bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biweekly gemcitabine and capecitabine in heavily pretreated patients with metastatic colorectal cancer (mCRC).
Authors: Solis Hernandez Maria Del Pilar , Jiménez Paula , Faez Garcia Laura , Alvarez Fernandez Carlos , Pérez Arnillas Quionia , Rodriguez Rubi David Jose , Ruiz Ana Lucrecia , Sánchez Lorenzo Luisa , Li Torres Walter Antonio , Uriol Esther , Menendez Prieto Maria Dolores , Vieitez de Prado Jose Maria 
Published: March 2020

e14617 Background: Some patients with mCRC are still susceptible to continue with active therapy after progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens due to their good performance status. Preclinical and clinical trials suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites. Their major mechanism of action is to incorporate dFdCTP into DNA and to introduce FUTP into RNA, respectively, affecting their processing and function. This study aims to describe patients profile and response to gemcitabine-capecitabine (GemCap) in heavily pretreated mCRC, and so possible predictive factors for survival. Methods: Between June 2001 and July 2011, 119 evaluable patients pretreated with oxaliplatin and irinotecan regimens were enrolled: ECOG 0-1 97%, male 68%, median age 63yo, range: 36-79, rectum 57%, 3rd line: 61%. Patients received Gem 1000 mg/m2 d2 and Cap 1000 mg/m2BID x 7d q2w. Survival analysis was determined by Kaplan-Meier and log-rank test. Results: ORR and clinical benefit were: 5% and 36%. Median PFS and OS were 2.83m (0.43-35) and 6.53m (0.47m-10yrs in patient with complete response). Most frequent toxicities were anemia (22%), thrombocytopenia (10%), hand-foot syndrome (9%) and grade ≥3 were diarrhea in 5%. There were no treatment-related deaths. Predictive factors for PFS and OS are shown in Table. Statistic significance was registered in favor of clinical benefit achieved and for those who had not previously received monoclonal Abs, for SLP and OS respectively. Moreover, patients under 65yo tend to have a better survival. Conclusions: These data suggest GemCap is a tolerable regimen that achieves maintained responses for non selected heavily preated mCRC patients, especially in those reaching radiological clinical benefit, without previous use of monoclonal Abs and younger patients. [Table: see text]
Pathway redundancy and feedback loop as drivers of nonresponse in colorectal cancer treatments.
Authors: Kim Hee Cheol , Kim Phillip Sangwook , Lee Jeeyun , Park Joon Oh , Lee Tani Ann T. , Liu Xinjun , Park Se Hoon , Kuller Anne , Singh Sharat , Kang Won Ki , Park Young Suk 
Published: March 2020

e14626 Background: There is urgent need for rational therapy selection based on functional-pathway characterization to achieve significantly improved clinical outcome. Methods: 207 CRC patients were evaluated for >100 signal transduction proteins. Receptor tyrosine kinases (RTKs, i.e. ErbBs, FGFRs, VEGFRs, cMET, IGF1R, etc) and non-RTKs (Src, FAK, etc) as well as Jak/Stat along with AKT and MAPK pathway proteins were analyzed for their level of expression and activation utilizing Collaborative Enzyme Enhanced Reactive (CEER) immunoarray. In addition to pathway profiling, samples were also molecularly characterized for 14 different mutations within the KRAS, BRAF and PIK3CA oncogenes. Results: Both ErbB/VEGFR driven and ErbB/VEGFR-independent signal transduction activation patterns were observed in the CRC patients with complex redundant pathway circuitry. Phosphorylated RTKs led to downstream AKT and MAPK pathway activation. Various mutations in KRAS, PIK3CA and BRAF were found in 42%, 11% and 4% of CRC patients, respectively. KRAS G12D and G13D mutations were the most frequent mutations. Percent of mutant alleles per input DNA increased in matching metastatic tumors when compared to the primary tumors. While downstream signal transduction via AKT and MAPK pathways were similar in both wild-type and mutant tumors, we observed higher levels of potential compensating non-ErbB driven RTK expression/activation in KRAS mutant patients. A significant pathway redundancy was detected in most tumors. Furthermore, pathway diversity in tumors with identical mutational background was evident in this analysis. Conclusions: CEER-based pathway analysis adds value towards understanding of CRC tumor¡&hibar;s potential response under various clinical scenarios. The comprehensive characterization of pathway redundancy allows for rational selection of a combination of targeted agents. A combination of Erbitux with anti-angiogenic therapy may provide most benefit for patients with concomitant EGFR and VEGFR2 activation. Based on pathway circuitry determined by CEER, clinicians can optimize clinical decisions in selecting more effective therapies that target relevant pathway proteins.
Thrombotic events in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab.
Authors: Al-Shamsi Humaid O. , Anjum Mahraz , Al Farsi Abdulaziz Mohammed , Shen Hua , Cook Richard J. , Linkins Lori-Ann , Major Pierre 
Published: March 2020

