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Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative risk(LSca

Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., link_to_OA_fulltext

Hyperplastic polyposis syndrome (HPS) is an uncommon disorder characterized by hyperplastic polyps (HP) occasionally associated with serrated adenomas (SA) or mixed polyps (MP) and defined by clinical criteria (OMS/Cleveland). HPS is heterogeneous regarding the number and size of polyps, and it is associated with colorectal cáncer (CRC) and a family history. Its genetic basis is unknow. We describe individuals with HPS criteria from a series of families assessed in our Unit of Genetic Advice for colonic polyposis. Our objective is to identify the clinical characteristics of this syndrome.Retrospective study of 197 families with colonic polyposis (1998-2011), identifying patients with HPS criteria. To know the number of polyps, we took into account polypectomies and/or the histologic study of surgical samples. Polyps were classified into adenomas, serrated lesiones (HP and SA) and MP. Genetic studies revealed: microsatellite instability (MSI), MUTYH gene variants (p.Tyr165Cys, p.Gly382Asp and p.Glu396GlyfsX43) and APC gene.Eighteen individuals, with a median age of 51.1 years, had criteria of HPS (11M/7F). Number of HP varied between 14 and 100 coexisting with classical adenomas, SA and MP in 14 individuals (77.8%). Localization of polyps: ascending and descending colon in 13 individuals (72.2%) and only descending colon in 5 (27.8%). A CRC was detected in 10/18 (55.6%) patients, and 3 of them had a double CRC, a family history in 3 patients (16.7%) and a history of HPS in one. IMS was not detected in 8 CRC nor in 3 adenomas studied; we detected 2/13 heterozygous mutations in the MUTYH gene (p.Gly382Asp) and one variant with an unknown biological significance in the APC gene (p.Ser926Pro).The phenotypic variability of HPS difficults its identification, hence it is important to adhere to the clinical criteria established for its classification as well as to establish screening guidelines for CRC on the basis of its high incidence.

It is known that chronic kidney disease (CKD) and senescence bring about a progressive reduction in glomerular filtration rate (GFR) and that in the former this is usually associated with an increase in the fractional excretion of calcium, phosphorus, magnesium, and uric acid. However, it has not yet been explained how these substances are excreted in the healthy oldest old. Thus, in the present study, we examined the renal handling of these substances in very aged people in comparison with CKD patients with similar GFR levels (stage III—CKD). Twenty volunteers were studied; 10 of them were healthy very old (VO) (≥75 years old) individuals and 10 were stage III CKD patients. Exclusion criteria were as follows: presence of altered (abnormally high or low) plasma calcium, phosphorus, magnesium and uric acid, as well as previous diagnoses of diabetes mellitus and obstructive uropathy and use of drugs that could alter plasma levels of the studied substances. All volunteers were on a diet with the same content of these elements (3-day dietary register). We measured calcium, phosphorus, magnesium, uric acid, creatinine in serum plasma and morning urine, as well as serum parathyroid hormone level, in each volunteer. From these data, fractional excretion (FE) of these substances was obtained. A statistical analysis was carried out using the Wilcoxon test. Serum creatinine: 1.8 ± 0.4 mg/dl (CKD) versus 0.8 ± 0.2 mg/dl (VO), p = 0.0002; serum calcium: 9.1 ± 0.3 mg/dl (CKD) versus 8.7 ± 0.4 (VO), p = 0.022; serum magnesium: 2.3 ± 0.2 mg/dl (CKD) versus 2.0 ± 0.1 (VO), p = 0.05; serum phosphorus: 3.9 ± 0.5 mg/dl (CKD) versus 3.0 ± 0.4 mg/dl (VO), p = 0.002; serum uric acid: 6.6 ± 1.5 (CKD) versus 5.2 ± 1.4 mg/dl (VO), p = 0.04; FE of calcium: 2.5 ± 1 % (CKD) versus 0.8 ± 0.3 % (VO), p = 0.04; FE of magnesium: 7.2 ± 4.1 % (CKD) versus 2.9 ± 0.9 % (VO), p = 0.02; FE of phosphorus: 25 ± 9 % (CKD) versus 9.1 ± 5.7(VO), p = 0.001; FE of uric acid: 10 ± 3 % (CKD) versus 8 ± 5 % (VO), p = 0.05. Serum levels and FE of calcium, phosphorus, magnesium and uric acid were significantly higher in CKD patients compared to healthy very old people with similar GFR, except for serum magnesium and FE of uric acid, which were similar in both groups.

