bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.
Authors: Budinska Eva , Wilding Jenny , Popovici Vlad Calin , Missiaglia Edoardo , Roth Arnaud , Bosman Fred , Delorenzi Mauro , Bodmer Walter , Tejpar Sabine 
Published: March 2020

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.
Safety and efficacy of 90y resin microspheres in elderly (≥70 years) compared to younger patients with colorectal liver metastases (mCRC).
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Moeslein Fred M , Nutting Charles W. , Putnam Samuel G. , Rose Steven C. , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric 
Published: March 2020

e14545 Background: The effects of advanced age on the clinical outcomes following 90Y treatment in elderly patients with mCRC are relatively unknown. Methods: A retrospective review was conducted to evaluate clinical outcomes among 160 elderly (≥70 years) and 446 younger (<70 years) patients with unresectable mCRC consecutively treated using 90Y resin microspheres (SIR-Spheres; Sirtex) from July 2002 to December 2011 at 11 US institutions. Data on background characteristics, prior chemotherapy or other procedures, 90Y therapy, subsequent adverse events and survival were documented. Results: The mean age (+ SD) of the elderly patients was 77.2 + 4.85 years and 55.9 + 9.45 years in the younger cohort. Regardless of age, patients receiving 90Y treatment were very similar in the elderly and younger cohorts in terms of sex, race, ECOG performance status and other characteristics. However, elderly patients were more likely to have had their primary resected (7.1% vs. 15.1%; p=0.009), received fewer lines of chemotherapy (p=0.036; 13.1% vs. 2.8% had no prior chemo, p<0.001), a longer period between diagnosis and 90Y therapy (median 26.9 vs. 20.5 months; p=0.011), and received only one 90Y treatment (58.8% vs. 46.4%; p=0.007). Overall survival following 90Y therapy did not deteriorate in elderly patients (median 9.3 vs. 9.7 months; p=0.335). 90Y treatment was equally well tolerated in both cohorts, with no significant increase in grade 3+ adverse events in elderly patients, but significantly fewer grade 1+ events for abdominal pain (26.3% vs. 41.3%; p<0.001) and nausea (20.6% vs. 29.4%; p=0.038). The most common grade 3+ events included: abdominal pain (3.1% vs. 6.1%), GI ulceration 0.6% vs. 1.3%), nausea (0.6% vs. 1.3%), vomiting (1.3% vs. 1.3%), fatigue (5.6% vs. 4.5%), ascites (1.3% vs. 2.0%), hyperbilirubinemia (3.8% vs. 2.7%) and anorexia (0.6% vs. 0.9%). Analysis of the 98 patients ≥75 years compared to younger patients confirmed equivalent outcomes for survival and toxicity. Conclusions: For patients with unresectable mCRC liver metastases that meet eligibility criteria, 90Y therapy appears to be as effective and well-tolerated for the elderly as it is for younger candidates.
Severe falls among older adults with resected stage II/III colon cancer receiving chemotherapy.
Authors: LoConte Noelle K. , Allen Glenn , Leal Ticiana A.B. , Weiss Jennifer , Neuman Heather B. , Greenblatt David Y , Schmacher Jessica , Gayle Arlene Angela , O'Connor Erin S , Smith Maureen 
Published: March 2020

