Effect of proton pump inhibitors on the development of hypomagnesemia induced by panitumumab.

Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.

Cyclic compressive loading on 3D tissue of human synovial fibroblasts upregulates prostaglandin E2 via COX-2 production without IL-1ß and TNF-α.

OBJECTIVE: Excessive mechanical stress on synovial joints causes osteoarthritis (OA) and results in the production of prostaglandin E2 (PGE2), a key molecule in arthritis, by synovial fibroblasts. However, the relationship between arthritis-related molecules and mechanical stress is still unclear. The purpose of this study was to examine the synovial fibroblast response to cyclic mechanical stress using an in vitro osteoarthritis model. METHOD: Human synovial fibroblasts were cultured on collagen scaffolds to produce three-dimensional constructs. A cyclic compressive loading of 40 kPa at 0.5 Hz was applied to the constructs, with or without the administration of a cyclooxygenase-2 (COX-2) selective inhibitor or dexamethasone, and then the concentrations of PGE2, interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), IL-6, IL-8 and COX-2 were measured. RESULTS: The concentrations of PGE2, IL-6 and IL-8 in the loaded samples were significantly higher than those of unloaded samples; however, the concentrations of IL-1ß and TNF-α were the same as the unloaded samples. After the administration of a COX-2 selective inhibitor, the increased concentration of PGE2 by cyclic compressive loading was impeded, but the concentrations of IL-6 and IL-8 remained high. With dexamethasone, upregulation of PGE2, IL-6 and IL-8 was suppressed. CONCLUSION: These results could be useful in revealing the molecular mechanism of mechanical stress in vivo for a better understanding of the pathology and therapy of OA. Cite this article: Bone Joint Res 2014;3:280-8.

The first clinical case of a mutation at residue K185 of Kir6.2 (KCNJ11): a major ATP-binding residue.

BACKGROUND: Closure of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel plays a key role in insulin secretion from the pancreatic beta-cells. Many mutations in KCNJ11 and ABCC8, which respectively encode the pore-forming (Kir6.2) and regulatory (SUR1) subunits of the K(ATP) channel, cause neonatal diabetes. All such mutations impair the ability of metabolically generated ATP to close the channel. Although lysine 185 is predicted to be a major contributor to the ATP-binding site of Kir6.2, no mutations at this residue have been found to cause neonatal diabetes to date. METHODS: We report a 3-year-old girl with permanent neonatal diabetes (PNDM) caused by a novel heterozygous mutation (K185Q) at residue K185 of KCNJ11. The patient presented with marked hyperglycaemia and ketoacidosis at 70 days after birth, and insulin therapy was commenced. RESULTS: Wild-type and mutant K(ATP) channels were expressed in Xenopus oocytes and the effects of intracellular ATP on macroscopic K(ATP) currents in inside-out membrane patches were measured. In the simulated heterozygous state, the K185Q mutation caused a substantial reduction in the ability of MgATP to inhibit the channel. Heterozygous K185Q channels were still blocked effectively by the sulphonylurea tolbutamide. CONCLUSIONS: We report the first clinical case of a PNDM caused by a mutation at K185. Functional studies indicate that the K185Q mutation causes PNDM by reducing the ATP sensitivity of the K(ATP) channel, probably via a reduction in ATP binding to Kir6.2. Based on the experimental data, the patient was successfully transferred to sulphonylurea therapy.

The effect of gantry and collimator angles on leaf limited velocity and position in dynamic multileaf collimator intensity-modulated radiation therapy.

