Kuniya Tanaka

Yokohama City University, Yokohama, Kanagawa, Japan

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Publications (148)300.15 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present study was to examine the efficacy of tumor-targeting Salmonella typhimurium A1-R treatment following anti-vascular endothelial growth factor (VEGF) therapy on VEGF-positive human pancreatic cancer. A pancreatic cancer patient-derived orthotopic xenograft (PDOX) that was VEGF-positive and an orthotopic VEGF-positive human pancreatic cancer cell line (MiaPaCa-2-GFP) as well as a VEGF-negative cell line (Panc-1) were tested. Nude mice with these tumors were treated with gemcitabine (GEM), bevacizumab (BEV), and S. typhimurium A1-R. BEV/GEM followed by S. typhimurium A1-R significantly reduced tumor weight compared to BEV/GEM treatment alone in the PDOX and MiaPaCa-2 models. Neither treatment was as effective in the VEGF-negative model as in the VEGF-positive models. These results demonstrate that S. typhimurium A1-R following anti-angiogenic therapy is effective on pancreatic cancer including the PDOX model, suggesting its clinical potential.
    Oncotarget 10/2014; · 6.64 Impact Factor
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    ABSTRACT: A survival benefit is generally considered unobtainable following incomplete hepatic resection in patients with colorectal liver metastases. However, this question should be readdressed considering recent chemotherapy, often combining a monoclonal antibody directed against colorectal cancer with various classic and improved strategies. We examined whether a survival benefit could be obtained from maximal reduction surgery for colorectal liver metastases.
    Anticancer research 10/2014; 34(10):5547-54. · 1.71 Impact Factor
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    ABSTRACT: The tumor-infiltrating lymphocyte (TIL) count in several types of cancer, including colorectal cancer and colorectal liver metastases (CRLM), reportedly predicts survival following resection; however, the prognostic significance of the TIL counts remains controversial.
    Annals of Surgical Oncology 08/2014; · 4.12 Impact Factor
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    ABSTRACT: A 65-year-old woman with carcinoma of the pancreatic body underwent Whipple's operation. After surgery, adjuvant chemotherapy with gemcitabine alone, and S-1 combined with gemcitabine was conducted. But one year later, a recurrent tumor was detected in the pancreatic tail. We administered FOLFIRINOX treatment for the recurrent tumor. After 6 courses, FOLFIRINOX treatment resulted in a partial response, and after 9 courses, a radiological complete response was achieved. We could then perform total pancreatotectomy and resection of the metastatic liver tumor. FOLFIRINOX as a second-line treat- ment was effective and safe in this case. In cases of gemcitabine and/or S-1 failure, FOLFIRINOX treatment should be consid- ered.
    Gan to kagaku ryoho. Cancer & chemotherapy 07/2014; 41(7):901-4.
  • Kuniya Tanaka, Itaru Endo
    Annals of surgery. 05/2014;
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    ABSTRACT: Background and Aim: The aim of the present study was to evaluate the efficacy of liver resection for multinodular hepatocellular carcinoma (MNHCC). A total of 399 patients who underwent R0 resection for HCC from 1992 to 2011 were subjected to analysis. Out of these 399 patients, 107 patients had multinodular HCC, while 292 had a single tumor. The 3- and 5-year overall survival rates of patients with MNHCC were 62.0% and 38.1% respectively. By a multivariate analysis of the survival of the 107 patients after liver resection for MNHCC, it was shown that the presence of four or more tumors and a lower serum albumin level were unfavorable prognostic factors for long-term survival. With respect to the patients with four or more HCCs, portal vein invasion was an independent unfavorable prognostic factor for long-term survival. However, in patients with four or more HCCs without portal vein invasion, overall survival rates of those with preoperative serum albumin level >4.0 mg/dl and a platelet count >10(5)/mm(3) were significantly higher than those of patients with albumin <4.0mg/dl or platelet count <10(5)/mm(3) (p=0.049). Liver resection can provide a survival benefit, even for patients with multiple HCCs. Even if patients have four or more tumors without portal vein invasion and with well-preserved liver function, resection for HCC may be the treatment of choice.