e14630 Background: To determine the incidence and risk factors for thrombotic events (TEs) (arterial and venous) in patients with metastatic colorectal cancer (mCRC) who received Bevacizumab and FOLFIRI (Leucovorin, Fluorouracil and Irinotican ) compared to FOLFIRI alone. Methods: Single institution retrospective study of 450 mCRC patients who received either Bevacizumab plus FOLFIRI or FOLFIRI alone between October 2006 and September 2012. Demographics , TE risk factors and treatment data were abstracted from patients records. Multivariate analysis was used to determine factors that contributed to increased TE incidence. Results: 261 mCRC patients received Bevacizumab plus FOLFIRI ( 64.8 % males , mean Body Mass Index (BMI) 26.1 ) compared to 189 control patients who received FOLFIRI alone ( 61.1 % males ,BMI 27). The incidence of TEs was 15 % (arterial 1.8% + venous 13.2%) in the Bevacizumab plus FOLFIRI group compared to 15.8% (arterial 2.1% + venous 13.7%) in the control groups. Multivariate analysis controlled for age, BMI, gender, malignancy, metastatic sites , line of treatment, and risk factors did not suggest a significant increase in risk of TE associated with Bevacizumab (OR=0.83 95% CI: 0.40 - 1.70; p=0.602). No difference in locations of TEs was observed between both groups . The only statistically significant factor for thrombosis in Bevacizumab group was increased BMI (OR=1.05; 95% CI: 1.01- 1.10; p=0.016). Conclusions: Our data suggest that bevacizumab did not significantly increase the rate of thrombosis in patients with mCRC when added to FOLFIRI. To our knowledge this is the first study reporting the rate of TEs (arterial and venous) in this population.Our data suggest that BMI may be a risk factor for increase risk of thrombosis in patients treated with bevacizumab . Clinician should consider risk factors assessment prior to initiating bevacizumab .
Association of increased levels of stem cell marker ALDH1 with overall survival in metastatic colon cancer.
Authors: Fitzgerald Timothy Louis , Partis William J , Starr Shane , Sigounas George 
Published: March 2020

e14635 Background: The clinical relevance of cancer stem cells (CSC’s) in solid organ malignancies is unclear. ALDH1 is thought to be a universal marker of stemness and is expressed in normal and neoplastic stem cells. We sought to determine the effects of stemness, expressed as levels of ALDH1, on survival for similarly staged metastatic colon cancer patients. Methods: Patients with lymph node positive colon cancer and unresectable liver metastasis diagnosed from 2004-2009 were identified. Sections were prepared from paraffin blocks and stained with an ALDH1 antibody. To determine quantitative expression of ALDH1, morphometric analysis with a Nikon microscope, SPOT video camera, and ImagePro software was performed with expression defined as stained area/total area. Ten to twenty randomly selected fields from were assessed. Patients were determined to have high expression of ALDH1 if respective levels were above the mean. Data analysis was performed with JMP. Results: A total of 16 patients were identified, with a median age of 64 years. The majority of patients were female (63%) and black (69%). Few primary tumors were poorly differentiated (25%). Median survival was 21.5 months (range: 1-47). Mean expression of ALDH1 was 0.041+0.01 for normal crypts, 0.031+0.01 for lymph node metastases, and 0.062+0.02 for primary tumors. ALDH1 expression was high in 31.3%, 20%, and 31.3% of patients for normal colon crypts, lymph node metastases, and primary cancers, respectively. Increased expression ALDH1 in tumors was strongly correlated with mortality (p=0.0013) and male sex (p=0.0166), but not with age (p=0.71) or race (p=0.50). Increased expression of ALDH1 in primary tumors was associated with a decreased overall survival, 27 vs. 6 months (p=0.0015). Increased expression of ALDH1 in normal colon crypts and lymph node metastases was not associated with survival, 27 vs. 19 (p=0.18) and 21 vs. 22 months (p=0.35), respectively. Conclusions: Increased stemness in primary colon cancers, expressed as ALDH1 levels, is associated with poor survival for similarly staged metastatic patients. These data suggest that an increase in stem cell fraction predicts a more aggressive clinical course.
DNA mutation frequencies in metastatic small bowel adenocarcinoma (mSBA) in comparison to gastric (mGC), colon (mCC), and rectal cancer (mRC): Continuum or cutpoint?
Authors: Murphy Janet E. , Russo Andrea Lyn , Szymonifka Jackie , Kwak Eunice Lee , Allen Jill N. , Zhu Andrew X. , Blaszkowsky Lawrence Scott , Clark Jeffrey W. , Ryan David P. , Hong Theodore S. , Borger Darrell R. 
Published: March 2020

