bluuebunny/crossref_metadata_2025_split huggingface dataset:
PKM2 as a biomarker for sensitivity to oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).
Authors: Papadaki C. , Saridaki Z. , Tzardi M. , Sfakianaki M. , Sfakiotaki G. , Trypaki M. , Messaritakis I. , Mavroudis D. , Georgoulias V. , Sougklakos I. 
Published: February 2017

434 Background: Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase (PKM2), which is a key enzyme that regulates aerobic glycolysis in tumor cells. Use of RNA interfering (RNAi) targeting PKM2 significantly inhibits tumor growth when combined with cisplatin in xenograft models. We evaluated the predictive significance of PKM2 in patients with mCRC treated with oxaliplatin- based chemotherapy in the first-line setting. Methods: FFPE primary tumors from 140 mCRC patients were analyzed for PKM2 mRNA expression by RT-qPCR. The analysis was performed with a set of primers and probes which amplify only the M2 isoform. Results: The patients' characteristics were all typical for mCRC (median age 65 years, 61% males, 75% colon cancer 25% rectal cancer, 41% undifferentiated tumors, 21% mucinous features). PKM2 was successfully amplified in all specimens. Time to tumor progression (TTP) was significantly lower in patients with overexpression of PKM2 (6.7 vs. 9.1 months for high and low expression, respectively, p=0.004). Similarly, median overall survival (mOS) was significantly decreased in patients with upregulation of PKM2 (21.9 vs. 30.2 months for high and low expression, respectively, p=0.004). Multivariate analysis revealed PKM2 high mRNA expression (HR: 1.7, p=0.005) and the presence of undifferantited tumors (HR: 2.2, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, PKM2 high mRNA expression (HR: 1.8, p=0.005) and the presence of undifferantited tumors (HR: 2.5, p<0.0001) were revealed as independent prognostic factors for decreased mOS. Conclusions: These results provide evidence that the PKM2 mRNA expression could be used as a predictive factor for sensitivity to oxaliplatin-based chemotherapy. The results should be validated prospectively in an independent patient cohort. No significant financial relationships to disclose.
Impact of KRAS, BRAF, and PIK3CA mutations, PTEN, AREG, and EREG expression, and skin rash in metastatic colorectal cancer patients treated with cetuximab-containing salvage treatment.
Authors: Saridaki Z. , Tzardi M. , Papadaki C. , Sfakianaki M. , Pega F. , Kalikaki A. , Tsakalaki E. , Mavroudis D. , Georgoulias V. , Sougklakos I. 
Published: February 2017

445 Background: To investigate the predictive significance of KRAS exon 2, BRAF V600E, PIK3CA exon 9 and 20 mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in patients with metastatic colorectal cancer (mCRC) treated with cetuximab containing salvage chemotherapy. Methods: Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded. Results: KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p=0.001 and p=0.026, respectively) or BRAF (p=0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p=0.018 and p=0.013, respectively) or EREG (p=0.002 and p=0.004, respectively) and in those with grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p=0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p=0.021 and p=0.004, respectively) or EREG (p=0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p=0.01) or lost PTEN (p=0.002). Multivariate analysis revealed KRAS (hazard ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low mRNA expression (HR: 1.6, p=0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p=0.01), BRAF mutation (HR: 3.0, p=0.001), EREG low mRNA expression (HR: 1.7, p=0.021), absecence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p=0.001) were revealed as independent prognostic factors for decreased OS. Conclusions: These results underscore the potential of advanced CRCs genetic profiling in order to identify patients with different treatment response. No significant financial relationships to disclose.
New analysis of the hypertension mechanism in bevacizumab-treated patients using 3-tesla dynamic contrast-enhanced magnetic resonance imaging.
Authors: Hirashima Y. , Yamada Y. , Tateishi U. , Kato K. , Miyake M. , Akiyoshi K. , Horita Y. , Nagashima K. , Shirao K. 
Published: February 2017