    Anticancer research 05/2014; 34(5):2421-6. · 1.71 Impact Factor
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    ABSTRACT: The prognostic factors for patients with colorectal cancer liver metastasis (L-Mets) have not been fully described. Resected specimens were obtained surgically from 1998 to 2008 at our university hospital. We investigated whether the status of two primary lesion cancer stem biomarkers, CD44 and CD133, were maintained in L-Mets and whether these markers were L-Mets prognostic factors. To investigate the CD133 and CD44 status, proliferation, invasiveness, and chemoresistance were examined immunohistochemically by using MIB-1, E-cadherin, and ABC-G2. The CD44-positive rate in primary lesions and L-Mets was 41.4 and 58.7 %, respectively. There was no correlation of CD44 expression between primary lesions and L-Mets (r = 0.250, p = 0.071). The CD133-positive rate in primary lesions and L-Mets was 53.6 and 44.6 %, respectively. There was no correlation of CD133 expression between primary lesions and L-Mets (r = 0.219, p = 0.135). In the CD133-negative group, the MIB-1 index was significantly higher than in the CD133-positive group (61.6 vs. 46.3 %, p = 0.003), and E-cadherin expression was significantly lower in the CD133-negative group compared with the CD133-positive group (29.3 vs. 46.8 %, p = 0.001). Absence of CD133 expression in L-Mets correlated with poor overall survival (p = 0.006), and multivariate regression analysis showed that it was an independent marker for poor survival (hazard ratio 0.320, p = 0.0016). The absence of CD133 expression in L-Mets was an independent marker and a poor prognostic factor, possibly because of increased proliferation and invasiveness.
    Annals of Surgical Oncology 02/2014; · 4.12 Impact Factor
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    ABSTRACT: Recent advances in multidetector computed tomography (MDCT) offer several benefits for management of perihilar tumors. Resection planning for perihilar cholangiocarcinoma should consider two factors: safety and curability. Recognition of individual anatomic variations is particularly important for avoiding intraoperative injury. In particular, hepatic arterial variations often restrict resection procedures. Extent of both longitudinal and vertical invasion by biliary tumors can be estimated from multiplanar reconstruction (MPR) images. Longitudinal extent of resection can be planned based on two anatomic landmarks, the U point and the P point, readily identifiable in preoperative 3-dimensional (3D) images and by intraoperative inspection. Concerning vertical invasion, when direct vascular invasion is suspected from a finding of attachment of tumor and vessels such as portal veins and/or hepatic arteries without a thin low-density plane of separation shown by MPR, these vessels should be resected en bloc with the tumor. Surgical team members can plan and simulate details of vascular resection and reconstruction using 3D images. Reduced operative morbidity and increased R0 resection rates are expected because of better planning of procedures. These techniques soon may increase long-term survival for patients with perihilar cholangiocarcinoma.
    Journal of hepato-biliary-pancreatic sciences. 02/2014;
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    ABSTRACT: Abstract Background: Fluorescence-guided surgery (FGS) can enable successful cancer surgery where bright-light surgery often cannot. There are three important issues for FGS going forward toward the clinic: (a) proper tumor labeling, (b) a simple portable imaging system for the operating room, and (c) patient-like mouse models in which to develop the technology. The present report addresses all three. Materials and Methods: Patient colon tumors were initially established subcutaneously in nonobese diabetic (NOD)/severe combined immune deficiency (SCID) mice immediately after surgery. The tumors were then harvested from NOD/SCID mice and passed orthotopically in nude mice to make patient-derived orthotopic xenograft (PDOX) models. Eight weeks after orthotopic implantation, a monoclonal anti-carcinoembryonic antigen (CEA) antibody conjugated with AlexaFluor(®) 488 (Molecular Probes Inc., Eugene, OR) was delivered to the PDOX models as a single intravenous dose 24 hours before laparotomy. A hand-held portable fluorescence imaging device was used. Results: The primary tumor was clearly visible at laparotomy with the portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX. The tumor was completely resected under fluorescence navigation. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins, indicating successful tumor resection. The FGS animals remained tumor free for over 6 months. Conclusions: The results of the present report indicate that FGS using a fluorophore-conjugated anti-CEA antibody and portable imaging system improves efficacy of resection for CEA-positive colorectal cancer. These data provide the basis for clinical trials.
