Influence of a ring-shaped pump beam on temperature distribution and thermal lensing in end-pumped solid state lasers.

A simple method for reducing thermal lensing in an end-pumped solid state laser using a ring-shaped pump beam is reported. Analytical expressions for the temperature distribution and the thermal lensing focal length in a laser medium end-pumped by a beam with a ring-shaped intensity profile are derived. The results indicate that thermal effects including thermal lensing can be significantly reduced due to a more uniform temperature distribution. This approach has been applied to a Nd:YVO4 amplifier operating at 1064 nm confirming that the brightness of the output beam can be remarkably improved at high power levels due to the better beam quality for the ring-shaped pumping compared to the conventional quasi-top-hat pumping. The prospects for power scaling and further improvement in laser performance will be discussed.

Locoregional relapse after gastrectomy with D2 lymphadenectomy for gastric cancer.

BACKGROUND: Risk for and site of locoregional relapse have not been well studied in patients undergoing gastrectomy with D2 lymphadenectomy for gastric cancer. METHODS: Patients who had undergone gastrectomy with D2 lymphadenectomy for gastric cancer between 2004 and 2007 were identified from an institutional database. The locoregional relapse rate was estimated by competing risk analysis, and risk groups were derived according to locoregional relapse risk using recursive partitioning analysis (RPA). The locations of nodal relapses were evaluated according to Japanese Classification of Gastric Carcinoma criteria. RESULTS: Some 2618 patients were included. With a median follow-up of 78·0 (range 28·5-122·6) months, relapse was diagnosed in 471 of 2618 patients (18·0 per cent). The cumulative incidence of locoregional relapse at 5 years was 8·5 (95 per cent c.i. 7·4 to 9·6) per cent. The 5-year locoregional recurrence rates for high-risk (N3), intermediate-risk (N1-2) and low-risk (N0) groups were 32·4, 12·3 and 1·7 per cent respectively (P < 0·001). Among patients with regional relapse, 90·4 per cent had involvement outside the D2 dissected area, and the most commonly involved site was station 16b1. This pattern was maintained in the RPA risk groups (P = 0·329). CONCLUSION: Locoregional relapse at 5 years after gastrectomy with D2 lymphadenectomy was 8·5 per cent, and was most often seen outside the D2 dissected area.

Minimally invasive surgery for serosa-positive gastric cancer (pT4a) in patients with preoperative diagnosis of cancer without serosal invasion.

BACKGROUND: Although surgeons normally use minimally invasive surgery (MIS) for patients with early gastric cancer, in Korea and Japan the procedure is also indicated for serosa-negative tumors. Serosal invasion is regarded to be a potential risk factor for peritoneal dissemination as a result of the effect of pneumoperitoneum and tumor manipulation during the operation. We compared operative outcomes between MIS and conventional open surgery for serosa-involved advanced gastric cancer patients who had a preoperative diagnosis of cancer without serosal invasion. METHODS: A total of 61 patients (39 patients treated by MIS and 22 by open surgery) treated between 2003 and 2009 who were first diagnosed preoperatively as serosa negative on the basis of computed tomography, endoscopy, and endoscopic ultrasound but then diagnosed as serosa positive upon final pathology were studied. We retrospectively compared recurrence and survival between the two treatment groups. RESULTS: Clinicopathologic characteristics, clinical stage, extent of surgery, and short-term operative outcome did not differ between the groups. 5-year overall survival (73.5 vs. 67.5 %, p = 0.518, respectively) and disease-free survival (67.8 vs. 54.2 %, p = 0.296, respectively) were comparable between the MIS and open surgery groups. There were recurrences in 12 patients in the MIS group and 11 patients in the open surgery group, with a median follow-up period of 64 months. Recurrence patterns did not differ between the groups; moreover, MIS did not increase peritoneal recurrences compared to open surgery (42.0 vs. 54.5 %, p = 0.537, respectively). In multivariate analyses, the type of surgery was not an independent prognostic factor. CONCLUSIONS: Similar survival and recurrence patterns were observed in advanced gastric cancer patients preoperatively diagnosed as serosa negative who were treated either by MIS or open surgery. MIS may be safely applied in patients with serosa-positive tumors.