e14636 Background: The small intestine is in continuity with the stomach and colon/rectum. However mGC and mCC/mRC differ in oncogene profiles. No study has evaluated the oncogene profile of mSBA on the continuum of mGC and mCC/mRC. This may give insight into biology and have implications for treatment. Methods: Respective analysis was performed on GI cancer patients who underwent tumor mutational profiling since 2010. Genotyping was performed on formalin-fixed and paraffin-embedded tumor tissue using a multiplexed mutational profiling platform. Here we report results for APC, BRAF, EGFR, IDH1, KRAS, NRAS, PI3K, PTEN, and TP53. Results: We identified 12 patients with mSBA (11/12 with clinical data, 11/12 with genotype data). Median age at stage IV diagnosis was 61.1y (49.3-71.5y). Four patients had duodenal, 3 jejeunal, 2 ileal, and 2 multiple/unknown primary sites. All patients received 5FU and ox, while 8/11 received irino, 5/11 bev, 3/11 cetux, 1/11 regorafenib and 1/11 capecitabine. Two patients had adjuvant RT (both duodenal) while 4/11 received palliative RT. Survival was calculated from the date of stage IV diagnosis until death, with data censored on 2/1/2013. Median survival was 24.0 months (95% CI 6.4 – 60.0 mo). We compared genotype frequencies of mSBA patients (11) with mGC (41), mCC (161), and mRC (64) using Fisher’s exact test for pairwise comparisons. Conclusions: While the small bowel sample size was small, a significant difference in KRAS mutation frequency was found when compared to gastric cancer. No significant differences in mutation frequencies were found when compared with colon or rectal cancer. [Table: see text]
Peripheral immunosuppressive cell levels as predictive marker for the clinical outcome in stage IV colorectal carcinoma.
Authors: Koutoulaki Anna , Zafeiriou Zafeiris , Skalidaki Dimitra , Aggouraki Despoina , Vetsika Kiriaki E , Mavroudis Dimitrios , Georgoulias Vassilis , Kotsakis Athanasios Panayotis 
Published: March 2020

e14639 Background: Immune suppressive cells,Myeloid-Derived Suppressor Cells (MDSCs) and T Regulatory Cells (Tregs) have been identified as negative prognostic biomarkers in distinct solid tumors. In colorectal cancer (CRC), increased peripheral levels of MDSCs have been correlated to worse survival (Solito S et al.; Blood 2011). Although Tregs infiltrated in tumors have been associated with favourable clinical outcome (Salama P et al.; JCO 2009), their significance in peripheral blood remains unclear. The aim of the present study was to evaluate the role of these cells in the peripheral blood as a prognostic marker in CRC patients. Methods: Blood sample was collected from 49 CRC naïve patients (Stage IV) prior to 1st line treatment and 33 healthy donors. Flow cytometric analysis of MDSCs (HLA-DR-Lin-/lowCD33+CD11b+) and Tregs (CD3+CD4+CD25 highCD127low/-FoxP3+CD39+) was performed in fresh samples. MDSC and Treg levels of patients and normal controls were analyzed by using unpaired t-test. ROC analysis (area = 0.8539) was used to define high versus low MDSC levels, whereas the median value of Tregs in normal controls was used as a cut-off. Among patients that relapsed, Kaplan-Meier analysis was used to compare time to tumor progression (TTP) with high and low levels of MDSCs and Tregs. Results: The median percentages of MDSCs and Tregs in patients were significantly increased compared to controls (Mann Whitney test: p < 0.0001; p = 0.0111, respectively). MDSCs were positively correlated to Treg levels (Spearman's r2 = +0.408; p = 0.048). Patients with high levels of MDSCs at baseline, but not Tregs (p = 0.7165), relapsed earlier to those with low levels (p= 0.0348; 9.83 vs. 4.93 months, respectively). Conclusions: CRC patients have elevated peripheral levels of immunosuppressive cells. MDSCs seem to be an independent prognostic factor for TTP. The significance of the observed correlation of MDSCs with Tregs and the suppressive mechanisms of these cells will be further investigated. Updated survival data will be presented in an increased cohort of patients.
Use of surgery and chemoradiation in stage II and III rectal cancer: A retrospective comparison of treatment modalities in major insurance types using the NCDB.
Authors: Warlaumont Mary , Brin Lauren , Fuller Timothy , Whittaker Naomi , Silberstein Peter T. 
Published: March 2020

