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Biomedical subjects

K K Tanabe

Publications and source records attributed to K K Tanabe.

At least 37 records · Page 2Linked to original sources
PubMed1999

Prognosis and survival in patients with gastrointestinal tract carcinoid tumors.

OBJECTIVE: To determine the impact of clinical presentation variables on the management and survival of patients with gastrointestinal (GI) tract carcinoid tumors. METHODS: A 20-year (1975-1995) retrospective analysis of 150 patients with GI tract carcinoid tumors at the Massachusetts General Hospital was conducted. Median follow-up was 66 months (range 1-378). Survival estimates for prognostic factors were calculated using Kaplan-Meier product limit estimators, with death from carcinoid as the outcome. Univariate analyses for each factor were obtained using a log-rank test, and multivariate survival analysis was performed. RESULTS: All but two patients underwent surgical intervention with the intent to cure (90%) or debulk the tumor (9%). Mean age at presentation was 55 +/- 18 years (range 11-90). There was a slight female/male predominance (80:70). Symptoms were nonspecific; the most common were abdominal pain (40%), nausea and vomiting (29%), weight loss (19%), and GI blood loss (15%). Incidental carcinoids, discovered at the time of another procedure, occurred in 40% of patients and were noted at multiple sites throughout the GI tract. The distribution of tumors was ileojejunum (37%), appendix (31 %), colon (13%), rectum (12%), stomach (4%), duodenum (1.3%), and Meckel's diverticulum (1.3%). Of the 27 patients with documented liver metastases, carcinoid syndrome developed in only 13 patients (48%), manifested by watery diarrhea (100%), upper body flushing (70%), asthma (38%), and tricuspid regurgitation (23%). All 13 patients with carcinoid syndrome had elevated levels of 5-HIAA, but the absolute levels did not correlate with the severity of symptoms. An additional 11 patients, 3 without liver metastases, had elevated levels of 5-HIAA without any evidence of carcinoid syndrome. Multicentric carcinoid tumors occurred in 15 patients (10%), and all but one of these tumors were centered around the ileocecal valve. There was no difference in the incidence of liver metastases between solitary (18%) and multicentric carcinoids (20%). Synchronous noncarcinoid tumors were present in 33 patients (22%), and metachronous tumors developed in an additional 14 patients (10%) in follow-up. Age and tumor size, depth, and location were significant predictors of metastases. By multivariate analysis, age > or = 50 years, metastases, and male gender were statistically significant predictors of death. CONCLUSIONS: Gastrointestinal tract carcinoid tumors have a nonspecific clinical presentation, except in the case of the carcinoid syndrome. Surgical resection is the treatment of choice for improving survival. Surgically treated patients with carcinoid tumor have an overall favorable 83% 5-year survival rate.

Carcinoid Tumor↗
PubMed1999

Surgical treatment and other regional treatments for colorectal cancer liver metastases.

The liver is the most common site of distant metastasis from colorectal cancer. About one-fourth of patients with liver metastases from colorectal cancer have no other sites of metastasis and can be treated with regional therapies directed toward their liver tumors. Surgical resection of colorectal cancer liver metastases can result in a 24%-38% five-year survival, but only a minority of patients are candidates for resection. Other regional therapies such as cryosurgery, radiofrequency ablation, and hepatic intra-arterial chemotherapy may be offered to patients with unresectable but isolated liver metastases. The efficacy of these treatments is still being determined. For most patients with spread of metastatic colorectal cancer beyond the liver, systemic chemotherapy rather than regional therapy is a more appropriate option.

Antineoplastic Agents↗
PubMed1998

Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma.

We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of the immune system in all patients, metastatic lesions resected after vaccination were densely infiltrated with T lymphocytes and plasma cells and showed extensive tumor destruction (at least 80%), fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic T cell and antibody responses were associated with tumor destruction. These results demonstrate that vaccination with irradiated autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor stimulates potent antitumor immunity in humans with metastatic melanoma.

Cancer Vaccines↗
PubMed1998

The carboxyl-terminal fragment of osteopontin suppresses arginine-glycine-asparatic acid-dependent cell adhesion.

