Disease In Colorectal Cancer Patients Research Articles

Discovery of prognostic lncRNAs in colorectal cancer using spatial transcriptomics

Colorectal cancer (CRC) exhibits significant genetic and epigenetic diversity, evolving into sub-clonal populations with varied metastatic potentials and treatment responses. Predicting metastatic disease in CRC patients remains challenging, underscoring the need for reliable biomarkers. While most research on therapeutic targets and biomarkers has focused on proteins, non-coding RNAs such as long non-coding RNAs (lncRNAs) comprise most of the transcriptome and demonstrate superior tissue- and cancer-specific expression. We utilised spatial transcriptomics to investigate lncRNAs in CRC tumours, offering more precise cell-type-specific expression data compared to bulk RNA sequencing. Our analysis identified 301 lncRNAs linked to malignant CRC regions, which we validated with public data. Further validation using RNA–FISH revealed three lncRNAs (LINC01978, PLAC4, and LINC01303) that are detectable in stage II tumours but not in normal epithelium and are upregulated in metastatic tissues. These lncRNAs hold potential as biomarkers for early risk assessment of metastatic disease.

Abstract 3685: Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm

Abstract Objective: Existing methods for detecting circulating-tumor DNA (ctDNA) through fixed panels exhibit constrained sensitivity, while customized panels are time-consuming and rely on prerequisite tumor mutation profiles. Here, we aimed to introduce an adaptive noise cancellation approach for efficient Minimal Residuals Disease (MRD) detection in colorectal cancer patients employing a fixed panel under both tumor-informed and tumor-naïve situations. Methods: 108 plasma samples were collected from 52 colorectal cancer patients (11 relapse, 41 non-relapse) at various post-surgical timepoints. Comprehensive mutational profiling of plasma samples was conducted using a fixed MRD panel (SHIELDINGTM ULTRA) that encompasses hotspots in 2365 cancer-related genes. Background errors were removed by an adaptive noise cancellation algorithm relying on DNA fragment profiling, normal pool, and white blood cell background and intra-run plasma sampling. Variants were called both with (tumor-informed) and without (tumor-naïve) the present of tumor tissue. Results: Our longitudinal analysis of 108 plasma samples yielded 90.9% sensitivity, 97.6% specificity and 97.6% negative predictive value in the tumor-informed scenario. The ctDNA positive patients exhibited significantly higher risk than those with negative ctDNA status (Hazard Ratio = 87.2, p = 3.5 × 10^(-5)). For landmark analysis, 33 plasma samples (≤7 days post-operation) were assessed, yielding a remarkable performance of 66.7% sensitivity and 100% specificity. Our approach showed robustness under tumor-naïve scenario, illustrating 90.9% sensitivity, 92.7% specificity and 97.4% NPV for the longitudinal analysis. This corresponded to an increased risk of 49 times in the ctDNA positive patients (HR = 49.0, p = 2.2 × 10^(-4)). Notably, the results of tumor-naïve samples closely aligned with those of tumor-informed samples, showing a concordance of 92.6% and substantial agreement (Cohen’s Kappa = 0.691). Conclusion: Our method stands as an ultra-sensitive tool for identifying colorectal patients at high risk of recurrence. By employing an adaptive noise cancellation algorithm, our fixed panel approach demonstrates superiority over existing fixed panels in accuracy and proves to be a cost-effective alternative to personalized panels. Significantly, it extends potential clinical utilization towards tumor-naïve patients, which is not feasible for personalized panels. Citation Format: Hua Bao, Wanxiangfu Tang, Ningyou Li, Min Wu, Jinfeng Zhang, Baihan Zhu, Xue Wu, Yang Shao. Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3685.

There are differences in body composition parameters according to site and stage of disease in colorectal cancer patients?

There are differences in body composition parameters according to site and stage of disease in colorectal cancer patients?

SPERT gene silencing inhibits the growth of human colon cancer xenograft tumor in nude mice via p38MAPK/HSP27 signaling pathway.