Ma et al 1 comprehensively assessed the association of previously reported genetic variants with colorectal cancer (CRC) risk. The meta-analyses revealed strong evidence for association with rare MUTYH variants, even when excluding cases with MUTYH-associated polyposis. An article by Nieuwenhuis et al 2 accurately defined the phenotypical features of MUTYH-associated polyposis. However, the study was performed on clinic-based series ascertained based on the inheritance model or the presence of polyps, which may miss additional phenotypes relevant to improve the disease characterisation and therefore, its genetic diagnosis. To illustrate this, we report a family with a clinical phenotype that resembled Lynch syndrome but was caused by MUTYH mutations. To identify novel hereditary CRC genes, we studied an Amsterdam I family (hereditary non-polyposis CRC) with no mutations in the DNA mismatch repair (MMR) genes (figure 1, table 1). By exome sequencing performed on four cancer-affected (II.2, II.6, III.1 and III.6) and one cancer-free (III.5) family members, we identified a total of 11 unreported or rare heterozygous variants present in the cancer-affected individuals (see online supplementary table S1). One of them was MUTYH c.1147delC …

To describe colorectal cancer (CRC) mortality trends during 1985-2004 and to estimate CRC mortality projections for the period 2005-2019 in Spain.A Bayesian age-period-cohort analysis has been carried out to investigate the effect of the age, period, and birth cohort on CRC mortality in Spain. Mortality projections until 2019 were based on the age-period-cohort model.During 1985-1994, CRC mortality increased in both sexes (3.9% yearly in men and 1.5% in women). After 1995, CRC mortality increased in men (1.6%) and leveled off in women (-0.6%). Colon cancer mortality increased for the whole period in men, this increase being lower in the second decade (1985-1994: 5.0%; 1995-2004: 1.8%). In women, colon cancer mortality increased in the first decade (2.8%) and leveled off during the second decade (-0.1%). Rectal cancer mortality increased in men (1.2%) and decreased in women (-1.1%) during the whole study period. Projections showed an increase in the number of CRC deaths in men older than 60 years and a level off in women.Although mass screening for CRC in Spain has not been available, the favorable recent changes in CRC mortality trends observed after 1995 could be related to progress in diagnosis and treatment. The projected number of deaths could be used as reference scenario for assessing future impact of new treatments as well as the potential impact of future population-based screening when introduced.

Colorectal cancer (CRC) screening effectiveness depends on the degree of implementation and population adherence. The goals of this study were to determine the number of CRC cases diagnosed in L'Hospitalet of Llobregat (Spain) and to identify the features of those cases detected by the population-based screening programme initiated in 2000 in this city.Patients aged 50-69 year-old with a CRC diagnosis identified by cancer registries from the hospitals of L'Hospitalet were included. Patients were classified in 4 groups according to participation in the screening programme: 1, no participants; 2 diagnosed by screening; 3 participants with a negative screening result; and 4, participants with an incomplete screening process.We found 510 patients diagnosed of CRC, 88% of whom had been invited to the screening programme. The distribution by tumour stage was: 0, 50 (9.8%); I, 53 (10.4%); II, 135 (26.5%); III, 154 (30.2%); IV, 105 (20.6%); and unknown, 13 (2.5%). The number of patients in each group was: 1, 350 (78.0%); 2, 58 (12.9%); 3, 29 (6.5%); and 4, 12 (2.7%). CRC detected by screening and by clinical diagnosis differed in some characteristics: cancer of colon (89.7% vs 66.2%, P.001), symptoms (32.8% vs 84.3%, P.001) and stages (0-II 75.9% vs 42.9%, III-IV 24.1% vs 54.2%, P.001).These results show the benefit of a population-based screening programme. CRC detected by the screening programme is diagnosed in early stages and before disease symptoms appear.

Objetivo: evaluar las lesiones detectadas en las dos rondas ya finalizadas del Programa Piloto de Cribado en Cáncer Colorrectal (CCR) llevado a cabo en L'Hospitalet de Llobregat (Barcelona). Material y métodos: el programa de cribado de CCR se inició en el año 2000. La población, comprendida entre 50 y 69 años residentes en el área, fue invitada a participar a través de la determinación bienal de sangre oculta en heces mediante el test guaiaco y colonoscopia en los participantes con test positivo. Se realizó polipectomía de las lesiones detectadas o biopsias cuando no era posible la extirpación. Los pólipos se clasificaron según criterios de la Organización Mundial de la Salud. Resultados: se realizaron 442 colonoscopias de los 495 test positivos. En 213 individuos, se detectaron: 36 cánceres invasivos, 121 adenomas de alto riesgo, 29 adenomas de bajo riesgo y 27 pólipos hiperplásicos. En el 25,8% de los casos, el tamaño de los adenomas fue < 10 mm. La mayoría de las lesiones diagnosticadas (37,2%) estaban localizadas en el colon distal, el 5,7% a nivel proximal y ambas localizaciones en el 5,2%. Las neoplasias avanzadas se asociaron significativamente al sexo masculino y la localización distal. La prevalencia de neoplasias avanzadas a nivel proximal entre los pacientes sin pólipos distales fue del 5,1%. Conclusiones: los adenomas de alto riesgo de localización distal han sido las lesiones detectadas con mayor frecuencia. El cribado poblacional mediante la determinación de sangre oculta en heces es un método factible para detectar pequeñas lesiones precancerosas, factor clave para disminuir la incidencia de CCR.

