Laparoscopic sentinel node navigation surgery versus laparoscopic gastrectomy with lymph node dissection for early gastric cancer: short-term outcomes of a multicentre randomized controlled trial (SENORITA).

BACKGROUND: Sentinel node navigation surgery reduces the extent of gastric and lymph node dissection, and may improve quality of life. The benefit and harm of laparoscopic sentinel node navigation surgery (LSNNS) for early gastric cancer is unknown. The SENORITA (SEntinel Node ORIented Tailored Approach) trial investigated the pathological and surgical outcomes of LSNNS compared with laparoscopic standard gastrectomy (LSG) with lymph node dissection. METHODS: The SENORITA trial was an investigator-initiated, open-label, parallel-assigned, non-inferiority, multicentre RCT conducted in Korea. The primary endpoint was 3-year disease-free survival. The secondary endpoints, morbidity and mortality within 30 days of surgery, are reported in the present study. RESULTS: A total of 580 patients were randomized to LSG (292) or LSNNS (288). Surgery was undertaken in 527 patients (LSG 269, LSNNS 258). LSNNS could be performed according to the protocol in 245 of 258 patients, and a sentinel node basin was detected in 237 (96·7 per cent) Stomach-preserving surgery was carried out in 210 of 258 patients (81·4 per cent). Postoperative complications occurred in 51 patients in the LSG group (19·0 per cent) and 40 (15·5 per cent) in the LSNNS group (P = 0·294). Complications with a Clavien-Dindo grade of III or higher occurred in 16 (5·9 per cent) and 13 (5·0 per cent) patients in the LSG and LSNNS groups respectively (P = 0·647). CONCLUSION: The rate and severity of complications following LSNNS for early gastric cancer are comparable to those after LSG with lymph node dissection. Registration number: NCT01804998 ( http://www.clinicaltrials.gov).

ANTECEDENTES: La cirugía de navegación del ganglio centinela (sentinel node navigation surgery, SNNS) reduce la extensión de la resección gástrica y ganglionar, y puede mejorar la calidad de vida. Se desconoce el beneficio y el daño de la cirugía de navegación del ganglio centinela por vía laparoscópica (laparoscopic sentinel node navigation surgery, LSNNS) para el cáncer gástrico precoz. El ensayo clínico SENORITA investigó los resultados patológicos y quirúrgicos de LSNNS en comparación con la gastrectomía laparoscópica estándar (laparoscopic gastrectomy, LSG) con disección ganglionar (lymph node dissection, LND). MÉTODOS: El ensayo SENORITA fue un ensayo multicéntrico aleatorizado y controlado, iniciado por investigadores, abierto, con asignación a grupos paralelos y de no inferioridad llevado a cabo en Corea. El resultado primario fue la supervivencia libre de enfermedad a los 3 años. En el presente estudio, se describen los resultados secundarios correspondientes a morbilidad y mortalidad a los 30 días del postoperatorio. RESULTADOS: Un total de 580 pacientes fueron aleatorizados a LG (n = 292) o LSNNS (n = 288). La cirugía se realizó en 527 pacientes (LG 269, LSNNS 258). LSNNS pudo ser realizada de acuerdo con el protocolo en 245 de 258 pacientes y en 237 de 245 pacientes (96,7%) se detectó un ganglio centinela. La cirugía con preservación del estómago se realizó en 210 de 258 pacientes (81,4%). Las complicaciones postoperatorias se presentaron en 51 pacientes del grupo LSG (19,0%) y en 40 pacientes (15,5%) del grupo LSNNS (P = 0,294). Las complicaciones grado III o mayor de Clavien-Dindo se detectaron en 16 (5,9%) y 13 pacientes (5,0%) de los grupos LSG y LSNNS, respectivamente (P = 0,647). CONCLUSIÓN: El porcentaje y la gravedad de las complicaciones tras LSNNS para cancer gástrico precoz son comparables a la LSG con LND.

Decreased detoxification genes and genome size make the human body louse an efficient model to study xenobiotic metabolism.