Colorectal cancer is one of the most common gastrointestinal malignancies and is also a disease of genetic heterogeneity. Our previous studies have shown that SPERT (sprermatid-associated protein) gene may be an underlying oncogene that is associated with the progression of the disease in colorectal cancer patients, and SPERT gene silencing can inhibit the proliferation of colorectal tumor cells and promote cell apoptosis. Here, we use the stably transfected human colorectal cancer cell line RKO to construct an animal xenograft model and study the effect of SPERT gene silencing on animal xenografts. The results showed that SPERT gene silencing can inhibit tumor growth in animals. In addition, through signaling pathway analysis, we found that the p38MAPK/HSP27 signaling pathway may be the molecular mechanism by which SPERT gene silencing inhibits the growth of xenograft tumors in nude mice. Combined with previous data, SPERT gene silencing has the same inhibitory effect on tumor growth in vitro and in vivo. These data suggest that SPERT gene may be a potential target for the treatment of colorectal cancer in clinic.

Alcohol Consumption is associated with Increased CEA Levels in Male Patients with Stage IV Colorectal Cancer- A Single-Institution Retrospective Analysis

Introduction: Alcohol use is an independent risk factor for liver metastasis, a major cause of morbidity and mortality in colorectal cancer (CRC) patients. Serum CEA level is an established prognostic indicator in CRC, yet the correlation with behavioral factors such as alcohol use remains to be defined. In a single-center review, we evaluated alcohol use, gender, and CEA levels in predicting advanced disease in CRC patients. Methods: Retrospective analysis of UNMC patients diagnosed with CRC as the primary cancer between 2012-2019, stages I-IV, and age >19 with documentation of alcohol use. Univariable statistics were performed using Chi-Square and non-parametric tests. Associations between stage, gender, and alcohol use (some vs. none) and the log-transformed CEA outcome (either initial or rate of change) were assessed using linear regressions. Results: Alcohol use was found to be reported in 333 of 1243 CRC patients. The cohort was comprised of 192 male and 141 female subjects. Elevated CEA levels at CRC diagnosis were associated with increased all-cause mortality (33.0% for CEA > 3.4ng/ml vs 10.4% for CEA < 3.4ng/ml). Model analysis found that stage IV male alcohol users showed an increase in serial CEA levels compared to males who did not use alcohol, but this pattern was not observed among stage IV females. Conclusions: Males with a history of alcohol use may be at risk for advanced CRC disease suggesting the utility of serial serum CEA monitoring in these patients. A detailed alcohol use history should be obtained in all patients with CRC as it has prognostic value and may allow for early intervention. This analysis was limited by missing alcohol use data for the majority (73.2%) of CRC patients evaluated. A prospective study is warranted to define the implications of alcohol use and risk of CRC liver metastasis.

