Extended surgical resection in T4 gastric cancer.

BACKGROUND: Some physicians still consider invasion of adjacent organs by the carcinoma of stomach as a sign of incurable disease. METHODS: This retrospective study has been done with particular reference to 353 T4 gastric cancer patients who underwent combined gastrectomies with adjacent organs. RESULTS: Subtotal gastrectomy was performed in 237 (67.1%) patients and total gastrectomy was performed in 116 (32.9%) patients. Organs most commonly resected with the stomach were the transverse colon in 159 (45%) cases, the tail of pancreas and spleen in 150 (42.5%), the left lobe of liver in 101 (28.5%), and the head of pancreas in 37 (10.5%) patients. A total of 110 postoperative complications occurred in this subset of patients corresponding to a complication rate of 31.2%. A total of 48 postoperative deaths occurred in this subset of patients corresponding to a mortality rate of 13.6%. The 5-year survival rate for all patients who underwent combined gastrectomy with adjacent organs was 25%. Of the node-negative T4 gastric cancer resections, 37% survived 5 years whereas the T4 node-positive resections have only a 15% 5-year survival. CONCLUSIONS: Patients who present with T4 gastric cancer (about 20% of the patient population) will benefit from aggressive en bloc surgical resection and should not be considered unresectable.

Apoptosis induced by hyperthermia and verapamil in vitro in a human colon cancer cell line.

The aim of this study was to determine the mechanisms responsible for the growth inhibitory effect of hyperthermia and verapamil in human colon cancer cell line HT-29. Apoptotic cell death was verified by flow cytometry analysis. The effect of treatment with hyperthermia and verapamil on the expression of apoptosis-associated proteins including Bcl-2, p53, bax, and c-Myc was studied by Western blot analysis. Changes in intracellular calcium homeostasis was analysed by fluorescence microscopy. The combination of 42 degrees C hyperthermia and verapamil caused a significant delay of human colon cancer cell proliferation as a result of apoptosis. Administration of these agents alone did not cause any cell inhibitory effect. Our experiments have shown that HT-29 cells constitutively express apoptosis-promoting proteins, such as Bax and c-Myc, while they fail to produce Bcl-2. Therefore, we hypothesize that HT-29 cells must have Bcl-2 independent pathways to protect cells against death-inducing signals. Also, apoptosis of HT-29 cells produced by hyperthermia in the presence of verapamil is a p53-independent process. Verapamil, when it did not act as a calcium channel blocker or inhibitor of release from intracellular storages under hyperthermic conditions, accelerated the increase of [Ca2+]i in HT-29 cells which resulted in programmed cell death (apoptosis).

Carcinoma of the stomach following the Chernobyl nuclear accident.

Medical consequences of many nuclear accidents on humans are well studied, but the results pertaining to gastric cancer patients who were exposed to radiation as a result of the Chernobyl nuclear accident have not been analysed. In this study, the outcome of the surgical treatment of 68 gastric cancer patients who were exposed to radiation as a result of the Chernobyl nuclear accident was compared with that of 117 consecutive gastric cancer patients from uncontaminated areas of the Ukraine. Patients in the study group was significantly younger than that of the control group. Comparative analysis showed the same frequency of regional metastases (65.7% versus 71.1%, P > 0.05), but a smaller number of distant metastases (23.8% versus 38.1%, P < 0.05) in the study group. 41.2% of patients in the study group underwent total gastrectomy compared to 19.6% of patients in the control group (P = 0.002). Postoperative complications developed in 13.2% of patients in the study group, while postoperative mortality in the study group was 7.3% compared to 1.7% in the control group. A significant decrease in CD16 cells was noted in patients from the study group following the operative procedure. Young age, invasive tumours with smaller number of distant metastases, frequent necessity for total gastrectomy and combined operations with adjacent organs, a higher level of postoperative morbidity and mortality and low levels of natural killer cells (CD16+) with a tendency to decrease after surgery are characteristic of patients with carcinoma of the stomach affected by the Chernobyl accident.

Hyperthermia and verapamil inhibit the growth of human colon cancer xenografts in vivo through apoptosis.