The human body louse, Pediculus humanus humanus, has one of the smallest insect genomes, containing ∼10 775 annotated genes. Annotation of detoxification [cytochrome P450 monooxygenase (P450), glutathione-S-transferase (GST), esterase (Est) and ATP-binding cassette transporter (ABC transporter)] genes revealed that they are dramatically reduced in P. h. humanus compared to other insects except for Apis mellifera. There are 37 P450, 13 GST and 17 Est genes present in P. h. humanus, approximately half the number found in Drosophila melanogaster and Anopheles gambiae. The number of putatively functional ABC transporter genes in P. h. humanus and Ap. mellifera are the same (36) but both have fewer than An. gambiae (44) or Dr. melanogaster (65). The reduction of detoxification genes in P. h. humanus may be a result of this louse's simple life history, in which it does not encounter a wide variety of xenobiotics. Neuronal component genes are highly conserved across different insect species as expected because of their critical function. Although reduced in number, P. h. humanus still retains at least a minimum repertoire of genes known to confer metabolic or toxicokinetic resistance to xenobiotics (eg Cyp3 clade P450s, Delta GSTs, B clade Ests and B/C subfamily ABC transporters), suggestive of its high potential for resistance development.

Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up.

BACKGROUND: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic-polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer. PATIENTS AND METHODS: From 1984 to 1989, patients who had D(2-3) curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m2 adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections. RESULTS: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T2-T4a), and lymph node status (N0-N2). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T3/T4a, N2, or stage III. Treatments were generally well tolerated in both arms. CONCLUSIONS: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.

Control of microorganisms and reduction of biogenic amines in chicken breast and thigh by irradiation and organic acids.

The effect of irradiation or organic acid treatment of raw chicken breast and thigh meat to control inoculated microorganisms and the production of biogenic amines (BA) was studied. Bacillus cereus, Enterobacter cloacae, and Alcaligenes faecalis were selected and inoculated into raw ground chicken breast and thigh meat at approximately 10(7) cfu/g. The samples were irradiated at 0, 0.5, 1, and 2 kGy or mixed with a 0.2 M solution of acetic, citric, or lactic acid (1 mL for 10 g of meat sample) for 24 h at 4 degrees C. Viable cell counts and BA contents were determined. Irradiation was effective in reducing the inoculated bacteria: 0.5 kGy achieved approximately a 2-log reduction, and no viable cells were detected at a dose of 2 kGy. In contrast, only up to a 1-log reduction was achieved by organic acid treatment except for citric acid, which achieved approximately a 3-log reduction of E. cloacae. Both the irradiation and organic acid treatment of raw chicken breast and thigh reduced the BA content, but the rate of BA reduction differed by inoculated organism and treatment (irradiation or organic acid). Although irradiation was an excellent method for controlling inoculated microorganisms, the content of BA produced was similar to that of the organic acid treatment of raw chicken breast and thigh meat.

Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability.

Microsatellite instability (MSI) and frameshift mutations in genes containing nucleotide repeats have been reported in a subset of colorectal and gastric carcinomas. This study describes the analysis of MSI-positive colorectal (39 cases) and gastric carcinomas (36 cases) for the presence of frameshift mutations of the six genes known to be involved in DNA repair and containing mononucleotide repeats in their coding region. Our mutational study of the 75 MSI-positive tumors revealed frequent mutations in hRAD50 (23 cases, 31%), BLM (16 cases, 21%), and hMSH6 (16 cases, 21%); rare mutations in BRCA1 (1 case, 1%) and ATM (3 cases, 4%); and no mutation in NBS1. In contrast, no frameshift mutation was found in 60 MSI-negative colorectal and gastric carcinomas. The mutation of hRAD50, a gene that is involved in the response to cellular DNA damage and forms a complex with hMRE11 and NBS1, has not been reported previously. Our results suggest that frameshift mutations of hRAD50, BLM, and hMSH6 are selected and play a role in the tumorigenesis of colorectal and gastric carcinomas with MSI. The MSI targeting of the hRAD50 and BLM genes represents an additional link between MSI and DNA repair because alteration of these genes could accelerate defective DNA repair.