Abstract 2880: CD36, a fatty acid translocase, promotes metastasis in CRC

Abstract Altered fatty acid metabolism, a hallmark of cancer, is an attractive target for therapeutic intervention. Fatty acid translocase (CD36), a multifunctional glycoprotein, has an important role in fatty acid metabolism: it serves as a fatty acid transporter. We have previously shown the importance of CD36 in promotion of colorectal cancer (CRC) cell proliferation and tumorigenesis and its role in compensation of de novo fatty acid synthesis inhibition. CD36 also plays important roles in migration, invasion and metastasis in gastric, ovarian and oral carcinomas. Cell lines with higher metastatic potential express higher levels of CD36; however, the role of CD36 in CRC metastasis has not been previously studied. The purpose of our study is (i) to determine the functional effect of CD36 on CRC metastasis, and (ii) to delineate the mechanistic pathways in which CD36 may regulate CRC metastasis. Methods: In this study we utilized HCT116 and HT29 CRC cell lines. The HT29 LuM3-GFP-Luc cell line was established from HT29 cells and has an increased propensity to metastasize to mouse lungs. The increase in metastatic capacity of HT29 LuM3 is associated with an increase in the expression of CD36. We utilized parental HT29-GFP-Luc and HT29 LuM3-GFP-Luc to overexpress and knockdown CD36, respectively, and we used a CD36 neutralizing antibody to block the activity of CD36 in HCT116 and HT29 LuM3 cells. To measure colonization, migration and invasion in vitro, we used soft agar colony formation assays, a wound healing assay, and spheroid and trans-well invasion assays. In vivo, we utilized the tail-vein injection model to study tumor cell colonization in mouse lungs, and the cecum injection model to study liver metastasis from the primary tumor. We analyzed samples with qRT-PCR, western blot and immunohistochemistry. Results: Knockdown of CD36 significantly reduced CRC cell invasion and colony formation in HCT116 and HT29 LuM3 in vitro. CRC cell invasion and colony formation increased with overexpression of CD36 in HCT116 cells. Overexpression of CD36 in established CRC cell lines increased markers of survival and invasion, such as phospho-Akt, P-Met, and MMP28. Most importantly, knockdown of CD36 in HT29 LuM3-GFP-Luc cells significantly reduced lung metastasis in vivo. Conclusions: CRC cells that have a higher propensity to initiate metastasis in vivo express higher levels of CD36. We showed that this upregulation of CD36 represents a unique advantage for CRC cells to initiate tumor colonies, migrate and invade both in vitro and in vivo. Thus, our study highlights the potential of CD36 as a viable target for metastatic disease in CRC patients. Citation Format: James Michael Drury, Piotr Rychahou, Heidi L. Weiss, Yekaterina Y. Zaytseva. CD36, a fatty acid translocase, promotes metastasis in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2880.

Detection of ctDNA biomarkers post resection and relationship to recurrent disease in colorectal cancer patients.

e15616Background: BCAT1 and IKZF1 are aberrantly methylated in almost all neoplastic colorectal tissue specimens. These biomarkers are detected in blood as circulating tumor DNA (ctDNA) in most pat...

Perioperative beta-adrenergic blockade and COX2 inhibition in colorectal cancer patients improves pro-metastatic indices in the excised tumor: EMT, tumor infiltrating lymphocytes (TILs), and gene regulatory pathways

Excess release of catecholamines and prostaglandins was shown to mediate pro-metastatic processes during the perioperative period. Here, in a randomized controlled biomarker clinical trial in colorectal cancer patients (CRCP) (n = 34), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 20 perioperative days, starting 5 days before surgery. Tumor samples were subjected to whole genome mRNA profiling and transcriptional control pathways analyses. Recurrence-free survival (RFS) is currently monitored. Drugs were well tolerated. Whole genome mRNA profiling indicated that drug treatment significantly reduced (i) markers of epithelial-to-mesenchymal- transition (EMT), (ii) tumor infiltrating CD14 + monocytes, and (iii) tumor infiltrating CD19 + B-cells, which are associated with tumor progression and metastatic disease in CRCP. Drug treatment increased tumor infiltrating CD56 + NK-cells, potentially improving anti-metastatic immunity, as the majority of colorectal tumors are susceptible to NK cytotoxicity. Lastly, drug treatment reduced the indicated activity of several pro-metastatic transcription factors (GATA1/GATA2, IRF1/ISRE, OCT1, c-MYB, HSF1, CREB), but increased the potentially tumor-promoting STAT1 activity. Two-year recurrence rates are 7% (1/15 patients) in the drug-treated group and 27% (5/19 patients) in the placebo group (p=0.35 – underpowered study for this index). Overall, CRCP undergoing curative surgery may benefit from the combined drug treatment through reduction of stress-mediated pro-metastatic pathways in the primary tumor and potentially residual disease. Long-term cancer outcomes should be studied to test clinical ramifications.

Can preoperative CEA and CA19-9 serum concentrations suggest metastatic disease in colorectal cancer patients?