External validation of nomogram for the prediction of recurrence after curative resection in early gastric cancer.

BACKGROUND: Nomograms are statistics-based tools that provide the overall probability of a specific outcome. In our previous study, we developed a nomogram that predicts recurrence of early gastric cancer (EGC) after curative resection. We carried out this study to externally validate our EGC nomogram. PATIENTS AND METHODS: The EGC nomogram was established from a retrospective EGC database that included 2923 consecutive patients. This nomogram was independently externally validated for a cohort of 1058 consecutive patients. For the EGC nomogram validation, we assessed both discrimination and calibration. RESULTS: Within the follow-up period (median 37 months), a total of 11 patients (1.1%) experienced recurrence. The concordance index (c-index) was 0.7 (P = 0.02) and the result of the overall C index was 0.82 [P = 0.006, 95% confidence interval (CI) 0.59-1.00]. The goodness of fit test showed that the EGC nomogram had significantly good fit for 1- and 2-year survival intervals (P = 0.998 and 0.879, respectively). The actual and predicted survival outcomes showed good agreement, suggesting that the survival predictions from the nomogram are well calibrated externally. CONCLUSIONS: A preexisting nomogram for predicting disease-free survival (DFS) of EGC after surgery was externally validated. The nomogram is useful for accurate and individual prediction of DFS, patient prognostication, counseling, and follow-up planning.

Major early complications following open, laparoscopic and robotic gastrectomy.

BACKGROUND: Laparoscopic and robotic gastrectomy have been adopted rapidly despite lack of evidence concerning technical safety and controversy regarding additional benefits. This study aimed to compare clinically relevant complications after open, laparoscopic and robotic gastrectomy. METHODS: This was a retrospective analysis of prospectively collected data on surgical complications in patients undergoing gastrectomy with curative intent for histologically proven adenocarcinoma between 2005 and 2010 at the Department of Surgery, Yonsei University College of Medicine in Seoul, Korea. Complications were categorized into wound infection, bleeding, anastomotic leak, obstruction, fluid collection and other. RESULTS: In a total of 5839 patients (4542 open, 861 laparoscopic and 436 robotic gastrectomies), overall complication, reoperation and mortality rates were 10·5, 1·0 and 0·4 per cent respectively. There were no significant differences between the three groups. Ileus (P = 0·001) and intra-abdominal fluid collections (P = 0·013) were commoner after conventional open surgery. However, tumour stage was higher and more complex resections were performed in the open group. Anastomotic leak, the leading cause of death, occurred more often after a minimally invasive approach (P = 0·017). CONCLUSION: Laparoscopic and robotic gastrectomy had overall complication and mortality rates similar to those of open surgery, but anastomotic leaks were more common with the minimally invasive techniques.

Relevance of lymph node metastasis along the superior mesenteric vein in gastric cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of lymph node metastasis along the superior mesenteric vein (station 14v) to determine the need for 14v dissection in gastric cancer surgery. METHODS: A total of 1104 patients with gastric cancer who underwent gastrectomy including 14v dissection were enrolled. Patients were categorized into two groups: those with and those without 14v lymph node involvement by metastasis. RESULTS: Of the total study population, 73 patients (6·6 per cent) had 14v-positive gastric cancer. These patients were more likely to have advanced tumour (T), node (N) and distant metastatic (M) status, and histologically undifferentiated gastric cancers. The 3- and 5-year survival rates of patients with 14v-positive disease were 24 and 9 per cent respectively. Survival in this group was similar to that of patients who had gastric cancer with distant metastasis (M1). Multivariable analysis demonstrated that 14v status was a significant prognostic factor for gastric cancer (hazard ratio 2·13; P < 0·001). After histologically complete (R0) resection, the overall survival of 14v-positive patients with any stage of cancer was significantly worse than that for 14v-negative patients with stage IV cancer (P = 0·006). CONCLUSION: 14v status is an independent prognostic factor for gastric cancer, with 14v-positive gastric cancer having a poor prognosis, similar to that of M1 disease. The exclusion of 14v in regional lymph node dissection should be considered.

Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer.

BACKGROUND: This phase II study describes the efficacy and safety of combination chemotherapy of 5-fluorouracil (5-FU), low-dose leucovorin, and oxaliplatin (FLOX regimen) for pretreated advanced gastric cancer. PATIENTS AND METHODS: Patients who had been previously treated with greater than or equal to one regimen were enrolled. Patients received an oxaliplatin 75 mg/m(2) on day 1, 5-FU 1000 mg/m(2) on days 1-3, and leucovorin 20 mg/m(2) on days 1-3, every 3 weeks. The primary end point was overall survival (OS). RESULTS: Among the 52 patients enrolled, 26 patients were treated as second line, and the remaining 26 patients were enrolled as third- or fourth line. A total of 203 cycles of chemotherapy were administered with the median being three cycles (range 1-15) per patient. The median OS was 6.6 months [95% confidence interval (CI) 4.5-8.8] and the median progression-free survival was 2.5 months (95% CI 1.9-3.0). The response rate was 4% (95% CI 0-9%), and the disease control rate was 48% (95% CI 34-62%). The most common toxic effects of grade 3/4 were neutropenia (16%) and vomiting (6%). CONCLUSIONS: The FLOX regimen showed modest activity as a salvage treatment in pretreated advanced gastric cancer with a favorable compliance.

Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases.

BACKGROUND: The benefit of surgical resection of liver metastases from gastric cancer has not been well established. The aim of this study was to evaluate the rationale for hepatic resection in patients with hepatic metastases from gastric cancer. METHODS: Among 10 259 patients diagnosed with gastric adenocarcinoma in the Yonsei University Health System from 1995 to 2005, we reviewed the records of 58 patients with liver-only metastases from gastric cancer who underwent gastric resection regardless of hepatic surgery. RESULTS: The overall 1-year, 3-year, and 5-year survival rates of 41 patients who underwent hepatic resection with curative intent were 75.3%, 31.7%, and 20.8%, respectively, and three patients survived >7 years. Of the 41 patients, 22 had complete resection and 19 had palliative resection. Between the curative and palliative resections, survival rates after curative intent were not different. The number of liver metastasis (solitary or multiple) was a marginally significant prognostic factor for survival. CONCLUSIONS: Surgery for liver metastases arising from gastric adenocarcinoma is reasonable if complete resection seems feasible after careful preoperative staging, even if complete resection is not actually achieved. Hepatic resection should be considered as an option for gastric cancer patients with hepatic metastases.

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.

Dynamic assembly of liquid crystalline graphene oxide gel fibers for ion transport.

Colloidal dispersions with liquid crystallinity hold great promise for fabricating their superstructures. As an example, when graphene oxide (GO) sheets are assembled in the liquid crystalline state, they can turn into ordered macroscopic forms of GO such as fibers via the wet spinning process. Here, we report that by reinforcing intersheet interactions, GO liquid crystals (LCs) turn into mechanically robust hydrogels that can be readily drawn into highly aligned fibrillar structures. GO hydrogel fibers with highly aligned sheets (orientation factor, f = 0.71) exhibit more than twice the ionic conductivity compared to those with partially aligned structures (f = 0.01). The hierarchically interconnected two-dimensional nanochannels within these neatly aligned GOLC hydrogel fibers may facilitate controlled transport of charge carriers and could be potentially explored as cables for interconnecting biosystems and/or human-made devices.

Factors influencing operation time of laparoscopy-assisted distal subtotal gastrectomy: analysis of consecutive 100 initial cases.