BACKGROUND: The long-term goal of this work is to develop a new therapeutic regimen for the treatment of colon cancer in humans which will include hyperthermic intraperitoneal perfusion of verapamil as an alternative to administration of chemotherapy. METHODS AND RESULTS: Hyperthermia and verapamil caused a significant inhibition of the growth of human colon cancer (HT-29) xenografts. Both apoptosis detection assays, TUNEL and H and E staining, have shown that approximately 50% of human colon cancer cells underwent apoptosis after hyperthermia and verapamil administration. The TUNEL assay has demonstrated that DNA strand breaks appeared fairly rapidly and maximum breakage occurred at 2 hours after the treatment. Histopathological assay has showed maximum apoptotic morphological changes at 12 hours after treatment. CONCLUSION: Thus, the results of our in vivo experiments confirmed our previously obtained in vitro data concerning the significant ability of the combination of hyperthermia and verapamil to inhibit human colon cancer cell growth through programmed cell death.

Primary non-Hodgkin's lymphoma of the stomach: three radical modalities of treatment in 75 patients.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) remains a rare form of gastric malignancy, with a rising incidence. Approaches to treatment vary from surgery alone to conservative management. METHODS: To determine the optimal scheme of treatment, a randomized clinical trial was undertaken. Seventy-five patients were randomized into three groups: A-surgery alone (25), B-surgery followed by chemotherapy (29), and C-radiation therapy followed by surgery and chemotherapy (21). Forty-nine patients had stage IE and 26 had stage IIE disease. Chemotherapy (COP and COPP) consisted of 6 courses during a 1-year period, with the courses being 6 weeks apart. RESULTS: Subtotal gastrectomy was performed in 26 patients. Forty-nine patients underwent total gastrectomy. Postoperative complications occurred in 6 (8%) patients: 3 (12%) in group A, 2 (6.9%) in group B, and 1 (4.7%) in group C. Postoperative mortality occurred in 2 (8%) patients in group A (2.7% of all patients). An increase in hospital admissions number per year and decrease of mean age of patients with NHL of the stomach after the Chernobyl accident on April 26, 1986 was noted. CONCLUSIONS: Improved survival in gastric NHL was achieved by a combination of preoperative radiation with surgery and postoperative chemotherapy, presumptively through the management of local and systemic disease.

The effect of 1, 25-dihydroxyvitamin D3 on the growth of soft-tissue sarcoma cells as mediated by the vitamin D receptor.

BACKGROUND: Soft-tissue sarcomas, malignant neoplasms originating from mesenchymal tissue, are rare but highly aggressive tumors. Present modes of therapy are associated with high rates of recurrence. 1, 25-Dihydroxyvitamin D3, the active metabolite of vitamin D, serves as a potent antiproliferative agent in human cancer cells. METHODS: In this study, six soft-tissue sarcoma cell lines were analyzed for vitamin D receptor (VDR) expression, which was then correlated with the degree of growth inhibition in response to 1, 25-dihydroxyvitamin D3. These cell lines included rhabdomyosarcoma (HS729, A204), fibrosarcoma (HS913t), synovial sarcoma (SW982), liposarcoma (SW872), and leiomyosarcoma (SKLMS-1). The level of VDR messenger RNA (mRNA) expression was determined using a ribonuclease protection assay, and functional receptor content was determined by using a ligand-binding assay. Growth studies, including [3H]thymidine uptake and growth curves, were performed on two of the six cell lines that expressed the highest and lowest receptor levels. RESULTS: Ribonuclease protection and ligand-binding assays demonstrated variable levels of VDR, with HS729 showing high expression and A204 showing no expression. In HS729, [3H]thymidine uptake was significantly decreased at 10(-7) M (33%) and 10(-6) M (40%) 1, 25-dihydroxyvitamin D3. Growth curve studies showed significant growth inhibition of 55% at 10(-6) M. A204 cells showed no growth inhibition upon treatment with 1, 25-dihydroxyvitamin D3. CONCLUSION: This study demonstrates the existence of VDR in soft-tissue sarcoma cells and suggests a correlation between the level of VDR in cells and the degree of growth inhibition caused by 1, 25-dihydroxyvitamin D3 which may potentially serve as an alternative form of therapy for soft-tissue sarcomas.