This study was designed to investigate the efficiency of preoperative serum carcinoembryonic antigen (CEA) and carbohydrate cancer antigen (CA19-9) levels for diagnosing synchronous liver metastases and lymph node in colorectal carcinoma (CRC) patients. A total of 300 patients with histologically diagnosed CRC were included in this study between May 2014 and March 2015. The data were obtained prospectively from patient's medical records: medical history, demographics, tumor location, differentiation (grade), depth of the tumor (T), lymph node metastases (N), distant metastases (M), lymphatics, venous and perineural invasion, and disease stage. Tumor markers were measured with an electrochemiluminescent assay and the reference value was 5ng/ml for CEA and for Ca19-9, 37u/ml. There was A high statistically significant difference in the levels of serum CEA and CA19-9 between different disease stages of CRC (P<0.001). Regarding different T stages of CRC, We noticed a significant statistical difference in CEA (stage I 3.76±8.73; II 5.68±17.27, III 7.56±14.81, and IV 70.90±253.23) and CA 19-9 levels (stage I 9.65±11.03, II 9.83±11.09; III 19.58±36.91, and IV 228.9±985.38, respectively). The mean CEA and CA19-9 serum levels were significantly higher in patients with regional lymph nodes involvement (CEA 37.21±177.85 vs 4.79±9.90, CA19-9 119.51±687.71 VS 12.24±17.69, respectively, P<0.05) and in liver metastases (CEA 86.56±277.65 vs. 5.98±12.98, and CA19-9 273.27±1073.46 vs. 4.98±3142, respectively, with P<0.001) in comparison to patients without lymph node involvement and liver metastases. We noticed a cut-off value for lymph nodes involvement, for CEA and CA 19-9, 3.5 ng/mL and 7.5 U/mL, respectively. While, a cut-off value for the presence of synchronous liver metastases of these two markers was 3.5ng/mL AND 5.5 U/mL. Our study showed that tumor makers, CEA and CA19-9, can be used as diagnostic factors regarding the severity of CRC specifically to suggest metastatic disease in CRC.

HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer.

Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.

Cell-free nucleic acids as noninvasive biomarkers for colorectal cancer detection.

Cell-free nucleic acids (CFNA) have been reported by several authors in blood, stool, and urine of patients with colorectal cancer (CRC). These genetic biomarkers can be an indication of neoplastic colorectal epithelial cells, and can thus potentially be used as noninvasive tests for the detection of the disease in CRC patients and monitor their staging, without the need to use heavier and invasive tools. In a number of test-trials, these genetic tests have shown the advantage of non-invasiveness, making them well accepted by most of the patients, without major side effects. They have also shown a promising sensitivity and specificity in the detection of malignant and premalignant neoplasms. Moreover, costs for performing such tests are very low. Several studies reported and confirmed the proof of the principle for these genetic tests for screening, diagnosis, and prognosis; the main challenge of translating this approach from research to clinical laboratory is the validation from large and long-term randomized trials to prove sustainable high sensitivity and specificity. In this paper, we present a review on the noninvasive genetics biomarkers for CRC detection described in the literature and the challenges that can be encountered for validation processes.

Targeted Chemoradiation in Metastatic Colorectal Cancer: A Phase I Trial of 131I-huA33 with Concurrent Capecitabine

huA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and more than 95% of human colon cancers but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 wk but eliminated from normal colonocytes within days. This phase I study used radiolabeled huA33 in combination with capecitabine to target chemoradiation to metastatic colorectal cancer. The primary objective was safety and tolerability of the combination of capecitabine and (131)I-huA33. Pharmacokinetics, biodistribution, immunogenicity, and tumor response were also assessed. Eligibility included measurable metastatic colorectal cancer, adequate hematologic and biochemical function, and informed consent. An outpatient scout (131)I-huA33 dose was followed by a single-therapy infusion 1 wk later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the 12-wk trial. Tumor targeting was assessed using a γ camera and SPECT imaging. Nineteen eligible patients were enrolled. The most frequently observed toxicity included myelosuppression, gastrointestinal symptoms, and asymptomatic hyperbilirubinemia. Biodistribution analysis demonstrated excellent tumor targeting of the known tumor sites, expected transient bowel uptake, but no other normal tissue uptake. (131)I-huA33 demonstrated a mean terminal half-life and serum clearance suited to radioimmunotherapy (T1/2β, 100.24 ± 20.92 h, and clearance, 36.72 ± 8.01 mL/h). The mean total tumor dose was 13.8 ± 7.6 Gy (range, 5.1-26.9 Gy). One patient had a partial response, and 10 patients had stable disease. (131)I-huA33 achieves specific targeting of radiotherapy to colorectal cancer metastases and can be safely combined with chemotherapy, providing an opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients.

