomly assigned to receive perioperative ON with BCAA (11 patients, BCAA group) or a usual diet (13 patients, control group). The BCAA group received a BCAA supplement twice daily plus a usual diet for 14 days before operation and on days 1 to 7 after operation. The control group received a usual diet alone. The primary end point was the improvement in postoperative biochemical measurements. Two of the 11 patients in the BCAA group developed postoperative complications, as compared with 3 of the 13 patients in the control group (18.2% vs. 23.1%, p = 0.7686). Serum levels of alanine aminotransferase, aspartate aminotransferase, and ammonia did not differ significantly between the BCAA group and control group; however, peak values were lower in the BCAA group. There was no difference between the groups in serum hemoglobin levels after operation. Among patients with hepatitis, serum erythropoietin (EPO) levels on POD 3, 5, and 7 were slightly but not significantly higher in the BCAA group than in the control group. Among patients with non-hepatitis, serum EPO levels on POD 3, 5, and 7 were significantly higher in the BCAA group than in the control group (p = 0.0174, p = 0.0141, and p = 0.0328, respectively). Short-term ON support with BCAA was associated with higher serum EPO levels than was a normal diet in patients with non-hepatitis who underwent curative hepatic resection. Higher EPO levels might be beneficial in protecting liver cells from ischemic injury and preventing intraoperative hemorrhage associated with lower perioperative levels of alanine aminotransferase and aspartate aminotransferase in serum. This is the first study to demonstrate an effect of EN support with BCAA in patients with non-hepatitis, as well as those with hepatitis.
    Hepato-gastroenterology 01/2010; 57(99-100):583-90. · 0.91 Impact Factor
  • Gastroenterology 01/2010; 138(5). · 12.82 Impact Factor
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    ABSTRACT: Survival of ABO-mismatched kidneys with stable renal function despite the persistence of anti-ABO antibodies is called accommodation. The mechanism of accommodation is unclear, but may involve complement regulatory proteins such as CD59. The development of alpha-1,3-galactosyltransferase knock-out (GalT-KO) swine that produce anti-Gal antibodies provides a large animal model capable of determining the role of complement regulatory proteins in accommodation. ELISA and antibody fluorescence-activated cell sorting were used to examine the rate of anti-Gal antibody expression as a function of age. Major histocompatibility complex-matched kidneys were transplanted from Gal-positive MGH miniature swine to MGH GalT-KO swine with systemic immunosuppression. One recipient underwent adsorbtion of anti-Gal antibodies before transplantation. Graft survival, antibody, and complement deposition patterns and CD59 expression were determined. Three animals rejected Gal-positive kidneys by humoral mechanisms. One animal with low titers of anti-Gal antibody displayed spontaneous accommodation and the animal that was treated with antibody adsorbtion also displayed accommodation. Rejected grafts had deposition of IgM, IgG, C3, and C5b-9 with low expression of CD59, whereas accommodated grafts had low deposition of C5b-9 and high expression of CD59. Retransplantation of one accommodated graft to a naïve GalT-KO animal confirmed that changes in the graft were responsible for the lack of C5b-9 deposition. GalT-KO miniature swine produce anti-Gal antibodies and titers increase with age. These anti-Gal antibodies can cause rejection of major histocompatibility complex-matched kidneys unless accommodation occurs. CD59 up-regulation seems to be involved in the mechanism of accommodation by preventing the formation of the membrane attack complex (MAC) on the accommodated graft.
    Transplantation 06/2009; 87(9):1308-17. · 3.78 Impact Factor
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    ABSTRACT: We compared two types of stents in patients who underwent surgery for hepatic hilar malignancies. Twenty-one patients with hepatic hilar malignancies who underwent hepatectomy were randomly assigned to one of two groups. A 5-Fr silicon drain with an internal lumen and side holes was used for the hepaticojejunostomy in one group (intraluminal stent group), and a 10-Fr silicon drain with channels along the sides was used in the other (channel stent group). Leakage developed in four patients (36.4%) in the intraluminal stent group versus two (20.0%) in the channel stent group. Cholangitis developed in three patients with leakage (27.3%) in the intraluminal stent group versus no patient in the channel stent group. After operation, the times required for the serum alkaline phosphatase and total bilirubin levels to return to the normal range were significantly shorter in the channel stent group (5.3 +/- 2.9, 3.8 +/- 2.2 days) than in the intraluminal stent group (17.0 +/- 5.8, 9.4 +/- 5.7 days) (P < 0.0001, P = 0.0093). A 10-Fr silicon drain with channels is superior to a 5-Fr silicon drain with an internal lumen for internal biliary stenting of hepaticojejunostomy in patients with hepatic hilar malignancies.
