APC I1307K mutations and forkhead box gene (FOXO1A): another piece of an interesting correlation.

PURPOSE: Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS). EXPERIMENTAL DESIGN: An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated. RESULTS: Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients. CONCLUSIONS: Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.

A ten markers panel provides a more accurate and complete microsatellite instability analysis in mismatch repair-deficient colorectal tumors.

UNLABELLED: Tumour microsatellite instability (MSI) is useful in identifying patients with hereditary non-polyposis colorectal cancer (HNPCC) with defective DNA mismatch repair (MMR) genes. A reference Bethesda panel has limitations resulting from the inclusion of dinucleotide markers, which are less sensitive and specific for detection of tumours with MMR deficiencies. We developed a multiplex PCR assay with additional four mononucleotide markers and one dinucleotide marker (NR-21, NR-24, BAT-40, TGF-BetaR and D18S58) for a rapid and proper classification of MSI-H, MSI-L and MSS colorectal cancers. Two tetranucleotide markers were added to identify sample mix-ups and/or contamination. RESULTS: all the 44 cases test cases were in agreement with previous classification except for three cases: one case MSI-H-Bethesda unstable only for dinucleotides markers shifted to MSI-L category and two cases MSI-L-Bethesda unstable for mononucleotide markers shifted to MSI-H category. Immunohistochemistry analysis revealed that these two MSI-H cases did not expressed hMLH1 and they were found to be methylated at the MLH1 promoter, while the first one that shifted to MSI-L showed MMR protein expression. CONCLUSION: a complete panel of ten markers including four dinucleotide and six mononucleotide microsatellites allows accurate evaluation of tumor MSI status.

Hepatic arterial infusion for unresectable colorectal liver metastases combined or not with systemic chemotherapy.

BACKGROUND: The hypothesis was tested that systemic chemotherapy might contribute to improving overall survival (OS) of patients with unresectable colorectal liver metastases treated with hepatic arterial infusion (HAI). PATIENTS AND METHODS: We considered 153 consecutive patients retrospectively divided into group A (n=72) treated with HAI alone (floxuridine [FUDR] + leucovorin [LV]), and group B (n=81) treated with HAI combined with systemic chemotherapy (5-fluorouracil [5FU] + LV). RESULTS: No significant difference in OS was observed between the two groups. Median OS was better in patients with <50% of liver involvement (21.3 vs. 13.2 months; p<0.0001) and in responders vs. non-responders (24.4 vs. 13.4 months; p<0.0001). The combination of low tumor load with good tumor response to HAI was the only variable retained on multivariate survival analysis, associated with a better clinical outcome (median OS: 34.2 months). CONCLUSION: Our study does not support the use of FUDR-based HAI combined or not with 5FU-based systemic chemotherapy as the first-line therapeutic approach to unresectable colorectal cancer liver metastases. The identification of responsive patients would improve the therapeutic index of this HAI regimen.

Multiplexed cell signaling analysis of metastatic and nonmetastatic colorectal cancer reveals COX2-EGFR signaling activation as a potential prognostic pathway biomarker.

The identification of prognostic determinants of colorectal cancer (CRC), including prediction of occult metastasis, is of urgent consideration, based on the tremendous differences in outcome and survival between patients who present with metastasis or develop metastasis versus those patients with organ-confined or nonrecurrent disease. Currently, a great deal of attention has been focused on using gene expression profiles of tumor specimens as a launch point for prognostic biomarker discovery. In our study, we chose to focus on functional protein-based pathway biomarkers as a new information archive because it is these proteins that form the functional signaling networks that control cell growth, motility, apoptosis, survival, and differentiation. We used reverse-phase protein microarray analysis of laser capture microdissected CRC tumor specimens to profile broad cell signaling pathways from patients who presented with liver metastasis versus patients who remained recurrence free after follow-up. Our results indicate that members of the EGFR and COX2 signaling pathways appear differentially activated in the primary tumors of patients with synchronous metastatic disease. If validated in larger study sets, this pathway defect might be useful as a prognostic clinical tool as well as a guide to potential therapeutic intervention strategies that target occult disease and/or preventative measure.