450 Background: Vascular endothelial growth factor (VEGF) signaling inhibitors, such as bevacizumab (BV), leads to endothelial dysfunction and microvascular rarefaction in noncancer tissue. Angiotensin II has been reported to induce VEGF production by inhibiting VEGF, but the reasons for activation of angiotensin II are unclear. We conducted a study to examine the relationship between renin-angiotensin axis and renal blood perfusion using dynamic contrast magnetic resonance imaging (DCE-MRI) in colorectal cancer patients. Methods: Sixteen patients with colorectal cancer were enrolled. They received BV+FOLFIRI regimen as second line. DCE-MRI was performed before the treatment and after 12th courses. Renin, angiotensin I, angiotensin II and aldosterone were examined before treatment and at 3, 5, 8, 12th courses. DCE-MRI parameters, Area under the time-intensity curve over the first 90 seconds after injection of contrast material (AUC90) and volume transfer constant of contrast material (Ktrans, Kep) were calculated in the normal kidney and examine the correlation with renin-angiotensin axis. Results: All DCE-MRI parameters decreased significantly after 12th courses compared with before treatment (Variables median: Ktrans -1.51, Kep -2.30, AUC90 -26.0, P < 0.001, all). A decrease in Kep correlated with higher renin, angiotensin I and angiotensin II (renin: P =0.001, angiotensin I: P =0.003, angiotensin II: P =0.002, respectively). A decrease in AUC90 correlated with higher aldosterone (P =0.005). Blood pressure did not correlate with each DCE-MRI parameters. Conclusions: VEGF inhibition decreases vessel permeability and raises interstitial pressure in normal kidney. Our data suggest that renin-angiotensin axis is also one mechanism of hypertension caused by BV. No significant financial relationships to disclose.
Predictive and prognostic implications of KRAS genotype in patients with metastatic colorectal cancer (MCRC) treated with FIr-B/FOx association.
Authors: Bruera G. , Cannita K. , Di Giacomo D. , Troncone G. , Marchetti A. , Coletti G. , Sabourin J. , Tosi M. , Ficorella C. , Ricevuto E. 
Published: February 2017

457 Background: FIr-B/FOx association, consisting of triplet chemotherapy (FIr/FOx) plus bevacizumab, increases activity, efficacy, and resection rate of liver metastases in MCRC patients (Bruera G et al, submitted 2010). Even if bevacizumab-containing chemotherapy is also active in KRAS m MCRC patients, ORR, PFS, and OS seem to be lower compared to KRAS wt patients (Hurwitz et al, Oncologist 2009). Present data evaluates activity and efficacy of FIr-B/FOX according to KRAS genotype. Methods: Treatment schedule: weekly alternating bevacizumab (5 mg/kg days 1,15)/irinotecan (160 mg/m2) or oxaliplatin (80 mg/m2) associated to weekly 5- fluorouracil (12h-timed-flat-infusion, 900 mg/m2/d 1-2, 8-9, 15-16, 22-23); every 4 weeks. KRAS genotype was analyzed by direct sequencing or SNaPshot (Di Fiore et al, BJC'07) for KRAS codon 12 and 13 mutations. Results: Forty-two (84%) out of 50 enrolled patients (pts) in the FIr-B/FOx phase II study were evaluated: ORR 86% (C.I. ± 11), median PFS 13 months (3-46+), median OS 28 months (8-47). Liver metastasectomies (LM) were performed in 11 pts (26%): 42% of the 26 liver-MCRC pts; 58% of the 19 pts with liver-only MCRC pts. Twenty-five pts (59.5%) were KRAS wild-type (wt), 17 pts (40.5%) KRAS mutated (m). Clinical features were balanced. Among the 25 KRAS wt pts: ORR 88% (C.I. ± 14); median PFS 14 months (3-46+); median OS 31 months (8-47). LM were performed in 9 KRAS wt pts (36%): 56% of the 16 liver-MCRC pts; 82% of the 11 liver-only MCRC pts. Among the 17 KRAS m pts: ORR 82% (C.I. ± 19); median PFS 12 months (4-37+); median OS 19 months (8-44). LM were performed in 3 KRAS m pts (18%): 30% of the 10 liver-MCRC pts; 37.5% of the 8 liver-only MCRC pts. Conclusions: Triplet chemotherapy plus bevacizumab (FIr-B/FOx association) shows equivalent high activity (ORR) and efficacy (PFS) in KRAS wt and KRAS m MCRC pts; a trend toward a worse prognosis (OS) is confirmed in KRAS m pts. No significant financial relationships to disclose.
Feasibility and potential benefit of neoadjuvant chemotherapy for colorectal liver metastasis: A single-centered retrospective study.
Authors: Kataoka K. , Kanazawa A. , Nakajima A. , Yamaguchi A. , Tuyuki S. , Arimoto A. , Kohno Y. 
Published: February 2017

