Do operations facilitate tumor growth? An experimental model in rats

Enhancement of tumor growth by operation is a concern often expressed by surgeons and patients anticipating cancer surgery. Two series of experiments were performed in which Fischer 344 rats and a carcinogen-induced transplantable rat colon cancer were used to test whether anesthesia and operation facilitate tumor implantation and growth. In the first experiments two groups of rats were given intraperitoneal tumor cells. One group underwent sham laparotomy; the second did not undergo surgery. In the second set of experiments rats were injected subcutaneously with tumor cells and then divided into four groups. The first group did not undergo laparotomy. The second underwent laparotomy on day 1, the third on day 15, and the fourth on days 15 and 29 after tumor implantation. Animals were followed for the incidence and growth rate of tumors that developed. The initial experiments demonstrated that 89% of the operated versus 49% of the nonoperated animals developed a tumor (p less than 0.001). The second experiment demonstrated that: animals undergoing multiple operations have a higher incidence of subcutaneous tumor nodules than nonoperated animals (p less than 0.05); animals undergoing multiple operations have a higher incidence of subcutaneous tumor nodules than animals undergoing a single operation (p less than 0.05); animals undergoing multiple operations had larger size tumor masses than the nonoperated animals (p less than 0.05) and than animals undergoing only one operation (p less than 0.04). This study supports the hypothesis that multiple operations and anesthesia may enhance tumor implantation and growth of metastases. This should be considered when designing therapy for patients with cancer.     

Intravesical ultrasonography for tumor staging in an orthotopically implanted rat model of bladder cancer

PURPOSE: Noninvasive and serial evaluation of tumor development and growth is important in an orthotopic animal bladder tumor model. However, to our knowledge a reliable method has not been established. We determined the usefulness of intravesical ultrasonography for tumor staging and volumetric assessment in an animal model. MATERIALS AND METHODS: Tumors with various stages were formed in 20 female Fischer F344 rats by implanting AY-27 rat bladder carcinoma cells. Cells were implanted by instilling a suspension (4x10 cells) into the bladder cavity after urothelial denudation using hydrochloric acid or by directly injecting the cell suspension into the bladder wall. Tumor volume and invasion depth were measured by intravesical ultrasonography using an ultrathin 2.5Fr intraluminal ultrasound catheter via the urethra 7 to 10 days after cancer cell implantation. The rats were then sacrificed for histopathological examination. RESULTS: All rats showed bladder tumors 7 to 10 days after cancer cell implantation, of which stages varied from superficial to advanced disease. Intravesical ultrasonography showed a clear cross-sectional view of all layers of the bladder wall and enabled visualization of bladder tumors (minimal 0.5 mm in diameter). This approach also provided an accurate diagnosis of tumor invasion into muscle layers and perivesical tissues with precise invasion depth and tumor size. The positive predictive ratio regarding tumor staging reached 85%. Repeat examinations were feasible without noticeable adverse effects. CONCLUSIONS: Intravesical ultrasonography is a reliable and appropriate noninvasive method for evaluating tumor stage and size in an orthotopic rat bladder tumor model.     

Identification of a quantitative trait locus on rat chromosome 4 that is strongly linked to femoral neck structure and strength

Risk factors for osteoporotic hip fracture include reduced bone mineral density and poor structure of the femoral neck, both of which are heritable traits. Previously, we showed that despite similar body size, Fischer 344 (F344) rats have significantly different skeletal traits compared with Lewis (LEW) rats. To identify a gene or genes regulating fracture risk at the femoral neck, we mapped quantitative trait loci (QTL) for femoral neck density and structure phenotypes using a 595 F2 progeny derived from the inbred F344 and LEW strains of rats. Femoral neck phenotypes included volumetric bone mineral density (vBMD), neck width, femoral neck cross-sectional area and polar moment of inertia (Ip). A 20-cM genome-wide scan was performed using 118 microsatellite markers and linkage analysis was conducted to identify chromosomal regions harbor QTL for femoral neck phenotypes. Strong evidence of linkage (P<0.01) to femoral neck vBMD was observed on chromosomes (Chrs) 1, 2, 4, 5, 7, 10 and 15. QTL affecting femoral neck structure and biomechanical properties were detected only on Chr 4 where the F344 alleles were shown to improve femoral neck structure, whereas these alleles had no effect on bone measurements at the lumbar spine and only modest effects at the femoral midshaft. In contrast, QTL on Chrs 1, 2 and 10 affected multiple skeletal sites. Several QTL regions in this study are homologous to human chromosomal regions, where linkage to femoral neck and related phenotypes has been reported previously. These findings represent an important first step in localizing and identifying genes that influence hip fragility.     