Osteopontin (OPN) is a secreted glycoprotein implicated in cell adhesion. It contains the arginine-glycine-asparatic acid (RGD) cell adhesive domain and the thrombin cleavage sequence. Although thrombin cleavage of OPN has been shown to be of physiological importance, the function of C-terminal OPN fragment cleaved by thrombin remains unknown. To determine its role, we performed cell adhesion assays using glutathione S-transferase-OPN fusion protein fragments and full-length OPN fusion protein. The N-terminal fragment containing RGD motif promoted enhanced adhesion of mouse and human fibroblasts by 2.9 and 2.8 folds in comparison with full-length OPN, respectively. The enhanced adhesion of both cells mediated by N-terminal fragment was significantly suppressed by addition of C-terminal fragment lacking RGD motif that has less cell adhesive property than full-length OPN. These results suggest that the C-terminal domain may play a pivotal role in regulating OPN functions by suppressing the RGD-dependent cell adhesion.

3T3 Cells↗
PubMed1998

Cancer gene therapy using a replication-competent herpes simplex virus type 1 vector.

OBJECTIVE: The authors investigate the efficacy of hrR3, a viral vector derived from herpes simplex virus type 1 (HSV 1), in destroying colon carcinoma cells in vitro and in vivo. The effect of adding the prodrug ganciclovir in combination with hrR3 infection also is assessed. SUMMARY BACKGROUND DATA: Most cancer gene therapy strategies use viral vectors that are incapable of replication. The HSV 1 vector hrR3 is capable of replication, and its replication is cytotoxic to cells. hrR3 also possesses the HSV-thymidine kinase gene, which converts ganciclovir into a toxic metabolite. Thus, the addition of ganciclovir to hrR3-infected cells may enhance the ability of hrR3 to destroy tumor cells. To increase specificity for tumor cells, hrR3 has a mutated ribonucleotide reductase gene and replicates selectively in cells with high levels of endogenous rbonucleotide reductase. Actively dividing cells such as tumor cells have high levels of endogenous ribonucleotide reductase for synthesis of DNA precursors. The authors are interested in the use of HSV 1 vectors to treat liver metastases from colorectal cancer. METHODS: Ribonucleotide reductase expression in several colon carcinoma cell lines and in primary cultures of human hepatocytes was determined by Western blot analysis. hrR3-mediated cytotoxicity in the colon carcinoma cell lines was determined using an in vitro assay. The human colon carcinoma cell line HT29 was injected into the flanks of nude mice followed by intratumoral injection of hrR3. Tumor growth rate was assessed with and without the addition of intraperitoneal ganciclovir. RESULTS: Ribonucleotide reductase levels in colon carcinoma cell lines are much higher than in primary cultures of human hepatocytes. hrR3 efficiently destroys colon carcinoma cell lines in vitro. A single intratumoral injection of hrR3 into HT29 flank tumors significantly reduces tumor growth rate, and the administration of ganciclovir has no additive effect. CONCLUSIONS: The inherent cytotoxicity of hrR3 replication effectively destroys colon carcinoma cells in vitro and in vivo. This cytotoxicity is not enhanced in vivo by the addition of ganciclovir. In the future, more efficacious and selective HSV 1 vectors may be useful in the treatment of cancer.

Animals↗
PubMed1998

Expression of CD44 splicing isoforms in lung cancers: dominant expression of CD44v8-10 in non-small cell lung carcinomas.

We examined CD44 isoform expression in 138 frozen tissue samples, which included primary lung carcinomas, adjacent non-tumorous lung tissues and benign lung diseases, by both reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical analyses. CD44v8-10 mRNA and protein were dominantly expressed in non-small cell lung carcinomas (NSCLC), while non-tumorous tissues principally expressed CD44s and small cell lung carcinomas (SCLC) expressed either CD44s or no detectable CD44. These results indicate that CD44v8-10 is the dominant splicing isoform in NSCLC and can be practically utilized as a diagnostic marker and therapeutical target in NSCLC.

Aged↗
PubMed1998

Cancer gene therapy.

Developments in molecular genetics, immunology, molecular and cellular biology, and tumor biology have given rise to the field of cancer gene therapy. Several gene delivery vehicles have been developed and are being examined in clinical trials. Most cancer gene therapy strategies involve introduction of genes to augment existing therapies. An overview is provided on gene delivery vehicles, gene therapy strategies, and cancer gene therapy clinical trials.

Animals↗
PubMed1998

Gene therapy for liver tumors.

The liver is a common site of metastases from solid tumors and the primary site for a number of malignancies. Cure rates for primary and metastatic liver tumors are low. Gene therapy is a novel approach to liver cancer that seeks to exploit differences between tumor cells and hepatocytes to achieve tumor eradication with preservation of normal hepatic parenchyma. Numerous strategies for tumor specific cytolysis are reviewed.

