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Kenneth K Tanabe

Publications and source records attributed to Kenneth K Tanabe.

34 records · Page 2Linked to original sources
PubMed2004

Cholangiocarcinoma in association with Thorotrast exposure.

Thorotrast is a colloidal suspension of thorium dioxide that was used as an intravascular contrast agent until the 1950's. It is retained by the reticuloendothelial system, and because it emits densely ionizing radioactivity thorium dioxide it is carcinogenic. Two patients with prior thorium dioxide exposure diagnosed with cholangiocarcinoma and recently treated at the Massachusetts General Hospital are presented. Radiology, treatment, pathologic findings, and relevant literature are discussed.

Aged↗
PubMed2003

The effect of tumor size and lymph node status on breast carcinoma lethality.

BACKGROUND: It has long been known that both tumor size and the presence of malignant disease in the regional lymph nodes are indicators of outcome for patients with invasive breast carcinoma; however, the way in which these two characteristics could be integrated into an overall assessment of prognosis has not been obvious. METHODS: Kaplan-Meier survival estimates (15 years) according to tumor size and lymph node status were obtained for women with invasive breast carcinoma who were observed at the University of Southern California/Van Nuys Breast Center (Van Nuys, California) or at Massachusetts General Hospital (Boston, Massachusetts). RESULTS: To isolate the individual contributions to death made by tumor size and lymph node status, data were sorted according to both of these variables. For women with tumors of equivalent size, lethality increased with increasing number of positive lymph nodes, such that there was an extra approximately 6% chance of death associated with each positive lymph node. For women with equivalent lymph node status, tumor size was associated with increased lethality, such that each millimeter of tumor diameter was associated with an additional approximately 1% chance of death. The overall lethality was equal to the sum of the contribution from lymph node status and the contribution from tumor size, and this finding led to the creation of a new technique (the Size+Nodes method) for predicting outcome. CONCLUSIONS: The Size+Nodes method was shown to be capable of accurately estimating the risk of death due to invasive breast carcinoma from information on the size of the primary tumor and the number of positive lymph nodes. In addition, this method was used to stratify women into groups according to breast carcinoma lethality. In contrast, classification of women according to lymph node positivity, T status, or disease stage created groups with wide and overlapping levels of lethality.

Adult↗
PubMed2003

Restoration of CD44S in non-small cell lung cancer cells enhanced their susceptibility to the macrophage cytotoxicity.

CD44 is a cell surface receptor for osteopontin (OPN) and hyaluronate. Transformation of normal tissue to a variety of cancers has been demonstrated to be associated with alterations of CD44 isoform expression. However, few reports have paid attention on differences in CD44S expression between non-small cell lung cancer (NSCLC) and adjacent normal lung tissue. In this study, we demonstrate that CD44S expression is down-regulated in NSCLC tissue when compared with paired normal lung tissue. To investigate the role of CD44S down-regulation in NSCLC cells, we reintroduced the CD44S back into the NSCLC cell line, H322 cells, which originally lack CD44S expression. The cytotoxicity by activated macrophage (RAW264.7 cells stimulated with lipopolysaccharide and interferon-gamma) against the H322 cells transfected with the CD44S gene (H322DeltaS) is more prominent than that against the H322 control transfectants (H322Deltaneo). The enhanced susceptibility of H322DeltaS cells to the activated macrophage cytotoxicity appears to be mediated by the interaction between CD44S expression on H322DeltaS cells and OPN produced by activated macrophages since it is completely blocked by either anti-OPN or anti-CD44 antibody. Moreover, H322DeltaS cells are attracted toward OPN produced by activated RAW264.7 cells to a much greater extent than H322Deltaneo cells. These findings suggest that CD44S down-regulation in NSCLC cells may confer a protective advantage of allowing escape from tumoricidal effector cells including activated macrophages of the host.

Blotting, Western↗
PubMed2003

Cost-effectiveness of hepatic metastasectomy in patients with metastatic colorectal carcinoma: a state-transition Monte Carlo decision analysis.