Angiogenesis Inhibitor Bevacizumab Increases the Risk of Ischemic Heart Disease Associated with Chemotherapy: A Meta-Analysis

Concerns have arisen regarding the risk of ischemic heart disease with the novel antiangiogenic agent bevacizumab, a recombinant humanised monoclonal antibody to the vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in ischemic heart disease is controversial. This meta-analysis was therefore performed to assess the overall risk of ischemic heart disease associated with the use of bevacizumab. The databases of PubMed, EMBASE and Web of Science were searched for English language studies of randomised controlled trials comparing bevacizumab with control therapy published through October 25, 2012. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 4,617 patients from 7 randomised controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%–1.4%). Patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with an RR of 2.49 (95% CI, 1.37–4.52) compared with controls. In addition, both high doses and low doses of bevacizumab increased the risk of cardiac ischemia (low dose at 2.5 mg/kg per week: RR, 2.14 [95% CI, 1.09–4.19]; high dose at 5 mg/kg per week: RR, 4.81 [95% CI, 1.03–22.42]). Bevacizumab was also found to significantly increase the risk of cardiac ischemia in patients with colorectal cancer (RR, 2.13; 95% CI, 1.11–4.06) compared with controls. This meta-analysis shows the use of bevacizumab was associated with an increased risk of developing ischemic heart disease in colorectal cancer patients receiving this drug. Our conclusions are limited by the available data. Further evaluations of high-quality RCTs are needed.

MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients

Background:Upregulation of the matrix metalloproteinases MMP-2 and MMP-9 in various cancers has been associated with worse survival of the patients.Methods:We assessed MMP-2 and MMP-9 levels in normal colorectal mucosa from colorectal cancer patients in relation to the course of the disease.Results:A high protein expression of MMP-2 as well as MMP-9 in normal mucosa was found to be correlated with worse 5-year survival. The combination of both parameters was an even stronger prognostic factor. These protein levels were found not to be related to the corresponding single nucleotide polymorphisms of MMP-2 (−1306C>T) and MMP-9 (−1562C>T). Multivariate analyses indicated that the MMP-2 and MMP-9 levels in normal mucosa are prognostic for survival, independent of TNM classification.Conclusion:MMP-2 and MMP-9 levels in normal mucosa are indicative of the course of disease in colorectal cancer patients.

What is the most accurate whole-body imaging modality for assessment of local and distant recurrent disease in colorectal cancer? A meta-analysis