Multiplexed Cell Signaling Analysis of Metastatic and Nonmetastatic Colorectal Cancer Reveals COX2-EGFR Signaling Activation as a Potential Prognostic Pathway Biomarker.

The identification of prognostic determinants of colorectal cancer (CRC), including prediction of occult metastasis, is of urgent consideration, based on the tremendous differences in outcome and survival between patients who present with metastasis or develop metastasis versus those patients with organ-confined or nonrecurrent disease. Currently, a great deal of attention has been focused on using gene expression profiles of tumor specimens as a launch point for prognostic biomarker discovery. In our study, we chose to focus on functional protein-based pathway biomarkers as a new information archive because it is these proteins that form the functional signaling networks that control cell growth, motility, apoptosis, survival, and differentiation. We used reverse-phase protein microarray analysis of laser capture microdissected CRC tumor specimens to profile broad cell signaling pathways from patients who presented with liver metastasis versus patients who remained recurrence free after follow-up. Our results indicate that members of the EGFR and COX2 signaling pathways appear differentially activated in the primary tumors of patients with synchronous metastatic disease. If validated in larger study sets, this pathway defect might be useful as a prognostic clinical tool as well as a guide to potential therapeutic intervention strategies that target occult disease and/or preventative measure.

Glutathione S-transferase P1 Ile105Val polymorphism is associated with haematological toxicity in elderly rectal cancer patients receiving preoperative chemoradiotherapy.

BACKGROUND: Increasing evidence suggests that common gene polymorphisms may influence the toxicity of various cytotoxic agents used in the treatment of cancer. OBJECTIVE: To evaluate the predictive value of acute toxicity of methylenetetrahydrofolate reductase 677T polymorphism, glutathione S-transferase P1 (GSTP1) substitution of isoleucine with valine at codon 105 (Ile105Val) polymorphism and the tandem repeat polymorphism in the thymidylate synthase gene promoter in elderly patients with rectal cancer receiving preoperative chemoradiotherapy (CRT). METHOD: From 1994 to 2002, 166 Caucasian patients underwent surgery following CRT for mid-low rectal cancer at a single institution, 42 (male-to-female ratio, 25 : 17) of whom were aged > or =65 years (median age 70 years, range 65-79). The pre-treatment clinical stage was tumour (T) stage 3-4 in 38 patients and node (N)-positive in 29 patients. Patients received external-beam radiotherapy with conventional fractionation and fluorouracil-based chemotherapy. Blood samples were used to extract and amplify DNA. Gene polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. Acute toxicity to preoperative therapy was reported according to the National Cancer Institute Common Toxicity Criteria, version 2. Univariate and multivariate analyses were performed using one-way analysis of variance and linear regression, respectively. RESULTS: Haematological toxicity (grade 1-2) was observed in 15 of 40 patients for whom toxicity data were available and gastrointestinal toxicity (grade 1-4) in 24 of these same 40 patients. At univariate analysis, female sex (p = 0.036) and GSTP1 Ile105Val (p = 0.0376) were associated with haematological toxicity. At multivariate analysis, GSTP1 Ile105Val polymorphism (p = 0.041) was the only factor found to be associated with haematological toxicity. Patients carrying the Val/Val genotype in the GSTP1 gene had a lower risk of haematological toxicity (odds ratio = 0.322, 95% CI 0.101, 0.957) than patients with the Ile/Ile genotype. CONCLUSION: GSTP1 Ile105Val polymorphism is a promising marker of potential haematological toxicity in elderly patients with rectal cancer receiving preoperative CRT.

Recent advances in conventional and molecular prognostic factors for gastric carcinoma.

Despite radical surgery, the prognosis of patients who have gastric carcinoma remains unsatisfactory because of the intrinsic but unpredictable aggressiveness of this malignancy. During the past decade an ever-growing list of molecular prognostic factors has been proposed based on the discovery of the mechanisms underlying gastric cancer aggressiveness. Studies performed in larger and more homogeneous series of patients and adequate statistical analysis are warranted before any of the candidate biomarkers can be implemented in the routine clinical setting for the identification of patients at higher risk and thus for the selection of candidates for adjuvant or more aggressive therapies.

The role of MYH gene in genetic predisposition to colorectal cancer: another piece of the puzzle.