Postoperative complications requiring relaparotomies after 700 gastretomies performed for gastric cancer.

BACKGROUND: Prevention of fatal postoperative complications and improved management of patients with complications are important means of increased survival in gastric cancer patients. PATIENTS AND METHODS: A study of 700 patients undergoing gastrectomy was performed to examine factors that contributed to a high rate of postoperative complications. RESULTS: Of 700 patients undergoing gastrectomy for adenocarcinoma, 40 (5.7%) underwent reexploration because of serious complications. The frequency of the relaparotomies varied from 2.1% and 4.4% after regular subtotal and total gastrectomies, respectively, to 20% and 30.4% after palliative and conventional total gastrectomies, respectively. The complications that required reexploration most frequently were anastomotic leakage and incompetence of sutures (11, 27.5%), intra-abdominal abscesses (8, 20%), and pancreatic necrosis (7, 17.5%). A combination of preventive measures allowed the attainment of low rates of esophagojejunal anastomotic leakage (0.8%). CONCLUSION: We believe that the decision to perform an urgent reexploration, based on clinical findings, should generally be made by a group of experienced surgeons (not only the primary surgeon). Timely relaparotomy prevented death in 37.5% of the patients with serious acute postoperative complications.

Vitamin D receptor and growth inhibition by 1,25-dihydroxyvitamin D3 in human malignant melanoma cell lines.

The expression of vitamin D receptors (VDR) and growth inhibition induced by 1,25-dihydroxyvitamin D3 have been noted in certain human malignant melanoma cell lines. In this study, widely disparate levels of VDR mRNA expression were demonstrated in a panel of eight human malignant melanoma cell lines. Quantitation of receptor level by ligand binding assay showed a similar pattern. Proliferation and growth curve analysis was performed in two cell lines: RPMI 7951 (high VDR) and SK-MEL-28 (low VDR). Significant growth inhibition was noted in RPMI 7951 cells at 10(-9) M 1,25-dihydroxyvitamin D3. SK-MEL-28 cells, which express much lower levels of VDR, did not show any growth inhibition except at extremely high concentrations of 1,25-dihydroxyvitamin D3, namely 10(-5) M. These findings suggest a receptor-mediated mechanism of growth inhibition for 1,25-dihydroxyvitamin D3 and a role for this hormone in the growth of malignant melanoma cells.

Modulation of vitamin D receptor and estrogen receptor by 1,25(OH)2-vitamin D3 in T-47D human breast cancer cells.

1,25(OH)2-Vitamin D3 inhibits breast cancer cell proliferation through interaction with the vitamin D receptor (VDR). Regulation of VDR is under the influence of several factors which include the functional ligand for this receptor (1,25(OH)2-vitamin D3) as well as heterologous steroid hormones. We evaluated the nature of homologous regulation in T-47D human breast cancer cells with a radiolabelled ligand binding assay and a ribonuclease protection assay for VDR. Significant VDR up-regulation, as measured by hormone binding assays, occurred with pre-incubations with 10(-9)M through 10(-6)M 1,25(OH)2-vitamin D3 (P < 0.05). A 7-fold VDR up-regulation with 10(-8)M 1,25(OH)2-vitamin D3 occurred at 4 h treatment and was not associated with an increase in VDR mRNA expression on ribonuclease protection assay. This supports the hypothesis that up-regulation of VDR is probably the result of ligand-induced stabilization of pre-existing receptor. All-trans-retinoic acid, the progesterone analog R-5020, and prednisone were found to induce heterologous up-regulation of the VDR. We then determined with ligand binding assays whether 1,25(OH)2-vitamin D3 could influence receptor levels for another hormone in a manner analogous to the heterologous regulation of VDR. Regulation of estrogen receptor (ER) by 1,25(OH)2-vitamin D3 was studied in T-47D and MDA-MB-231 breast cancer cells. Incubation of T-47D cells, which are ER (+), with 10(-8)M 1,25(OH)2-vitamin D3 did not result in up-regulation of ER. Yet estrogen binding was significantly up-regulated in a cell line that is ER(-), MDA-MB-231. The increased estrogen binding was associated with a shift in binding affinity and ribonuclease protection assay showed absence of ER mRNA in these cells, suggesting an up-regulation of estrogen binding proteins and not of the ER itself.