The physical properties (specific gravity, moisture content, thickness swelling and water absorption) and mechanical properties (internal bond strength, bending strength and modulus of elasticity) were determined on 93 Spanish-manufactured standard particleboards of different thicknesses selected randomly at the end of the production process. The testing methods of the corresponding European standards (EN) were used, except in the case of the thickness swelling and absorption tests, for which the Spanish UNE standard was used. The thickness and the values obtained for the physical properties were entered into an artificial neural network in order to predict the mechanical properties of the board. The fit was compared with the usual multivariate regression models. The use of a neural network made it possible to obtain the values of bending strength, modulus of elasticity and internal bond strength of the boards utilizing the known data, not only of thickness, moisture content and specific gravity, but also of thickness swelling and water absorption. The neural network proposed is much better adapted to the observed values than any of the multivariate regression models obtained. Se han determinado las propiedades físicas (densidad, humedad, hinchazón en espesor y absorción de agua) y mecánicas (tracción perpendicular a las caras, resistencia a flexión y módulo de elasticidad) de 93 tableros de partículas estándar de diferentes espesores, de fabricación española, elegidos aleatoriamente a la salida del proceso de producción, utilizando los métodos de ensayo recogidos en las normas EN correspondientes, excepto en los ensayos de hinchazón y absorción que se ha utilizado norma UNE (española). El espesor y los valores obtenidos de las propiedades físicas han sido introducidos en una red neuronal artificial (RNA) para predecir las propiedades mecánicas del tablero. El ajuste se ha comparado con los habituales modelos de regresión multivariante. La utilización de una red neuronal ha permitido obtener los valores de resistencia a flexión, módulo de elasticidad y resistencia a la tracción perpendicular a las caras de los tableros de partículas a través de los datos conocidos, no sólo de espesor, humedad y densidad sino también de hinchazón en espesor y absorción de agua. La red neuronal propuesta tiene una adecuación a los valores experimentales muy superior a cualquiera de los modelos de regresión multivariante obtenidos.

To assess the impact on the medicines budget of the introduction of new treatments in colorectal cancer, as monoclonal antibodies cetuximab and bevacizumab and oxaliplatin in the adjuvant setting, for the Catalan health public system in 2006.In advanced stages of the disease, the medicines budget impact of the introduction of cetuximab and bevacizumab in relation to the standard treatment (FOLFIRI and FOLFOX regimes) was evaluated. In adjuvant treatment stage II-III, the medicines budget impact of the utilization of FOLFOX regime compared to the combination of fluorouracil and folinic acid was evaluated.The medicines budget impact of the new therapies is evaluated at 27.9 million euros and 18.3 million euros in advanced stages of the disease and the adjuvant setting, respectively. In the adjuvant setting, the impact assessed depends on the number of new cases estimated.The impact on the health budget in Catalonia will be of great magnitude, and it could be higher considering these drugs are just only an example. Health policy should take this impact into account when future costs of health care are assessed in the public sector.

Study objective: To assess the feasibility of a colorectal cancer population-based screening programme in Catalonia (Spain). Design and setting: A pilot colorectal cancer screening programme based on faecal occult blood (FOB) test was introduced in February 2000 in Hospitalet de Llobregat (Barcelona, Spain), a city of 239,000 inhabitants. Participants: All the residents from the selected area, aged 50–69 years old, were invited by mail to participate in the screening programme. Overall, 63,880 persons were invited to the first screening round and 66,534, to the second round. Colonoscopy was the first choice of procedure for the positive FOB test. Results: The participation rate was 17.2% in the first screening round and 22.3% in the second round. The overall rate of positive FOBT was 3.4% in the first round and 0.8% in the second round. In the first round, the prevalence of screen-detected cancer was 2.1 per 1000 screened people, 7.2 for high-risk adenomas (HRA) and 11.3 for neoplasm (cancer and/or adenoma). The positive predictive value (PPV) was 6.2% for cancer, 21.2% for HRA and 33.3% for advanced neoplasm. In the second round, the prevalence of screen-detected cancer was 0.9 per 1000 people screened, 2.8 per 1000 for HRA and 4.2 per 1000 for neoplasm. The PPV was 10.6% for cancer, 34.1% for HRA and 50.4% for any neoplasm. Conclusions: Regardless of the moderate participation rate, population-based colorectal cancer screening would be feasible in Catalonia, with good results in terms of prevalence of screen-detected neoplasms.

The aim of this study was to analyze the prognostic value of TP53 mutations in a consecutive series of patients with hepatic metastases (HMs) from colorectal cancer undergoing surgical resection. Ninety-one patients with liver metastases from colorectal carcinoma were included. Mutational analysis of TP53, exons 4-10, was performed by single-strand conformation polymorphism and sequencing. P53 and P21 protein immunostaining was assessed. Multivariate Cox models were adjusted for gender, number of metastasis, resection margin, presence of TP53 mutations and chemotherapy treatment. Forty-six of 91 (50.05%) metastases showed mutations in TP53, observed mainly in exons 5-8, although 14.3% (n = 13) were located in exons 9 and 10. Forty percent (n = 22) were protein-truncating mutations. TP53 status associated with multiple (or =3) metastases (65.6%, P = 0.033), advanced primary tumor Dukes' stage (P = 0.011) and younger age (57 years old, P = 0.03). Presence of mutation associated with poor prognosis in univariate (P = 0.017) and multivariate Cox model [hazard ratio (HR) = 1.80, 95% confidence interval (CI) = 1.07-3.06, P = 0.028]. Prognostic value was maintained in patients undergoing radical resection (R0 series, n = 79, P = 0.014). Mutation associated with a worse outcome in chemotherapy-treated patients (HR = 2.54, 95% CI = 1.12-5.75, P = 0.026). The combination ofor =3 metastases and TP53 mutation identified a subset of patients with very poor prognosis (P = 0.009). P53 and P21 protein immunostaining did not show correlation with survival. TP53 mutational status seems to be an important prognostic factor in patients undergoing surgical resection of colorectal cancer HMs.

