bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel drug discovery by pharmacogenomic profiling of 36 colorectal cancer cell lines.
Authors: Eide Peter , Bruun Jarle , Sveen Anita , MurumÃƒÂ¤gi Astrid , Mpindi John , Arjama Mariliina , Kallioniemi Olli , Lothe Ragnhild A 
Published: February 2017

604 Background: Patients with advanced colorectal cancer (CRC) are commonly administered chemotherapy by 5-Fluorouracil in various combinations with leucovorin, oxaliplatin and irinotecan. Metastatic CRCs are additionally eligible for targeted anti-VEGF treatment and anti-EGFR therapy if the tumor is KRASwt. Unfortunately, the response rates are low and novel drugs are needed. Cell lines have successfully been employed to predict drug response and several studies have demonstrated that CRC cell lines recapitulate the genetic variation among primary CRCs. Methods: We performed a high-throughput drug screen (n= 461) of 36 CRC cell lines. A multiplexed assay assessed drug effects on cell viability and cytotoxicity from a five-fold concentration range. Sensitivities were measured by calculating a drug sensitivity score for each drug using a validated algorithm that estimates the relative inhibition by normalization against the top asymptote of the drug concentration curve. By integrating drug sensitivity data with in-house datasets on DNA copy number, gene expression and deep DNA sequencing, we aimed to validate genetically indicated drug sensitivities and identify novel drug sensitivities among subsets of CRCs. Results: Pharmacological relationships for molecular subgroups of CRC were revealed by clustering analyses, outlier analysis and t-tests of the drug sensitivity scores. We found robust correlations between BRAF-mutation status and response to BRAF-inhibitors, and lack of response to Fluorouracil and its prodrug Capecitabine for cell lines with microsatelite instability. These cell lines were sensitive to Topoisomerase I-inhibitors, such as Irinotecan, Valrubicin and Idarubicin. Cell lines with TP53wt were sensitive to the TP53-MDM2 interaction inhibitor Nutlin-3. We additionally identified a more potent novel TP53-MDM2 interaction inhibitor. Pharmacologic correlations for drug classes such as MEK-, EGFR-, Aurora A/B-, PI3K/AKT-, HSP90 and IGF1R-inhibitors were also found. Conclusions: A comprehensive drug screen of 36 CRC cell lines confirms pharmacogenomic relationships and reveals novel potentially relevant therapies for CRC.
Signal transduction and activator of transcription 3 (STAT3), host inflammatory responses and survival of patients with colorectal cancer.
Authors: Park James Hugh , Mcmillan Donald C. , Clark Jennifer , Horgan Paul G. , Roxburgh Campbell S.D. , Edwards Joanne 
Published: February 2017

606 Background: In patients with colorectal cancer (CRC), the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression, and may be linked by activation of the IL-6/JAK/STAT3 pathway. The present study examines the associations between STAT3 expression and activation with LIR and SIR of patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and who were included in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic total STAT3 and nuclear phosphorylated STAT3Tyr705 (pSTAT3) expression. The relationship between STAT3/pSTAT3 expression and clinicopathological characteristics, LIR (Klintrup-Makinen (KM) grade, CD3+ and CD8+T-cell density) and SIR (modified Glasgow Prognostic Score (mGPS)) and cancer-specific survival (CSS) was examined. Results: 201 patients were included. Cytoplasmic STAT3 expression was associated with nuclear pSTAT3 expression (P= 0.019). Increased cytoplasmic STAT3 expression was associated with high density of T-cells within the intraepithelial compartment (CD3+: low STAT3 – 49% vs. high STAT3 – 29%, P= 0.008; CD8+: low STAT3 – 43% vs. high STAT3 – 20%, P = 0.002) and with an elevated mGPS (mGPS > 1: low STAT3 – 31% vs. high STAT3 – 49%, P= 0.003) but not with any other clinicopathological features. Increased nuclear pSTAT3 expression was associated with younger age and lymph node involvement (P< 0.05) but was not associated with the LIR or SIR. Combined assessment of cytoplasmic STAT3 and nuclear pSTAT3 expression stratified 5-year CSS from 78% (both low) to 50% (both high) (P= 0.006). Conclusions: Activation of the IL-6/JAK/STAT3 pathway may be an important determinant of the LIR and SIR in patients with colorectal cancer. Furthermore, assessment of host inflammatory responses may identify patients likely to benefit from therapies targeting this pathway. Taken together with the results of recent clinical trials, the results of the present study suggest that recruitment of patients into future trials of such agents should be stratified by the inflammatory status of the patient.
Prognostic significance of programmed death-ligand 1 (PD-L1) expression on tumor infiltrating immune cells (IC) in patients with stage IIIb colorectal cancer.
Authors: Koganemaru Shigehiro , Inoshita Naoko , Miura Yuji , Fukui Yudai , Ozaki Yukinori , Tomizawa Kenji , Hanaoka Yutaka , Toda Shigeo , Suyama Koichi , Tanabe Yuko , Moriyama Jin , Fujii Takeshi , Matoba Shuichiro , Kuroyanagi Hiroya , Takano Toshimi 
Published: February 2017

