bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smoothelin as a marker of muscularis propria in biopsies of colorectal carcinomas.
Authors: Stoemmer Peter E. , Torres-Galea Patricia 
Published: March 2020

e14076 Background: Preoperative staging is of eminent importance for the treatment of colorectal carcinomas (CRCs). Especially the distinction of carcinoma in situ (not permigrating the muscularis mucosae (MM)), the pT1 stage (limited to the submucosa) and pT2 and above, infiltrating the muscularis propria(MP) in endoscopic biopsies could change the therapeutic regimen. Smoothelin (SMT) is a robust marker of the MP in normal colon, which is not expressed in MM; therefore, we analysed its expression in biopsies and resections of CRCs, to test its predictive value in staging of CRCs. Methods: 50 CRCs, diagnosed in biopsy particles and staged in the surgical specimens were analysed by IHC for expression of smoothelin (MoAb R4A, DCS Hamburg), Desmin and smooth muscle antigen SMA (all DAKO ) in MP and MM in the vicinity of invading carcinoma cells and in distance to the tumor. Semiquantitative grading REMMELE. Results: Desmin and SMA were consistently expressed in the smooth muscle cells of MM and MP near and distant to carcinoma cells. SMT showed no or little expression in the muscle cells of MM. The penetration of the MM by tumorcells did not alter their reactivity. In the MP however, the invasion by carcinoma cells caused a total or subtotal loss of SMT in the cytoplasm of the smooth muscle cells. The diameter of the nucleus and the longitudinal axis in SMT-deprivated cells did not change, but the transversal diameters of the cells were decreased. Reducing the mechanical stress of smooth muscle cells diminishes also the expression of SMT. No predictive correlation between biopsy-estimated depth and real depth of tumorinfiltration was seen. Conclusions: Expression of SMT correlates to functional status of the cells. The reliable difference in the IHC-expression of SMT in MM and MP in normal colon is not seen in the colon near carcinomas: the muscle cells of MP also lose their STM expression. Thus, negativity for SMT in smooth muscle cells near tumorcells does not necessarely proof, that this will be MM; as well, it could be SMT-deprivated cells of the MP. To rely upon SMT in biopsies for the determination of the depth of invasion is highly dangerous.
Predictive biomarkers of response to cetuximab in Chinese patients with metastatic colorectal cancer.
Authors: Ma Brigette , Loong Herbert , Liem Giok Siong , Mo Frankie , Tong Joanna , Wong SC Cesar , Chan Anthony T. C. , To Ka Fai 
Published: March 2020

e14085 Background: The paraffin-embedded tumor samples of 183 Chinese patients (pts) with metastatic colorectal cancer (mCRC) who had chemotherapy (chemo) over a period of 3.3 years were analyzed for the presence of KRAS, PIK3CA and BRAF mutations. Methods: PCR-direct sequencing was performed in micro-dissected tumor cells. The relationship between mutation and survival was evaluated using the Proportional Hazard Model, and relationship with drug response was evaluated with logistic regression. Multivariate analysis was used to adjust for the influence of age, sex, prior lines of chemo, use of bevacizumab (Bev) and the number of sites of metastases. Results: The median age was 58 yrs, over 50% of pts had > 2 lines of chemo and 50% had cetuximab. The prevalence of KRAS, BRAF and PI3KCA mutations were: 55%, 5%, 20% respectively. The prevalence of each KRAS mutation subtype was: G12D (36%), G12V (22%) and G13D (16%). KRAS mutation and prior use of Bev were independent prognostic factors with respective hazard ratios (HR) of 1.5 (95% CI = 1.05-2.16, p = 0.03) and 0.51 (95% CI = 0.3-0.87, p = 0.01). In the subgroup of patients who received cetuximab and chemotherapy in the first-line setting, KRAS mutation was associated with a lack of response to chemo with odd ratio (OR) of 0.1 (95% CI = 0.01-0.79, p=0.03). There was no correlation between the presence of BRAF and/ or PIK3CA mutations and OS or drug response. Five pts had co-expression of KRAS and PIK3CA mutations and none of them responded to cetuximab. Of the 14 pts who had complete response or prolonged disease stabilization to cetuximab-chemo, 4 had KRAS mutation, 1 had PIK3CA mutation and none had BRAF mutations. Conclusions: The prevalence of KRAS, BRAF and PIK3CA mutations reported in this Chinese cohort is consistent with reports from other non-Asian populations. KRAS mutation is an independent negative prognostic factor in chemo-treated pts with mCRC. KRAS mutation was associated with poorer response to 1st line cetuximab-based chemo.
Frequency of KRAS mutations in female colorectal cancer (CRC) patients: Findings of a Brazilian cohort of 8,234 cases.
Authors: Ferreira Carlos G. M. , Zalis Mariano , Zalcberg-Renault Ilana , Bonamino Martin H , de Pinho Marcos Barcelos , Helal Rafaela Cordeiro , Salem Jonas Hauben , Victorino Ana Paula Ornelas , Vieira Fernando Meton 
Published: March 2020