Background and aims: The prognostic value of the degree of apoptosis in colorectal cancer is controversial. This study evaluates the putative clinical usefulness of measuring caspase-3 activity as a prognostic factor in colonic cancer patients receiving 5-fluoracil adjuvant chemotherapy. Materials and methods: We evaluated caspase-3-like protease activity in tumours and in normal colon tissue. Specimens were studied from 54 patients. These patients had either stage III cancer (Dukes stage C) or high-risk stage II cancer (Dukes stage B2 with invasion of adjacent organs, lymphatic or vascular infiltration or carcinoembryonic antigen [CEA]>5). Median follow-up was 73 months. Univariate analysis was performed previously to explore the relation of different variables (age, sex, preoperative CEA, tumour size, Dukes stage, vascular invasion, lymphatic invasion, caspase-3 activity in tumour and caspase-3 activity in normal mucosa) as prognostic factors of tumour recurrence after chemotherapy treatment. Subsequently, a multivariate Cox regression model was performed. Results: Median values of caspase-3 activity in tumours were more than twice those in normal mucosa (88.1 vs 40.6 U, p=0.001), showing a statistically significant correlation (r=0.34). Significant prognostic factors of recurrence in multivariate analysis were: male sex (odds ratio, OR=3.53 [1.13-10.90], p=0.02), age (OR=1.09 [1.01-1.18], p=0.03), Dukes stage (OR=1.93 [1.01-3.70]), caspase-3 activity in normal mucosa (OR=1.02 [1.01-1.04], p=0.017) and caspase-3 activity in tumour (OR=1.02 [1.01-1.03], p=0.013). Conclusion: Low caspase-3 activity in the normalmucosa and tumour are independent prognostic factors of tumour recurrence in patients receiving adjuvant 5-fluoracil-based treatment in colon cancer, correlating with poor disease-free survival and higher recurrence rate. © Springer-Verlag 2007., This work was supported by the Spanish government through project FISS 01/1260

In the article by Sanz-Pamplona and colleagues ([1][1]), functionally relevant mutations in AMER1 were identified in approximately 10% of stage II colorectal tumors, reinforcing its role as a driver gene in colorectal cancer, as occurs with APC , KRAS , or TP53 . AMER1 codifies a membrane protein

PurposeThe purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment.Patients and MethodsOne hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location.ResultsTumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/–6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed.ConclusionTumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.

Purpose: The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. Methods and Materials: Patients with resectable T3–T4 rectal cancer and Eastern Cooperative Oncology Group performance status 2 weekly) and 5-FU (225 mg/m 2 /day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. Results: A total of 74 patients were enrolled: mean age, 59 years (20–74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8–23.7) had a pathologic complete response and 49.3% (95% CI, 37.4–61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1–80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. Conclusions: This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.

The aim of this study was to determine the safety and feasibility profile of paclitaxel (PTX) and docetaxel (DTX) in combination and the pharmacokinetic and pharmacodynamic interaction between these two drugs in two different alternated sequences of administration. The starting dose was PTX (100 mg/m2) as a 3-h IV infusion followed by DTX (50 mg/m2) as 1-h IV infusion or the alternative sequence in every other patient. The sequence was alternated in the second course in each patient treated. Cycle duration was 21 days. Twenty patients received 103 cycles of treatment through three dose levels. Febrile neutropenia and grade 4 neutropenia lasting longer than 7 days were dose-limiting and defined the toxic dose of DTX (50 mg/m2) and PTX (135 mg/m2) in patients with prior treatment and the recommended dose in patients without prior treatment. Non-hematological toxicities included asthenia, neuropathy, arthralgia/myalgia and stomatitis. Pharmacokinetics of DTX were significantly affected by the sequence. Nadir ANC was more profound when DTX was administered first (P = 0.022). There were one complete response and six partial responses, giving an overall response rate of 35%. DTX (50 mg/m2) followed by PTX (135 mg/m2) can be administered safely and it is an active regimen. The pharmacokinetics of PTX are not influenced by DTX but DTX pharmacokinetics depend on the sequence of administration, which influences its haematological toxicity profile.