611 Background: Programmed death 1 (PD-1)/ PD-L1 pathway is a negative feedback mechanism that suppresses the activity of T cells. Some previous studies showed that positive PD-L1 expression on tumor cells (TC) was poor prognostic factor in patients with colorectal cancer; however, recent studies suggest that IC also play important roles to determine the prognosis in cancer patients. The aim of this study is to investigate the association of clinical and pathological features with PD-L1 expression on TC and IC. Methods: We retrospectively reviewed data of consecutive patients with stage IIIb colorectal cancer (Japanese classification of colorectal carcinoma The 8th Edition), who underwent surgery and received adjuvant chemotherapy in our institution between January 2009 and July 2012. PD-L1 expression was evaluated by immunohistochemistry (IHC) on TC and IC. Specimens were scored as IHC low (L) or high (H), if < 5% or ≥ 5% of cells were PD-L1 positive, respectively. Results: Seventy-four patients were included in this analysis. Median age was 61 years (range 32-84). Thirty-one (41.9%) and 43 (58.1%) patients received fluoropyrimidine and fluoropyrimidine combined with oxaliplatin as adjuvant chemotherapy, respectively. The median follow-up time was 51.3 months (range 4.6-75.9). The number of patients with PD-L1 expression on TC/IC (H/H, H/L, L/H, and L/L) were 0, 12, 11, and 51, respectively. The median disease-free survival (DFS) in patients with high and low PD-L1 expression on TC were 29.9 months and “not reached”, respectively (hazard ratio [HR] 2.02; 95% confidence interval [CI], 0.85-4.30; P = 0.11). The median DFS in patients with high and low PD-L1 expression on IC were “not reached” and 55.1 months, respectively (HR 0.29; 95%CI, 0.05-0.95; P = 0.04). Conclusions: Although high PD-L1 expression on TC is associated with poor prognosis, high PD-L1 expression on IC positively affects the survival in patients with stage IIIb colorectal cancer.
Thrombin activatable fibrinolysis inhibitor, tissue factor pathway inhibitor, and prothrombin fragment 1+2 levels in patients with advanced colorectal cancer.
Authors: Salman Tarik , Bilici Ahmet , Arslan Cagatay , Varol Umut , Yildiz Ibrahim , Akyol Murat , Yildiz Yasar , Kucukzeybek Yuksel , Alacacioglu Ahmet , Yilmaz Ugur 
Published: February 2017

615 Background: Thromboembolism is common in cancer patients.Thrombin activatable fibrinolysis inhibitor (TAFI), tissue factor pathway inhibitor (TFPI) and prothrombin fragment 1+2 (F1+2) are newly identified molecules involved in coagulation and fibrinolysis. The aim of this study was to investigate the relationship between clinicopathologic characteristics and TAFI, TFPI and F1+2 levels in patients with advanced colorectal cancer. Methods: Eighty-two patients (32 metastatic, 50 locally advanced disease) diagnosed with colorectal cancer in the medical oncology clinic, without history of thromboembolism, had not undergone an intervention, and not on medication affecting coagulation were included in the study. Serum TAFI, TFPI, and prothrombin F1+2 levels were evaluated via enzyme-linked immunosorbent assay. Clinicopathologic characteristics of the patients were investigated retrospectively from the medical records of the patients. Results: The plasma TAFI, TFPI, and prothrombin F1+2 levels were high in 70, 71, and 96% of the patients, respectively. Prothrombin F1+2 levels were higher among patients with lower performance scores. TFPI levels were higher among patients with tumor grades of 2 and 3. TAFI levels were higher among rectal cancer cases. Conclusions: There is an association between tumor grade and coagulation cascade. The higher prothrombin F1+2 levels, an indicator of active coagulation cascade, among patients with low performance scores may indicate that the coagulation cascade of these patients is more active. Higher TAFI levels among rectal cancer patients may be related to the natural course of the disease
Phase II study of dovitinib in patients (Pts) progressing on anti-vascular endothelial growth factor (VEGF) therapy.
Authors: Semrad Thomas John , Kim Edward Jae-hoon , Tanaka Michael S. , Sands Jacob , Roberts Chris , Astrow Stephanie H. , Stephens Craig , Moran Miriana , Burich Rebekah , Li Yu , Gandara David R. , Lara Primo , Mack Philip C. 
Published: February 2017