Biallelic germline mutations in the MYH gene cause MYH-Associated Polyposis but patients with a single mutation possibly have an increased colorectal cancer (CRC) risk. Using DNA from consecutive CRC patients we carried out a case-control study, with the aim to contribute data on the Italian population. Genotyping of four MYH mutations found two biallelic and two monoallelic carriers among 439 cases, and only one heterozygous individual among 247 age-matched controls. The frequencies of the mutant alleles were 0.68% (6/878) and 0.20% (1/494), respectively. These differences were not statistically significant. Results on the monoallelic carriers were combined with those from 11 studies on other populations, and the risk of developing a CRC was estimated with an OR=1.11 (95% CI=0.90; 1.36), yet not reaching a significant evidence of increased CRC risk.

TNF-based isolated limb perfusion followed by consolidation biotherapy with systemic low-dose interferon alpha 2b in patients with in-transit melanoma metastases: a pilot trial.

BACKGROUND: Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon alpha-2b (LDI) might consolidate the therapeutic effect of ILP. METHODS: A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B). RESULTS: In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP. CONCLUSIONS: These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP.

Factors predictive of nonsentinel lymph node involvement and clinical outcome in melanoma patients with metastatic sentinel lymph node.

BACKGROUND: Identification of melanoma patients who need completion lymphadenectomy and adjuvant treatment after positive sentinel lymph node (SLN) biopsy would be a fundamental step forward toward personalized medicine. This study tested the hypothesis that the microscopic features of metastatic SLNs might predict not only nonsentinel lymph node (NSLN) status, but also patients' clinical outcomes. METHODS: A retrospective analysis was performed on 96 consecutive melanoma patients who underwent completion lymphadenectomy after positive SLN biopsy. Patients' age and sex, primary tumor Breslow thickness, number of positive SLNs, the largest diameter and depth of invasion of metastatic deposits in the SLN, S stage, and pattern of nodal involvement were correlated with the presence of metastatic disease in NSLNs as well as with the likelihood of tumor recurrence and patient death. RESULTS: At pathological examination, 20 patients (20.8%) had metastatic melanoma in the NSLN. Pattern of nodal involvement, depth of invasion of SLN by metastatic disease, and S stage were statistically significantly associated with the presence of metastatic disease in NSLN. Multivariate analysis revealed that only the SLN depth of invasion was an independent predictor of NSLN status (P = .0035). This parameter was also significantly associated with disease-free and overall survival, both by univariate (P < .0001 and P = .0006, respectively) and multivariate (P < .0001 and P = .0013, respectively) survival analysis. CONCLUSIONS: These findings support further investigation of SLN depth of invasion as a predictive factor of potential clinical use to select patients as candidates for completion lymphadenectomy and adjuvant treatment.

Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era?

PURPOSE: The treatment of unresectable liver-confined metastatic disease from colorectal cancer (CRC) is a challenging issue. Although locoregional treatments such as hepatic arterial infusion (HAI) claim the advantage of delivering higher doses of anticancer agents directly into the affected organ, the benefit in terms of overall survival (OS) is unclear. We quantitatively summarized the results of randomized controlled trials (RCT) comparing HAI with systemic chemotherapy (SCT). METHODS: To date, 10 RCTs have been published, for a total of 1,277 patients enrolled. For tumor response rates, relative risks (RR) and their 95% CIs were obtained from raw data; for OS, hazard ratios (HRs) and their 95% CIs were extrapolated from the Kaplan-Meier survival curves. RESULTS: HAI regimens were based on floxuridine (FUDR) in nine of 10 RCTs, whereas in one RCT, fluorouracil (FU) + leucovorin was used. SCT consisted of FUDR, FU, FU + leucovorin, or a miscellany of FU and best supportive care in three, one, four, and two studies, respectively. Pooling the data, tumor response rate was 42.9% and 18.4% for HAI and SCT, respectively (RR = 2.26; 95% CI, 1.80 to 2.84; P < .0001). Mean weighted median OS times were 15.9 and 12.4 months for HAI and SCT, respectively; the meta-risk of death was not statistically different between the two study groups (HR = 0.90; 95% CI, 0.76 to 1.07; P = .24). CONCLUSION: Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.