e14641 Background: The preferred method of care for stage II/III rectal cancer is trimodal therapy: neoadjuvant chemoradiation plus surgical resection. We aim to compare the treatment practices for patients with stage II/III rectal cancer in major insurance types. Methods: Using data from the National Cancer Database (NCDB), we analyzed the treatment patterns of 91,782 patients diagnosed with stage II/III rectal cancer from 2000-2009. The NCDB includes data from 70% of all U.S. cancer patients. This is the largest study of this kind to date. Results: In stage II/III rectal cancer, patients with private insurance received more trimodal therapy (70.3%) than patients with VA Insurance (56.6%), Medicare (46.9%), Medicaid (66.5%), or no insurance (61.7%) (p<.0001). VA patients received less trimodal therapy than Medicaid or non-insured patients (p<.0001). Medicare patients (26.9%) were treated with surgery alone more often than patients with private insurance (9.8%), Medicaid (10.4%), VAH (12.2%) or no insurance (9.4%) (p<.0001). VA (4.8%) and Medicare (4.3%) patients were more likely to not receive any “First Course Treatment” than patients with private insurance (1.3%) (p<.0001). Patients over 70yo received less trimodal therapy (42.2%) than patients under 70yo (68.9%) (p<.0001) and received more surgery without chemotherapy or radiation (29.3%) than patients less than 70yo (9.2%) (p<.0001). Conclusions: Stage II/III rectal cancer patients with private insurance received more trimodal therapy than VA, Medicare, Medicaid, or uninsured patients. VA patients received less trimodal therapy than Medicaid or uninsured patients. [Table: see text]
Choice of therapy and time to first treatment for patients with colon cancer: A National Cancer Database analysis.
Authors: Olson David C. , Abou El-Ezz Khaled Mohamed , Silberstein Peter T. 
Published: March 2020

e14642 Background: Insurance status has been shown to affect adherence to guidelines in the treatment of colon cancer1. This study aims to investigate trends in management of colon cancer and time to first treatment in patients with various insurance types using the National Cancer Database (NCDB). Methods: Treatment data for 845,121 patients and time to first treatment data for 497,993 patients diagnosed with colon cancer between 2000 and 2010 were identified using the NCDB. Reported utilization of treatment and time to first treatment were analyzed by insurance status. Results: Among all stages of colon cancer, no treatment was received more often by Veteran Affairs (10.5%) and Medicare (10.9%) patients than uninsured (8.8%), managed care (4.5%), private insurance (4.7%), Medicaid (8.4%) or Medicare with supplement (7.7%). Among stage I colon cancer, surgery was received less often by uninsured (90.9%) than other insurance types. Stage III colon cancer patients enrolled in Medicare with/without supplement received chemotherapy less often than other insurance types (49.9% and 46%). Stage IV Medicare patients with/without supplement also received chemotherapy less than other insurance types (59.5% and 52.9%). Surgery as monotherapy was the most common treatment received among all insurance types and stages. More uninsured patients received treatment within 3 days than any other insurance types (61%). A delay of at least 17days occurred more in Veteran Affairs patients than other insurance types (40.6%). Conclusions: This is the largest study to date to have examined treatment trends and time to first treatment. Among all insurance types, Medicare without supplement and Veteran Affairs patients were most likely to receive no treatment. Uninsured were less likely to receive the standard of care treatment with stage I cancers. Medicare patients were less likely to receive the standard of care for stage III and stage IV cancers than other insurance types. Veteran Affairs patients had treatment delayed significantly more than other insurance types. Future studies are needed to assess factors leading to receipt of substandard care.
Evolving disparities in colorectal cancer control in Texas in the first decade of twenty-first century and implications for cancer control.
Authors: Vugrin Davor 
Published: March 2020

