Upon the completion of national road projects, their cost and time deviations are often reported. These deviations from the projected values are a result of complications in the time and cost management of such projects. Controlling the cost and time overrun of projects is important for successful implementation and efficient project management. However, few studies have attempted to measure the project cost and time management efficiency in civil engineering. Thus, this issue requires further investigation. In this study, large road projects that had poor cost and time management were selected. The chosen projects were configured as Decision Making Units (DMUs) in a Data Envelopment Analysis (DEA). DEA is a non-parametric modern mathematical tool for measuring relative managerial performance and determining efficient DMUs. A list containing the causes of cost and time deviations and the percentage deviation for each DMU was prepared. The cost and time management efficiency of the DMUs was calculated using DEA, and the resulting values were ordered according to importance. It is believed that this process will contribute to better cost and time management.

The successful application of extrusion-based 3D-printed geopolymer mortars largely depends on precursor chemistry, activator composition, mixture proportions, and fresh-state behavior, which is highly sensitive to time-dependent structural build-up. This review examines the relationships among mix design, geopolymerization chemistry, rheological properties, and printability requirements for 3D-printed geopolymer mortars. Particular emphasis is placed on the effects of precursor type, alkaline activator characteristics, liquid-to-solid ratio, additives, and fibers on flowability, yield stress, viscosity, extrudability, buildability, shape retention, and interlayer bonding. The review further discusses how geopolymerization kinetics influence the evolution of fresh-state properties, the printable time window, and the transition from extrusion to structural stability. In addition, early-age performance is evaluated in terms of setting behavior, green strength development, and layer-interface integrity. Current challenges, including the lack of standardized test methods, limited comparability among published studies, and the complex coupling between material design and process parameters, are also highlighted. Finally, the review identifies key research gaps and proposes future directions for developing robust, printable, and sustainable geopolymer mortar systems for additive manufacturing in construction.

Squamous cell carcinomas have a range of histopathological manifestations. The parameters that determine this clinically observed heterogeneity are not fully understood. Here, we report the generation of a cell culture model that reflects part of this heterogeneity. We have used the catalytic subunit of human telomerase hTERT and large T to immortalize primary UV-unexposed keratinocytes. Then, mutant HRAS G12V has been introduced to transform these immortal keratinocytes. When injected into immunosuppressed mice, transformed cells grew as xenografts with distinct histopathological characteristics. We observed three major tissue architectures: solid, sarcomatoid and cystic growth types, which were primarily composed of pleomorphic and basaloid cells but in some cases displayed focal apocrine differentiation. We demonstrate that the cells generated represent different stages of skin cancerogenesis and as such can be used to identify novel tumor-promoting alterations such as the overexpression of the PADI2 oncogene in solid-type SCC. Importantly, the cultured cells maintain the characteristics from the xenograft they were derived from while being amenable to manipulation and analysis. The availability of cell lines representing different clinical manifestations opens a new tool to study the stochastic and deterministic factors that cause case-to-case heterogeneity despite departing from the same set of oncogenes and the same genetic background.

Recently, the copper efflux transporters ATP7B and ATP7A have been implicated in the transport of and resistance to platinum drugs in breast and ovarian cancers. Because of the extensive use of oxaliplatin in colorectal cancer (CRC), we examined the expression of both transporters in tumors from CRC patients treated with oxaliplatin/5FU and sought to determine whether their expression can predict clinical outcome in these patients. ATP7B and ATP7A levels were determined by quantitative real-time PCR in 50 primary tumors of previously untreated patients with advanced colorectal adenocarcinoma who were subsequently treated with oxaliplatin/5FU. Additionally, ATP7B protein expression was assessed by immunohistochemical staining using a tissue microarray. Patients with the lowest mRNA expression levels of ATP7B had a significantly longer time to progression (TTP) (p = 0.0009) than patients with the highest levels (12.14 months vs. 6.43 months) who also had an increased risk of progression (HR = 3.56; 95% CI, 1.6-7.9; p = 0.002). Furthermore, patients with low levels of both protein and mRNA of ATP7B derived the maximum benefit from oxaliplatin/5FU with the longest TTP as compared with patients with high levels of ATP7B protein and mRNA (14.64 months vs. 4.63 months, respectively, p = 0.01) and showed a nonsignificant trend toward a lower response rate (37.5% and 75%, respectively). In conclusion, ATP7B mRNA and protein expression in colorectal tumors is associated with clinical outcome to oxaliplatin/5FU. Prospective studies are required to evaluate the role of this marker in tailoring chemotherapy.