Effects of vitamin D (calcitriol) on transitional cell carcinoma of the bladder in vitro and in vivo

PURPOSE: Vitamin D (calcitriol) has significant antiproliferative effects on various tumor cells in vitro and in vivo. In the clinical situation a major impediment to systemic administration of calcitriol is the side effect of hypercalcemia. To test the potential usefulness of calcitriol for bladder cancer treatment, we studied the antiproliferative effect of vitamin D on 2 human bladder cancer cell lines, 253j and T-24, in vitro. We also examined the in vivo effects of calcitriol in an animal model of bladder cancer using intravesical administration to avoid the toxicity of systemic calcitriol therapy. MATERIALS AND METHODS: The presence of vitamin D receptors in normal and neoplastic human bladder tissue, and tumor cells T-24 and 253j was determined by immunoblot analysis. Tumor cell proliferation in the presence or absence of calcitriol was determined using a crystal violet assay. Calcitriol induced apoptosis was determined by morphology, polyadenosine diphosphate ribose polymerase cleavage and annexin V binding. In vivo studies were performed by weekly intravesical instillation of calcitriol in female Fischer 344 rats after induction of tumors by N-methyl nitrosourea. Calcitriol administration was started 3 weeks after tumor induction for 7 doses at weekly intervals. RESULTS: Normal and neoplastic human bladder tissue, and the cell lines expressed vitamin D receptors. In the 253j and T-24 cell lines proliferation was significantly inhibited by calcitriol. Progressive cleavage of full length polyadenosine diphosphate ribose polymerase was observed in calcitriol treated cells starting as early as 4 hours after exposure. Similar changes were not observed in the control cells treated with vehicle (ethanol) alone. After 24 hours of treatment with calcitriol 45.8% of 253j cells bound annexin compared to 16.5% of control cells (chi-square p <0.001). Of the control animals 66% developed bladder tumors and 55% of the animals treated with calcitriol early (3 weeks) after tumor induction developed bladder tumors. Almost all of the tumors that developed in the calcitriol group were unifocal, and only 20% were invasive compared to 50% of those in the control animals. CONCLUSIONS: These results demonstrate that calcitriol inhibits proliferation and induces apoptosis in human bladder tumor cells in vitro, and may have therapeutic potential in bladder cancer. In vivo studies using an N-methylnitrosourea induced model of bladder cancer demonstrate that early institution of intravesical calcitriol therapy after carcinogen exposure results in fewer tumors, which are also less likely to be multifocal, high grade or invasive. With our protocol a short course of intravesical calcitriol administration did not result in any significant toxicity.     

Setup and characterization of a human head and neck squamous cell carcinoma xenograft model in nude rats

OBJECTIVE: To develop and characterize a new head and neck cancer animal model. STUDY DESIGN: A human head and neck squamous cell carcinoma (HNSCC) xenograft model in nude rats was established via subcutaneous inoculation of a human-origin HNSCC cell line, SCC-4. The tumor was evaluated for growth characteristics, pathologic features by hematoxylin-eosin (HE) staining, and immunohistochemistry of epidermal growth factor receptor (EGFR). 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) imaging characteristics were studied too. RESULTS: A new HNSCC animal model was successfully established. Tumor sizes reached about 1 cm3 on day 15 after tumor cell inoculation. HE staining pathology has confirmed that this tumor is a typical SCC. EGFR immunohistochemistry demonstrated this tumor model to be strongly EGFR positive. 18F-FDG PET study has shown that 18F-FDG accumulated in tumors. CONCLUSIONS: This study has demonstrated that this tumor model is an appropriate HNSCC tumor model for animal studies on HNSCC.     