OBJECTIVE: To evaluate the cost-effectiveness of hepatic resection ("metastasectomy") in patients with metachronous liver metastases from colorectal carcinoma (CRC), and to investigate the impact of operative and follow-up strategies on outcomes, cost, and cost-effectiveness. SUMMARY BACKGROUND DATA: There is substantial evidence that resection of CRC liver metastases can result in long-term survival in some patients. However, several unresolved issues are difficult to address using currently available clinical data. These include the appropriate threshold for resection, whether to perform repeat resection, and the relative cost-effectiveness of the procedure(s). METHODS: The authors developed a state-transition Monte Carlo decision model to evaluate the (societal) cost-effectiveness of hepatic metastasectomy in patients with metachronous CRC liver metastases. The model tracks the presence, number, size, location, growth, detection, and removal of up to 15 individual metastases in each patient. Survival, quality of life, and cost are predicted on the basis of disease extent. Imaging and surgery affect outcomes via detection and removal of individual metastases. Several patient management strategies were developed and compared with respect to cost, effectiveness, and incremental cost-effectiveness ($/quality-adjusted life year [QALY]). A reference strategy in which metastasectomy is not offered and imaging is not performed for the purpose of assessing resectability or operative planning ("no-surgery" strategy) was included for comparison. Extensive sensitivity analysis was performed to evaluate the impact of alternative model assumptions on results. RESULTS: A strategy permitting resection of up to six metastases and one repeat resection, with CT follow-up every 6 months, resulted in a gain of 2.63 QALYs relative to the no-test/no-treat strategy, at an incremental cost of 18,100 US dollars/QALY. When additional surgical strategies were considered, the incremental cost-effectiveness ratio (ICER; relative to the next least effective strategy) of the six metastases, one repeat, 6-month strategy was 31,700 US dollars/QALY. Across a range of model assumptions, more aggressive treatment strategies (i.e., resection of more metastases, resection of recurrent metastases) were superior to less aggressive strategies and had ICERs below 35,000 US dollars/QALY. Findings were insensitive to changes in most model parameters but somewhat sensitive to changes in surgery and treatment costs. CONCLUSIONS: Hepatic metastasectomy is a cost-effective option for selected patients with metachronous CRC metastases limited to the liver. When considering metastasectomy, more aggressive approaches are generally preferred to less aggressive approaches. Overall, surgeons should be encouraged to consider resection for all patients whose metastases can technically be removed.

Aged↗
PubMed2003

Lymphoscintigraphy and sentinel node biopsy accurately stage melanoma in patients presenting after wide local excision.

BACKGROUND: Patients have traditionally been considered candidates for sentinel node biopsy (SNBx) only at the time of wide local excision (WLE). We hypothesized that patients with prior WLE may also be staged accurately with SNBx. METHODS: Seventy-six patients, including 18 patients from the University of Virginia and 58 from a multicenter study of SNBx led by investigators at the University of Vermont, who had previous WLE for clinically localized melanoma underwent lymphoscintigraphy with SNBx. Median follow-up time was 38 months. RESULTS: Intraoperative identification of at least 1 sentinel node was accomplished in 75 patients (98.6%). The mean number of sentinel nodes removed per patient was 2.0. Eleven patients (15%) had positive sentinel nodes. Among the 64 patients with negative SNBx, 3 (4%) developed nodal recurrences in a sentinel node-negative basin simultaneous with systemic metastasis, and 1 (1%) developed an isolated first recurrence in a lymph node. CONCLUSIONS: This multicenter study more than doubles the published experience with SNBx after WLE and provides much-needed outcome data on recurrence after SNBx in these patients. These outcomes compare favorably with the reported literature for patients with SNBx at the time of WLE, suggesting that accurate staging of the regional lymph node bed is possible in patients after WLE.

Female↗
PubMed2003

Viral oncolysis for malignant liver tumors.