The antiproliferative effect of vitamin D analogs on MCF-7 human breast cancer cells.

We analyzed the antiproliferative effect of 1,25-dihydroxyvitamin D3 and four vitamin D analogs on MCF-7, a human breast cancer cell line known to express the vitamin D receptor. Growth curve studies and [3H]thymidine incorporation assays were used to assess the antiproliferative effect of 1,25-dihydroxyvitamin D3 (vitamin D), Ro 23-7553, Ro 24-5531, Ro 25-5317, and Ro 24-5583. Growth of MCF-7 cells was significantly inhibited by 1,25-dihydroxyvitamin D3 and all four analogs at 10(-8) M (P < 0.05). MCF-7 cells treated with analog had significantly less [3H]thymidine incorporation than cells treated with 1,25-dihydroxyvitamin D3 (P < 0.05). The affinity of the analogs for the vitamin D receptor was similar to that of 1,25-dihydroxyvitamin D3. These results demonstrate that analogs of 1,25-dihydroxyvitamin D3 are potent antiproliferative agents on human breast cancer cells and that this activity is likely mediated through the vitamin D receptor.

Radical treatment of locally recurrent gastric cancer.

Locally recurrent gastric cancer develops in 45 per cent of resected patients. This study assessed the impact of an aggressive search for recurrence after radical operations and the use of reoperative and adjuvant therapy in this setting. From 1983 to 1990, 75 patients were explored for regionally recurrent gastric cancer. Resection was possible in 40 (53.5%), and palliative bypass was possible in 19 (25.3%); exploration only was performed in 16 (21.4%). Among resectable patients, gastrectomy was performed in 22 (55%) and gastrectomy with adjacent organ resection in 18 (45%) with an overall operative mortality of 15% (6 patients). Mean duration of life after bypass was 3.1 months; after exploration 4.5 months. Fifteen (40.6%) were not candidates for radiation or chemotherapy, 13 (31.2%) received preoperative radiotherapy (20 Gy), and 12 (28.2%) received postoperative systemic chemotherapy. Two-year survival after radical treatment was as follows: surgery alone 20%; radiotherapy and surgery 31.3%; surgery and chemotherapy 66.4%. These preliminary results indicate that re-excision benefits selected patients with recurrent gastric cancer. Patients receiving radiotherapy and chemotherapy tended toward improved survival.

The effect of extracellular calcium on colonocytes: evidence for differential responsiveness based upon degree of cell differentiation.

Calcium supplementation decreases the incidence of colon cancer in animal models and may prevent colon cancer in man. Potential mechanisms include binding of mitogens and direct effects of calcium on colonic epithelial cells. In this study, the effects of extracellular calcium on epithelial cell growth and differentiation were studied in three colon carcinoma and two colonic adenoma cell lines. The characteristics studied included morphology, cell cycle kinetics, [Ca2+]IC (intracellular calcium concentration), proliferation, and expression of differentiation markers such as carcinoembryonic antigen (CEA) and alkaline phosphatase (AP). Sodium butyrate (NaB) and 1,25-dihydroxyvitamin D3 were used as controls in the latter three assays as these two agents are known differentiating agents. Alteration of [Ca+2]EC (extracellular calcium concentration) did not affect carcinoembryonic antigen (CEA) or alkaline phosphatase (AP) expression. NaB enhanced the expression of AP three-fold and CEA five-fold. This effect was augmented by increasing [Ca2+]EC. The exposure of cells to 1,25-(OH)2-Vitamin D3 increased CEA but not AP. [Ca2+]IC increased in response to 1,25-(OH)2-vitamin D3 and NaB but not with variation in [Ca2+]EC. Increased [Ca2+]EC inhibited proliferation of well-differentiated cells, but had no effect on poorly-differentiated cells. Morphological studies showed that extracellular calcium was necessary for normal cell-cell interactions. These studies have demonstrated direct effects of calcium on colonic epithelial cells which may contribute to the protective effects of dietary calcium against colon cancer. Loss of responsiveness to the antiproliferative effects of [Ca2+]EC with de-differentiation suggests that calcium supplementation may be most beneficial prior to the development of neoplastic changes in colonic epithelium.

