Biomedical subjects

P J K Kuppen

Publications and source records attributed to P J K Kuppen.

9 recordsLinked to original sources

PubMed2006

Prognostic relevance of occult tumour cells in lymph nodes in colorectal cancer.

AIMS: Presently, in Europe the treatment of node-negative colorectal cancer (CRC) patients consists of surgical resection of the primary tumour without adjuvant systemic therapy. However, up to 30% of these patients will develop disease recurrence. These high-risk patients are possibly identified by occult tumour cell (OTC) assessment in lymph nodes. In this paper, studies on the clinical relevance of OTC in lymph nodes are reviewed. METHODS: A literature search was conducted in the National Library of Medicine by using the keywords colonic, rectal, colorectal, neoplasm, adenocarcinoma, cancer, lymph node, polymerase chain reaction, mRNA, immunohistochemistry, micrometastases and isolated tumour cells. Additional articles were identified by cross-referencing from papers retrieved in the initial search. RESULTS: The upstaging percentages through OTC assessment and the prognostic relevance of OTC in lymph nodes vary among studies, which is related to differences in techniques used to detect OTC. CONCLUSIONS: We conclude that OTC examination techniques should be standardized to illuminate whether OTC in lymph nodes can reliably identify high-risk node-negative patients.

Antibodies, Neoplasm↗

PubMed2005

Locoregional therapies of liver metastases in a rat CC531 coloncarcinoma model results in increased resistance to tumour rechallenge.

BACKGROUND: Locoregional treatments like photodynamic therapy (PDT), radiofrequency ablation (RFA) or hepatic artery infusion (HAI) of chemotherapeutics may be applied for unresectable colorectal liver metastases. We evaluated the effect of these treatments on the immune response in a rat colon tumour liver metastases model. METHOD: Wag/Rij rats were inoculated at day 0 with CC531 tumour cells at two sites in the liver. At day 15, one of two tumours was treated with RFA or PDT, or the liver was treated by HAI. Twelve days later (day 27), rats were rechallenged locally with CC531 cells in the liver or systemically with CC531 cells in the femoral vein. At day 42, tumour growth in liver and lungs was determined. RESULTS: RFA, PDT and HAI were very effective in liver tumour eradication, but following RFA or PDT there was no inhibitory effect on untreated nearby liver tumours. Outgrowth after local rechallenge was, however, significantly inhibited in RFA-, PDT- and HAI-treated rats, whereas all control rats showed outgrowth of a third liver tumour. After systemic rechallenge, control rats developed lung metastases whereas treated rats did not, but this difference was not statistically significant. CONCLUSION: These results show that following PDT, RFA and HAI resistance to local and possibly systemic tumour rechallenge is increased. This may be partly due to the induction or enhancement of a cellular immune response.

Animals↗

PubMed2005

The feasibility and reliability of sentinel node mapping in colorectal cancer.

AIMS: Sentinel node mapping (SNM) has been introduced in colorectal cancer (CRC) to improve staging by facilitating occult tumour cell (OTC) assessment in lymph nodes that are most likely to be tumour-positive. In this paper, studies on the feasibility and reliability of SNM in CRC are reviewed. METHODS: A literature search was conducted in the National Library of Medicine by using the keywords colonic, rectal, colorectal, neoplasm, adenocarcinoma, cancer and sentinel. Additional articles were identified by cross-referencing from papers retrieved in the initial search. RESULTS: There is a large variation in identification rates and false-negative rates mainly due to the learning curve effect, differences in SNM technique and tumour stage. CONCLUSIONS: We conclude that SNM in CRC is technically feasible. Standardization of SNM procedures is mandatory to resolve the debate on the reliability of sentinel node status for predicting the tumour status of all lymph nodes. Only then can adjuvant treatment of patients upstaged by OTC detection in sentinel nodes be justified.

Colonic Neoplasms↗

PubMed2005

Natural killer cells infiltrating colorectal cancer and MHC class I expression.