Viral oncolysis represents a unique strategy to exploit the natural process of viral replication to kill tumor cells. Although this concept dates back nearly a century, recent advances in the fields of molecular biology and virology have enabled investigators to genetically engineer viruses with greater potency and tumor specificity. In this article we review the general mechanisms by which oncolytic viruses achieve their antineoplastic efficacy and specificity. We focus on the development of several classes of oncolytic viruses for the treatment of malignant liver tumors, including adenoviruses, vaccinia viruses, and herpes simplex viruses, and discuss the results of clinical trials for these viruses. We also describe results from our laboratory research program, which is focused on developing effective, liver tumor-specific Herpes simplex virus 1 mutants.

Adenoviridae↗
PubMed2002

Prodrug bioactivation and oncolysis of diffuse liver metastases by a herpes simplex virus 1 mutant that expresses the CYP2B1 transgene.

BACKGROUND: Herpes simplex virus 1 (HSV-1) infection of cancer cells results in viral replication with cell destruction and liberation of progeny virion that infect adjacent tumor cells. rRp450 is a novel replication-conditional HSV-1 mutant that expresses both the endogenous herpes viral thymidine kinase gene and the rat p450 CYP2B1 transgene; p450 bioactivates such cancer prodrugs as cyclophosphamide. METHODS: Viral cytotoxicity and replication assays were performed in colon carcinoma cells as well as primary human hepatocytes. For in vivo studies, diffuse liver metastases were generated by inoculating MC26 cells into the portal system of BALB/c mice. Mice were treated with control media, rRp450, or rRp450 plus cyclophosphamide. RESULTS: Cytopathic effects induced by rRp450 replication in colon carcinoma cells were equivalent to those induced by wild type HSV-1 in vitro. Assays developed to separate cytotoxicity mediated by viral replication from cytotoxicity mediated by chemotherapy confirmed that HSV-1 thymidine kinase bioactivates ganciclovir and CYP2B1 bioactivates cyclophosphamide in rRp450-infected cells. rRp450 mediated cytotoxicity in the presence of cyclophosphamide was increased by 21% to 30% above that achieved by viral replication alone. Cyclophosphamide bioactivation produced bystander killing of colon carcinoma cells but not hepatocytes. In contrast to these effects of cyclophosphamide, rRp450 mediated cytotoxicity was reduced in the presence of ganciclovir. These findings are explained by further experiments showing that bioactivation of cyclophosphamide only minimally affected HSV-1 replication in colon carcinoma cells, whereas bioactivation of ganciclovir markedly attenuated HSV-1 replication. In vivo studies revealed a substantial decrease in hepatic tumor burden in all rRp450-treated animals compared to controls. The addition of cyclophosphamide augmented rRp450's in vivo anti-neoplastic effect. CONCLUSIONS: The rRp450 mutant HSV-1 is highly oncolytic against colon carcinoma cells both in vitro and in vivo. rRp450 displays preferential replication in colon carcinoma cells compared to normal hepatocytes. Activation of cyclophosphamide by the p450 transgene augmented the anti-neoplastic effects of rRp450 without simultaneously decreasing viral replication. Oncolysis induced by HSV-1 replication combined with cyclophosphamide prodrug activation warrants further investigation as a potential therapy for colon carcinoma liver metastases.

Antineoplastic Agents, Alkylating↗
PubMed2002

Viral oncolysis.

Although the concept of using viruses as antineoplastic agents dates back nearly a century, recent advances in the fields of molecular biology, genetics, and virology have enabled investigators to engineer viruses with greater potency and tumor specificity. Further enhancements involve arming these viruses with therapeutic transgenes, and combining the traditional modalities of chemotherapy and radiation therapy with oncolytic viral therapy in hopes of reducing the chance of developing resistant tumor cell clones. Another means of augmenting the antineoplastic effect of these viruses involves modulating the immune response to minimize antiviral immunity, while at the same time maximizing antitumor immunity. A better understanding of mechanisms that viruses use to overcome cellular defenses to achieve robust replication within the cell will lead to development of oncolytic viruses with better tumor specificity and reduced toxicity. Initial clinical studies have shown that oncolytic viral therapy for metastatic disease is safe and well tolerated. In addition, using similar genetic modification strategies, these viruses have demonstrated antineoplastic effects in humans similar to those seen in preclinical animal models.