Objective Pre-operative treatment with chemoradiotherapy (CRT) seems to improve local control and overall survival in patients with rectal cancer. The aims of the study were to analyse the impact on overall, disease free and cancer related survival of tumour response to pre-operative CRT and to analyse the influence of the degree of response on long-terms results. Patients and methods Patients with a locally advanced rectal cancer, treated by pre-operative CRT were studied. A radical resection of the rectal tumour with mesorectal excision was performed within 6–8 weeks. Judged on the final TNM classification patients were considered responders when the tumour showed histologically a complete response, microscopic residual disease or a partial response. Non-responders were those in whom the extent of disease remained stable or progressed. Results Radical excision was performed in 103 patients, and a palliative resection in five. Forty-three patients underwent abdominoperineal resection and 65 anterior resection of the rectum. Seventy-one (65.7%) patients showed a response to CRT, while 37 (34.3%) did not. The overall local and distant recurrence rates were 6.8% and 21.3%. Tumour recurrence (P

Sporadic colorectal cancer is considered a multifactorial disease in which multiple exposures interact with the individual genetic background resulting in risk modulation. Recent experimental data suggest a role of dopamine and dopamine receptors in the control of proliferation of the cells of colon and gastrointestinal tract. To investigate whether polymorphisms within dopamine receptors genes could have a role in modulating the risk of sporadic colorectal cancer, we did a case-control association study and genotyped 370 cases and 327 controls for seven single-nucleotide polymorphisms (SNP) of DRD2 (−141Cdel, 957T>C, TaqIB, TaqIA, 1412A>G, S311C, and 3208G>T) by a microarray-based technique. Three SNPs within DRD2 were associated with colorectal cancer, with a maximum odds ratio of 2.28 (95% confidence interval, 1.38-3.76) for carriers of the functional SNP −141Cdel. The haplotype which includes −141Cdel, together with the variants 957C and 1412G, shows an odds ratio of 2.86 (95% confidence interval, 1.58-5.18), as compared with the most frequent haplotype. The SNPs within DRD2 associated with colorectal cancer are known to be related to reduced levels of D2 dopamine receptor. Thus, our data point to a possible role of dopamine receptor DRD2 in modulating the risk of colorectal cancer. Future studies on dopamine receptor–mediated signal transduction may provide new insight into the mechanisms of colorectal cancer and suggest new therapeutic strategies.

Current issues of adjuvant therapy for colon cancer concern the introduction of drugs other than fluorouracil-5/leucovorin (5-FU/LV), the benefits for stage II patients, the use of new primary endpoints and the influence of age on treatment benefits. These issues were addressed in a panel discussion and the conclusions were the following: FOLFOX4 is the first regimen that shows superiority over 5-FU/LV. The use of 3-year disease-free survival as primary endpoint could encourage the quicker adoption of improved therapeutic strategies into clinical practice. Available data suggest that there are some benefits for stage II patients, and the decision needs to be individualised for each patient. Further, therapeutic decisions based solely on the patient's age are inappropriate, and geriatric assessment tools will help in making this decision. This information would improve patient and physician understanding of the recent data regarding the potential benefits of adjuvant therapy.

Colorectal cancer is one of the most frequent causes of death in the general population. Our aim was to analyze our experience in the multidisciplinary approach of colorectal carcinoma during a three year period.Between January 1996 and December 1998, we studied prospectively 807 patients with colorectal cancer. The epidemiology, treatment and outcome(recurrence and survival) were analyzed. The minimum follow-up was 3 years.There were 598 colon (65.5%) and 279 rectal (34.5%) tumors in all the series. Surgical treatment was elective in 84% and urgent in 16%, and was considered radical in 598 cases (74.1%). Chemotherapy or radiotherapy was administered in 49.6% and 18.3% patients, respectively. The overall 3-year survival was as follows: stage I 97.5%, stage II 90.6%, stage III 75.2%, and stage IV 12.6%. The 3-year free-disease survival was as follows: in colon cancer 97.8% for stage I, 87.3% for stage II, and 71.4% for stage III; and in rectal cancer 96.8% for stage I, 85.1% for stage II, and 75.4% for stage III. During the follow-up 124 patients (20.7%) developed recurrence: local (2.8%), systemic (15.9%) or both (2%). The three-year survival in operated patients with liver metastases was 61.9%.We have observed adequate survival and recurrence rates which are the result are of systematic protocols established by a multidisciplinary team.

Background Although a significantly decreased long-term survival has been observed in patients undergoing surgery for complicated colorectal tumors compared with uncomplicated ones, the role of radical oncologic surgery on emergency colonic cancer is not defined clearly. The aim of this study was to analyze the efficacy of a curative emergency surgery in terms of tumor recurrence and cancer-related survival compared with elective colonic surgery. Methods Between January 1996 and December 1998, all patients with colonic cancer deemed to have undergone a curative resection were considered for inclusion in this prospective study. Patients were classified into 2 groups: group 1, after emergency surgery for complicated colonic cancer, and group 2, patients undergoing elective surgery. The main end points were cancer-related survival and the probability of being free from recurrence at 3 years. Results Of the 266 patients included in the study, 59 patients (22.2 % ) were in group 1 and 207 patients (77.8 % ) were in group 2. Postoperative mortality was higher in group 1 ( P = .0004). After patients were stratified by the tumor node metastasis system, differences between the groups with respect to overall survival of stage II tumors ( P = .0728), the probability of being free from recurrence ( P = .0827), and cancer-related survival ( P = .1071) of stage III cancers did not reach statistical significance. Differences were observed for the overall survival in stage III tumors ( P = .0007), and for the probability of being free from recurrence ( P = .0011) and cancer-related survival ( P = .0029) in stage II cancers. When patients with elective stage II tumors presenting 1 or more negative prognostic factor were compared with emergency patients affected by a stage II colonic cancer, no differences were observed. Conclusion Curative surgeries for complicated colonic cancer are acceptable in emergency conditions. Cancer-related survival and recurrence in patients with complicated colonic cancers may approach that of elective surgery if a surgical treatment with radical oncologic criteria is performed.