Genetic Therapy↗
PubMed1997

The effect of ganciclovir on herpes simplex virus-mediated oncolysis.

Entry of herpes simplex virus (HSV) into tumor cells results in viral gene expression followed by cellular lysis. Attenuated HSVs selectively destroy tumors with sparing of surrounding normal tissue. HSV encodes a thymidine kinase (TK) that converts ganciclovir to a toxic metabolite. This metabolite may be transferred between cells and lead to the death of neighboring uninfected cells, termed bystanders. We sought to determine if HSV-mediated oncolysis is enhanced by ganciclovir treatment. In addition, we examined bystander killing in cocultures of TK transfectants and parental cells. hrR3, an attenuated HSV, expresses TK. The 50% lethal dose of hrR3 for a rat gliosarcoma (9L) and three human colorectal carcinomas (HT29, KM12C6, and KM12L4) was determined. Cells were infected with a 50% lethal dose of hrR3, followed by treatment with ganciclovir, and then cell survival was quantitated. In separate experiments 9L and HT29 cells were transfected with TK. Parental cells and TK transfectants were cocultured in various ratios, in the presence of ganciclovir, and cell survival was quantitated. hrR3-mediated oncolysis was enhanced by ganciclovir in the gliosarcoma but not in the three colorectal carcinomas. Cocultures of both 9L and HT29 parental cells with their corresponding TK transfectants demonstrated bystander killing. The mortality of 9L cocultures was 54% greater than that predicted for exclusive killing of transfectants. HT29 mortality was 8% greater than predicted. The ability of ganciclovir to augment hrR3-mediated oncolysis varies significantly between tumor cells lines. The extent of ganciclovir-mediated killing of neighboring nontransduced parental cells similarly varies. Consideration should be given to these factors in the design of gene therapy strategies using HSV vectors as oncolytic agents.

Animals↗
PubMed1997

Surgical management of primary cutaneous melanomas of the hands and feet.

OBJECTIVE: The purpose of the study was to investigate the surgical management of cutaneous melanomas of the hands and feet. SUMMARY BACKGROUND DATA: Prior studies suggest that patients with melanomes > 1-mm thick should be treated with excision with a 2-cm margin and undergo elective lymphadenectomy in selected circumstances. These recommendations are based primarily on data from melanomas of the trunk and extremities. Melanomas of the hands and feet are less common and less well studied. They pose a surgical challenge because primary wound closure often is difficult, and the incidence and management of regional node metastases are unclear. METHODS: Charts of patients with melanomas of the hands or feet treated at the Massachusetts General Hospital between 1980 and 1994 were reviewed retrospectively. Local recurrence rates and the incidence of regional node metastases were analyzed as a function of histology, margin of excision, and microscopic thickness of the melanoma. RESULTS: Data from 116 patients (39 men, 77 women) with melanomas of the hands (n = 26) and feet (n = 90) were evaluated. Pathologic diagnoses were: acral lentiginous melanoma (48 patients); subungual melanoma (13 patients), and skin of dorsum of the hand or foot (n = 55). Digital amputation was required in all 13 patients with subungual melanoma to maintain local control; still, nodal metastases developed in 46% of patients within 1 year. Seventy-one percent of patients with acral lentiginous melanoma presented with lesions > or = 1.5 mm, and nodes or systemic disease or both developed in 56% of patients. Acral lentiginous melanoma lesions < 1.5-mm thick were treated principally by excision with a 1-cm margin; a local recurrence or metastases did not develop in any of the patients. None of the patients with melanomas on the dorsum of the hand or foot < 1.5-mm thick had a local recurrence, but regional or systemic disease developed in > 50%. Local control in patients with lesions > 1.5-mm thick frequently required skin grafting or amputation. The majority of patients with melanomas > or = 1.5 mm in thickness undergoing elective lymph node dissection had histologically positive nodes for melanoma. CONCLUSIONS: Melanomas of the hands and feet < 1.5-mm thick have a low incidence of nodal metastases and are treated effectively with wide excision of the primary with a 1-cm margin. Thicker melanomas are associated with a > 50% rate of regional or systemic failure. In the absence of metastatic disease, these individuals should undergo local excision with a 2-cm margin and intraoperative lymphatic mapping followed by lymphadenectomy if the sentinel node is positive.

Adolescent↗
PubMed1997

Lymphatic mapping and sentinel node biopsy in patients with malignant melanoma.