A majority of colorectal adenocarcinomas displays diminished MHC class I expression, making them particularly vulnerable for NK cell-mediated killing. Generally, these tumors also show a substantial inflammatory infiltrate. Most inflammatory cells, however, reside in the tumor stroma, where they do not have direct contact with tumor cells in the tumor epithelium. In this study, we investigated the correlation between colorectal tumor MHC class I aberrations and infiltration of NK cells. We studied 88 tumor specimens obtained from 88 colorectal cancer patients for locus-specific HLA aberrations and correlated these data to infiltration of CD4, CD8+ and CD56+ lymphocytes. The lymphocyte markers were individually combined with laminin as a second marker to facilitate quantification in the different tumor compartments, i.e. tumor epithelium and tumor stroma. Locus-specific partial or total HLA class I loss was detected in 72% of the tumors studied. Twenty-eight percent had no HLA loss at all. Mean overall intra-epithelial infiltration of CD56+ lymphocytes was 7 cells/mm(2) compared to 76 cells/mm(2) for CD8 and 19 cells/mm(2) for CD4+ lymphocytes. Locus-specific partial or total loss of tumor cell MHC class I expression was positively correlated with the intra-epithelial infiltration of CD8+ cells (P = 0.01), but not with CD4+ or CD56+ lymphocytes. Triple immunofluorescence staining showed that these cells were CD8 and granzyme-B positive T-lymphocytes. Our data showed that colorectal tumors are sparsely infiltrated by CD56+ cells compared to CD8+ T-cells and that loss of MHC is associated with T-cell infiltration instead of NK cell infiltration. Considering the fact that MHC loss is quite common in colorectal cancer and that, due to local absence of NK cells, it is unlikely that there has been selection for NK-escape variants, improvement of the intra-epithelial infiltration/migration of NK cells may be an important basis for the development of an effective adjuvant NK-based immunotherapy of colorectal cancer.

Adenocarcinoma↗

PubMed2004

Dendritic cells in colorectal cancer correlate with other tumor-infiltrating immune cells.

Dendritic cells (DCs) are the most efficient antigen-presenting cells and play a key role in a cellular antitumor immune response. In this study we investigated the exact localization of DCs within colorectal tumors and their relationship to tumor-infiltrating lymphocytes as well as clinical outcome of the patients. Primary tumor specimens of 104 patients with a diagnosis of colorectal cancer were identified retrospectively and analyzed with the dendritic cell markers S-100 protein and human leukocyte antigens (HLA) class II. The markers were individually combined with laminin as a second marker to facilitate the observation of the different tumor localizations. S-100 or HLA class II positive cells were found in the three different compartments of colorectal tumors: tumor epithelium, tumor stroma, and advancing tumor margin, but mainly present in tumor stroma and advancing tumor margin. S-100-positive tumor-infiltrating DCs in direct contact with tumor cells, i.e., in tumor epithelium, significantly correlated to the intraepithelial infiltration of CD4+ (p=0.02) and CD8+ (p=0.01) lymphocytes. High HLA class II+ cell infiltration in the tumor stroma correlated to a lower intraepithelial infiltration of CD8+ (p=0.02) lymphocytes. High intraepithelial infiltration of S-100-positive DCs suggested increased disease-free survival, but was not statistically significant, while high amounts of HLA class II+ cells in the tumor stroma correlated with an adverse survival outcome. Our results show that the infiltration of DCs in colorectal cancer, depending on both location and type of marker, is correlated with local immune interactions and patient prognosis, suggesting a central role for DCs in controlling local tumor immunity.

Adult↗

PubMed2004

Isolated hepatic perfusion for the treatment of colorectal metastases confined to the liver: recent trends and perspectives.

Isolated hepatic perfusion (IHP) involves a method of complete vascular isolation of the liver to allow treatment of liver tumours with toxic systemic doses. The recent clinical studies mainly employed IHP with melphalan with or without tumour necrosis factor-alpha (TNF-alpha) and mild hyperthermia. The results of these studies show that high response rates and high survival rates can be achieved by IHP. In this article, the current status, recent developments and future perspectives of IHP are discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver.