The objective of this study was to evaluate the activity and toxicity of tegafur and uracil (UFT; 1:4 molar ratio) plus leucovorin (LV) in patients with advanced colorectal cancer. One hundred forty-one patients were entered into the study. The treatment schedule consisted of UFT 300 mg/m2/day (in three divided doses) plus oral LV 150 mg/day (50 mg t.i.d.) over 28 days. The treatment cycle was repeated every 5 weeks until progression or unacceptable toxicity was observed. The treatment was interrupted if grade 3/4 toxicity appeared and was resumed at the same dosage on recovery. One hundred thirty-six patients were evaluable for response and 141 were evaluable for toxicity. The response rate was 19.9% (95% confidence interval: 12%-28%). The total number of patients without progression (objective response + stable disease) was 76 (55.9%). The median time to progression was 5.6 months, and the overall survival was 11.6 months. The toxicity profile was low, with 11% of patients experiencing grade 3/4 nausea and vomiting, while 17% had grade 3/4 diarrhea. Oral administration of UFT modulated with LV is a comfortable regimen of chemotherapy for patients with advanced colorectal cancer.

Adjuvant chemotherapy has been established since 1990 as standard treatment for patients with colon cancer stage III (Dukes' C). Chemotherapeutic schemes combining 5-fluorouracil with levamisole or leucovorin have shown significant advantage over surgery alone. Adjuvant trials are being currently implemented to investigate some relevant questions, such as which is the optimal duration of chemotherapy, as well as the possible advantage of levamisol versus leucovorin schedules, and of high-dose versus low-dose leucovorin. While these trials are ongoing, a retrospective evaluation of the toxicity associated with the different chemotherapeutic schemes might be of help when choosing the most appropriate regimen for individual patients not involved in clinical trials. A total of 519 patients subjected to three different schedules of adjuvant chemotherapy between 1993 and 1996, were evaluated for toxicity according to the NCI-CTC criteria. Chemotherapeutic regimens were: 5-fluorouracil plus levamisole (5-Fu+Lev; Moertel schedule), 5-fluorouracil plus low-dose leucovorin (5-Fu+LVLD; NCCTG schedule) and 5-fluorouracil plus high-dose leucovorin (5-Fu+LVHD; IMPACT-modified schedule). 5-Fu+LVLD is significantly more toxic than the other two regimens in terms of neutropenia, mucositis and diarrhea. delay in chemotherapy and dose reduction of 5-fluorouracil were also more frequent in the 5-Fu+LVLD group. However, the percentage of prematurely discontinued treatments was significantly higher in the 5-Fu+Lev group. Information on toxicity of adjuvant chemotherapy for colon cancer may help medical oncologists to choose the most appropriate regimen for individual patients not involved in clinical trials.

Summary Background In phase II trials, irinotecan is active in patients with advanced colorectal cancer, but the survival and clinical benefit of irinotecan compared with secondline fluorouracil by continuous infusion is not known. Methods 267 patients who had failed to respond to firstline fluorouracil, or whose disease had progressed after treatment with first-line fluorouracil were randomly allocated irinotecan 300–350 mg/m 2 infused once every 3 weeks or fluorouracil by continuous infusion. Treatment was given until disease progression, unacceptable toxic effects, or the patient refused to continue treatment. The primary endpoint was survival, while progression-free survival, response rate, symptom-free survival, adverse events, and quality of life (QoL) were secondary endpoints. Findings 133 patients were randomly allocated irinotecan and 134 were allocated fluorouracil by continuous infusion. Patients treated with irinotecan lived for significantly longer than patients on fluorouracil (p=0·035). Survival at 1 year was increased from 32% in the fluorouracil group to 45% in the irinotecan group. Median survival was 10·8 months in the irinotecan group and 8·5 months in the fluorouracil group. Median progression-free survival was longer with irinotecan (4·2 vs 2·9 months for irinotecan vs fluorouracil, respectively; p=0·030). The median pain-free survival was 10·3 months and 8·5 months (p=0·06) for irinotecan and fluorouracil, respectively. Both treatments were equally well tolerated. QoL was similar in both groups. Interpretation Compared with fluorouracil by continuous infusion second-line irinotecan significantly improved survival in patients with advanced colorectal cancer.

Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

Lynch syndrome is associated with germline mutations in DNA mismatch repair (MMR) genes. Up to 30% of DNA changes found are variants of unknown significance (VUS). Our aim was to assess the pathogenicity of eight MLH1 VUS identified in patients suspected of Lynch syndrome. All of them are novel or not previously characterized. For their classification, we followed a strategy that integrates family history, tumor pathology, and control frequency data with a variety of in silico and in vitro analyses at RNA and protein level, such as MMR assay, MLH1 and PMS2 expression, and subcellular localization. Five MLH1 VUS were classified as pathogenic: c.[248G>T(;)306G>C], c.[780C>G;788A>C], and c.791-7T>A affected mRNA processing, whereas c.218T>C (p.L73P) and c.244A>G [corrected] (p.T82A) impaired MMR activity. Two other VUS were considered likely neutral: the silent c.702G>A variant did not affect mRNA processing or stability, and c.974G>A (p.R325Q) did not influence MMR function. In contrast, variant c.25C>T (p.R9W) could not be classified, as it associated with intermediate levels of MMR activity. Comprehensive functional assessment of MLH1 variants was useful in their classification and became relevant in the diagnosis and genetic counseling of carrier families.

Introduction: The low sensitivity of the fecal occult blood tests (FOBT) based on the guaiac have made to develop new immunochemical tests with an efficiency to detect advanced neoplasia (advanced adenoma and colorectal cancer) still not well established. Aim: Determine the sensitivity and specificity of a FOBT based on the guaiac (FOBTg) with a quantitative immunochemical FOBT (FOBTi) to detect advanced neoplasia. Material and methods: Patients: all individuals with a colonoscopy programmed by any cause (screening, surveillance or symptoms) were included. Individuals with personal history of inflammatory bowel diseases or colorectal cancer were excluded. During the days previous to the exploration three high sensitivity FOBTg and two FOBTi (positive test ≥100ng/ml) were completed. The sample was calculated for demonstrating the superiority of the FOBTi of 15% of sensitivity with a final sample of 700 individuals. Results We presented the results of the first 140 individuals. The colonoscopy was performed for symptoms in 66% of cases and for screening or surveillance in 34% of cases. The colonoscopy detected 16 individuals (11%) with an advanced neoplasia (2 infiltrant carcinoma and 14 advanced adenomes). Other finds were: 20 patients with non advanced adenomes, 11 with polyps not adenomatous and 4 inflammatory colitis. The colonoscopy was normal in 88 (63%) individuals. The percentage of positive test was from 3,5% (5/140) and 16,5% (23/140) for the FOBTg and FOBTi, respectively. The sensitivity, specificity, positive predictive value and negative predictive value to detect an advanced neoplasia were 12%, 97%, 40% and 89% with the FOBTg and of 62,5%, 89%, 60,8%, 81% for the FOBTi. If considered only the first immunochemical test, the sensitivity, specificity, positive predictive value and negative predictive value were 43,7%, 92,7%, 43,7%, 92,7%, respectively. Conclusion The FOBTi is very superior to the FOBTg to detect advanced neoplasia although the high number of false positives could limit its use. The utilization of one or two FOBTi should be appraised depending on the disposable endoscopic resources.

Introduccion La baja sensibilidad de los test de sangre oculta en heces (TSOH) basados en el guayaco, ha hecho desarrollar nuevos tests inmunologicos con una eficacia para detectar neoplasia avanzada (adenoma avanzado y cancer colorrectal) todavia no bien establecida. Objetivo Determinar la sensibilidad y especificidad de un TSOH basado en el guayaco (TSOHg) de alta sensibilidad con un TSOH inmunologico cuantitativo (TSOHi) para detectar neoplasia avanzada. Material y metodos Poblacion: individuos con una colonoscopia programada por cualquier motivo (cribado, vigilancia o sintomas). Se excluyeron los individuos con enfermedad inflamatoria intestinal conocida y los pacientes con antecedentes de CCR intervenido. En los dias previos a la exploracion, se completaron 3 TSOHg (Hema-Screen) y 2 TSOHi (OC Senseor, test positivo ⩾100 ng/ml). Se calculo el tamano de la muestra para demostrar la superioridad del TSOHi de un 15% de sensibilidad, con un tamano final de 700 individuos. Resultados Se evaluan los resultados de los primeros 140 individuos. Al 66% se les realizo la colonoscopia por sintomas y al resto por riesgo familiar o personal de CCR. La colonoscopia detecto 16 individuos (11%) con una neoplasia avanzada (2 carcinomas infiltrantes y 14 adenomas avanzados). El resto de lesiones encontradas fueron: 20 individuos con adenomas no avanzados, 11 con polipos no adenomatosos y 4 colitis inflamatorias. La colonoscopia fue normal en 88 (63%) individuos. El porcentaje de tests positivos fue de 3.5% (5/140) y 16,5% (23/140) para el TSOHg y TSOHi respectivamente. La sensibilidad, especificidad, VPP y VPN para detectar neoplasia avanzada fue de 12%, 97%, 40% y 89% para el TSOHg y de 62,5%, 89%, 60,8% y 81para el TSOHi. En caso de considerar unicamente el primer test inmunologico, la sensibilidad, especificidad, VPP y VPN fue de 43,7%, 92%, 43,7% y 92,7% respectivamente. Conclusion El TSOHi es muy superior al TSOHg para detectar neoplasia avanzada, aunque el elevado numero de falsos positivos podria limitar su uso. La utilizacion de uno o dos TSOHi deberia evaluarse en funcion de los recursos endoscopicos disponibles.