616 Background: Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-VEGF therapy. We tested dovitinib, an oral inhibitor of both FGFRs and VEGFRs in pts progressing on anti-VEGF treatment. Methods: Pts with measurable advanced colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) with progression despite treatment with an anti-VEGF agent within 56 days, good performance status (PS) and adequate organ function were eligible. A pre-treatment tumor biopsy was followed by treatment with dovitinib 500 mg on a 5 day on / 2 day off schedule for 28-day cycles. The primary endpoint of response (RECIST 1.1) was evaluated every 2 cycles. Secondary endpoints included toxicity and the disease control rate at 8 weeks. Intratumor mRNA expression was analyzed using a Next Generation Sequencing based expression array and circulating angiogenic factors analyzed by a multiplex bead-based assays and ELISAs. Results: Ten pts (9 CRC, 1 NSCLC) treated previously with bevacizumab (8) or ziv-aflibercept (2) enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable pts; 3 withdrew consent during cycle 1. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All pts experienced at least 1 grade 3 or higher treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. Dovitinib modulated circulating VEGF pathway components; however, no hyperphosphatemia was observed and plasma FGF2 increased continuously. Conclusions: We found no evidence for the activity of dovitinib in pts with CRC progressing on anti-VEGF therapy and could not confirm potent FGFR inhibition. Toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway. Clinical trial information: NCT01676714.
C6-ceramide's effect on KRAS-defined colorectal cancer cells treated with oxaliplatin, 5-fluoruracil with and without cetuximab.
Authors: Menendez Alvaro G. , Curzake Daniel J. , Luo LuGuang , Wanebo Harold J. 
Published: February 2017

619 Background: Cetuximab (Cet) is beneficial for patients with metastatic KRAS Wild type (WT) colorectal cancer (mCRC) only. C6-Ceramide (C6-Cer) can act synergistically with chemotherapy to induce cancer cell death. The aim of this study was to compare growth inhibition percentage (GIP) of cytostatics 5-fluoruracil (5-FU), oxaliplatin (Ox) and Cet with or without C6-Cer in KRAS WT and KRAS mutant (KRAS Mut) CRC cell lines (SW48 and SW480, respectively). Methods: Both cell lines were incubated with IC50 concentrations of test drugs. Drug concentrations included 0.8µM for 5-FU, 0.04µM for Ox, 25 µg/mL for Cet, and C6-Cer concentrations ranged from 5 to 10 µM. Cell survival was assessed 72h after using 0.4% Trypan Blue. Results: With above mentioned concentrations, C6-Cer’s GIP was 78.3% for SW-480 (vs. 33.33% for SW-48). It was also noted that the addition of C6-Cer to a combination of steady concentrations of Ox, Cet and 5-FU increased GIP with an especially significant effect on SW-480. Addition of 5 and 7.5µM resulted in doubling of GIP (75% and 86.25%, respectively, vs 32.5% of 5-FU + Ox + Cet). The greatest effect was seen when 10µM of C6-Cer was added to the IC50 concentrations of chemotherapeutic agents (using the 25µg/mL concentration of Cet), where GIP increased from 32.5% to 92.5% in SW-480. Same concentration of drugs increased GIP for SW-48 to a similar 93.5%. Conclusions: C6-Cer appears to have direct inhibitory properties, especially on KRAS Mut cells. Additionally when added to Ox, 5-FU and Cet, C6-Cer reversed the apparent insensitivity of KRAS Mut to Cet. Also, the study showed C6-Cer can provide additional synergism to their cytostatic properties in KRAS WT CRC cell lines. The true mechanism of these observations is still undergoing analysis, however the effect of isolated C6-Cer on KRAS Mut raises possibility of a different pathway that could bypass EFGR pathway. We believe the results of this study provide a starting point for clinical studies with C6-Ceramide in patients with relapsing or metastatic KRAS Mut CRC in combination with standard chemotherapy plus molecular target agents hoping they will translate into clinical benefit for this difficult to treat patient population.
A single institution experience of EGFR inhibitors in patients with advanced squamous cell anal carcinomas (SCAC).
Authors: Kim Dae Won , Byer Jennifer Elizabeth , Kothari Nishi , Mahipal Amit , Kim Richard D. 
Published: February 2017