The purpose of the study is to evaluate the limiting velocity (LV) of a multileaf collimator and the leaf position in various collimator and gantry angles. Both leading leaves and trailing leaves began to move with a constant acceleration from 0 to 4 cm s(-1). When the beam hold occurred, the leaf velocity was defined as the leaf LV. Dynamic irradiation was performed at eight gantry angles of every 45 degrees with three different collimator angles. The analysis of the LV and the leaf position was performed with a log file from a leaf motion controller. The mean LVs for Varian Clinac 21EX (21EX) ranged from 2.51 to 3.10 cm s(-1). The mean LVs for Clinac 600C ranged from 2.91 to 3.12 cm s(-1). When only central 5 mm leaves of 21EX moved, LVs were significantly higher than those when all 60 pairs of leaf moved, while the leaf position inconsistencies of the two accelerators were within 1 mm at the leaf velocities from 0.5 to 2.0 cm s(-1). It was recognized that the LV was affected by gravity. This measurement method can be utilized as routine quality assurance for a dynamic multileaf collimator (DMLC) is and easily reproducible.

Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.

BACKGROUND: Regenerating gene type IV (RegIV) is a candidate marker for cancer and inflammatory bowel disease. In this study, its potential as a novel marker for the detection of gastric cancer peritoneal micrometastases was examined. PATIENTS AND METHODS: RegIV mRNA levels in the peritoneal washes of 95 gastric cancer patients and 22 with benign disease were quantified by real-time RT-PCR. To examine whether expression of RegIV enhance tumorigenicity or not, thirty two mice were injected intraperitoneally or subcutaneously with RegIV transfectants of TMK-1 cells, parental TMK-1 cells, or neomycin control transfectants. RESULTS: RegIV expression was markedly higher in patients with peritoneal metastases compared to those without. The level of RegIV mRNA in gastric cancer patients was related to the extent of wall penetration. A cut-off value for RegIV-positive expression was based on an analysis of negative control patients with benign disease, and gastric cancer patients above the cut-off value constituted the micrometastasis (MM+) group. Based on this criteria, 3 out of 43 T1 or T2 cases were MM+ (93% specificity). Among 15 patients with peritoneal dissemination (7 out of 15 cases were positive by cytology), 14 cases were positive for RegIV expression (93% sensitivity), while analysis of carcinoembryonic antigen (CEA) mRNA failed to detect micrometastases in 4 cases (73% sensitivity). Combined analysis of CEA and RegIV improved the accuracy of diagnosis to 100%. The prognosis of RegIV-positive cases was significantly worse than that of RegIV-negative cases. Multivariate analysis using the Cox proportional hazards model suggested that RegIV may be an independent prognostic factor. Stable expression of RegIV significantly enhanced peritoneal metastasis in an animal model of gastric cancer. CONCLUSION: These findings suggest that RegIV mRNA expression has the potential to serve as a novel marker for detecting peritoneal dissemination in gastric cancer.

Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography.

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P<0.05). Within the tumour, downregulation of RUNX3 expression ranged from 74.7 to 85.7% in the three groups. The rate of downregulation of RUNX3 of adjacent mucosa was 39.2% (11 in 28 cases) in RB and 47.6% (10 in 21 cases) in RM, which are significantly higher than that of the GCI group (19.5%, 17 in 87 cases). In noncancerous mucosa of the remnant stomach in the RB group, RUNX3 expression decreased more near the anastomosis area. In the RM group, however, there were no significant differences in RUNX3 expression by sampling location. Based on RUNX3 downregulation and clinical features, residual stomach mucosa of the RM group would have a higher potential of gastric carcinogenesis compared to the RB or GCI group. Gastric stump mucosa of the RB group has higher potential especially than other areas of residual stomach mucosa. Measurement of RUNX3 expression and detection of RUNX3 methylation in remnant gastric mucosa may estimate the forward risk of carcinogenesis in the remnant stomach.

Overexpression of dopa decarboxylase in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastases with real-time RT-PCR.