Experimental intravesical therapy for superficial transitional cell carcinoma in a rat bladder tumor model

A rodent bladder cancer model that is induced by intravesical instillation of N-methyl-N-nitrosourea (MNU) was characterized. Cohorts of four to five week old female Fisher 344 rats received four biweekly 1.5 mg. doses of intravesical MNU and were sacrificed at various intervals. By week 13 all animals had flat atypia and/or papillary transitional cell tumors, and 67% of the lesions were moderately (grade II) or poorly differentiated (grade III). By week 20, 83% had gross muscle invasive tumors that eventually killed the host. A cohort of 40 MNU treated animals was subsequently treated commencing at week 17 after initiation of MNU with one of three intravesical six week regimens: 1) saline; 2) BCG (Tice strain); or 3) recombinant human tumor necrosis factor (RTNF) plus adriamycin. There was no difference in animal survival or tumor growth in any group of animals commencing therapy at week 17. A second cohort of 107 animals commenced therapy at 13 weeks after initiation of MNU with one of five intravesical six week regimens: 1) intravesical BCG (Tice strain); 2) adriamycin; 3) recombinant human tumor necrosis factor (RTNF); 4) RTNF plus adriamycin; or 5) BCG plus adriamycin. BCG, RTNF or adriamycin alone had no effect on tumor growth; however, BCG plus adriamycin and RTNF plus adriamycin commencing at week 13 significantly inhibited tumor growth and progression. In conclusion, this autochthonous intravesical rodent transitional cell carcinoma model appears useful for the following reasons: 1) it closely resembles human transitional cell carcinoma histologically and biologically in that all animals develop neoplastic changes in-situ that progress to muscle invasion and kill the host; 2) as with human bladder cancer these tumors do not respond to intravesical therapy if treated when tumor burden is large; however, tumor growth is inhibited when treated early; and 3) this model appears appropriate for screening and developing new intravesical treatments for superficial bladder cancer.     

Fractionated, single-port radiotherapy delays paresis in a metastatic spinal tumor model in rats

OBJECT: Spinal column metastatic disease affects thousands of cancer patients every year. Radiation therapy frequently represents the primary treatment for this condition. Despite the enormous clinical impact of spinal column metastatic disease, the literature currently lacks an accurate animal model for testing the efficacy of irradiation on spinal column metastases. METHODS: After anesthesia was induced, female Fischer 344 rats underwent a transabdominal approach to the ventral vertebral body (VB) of L-6. A 2- to 3-mm-diameter bur hole was drilled for the implantation of a section of CRL-1666 breast adenocarcinoma. After the animals had recovered from the surgery, they underwent fractionated, single-port radiotherapy beginning on postoperative Day 7. Each group of animals underwent five daily fractions of radiation treatment. Group I animals received a total dose of 10 Gy in 200-cGy daily fractions, Group II animals received a total dose of 20 Gy in 400-cGy daily fractions, and Group III animals received a total dose of 30 Gy in 600-cGy daily fractions. A control group of rats with implanted VB lesions did not receive radiation. To test the effects of radiation toxicity alone, additional rats without implanted tumors received radiation treatments in the same fractions as the rats with tumors. Hindlimb function in all rats was rated before and after radiation treatment using the Basso-Beattie-Bresnahan locomotor rating scale. Histological analysis of spinal cord and vertebral column sections was performed after each animal's death. RESULTS: Functional assessments demonstrated a statistically significant delay in the onset of paresis between the three treatment groups and the control group (tumor implanted but no radiotherapy). The rats in the three treatment groups, however, did not exhibit any significant differences related to hindlimb function. A dose-dependent relationship was found for the percentage of animals who had become paralyzed at the time of death, with all members of the control group and no members of the 30-Gy group exhibiting paralysis. The results of this study do not indicate any overall survival benefit for any level of radiation dose. CONCLUSIONS: These findings demonstrate the efficacy of focal spinal irradiation in delaying the onset of paralysis in a rat metastatic spine tumor model, but without a clear survival benefit. Because of the dose-related toxicity observed in the rats treated with 30 Gy, this effect was most profound for the 20-Gy group. This finding parallels the observed clinical course of spinal column metastatic disease in humans and provides a basis for the future comparison of novel local and systemic treatments to augment the observed effects of focal irradiation.     