e14550 Background: Falls have significant implications for morbidity and mortality. The etiology of falls in elders includes cognitive change, polypharmacy, dizziness and anemia, all of which can be exacerbated by chemotherapy (chemo). We sought to determine the relation between chemotherapy receipt and falls resulting in injury and/or death among elders with colon cancer. Methods: Medicare beneficiaries >64 years with resected stage II or III colon cancer diagnosed from 1992-2005 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Falls within one year of surgery that resulted in hospitalization or ER visit were defined by E-codes. χ2 and 2-way ANOVA assessed differences in falls resulting or not resulting in death. Multivariable multinomial logistic regression models predicted a four-level falling/mortality variable (not falling (death), falling (death), not falling (no death), and falling (no death)) for patients receiving or not receiving chemo. Models controlled for patient demographics and tumor characteristics. We further controlled for use of mobility device, surgical complications, falls, hospitalizations and ER visits in the year before surgery, comorbidity risk score, frailty including dementia, and Medicaid status. Adjusted predicted probabilities and 95% CIs were calculated to assess the probability of each of the four outcome categories by receipt of chemotherapy. Results: Among 36,781 elders, falling was not increased among those who received adjuvant chemo. 14% of the total population fell during the year following surgery. The receipt of chemotherapy was not associated with increased rates of falls. Conclusions: Falling is not increased with the use of adjuvant chemo for stage II and III colon cancer among adults aged 65 years and above. The results suggest that oncologists may choose patients at least risk for functional decline when deciding upon chemo. [Table: see text]
Association between angiotensin-converting enzyme I gene I/d polymorphism and bevacizumab activity in advanced colorectal neoplasm.
Authors: E Aranda , de la Haba-Rodriguez Juan , A Martinez , Gomez M.Auxiliadora , G Pulido , R Serrano , B Rodriguez , R Rodriguez , P Cantizani , Antonio Rodriguez 
Published: March 2020

e14559 Background: Previous studies have found relation between the secondary hypertension to bevacizumab treatment and response in colorectal cancer. Some authors have suggested a critical role of the angiotensin converting enzyme (ACE) in blood pressure regulation. Furthermore, up-regulation of ACE gene expression has been observed in patients with hypertension. Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has been extensively investigated and a positive association between the DD genotype and an increased risk of in hypertension has been demonstrated. We have studied the association between the ACE I/D polymorphism and the response and time to progression to bevacizumab treatment in advanced colorectal cancer. Methods: Sixty-four patients treated with the combination of fluoropirimidins oxaliplatin and bevacizumab were included in this study. The median of time to progression was 37 weeks(CI95%:9528.7-45.23) with a global rate response of 73.4%(CR:9.4%, PR:35.9%, SD:28.1%). Genomic DNA is purified from peripheral blood using the MagNaPure LC DNA isolation kit I. The ACE insertion / deletion (I / D) polymorphisms (rs1799752) was analyzed by real time PCR. We will perform SNP genotyping with SimpleProbe probes in a LightCycler 480 Real-Time PCR System (Roche Applied Science), in a 96 multiwell-plated format. We analyzed the serum levels of ECA and VEGF-A by ELISA. Results: We found a higher rate global response in the genotype D/D (In/In:57.2%, In/Del: 93.1% and Del/Del: 100%) X2:16.887 p:0.031. The worst time to progression was observed in the genotype In/In.(In/In:14w, In/Del:37w and Del/Del: 36w) p:n.s. There was a significant correlation between the ACE and VEGF-A serum levels (Pearson test:0.201, p:0.03). Conclusions: There is an association between angiotensin-converting enzyme I gene I/D polymorphism and the activity of bevacizumab plus chemotherapy in advanced colorectal neoplasm. These results strongly support the hypothesis for a relationship between response to antiangiogenic therapy and hypertension.
Safety and efficacy of the addition of simvastatin to cetuximab in KRAS mutant metastatic colorectal cancer patients.
Authors: Baas Jara M , Krens Lisanne , Ten Tije Albert J. , Erdkamp Frans , Guchelaar Henk-jan , Gelderblom Hans 
Published: March 2020