We previously performed a global analysis of the gene expression of gastric cancer cell lines established from metastases to the peritoneal cavity with the cDNA microarray method, which made it possible to analyse the expression of approximately 21168 genes for the identification of novel markers for the detection of micrometastases in the peritoneal cavity. One of the upregulated genes is dopa decarboxylase (DDC), which is responsible for the synthesis of the key neurotransmitters dopamine and serotonine. We have examined its potential as a novel marker for the detection of peritoneal micrometastases of gastric cancer.DDC mRNA in the peritoneal wash from 112 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) with a fluorescently labelled probe to predict peritoneal recurrence. The quantity of DDC and CEA correlated with wall penetration. Real-time RT-PCR could quantitate 10-10(6) DDC-expressing gastric cancer cells per 10(7) mesothelial cells. The cutoff value was set at the upper limit of the quantitative value for noncancer patients, and those above this cutoff value constituted the micrometastasis (MM+) group. Of 15 cases with peritoneal dissemination, 13 were MM+DDC (87% sensitivity), and one of 48 t1 cases was MM+ (98% specificity). DDC levels in peritoneal washes from patients with synchronous peritoneal metastases were more than 50 times higher than in those from patients without metastasis (P<0.01). For 15 cases of peritoneal dissemination (seven cases were cytologically positive), DDC was positive in 13 cases (87% sensitivity), but CEA failed to detect micrometastases in four cases (73% sensitivity), indicating that DDC is in some cases superior to CEA for the detection of peritoneal micrometastases of gastric cancer in terms of sensitivity as well as specificity, especially for poorly differentiated adenocarcinomas. A combination of CEA and DDC improved the accuracy of diagnosis up to 94%. These results suggest that DDC is potentially a novel marker for peritoneal dissemination of gastric cancer and that quantitative RT-PCR of DDC is reliable and efficient for the selection of patients for adjuvant intraperitoneal chemotherapy to prevent peritoneal recurrence.

Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites.

Advanced gastric cancer is often accompanied by metastasis to the peritoneum, resulting in a high mortality rate. Mechanisms involved in gastric cancer metastasis have not been fully clarified because metastasis involves multiple steps and requires a combination of altered expressions of many different genes. Thus, independent analysis of any single gene would be insufficient to understand all of the aspects of gastric cancer peritoneal dissemination. In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumour (SNU-1) and of other cell lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray method made it possible to analyse the expression of approximately 21 168 genes. Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24 genes were up-regulated and 17 genes down-regulated besides expression sequence tags. The analysis revealed the following altered expression such as: (a) up-regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker), aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal transduction); (b) down-regulation of IL2 receptor gamma, IL4-Stat (immune response), p27 (cell cycle) and integrin beta4 (adhesion) in gastric cancer cells from malignant ascites. We then analysed eight gastric cancer cell lines with Northern blot and observed preferential up-regulation and down-regulation of these selected genes in cells prone to peritoneal dissemination. Reverse transcriptase-polymerase chain reaction confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination, promise to provide a new insight into the study of human gastric cancer peritoneal dissemination.

Development of an ultrasonically activated trocar system.

BACKGROUND: Although rare, visceral and vascular injuries related to the insertion of conventional laparoscopic trocars may have disastrous consequences. Most of these injuries are due to the high puncture force applied to the trocar. We present the results of an animal laboratory evaluation of a newly developed ultrasonically activated trocar. METHODS: A total of 40 punctures were made in four pigs with an average weight of 53 kg. An 11-mmHg pneumoperitoneum was created through a Veress needle. A 10-mm diameter trocar was inserted in the midline for a laparoscope. A series of five trocars were then inserted on each lateral wall under laparoscopic control. Twenty punctures were made with a conventional reusable 11-mm trocar (CT) whose tip was sharp and conical. Twenty punctures were made with an 11-mm ultrasonically activated trocar (UT), whose fequency was 23.5 KHz and amplitude 150 mm. The cutaneous incision was made large enough so that the skin did not interfere with the trocar insertion. The force applied to the trocar was measured with a push-pull gauge connected to a computer. The following data were recorded: maximal force applied to the trocar to obtain insertion of the tip through the abdominal wall, maximum abdominal pressure increase during trocar insertion, and time for abdominal penetration. RESULTS: The average time needed for trocar penetration was 12.8 s with CT and 4.5 s with UT (p < 0.001). The average maximal force was 6.8 kgF with CT and 0.4 kgF with UT (p < 0.001). The average abdominal pressure increase was 7.6 mmHg with CT and 0.8 mmHg with UT (p < 0.001). At 30 days, no necrosis was found. Pathological findings were similar in both groups. CONCLUSION: Ultrasonically activated trocars required less time and much less force to be inserted. This may be a breakthrough in the safety of trocar insertion.