    Journal of Laparoendoscopic & Advanced Surgical Techniques 02/2014; · 1.07 Impact Factor
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    ABSTRACT: The inflammation-based Glasgow prognostic score (GPS) has been demonstrated to be prognostic for various tumors. We investigated the value of the modified GPS (mGPS) for the prognosis of patients undergoing curative resection for colorectal liver metastases (CRLM). A total of 343 patients were enrolled onto this study. The mGPS was calculated as follows: mGPS-0, C-reactive protein (CRP) ≤10 mg/L; mGPS-1, CRP >10 mg/L and albumin ≥35 g/L; and mGPS-2, CRP >10 mg/L and albumin <35 g/L. Prognostic significance was retrospectively analyzed by univariate and multivariate analyses. Of the 343 patients, 295 (86.0 %) were assigned to mGPS-0, 33 (9.6 %) to mGPS-1, and 15 (4.4 %) to mGPS-2. The median disease-free survival of patients with mGPS-0, -1, and -2 was 18.3, 15.5, and 5.2 months, respectively. The median cancer-specific survival (CSS) of patients with mGPS-0, -1, and -2 was 89.5, 62.2, and 25.8 months, respectively. The CSS of patients with mGPS-0 was significantly longer than that of patients with mGPS-2. Multivariate analysis revealed a significant association between cancer-related postoperative mortality and mGPS and carcinoembryonic antigen level. The preoperative mGPS is a useful prognostic factor for postoperative survival in patients undergoing curative resection for CRLM.
    Annals of Surgical Oncology 01/2014; · 4.12 Impact Factor
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    ABSTRACT: The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on a pancreatic cancer patient-derived orthotopic xenografts (PDOX). The PDOX model was originally established from a pancreatic cancer patient in SCID-NOD mice. The pancreatic cancer PDOX was subsequently transplanted by surgical orthotopic implantation (SOI) in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX stably acquired red fluorescent protein (RFP)-expressing stroma for the purposes of imaging the tumor after passage to non-transgenic nude mice in order to visualize tumor growth and drug efficacy. The nude mice with human pancreatic PDOX were treated with A1-R or standard chemotherapy, including gemcitabine (GEM), which is first-line therapy for pancreatic cancer, for comparison of efficacy. A1-R treatment significantly reduced tumor weight, as well as tumor fluorescence area, compared to untreated control (P = 0.011), with comparable efficacy of GEM, CDDP, and 5-FU. Histopathological response to treatment was defined according to Evans's criteria and A1-R had increased efficacy compared to standard chemotherapy. The present report is the first to show that A1-R is effective against a very low-passage patient tumor, in this case, pancreatic cancer. The data of the present report suggest A1-1 will have clinical activity in pancreatic cancer, a highly lethal and treatment-resistant disease and may be most effectively used in combination with other agents.
    Journal of Cellular Biochemistry 01/2014; · 3.06 Impact Factor
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    ABSTRACT: The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model. A PDOX model was established from a CA19-9-positive, CEA-negative tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS+NAC; FGS only; and FGS+NAC. An anti-CA19-9 or anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with the pancreatic cancer PDOX 24 hours before surgery. The PDOX was brightly labeled with fluorophore-conjugated anti-CA19-9, but not with a fluorophore-conjugated anti-CEA antibody. FGS was performed using the fluorophore-conjugated anti-CA19-9 antibody. FGS had no benefit over BLS to prevent metastatic recurrence. NAC in combination with BLS did not convey an advantage over BLS to prevent metastatic recurrence. However, FGS+NAC significantly reduced the metastatic recurrence frequency to one of 8 mice, compared to FGS only after which metastasis recurred in 6 out of 8 mice, and BLS+NAC with metastatic recurrence in 7 out of 8 mice (p = 0.041). Thus NAC in combination with FGS can reduce or even eliminate metastatic recurrence of pancreatic cancer sensitive to NAC. The present study further emphasizes the power of the PDOX model which enables metastasis to occur and thereby identify the efficacy of NAC in combination with FGS on metastatic recurrence.
    PLoS ONE 01/2014; 9(12):e114310. · 3.53 Impact Factor
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    ABSTRACT: The aim of this study is to determine if ultraviolet light (UVC) irradiation in combination with fluorescence-guided surgery (FGS) can eradicate metastatic human pancreatic cancer in orthotopic nude-mouse models. Two weeks after orthotopic implantation of human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 24). After BLS, mice were randomized into 3 treatment groups; BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8). The residual tumors were resected using a hand-held portable imaging system under fluorescence navigation in mice treated with FGS and FGS-UVC. The surgical resection bed was irradiated with 2700 J/m2 UVC (254 nm) in the mice treated with FGS-UVC. The average residual tumor area after FGS (n = 16) was significantly smaller than after BLS only (n = 24) (0.135±0.137 mm2 and 3.338±2.929 mm2, respectively; p = 0.007). The BLS treated mice had significantly reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p<0.001 and p<0.001, respectively) and overall survival (OS) (p<0.001 and p<0.001, respectively). FGS-UVC-treated mice had increased RFS and OS compared to FGS-only treated mice (p = 0.008 and p = 0.025, respectively); with RFS lasting at least 150 days indicating the animals were cured. The results of the present study suggest that UVC irradiation in combination with FGS has clinical potential to increase survival.