PurposeThe objective of this study was to compare the diagnostic performance of positron emission tomography (PET), PET/CT, CT and MRI as whole-body imaging modalities for the detection of local and/or distant recurrent disease in colorectal cancer (CRC) patients who have a (high) suspicion of recurrent disease, based on clinical findings or rise in carcinoembryonic antigen (CEA).MethodsA meta-analysis was undertaken. PubMed and Embase were searched for studies on the accuracy of whole-body imaging for patients with suspected local and/or distant recurrence of their CRC. Additionally, studies had to have included at least 20 patients with CRC and 2 × 2 contingency tables had to be provided or derivable. Articles evaluating only local recurrence or liver metastasis were excluded. Summary receiver-operating characteristic (ROC) curves were constructed from the data on sensitivity and specificity of individual studies and pooled estimates of diagnostic odds ratios (DORs) and areas under the ROC curve (AUCs) were calculated. To test for heterogeneity the Cochran Q test was used.ResultsFourteen observational studies were included which evaluated PET, PET/CT, CT and/or MRI. Study results were available in 12 studies for PET, in 5 studies for CT, in 5 studies for PET/CT and in 1 study for MRI. AUCs for PET, PET/CT and CT were 0.94 (0.90–0.97), 0.94 (0.87–0.98) and 0.83 (0.72–0.90), respectively. In patient based analyses PET/CT had a higher diagnostic performance than PET with an AUC of 0.95 (0.89–0.97) for PET/CT vs 0.92 (0.86–0.96) for PET.ConclusionBoth whole-body PET and PET/CT are very accurate for the detection of local and/or distant recurrent disease in CRC patients with a (high) suspicion of recurrent disease. CT has the lowest diagnostic performance. This difference is probably mainly due to the lower accuracy of CT for detection of extrahepatic metastases (including local recurrence). For clinical practice PET/CT might be the modality of choice when evaluating patients with a (high) suspicion of recurrent disease, because of its best performance in patient based analyses and confident prediction of disease status.

Cytomegalovirus colitis after systemic chemotherapy in a patient with recurrent colon cancer: A case report

IntroductionThe occurrence of cytomegalovirus colitis is well known in immunosuppressed patients, such as neoplastic patients following chemotherapy, although its exact etiology remains unclear.Case presentationWe present a case of cytomegalovirus colitis occurring in a 77-year-old man with vomiting and diarrhea 2 weeks after initial systemic chemotherapy consisting of 5-fluorouracil, leucovorin and irinotecan for a recurrent colorectal cancer. Initial colonoscopy revealed multiple punched-out ulcers in the transverse colon and the diagnosis of cytomegalovirus was based on positive cytomegalovirus antigen detected by indirect enzyme antibody method, although immunohistological examination of tissues biopsied at colonoscopy was negative. The symptoms ceased under ganciclovir and octreotide treatment, and the patient recovered gradually.ConclusionThe most probable cause of the cytomegalovirus colitis in this case was impaired immunity following chemotherapy. Cytomegalovirus infection should be included in the differential diagnosis of gastrointestinal disease in colorectal cancer patients after chemotherapy and, when suspected, the clinician should pursue appropriate diagnostic interventions including colonoscopy.

Targeted chemoradiation for metastatic colorectal cancer: A phase I trial of oral capecitabine combined with 131I- huA33

4078 Background: HuA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and &gt;95% of human colon cancers, but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 weeks, but eliminated from normal colonocytes within days. This phase 1 study used radio-labeled huA33 in combination with capecitabine chemotherapy to target chemoradiation to metastatic colorectal cancer. Methods: The primary objective was safety and tolerability of the combination of capecitabine and 131I-huA33. Pharmacokinetics, biodistribution, immunogenicity, and tumor response were also assessed. Eligibility included measurable metastatic colorectal cancer, adequate hematological and biochemical function, and informed consent. An outpatient scout 131I-huA33 dose was followed by a single therapy infusion one week later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the12 week trial. Tumor targeting was assessed using gamma camera and single photon emission computerized tomography (SPECT) imaging. Results: 16 patients have enrolled with 2 currently on treatment, including one in the final dose cohort. Accrual will be completed by March 2007. The dose escalation protocol was amended following 2 dose limiting toxicities in the second cohort, but subsequent cohorts demonstrated good tolerability. Biodistribution analysis demonstrated excellent tumor targeting of the known tumor sites, expected transient bowel uptake, but no other normal tissue uptake. Maximal duration of stable disease is currently 3 years. Conclusions: 131I-huA33 achieves specific targeting of radiotherapy to sites of metastasis and can be safely combined with chemotherapy. This provides an opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients. [Table: see text] No significant financial relationships to disclose.