[Intraoperative coating of tumor surface using fibrin glue as a prophylaxis for cancer cell detachment].

With the aim of preventing cancer cells from becoming detached and spreading into the abdominal cavity by operative procedures during surgical resection of cancer infiltrating into gastrointestinal serosa, the exposed area of the serosa in mice was coated with fibrin glue, a biological tissue adhesive, prior to resection. We then determined whether the coating could reduce the detachment and spread of cancer cells during the surgical procedure, and thus be capable of inhibiting the occurrence of peritonitis carcinomatosa. In vitro experiments demonstrated that the fibrin glue uniformly and strongly coated the exposed area of cancer, and furthermore, that the presence of fibrin glue coating significantly reduced the number of cancer cells which became detached. As a result of using this glue, the number of deaths due to peritonitis carcinomatosa among assay mice was significantly decreased. It is therefore considered that coating the exposed area of cancer with fibrin glue inhibits cancer cells from being detached and spread during an operation, and thus can be an effective means of preventing the recurrence of peritonitis.

[Analysis of the action of dextran sulfate as a prophylaxis for peritoneal cancer metastasis, and its acting mechanism].

Although peritoneal cancer metastasis has the highest frequency of postoperative recurrence among digestive organ malignant tumors, there is no still decisive treatment. Dextran sulfate (DS) as a prophylaxis for cancer metastasis was examined with respect to its effect on cultured cells. DS was made to act on a strong adhesive neoplasm cell, and the action and acting mechanism were examined with respect to 1. readhesiveness, 2. cell cycle, and 3. gene analysis. The results suggest that: i) Once tumor cells are detached by DS, the free cells do not attach even when DS is removed, and ii) DS causes the cells to stop in the G1/G0 phase.

[Usefulness of local administration of methotrexate bound to activated carbon particles (MTX-CH)].

We developed a new dosage formulation, methotrexate bound to activated carbon particles (MTX-CH), and used it to reduce tumors via its long-acting effect at the administration sites. MTX-CH was injected locally into tumors on the back of BALB/c mice, 30 mg/mouse, as MTX and compared with mice treated with MTX aqueous solution, saline solution, activated carbon particles (CH-40) and non-treated mice. The MTX concentration at the administration sites was higher in the MTX-CH group than in the MTX aqueous solution group. A marked effect on the control of tumor growth by MTX-CH was noted after repeated administration (every 3 days, total 4 times) throughout the observation period. Although tumor size was not reduced, necrosis was microscopically observed around the site of MTX-CH administration. For the reasons mentioned above, MTX-CH is superior to MTX aqueous solution in terms of long-acting effect at the administration sites and the control of tumor growth.

Minilaparotomy wound edge protector (Lap-Protector): a new device.

Laparoscopic-assisted or minimally invasive surgery involving minilaparotomy is occasionally complicated by infection of the minilaparotomy wound caused by intestinal bacteria. Furthermore, when this procedure is performed to excise colorectal or gastric cancer, tumor recurrence may develop in the minilaparotomy wound. In an attempt to minimize the risk of these complications, we developed a new, easy-to-use device which we named the "Lap-Protector." Minilaparotomy was performed using the Lap-Protector in 28 patients with colon cancer and eight patients with early gastric cancer who underwent minimally invasive surgery between January and September, 1999. During a median follow-up period of 15.9 (range 12.4-21.0) months, none of the 36 patients showed any sign of wound infection or tumor recurrence in the minilaparotomy wound. These results indicated that the Lap-Protector is a safe and useful device that may help to prevent infections and cancer cell contamination of the minilaparotomy wound.

Polymerase chain reaction for detection of carcinoembryonic antigen-expressing tumor cells on milky spots of the greater omentum in gastric cancer patients: a pilot study.