Successful diagnosis of orthotopic rat superficial bladder tumor model by ultrathin cystoscopy

PURPOSE: In the orthotopic animal bladder tumor model noninvasive evaluation of the tumor establishment and the therapeutic effect has been difficult. To our knowledge we present the first diagnosis of orthotopic rat superficial bladder tumor model by ultrathin cystoscopy. MATERIALS AND METHODS: The established AY-27 rat bladder carcinoma cell line was transplanted orthotopically into 22 female Fischer F344 rats. A cell suspension containing 4 x 10 AY-27 cells was instilled into the bladder, which had been conditioned with mild acid washing. To evaluate tumor growth serial cystoscopy was performed via the urethra with an ultrathin endoscope (diameter 0.75 mm.) 5 to 14 days after tumor cell inoculation. At intervals after cystoscopic tumor detection the rats were sacrificed for autopsy and histological examination. RESULTS: In all 22 rats the orthotopic bladder tumor was established 7 to 10 days after tumor cell implantation and in most it was superficial. Cystoscopy permitted inspection of the urethra and whole bladder surface. We detected all tumors as broad based papillary mass (minimal lesion 1 mm. or less) and inspected its detailed appearance and accurate location. CONCLUSIONS: The orthotopic rat superficial bladder tumor model and the diagnostic procedure by ultrathin cystoscopy would be ideal system for preclinical evaluation of new potential intravesical therapies.     

Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.

OBJECT: An approach toward the treatment of intracranial gliomas was developed in a rat experimental model. The authors investigated the ability of "professional" antigen-presenting cells (dendritic cells) to enhance host antitumor immune responses when injected as a vaccine into tumor-bearing animals. METHODS: Dendritic cells, the most potent antigen-presenting cells in the body, were isolated from rat bone marrow precursors stimulated in vitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. Cultured cell populations were confirmed to be functional antigen-presenting cells on the basis of expressed major histocompatibility molecules, as analyzed by fluorescence-activated cell sorter cytofluorography. These dendritic cells were then pulsed (cocultured) ex vivo with acid-eluted tumor antigens from 9L glioma cells. Thirty-eight adult female Fischer 344 rats harboring 7-day-old intracranial 9L tumors were treated with three weekly subcutaneous injections of either control media (10 animals), unpulsed dendritic cells (six animals), dendritic cells pulsed with peptides extracted from normal rat astrocytes (10 animals), or 9L tumor antigen-pulsed dendritic cells (12 animals). The animals were followed for survival. At necropsy, the rat brains were removed and examined histologically, and spleens were harvested for cell-mediated cytotoxicity assays. The results indicate that tumor peptide-pulsed dendritic cell therapy led to prolonged survival in rats with established intracranial 9L tumors implanted 7 days prior to the initiation of vaccine therapy in vivo. Immunohistochemical analyses were used to document a significantly increased perilesional and intratumoral infiltration of CD8+ and CD4+ T cells in the groups treated with tumor antigen-pulsed dendritic cells compared with the control groups. In addition, the results of in vitro cytotoxicity assays suggest that vaccination with these peptide-pulsed dendritic cells can induce specific cytotoxic T lymphocytes against 9L tumor cells. CONCLUSIONS: Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.     