623 Background: Although SCAC are relatively rare, their incidence has been increasing steadily. Because of limited data, treatment of metastatic disease is a major therapeutic challenge. Recent data has demonstrated a low rate of KRAS and EGFR mutations, suggesting a potential target of EGFR inhibitors. In this study, we report the safety and efficacy of EGFR inhibitors in patients (pts) with advanced SCAC. Methods: A retrospective analysis was conducted using the Moffitt Cancer tumor registry from 1/2009 to 1/2014. Eligible pts had advanced SCAC and received an EGFR inhibitor as part of their treatment. Results: 13 pts were identified for analysis. Median age was 59 years (range: 41-68). All pts received concurrent chemoradiation (Nigro regimen) as initial treatment and subsequently had recurrence. Upon diagnosis of recurrent disease, 5 pts received 2 lines of systemic chemotherapy, 5 pts received 1 line and 3 did not receive any treatment prior to receiving EGFR inhibitors. 5 pts received single agent cetuximab (4) or panitumumab (1) and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. Pts received a median EGFR inhibitor dose of 8 (range: 2-45). Objective response rates were 30.8% (1 CR, 3 PR) and disease control rates were 46.2%. 1 pt with CR was on single agent cetuximab as second line therapy and 3 pts with PR were on cetuximab plus chemotherapy as front-line. With a median follow-up of 9.6 months (mo), the median PFS and median OS were 4.4 mo (95% confidence interval (CI) 2.99-5.81) and 11.4 mo (95% CI 7.93-14.87), respectively. No KRAS mutation was detected in 8 pts and KRAS testing was not done on 5 other pts. Grade 3 toxicities included anemia (n = 2), fatigue (n = 1), depression (n = 1), dyspnea (n = 1), anorexia (n = 1), nausea (n = 1) and diarrhea (n = 1). No grade 4 toxicities were observed. Conclusions: Our analysis suggests that EFGF inhibitors have potential efficacy and are reasonably well tolerated in patients with SCAC. These findings warrant further evaluation in a large prospective trial.
BASAL immunologic response and its modifications after treatment with ANTI-EGFR in patients with advanced colorectal cancer.
Authors: Vieitez Jose M , Moro-Garcia Marco , Jiménez-Fonseca Paula , Echeverria de Carlos A , Iglesias Escudero Mar , Sánchez Lorenzo Luisa , Solis Hernandez Maria Del Pilar , Alonso Rebeca 
Published: February 2017

626 Background: CRC patients treated with anti-EGFR having skin reactions tend to have a better outcome regardless of the presence of mutations in the RAS. This fact, repeated with various antibodies makes us think that the basal immunology, or its ability to react to these proteins is actually responsible for this phenomenon. We initiated an exploratory study to identify which parameters/immunological pathways might be related to skin reactions. Methods: Seric levels of immunoglobulins (IgG, IgA, and IgM) and complement factors (c3 and c4) were measured. Leukocyte and lymphocyte subsets were also quantified in peripheral blood. We evaluated cytotoxic activity of NK lymphocytes (CD107a expression in response to K562 cells) and activation of CD4+ and CD8+ T-lymphocytes in response to anti-CD3 stimulation (expression of CD38, HLA-DR, CD25 and CD69). Results: 17 consecutive patients were included from 29/08/2012 to 17/11/14. Median age was 66 (range 50-80), median number of organ affected 1 (range 1-3), liver affected in 8 patients. 9 Patients were treated with folfiri/panitumumab, 4 cpt11/panitumumab, 4 with panitumumab monochemotherapy. Two patients presented a partial response, median days to progression were 176 days (range 15-652). Levels of immunoglobulins, complement factors, and leukocyte subsets showed no differences between both groups of patients (with or without skin reactions). Increased T-lymphocyte percentages were found in patients without skin reactions, mainly explained by higher levels of CD8+ T-lymphocytes but with a more differentiated phenotype. Neither frequencies nor cytotoxic activity of NK-lymphocytes showed differences between patients. However, anti-CD3 stimulation induced higher activation status in CD4+ and CD8+ T-lymphocytes in patients having skin reactions, with increased levels of activation marker expression of CD38, HLA-DR, CD25 and mainly CD69. Conclusions: T-lymphocytes of CRC-patients having skin reaction in response to anti-EGFR treatment seem to have a less differentiated status and a higher ability to be activated by anti-CD3 stimulation in vitro.
Clinical study on medical value of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer (COMVI study).
Authors: Yoshida Yoichiro , Naito Masayasu , Yamada Teppei , Aisu Naoya , Kojima Daibo , Mera Toshiyuki , Tanimura Syu , Tanaka Toshihiro , Naitoh Keiko , Yasumoto Kosei , Kamigaki Takashi , Goto Shigenori , Yamashita Yuichi 
Published: February 2017