e14101 Background: Although major advances in the last decades, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. Some groups, including ours, observed that KRAS mutation may be more frequent in female than male (Ferreira C.G. et al. J Clin Oncol 28: 2010 suppl abstr 3614; Uetake H. et al. J Clin Oncol 29: 2011 suppl abstr 3605). Methods: Between July 2008 and July 2011, we analyzed 8,234 consecutive patient samples sent to a reference laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and well balanced according to gender with 51.9% of male and 48.1% female patients. The percentage of wild-type and mutated KRAS was 66.4 and 33.6%, respectively. Corroborating previous findings a significant difference in the percentage of mutated KRAS patients was observed between female and male (34.8% versus 32.5%, p = 0.03). However there were no differences in the distribution of any specific KRAS mutation according to gender. Among the 2,626 mutated cases, 83% were in codon 12 versus 17% in codon 13. Mutation Gly12Asp was the most common being detected in 36% of the mutated cases. Conclusions: This is one of the largest cohorts of KRAS genotyping in CRC patients. In line with previous data our present findings indicate that KRAS-mutations are more frequent in female than male. Further research is required to better address the impact of gender differences and/or hormones as potential drivers of CRC carcinogenesis.
Baseline predictors of survival in metastatic colorectal cancer.
Authors: Jensen Anni Ravnsbæk , Kronborg Camilla J S 
Published: March 2020

e14105 Background: Patients with non-resectable metastatic colorectal cancer can survive several years with palliative chemotherapy and newer biological agents. However, survival varies greatly within this group. The aim of the present study was to identify baseline predictors of overall mortality in an unselected cohort of patients with metastatic colorectal cancer. Methods: Clinical information was collected from patient files in consecutive patients treated with palliative chemotherapy from August 2007 until June 2011. The primary outcome was overall survival. Cox regression analysis was used to examine the effect of predictive variables on time to outcome. The variables analysed were: Gender, age, performance status, primary tumor site (colon or rectum), status of primary tumor (resected or un-resected), metachronous metastases, more than two metastatic sites, liver-only metastases, and low albumin. Results: We included 314 patients (Median age 64.5 IQ (57-70) years, 194 (61.8%) male). Median follow-up for survival was 471 days IQ (257-708). One-year survival was 79%, CI (74-84%). Median overall survival was 676 days, CI (577-750). Following baseline variables were independent predictors of all-cause mortality: Primary tumor site colon HR: 1.49, CI (1.03-2.16), p=0.036, un-resected primary tumor HR 2.92, CI (1.85-4.62), p<0.001, metachronous metastases HR 1.72, CI (1.06-2.79), p=0.027 and more than two metastatic sites HR 3.46, CI (1.71-6.99), p=0.001. Both Performance status and low albumin were statistically significant in the univariate analysis, but not in the multivariate analysis. Conclusions: In daily clinical practice, baseline predictors of mortality in metastatic colorectal cancer were colon as the primary tumor site, un-resected primary tumor, metachronous metastases, and more than two metastatic sites.
Baseline lymphopenia as a prognostic marker for colorectal carcinoma.
Authors: Erdem Dilek , Yucel Idris , Yilmaz Bahiddin , Demirag Guzin , Kemal Yasemin , Teker Fatih 
Published: March 2020