Our recent studies indicate that omental milky spots are frequently involved in the early stage of peritoneal cancer dissemination. We have used carcinoembryonic antigen (CEA)-specific RT-PCR for omental milky spots to predict peritoneal recurrence in gastric cancer patients. CEA mRNA was found to be positive in both 10 peritoneal washes and 16 greater omenta of 30 gastric cancer patients, including all 6 patients who showed positive results for both cytology and RT-PCR of peritoneal wash and omentum. Three of the 6 cases with positive RT-PCR in the greater omentum but not in the peritoneal wash showed recurrence of peritoneal carcinomatosa within 2 years after operation. Micrometastasis on omental milky spots was histologically confirmed in 6 of 30 gastric cancer cases. Non-specific band was detected only in the omentum of 1 case of 15 benign disease (7%), but not in peritoneal washes (0%), probably due to weak expression of CEA in mesothelial cells. Our results show that CEA-specific RT-PCR targeting micro-metastases on omental milky spots is more sensitive than targeting the peritoneal wash or conventional cytology, and suggest that this method is useful for the prediction of peritoneal recurrence in gastric cancer patients.

An ellagic compound and iridoids from Cornus capitata root cultures.

An ellagic acid derivative, 3,3'-di-O-methylellagic acid 4-(5"-acetyl)-alpha-L-arabinofuranoside, and two iridoid glucosides, 6alpha-dihydrocornic acid and 6beta-dihydrocornic acid, were isolated from Cornus capitata adventitious roots cultured in Murashige-Skoog (Murashige, T., Skoog, F., 1962. A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol. Plant. 15, 473-487) liquid medium containing 10 microM CuSO(4). Three known related metabolites, i.e. stenophyllin H1, dihydrocornin and cornin were also produced in the root cultures. The chemical structures were characterized by analysis of spectroscopic data.

A novel dark-inducible protein, LeDI-2, and its involvement in root-specific secondary metabolism in Lithospermum erythrorhizon.

Lithospermum erythrorhizon produces red naphthoquinone pigments that are shikonin derivatives. They are accumulated exclusively in the roots of this plant. The biosynthesis of shikonin is strongly inhibited by light, even though other environmental conditions are optimized. Thus, L. erythrorhizon dark-inducible genes (LeDIs) were isolated to investigate the regulatory mechanism of shikonin biosynthesis. LeDI-2, showing the strict dark-specific expression, was further characterized by use of cell suspension cultures and hairy root cultures as model systems. Its mRNA accumulation showed a similar pattern with that of shikonin. In the intact plants LeDI-2 expression was observed solely in the root, and the longitudinal distribution of its mRNA was also in accordance to that of shikonin. LeDI-2 encoded a very hydrophobic polypeptide of 114 amino acids that shared significant similarities with some root-specific polypeptides such as ZRP3 (maize) and RcC3 (rice). Reduction of LeDI-2 expression by its antisense DNA in hairy roots of L. erythrorhizon decreased the shikonin accumulation, whereas other biosynthetic enzymes, e.g. p-hydroxybenzoic acid:geranyltransferase, which catalyzed a critical biosynthetic step, showed similar activity as the wild-type clone. This is the first report of the gene that is involved in production of secondary metabolites without affecting biosynthetic enzyme activities.

Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation.

Our recent analysis of gastric cancers using comparative genomic hybridization (CGH) revealed a novel high frequent copy number increase in the long arm of chromosome 20. Tumour-amplified kinase BTAK was recently cloned from breast cancers and mapped on 20q13 as a target gene for this amplification in human breast cancers. In the study presented here, we analysed BTAK copy-number and expression, and their relation to the ploidy pattern in 72 primary gastric cancers. Furthermore, wild-type BTAK and its deletion mutants were transfected to gastric cancers to examine changes in cell proliferation and DNA ploidy pattern. Evaluation of 72 unselected primary gastric cancers found BTAK amplification in 5% and overexpression in more than 50%. All four clinical samples with BTAK amplification showed aneuploidy and poor prognosis. Transfection of BTAK in near-diploid gastric cancers induced another aneuploid cell population. In contrast, the c-terminal-deleted mutant of BTAK induced no effect in DNA ploidy pattern and inhibited gastric cancer cell proliferation. These results suggest that BTAK may be involved in gastric cancer cell aneuploid formation, and is a candidate gene for the increase in the number of copies of the 20q, and thus may contribute to an increase in the malignant phenotype of gastric cancer.