BACKGROUND: Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome-wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population. RESULTS: A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10(-8)), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10(-11)). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235). CONCLUSIONS: Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses.

BACKGROUND To assess the putative prognostic value of K-ras mutations in nonmucinous ovarian tumors, the authors looked for K-ras point mutations at codons 12 and 13 in 144 nonmucinous ovarian tumors. METHODS A series of 144 consecutive, unselected, archival, nonmucinous ovarian tumors (35 benign, 12 borderline, and 97 malignant) were studied. K-ras mutations at codons 12 and 13 were determined by polymerase chain reaction using the restriction fragment length polymorphism method with mismatched nested primers. Extensive clinicopathologic and follow-up data on all patients were evaluated. RESULTS The overall prevalence of K-ras mutations at codons 12 and 13 was 30.5% (44/144). In benign tumors, it was 20% (7/35); in borderline tumors, 25% (3/12); and in carcinomas, 35% (34/97). The presence of K-ras point mutations did not correlate with survival. Among the benign tumors, K-ras mutations were detected in three Brenner tumors with a mucinous component. CONCLUSIONS These results indicate that K-ras mutations are not initial events in the pathogenesis of nonmucinous ovarian tumors and do not appear to be related to survival. Cancer 1998;82:1088-95. © 1998 American Cancer Society.

Idiopathic pylephlebitis and primary sclerosing peritonitis are two highly unusual entities. To our knowledge, the association of the two diseases has not been described previously. We report a 42-year-old patient with a protein S deficiency who presented with fever and chills, in whom idiopathic pylephlebitis was diagnosed. A year later, the patient was readmitted because of recurrent vomiting and weight loss. An exploratory laparotomy yielded diagnosis of sclerosing peritonitis, which resolved after surgery. The short time interval between the processes suggests that they were related to each other, and also to the protein S deficiency.

BACKGROUND: Progression from actinic keratosis (AK) to invasive squamous cell carcinoma (iSCC) of the skin is thought to occur after the development of full thickness epidermal neoplasia, as in the classic pathway of cervical cancer. Nevertheless, cutaneous iSCC may also directly arise from a proliferation of atypical basaloid cells limited mostly to the epidermal basal layer (AK I), akin to what happens in the 'differentiated pathway' of iSCC of the vulva, oral cavity and other locations. OBJECTIVE: To evaluate the prevalence of classic and differentiated pathways in the development of cutaneous iSCC. METHODS: The epidermis adjacent to and overlying iSCC, assumed to be representative of pre-existing lesions, was histologically studied in 196 skin biopsy specimens showing iSCC. RESULTS: AK I, AK II and AK III lesions overlying iSCC were present in 63.8%, 17.9% and 18.4% of cases respectively. The corresponding percentages in the epidermis adjacent to iSCC were 77.9%, 6.6% and 8.3% respectively (stage could not be assessed in 8.1% of cases). Focal epidermal ulceration overlying iSCC was seen in 32% of AK I, 28.6% of AK II and 33.3% of AK III instances. Adnexal involvement by atypical keratinocytes (proliferative AK) was present more frequently in cases with overlying AK I (39/125, 31.2%) than with AK II (8/35, 22.9%) and AKII I (5/36, 13.9%). CONCLUSION: Direct invasion from proliferating basaloid atypical keratinocytes limited to the epidermal basal layer (AK I), known as the differentiated pathway, was the most common form of progression to cutaneous iSCC in our series. On the other hand, stepwise progression from AK I to AK II and AK III (classic pathway) was seen to be operative in a substantial proportion of iSCC cases. All AK lesions, irrespective of intraepidermal neoplasia thickness, are therefore potentially invasive and tumour advance along adnexal structures might facilitate iSCC development from AK I lesions.