e14107 Background: Baseline lymphopenia has been proved to be a marker for poor prognosis, chemotherapy-induced toxicity and increased risk of febrile neutropenia, trombocytopenia and anemia in advanced solid neoplasms. This study aims to evaluate the effect of pretreatment lymphopenia on prognosis and hematological toxicity in colorectal cancer patients who received first line systemic chemotherapy. Methods: Lymphocyte count was evaluated in 386 pretreated colorectal cancer patients who do not have a seconder malignancy, HIV infection, bone involvement and primary G-CSF prophylaxis. Overall survival, progression free survival and disease free survival were calculated from date of diagnosis to date of relapse, progression and death. Kaplan-Meier, chi-square and Student-t test were used. Results: Mean follow-up was 30 months (range 1-180 months). Mean age was 57.4±12.5 years. Of all patients, 160 (41 %) were women. Rectum ( 26.2 %) and transvers colon (4.7 %) were the most and the least common anatomic locations, respectively. Mean lymphocyte count before treatment was 1964/µl (170-7000/µl). There were no relationship between lymphopenia and age, sex, performans status, presence of initial metastasis, adjuvant or palliative chemotherapy and hematological toxicity (p>0.05). Grade 3-4 hematological toxicity was found in 40 patients and was significantly higher in patients receiving bi- or tri-chemotherapy regimen (p:0.017). Among 208 patients with relapse or progression, 40 patients had lymphopenia (19.2 %). 1, 3 and 5-year OS were significantly lower in lymphopenic patients (p:0.033). DFS was longer in non-lymphopenic patients but this data didn’t have statistical significance (p>0.05). Conclusions: This study support that lymphocyte number prior to chemotherapy may be a simple but useful prognostic and predictive marker in untreated colorectal cancer patients. Patients with lower pretreatment lymphopenia have lower OS when compared to others (p<0.05). This study has the highest colorectal cancer population in the literature.
The relationship between serum and tumoral CRP, Akt, MAPK, and survival in patients undergoing potentially curative resection for colorectal cancer.
Authors: Powell Arfon , Shepherd Scott , Orange Clare , Mcmillan Donald C. , Horgan Paul G , Edwards Joanne E. 
Published: March 2020

e14110 Background: Serum CRP was previously reported in myeloma to activate membrane bound Fcγ receptors which in turn activated Akt, and MAP kinase and inhibited caspase cascade activation resulting in increased tumour cell proliferation and inhibition of apoptosis. This study investigated the hypothesis that serum C-reactive protein (CRP) may activate signalling pathways in colorectal tumour cells. Methods: A cohort of 147 colorectal tumours was established and immunohistochemistry performed to assess protein expression of CRP, MAP kinase and Akt phosphorylated at serine 473 (pAkt). In addition, reverse transcriptase PCR for CRP mRNA expression was performed on 31 malignant colorectal specimens, 20 non-malignant colorectal specimens and 30 liver specimens. Results: No association between patient survival and tumour expression of CRP, pAkt and MAPK was observed, but serum CRP was independently associated with cancer-specific survival (p<0.001). When analysed according to tumour site, cytoplasmic CRP expression was associated with cancer specific survival in left sided tumours (p=0.022) and cytoplasmic pAkt was associated with cancer specific survival (p=0.029) in rectal tumours. No correlations were observed between serum CRP and tumour expression of CRP, pAkt and MAPK in the cohort as a whole or when subdivided by site. Conclusions: No link was established between serum CRP and signalling within the tumour. However, our results do support the concept of colorectal tumour heterogeneity, as different proteins were associated with patient survival depending on site. Further work is therefore required to elucidate the mechanisms underlying colorectal development and progression in tumour subtypes.
Evaluation of cost-effectiveness of early KRAS testing in high-risk recurrence colorectal cancer patients in Italy.
Authors: Pinto Carmine , Barone Carlo , Normanno Nicola , Cognetti Francesco , Falcone Alfredo , Capussotti Lorenzo , Mantovani Lorenzo 
Published: March 2020