Preoperative Serum Vascular Endothelial Growth Factor Is Not a Marker for Subsequent Recurrence During Long-Term Follow-Up of Colorectal Cancer Patients

Serum vascular endothelial growth factor has been associated with stage of disease in colorectal cancer patients. We investigated whether preoperative serum vascular endothelial growth factor can provide any relevant clinical prognostic information during long-term follow-up of colorectal cancer patients. Preoperative serum samples of 79 colorectal cancer patients and serum of 28 healthy controls were stored at -80 degrees C until later vascular endothelial growth factor analysis by enzyme-linked immunosorbent assay technique and carcinoembryogenic antigen concentration measurement were performed. There were three patient groups for comparison: 21 patients with overt liver metastases, 18 patients who developed recurrent disease after initial curative surgery, and 40 patients who remained disease-free for at least five years. We could not demonstrate any significant difference in serum vascular endothelial growth factor values between the patient groups and controls, nor between the three patient groups (Mann-Whitney U test). There was no relevant correlation between serum vascular endothelial growth factor and carcinoembryogenic antigen concentrations (Pearson r = 0.2; P = 0.07). Although vascular endothelial growth factor has been shown in previous studies to be a potent inducer of angiogenesis and metastases formation, the present data demonstrate that preoperative serum vascular endothelial growth factor concentration does not provide any relevant individual prognostic information in patients with colorectal cancer.

Thymidylate synthase (TS) gene polymorphisms affect disease free- (DFS) and overall (OS) survival of colorectal cancer (CRC) patients treated with adjuvant 5-fluorouracil-folinic acid (FUFA)

3581 Background: TS, the target enzym of 5-FU has a 28 bp polymorphism in the promoter region containing commonly double of triple tandem repeats of a 28 bp sequence (2R or 3R), and a 6bp ins/del polymorphism on the 3'UTR. Our aim was to study the influence of these TS polymorphisms on tumor response to adjuvant FUFA therapy in CRC patients. Methods: : 89 CRC patients receiving adjuvant FUFA were involved in the study. FUFA was given as bolus (Mayo regimen) or continuous infusion (de Gramont protocoll). TS polymorphisms were determined by PCR PAGE and RFLP method. Results: DFS was significantly longer (p=0,036 logrank test) in patients with +6/+6,+6/-6 genotypes than in –6/-6 genotype.OS was significantly longer (p=0,025) in 3/3 genotype than in 2/3and 2/2 genotype. In rectal cancer +/+ and +/- 3'UTR patients had longer OS than -/- patients (p=0,007).No significant correlation between gene polymorphisms, age, gender, and localization were found. Conclusions: Both TS polymorphisms studied do affect the clinical outcome of the disease in CRC patients treated with adjuvant FUFA chemotherapy. Supported by the NKFP1/48/2001 grant. No significant financial relationships to disclose.

Results of R0 resection for colorectal liver metastases associated with extrahepatic disease.

Extrahepatic malignant disease has always been considered an absolute contraindication to hepatectomy for colorectal liver metastases. This study reports the long-term outcome and prognostic factors of patients undergoing extrahepatic disease resection simultaneously with hepatectomy for liver metastases. From January 1987 to January 2001, 75 patients underwent a complete R0 resection of extrahepatic disease simultaneously with hepatectomy for colorectal liver metastases. They were inscribed in a registry and then prospectively followed up. They represented 25% of the 294 patients who underwent an R0 hepatectomy for colorectal liver metastases during the same period. The mortality rate was 2.7%, and morbidity was 25%. After a median follow-up of 4.9 years (range, 1.7-13.4 years), the overall 3- and 5-year survival rates were 45% and 28%, respectively. By using a Cox model, there was a significant difference in survival between patients with single versus multiple sites of extrahepatic disease. Also, the presence of more than five liver metastases was a significant parameter. Extrahepatic disease in colorectal cancer patients with liver metastases should no longer be considered as a contraindication to hepatectomy. However, this intended R0 resection cannot be performed in 50% of laparotomized patients, and negative prognostic factors for surgery include the presence of multiple extrahepatic disease sites or more than five liver metastases.