Antitumour activity of 5-fluorouracil, verapamil and hyperthermia against human gastric adenocarcinoma cell (AGS) in vitro.

The purpose of this study was to assess the efficacy of verapamil (20 microM) and hyperthermia (42 degrees C) as modifiers of 5-fluorouracil (5-FU), used at different concentrations, in inhibiting the growth of gastric adenocarcinoma cells. Combined verapamil and hyperthermia treatment showed a significant decrease in cell count when compared to control (72.2%), hyperthermia alone (68.4%), or verapamil alone (65%). At a high concentration of 5-FU (50 micrograms/ml), verapamil and hyperthermia had an additive growth inhibitory effect over a 4-day period when compared to control. A combination of 5-FU at low concentration (0.5 microgram/ml) with verapamil significantly suppressed growth by 31.2% in comparison to control--with this effect being independent of the duration of treatment. The modalities analysed in this study require further investigation and have potential for clinical applicability to gastric cancer therapy in the future.

In vitro effect of 5-fluorouracil, verapamil and hyperthermia on the human pancreatic adenocarcinoma cell line ASPC-1.

The purpose of this study was to assess the efficacy of verapamil (20 microM) and hyperthermia (42 degrees C) as modifiers of 5-fluorouracil (5-FU) used at different concentrations, in inhibiting the growth of human pancreatic adenocarcinoma cells. Combined verapamil and hyperthermia treatment significantly decreased cell count by 63.8% when compared to the control. Verapamil drastically enhanced the growth inhibitory effect of 5-FU at all concentrations. At high-concentration 5-FU (50 micrograms/ml), verapamil and hyperthermia had a synergistic growth-inhibitory effect and caused a significant decrease in cell count by 81.4% in comparison to the control. The modalities analyzed in this study require further investigation and have potential for clinical applicability to pancreatic cancer therapy in the future.

Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihydroxyvitamin D3.

The use of 1,25-dihydroxyvitamin D3 as an antiproliferative agent in the treatment of cancer is limited by its hypercalcemic effects. Analogues with equivalent or greater antiproliferative activities but smaller hypercalcemic effects have been developed. The antiproliferative effects of 1,25-dihydroxyvitamin D3 and four analogues were studied in HT-29 and SW620 human colon cancer cell lines, moderate and low expressors of the vitamin D receptor, respectively. HT-29 is a primary, moderately differentiated, cell line, while SW620 is metastatic and poorly differentiated. Growth curve studies, proliferation assays, and clonogenic assays were used to assess the antiproliferative effects of 1,25-dihydroxyvitamin D3, 1,25-dihydroxy-16-ene-23-yne-D3, 1,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne-D3, 1,25-dihydroxy-16,23E-diene-26,27-hexafluoro-D3, and 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-D3. Growth of HT-29 cells was significantly inhibited by all four analogues at 10(-8) M (P < 0.05). Analogues 1,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne-D3, 1,25-dihydroxy-16,23E-diene-26,27-hexafluoro-D3, and 1,25-dihydroxy-16,23Z-diene-26,27-hexafluoro-D3 were 2 times as potent as analogue 1,25-dihydroxy-16-ene-23-yne-D3 and 1,25-dihydroxyvitamin D3. SW620 cells did not show any growth inhibition with any of the compounds tested. The affinities of the three most potent analogues for the vitamin D receptor were similar to that of 1,25-dihydroxyvitamin D3, while that of analogue 1,25-dihydroxy-16-ene-23-yne-D3 was lower. These results demonstrate that, as in leukemic cells, analogues of 1,25-dihydroxyvitamin D3 are potent antiproliferative agents in colon cancer cells and this activity is most likely mediated through the vitamin D receptor.