e14113 Background: KRAS testing is relevant for the choice of the most appropriate first-line therapy for metastatic colorectal cancer (CRC) patients (pts). Early KRAS testing in surgically resected CRC pts at high risk of recurrence might result cost-effective when the results of KRAS test are not available in acceptable time following the diagnosis of metastatic disease. Methods: This study adopted the Delphi technique to reach a consensus to define high risk recurrence CRC and KRAS test optimal timing. We used validated decision analyses models employed by technology assessment agencies (NICE and SMC) for the assessment of KRAS wild-type CRC pts. Alternative therapeutic strategies include FOLFOX4, FOLFIRI, FOLFOX4 + cetuximab, FOLFIRI + cetuximab, FOLFOX4 + bevacizumab. We adapted the models to take into account early KRAS testing in high risk pts for which the test would not be available on time to drive appropriate treatment. The models have been populated with Italian specific cost data incorporating pts’ access schemes. Results: Issues related to KRAS testing were proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The following parameters to define CRC pts at high risk of recurrence were identified: pT4, high grading, pN2, intestinal occlusion-perforation, isolated peritoneal carcinomatosis surgically removed and/or positive peritoneal washing and/or removed ovarian metastases. A time interval of more than 10-15 days for KRAS testing was defined as a limit for the therapeutic choices. Early KRAS testing in high risk CRC pts generates incremental cost effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained, depending on alternative treatment of choice. In extensive sensitivity analyses, ICER’s were always below 15,000 Euro per QALY gained, far within the 60,000 Euro/QALY gained threshold currently accepted in Italy. Conclusions: In metastatic CRC a time interval of more than 10-15 days for the response of KRAS testing limits the therapeutic choices. Early KRAS testing in high-risk CRC pts who would not have KRAS test in a reasonable time when they develop metastases is a cost effective strategy.
Impact of diabetes on site-specific oncologic outcome in stage I-III colorectal cancer.
Authors: Jeon Justin Y , Jeong Deok Hyun , Park Min Keun , Ligibel Jennifer A. , Meyerhardt Jeffrey A. , Kim Nam Kyu 
Published: March 2020

e14114 Background: Background: Conflicting results have been reported whether pre diagnosis diabetes mellitus (DM) influence survival of colorectal cancer patients or not. Therefore, we determine the influence of DM on long-term outcomes of stage 1-3 patients with resected colon and rectal cancer. Methods: This prospective study include a total of 4,131 participants who were treated for cancer between 1995 and 2005 in South Korea in a single hospital (Non DM: 3,614 patients, DM: 517 patients) with average follow up period of 12 years. We analyzed differences in all cause mortality, disease free survival (DFS), recurrence free survival (RFS) and colorectal cancer-specific mortality between colorectal patients with DM and those without DM. Results: After adjustment for potential confounders, pre-diagnosis DM significantly associated with increased all cause mortality (HR: 1.46, 95% CI: 1.11-1.92), and recurrence free survival reduced DFS (HR: 1.45, 95%CI: 1.15-1.84) and RFS (HR: 1.32, 95% CI: 0.98-1.76) in colon cancer patients but not in rectal cancer patients. In colon cancer patients, DM negatively affects the survival outcome of proximal colon cancer (HR: 2.08, 95%CI: 1.38-3.13), but not of distal cancer (HR:1.34, 95% CI: 0.92-1.96). Conclusions: To our knowledge, the current study first reported the effects of pre-diagnosis DM on survival outcome of colorectal cancer are site specific (proximal colon, distal colon and rectum). The current study was supported by the National Research Foundation of Korea (KRF) (No. 2011-0004892) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120230). [Table: see text]
Involvement of K-RAS mutations and amino acid substitutions in the survival of metastatic colorectal cancer patients.
Authors: Pérez-Ruiz Elisabeth , Alcaide Julia , Pereda Teresa , Bautista Dolores , Rivas Ruiz Francisco , Villatoro R. , Redondo Maximino , Perez Diego , Rueda Antonio 
Published: March 2020