e14586 Background: Epithelial growth factor receptor (EGFR) inhibitors are not effective in KRAS mutant colorectal tumors. In these tumors the k-ras protein is activated by post-translational modification by binding farnesyl (C15) and geranylgeranyl (C17) moieties. Both are products of the mevalonate pathway, as is cholesterol. Statins (HMG-CoA-reductase inhibitors) not only inhibit synthesis of cholesterol, but also of C15 and C17 and thus may reduce post-translational activation of ras proteins. Therefore, statins may inhibit the expression of the mutant KRAS phenotype and normalize the phenotype into KRAS wild type. In a phase II study we investigated whether simvastatin treatment renders KRAS mutant colorectal tumors sensitive to cetuximab. Methods: Major eligibility criteria were metastatic colorectal cancer failing 5-FU, oxaliplatin and irinotecan containing regimens, with a mutation in codon 12, 13 or 61 of KRAS gene in a tumor sample. Patients were treated with simvastatin 80mg once daily and cetuximab 250mg/m2 weekly (after a starting dose of 400mg/m2). Primary objective was to investigate the percentage of patients free from progression and alive 12.5 weeks after the first administration of cetuximab, similar to the results of the KRAS wild type population of the phase III study. This phase II study was performed in a Simon two stage design, performing an interim analysis after enrolment of 15 patients. If at least 6 of these patients (i.e. 40%) were to be alive and free from progression at 12.5 weeks after the start of cetuximab, another 31 patients would be included during stage II. Results: Fifteen evaluable patients were enrolled at 3 study sites. Four patients (i.e. 27%) were free from progression at time of the primary endpoint. Three patients experienced serious adverse events; an allergic reaction during cetuximab infusion, rhabdomyolysis and intracranial haemorrhage due to cerebral metastases. Conclusions: Though 4 patients experienced stable disease at 12.5 weeks, the predefined efficacy boundary was not met in order to continue enrolment to stage II. Simvastatin 80mg once daily does not induce sensitivity to cetuximab in colorectal cancer patients with a mutation in the KRAS gene. Clinical trial information: NCT01190462.
TGFBR1 SNP’s are a genetic marker potentially useful for colorectal cancer screening.
Authors: Pauly Marc , Mahon Garry , Metzger Brigitte , Menzel Alain , Weber Ben , Dicato Mario-A 
Published: March 2020

e14591 Background: Colonoscopy (CS) used for colorectal cancer (CRC) screening is relatively expensive and intrusive. We have shown that CRC in Caucasian patients have a high frequency of certain TGFBR1 SNP’s relative to normal controls. Here we extend the results to these SNP frequencies in normal tissue of the patients and the concordance of three different SNP’s in the TGFBR1 gene across patients and subjects. Methods: Tumor samples were obtained from 188 CRC patients and from 98 healthy control. After gDNA extraction, selected amplicons were amplified by PCR, followed by melting curve analysis. The statistical evaluation of the genotype frequency for the different SNPs comparing CRC patients with controls was carried out using logistic regression. Results: Results previously reported were confirmed:- a highly significant association between TGFBR1 SNP genotype and colorectal cancer (P<0.000001). For example, with the TGFBR1 SNP rs334348, the frequency of the GG genotype was 43% for patients but 11% for controls, while the AA frequency was only 18% for patients and 43% for controls. All CRC patients and controls were typed for three SNP's in the TGFBR1 gene and the concordance was found to be perfect. That is, only 3 of the 27 possible genotypes were observed:- (i) rs334348, AA; rs334349, AA; rs1591, CC; (ii) rs334348, AG; rs334349, AC; rs1591, CT; and (iii) rs334348, GG; rs334349, CC; rs1591, TT. Blood and tumor samples from patients had the same identical SNP pattern. Conclusions: The perfect concordance of the three SNP types in tumors and leukocytes shows that it reflects the underlying genotype of the patient rather than a somatic mutation in the tumour. Thus SNP type is a characteristic of subjects and a potential genetic marker for CRC susceptibility. We suggest that subjects aged 50 years or older be offered a test for a TGFBR1 variant. In case of a positive result, subjects should be informed that they are at risk of CRC, and strongly encouraged to have a colonoscopy. For this suggestion to become a definitive recommendation a cost-effectiveness analysis of the use of TGFBR1 SNP typing would be useful ( although such typing is inexpensive) and a prospective study of colonoscopy with TGFBR1 typing is mandatory.
Oxaliplatin given by hepatic arterial infusion (HAI) or systemic (SYS) with capecitabine in patients (pts) with unresectable liverlimited metastasis (Ur-LLM) from colorectal cancer (CRC).
Authors: Jensen Benny Vittrup , Noergaard Henrik , Bergenfeldt Magnus , Larsen Ole , Hoegdall Estrid Vilma Solyom , Johansen Jakob , Hermann Kirstine , Nielsen Dorte 
Published: March 2020