BACKGROUND: Isolated hepatic perfusion (IHP) involves complete vascular isolation of the liver to allow treatment with doses that would be toxic if delivered systemically. A phase II study of IHP in patients with colorectal metastases confined to the liver was performed. METHODS: Seventy-three patients with irresectable colorectal metastases underwent IHP with high-dose melphalan (200 mg) for 1 h. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria and tumour response was assessed according to World Health Organization criteria. RESULTS: Seventy-one patients were perfused according to the protocol. Four patients died within 30 days after IHP, resulting in an operative mortality rate of 5.6 per cent. Sixteen patients (22.5 per cent) experienced grade 3-4 hepatotoxicity 1 week after IHP, which was transient and resolved within 3 months in all patients. The tumour response rate (complete or partial remission) was 59 per cent. Median time to progression was 7.7 (range 2.3-31.4) months. Overall median survival after IHP was 28.8 months with a 3-year survival rate of 37 per cent. CONCLUSION: IHP for irresectable colorectal metastases confined to the liver resulted in good response rates and long-term survival in a selected group of patients.

Adult↗

PubMed2003

An experimental minimally invasive perfusion technique for the treatment of liver metastases.

AIM: Isolated hepatic perfusion (IHP) is an invasive, technically difficult, non-repeatable and demanding operation. In this study we report the development of a less invasive alternative for the surgical IHP in a pig model. METHODS: Our technique was tested in 8 Yorkshire pigs (60 kg). The liver was isolated from the systemic circuit using minimally invasive techniques: an occlusion stent-graft and balloon catheters, with reversal of the blood flow through the liver during IHP. RESULTS: Tests with varying pressures applied at the PV revealed a clear relation between the suction pressure at the outflow site (PV), intrahepatic pressure and systemic leakage of 99mTc. A leakage-free IHP could be obtained in seven separate experiments. CONCLUSION: Isolated hepatic perfusion using minimally invasive techniques is feasible in pigs when the intrahepatic pressure is controlled. This technique has yet to be tested in patients.

Animals↗

PubMed2003

Membrane-bound complement regulatory proteins inhibit complement activation by an immunotherapeutic mAb in a syngeneic rat colorectal cancer model.

MAb-mediated immunotherapy offers a potential tool for destroying metastasizing colorectal tumor cells. Promising results have been obtained by using xenograft models. However, overexpression of membrane-bound complement regulatory proteins (mCRP) impedes complement-mediated destruction of tumor cells in vitro. mCRP operate in a species selective manner. Therefore a syngeneic animal model is needed to investigate the contribution of mCRP in mAb-mediated immunotherapy. Here we present a syngeneic rat colorectal carcinoma model, which fulfills the conditions necessary to investigate the effect of mCRP expression on mAb-mediated immunotherapy of metastases of solid tumors.CC531 rat colorectal cancer cells were injected subcapsularly into the liver of syngeneic WAG/Rij rats. Four mAb (MG1(IgG2a), MG2(IgG2a), MG3(IgG3) and MG4(2a)(IgG2a)) directed against CC531 cells, were tested for their complement activating abilities in vitro and tumor homing capacities in vivo. Only MG4(2a) was found to activate complement in vitro and home to the tumor cells in vivo. This mAb induced C3-deposition and C-mediated lysis of CC531 cells in vitro when the effects of the C-inhibitors Crry/p65 and CD59 were neutralized. This implies an important role for these mCRP in restricting the effector functions of tumor-associated mAb on these cells. Although C activation could be induced by MG4(2a) in situ on tumor tissue sections, no deposition of C3 could be found on the tumor cells positive for MG4(2a) in vivo. This suggests that complement activation in vivo was inhibited by mCRP. The results indicate the suitability of this syngeneic animal model for studying the effects of mAb immunotherapy. However, the effect of mCRP on tumor cells need to be overcome, e.g. by the use of mAb against tumor antigens and mCRP.

Animals↗