e14116 Background: The efficacy against of epidermal growth factor therapy was found to be limited to those wild-type K-RAS tumours, suggesting a predictive value of response. However, the prognostic value of K-RAS status is controversial. The aim is to determine the relationship between K-RAS mutations and types of amino acid changes with the survival (OS) of metastatic colorectal patients (mCRC). Methods: The retrospective analysis included 120 patients diagnosed of mCRC. The presence and type of K-RAS mutations were analysed. Similarly, the clinical and pathological variables were also collected including OS. Results: The sample characteristics were summarized in Table 1. 53.3% of tumours were wild-type and 46.7 mutated KRAS. In mutated patients, codon 12 was affected in 76.79% and codon 13 in 23.21%. The median OS for wild-type was 31.6 months. In mutated patients (codon 12 or 13), median OS was 24.8 and 17.8 months (p=0.37), respectively. In the univariate analysis, mutated K-RAS was associated with stage IV at diagnosis (p<0.005). The relationship between OS and amino acid mutation are summarized in table 1. Conclusions: Our study suggest that the types of mutation or amino acid changes of KRAS in mCRC provides prognostic information. These data need to be confirmed in prospective or controlled trials. [Table: see text]
Comorbidity and other predictors of survival in veterans with colorectal cancer (CRC).
Authors: Zhong Fengming , Wang Trent P , Barnes Tanganyika , Gonzalez Melanie L. , Chang Victor T , Einhorn Jan , Sullivan Maryann , Kasimis Basil 
Published: March 2020

e14125 Background: The role of comorbidity as a prognostic marker is an area of great interest. This study aimed to determine whether comorbidity indices predict survival in Veterans with CRC. Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA Medical Center from 1/1/2003 to 12/31/2007. Demographics, stage, grade, ECOG performance status (PS), CEA, hemoglobin (HGB), Albumin (ALB) at diagnosis, history of surgical resection (SR) were abstracted. Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Kaplan-Feinstein Index (KFI), the Cumulative Illness Rating Scale (CIRS), and VA Comorbidity Scale (VACS). We developed a survival model with stage, ECOG PS, HGB, ALB, SR, and ECOG PS. Comorbidity indices were tested by determining if they were independent predictors of survival after inclusion in this model. Cox regression analyses were performed with SAS V9.2. Results: There were 175 pts with colorectal ca with 111 colon (C) and 64 rectal ca (R) pts. The median (M) age at diagnosis was 71 (45-90). 54% of study population was deceased at the time of data collection. Median survival was 1157 days (5-3256). Results of multivariate analyses with comorbidity indices are summarized in the table. Conclusions: Charlson, CIRS 16 and CIRS 19 comorbidity indices were significant predictors for veterans with colorectal cancer and appear to be important for the subset of veterans with colon cancer. Confirmatory studies should be done in larger populatins. These indices may be used in the design of future clinical trials. This was supported by the New Jersey Commission for Cancer Research 09-1133-CCR-EO. [Table: see text]
Comparison of long-term survival outcomes of operative versus nonoperative management of recurrent rectal cancer.
Authors: Bhangu Aneel , Ali Mohammed , Cunningham David , Brown Gina , Tekkis Paris P 
Published: March 2020

e14132 Background: Complete surgical resection is considered the best treatment for recurrent rectal cancer (RRC). The aim of the study was to compare survival outcomes from operative and non-operative patients presenting with RRC. Methods: Patients with RRC whose management was discussed by a tertiary referral specialist multidisciplinary team between January 2007 and August 2011 were identified from a prospectively maintained database. The primary endpoint was 5-year overall survival estimated by Kaplan-Meier survival method. Results: Of 127 patients with RRC, 105 were isolated to the pelvis and 22 were associated with distant disease at presentation. From the time of primary surgery to first recurrence, 1, 3, 5 and 10-year local recurrence rates were 22%, 72%, 85% and 96% respectively. Of 70 patients (55%, 70/127) who underwent pelvic resection of recurrence, 64% underwent R0, 20% R1 and 16% R2 resections. Corresponding 5-year overall survival was R0: 60%, R1: 42% and R2: 0% (log-rank p=0.004). There was no significant difference in survival between R2 resection and those managed non-operatively (hazard ratio 0.738, 95% confidence interval 0.341-1.600, p=0.559). Five year disease-free survival was 53% with R0 resection and 30% with R1 resection. Conclusions: Most recurrences occur within 5 years of primary surgery, although some occur up to 10 years later. R0 resection is the treatment of choice that leads to long-term survival and is suitable as an early surrogate marker for long-term survival. There was no survival benefit of R2 resection over non-resected recurrences.