Adenoviridae↗
PubMed2002

Introduction to cancer gene therapy.

Over the past decade, the unprecedented growth in science and technology has fueled the development of novel treatment strategies to combat disease. The creative and innovative efforts of scientists and clinicians to overcome the multitude of unforeseen obstacles to success is no better exemplified than in the field of cancer gene therapy. Since its inception, developers of cancer gene therapy have been charged with the challenge of altering basic tumor biology or, alternatively, the host responses for the purpose of tumor eradication and prevention. Several major therapeutic strategies have emerged from preclinical studies, and results from these early studies hold promise for altering the clinical outcome in a variety of malignancies. These strategies may be broadly subcategorized and range in intent from alteration of the tumor cell phenotype by replacement of defective cellular response genes (e.g., mutated or deleted tumor suppressor genes) to the enhancement of the immunological response to cancer (e.g., amplification of the cell surface antigen signature or modulation of the host response). Not surprisingly, the increasingly intricate nature of tumor biology revealed over the past several years has effectively raised the bar of success for those involved in the development of effective molecular and cancer gene therapy strategies. This, in turn, has led to the development of more complex therapies that frequently draw upon multiple disciplines in an effort to optimize treatment response.

Cancer Vaccines↗
PubMed2002

Regulation of herpes simplex virus 1 replication using tumor-associated promoters.

OBJECTIVE: To investigate use of transcriptional regulatory elements (promoters) for tumor-associated antigens to achieve HSV-1 replication preferentially in cells that overexpress the tumor-associated antigens. SUMMARY BACKGROUND DATA: An important advantage of replicating viruses for cancer therapy is their ability to simultaneously destroy tumor cells by replication and release progeny virion to infect and destroy adjacent cancer cells. This strategy requires regulation of the viral life cycle to obtain robust replication in neoplastic cells and minimize replication in nonneoplastic cells. METHODS: Promoters for the human carcinoembryonic antigen (CEA) and MUC1/DF3 tumor-associated antigens were characterized and cloned into HSV-1 mutants as heterologous promoters regulating expression of two different HSV-1 genes. Viral replication in tumor cells and cytotoxicity was quantified with in vitro assays. Antineoplastic efficacy was characterized in a flank tumor xenograft model. RESULTS: Several CEA promoters were cloned and characterized using luciferase reporter assays. The most specific promoter was used to construct and isolate two different HSV-1 mutants in which critical genes are regulated by this promoter (ICP4 and gamma(1) 34.5). Similarly, the promoter for the DF3/MUC1 tumor-associated antigen was cloned into a third HSV-1 mutant such that it regulates expression of gamma(1) 34.5. Regulation of ICP4 expression by the CEA promoter during HSV-1 infection overly attenuates viral replication. Regulation of gamma(1) 34.5 expression by either the CEA promoter or the MUC1/DF3 promoter during HSV-1 infection modulates viral replication, with preferential replication in cells that overexpress the corresponding tumor-associated antigen. A single intratumoral inoculation of an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression results in significant antineoplastic activity in MUC1-positive pancreatic carcinoma xenografts as compared to mock inoculation. CONCLUSIONS: Promoters for tumor-associated antigens may be incorporated into the HSV-1 genome to regulate HSV-1 replication. The choices of HSV-1 gene and tumor-associated promoter are important determinants of success of this strategy. Because of its preferential replication in MUC1-positive tumors, an HSV-1 mutant with the MUC1/DF3 promoter regulating gamma(1) 34.5 expression will undergo further examination as a novel cancer therapy agent.

Animals↗
PubMed2002

Molecular and functional analysis of glutamine uptake in human hepatoma and liver-derived cells.