e14643 Background: Colorectal cancer (CRC) is the 2nd leading cause of cancer death among Texans although it is potentially one of the most preventable and curable cancers. In 2000, an intensive public education and screening was launched throughout Texas with goal by 2015 to increase up to 75% the number of 50 year and older individuals undergoing screening per the national guidelines, to reduce age-adjusted CRC incidence to 34.8/100,000 and mortality to 12.0/100,000. The purpose of this study is to identify disparities challenging meeting the 2015 objectives. Methods: The Texas Cancer Registry 2000 to 2009 data of the at risk population was queried for CRC cases diagnosed, number of deaths, age-adjusted incidence and mortality rates, and correlation with gender, race and anatomical location and evolving 10 year trend. Results: Incidence: of 91,260 CRC diagnosed 71.8% originated in colon (CoCa), 19.7 in rectum (ReCa) and 8.5 % in Rectosigmoid juction (RSJ). Age-adjusted rates (AAR) declined for CoCa by 6.6/100,000 (18%) and ReCa by 0.8 (8.6%). AAR for Non Hispanic White (NHW) declined by 10.0/100,000 (19.7%), Blacks (B) 9.8/ (15.3%) and Hispanics (H) 5.1/ (12.0%). Males AAR declined by 11.8/100,000 (19.7%) and women 18.1. 10 yr cumulative AAR for Black Males was 74.7/100,000, B female53.6/ with with lower AAR for other groups. Mortality: Of 32,929 death CoCa accounted for 83.5% and ReCa + RSJ for 16.5% cases. CoCa AAR mortality declined but for ReCa +RSJ was insignificant. Decline for NHW was –4.2 (22.0%), B – 5.6 (18.5%) and H – 1.5 (10.4%), males – 4.3 (18.5% and females – 3.7 (22.7%). AAR mortality rate in B males (35.0/100,000 and B females (23.2/) was higher than for other groups. Conclusions: Disparities in CRC control have been evolving over 10 yr study period based on anatomic site, gender, race/etnicity and their combination. Our targeted cancer control activities need to be adjusted to neutralize observed disparities in order to reach 2015 objective.
Preclinical activity of lenalidomide in metastatic colorectal cancer.
Authors: Leuci Valeria , Maione Federica , Todorovic Maja , Giraudo Enrico , Gammaitoni Loretta , Migliardi Giorgia , Aglietta Massimo , Leone Francesco , Trusolino Livio , Bertotti Andrea , Sangiolo Dario 
Published: March 2020

e14654 Background: Metastatic colorectal cancer (mCRC) is currently considered incurable. Recent evidences support the importance of micro-environment and angiogenesis on survival and propagation of mCRC. Lenalidomide is a derivative of thalidomide, effective in several hematologic disorders, whose activity includes modulation on tumor microenvironment and inhibition of angiogenesis. We investigated the preclinical activity of lenalidomide against mCRC in vitro and in vivo. Methods: CRC cell lines and primary mCRC cells were treated with scalar concentrations of lenalidomide (10 to 150 µM). Two cohorts of NOD/SCID mice (n=8) implanted with mCRC xenografts derived from two different patients were treated orally for 21 consecutive days with Lenalidomide (50 mg/Kg/die). Results: In vivo a significant reduction of tumor growth was observed in one cohort compared to untreated controls (n=8), 247±118 mm3 vs. 567±216 mm3 (P=0.02), while no significant differences occurred in the second cohort. Pathology review on tumor samples removed from the mice revealed a trend toward the restoration of normal colon tissue morphology and architecture in lenalidomide treated samples compared to untreated controls. Quantitative evaluation of tumor angiogenesis on the responsive cohort, by immunohistochemistry for factor VIII, revealed a tumor-vessel reduction of 49% with lenalidomide compared to controls. Moreover, necrotic-hypoxic areas were reduced by 6 fold in lenalidomide treated xenografts compared to untreated controls (P<0.001). Treatment in vitro did not result in any direct antitumor effect. The average rate of cell death in treated samples was 15.5±2.1%, 15.3±6.7%, and 11.5±3.4% at lenalidomide doses of 10, 40 and 150 µM respectively, compared to 14.6±2.6% of untreated controls. Conclusions: Our data indicate a potential activity of lenalidomide against mCRC. The beneficial effect was limited in-vivo, supporting the hypothesis that the main activity of lenalidomide is exerted through modulation of tumor microenvironment and angiogenesis rather than a direct antitumor effect. Our findings may be of clinical relevance and support further investigations to explore the benefit of lenalidomide in the challenging setting of mCRC.