465 Background: Recently, several papers have reported the advantage of neoadjuvant chemotherapy for liver limited metastatic colorectal cancer. In these papers, most study groups used criteria for non-resectability due to size and/or number of metastases. Our criteria for resectability of colorectal liver metastases (CLM) depends on the size of remnant liver volume (>30%) and expected function after the removal of all metastases. Then, we assessed the feasibility and potential benefits of chemotherapy administered before surgery to patients with CLM retrospectively. Methods: From January 2007 to April 2010, 67 chemotherapy-naive patients were diagnosed as CLM without extra-hepatic metastases. After chemotherapy, we assessed the resectability with radiological examination.Then, each case was divided in two groups, resected group and unresected group. Overall survival, median disease-free survival and postoperative complications were analyzed. Results: 63 patients received oxaliplatin-based combination regimen and 4 patients other regimen. 30 patients (resected group) received R0 resection and 37 patients (unresected group) were considered as unresectable. No serious postoperative complications were observed. Overall survival was significantly higher in resected group than in unresected group (42.3 month and 29.1 month; P<0.001). Median disease-free survival was 18.8 months in resected group (95% CI:3.02 to 31.33). According to our retrospective review, resectable cases increased from 28 of 67 patients at baseline to 33 after chemotherapy (including 3 cases considered as CR after chemotherapy only). Conclusions: Intensive treatment with neoadjuvant chemotherapy for CLM is well tolerated. Curative surgery improved significantly overall survival in patients with CLM. Neoadjuvant chemotherapy such as mFOLFOX6 may lead to increased resectability but do not increase postoperative complications. For most patients with resectable CLM, neoadjuvant chemotherapy should be considered the standard treatment. No significant financial relationships to disclose.
Association of survivin expression following neoadjuvant radiochemotherapy in rectal cancer with distant metastases and survival.
Authors: Sprenger T. , Rödel F. , Beissbarth T. , Conradi L. , Homayounfar K. , Ghadimi B. M. , Yildrim M. , Becker H. , Rödel C. , Liersch T. 
Published: February 2017

483 Background: Valid molecular markers need to be implemented in clinical trials to fulfill the demand of a risk-adapted and more individualized multimodal therapy of locally advanced primary rectal cancer. In the present study the expression of the inhibitor-of-apoptosis (IAP) protein Survivin was evaluated in pre-treatment biopsies and corresponding post-treatment resection specimens, and was correlated to histo-pathological tumor characteristics and clinical follow-up. Methods: 116 patients with stage II/III rectal cancer treated with 5-FU-based neoadjuvant radiochemotherapy (RCT) within the German Rectal Cancer Trials were investigated. Survivin expression in pre-treatment biopsies and surgical resection specimens were determined by immunohistochemistry by two independent institutions and correlated with histopathologic parameters, tumor recurrences, disease-free and overall cancer-specific survival. Results: In pre-treatment biopsies, a higher Survivin expression correlated with advanced ypT (p=0.026) and ypUICC (p=0.05) stage as well as decreased disease-free survival (p=0.038) after preoperative RCT. High post-treatment Survivin levels were associated with advanced ypT stage (p=0.03) and residual lymph node metastases (p=0.04). Moreover, neoadjuvant RCT resulted in a significant down-regulation of Survivin expression (p < 0.0001). A failure of RCT-induced down-regulation was associated with development of distant metastases (p=0.0056) and cancer-related death (p=0.026), and was significantly correlated with disease-free (p=0.011*/0.02**) and cancer-specific survival (p=0.0017*/0.01**) in uni*- and multivariate** analyses. Conclusions: Survivin expression displays a marker with prognostic validity in rectal cancers. These results underline the usefulness of Survivin to monitor individual response to RCT in rectal cancer, and encourage anti-Survivin strategies in multimodal rectal cancer therapy within future randomised clinical trials. No significant financial relationships to disclose.
Two bi-institutional prospective studies using intraperitoneal oxaliplatin with or without irinotecan during HIPEC following complete cytoreductive surgery for colorectal carcinomatosis.
Authors: Quenet F. , Goéré D. , Mehta S. , Roca L. , Dumont F. , Essissen M. , Sain-Aubert B. , Elias D. 
Published: February 2017