Preoperative assessment of elderly cancer patients.

The incidence of most types of cancers is age-dependent and progressive ageing is rapidly increasing the number of elderly people who need treatment for cancer. It is an ethical dilemma how aggressive one should be when it comes to treating cancer in the older population. Presumed fear of increased postoperative morbidity and mortality often results in delivery of sub-optimal cancer surgery. A careful evaluation of the general and organ-related conditions of the patients is absolutely necessary for planning the right treatment. Nevertheless, preoperative removal of risk factors and postoperative rehabilitation are as important as the use of the best techniques of anaesthesia and surgery to achieve good postoperative outcomes in these patients. In this review article we take into consideration physiology of the aged and tools available to assess surgical risks in elderly patients, in the aim of increasing awareness on optimising surgical management of elderly patients with cancer. MEDLINE and EMBASE.com (search terms: "elderly", "preoperative", "surgery"), bibliographies of articles retrieved and the authors' reference files have been used as data sources. Independent extraction has been performed by the authors using predefined criteria, including study quality indicators.

Determining therapeutic approaches in the elderly with rectal cancer.

BACKGROUND: To evaluate the toxicity and feasibility of pelvic radiotherapy (RT) and/or surgery in elderly patients with locally advanced low-lying rectal cancer. PATIENTS AND METHODS: From November 1999 to November 2005, 51 patients aged >or=70 years who underwent RT for locally advanced low-lying rectal cancer were retrospectively examined. Variables considered were age, co-morbidities (evaluated according to the Charlson score and the Cumulative Illness Rating Scale-Geriatric [CIRS-G] score) and surgery versus no surgery. RESULTS: The median age was 80 years (range 70-94 years) and the male : female ratio was 33 : 18. A total of 5.9% of patients were considered 'fit', 72.5% had one or more CIRS-G grade 1 or 2 co-morbidities and 21.6% had one or more CIRS-G grade 3 co-morbidities. 54.9% of patients underwent surgery and 45.1% underwent RT. Only 9 of 21 (42.8%) patients who underwent radical resection received the full course of adjuvant RT and only seven (50%) of all patients treated with RT alone received the full dose of therapy. Patients with one or more CIRS-G grade 3 co-morbidities reported similar numbers of grade 1-2 toxicities as patients with one or more CIRS-G grade 2 co-morbidities. CONCLUSION: Notwithstanding the small number of patients analysed, the findings of this study indicate that elderly patients with rectal cancer and mild co-morbidities could probably receive the same treatment as fit elderly patients, given that tolerability appeared to be similar in both categories of patients. Neither age nor co-morbidities should be considered reasons to deny the patient the possible benefits of receiving complete treatment. Moreover, Multidimensional Geriatric Assessment should always be undertaken to help clinicians make better decisions about treatment. Further prospective trials are needed to confirm these results.

Serum proteomic analysis identifies a highly sensitive and specific discriminatory pattern in stage 1 breast cancer.

BACKGROUND: Mass spectrometry (MS)-based profiling was used to determine whether ion fingerprints could distinguish women with stage 1 breast cancer from women without breast cancer. METHODS: The initial study population consisted of 310 subjects: 155 women with yearly negative breast examination and negative mammography findings for at least 4 years, and 155 women undergoing surgery for pathology-proven stage 1 invasive ductal carcinoma. High-resolution SELDI-TOF (surface-enhanced laser desorption ionization-time of flight) analysis was performed on serum obtained from blood samples collected before mammography in controls, and before surgery in patients with breast cancer. Samples were divided into a training (109 controls and 109 cancers) and blinded (46 controls and 46 cancers) testing set; each group had similar age demographics. In addition, an independent study set of 46 serum samples was analyzed 14 months after the initial study to validate the robustness of the classifier. RESULTS: A discriminatory profile consisting of seven ion peaks found in the training set, when applied to the blinded test set, achieved a sensitivity and specificity of 95.6% and 86.5%, respectively. This same seven-peak profile achieved a 96.5% sensitivity and 85.7% specificity, with correct identification of all of 17 T1a tumors when applied to the validation study set. CONCLUSIONS: Mass spectrometry profiling of human serum generated a robust classifier composed of seven low-molecular-weight ions that yielded a highly sensitive and specific diagnostic procedure for the discrimination of women with stage 1 breast cancer compared with women without breast cancer in this research study set.