Preoperative chemoradiotherapy with oral doxifluridine plus low-dose oral leucovorin in unresectable primary rectal cancer.

PURPOSE: The use of oral chemotherapeutic agents in chemoradiotherapy provides several advantages. Doxifluridine, an oral 5-FU prodrug, has been shown to be effective in colorectal cancer. We attempted a Phase II trial of preoperative chemoradiotherapy with doxifluridine plus a low-dose oral leucovorin in unresectable primary rectal cancer patients. In this study, toxicity and efficacy were evaluated. METHODS AND MATERIALS: There were 23 patients with primary unresectable rectal cancer in this trial, 21 of whom were available for analysis. The patients were treated with oral doxifluridine (900 mg/day) plus oral leucovorin (30 mg/day) from days 1 to 35, and pelvic radiation of 45 Gy over 5 weeks. Surgical resection was performed 5-6 weeks after the treatment. RESULTS: Acute toxicity involved thrombocytopenia, nausea/vomiting, diarrhea, and skin reaction. All were in Grade 1/2, except diarrhea, which was not only the most frequent (7 patients, 33.3%), but also the only toxicity of Grade 3 (2 patients). The clinical tumor response was shown in 5 patients (23.8%) as a complete response and 13 patients (61.9%) as a partial response. A complete resection with negative resection margin was done in 18 patients (85.7%), in 2 of whom a pathologic complete response was shown (9.5%). The overall downstaging rate in the T- and N-stage groupings was 71.4% (15 patients). CONCLUSION: This study demonstrated the efficacy and low toxicity of chemoradiotherapy with doxifluridine. Currently, a Phase III randomized trial of chemoradiotherapy is ongoing at our institute to compare the therapeutic efficacy of oral 5-FU with respect to i.v. 5-FU in locally advanced and unresectable rectal cancer.

Assessment of biomarkers in paired primary and recurrent colorectal adenocarcinomas.

PURPOSE: Recurrent colorectal cancers respond poorly to anticancer treatment including radiotherapy. To better understand the biological characteristics of the recurrent colorectal tumor, we investigated various biomarkers regulating cell proliferation and cell loss in paired primary and recurrent colorectal tumor specimens within each individual. METHODS AND MATERIALS: From a total of 11 colorectal adenocarcinoma patients, 22 specimens of paired primary and recurrent tumors were obtained for analysis. Apoptosis was evaluated by TUNEL labeling of apoptotic DNA fragmentation. Other biomarkers including proliferating cell nuclear antigen (PCNA), p53, WAF1, p34cdc2, and cyclins B1 and D1 were analyzed by immunohistochemical stains. RESULTS: PCNA index (PCNAI) showed an increase in 6 and a decrease in 5 recurrent tumors compared to primary tumors. Median PCNAI in primary and recurrent tumors were 33.5 and 48.3, respectively (p = 0.16). In contrast, the apoptotic index (AI) decreased in 9 of 11 recurrent tumors compared to primary tumors. Median AI decreased from 4.3 in primary tumors to 1.4 in recurrent tumors (p = 0.04). The p53 expression increased in more than half of recurrent tumors compared to primary tumors. Mean staining score increased from 0.7 in primary tumors to 1.2 in recurrent tumors (p = 0.059). WAF1 and cyclin B1 did not show significant change. In contrast, both cyclin D1 and p34cdc2 increased significantly in recurrent tumors. These two biomarkers showed increased expression in 8 (cyclin D1) and 7 (p34cdc2) recurrent tumors, respectively, compared to their primary counterparts. Mean staining scores of both biomarkers in recurrent tumors increased by more than twofold compared to those in primary tumors and these differences were statistically significant (cyclin D1, p = 0.007; p34cdc2, p = 0.008). CONCLUSION: This study showed significantly decreased apoptosis in recurrent colorectal tumors compared to their primary counterparts. The underlying regulatory mechanisms included increased expression of p53 and altered cell cycle regulators such as increased cyclin D1 and p34cdc2. With further study, it may be used for developing a new therapeutic strategy for the treatment of recurrent colorectal cancer.

Correlation of tissue and blood plasminogen activation system in breast cancer.