3750 Background: Colon cancer is the second neoplasm in men and women. Its prognostic depends on TNM staging at diagnosis. The treatment seems to improve the survival. The aim of this study is to analyze our series of surgical colon cancer from 1996 to 2001. Methods: We analyzed 422 surgical colon cancer. 70 patients were metastatic at the time of diagnosis or behind surgery (5 months). The remainder 352 patients without metastases were analyzed. The prognosis factors were: age at diagnosis, gender, locations in the large bowel, kind of surgery, pT, pN, stage, use of chemotherapy, disease free survival (DFS) and overall survival (OS). Results: The 352 non metastatic surgical colon cancer presented a mean age at diagnosis of 70,22 years (24 to 101). The ratio male/female was 197/155. The location in the bowel was: right 149 cases and left 203 cases. pT: pTis 6, pT114, pT2 43, pT3 244, pT4 41. pN: pN0 + pNX 229, pN1 70, pN2 52. 145 patients received adjuvant chemotherapy. Stage: I:49; II:171; III:122.pT: DFS was pT1=100%, pT2=93%, pT3=73%, pT4=51,2%. OS was pT1=71,4%, pT2=83,7%, pT3=66%, pT4=48,8%.pN: DFS was pN0=83,4%, pN1=64,3%,pN2=50%. OS was pN0=70,3%, pN1=61,4%, pN2=55,8%. Stage: OS was I=80%, II=68%, III=59%. Conclusions: The main prognostic factor for survival in colon cancer was the staging at diagnosis. Patients with pT4 or pN2 should received aggressive treatments for the high risk of metastasis. No significant financial relationships to disclose.

We aimed to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer by using a proteomic approach. A 5-fold oxaliplatin-resistant cell line, HTOXAR3, was compared with its parental cell line, HT29, using two-dimensional PAGE. Mass spectrometry, Western blot, and real-time quantitative PCR confirmed the down-regulation of pyruvate kinase M2 (PK-M2) in HTOXAR3 cells. In a panel of eight colorectal cancer cell lines, we found a negative correlation between oxaliplatin resistance and PK-M2 mRNA levels (Spearman r=-0.846, P=0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PK-M2 mRNA up-regulation. PK-M2 mRNA levels were measured by real-time quantitative PCR in 41 tumors treated with oxaliplatin/5-fluorouracil. Tumors with the lowest PK-M2 levels attained the lowest response rates (20% versus 64.5%, P=0.026). High PK-M2 levels were associated with high p53 levels (P=0.032). In conclusion, the data provided clearly link PK-M2 expression and oxaliplatin resistance mechanisms and further implicate PK-M2 as a predictive marker of response in patients with oxaliplatin-treated colorectal cancer.

In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future.

4121 Background: Resistance to anticancer drugs is a major obstacle preventing effective treatment of disseminated cancers. Understanding the molecular basis to chemoresistance is likely to provide better treatment. The aim of this work was to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer (CRC) cells by using a proteomic approach and translate it to the clinical setting. Methods: An oxaliplatin resistant cell line (HTOXAR3) was established from human HT29 CRC cells. Proteins were extracted and analyzed through comparative proteomics. Results were confirmed by western blotting (WB) and Real Time Quantitative PCR. A tissue microarray constructed with 41 metastatic paraffin-embedded colorectal adenocarcinomas from patients treated with oxaliplatin + 5FU was used to determine p53, Ki-67 and bcl-2 expression. RNA from these tumors was subjected to RTQPCR to assess PKM2 mRNA expression. Differences in response were analyzed by contingency tables and chi-square test. Results: HTOXAR3 were 6 fold-resistant as compared to HT29 cells. Of the 47 spots >4 fold over-expressed or down-regulated in HTOXAR3 vs. HT29 cells, Mass Spectrometry, WB and RTQPCR confirmed down-regulation of PKM2 in HTOXAR3. In a panel of 8 CRC cell lines, we found a negative correlation between OXA resistance and PKM2 mRNA levels (spearman r = -0.846, p = 0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PKM2 mRNA up-regulation. Patients with the lowest PKM2 levels had lower response rates to oxaliplatin-based treatment (20% vs. 64.5% p =0.026) and overexpressed p53 (90% vs. 50%, p = 0.032). High PKM2 levels were associated with high ki-67 levels (p = 0.048). Conclusions: By using proteomics we have identified PKM2 as a putative predictive marker of response in CRC patients treated with oxaliplatin plus 5FU as first line chemotherapy. No significant financial relationships to disclose.