Establishment of a syngeneic model of hepatic colorectal oligometastases

BACKGROUND: Regional and systemic therapies aimed at improving the outcome for patients with colorectal hepatic metastases have met with modest yet tangible success. Currently, liver resection remains the only curative treatment, but only a minority of patients are candidates for surgery. Animal models are an ideal way to study new treatments for patients with metastatic colorectal cancer. We propose a syngeneic animal model of hepatic colorectal metastases that simulates oligometastases, which is a clinical state considered amenable to regional therapeutic strategies. MATERIALS AND METHODS: BDIX (BD-9) rats underwent intrasplenic injection of DHD/K12/TRb (Prob/K12) cells to create hepatic metastases via the portal system. After injection of 5 x 10(6) cells, rats underwent laparotomy to determine metastatic burden. Histological analysis confirmed the presence of metastases from resected tumors. RESULTS: Fifty-three animals were prospectively treated and observed for the development of oligometastases defined as between 1 and 10 hepatic lesions. Thirty-six (68%) of the animals developed detectable metastases while 32 (60%) developed oligometastases (average = 4.40 +/- 2.67). Four animals had overwhelming metastatic liver and peritoneal disease. All animals underwent peritoneal examination and thoracotomy to ensure localized disease. Histological analysis of five hepatectomy specimens confirmed the presence of metastatic cancer. Animals with oligometastases were healthy as evidenced by normal feeding and grooming behavior. CONCLUSIONS: An animal model of oligometastatic colorectal cancer to the liver can reproducibly mimic the stage IV state in humans conducive to regional therapy and can be used reliably to test novel treatments and mechanisms of metastatic colorectal cancer.     

Tumor resistance in rats immunized to fetal tissues

Inbred Fischer 344/N rats were immunized with irradiated cells of either a MCA-induced syngeneic fibrosarcoma (MCA-R), syngeneic second trimester fetal tissue, or allogeneic, Marshall 520 splenic lymphocytes. Animals injected intradermally with soluble antigen extracts (SAE) of MCA-R and normal Fischer 344/N tissues were evaluated for development of delayed cutaneous hypersensitivity reactions (DCHR). Fischer rats immune to allogeneic tissue gave no positive DCHR to either SAE. Ten of 11 rats immune to MCA-R and 6 of 9 immune to second trimester fetal tissue gave positive reactions to MCA-R SAE but none to normal tissue SAE. In a second experiment immunized rats were challenged subcutaneously with viable MCA-R tumor cells. Significant resistance to tumor growth was demonstrated by animals immune to MCA-R and by animals immune to second trimester fetal tissue. This resistance was unrelated to sex. Immunological similarity between fetal antigens and tumor associated transplantation antigens is suggested.     

Comparison of Two Syngeneic Orthotopic Murine Models of Pancreatic Adenocarcinoma

ABSTRACT

Background: Pancreatic adenocarcinoma has an extremely poor prognosis. The use of appropriate in vivo models is essential in devising methods to improve treatment outcomes. Methods: A pancreatic adenocarcinoma model based on tumor injection into the pancreatic head was compared with a pancreatic tail injection model in C57/BL6 mice. The murine pancreatic adenocarcinoma cell line PAN02, dispersed in Matrigel^TM, was used for tumor induction. Results: Tumors developed in all animals in both models. Tumor size was more consistent within the pancreatic tail group at 20 days following induction, with no evidence of metastatic disease. Animals in the pancreatic head injection group showed signs of reduced health by 20 days following injection and developed jaundice. Microscopic liver metastases were noted in some of these animals at this time point. The overall survival of animals at 40 days following tumor induction was significantly lower in the pancreatic head injection group (0% vs. 35%; p < .001). Multiple liver metastases were noted in five of 10 (50%) animals in the head injection group, without evidence of peritoneal metastases. In the pancreatic tail injection group, 18 of 20 (90%) animals had multiple peritoneal metastases, and nine of 20 (45%) animals had evidence of isolated liver deposits. Tumors in both regions of the pancreas had similar histologic characteristics, with a dense fibrotic stroma at the interface between the tumor and the normal pancreas. Conclusion: Pancreatic head and tail orthotopic cancer models produce consistent tumors, but the patterns of tumor spread and survival differ according to the site of injection.     

Improved treatment of a brain-tumor model. Part 2: Sequential therapy with BCNU and 5-fluorouracil

A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.     

Fusogenic vesicular stomatitis virus for the treatment of head and neck squamous carcinomas.