AIMS: There is little information on patient selection criteria for laparoscopy-assisted distal gastrectomy (LADG) that would facilitate a successful initial experience for a surgeon new to the procedure. This study aimed to establish patient selection criteria that will allow increased proficiency and shorter operation times for the LADG procedure. METHOD: One hundred LADG with lymphadenectomy and no other combined procedures were consecutively performed by one surgeon. These 100 consecutive LADG procedures were analyzed retrospectively from a prospectively designed computer database. Uni- and multivariate analyses were performed to identify factors influencing operation time. RESULTS: According to univariate analysis, operation time was influenced by sex, BMI, surgical experience, and tumor location, whereas multivariate analysis indicated that operation time was significantly influenced only by BMI and surgical experience. The same analyses of only the first 50 cases showed that sex, BMI, surgical experience, and tumor location were independently associated with operation time. As BMI increased, so did operation time, whereas operation time decreased with increasing surgical experience. CONCLUSION: This study suggests that surgeons who have limited experience with this advanced procedure may shorten operation time by considering patient and tumor characteristics in their early attempts at LADG. With a shortened operation time, surgeon with limited experience may become proficient to LADG rapidly.

Metastasis in para-aortic lymph nodes in patients with advanced gastric cancer, treated with extended lymphadenectomy.

BACKGROUND/AIMS: Lymph node dissection is an essential component of curative resection for advanced gastric cancer. To improve the survival of N2 patients, Asian surgeons have been performing D2+para-aortic lymph node dissection. The current study presents the results of lymph node status from multicenter trial of D2 and D2 + para-aortic nodal (No.16) dissection (D4 dissection). METHODOLOGY: Patients enrolled in the study had potentially curable gastric adenocarcinoma in an advanced stage, T2, T3 or T4/N1 or N2. Patients were randomized to undergo either D2 or D4 gastrectomy. RESULTS: Two hundred and seventy patients were registered and 136 and 134 patients were allocated into the D2 or D4 group, respectively. The average nodal yield of No.16 in D4 group was 18.4 +/- 14.1, ranging from 2 to 84. No.16 metastasis was detected in 12 (9.0%) of 134 D4 patients. One, 9 and 2 patients had simultaneous involvement in N1, N2, and N3 (No.8p, 12, 13 or 14). Namely, in 39 patients who were diagnosed as N2 from the lymph node status in N1 and N2 levels, nine (23.0%) patients had No.16 metastasis. The stage migration by D4 was found in 10 (7.5%). Logistic regression analysis revealed that the stations of No.7 and No.8 were the significant predictors of No.16 involvement. CONCLUSIONS: The present study may strongly suggest that prophylactic D4 dissection may be indicated for patients with N2 involvement, and that No.7 and No.8 are the junctional nodes for D4 dissection.

Operative morbidity and mortality after D2 and D4 extended dissection for advanced gastric cancer: a prospective randomized trial conducted by Asian surgeons.

BACKGROUND/AIMS: A randomized study was performed to evaluate morbidity and mortality after D2 (level 1 and 2 lymphadenectomy) and D4 (D2 plus lymphadenectomy of para-aortic lymph nodes) dissection for advanced gastric cancer. METHODOLOGY: Two hundred and fifty-six patients with advanced gastric adenocarcinoma were enrolled (128 to each group). Patients were randomly allocated into D2 (N = 128) or D4 (N = 128) group. The first and second tiers of lymph nodes are removed in D2 dissection. In D4 gastrectomy, the paraaortic lymph nodes were additionally removed. RESULTS: There was no indication of significant distribution bias with regard to age, sex, T-grade, and N-grade between the two groups. Operation time of D4 gastrectomy (369 +/- 120 min) was significantly longer than that of D2 gastrectomy (273 +/- 1103 min), and blood loss of the D4 group (872 +/- 683 mL) was significantly greater than that of the D2 group 571 +/- 527 mL (P < 0.001). Five (4%) and two (2%) medical complications developed in the D2 and D4 groups, respectively. Surgical complications developed in 28 (22%) and 48 patients (38%) after D2 and D4 gastrectomy. The most common complications were anastomotic leakage, pancreatic fistula, and abdominal abscess. Pancreatic fistula developed in 6 (19%) of 32 patients after D4 plus pancreatosplenectomy, but the incidence of pancreatic fistula after D2 gastrectomy plus pancreatosplenectomy was low (6%, 1/16). Two patients died within 30 days of operation (0.8%, 2/256), and each patient belonged to the D2 and D4 group. CONCLUSIONS: Although there is a significantly higher surgical complication rate in D4 dissection, D4 dissection can be done safely as D2 dissection when performed by well-trained surgeons.