Tumor immunology.

Advances in tumor immunology are supporting the clinical implementation of several immunological approaches to cancer in the clinical setting. However, the alternate success of current immunotherapeutic regimens underscores the fact that the molecular mechanisms underlying immune-mediated tumor rejection are still poorly understood. Given the complexity of the immune system network and the multidimensionality of tumor/host interactions, the comprehension of tumor immunology might greatly benefit from high-throughput microarray analysis, which can portrait the molecular kinetics of immune response on a genome-wide scale, thus accelerating the discovery pace and ultimately catalyzing the development of new hypotheses in cell biology. Although in its infancy, the implementation of microarray technology in tumor immunology studies has already provided investigators with novel data and intriguing new hypotheses on the molecular cascade leading to an effective immune response against cancer. Although the general principles of microarray-based gene profiling have rapidly spread in the scientific community, the need for mastering this technique to produce meaningful data and correctly interpret the enormous output of information generated by this technology is critical and represents a tremendous challenge for investigators, as outlined in the first section of this book. In the present Chapter, we report on some of the most significant results obtained with the application of DNA microarray in this oncology field.

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease.

BACKGROUND: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. PATIENTS AND METHODS: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement

Gene expression profile of primary gastric cancer: towards the prediction of lymph node status.

BACKGROUND: The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status. METHODS: The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N-) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation. RESULTS: All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N-). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value <.05). Of these 136 genes, 5 were differentially expressed (adjusted P value <.05). After a stepwise gene selection, only three genes (Bik, aurora kinase B, eIF5A2) were retained in the logistic model, which could correctly predict lymph node status in 30 of 32 cases. CONCLUSIONS: If our findings were confirmed, the identified gene pattern might be used to tailor the extent of lymph node dissection on a single patient basis.

Multivariate analysis approach to the plasma protein profile of patients with advanced colorectal cancer.

The aim of the present study was to identify the pattern of plasma protein species of interest as markers of colorectal cancer (CRC). Using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), the plasma protein profile was determined in nine stage IV CRC patients (study group) and nine clean-colon healthy subjects (control group). Multivariate analysis methods were employed to identify distinctive disease patterns at protein spectrum. In the study and control groups, cluster analysis (CA) on the complete MALDI-MS spectra plasma protein profile showed a distinction between CRC patients and healthy subjects, thus allowing the identification of the most discriminating ionic species. Principal component analysis (PCA) and linear discriminant analysis (LDA) yielded similar grouping results. LDA with leave-one-out cross validation achieved a correct classification rate of 89% in both the patients and the healthy subjects.

A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation.

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.

5-fluorouracil and weekly oxaliplatin combined with radiotherapy for locally advanced rectal cancer: surgical complications and long-term results.

BACKGROUND: We undertook this study to evaluate early surgical complications and long-term results after preoperative radiotherapy and chemotherapy (RCT) using 5-fluorouracil (5-FU) and oxaliplatin (OXA) for rectal cancer. METHODS: Forty six TNM stage II-III rectal cancer patients were studied, who were given preoperative RT (50.4 Gy/28 fractions) combined with 5-FU (200-225 mg/m(2)/day by continuous venous infusion) and weekly OXA (25-60 mg/m(2)). Major complications and reoperations were recorded overall, whereas outcome analyses were performed only for patients who received the recommended regimen dosage. RESULTS: Forty three patients (M:F, 25:18; median age 59 years) were available for analysis. All patients received the planned RT dose. There were no postoperative deaths; seven patients had early major surgical complications, four requiring re-operation. One additional patient had a second surgical procedure due to a duodenal fistula complicating the resection of an aortic aneurysm performed concomitantly with rectal cancer surgery. At a median follow-up of 49 months, two of the 23 patients treated at the recommended doses developed recurrence (one local, and one local and distant), and two died of cancer progression. Following the Kaplan-Meier method, the estimated 5-year overall and disease-free survival rates were 92 and 89%, respectively. CONCLUSIONS: The preoperative RCT regimen used in the present study incurs a low rate of recurrence with an acceptable surgical morbidity.