The plasminogen activation system plays a crucial role during cancer invasion and metastasis. In the solid tumor, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor type-1 (PAI-1) and uPA receptor (uPAR) are considered as prognostic factors. In this study, we have investigated whether secretion of the uPA, PAI-1 and uPAR from the primary breast cancer tissue can be detected in the blood of the patients using the ELISA assay. We have found that the plasminogen activation system (uPA, PAI-1, uPAR) of tumor tissue is activated from the early stage of breast cancer. However, only a number of metastatic lymph nodes was a prognostic factor in multivariate analysis for relapse. The blood level of the plasminogen activation system correlated with that of tissue in an order of uPAR (r(2)=0.61; P=0.001), uPA (r(2)=0.35; P=0.001) and PAI-1 (r(2)=0.11; P=0.001). We conclude that the total uPAR level of cancer tissue can be substituted by that which is detected in the blood for further clinical applications.

Comparison of biological phenotypes according to midkine expression in gastric cancer cells and their autocrine activities could be modulated by pentosan polysulfate.

We studied biological phenotypes of gastric cancer cell lines based on a novel heparin-binding growth/differentiation factor (midkine (MK)) expression. MK expression was found in 67% (6/9) of the gastric cancer cell lines and 56% (14/25) of the primary cancer tissues. Gastric cancer cell lines with MK expression showed higher colony forming activity in soft agar assay and endothelial cell growth stimulatory effect in cross-feeding assay than cells which did not express MK. However, urokinase-type plasminogen activator (uPA) expression and tumor invasiveness did not correlate with MK expression. Growth of MK expressing cells was inhibited by a heparin-binding blocking agent, pentosan polysulfate (PPS). In cancer tissues, MK expression correlated with tumor size, suggesting in vivo autocrine and paracrine activity. This proliferation promoting activity of MK can be targeted by an anti-heparin binding agent as a biotherapy model in gastric cancer.

Monthly 5-days 5-fluorouracil and low-dose leucovorin for adjuvant chemotherapy in colon cancer.

We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes' B2 and C2 stage disease. Chemotherapy consisted of 400 mg/m(2) of 5-FU and 20 mg/m(2) of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (P=0.0018, P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes' C2 (P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (P=0.0016, P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.

Changes of telomerase and telomere lengths in paired normal and cancer tissues of breast.

To attain the immortal phenotype, cancer cells must overcome the mitotic clock. Telomerase activity has been identified to be activated in malignant tumors including breast cancer. Telomerase activity was evaluated in 71 breast cancer tissues and paired normal tissues with the TRAP (telomerase repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. In 59 paired breast tissues with telomerase activity, terminal restriction fragment (TRF) lengths were measured using Southern blotting. Relative inhibition (RI), the ratio of inhibited telomerase activity in each tumor tissue compared to that of the 293 control cell line after pre-treatment with 150 microg/ml of RNAse A, was measured. Sixty-three of 71 cancer tissues showed telomerase activity (88.7%) with 75.3+/-17.9 units in densitometry, while no telomerase activity was detected in their paired normal tissues. Telomerase activity was correlated to node metastasis (p=0.02) and stage (p=0.005), but not to tumor size or the hormonal receptor status. TRF lengths were 11. 0+/-4.7 kb in 59 tumor tissues and 11.7+/-2.2 kb in paired normal tissues. TRF lengths did not correlate to any of the clinical parameters. However changes of TRF lengths in tumor tissues compared to those of normal tissues correlated to telomerase activity. RI in the tumor tissues was proportional to telomerase activity without RNAse A pre-treatment. In breast cancer, telomerase activity was specific to tumor tissues and increased with tumor progression. Telomerase activity and changes in TRF lengths can be used as guidelines in detecting candidates for the telomerase inhibitor.

Telomerase activity and telomere lengths in various cell lines: changes of telomerase activity can be another method for chemosensitivity evaluation.