e14593 Background: Whether therapy of Ur-LLM from CRC by HAI is superior to SYS is unknown. Methods: First line phase II study of pts. with Ur-LLM from CRC. Included were 88 pts. HAI oxaliplatin (100 mg/m2) was given to 66 pts. every 2nd week (wk) for a median of 11 series (1-12) and capecitabine 3500 mg/m2 day 1-7 every 2nd wk for a median of 12 (2-14) series. Vessel variation made HAI unsuitable for 22 pts. They had systemic oxaliplatin (130 mg/m2) for a median of 8 (1-10) series with capecitabine 2000 mg/m2 day 1-14 every 3rd wk for a median of 8 series (1-45) with bevacizumab 7½ mg/kg day 1 in 14 pts. Primary endpoints were response, secondary median overall and therapy free survival (mOS) and toxicity. KRAS mutation status was determined in all pts. with the DxS kit. Survival was evaluated by the Kaplan Meier method and differences with the log rank test. 95% confidence interval are given in brackets. Results: Pts. treated with HAI and SYS were comparable. HAI yielded higher response rates than SYS (table 1). Pts. with KRAS-WT tumors treated with HAI had a mOS of 61 (43-80) mths, with KRAS-MT tumors 28 (21-35) mths (p< 0.0001). SYS in KRAS-WT and MT types yielded equal mOS 36 (27-45) mths and 27 (12-44) mths. Pts. with KRAS-WT tumors treated with HAI lived longer than when treated with SYS (p=0.05). Pts. with HAI with KRAS-WT tumors lived without any kind of therapy for a median of 27 (16-37) mths with 42% living more than 40 mths. with KRAS-MT tumors 8 (3-13) mths (p<0.0001) with 12% living more than 40 mths. Therapy free mOS with SYS in patients with KRAS-WT and KRAS-MT tumors was19 (0-39) mths.for pts. and 12 (4-20) mths respectively with 17% and 22% living more than 2 years.The findings were independent of cetuximab-based therapy in later lines. The toxicity was comparable. Conclusions: Effect of HAI oxaliplatin combined with capecitabine on response and survival is restricted to pts. with KRAS-WT tumors. [Table: see text]
Expression of serpin B5 in colorectal cancer: Its relationship with CEA expression.
Authors: Baek Ji Yeon , Kim Sun Young , Chang Hee Jin , Park Ji Won , Choi Hyo Seong , Kim Dae Yong , Oh Jae Hwan , Yeo Hyun Yang , Kim Kyunghee 
Published: March 2020

e14606 Background: Serpin B5 is a candidate tumor suppressor but its oncogenic activity has been also reported. Its function may be affected by interacting proteins. The aim of this study was to assess the relationship between serpin B5 and carcinoembryonic antigen (CEA) expressions in CRC. We also analyzed the clinicopathological significance of serpin B5 expression in colorectal cancer (CRC) patients. Methods: Two-dimensional gel electrophoresis (2-DE) analysis and matrix-associated laser desorption ionization mass spectrometry (MALDI-MS) were used to identify differentially expressing proteins according to CEA suppression. Serpin B5 and CEA expressions were evaluated by western blot and ELISA assays. Immunohistochemical expression of serpin B5 was assessed retrospectively in tissues from 377 CRC patients, and correlations between serpin B5 and clinicopathological parameters were analyzed. Results: Downregulation of serpin B5 was identified in CEA-suppressed LoVo cell line using 2-DE and MALDI-MS analyses, and further significant positive correlations between serpin B5 and CEA levels were also found in human CRC cell lines and in blood of CRC patients. Tissue expression of serpin B5 in CRC was significantly associated with serum CEA, histologic grade, stage, lymph node metastasis, liver metastasis, lymphatic and perineural invasion, and infiltrative border. High expression of serpin B5 was also associated with a reduced DFS (P = 0.001) and OS (P = 0.017). Conclusions: This is the first study describing relationship between serpin B5 and CEA expression in CRC. High expression of serpin B5 was also associated with worse prognosis in patients with CRC, and its expression may correlate with CEA levels in CRC.
hSRBC promoter CpG island hypermethylation as resistant predictive biomarker of oxaliplatin based chemotherapy in metastasic colorectal cancer patients.
Authors: Moutinho Catia , Martinez-Cardus Anna , Santos Cristina , Navarro-Perez Valentín , Martinez-Balibrea Eva , Abad Esteve Albert , Salazar Ramon , Esteller Manel 
Published: March 2020