Three-dimensional models of the abdominal vasculature based on helical CT: usefulness in patients with pancreatic neoplasms.

Three-dimensional (3D) rendering of helical (spiral) CT data is used increasingly to show abnormalities of the vascular system [1]. Abdominal applications have focused mainly on the arterial system, but the portal venous system also can be depicted effectively with this technique. In patients with pancreaticobiliary neoplasms, axial display of helical CT images generally allows accurate staging of the lesion [2, 3]. Many surgeons, however, continue to request arteriography to specifically look for evidence of vascular encasement that would preclude surgery or vascular anomalies that would alter the surgical approach [4, 5]. The purpose of this essay is to illustrate the value of 3D rendering of CT data in providing useful information for surgical planning and showing the extent of vascular involvement by tumor.

Apoptosis of human primary and metastatic colon adenocarcinoma cell lines in vitro induced by 5-fluorouracil, verapamil, and hyperthermia.

Combined verapamil(V) and hyperthermia(HT) showed a significant decrease in HT29 and SW-620 cell counts by 61.5% and 77.6%, respectively, when compared to control. V in conjunction with 5-FU significantly reduced HT-29 count by 37% in comparison to 5-FU alone, and did not enhance the growth inhibitory effect of 5-FU on SW-620. HT did not enhance the growth inhibition seen with 5-FU treatment alone on HT-29, while this combination significantly decreased SW-620 cell count by 28.9% in comparison to administration of 5-FU alone. Joint administration of V and HT with 5-FU appeared to have a possible synergistic effect and reduced HT-29 count by 90% when compared to control. 5-FU alone or in different combinations with V and HT, as well as combination V+HT, results in apoptosis.

Intensive preoperative radiotherapy with local hyperthermia for the treatment of gastric carcinoma.

In order to devitalize maximally tumour tissue and improve the prognosis of gastric cancer patients, a method employing preoperative intensive radiotherapy with local hyperthermia as adjuvant treatment was evaluated. In order to estimate the effectiveness of preoperative intensive radiation and radiation with local microwave hyperthermia in radical gastric cancer treatment, 293 patients were randomized into three respective treatment groups: surgery alone, surgery preceded by preoperative radiation; and surgery followed by preoperative radiation and hyperthermia. Preoperative radiation therapy to a total dose of 20 Gy in four 5 Gy fractions did not improve 3- or 5-year survival in gastric cancer patients in comparison with surgery alone. Local hyperthermia in combination with radiation therapy followed by surgery produced a significant improvement in 3-year survival of 22.1% (from 35.5 +/- 4.9% to 57.6 +/- 6.3%, P < 0.05) and 5-year survival of 21.3% (from 30.1 +/- 4.7 to 51.4 +/- 6.6%, P < 0.05). In unresectable gastric cancer patients, radiation therapy and radiation therapy with hyperthermia both increase mean survival. In conclusion; intensive preoperative radiation therapy in total dose 20 Gy plus local microwave hyperthermia significantly improved 3- and 5-year survival in comparison with surgery alone. Further development and evaluation of equipment to produce reliable and safe delivery systems for hyperthermia is needed.

Effect of mitomycin C, verapamil, and hyperthermia on human gastric adenocarcinoma.

The purpose of this study was to assess the efficacy of verapamil (20 microM) and hyperthermia (42 degrees C) as modifiers of mitomycin C (MMC), used at different concentrations, in inhibiting the growth of human gastric adenocarcinoma (AGS) cells. Combined verapamil and hyperthermia treatment resulted in a significant decrease in cell count by 72.2% as compared with the control value. Verapamil drastically enhanced the growth-inhibitory activity of MMC at high concentration against AGS cells by 67.5% and had no effect at intermediate and low concentrations. Hyperthermia did not enhance the effect of MMC on AGS cells. The modalities analyzed in this study require further investigation and may have potential for in vivo studies on gastric cancer therapy in the near future.