    Journal of Gastroenterology and Hepatology 05/2009; 24(5):752-6. · 3.33 Impact Factor
  • Gastroenterology 05/2009; 136(5). · 12.82 Impact Factor
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    ABSTRACT: Refractory hepatic encephalopathy (HE) frequently develops in patients with cirrhosis and portal-systemic shunt. Recently, patients with refractory HE associated with portal-systemic shunt have been treated with interventional radiology. We describe a promising new treatment for portal-systemic shunt, ligation of the patent paraumbilical vein (PUV) after partial splenic embolization, in patients with refractory HE. Four patients with cirrhosis (3 women and 1 man; mean age, 56 years) and refractory HE due to a patent PUV were studied. Patency of the PUV had recurred in 1 patient after primary occlusion by interventional radiological procedures. The Child-Pugh class was B in 2 patients and C in 2. Before the present treatment, all patients had been hospitalized at least 3 times because of recurrent HE. Partial splenic embolization was performed in all patients to decrease portal venous pressure before surgery. Surgical ligation of the patent PUV was performed under epidural anesthesia. The patent PUV was carefully skeletonized and doubly ligated. Esophageal varices were evaluated with upper gastrointestinal endoscopy before and after surgery. The mean follow-up duration was 15.8 months. After ligation, there were no clinically significant complications. Esophageal varices were unchanged. The serum ammonia level was higher before surgery (162.3 +/- 56.4 mug/dL, mean +/- SD) than after surgery (41.8 +/- 20.2 mug/dL; p=0.0299). No patient had symptoms of HE. Ligation of the patent PUV is an effective treatment for patients with refractory HE.
    Journal of Nippon Medical School 06/2008; 75(3):152-6. · 0.59 Impact Factor
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    ABSTRACT: Although most patients with colonic diverticula have no symptoms, perforation or bleeding can be troublesome. Recently, we treated an elderly patient with a diverticular perforation of the sigmoid colon who required a loop colostomy and later resection of the diseased colon. Between the operations, the colostomy resembled a sea slug with horns, which represented eversions of the diverticula. This interesting phenomenon suggests that diverticula may be everted as pseudopolyps and ligated endoscopically. Therefore, the procedure was tested on a Landrace pig, of which the large bowel wall was pulled with an endoscope at 9 different sites using forceps (n=6) or suction (n=3) and ligated. Four days later, reexamination revealed total necrosis at 8 sites and ulceration at 1. The animal was well. The bowel removed 2 weeks later showed mucosal fold convergences without perforations. Our procedure can be used for prophylactic or therapeutic treatment of patients with colonic diverticula.
    Journal of Nippon Medical School 06/2008; 75(3):157-61. · 0.59 Impact Factor
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    ABSTRACT: According to the General rules for the clinical and pathological study of primary liver cancer, compiled by the Liver Cancer Study Group of Japan, ruptured hepatocellular carcinoma (HCC) is classified as stage 4, even if the tumor is small and solitary. We examined the long-term results of elective hepatectomy for the treatment of ruptured HCC. A first hepatectomy was performed without operative death in 193 patients with HCC. Ten patients had ruptured HCC (ruptured group) and 183 patients had nonruptured HCC (nonruptured group). The extension of HCC was macroscopically classified as stage 1 in 23 patients, stage 2 in 71, stage 3 in 53, and stage 4 in 46. Cumulative survival rates in the ruptured group at 1, 5, and 10 years were 90.0%, 67.5%, and 20.3%, respectively. The cumulative survival rate was lower in patients with stage 4 disease in the nonruptured group than that in patients in the ruptured group (P < 0.05). Cumulative survival rates did not differ significantly between patients in the ruptured group and those with stage 2 or stage 3 disease. Survival rates after elective hepatectomy in patients with ruptured HCC are good, even if the disease is classified as stage 4.
    Journal of Hepato-Biliary-Pancreatic Surgery 03/2008; 15(2):178-82. · 1.60 Impact Factor
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    ABSTRACT: The use of expandable metallic stents (EMSs) for the management of gastrointestinal obstruction is increasing. Traditionally, EMSs have been used for the treatment of malignant esophageal and biliary strictures; however, several groups are examining their use in different organs, including the stomach, duodenum, and colon. We describe a new method for the transhepatic insertion of an EMS together with a double-pigtail catheter, placed from the bile duct to the EMS to prevent migration, in a patient with afferent loop obstruction caused by recurrent gastric carcinoma.