OBJECTIVES: This study investigates the efficacy of recombinant fusogenic VSV [rVSV-NDV/F(L289A) or rVSV-F] in the treatment of head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN AND SETTING: The in vitro replication and cytotoxicity of rVSV-F were studied in two human SCC cell lines, in one murine SCC cell line, and in human keratinocytes. The effects on tumor size and animal survival were investigated following in vivo rVSV-F treatment of floor-of-mouth tumor model C3H/HeJ mice. RESULTS: Recombinant VSV-F preferentially induced rapid syncytia formation, and replicated in (P < 0.04) and killed (P < 1 x 10(-13)) all three SCC lines tested. The virus had no observable effect on human keratinocytes. Tumor size was smaller (P < 0.03) and overall survival was better (P < 0.001) for treated animals than for control animals. CONCLUSION/SIGNIFICANCE: Recombinant VSV-F confers a modest survival benefit for HNSCC in this orthotopic murine model. This oncolytic virus holds promise as a novel cancer treatment for recurrent HNSCC.     

Site-directed metastasis: a model to study site variations in treatment response

A model for the site-directed metastasis of a transplantable rat mammary carcinoma is described. The R3230AC tumor is a moderately well differentiated, phenotypically stable tumor which arose in a Fischer 344 rat and resembles human breast carcinoma in being hormonally sensitive, poorly immunogenic, and sensitive to radiation and chemotherapeutic agents. Metastases with this tumor can be consistently produced at specific sites (lung, liver, or subcutaneous) in a reproducible manner by the methods described in this paper. This model appears ideal for the evaluation of site-specific variation in response to treatment modalities.     

Effects of laparoscopy on intraperitoneal tumor growth and distant metastases in an animal model.

BACKGROUND AND AIMS: Laparoscopic surgery for colorectal cancer is currently being evaluated in humans. The aim of this study was to examine the effect of laparoscopy on intraperitoneal tumor growth and distant metastases in an animal model. We also examined the effect of combining laparotomy with laparoscopy and on infusing the peritoneal cavity with normal saline solution (NaCl), water, and sodium hypochlorite after laparoscopy on intraperitoneal tumor growth. MATERIAL AND METHODS: Female Fischer rats were given MtLn3 adenocarcinoma cells by intraperitoneal injection to produce intraperitoneal tumor growth and by tail vein injection to produce lung metastases. A pneumoperitoneum was then induced to a pressure of 8 mm Hg with carbon dioxide (CO2), helium, or room air. After this, animals were allowed to either recover or underwent laparotomy or infusion of NaCl, water, or sodium hypochlorite before recovery, depending on the experiment. At 21 days all animals were killed and intraperitoneal tumor growth was assessed by counting the number of peritoneal and serosal nodules and by weighing the omental pad of tumor. Lung metastases were assessed by counting the number of metastases after fixation. RESULTS: Laparoscopy caused a marked intraperitoneal dissemination of tumor with a median of 17 (10 to 20) peritoneal and serosal nodules for CO2, 19.5 (12.5 to 25) for helium, and 15.0 (9.5 to 17.7) for room air compared with 0 (0 to 1) for controls (P < .0001). The weight of omental tumor was also significantly increased (P < .02) in the CO2, helium, and room air groups. Infusion with NaCl, water, or sodium hypochlorite had no effect on tumor dissemination after laparoscopy. The combination of laparoscopy and laparotomy caused a significant reduction (P < .05) in the number of peritoneal nodules but had no significant effect on omental tumor growth. Laparoscopy also had no effect on the number of pulmonary metastases induced compared with controls. CONCLUSIONS: This study shows that laparoscopy promotes intraperitoneal dissemination of tumor. This effect is independent of the insufflating gas used and is not affected by use of a cytotoxic agent. The use of gasless laparoscopy should be encouraged by those undertaking curative laparoscopic surgery for colorectal cancer.     

Antimetastatic Effect of Hepatotropic Liposomal Adriamycin on Human Metastatic Liver Tumors