Intra-operative sentinel lymph node (SLN) mapping and biopsy is a procedure that accurately stages the regional lymph node basin. Defined patterns of lymphatic drainage allow intra-operative determination of the first (sentinel) lymph node in the regional basin, and the absence of metastatic disease in the SLN accurately reflects the absence of melanoma in the remaining regional nodes. The use of a radiocolloid and a handheld gamma probe together with a vital blue dye provides optimal results, and allows for the successful identification of the SLN(s) in over 98 percent of the procedures. Close collaboration between surgeons, nuclear radiologists and pathologists is required to ensure optimal results. Surgical excision of the SLN allows for a more thorough and focused pathological examination of one or two nodes. Examination of serially sectioned SLNs by H&E staining, immunohistochemical staining and perhaps RT-PCR should reduce the number of patients with missed microscopic melanoma in the regional lymph nodes. Recently reported survival data from the Intergroup Melanoma Trial suggest that patients may benefit from identification and removal of regional lymph nodes that contain metastatic melanoma. Furthermore, the survival benefit recently reported in patients with melanoma metastatic to regional nodes prospectively randomized to receive high dose Interferon alfa-2b signals that the surgeons should aggressively examine patients for the presence of occult regional melanoma metastases. Intra-operative SLN mapping and SLN biopsy is a cost-effective procedure that allows accurate identification of regional lymph nodes that contain metastatic melanoma.

Antineoplastic Agents↗
PubMed1996

O-linked glycosylation modifies CD44 adhesion to hyaluronate in colon carcinoma cells.

CD44 alternative splicing patterns differ between normal and malignant tissue, and accordingly, modulation of CD44 splicing has received the most attention in studies that have examined the role of CD44 in tumor progression. Many investigators have examined functional differences between individual CD44 alternative splice variants. However, specific CD44 isoforms function uniquely depending on the type of cell on which they are expressed, thereby suggesting that additional tissue-specific mechanisms regulate CD44 function. In the present study we have demonstrated that colon carcinoma cells modify CD44 with O-linked glycosyl groups, and blockade of this glycosylation enhances their CD44-mediated adhesion to hyaluronate. This enhancement is attributable principally to CD44H (CD44s) rather than high molecular weight CD44 variants. Use of site-directed mutant CD44H cDNA transfectants demonstrated that CD44 O-linked glycosylation modulates interaction between hyaluronate and the B loop domain of CD44. The influence of glycosylation on CD44 function in colon carcinoma cells is specific to the presence of O-linked sugars; inhibition of N-linked glycosylation had minimal influence on CD44 function. These findings indicate that O-linked glycosylation may be as important as alternative splicing in the regulation of CD44 function and the broad spectrum of biological processes attributed to it, including normal development, tumor metastases, and lymphocyte function.

Alternative Splicing↗
PubMed1996

Keratan sulfate modification of CD44 modulates adhesion to hyaluronate.

CD44 alternative splicing has been implicated in the regulation of CD44 function. CD44 undergoes significant posttranslational modification in all cells, but the functional consequences of these modifications are poorly understood. In the current study, we have demonstrated that keratan sulfate modification of CD44 significantly modulates its ability to bind to hyaluronate. We observed naturally occurring differences in CD44 keratan sulfate substitution between two clonal variants of the KM12 human colon carcinoma cell line. CD44 on the highly metastatic KM12L4 clone is more heavily substituted with keratan sulfate than CD44 on the poorly metastatic KM12C6 clone. Moreover, CD44H on KM12L4 bound to hyaluronate poorly compared to CD44H on KM12C6. Removal of keratan sulfate from CD44 greatly enhanced CD44-mediated cell adhesion to hyaluronate. Removal of keratan sulfate from CD44H-immunoglobulin fusion proteins also enhanced their adhesion to hyaluronate. The influence of glycosaminoglycan substitution on CD44 function was specific to keratan sulfate substitution; treatment to remove chondroitin sulfate, heparan sulfate, or hyaluronate did not affect CD44-mediated cell adhesion to hyaluronate. Use of site-directed CD44H cDNA mutants with arginine changed to alanine at position 41 indicated that keratan sulfate modification of CD44 modulates hyaluronate adhesion through its B loop domain. These findings suggest that keratan sulfate modification of CD44 may play an important regulatory role in the broad spectrum of biological processes attributed to CD44, including normal development, tumor progression, and lymphocyte function.

Alternative Splicing↗
PubMed1996

Attitudes and opinions toward surgical research. A survey of surgical residents and their chairpersons.