15013 Background: The aim of the study was to evaluate the efficacy of preoperative treatment with weekly Oxaliplatin and Capecitabine in combination with radiation therapy (RT) in patients with lo...

LBA4013 Background: 5FU regimens have been suggested to be effective in the adjuvant setting after LMCRC. Irinotecan (IRI) combined with infused 5FU regimens showed improvement in outcome of advanc...

4007 Background: The MOSAIC study was designed to evaluate the effects of the FOLFOX4 regimen (5-FU/LV + oxaliplatin) on 3- year disease free survival (DFS) probability in patients with stage II and III colon cancer. Methods: Patients (n=2246) with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive 5-FU/LV (LV5FU2) or FOLFOX4 every 2 weeks for 12 cycles. Results: Results for the primary endpoint of the study (for the overall population, with a median follow-up [FU] of 3 years), showed a significant benefit in DFS for the FOLFOX4-treated patients (78.2% vs 72.9%; HR: 0.77, p=0.002) (André et al, NEJM, 2004). Patients were followed beyond the 3-year cut-off for DFS and overall survival (OS) updates. Final DFS, at 5 years FU, are consistent with earlier results (HR: 0.80, p = 0.003). In addition, at a median FU of 6 years, the study demonstrates a significant benefit in OS for the stage III patients. Summary of OS results (median FU 6 years) Long-term safety update shows no increase in the rate of secondary cancer (5.0% in both treatment arms). Conclusions: These results confirm the benefit of the FOLFOX4 regimen in adjuvant colon cancer patients. [Table: see text] No significant financial relationships to disclose.

3618 Background: OXA, IRI and 5FU have shown its efficacy in ACRC. The synergism of these three drugs has been shown in vitro and in vivo models. The purpose of this trial was to determine the resp...

3653 Background: Surveillance in patients (pts) with CRC remains a controversial issue except detection of antigen carcinoembryonic (CEA) and colonoscopy. Better surgery and locoregional techniques...

3703 Background: Chemotherapy (CT) improves overall survival and quality of life in advanced unresectable colorectal cancer (auCRC) and CT has better outcome when administered early. Several schedules are active in auCRC, but optimal duration remains uncertain and general practice results in administering CT until progression, toxicity or patient's decision. The purpose of this study is to identify which auCRC patients (pts) could benefit from stopping first line CT although no progressive disease has been observed without detriment in overall survival.

3501 Background: MOSAIC trial was designed to demonstrate an increase in Disease Free Survival (DFS) in stage II and III colon cancer. Methods: 2246 patients with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive LV5FU2 or FOLFOX4 every 2 weeks for 12 cycles. Results: Final results of the study have been reported for the overall population, with a median follow-up (mFUP) of 3 years (Andre et Al, NEJM, 2004). With a mFUP of 4 years (48.6 months), a 24% reduction in the relative risk of relapse was observed with the FOLFOX4 combination in the overall population (p=0.0008). For stage III patients, the probability of remaining disease free at 4 years is 61.0% in the LV5FU2 arm and 69.7% in the FOLFOX4 arm, translating into a relative risk reduction of 25% in this subset of patients For stage II patients, 4-year DFS was 81.3% in the LV5FU2 arm versus 85.1% in the FOLFOX4 arm (relative risk reduction of 20%). In the overall population, 84.3% and 82.7% patients are st...

3588 Background: Adjuvant chemotherapy treatment, mainly based in the inhibition of thymidylate synthase (TS) enzyme with 5-FU (5-fluorouracil) is offered to all Dukes C and indications for Dukes B...

4179 Background: This phase II trial was designed to determine the pathological response rate of preoperative chemo-radiotherapy. Secondary objectives were: to evaluate the toxicity profile, to determine the disease-free survival (DFS) and overall survival (OS) and the rate of conservative surgery. Methods: Patients with histologically confirmed locally advanced adenocarcinoma of the rectum, (T3 or T4 resectable tumors +/- regional lymph node metastases), no prior treatment for neoplasia, performance status (PS) 0–1, adequate bone marrow, renal and hepatic function. Treatment: CPT-11 50 mg/m2 as a 30 minutes i.v. infusion on days 1, 8, 15, 22 and 29; 5-FU 225 mg/m2/day as a continuous infusion (c.i.) on days 1–5 weekly during the period of RT. Total RT dose: 45 Gy at 1.8 Gy daily during 5 sessions per week (5 weeks treatment duration). Surgery was performed 6–8 weeks following completion of therapy. Results: To date, 74 pts have been included: 49 male, 25 female; median age 63 years (range 20–74); Median ...