e14609 Background: Resistance acquisition to chemotherapeutic agents is one of the main problems that come up during cancer treatment. hSRBC is a tumor suppressor gene whose inactivation has been associated with malignant tumor progression. In a previous work, we investigated the influence of hSRBC promoter methylation alterations in oxaliplatin (OXA) resistance acquisition by using a CRC “in vitro” model, detecting an hSRBC promoter hypermethylation in OXA–resistant derived cells when compared with the sensitive counterpart. These results were validated by functional analyses in the same model. Taking this into account, our aim in the present work is to determine the role of hSRBC methylation status as a potential biomarker of OXA resistance, in metastatic CRC patients, treated at first line with fluouropirimidines plus OXA based chemotherapy. Methods: hSRBC promoter hypermethylation was analyzed in DNA extracted from paraffin embebbed tissue of 111 metastatic CRC tumors by using Methylation Specific PCR. Methylation data was correlated to overall response (OR) and progression free survival (PFS) by using F-Fisher test and Kaplan-Meyer Survival curves respectively. A multivariate analysis was carried out by Cox regression. p-values under 0.05 were considered statistic significant. Results: Two independent cohorts of stage IV CRC tumors were included. Twenty-two out of 111 patients received radical surgery for metastasis, that became to be a positive prognostic factor (p-value = 0.04). Gene hypermethylation was detected in a 33% of cases. Although OR was not associated with hSRBC methylation, we observed a significant correlation between hypermethylation of gene and a worse PFS in patients without metastasis surgery (Log Rank; p-value = 0.04). Conclusions: Remarkably, hSRBC promoter hypermethylation is associated with worse PFS in metastatic CRC patients. We suggest hSRBC methylation status as a predictive biomarker of OXA-based treatment outcome in metastatic CRC patients. However, further studies are warranted in order to elucidate the clinical application of these findings.
Multiplatform assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in signet ring cell carcinoma of the gastrointestinal tract.
Authors: Alese Olatunji Boladale , El-Rayes Bassel F. , Sica Gabriel , Zhang Guojing , Rossi Michael R. , Adsay Volkan , Alexis Dianne , La Rosa Francisco G. , Varella-Garcia Marileila , Chen Zhengjia , Kauh John S. , Ramalingam Suresh S. , Khuri Fadlo Raja , Owonikoko Taofeek Kunle 
Published: March 2020

e14612 Background: ALK-EML4 translocation is an established driver aberration in NSCLC, with reported predilection for cases with signet ring histology. We assessed the presence of ALK gene rearrangements in signet ring cancers arising in the stomach and colon. Methods: Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified from the pathology archive of Emory University Hospital. Presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) method. Cases showing break-apart signal in more than 15% of enumerated cells were considered positive; at least 10% of enumerated cells was considered “possibly positive”. Immunohistochemistry of the fused gene product was assessed using previously validated antibodies ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) and positive controls of ALK-translocated lung cancer. Positive or possibly positive cases by FISH were further analyzed by RT-PCR using specific primers for the most common translocation pairs (EML4 Ex13/ALK Ex20 and EML4 Ex6/ALK Ex20) along with positive (H228, HEK293) and negative (H460, H1975) control cell lines. Results: We retrieved 44 cases of signet ring carcinoma diagnosed between 2001 and 2011; 26 gastric and 18 colon cancer. Median age - 63 yrs; M/F 17/27; Black - 47.5%; White - 47.5%; Others - 5%; Stage I - 21.4%; II - 31%; III - 26.2; IV - 21.4%. One of 44 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50-70 cells counted per case). 7 cases (16%) were considered possibly positive [1 of 18 (6%) colon cancer and 6 of 26 (26%) gastric cancer cases]. IHC showed 0 of 44 (0%) cases positive. Molecular analysis using RT-PCR did not confirm the suspected ALK gene rearrangements in any of the 7 cases considered possibly positive by FISH. Conclusions: The overall frequency of ALK gene rearrangement detected by FISH in signet ring cancer of the GI tract was low, but appears comparable to the reported frequency in lung cancer. Signet ring histology failed to enrich for cases with ALK gene translocation in this histologic subtype.