For the cancer cells which have overcome the second mitotic clock (M2), activated telomerase is essential and used as another marker of immortality. Many trials had been initiated to target telomerase, which is known to be specific to tumors. To determine the best in vitro cell system for testing the efficacy of telomerase inhibitors, we evaluated the telomerase activity of various cancer cell lines and measured their telomere lengths. We also treated some cancer cell lines with adriamycin and measured the changes of telomerase activity. Telomerase activity was evaluated in various cell lines with the TRAP (telomeric repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. Also, terminal restriction fragment lengths were measured using Southern blotting. We also measured telomerase activity and telomere lengths in 11 benign breast tumor tissues and 19 paired stomach cancer and normal tissues. Cancer cell lines treated with adriamycin we evaluated for changes of telomerase activity and the cell proliferation by MTT assay and dye exclusion test. Telomerase activity of cell lines was 95.3 24.1 unit with a range of 27.6-129.6 unit, while the telomere lengths of those cell lines were variable from 5.0 to 10.4 kbp with a median of 6 kbp. In 11 cancer cell lines which were not yet firmly established, we could not detect any telomerase activity. Low telomerase activity was detected in only 2 benign tumor tissues of breast with a median telomere length of 8.8 (7-10.5) kbp. Among paired 19 gastric cancer and normal tissues, only 7 cancer tissues showed weak telomerase activity. After adriamycin treatment, telomerase activity in YCC-S-1, YCC-S-3, MCF-7 and MCF-7/ADR was decreased in accordance with the changes of the cell numbers. Telomerase is specific to cancer tissues and is expressed differently from organ to organ. Telomerase activity by TRAP assay could be used as a chemosensitivity assay.

Different expression patterns of MMP-2 and MMP-9 in breast cancer.

Among the many biological characteristics of cancer, the matrix metalloproteinase (MMPs) is essential for tumor invasion and metastasis. The relationship between MMP-2 and MMP-9 according to tumor progression has not been studied yet. We evaluated the synchronous expression and activation rate of MMP-2 and MMP-9 in breast cancer tissues and compared them to the clinical parameters in order to determine the clinical significance of MMPs and the possibilities of using them as a therapeutic target. The activity of MMPs was evaluated in 121 breast cancer tissues using zymography and the area of activation was calculated by computer-assisted densitometry in comparison to the activity of a positive control (HT-1080). In 121 tumor tissues, 32 (26.4%) did not express any form of MMPs and 19 (15.7%) showed both expression of MMP-2 and MMP-9. We observed that only one tissue expressed MMP-9 alone, while MMP-2 alone was expressed in 69 tissues. In 88 patients with MMP-2 and/or MMP-9 expression, we were unable to observe any correlation between the activity of MMPs expression or activation rate and the clinical parameters. But MMP-2 and MMP-9 activity increased according to T factor. Rapid production of MMP-9 occurred from T2 (p=0.046), while that of MMP-2 occurred from T3 (p=0.004). In conclusion, MMPs activity was organ specific. The major MMPs in breast cancer was MMP-2 and MMPs activity was different with tumor progression. When MMPs are a specific therapeutic target, we should use different inhibitors according to tumor size, in patients at the same stage.

Effects of interleukin-2 transduction on the human hepatoma cell lines using retroviral vector.