Intraoperative tumor localization using laparoscopic ultrasonography in laparoscopic-assisted gastrectomy.

BACKGROUND: During laparoscopic-assisted gastrectomy, it is impossible to identify early gastric cancer (EGC) lesions; therefore, a precise localization technique is needed. In this study, we used laparoscopic ultrasonography (LUS) after endoscopic clipping as a method of localizing EGC and evaluated the effectiveness of this method. METHODS: A prospective study of 17 patients who had undergone laparoscopic-assisted gastrectomy was performed. Three endoscopic clips were applied just proximal to the tumor during the preoperative endoscopy. The applied clips were detected from the serosal side of the stomach using LUS. The serosal surface of the lesion was marked with dye. RESULTS: In all patients, endoscopic clips were applied proximal to the lesion without complications, and the applied clips were confirmed by plain abdominal radiography. The clips were successfully detected by LUS in all patients. In the resected specimen, the serosal surface, marked with dye, was always just above the clips in the anterior wall or on the anterior wall opposite the clips applied in the posterior wall. The mean detection time was 4.7 min (range, 2-8). With this procedure, two patients underwent total gastrectomy and 15 patients underwent distal subtotal gastrectomy with gastroduodenostomy or gastrojejunostomy. Histological examination confirmed that the resection margins were tumor free in all patients. There was no operative morbidity related to the LUS procedure. CONCLUSIONS: Using LUS to detect endoscopic clips is an easy, safe, and accurate method to localize EGC lesions in laparoscopic-assisted gastrectomy.

Differential expression of nitric oxide synthase in human stomach cancer.

The level of expression and cellular localization of isoenzymes of nitric oxide synthase (NOS) was detected in human stomach tumor tissues. Tumor tissues showed 70% higher activity of NOS than that of normal tissues (P < 0.01). Poorly differentiated adenocarcinoma tend to have higher activity (P < 0.05) than well differentiated and moderately differentiated tumor tissues. Aminoguanidine (AG), 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), NG-monomethyl-L-arginine (L-NMMA), and Nomega-nitro-L-arginine (L-NNA) inhibited NOS activity in tumor tissues by 18, 14, 11 and 13%, respectively. The TNF-alpha mRNA expression was correlated with the inducible NOS (iNOS) level, which was high in adenocarcinomas and low in normal tissues. Tumor tissues showed higher expression of iNOS in gland epithelial cells but the level of eNOS was significantly decreased with an exception of concentrated localization in the proliferating capillary endothelium. These results revealed that isoforms of NOS might contribute differentially to growth and progression of human stomach tumor.

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.

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.

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.

Retrospective comparison of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (modified FAM) combination chemotherapy versus palliative therapy in treatment of advanced gastric cancer.

About one-third of patients with gastric cancer are unresectable at the time of diagnosis. Their median survival is < 6 months, with a grave prognosis. The purpose of this study was to assess the efficacy of a modified FAM (mFAM) regimen in advanced gastric cancer. We retrospectively reviewed the clinical records of 409 advanced gastric cancer patients who had not received curative surgery. Among 409 patients, 202 patients were treated with an mFAM regimen (infusional 5-FU + doxorubocin + mitomycin-C), and 207 patients received no chemotherapy (control group). No differences were found in clinical parameters between the two groups. The 1-year survival rates were 34.1% for the mFAM-treated group and 22.5% for the control group (p = 0.0135). In subset analysis, a higher 1-year survival rate was demonstrated in patients with mFAM and palliative surgery. Of the 154 evaluable patients in the mFAM-treated group, the response rate was 17.5%. In these patients, median response duration was 30 weeks, and progression-free survival was 23 weeks. Overall toxicity of mFAM regimen was relatively tolerable and reversible. In conclusion, FAM combination chemotherapy, which has been used as a standard therapy, prolonged survival after modification of the administration schedule and combination with palliative surgery. A prospective randomized study is warranted to confirm this conclusion from our retrospective study.