628 Background: Adoptive immunotherapy of cancer is evolving with the development of novel technologies for generating a large number of activated killer cells such as αβ T cells, γδ T cells, and natural killer (NK) cells. We conducted a pilot study to evaluate the safety and feasibility of the combination treatment of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer. Methods: The COMVI study was a prospective and single-arm pilot trial. Therapy in each 21-day treatment cycle consisted of XELOX (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1–14), bevacizumab (7.5 mg/kg on day 1) and αβ T lymphocytes (over 5 ×109 on day 18) cultured ex vivo with an immobilized anti-CD3 antibody and interleukin-2. Results: A total of 6 patients were enrolled from June 2013 to September 2014. Baseline characteristics included a median age of 66 years (range: 55-75) for 2 men and 4women. Median PFS was 567 days. Overall response rate was 100 % (CR 33.3%, PR 66.7%, SD 0%, PD 0%). The tumor reduction rate was 53% (38.0–100%). The majority of adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 6 patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study. Conclusions: The combination treatment of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are warranted to confirm the safety and efficacy of this chemoimmunotherapy. Clinical trial information: UMIN000010908.
Frequency of unplanned surgical intervention in patients with stage IV colorectal cancer receiving palliative chemotherapy: An analysis of SEER-Medicare.
Authors: Lorimer Patrick D. , Walsh Kendall K , Kirks Russell C. , Han Yimei , Hwang Jimmy J. , Salo Jonathan C. , Hill Joshua S. 
Published: February 2017

640 Background: Patients (pts) with synchronous stage IV colorectal cancer commonly begin palliative chemotherapy while the primary tumor remains. Single institution series report low rates of surgical intervention, but this has not been examined nationally. The present study utilizes a large national dataset to examine the natural history of unplanned surgical intervention in stage IV colorectal cancer pts on palliative chemotherapy. Methods: SEER-Medicare was queried for pts with metastatic colorectal cancer (1998-2009) who underwent resection or diversion (ICD9 procedure/CPT). The cohort was separated into 3 groups: elective (surgery on admission without urgent/emergent flag), urgent (surgery not on day of admission but within hospitalization or with urgent flag) and emergent (emergent flag). Pts who underwent any procedure for curative intent (elective colorectal surgery, liver directed therapy or surgery for pulmonary metastases) at any time were excluded. Demographics, tumor grade and comorbidities were analyzed for effect on intervention rate. Time to event for either urgent or emergent surgical intervention or censorship by death, were measured. Conditional analyses were performed to determine the risk of surgical intervention at 6 months, 1 and 2 years post diagnosis. Results: 3,992 pts met inclusion criteria. Median age=73; 53% male. White 79%, black 11% and other 10%. The overall intervention rate was 6%; 35% emergent, 65% urgent. At 42 months, 90% of the pts had died. The probability of requiring unplanned surgery between 6-12 months was 2.5%; 12-24 months=1.9%, and >24 months=0.8%. Charlson comorbidity score of 1 was a significant predictor of surgical intervention (HR 1.64 [1.24, 2.19]). Sex, age and race had no influence on the likelihood of surgical intervention. Conclusions: This study represents a large series of stage IV colorectal cancer pts and the frequency of unplanned surgery in pts receiving palliative chemotherapy. Pts treated with palliative chemotherapy are unlikely to require urgent or emergent surgery, and therefore prophylactic surgery to reduce the risk of perforation or obstruction should not be routinely performed.