    Hepato-gastroenterology 01/2008; 55(86-87):1767-9. · 0.91 Impact Factor
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    ABSTRACT: Dihydropyrimidine dehydrogenase is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil. The aim of this study was to determine the levels of messenger RNA for 5-fluorouracil-related metabolic enzymes in cirrhotic liver and to assess the correlation between these mRNA levels and clinicopathological features. The study material consisted of 33 liver samples. The levels of mRNA for the 5- fluorouracil-related metabolic enzymes were quantified by real-time reverse transcription polymerase chain reaction combined with laser-captured microdissection. The Dihydropyrimidine dehydrogenase mRNA level in patients with grade B liver damage was significantly lower than that in patients with grade A liver damage (p=0.009). The Dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase mRNA level in al samples was higher than that in a2 and a3 samples (p= 0.01 and 0.013, respectively). Statistically significant correlations were found between the hyaluronic acid and the thymidylate phosphorylase mRNA level (p= 0.0001), and the T-BIL and the dihydropyrimidine dehydrogenase mRNA level (p=0.01). The level of Dihydropyrimidine dehydrogenase mRNA may be affected by the clinicopathological status of patients with cirrhosis.
    Hepato-gastroenterology 01/2008; 55(84):826-30. · 0.91 Impact Factor
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    ABSTRACT: Primary hepatic gastrinoma is very rare, with fewer than 20 cases reported. We describe a 44-year-old woman in whom primary hepatic gastrinoma was strongly suspected clinically. The patient was referred to our hospital because of intractable diarrhea. She had elevated serum levels of alanine aminotransferase, aspartate aminotransferase, and fasting gastrin. A calcium provocative test showed a marked elevated serum gastrin level (17,000 pg/ml). Abdominal ultrasonography, computed tomography, and magnetic resonance imaging revealed a tumor in the right lobe of the liver, measuring 38 x 33 mm. No other tumor was detected in the pancreas, duodenum, or local lymph nodes on preoperative radiological imaging or endoscopic ultrasonography. The hepatic tumor was resected. Total intraoperative ultra-sonography and intraoperative exploratory palpation of the duodenum, pancreas, and lymph nodes showed no evidence of an extrahepatic tumor. Pathological findings and immunohistochemical studies revealed a neuroendocrine tumor with increased production of gastrin. Postoperatively, the serum gastrin level returned to normal.
    Hepato-gastroenterology 01/2008; 55(88):2224-7. · 0.91 Impact Factor
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    ABSTRACT: Malignant ascites may produce a cluster of symptoms that include abdominal distention, early satiety, respiratory embarrassment, impaired mobility, and lethargy, and relief of these symptoms is often difficult to achieve. We report on the placement of peritoneovenous shunts (PVSs) in a group of patients with malignant ascites, with particular reference to the effectiveness and complications of the procedure. PVSs were inserted in 9 patients with malignant ascites after obtaining their informed consent. The patients were 6 men and 3 women with a median age of 59 years. All had previously been treated with vigorous diuretic therapy or repeated paracentesis or both. Shunt insertion was carried out via a percutaneous approach under local anesthesia. The procedure was well tolerated by all patients. The abdominal distention resolved in all patients, and urine volume increased significantly, demonstrating that the PVS did not affect renal function. The platelet count was reduced, and prothrombin time was prolonged. Two patients had the complication of shunt occlusion, and both patients underwent shunt replacement. There were no lethal complications. Median survival time after PVS placement was 21 days (range, 10 approximately 90 days), and the shunt was functioning at the time of death with good control of ascites in all patients. Malignant ascites produces troublesome symptoms for patients, who may live for some time. Placement of a PVS is a well-tolerated, relatively minor surgical procedure that can provide excellent control of ascites in most patients selected. The selection of optimal patients requires further study.