Gene therapy, using cytokine gene transduction, aims to increase the antigenicity of tumor cells, and to activate the immune effector cells, and thereby inducing tumor regression. With regards to in vitro sensitivity to peripheral blood monocytes and in vivo tumorigenic activity we compared the differences between parent hepatoma cell lines and interleukin-2 (IL-2) transduced hepatoma cell lines using N2A/IL-2 and LNC/IL-2 retrovirus. IL-2 secretion was 186 pg/10(6) cells/24 h in SK-Hep1 cell line and 147 pg/106 cells/24 h in Hep-3B cell line with N2A/IL-2 retroviral vector and was 55,000 pg/10(6) cells/24 h in Hep-3B cell line with LNC/IL-2 retroviral vector. in vitro sensitivity to peripheral blood monocytes was increased by 163.8-254% in IL-2 transduced hepatoma cell lines (Hep-3B/LNC/IL-2, Hep-G2/LNC/IL-2) compared to those of the parent cell lines. The tumor was formed in 1 of 3 BALB/c mice and all 3 nude mice with the injection of 1x107 cells. Simultaneous injection of 1x10(7) cells of the parent cell line (Hep-3B) into the right flank and IL-2 transduced cell line (Hep-3B/LNC/IL-2) into the left flank of the three BALB/c mice and of 5x10(5) cells for the three nude mice resulted in a complete regression of the IL-2 modified tumor cell line (Hep-3B/LNC/IL-2) in 3 weeks and the parent cell line (Hep-3B) in 5 weeks. After injection of 1x10(7) cells into five other nude mice, the tumor of the IL-2 transduced hepatoma cells (Hep-3B/LNC/IL-2) gradually disappeared, however, the tumor of the parent hepatoma cell line initially decreased and then gradually regrew 20 days later. In conclusion, IL-2 transduced hepatoma cell lines secreting IL-2 became more sensitive to peripheral blood monocytes. IL-2 secretion by LNC/IL-2 retrovirus from the hepatoma cell lines was more prominent compared with that by N2A/IL-2 retrovirus. IL-2 transduction into the hepatoma cells resulted in increased antigenicity to the tumors formed by IL-2 transduced hepatoma cell line and parent cell line, which leads the regression of the tumors. However, the higher the tumor burden, the less efficient tumor regression by IL-2 transduction into the hepatoma cell line in nude mice was observed.

Alpha-fetoprotein-producing gastric cancer.

We measured the sero-positivity rate of serum alpha-fetoprotein (alphaFP) of gastric cancer patients by ELISA assay; forty-two curatively resected patients, 14 palliatively resected patients, 8 who received explo-laparotomy or bypass surgery and 18 patients with systemic metastasis. The sero-positive rate was 9.8% (8/82) and the positivity increased with cancer progression. Sex, age and pathological type were similar between alphaFP-positive and -negative patients. The overall synchronous hepatic metastasis rates in alphaFP-positive and alphaFP-negative groups were 37.5% (3/8) and 12.2% (9/74), respectively (p=0.08). The predictability of synchronous liver metastasis in eight alphaFP-positive patients were as follows: 37. 5% of total patients (3/8), 50.0% (3/6) of unresectable patients, and 60.0% (3/5) of patients with systemic metastasis. In three alphaFP-positive patient with liver metastasis, all the hepatic lesions were intrahepatic and multiple, while in alphaFP-negative patients, 67% (6/9) of the hepatic lesions was single intrahepatic lesion or surface nodule. The predictability of both synchronous and metachronous liver metastasis in alphaFP-positive gastric cancer patients was 75%. These findings suggested that, in advanced stomach cancer patients, especially in stage IV, alphaFP can be used in predicting liver metastasis during follow-up.

Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer.

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specific biological phenotypes and increase the anti-tumor effect when combined with chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The effects of each drug on colony formation and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by zymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Migration capacity using Boyden chamber assay was more closely correlated with adhesive capacity than uPA or MMP-2 expression. The motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell line, which expressed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC-1. The combination of Lovastatin and Adriamycin did not show any combined effects in any of the cell lines. In conclusion, a synergistic anti-proliferative effect (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells with specific biological target, MK. The anti-motility effect was the greatest when the gastric cancer cells expressed all the specific biological phenotypes.

Tissue urokinase-type plasminogen activator receptor levels in breast cancer.

Cancer invasion is induced by several proteolytic enzyme systems associated with the destruction of basement membrane and extracellular matrix. Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have been reported as prognostic factors in breast cancer patients and plasminogen activation is regulated by various factors such as uPAR and growth factors. Thus, we examined the tissue levels of urokinase-type plasminogen activator receptor (uPAR) in breast cancer patients. Tissue uPAR levels were measured by ELISA assay in 268 breast cancer patients. The median and mean values of tissue uPAR level in breast cancer were 3.5 ng/mg cytosol protein and 4.8+/-3.6 ng/mg cytosol protein, respectively. Tissue uPAR level was the highest in T1 stage, but there was no statistical significance between the T stages (p>0.05), nor in nodal stage, in the value of uPAR according to progression. And the value of uPAR expression was not associated with estrogen and progesterone receptor status, number of involved node and percent of node involvement. In TNM stage, tissue uPAR levels were higher in patients with stage I-II than in patients with stage III-IV (p=0.027). In univariate analysis, nodal factor (p=0.002) and TNM stage (p=0.0004) were significant. But, multivariate analysis showed that TNM stage was the only significant prognostic factor (p=0.0002). These results suggest that uPAR is mainly associated with initial tumor invasion and other factors might be involved in later stages of cancer progression.

Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer.

We investigated whether blood angiogenic factor (vascular endothelial growth factor, VEGF; angiogenin; basic fibroblast growth factor, bFGF; platelet-derived growth factor-AB, PDGF-AB) levels change during menstrual cycle of healthy premenopausal females or after menopause. We also measured the serum angiogenic factor levels in 34 operable breast cancer patients and compared them to those of healthy volunteer controls. No differences in the four angiogenic factor levels were found between the follicular and luteal phases of normal menstruation. However, angiogenin and bFGF levels were higher in pre-menopausal females than post-menopausal female and young male healthy volunteers. In cancer patients, the sero-positivity rate of the bFGF was 8.8% with menstrual-state-unmatched cut-off points, which increased to 36.4% with menstrual-state-matched cut-off points. This discrepancy was especially high in post-menopausal cancer patients. In conclusion, physiological elevation of the bFGF during normal menstruation can influence the precise interpretation of the pathological elevation of the bFGF in pre-menopausal breast cancer patients.

A comparative study of intravenous granisetron versus intravenous and oral ondansetron in the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy.

We conducted a prospective, randomized, open, single-center, parallel group study comparing the anti-emetic efficacy and toxicity of granisetron with that of ondansetron in patients receiving moderately emetogenic chemotherapy. From December 1994 to May 1995, patients who were to receive moderately emetogenic chemotherapy for the first time or who had not received chemotherapy (80 to 100 mg/m2 of cisplatin or 40 mg/m2 of doxorubicin) within 4 weeks previously were enrolled in this study. The following anti-emetic regimens were used: 3 mg of granisetron were given intravenously before chemotherapy for a single dose; 8 mg of ondansetron were given intravenously before chemotherapy and then every 8 hours for a total of 3 doses, plus 8 mg of an oral maintenance dose every 12 hours for 5 consecutive days. We evaluated 97 patients (48 received granisetron and 49 received ondansetron). In the first 24 hours after chemotherapy, complete and major responses were achieved in 76.6% of the patients receiving granisetron and in 72.9% of patients receiving ondansetron (p = 0.9033). Additionally, there was no difference in the control of delayed nausea and vomiting between the two groups (51.1% versus 54.2%, p = 0.9200), and there were no significant adverse effects or toxicities. We have concluded that a single dose of granisetron is as effective in prophylaxis of emesis induced by moderately emetogenic chemotherapy as a triple dose of ondansetron plus oral maintenance.

Gastric cancer in young patients who underwent curative resection. Comparative study with older patients.

Although several studies demonstrated the poor prognosis of young patients with gastric cancer, there were few reports about the survival of young patients who underwent radical surgery. We retrospectively reviewed the hospital records of 697 patients with curatively resected locally advanced gastric cancer to compare the pathologic findings and prognosis of young patients (aged < 40 years; 91 patients) with those of older (aged > or = 40 years; 606 patients) patients. There were no significant differences in location of tumors, Borrmann types, tumor invasion, and pathologic stage between both age groups. Despite the male predominance in older patients, the male-to-female ratio was nearly equal in young patients (p = 0.022). A significantly higher percentage of young patients showed poorly differentiated histology including signet ring cell and undifferentiated carcinoma than older patients (p < 0.0001). Adjuvant chemotherapy was more frequently performed in the young patients with a variety of different regimens (85.7 vs. 72.3%; p = 0.009). The 5-year overall survival rate revealed no statistically significant differences between the young and older patients (53.1 vs. 56.6%; p = 0.820). In conclusion, the young patients with curatively resected locally advanced gastric cancer showed similar survival compared to that of older patients.