Human hepatoma cells take up glutamine at rates severalfold faster than the system N-mediated transport rates observed in normal human hepatocytes. Amino acid inhibition, kinetic, Northern blotting, RT-PCR, and restriction enzyme analyses collectively identified the transporter responsible in six human hepatoma cell lines as amino acid transporter B(0) (ATB(0)), the human ortholog of rodent ASCT2. The majority of glutamine uptake in liver fibroblasts and an immortalized human liver epithelial cell line (THLE-5B) was also mediated by ATB(0). The 2.9-kb ATB(0) mRNA was equally expressed in all cell lines, whereas expression of the system A transporters ATA2 and ATA3 was variable. In contrast, the system N isoforms (SN1 and SN2) were expressed only in well-differentiated hepatomas. ATB(0) mRNA was also expressed in cirrhotic liver and adult and pediatric liver cancer biopsies but was not detectable in isolated human hepatocytes or fetal liver. Although the growth of all hepatomas was glutamine dependent, competitive inhibition of ATB(0)-mediated glutamine uptake blocked proliferation only in poorly differentiated cells lacking SN1 or SN2 expression and exhibiting low glutamine synthetase mRNA levels.

Amino Acid Transport System ASC↗
PubMed2002

Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5.

Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of gamma(1)34.5 (a viral gene product that promotes the dephosphorylation of eIF-2alpha) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). gamma(1)34.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2alpha dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in gamma(1)34.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2alpha dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in gamma(1)34.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective gamma(1)34.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type gamma(1)34.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type gamma(1)34.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab's to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo.

Animals↗
PubMed2002

Viral oncolysis.

The concept of using replicating viruses as anticancer agents is not a new one, but the ability to genetically modify these viruses into increasingly potent and tumor-specific vectors is a recent phenomenon. As more is learned about the functions of viral gene products in controlling the mammalian cell cycle and in disabling cellular defense mechanisms, specific viral functions can be augmented or eliminated to enhance antineoplastic efficacy. In this article, general mechanisms by which oncolytic viruses achieve their antitumor efficacy and specificity are reviewed. The paradoxical roles of the immune response are addressed with respect to oncolytic viral therapy, as it, on one hand, impedes the spread of viral infection, and on the other, augments tumor cell destruction through the recruitment of T cells "vaccinated" against tumor antigens. The most commonly used oncolytic viruses are each reviewed in turn, including adenoviruses, herpes simplex viruses, vaccinia viruses, reoviruses, and Newcastle disease viruses. Special attention is focused on the unique biology of each of these viruses as well as the status of several of these mutants in clinical trials.

Animals↗
PubMed2002

Using multidetector CT for preoperative vascular evaluation of liver neoplasms: technique and results.

OBJECTIVE: The purpose of our study was to evaluate the performance of CT angiography using multidetector CT (MDCT) for preoperative vascular evaluation in candidates who were scheduled for liver neoplasm resection. SUBJECTS AND METHODS: Forty-two consecutive subjects with malignant liver tumors scheduled for resection were studied with multiphase MDCT. The first 22 subjects underwent both multiphase MDCT angiography and catheter angiography before surgery. The subsequent 20 subjects underwent only preoperative CT angiography. Postprocessing was performed, and the images were analyzed for the depiction of arterial, portal vein, and hepatic vein anatomy and for the identification of important vascular variants. The postprocessing findings were compared and correlated with the findings from catheter angiography (22/42) or intraoperative sonography (42/42) and surgery (42/42). RESULTS: Arterial anomalies were detected on the images of 17 of 42 patients, including a replaced right hepatic artery in five, replaced left hepatic artery in six, accessory right and left hepatic arteries in two, common trunk for the celiac and superior mesenteric arteries in one, and early bifurcation of the celiac artery in one. In 22 patients in whom catheter angiography confirmation was available, the number of arteries and almost all the significant anomalies were correctly identified on CT angiography (accuracy, 97%; sensitivity, 94%; specificity, 100%). In the subset of 20 patients who underwent MDCT angiography without catheter angiography confirmation, all clinically relevant information was provided by CT angiography. The portal and hepatic vein anatomy and the relationships of the liver tumors to the neighboring venous structures were shown on CT. CONCLUSION: Multidetector CT provides valuable preoperative information about hepatic vascular architecture and can be used as a noninvasive alternative to catheter angiography before oncologic liver surgery.

Adult↗