    Journal of Nippon Medical School 11/2007; 74(5):355-8. · 0.59 Impact Factor
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    ABSTRACT: 5-fluorouracil (5-FU)-related metabolic enzymes, including dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), thymidylate phosphorylase (TP), and orotate phosphoribosyl transferase (OPRT) are initial, rate-limiting enzymes in the metabolism of 5-FU. The therapeutic implications of these enzymes in hepatocellular carcinoma (HCC) remain poorly understood. We used a newly developed laser-captured microdissection technique combined with RNA extraction to examine the mRNA levels of 5-FU-related metabolic enzymes in HCC and adjacent liver tissue. The study material comprised 43 paired specimens of HCC and adjacent liver tissue. The mRNA levels of 5-FU-related metabolic enzymes were quantified by real-time reverse-transcriptase polymerase chain reaction combined with laser-captured microdissection. The DPD mRNA level in HCC (4.31 +/- 4.21) was lower than that in adjacent liver (6.53 +/- 2.93) (p < 0.001). The TS mRNA level in HCC (3.55 +/- 2.54) was higher than that in adjacent liver (1.90 +/- 0.11) p < 0.001). The TP and the OPRT mRNA levels did not differ significantly between HCC and adjacent liver. The TS mRNA level of HCC with portal invasion (4.47 +/- 2.76) was higher than that of HCC without portal invasion (2.71 +/- 1.96) (p = 0.015). The DPD mRNA level of HCC with septum formation (4.89 +/- 4.82) was significantly higher than that of HCC without septum formation (2.12 +/- 0.61) (p < 0.027). The OPRT mRNA level of poorly differentiated HCC (1.18 +/- 0.49) was lower than that of moderately or well-differentiated HCC (2.42 +/- 1.82) (p = 0.037). The DPD mRNA level was lower and the TS mRNA level was higher in HCC than in adjacent liver. Our results will hopefully stimulate further investigations designed to optimize the use of 5-FU in patients with HCC.
    Hepato-gastroenterology 09/2007; 54(78):1612-6. · 0.91 Impact Factor
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    ABSTRACT: A case of hepatocellular carcinoma (HCC) causing a major arterioportal (A-P) shunt is reported. The patient exhibited massive ascites and tested positive for hepatitis B surface antigen. An abdominal computed tomography (CT) examination showed a low-density lesion in the left lobe of the liver and an A-P shunt, but no tumor stain was visible. Upper gastrointestinal endoscopy revealed severe esophageal varices. Because the tumor marker level was abnormally high, an HCC causing an A-P shunt in a cirrhotic liver background with severe esophageal varices as a result of portal hypertension was diagnosed. We performed endoscopic variceal ligation to treat the severe esophageal varices and interventional radiology treatment for the A-P shunt and HCC, but the patients condition was unchanged. Because the patients liver function gradually improved, surgical treatment was selected. The patient underwent left hepatectomy. Pathological examination revealed a poorly differentiated HCC in a cirrhotic liver background. The postoperative course was uneventful, and the patient was discharged 2 weeks after the operation. The patient subsequently underwent transcatheter arterial embolization therapy for recurrent HCC in the right lobe of the liver, but the esophageal varices disappeared.
    Journal of Nippon Medical School 09/2007; 74(4):314-8. · 0.59 Impact Factor
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    ABSTRACT: We report a case of splenic abscess that was successfully treated with percutaneous ultrasound-guided drainage and without splenectomy. A 40-year-old woman was admitted to Nippon Medical School Hospital because of pyrexia and left upper quadrant pain, which had persisted despite antibiotic treatment. On admission, computed tomography demonstrated a low-density area in the spleen, which had been been seen on computed tomography 3 months earlier. Ultrasonography demonstrated a hypoechoic area in the spleen. Initial laboratory tests revealed a serum C-reactive protein concentration of 19.7 mg/dl and a white blood cell count of 15,800 /microl. The serum glucose concentration was 267 mg/dl, and the glycolated hemoglobin value was 7.7%. A splenic abscess was diagnosed and was treated with percutaneous drainage. Milky yellow fluid was obtained, and the patients left upper quadrant abdominal pain and pyrexia resolved. A culture of the drainage fluid yielded Escherichia coli. The drainage catheter was removed 12 days after insertion. The patient was discharged 6 days later. The splenic abscess has not recurred during 3 months of follow-up. Our results suggest that ultrasound-guided percutaneous drainage is a safe and effective alternative to surgery for the treatment of splenic abscess and allows preservation of the spleen.
    Journal of Nippon Medical School 07/2007; 74(3):257-60. · 0.59 Impact Factor

Publication Stats

111 Citations
75.13 Total Impact Points


  • 2010
    • Massachusetts General Hospital
      • Transplantation Biology Research Center
      Boston, MA, United States
  • 2009–2010
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2005–2010
    • Nippon Medical School
      • Department of Surgery
      Tokyo, Tokyo-to, Japan