OBJECTIVE: To learn more about how research in academic surgery is viewed by surgical residents and their chairpersons. SUMMARY BACKGROUND DATA: There is a general perception that a productive experience in a basic science laboratory is an important prerequisite for a successful career in academic surgery. METHODS: An anonymous mail survey of 189 surgical residents entering the laboratory and their chairpersons (n=81) was done. Questions included how a laboratory was chosen by the resident, the importance of a basic science laboratory experience as a prerequisite to an academic career, and the perceived goal or goals of the laboratory experience. Data were analyzed by chi square analysis. RESULTS: The response rate from each group was excellent (80% response for residents, 90% from chairpersons). Of the residents surveyed, 78% were men and 22% were women; 51% entered the laboratory after 2 years of clinical training and 34% after 3 years; 84% did their research at their home institution and 91% worked in a surgeon's laboratory; 51% were scheduled to be in the laboratory for 1 year, 41% for 2 years, and 7% for 3 years. Two thirds of the residents were salaried by the surgery department. Both residents (70%) and chairpersons (86%) felt that the best surgical journal was Annals of Surgery. Both groups ranked Science as the top basic science journal. Twenty-four percent of the residents felt their peers offered the best advice in choosing a laboratory compared to 0% of the chairpersons (p<0.01); chairpersons felt they themselves or the program director were better advisors (chairpersons, 44%, vs. residents, 27%; p<0.01). Chairpersons believed that the principal investigators' previous success with residents was the major factor in determining in which laboratory to work; the residents placed more value on their interest in the project. Eighty-nine percent of women requested to go into the laboratory versus 66% of men (p<0.05). Half of the chairpersons and residents believed the faculty felt pressure on them to get grants; however, 71% of postgraduate year (PGY) residents who were PGY3 sensed this pressure compared to 44% of the PGY2 residents (p<0.01). Being in debt did not adversely influence the decision of 77% of these residents to do research. The residents felt more so than did their chairpersons that basic science research was necessary to be a successful academic surgeon (p<0.01). CONCLUSIONS: Although there are some differences in opinions between surgical residents and surgical chairpersons about the value and purpose of basic science research, these differences should be embraced and serve to enhance openness and discussion. Overall, surgical residents viewed the research experience away from clinical surgery as a positive one. The main reason for going into the laboratory was because of a genuine interest in the scientific method and the academic mission.

Attitude of Health Personnel↗
PubMed1996

Glucocorticoid-dependent induction of interleukin-6 receptor expression in human hepatocytes facilitates interleukin-6 stimulation of amino acid transport.

OBJECTIVE: The authors studied the effects of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on glutamine and alanine transport in isolated human hepatocytes. They also evaluated the role of dexamethasone in modulating this response and its effects on the expression of the plasma membrane high-affinity IL-6 receptor. SUMMARY BACKGROUND DATA: Animal studies indicate that cytokines are important mediators of the increased hepatic amino acid uptake that occurs during cancer and sepsis, but studies in human tissues are lacking. The control of transport by cytokines and cytokine receptor expression in the liver may provide a mechanism by which hepatocytes can modulate amino acid availability during catabolic disease states. METHODS: Human hepatocytes were isolated from wedge biopsy specimens and plated in 24-well trays. Interleukin-6 and TNF-alpha, in combination with the synthetic glucocorticoid dexamethasone, were added to hepatocytes in culture, and the transport of radiolabeled glutamine and alanine was measured. Fluorescent-activated cell sorter (FACS) analysis was used to study the effects of dexamethasone on IL-6 receptor number in the well-differentiated human hepatoma HepG2. RESULTS: Both IL-6 and TNF-alpha exerted a small stimulatory effect on alanine and glutamine transport. Dexamethasone alone did not alter transport rates, but pretreatment of cells augmented the effects of both cytokines on carrier-mediated amino acid uptake. Dexamethasone pretreatment and a combination of IL-6 and TNF-alpha resulted in a greater than twofold increase in transport activity. Fluorescent-activated cell sorter analysis demonstrated that dexamethasone induced a threefold increase in the expression of high-affinity IL-6 receptors. CONCLUSIONS: Interleukin-6 and TNF-alpha work coordinately with glucocorticoids to stimulate amino acid uptake in human hepatocytes. Dexamethasone exerts a permissive effect on cytokine-mediated increases in transport by increasing IL-6 receptor expression on the cell surface. It is likely that this upregulation of IL-6 receptors "primes" human liver cells for subsequent stimulation by cytokines. The resulting increase in hepatic amino acid transport provides the liver with substrate to support key metabolic pathways during catabolic states.

Amino Acids↗