    PLoS ONE 01/2014; 9(6):e99977. · 3.53 Impact Factor
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    ABSTRACT: We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as "tumor-educated-macrophages" (Edu) and macrophages harvested from mice without tumors as "naïve-macrophages" (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P = 0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P = 0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P = 0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P = 0.006) and prevented metastasis (P = 0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages.
    PLoS ONE 01/2014; 9(8):e103382. · 3.53 Impact Factor
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    ABSTRACT: Little is known about the immunological effect of neoadjuvant chemoradiotherapy (NACRT) in the tumor microenvironment of pancreatic ductal adenocarcinoma. The objective of this study was to examine the immunological modifications induced by NACRT in patients with pancreatic cancer. Fifty-two patients with pancreatic cancer who underwent surgical resection were enrolled in this study. NACRT was administered to 22 patients, whereas the other 30 patients underwent surgical resection without NACRT. The resected tumor specimens were analyzed for the presence of tumor-infiltrating lymphocytes by using immunohistochemical staining for CD4, CD8, CD68, CD163, Foxp3, and major histocompatibility complex class I (MHC class I) antigen. The number of CD4+ and CD8+ lymphocytes was significantly higher in patients who received NACRT than in those who did not receive NACRT. No significant difference in MHC class I expression was observed between the groups. In the NACRT group, patients with a high accumulation of CD8+ cells experienced longer overall survival than those with a low number of CD8+ cells. NACRT may induce the accumulation of CD4+ and CD8+ cells in the tumor microenvironment and a high accumulation of CD8+ cells might be a good prognostic marker for pancreatic cancer treated with NACRT.
    Annals of Surgical Oncology 12/2013; · 4.12 Impact Factor
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    ABSTRACT: The optimal cut-off value of the number of colorectal liver metastases (CRLM) to predict prognosis after hepatic resection remains unclear. This study was conducted to determine a suitable cut-off value. A total of 727 hepatectomized patients with CRLM were evaluated. We proposed the following optimal cut-off values: first, a small P-value for the log-rank test with no overlapping of the 95% confidence interval (CI) for median survival time using the Kaplan-Meier method and the hazard ratio (HR) using the Cox proportional hazards model and, second, the maximum HR value for accurate separation. For disease-free survival analysis, of the three group separations, A2 (1, 2-4, and ≥5) showed a small P-value and the largest HR, whereas two group separations, B2, B3 and B4 showed similarly small P-values, but B4 (1-4, ≥5) indicated the largest HR. Regarding the overall survival analysis, of the three group separations, A2 showed the smallest P-value, whereas the two group separations, B4 showed similarly small P-values, with the largest HR. Tumor number separation in patients with CRLM after hepatic resection should be performed using the A2 (1, 2-4, and ≥5) or B4 (1-4 and ≥5) classifications.
    Journal of hepato-biliary-pancreatic sciences. 12/2013;
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    ABSTRACT: Background and Aim: Advanced hepatocellular carcinoma (HCC) with portal vein invasion or intrahepatic metastases has an unfavorable prognosis, even after curative hepatic resection. The aim of the present study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy with 5-fluorouracil (5-FU) and systemic interferon (IFN). Patients who were diagnosed as having HCC with portal vein invasion or intrahepatic metastases were included in the study (n=33). Out of these patients, 16 were treated with adjuvant therapy consisting of continuous arterial infusion of 5-FU and subcutaneous injection of IFN-α. Another 17 patients who underwent hepatic resection without adjuvant chemotherapy served as controls. The five-year cumulative survival rate was significantly higher in the adjuvant treatment group (71.1%) than in the control group (44.0%; p=0.023). The rate of patients with multiple (≥4) recurrent intrahepatic nodules was significantly lower in the adjuvant group (44.4%) than in the control group (100%; p=0.040). The development of intrahepatic recurrence within 12 months was significantly lower in the adjuvant group (33.3%) than in the control group (80.0%; p=0.040). Our data suggest that this adjuvant chemotherapy can improve postoperative prognosis by reducing intrahepatic recurrence.