The influence of different insufflation pressures during carbon dioxide pneumoperitoneum on the development of pulmonary metastasis in a mouse model.

BACKGROUND: The effects of different insufflation pressures on the development of pulmonary metastasis was investigated in a mouse laparoscopy model. METHODS: BALB/C mice intravenously inoculated with colon 26 cells were randomized to one of five treatment groups (10 mice per group): pneumoperitoneum at different pressures of 5, 10 or 15 mmHg; full laparotomy for 60 min; or anesthesia control. Cancer nodules on the lung surface 19 days postoperatively were compared between groups. RESULTS: (a) As compared with the control group, pneumoperitoneum at 10 and 15 mmHg and laparotomy enhanced the growth of pulmonary metastases (p < 0.01). (b) The growth of metastases also was greater in laparotomy group mice than in mice undergoing pneumoperitoneum at 5 and 10 mmHg (p < 0.05). CONCLUSIONS: These results suggest that the effects of different insufflation pressures on the growth of pulmonary metastases are not identical, and that pneumoperitoneum with high pressure may promote pulmonary metastases similar to those with laparotomy.

Effect of CO(2) pneumoperitoneum on growth of liver micrometastases in a rabbit model.

Little is known about the risk of metachronous liver metastases following laparoscopic resection for gastrointestinal malignancies. The effect of CO(2) pneumoperitoneum on the growth of established liver micrometastases was investigated in a rabbit model. Male Japanese white rabbits weighing 2.8 to 3.3 kg were randomized to three groups (n = 15 per group) 3 days following intraportal inoculation of a tumor suspension containing 5 x 10(4) cells of VX(2) cancer. In the pneumoperitoneum group, insufflation with CO(2) was maintained at a pressure of 10 mmHg for 30 minutes. In the laparotomy group the abdominal cavity remained open through a 45 mm midline incision for 30 minutes; in the control group no treatment other than anesthesia was performed. Cancer nodules on the liver surface were compared among the three groups on day 17. There was no difference in the number of cancer nodules among the groups (p = 0. 72). A significant difference in the total area of cancer nodules (mean +/- SEM) was found only between the pneumoperitoneum group (696.0 +/- 177.0 mm(2)) and the control group (247.2 +/- 60.7 mm(2)) (p < 0.05). The frequency of cancer nodules larger than 3.0 mm in maximal diameter tended to be highest in the pneumoperitoneum group (p = 0.053). These results suggests that CO(2) pneumoperitoneum may promote the growth of established liver micrometastases in this animal model.

Pneumoperitoneum with carbon dioxide enhances liver metastases of cancer cells implanted into the portal vein in rabbits.

BACKGROUND: Little is known about the role of the CO2 pneumoperitoneum on tumor cells that spread from the portal system into the liver during laparoscopic surgery for gastrointestinal malignancies. Therefore, we designed a study to investigate the effect of CO2 pneumoperitoneum on cancer cells implanted in the portal vein in a rabbit model. METHODS: Immediately after intraportal inoculation of 2.5x10(5) cells of VX2 cancer, the rabbits received either CO2 pneumoperitoneum at a pressure of 10 mm Hg for 30 min (pneumoperitoneum group, n = 14) or laparotomy alone for 30 min (laparotomy group, n = 14). RESULTS: The number (p<0.01) and area of cancer nodules (p = 0.045) on the liver surface on day 17 were greater in the pneumoperitoneum group than in the laparotomy group. The frequency of cancer nodules >3.0 mm in diameter was higher in the pneumoperitoneum group than in the laparotomy group (p<0.001). CONCLUSIONS: Compared with laparotomy, CO2 pneumoperitoneum enhanced the development of liver metastases in this experimental model.