Adriamycin (ADM) was encapsulated in a galactose-conjugated hepatotropic liposome (hLip-ADM) and its ability to enhance the antitumor effect while reducing toxicity was compared with that of free ADM and a control Lip-ADM (cLip-ADM), in two in vitro animal models. Liver metastases were induced in rats by an intravenous injection of 8 × 10⁶ AH-130 rat hepatoma tumor cells. All forms of the ADM completely inhibited liver metastasis when given at a dose of 5 mg/kg on day 14 after tumor implantation, whereas liver metastatic foci were observed in six of ten rats in the control group. The reduction in ADM toxicity by liposomalization was remarkable, as significant body weight loss was observed only in the free ADM group, in which four of ten rats died. Additional experiments utilized a human colon cancer xenograft (TK-4) to induce the growth of the liver metastases in mice by orthotopic implantation. The hLip-ADM completely inhibited liver metastasis in rats (0/11), whereas liver metastases developed in 10 of 12 mice in the control group and in 5 of 12 mice given cLip-ADM. Interestingly, liposomal ADM did not have a significant inhibitory effect on transplanted tumor growth assessed 6 weeks after transplantation. These findings indicate that hLip-ADM may be an effective strategy for inhibiting liver metastases from human colon cancer. Received: June 15, 2000 / Accepted: November 20, 2000     

Effective antitumor immunity following elimination of suppressor T cell function.

An increased resistance to a transplantable tumor was demonstrable in Fischer (F344) strain rats after thymectomy and high doses of total body irradiation, followed by bone marrow cell repopulation if the animals were allowed to recover for 6 to 8 weeks. Further experiments demonstrated that removal of a subpopulation of T cells by lower doses of radiation plus thymectomy could (1) reduce recurrences after surgical excision, and (2) prolong survival of animals with established pulmonary metastases. It was found that thymectomy + 50 leads to 100 R total body irradiation could eliminate a T cell-mediated suppression of effective antitumor immunity. The removal of the suppressor cell component by lower doses of irradiation was dependent on pre-exposure of the animals to tumor antigen. These experiments indicate the specificity of suppressor T cells to tumor antigen and their exquisite sensitivity to radiation in appropriate circumstances.     

Prevention of rat colon cancer metastases by perioperative immunostimulation

Major intra-abdominal operations result in profound immunodepression. In addition, manipulation of malignant tumors may release tumor cells into the systemic and portal circulations. The additive effects of immunodepression and tumor cell release may enhance the metastatic potential of tumors. Perioperative correction of immune depression by levamisole can restore lymphocyte proliferation levels in rats. We have developed a model in which rat colon carcinoma cells transplanted into the portal venous system consistently induce hepatic metastases by 4 weeks and death within 9 weeks. Rats pretreated with levamisole (4 mg/kg administered intraperitoneally) the day before and the day of tumor implantation developed fewer metastases (41% of animals treated with levamisole compared with 6% of animals not treated with levamisole had less than or equal to two metastases per liver). Twenty percent of the rats treated with levamisole developed no hepatic metastases. Comparison of median liver weights between the group treated with levamisole and the nontreated, tumor-bearing group was highly significant (p less than 0.005). We conclude that the perioperative period is critical for the implantation and growth of metastases and that perioperative immunostimulation may be a factor in decreasing the incidence of metastases. This model may have relevance to the adjuvant treatment of human colon cancer.     

Small bowel metastases from head and neck cancers

AIM OF THE STUDY: Small bowel metastases represent less than 10% of malignant tumours of the small bowel. Among primitive cancers with small bowel metastases, head and neck cancers are exceptional. The aim of the study was to evaluate clinical and evolutive characteristics of patients with small bowel metastases from head and neck cancers. PATIENTS AND METHODS: Analyse of a reported case and bibliographic study by asking the Medline database and gathering anamnestic, clinical and evolutive data from observations of small bowel metastases from head and neck cancers. RESULTS: We report the case of a 63 years-old male patient with a small bowel metastasis from a head and neck cancer. Nine other observations have been published in the international literature. Analysis of this 10 patient-series shows that small bowel metastases of head and neck cancers occur rather in old male patients (mean age: 71 years). They are usually discovered after primitive cancer diagnosis, always because of occlusive, perforative or bleeding complications. Jejunal metastases are rather complicated by perforation whereas ileal ones rather induce occlusion or digestive bleeding. Discovering a small bowel metastasis in the context of head and neck cancer is highly indicative of a poor prognosis. In these 10 patients, deaths occurred within the 8 months following the diagnosis, because of postoperative complication or neoplastic evolution. CONCLUSIONS: Small bowel metastases from head and neck cancers usually occur as emergent complications. They are indicative of an advanced disease and the prognosis is extremely poor. The aim of the management is to afford the best quality of life as possible.