    Anticancer research 12/2013; 33(12):5585-90. · 1.71 Impact Factor
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    ABSTRACT: Efficacy of circadian chronotherapy for liver metastases from colorectal cancer was evaluated. Chronomodulated infusion of anticancer drugs via the hepatic artery(HAI) was applied for patients with marginally resectable or unresectable liver metastases at initial diagnosis. Response rate of chemotherapy and frequency of liver resection after chemotherapy of patients treated with chronomodulated HAI were higher than those treated with flat HAI. Further, combination of chronomodulated regional HAI and systemic chemotherapy was the most effective prehepatectomy chemotherapy for the treatment of patients with advanced colorectal liver metastases. Based on these results, we are now performing phase II non-randomized open labeled trial of chronomodulated HAI with systemic administration of panitumumab for patients with such advanced liver metastases (ccFLAP trial). Circadian chronotherapy is an effective prehepatectomy chemotherapy for the treatment of patients with advanced and aggressive liver metastases from colorectal cancer.
    Nippon rinsho. Japanese journal of clinical medicine 12/2013; 71(12):2158-64.
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    ABSTRACT: In this study, we investigated the advantages of fluorescence-guided surgery (FGS) in mice of a portable hand-sized imaging system compared with a large fluorescence imaging system or a long-working-distance fluorescence microscope. Mouse models of human pancreatic cancer for FGS included the following: (1) MiaPaCa-2-expressing green fluorescent protein, (2) BxPC3 labeled with Alexa Fluor 488-conjucated anti-carcinoembryonic antigen (CEA) antibody, and (3) patient-derived orthotopic xenograft (PDOX) labeled with Alexa Fluor 488-conjugated anti-carbohydrate antigen 19-9 antibody. Each device could clearly detect the primary MiaPaCa-2-green fluorescent protein tumor and any residual tumor after FGS. In the BxPC3 model labeled with Alexa Fluor 488-conjugated anti-CEA, each device could detect the primary tumor, but the MVX10 could not clearly detect the residual tumor remaining after FGS whereas the other devices could. In the PDOX model labeled with Alexa Fluor 488-conjugated anti-carbohydrate antigen 19-9, only the portable hand-held device could distinguish the residual tumor from the background, and complete resection of the residual tumor was achieved under fluorescence navigation. The results described in the present report suggest that the hand-held mobile imaging system can be applied to the clinic for FGS because of its convenient size and high sensitivity which should help make FGS widely used.
    Journal of Surgical Research 11/2013; · 2.02 Impact Factor
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    ABSTRACT: The use of immunosuppressants after liver transplantation (LT) is associated with postoperative complications, including infections. A 49-year-old male underwent living-donor (LD) LT because of primary sclerosing cholangitis. He was treated with tacrolimus, mycophenolate mofetil, and steroids as immunosuppressants, discharged on postoperative day (POD) 40, and re-admitted because of severe acute cellular rejection on POD 48. Three courses of steroid pulse therapy were performed, and continuous peripheral intravenous drip infusion therapy via the left forearm was necessary for 20 days because of appetite loss. The patient was discharged on POD 83, but re-admitted on POD 87 with pyrexia. A subcutaneous abscess was present at a puncture wound on the left forearm formed by an intravenous drip during the last hospital stay. Furthermore, computed tomography showed five pieces of cavitary or wedge-shaped nodules in the bilateral lung. Because sputum revealed the presence of Gram-positive coccus, and subcutaneous abscess and blood cultures revealed Staphylococcus aureus, the pathogenesis was septic pulmonary embolism (SPE) secondary to S. aureus septicemia originating from a subcutaneous abscess formed by an intravenous drip. The patient was treated with drainage of the subcutaneous abscess and antibiotic therapy, and recovered immediately. Although there have been few reports of SPE after LDLT, SPE is fatal in up to 13.3 % of patients. Early diagnosis, drainage of the infectious source, and appropriate use of antimicrobial therapy should be necessary to overcome SPE. Furthermore, the identical intravenous catheters should be removed whenever possible to avoid infectious complications including SPE for patients who receive steroid pulse therapy after LDLT.
    Clinical Journal of Gastroenterology 10/2013; 6:378-382.

Publication Stats

1k Citations
300.15 Total Impact Points

Institutions

  • 1996–2014
    • Yokohama City University
      • Department of Medicine
      Yokohama, Kanagawa, Japan
  • 2013
    • King Hussein Cancer Center
      `Ammān, Amman, Jordan
    • University of California, San Diego
      • Department of Surgery
      San Diego, CA, United States