486 Background: In treatment of peritoneal carcinomatosis (PC) of colorectal origin, studies combining cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC) have shown encouraging survival results. Intraperitoneal drugs usually used are mitomycin C or oxaliplatin in monotherapy. The aim of this study was to assess long-term survival in patients treated with a new combination of oxaliplatin and irinotecan (ox-irino) and to compare it with that obtained with oxaliplatin alone (ox-alone). Methods: Two bi-institutional prospective studies were carried out. All patients with PC who had undergone CRS with HIPEC using either ox-alone 460 mg/m2 or ox-irino (ox: 300 mg/m2 and irino: 200 mg/m2) from January 1998 to December 2007 were included. Results: 146 patient underwent CRS + HIPEC for PC from colorectal carcinoma. 103 patients received ox-irino and 43 patients received ox-alone HIPEC. The overall mortality rate was 4.1%. The overall morbidity rate was 47.2%. It was significantly lower in the ox-alone group compared to the ox-irino group (34.9% vs. 52.4%, p =0.05). After a median follow-up of 48.5 months, (95%CI 41.0-56.3), the median OS was 41 months (95%CI 32-60) and the median RFS was 15.7 months (95%CI 12-18). The median RFS of the ox-alone group was 16.8 months (95%CI 11-25) and was not significantly different from that of ox-irino group (15.7 months, 95%CI 11-18, p = 0.93). There was no significant difference between the median OS of the ox-alone group (40.83 months, 95%CI 29–61) and the ox-irino group (47 months, 95%CI 32-61, p = 0.94). At 5 years, the OS and the RFS rates were respectively 41.8% (95% CI 25.20-57.58) and 13.8% (95% CI 4.66-27.84) in the ox-alone group and 42.4% (95% CI 28.52-56.09) and 14.2% (95% CI 6.27-25.20) in the ox-irino group. Conclusions: This study confirms the interesting survival results of CRS + HIPEC to treat colorectal PC. 460 mg/m2 of oxaliplatin alone HIPEC is as efficient as 300 mg/m2 of oxaliplatin associated with 200 mg/m2 of irinotecan, but with lower morbidity. Ox-alone HIPEC, should remain the current gold standard. No significant financial relationships to disclose.
Catumaxomab therapy in peritoneal carcinomatosis from colon cancer: Clinical benefit in comparison to systemic chemotherapy alone and cytoreductive surgery/hyperthermic chemoperfusion.
Authors: Ströhlein M. A. , Heiss M. M. 
Published: February 2017

488 Background: There is still no effective treatment for the majority of patients suffering from peritoneal carcinomatosis (PC) of colon cancer. Palliative chemotherapy (CHEM) had limited efficacy. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) showed promising results, but was manageable in early stage PC patients only. Catumaxomab therapy (CATU) offers a new option for intraperitoneal treatment in all stages of PC. Aim of the study was to evaluate CATU therapy in comparison to HIPEC and systemic therapy. Methods: Between 2005 and 2008, 76 patients suffering from PC of colon cancer were included and treated with systemic chemotherapy alone (35), HIPEC +/- systemic chemotherapy (21) and CATU +/- chemotherapy (22). All patients were assessed for therapy-related severe side effects, incidence of intestinal obstruction-ileus and ascites and for overall survival. Results: Grade IV side effects were observed in 9.1% of CATU patients, 14.3% after HIPEC and 5.7% after CHEM. Ascites was found in not a single patient after CATU vs. one patient after HIPEC (4.5%) and 7 patients after chemotherapy (20%, p<0.03). Intestinal obstruction was found in 22.7% of patients after CATU vs. 14.3% after HIPEC and in 42.9% of patients after chemotherapy (p<0.04). In comparison to systemic chemotherapy, overall survival was significantly increased after CATU (15.2 months, p=0.03) and HIPEC (20.1 months, p=0.02; median follow-up 17 months). Conclusions: Catumaxomab therapy of patients with PC from colon cancer was associated with a preventive effect for accumulation of malignant ascites and intestinal obstruction. Patients receiving CATU or HIPEC therapy concepts showed a survival benefit compared to systemic chemotherapy alone. Therapy strategies containing intraperitoneal catumaxomab treatment may be beneficial in patients with PC from colon cancer, even in advanced PC disease, when HIPEC was not feasible. [Table: see text]
Microsatellite instability status as a predictive marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer.
Authors: Zaanan A. , Flejou J. , Emile J. , Validire P. , Louvet C. , Rougier P. , De Gramont A. , Praz F. , Taïeb J. 
Published: February 2017

493 Background: The addition of oxaliplatin to 5-fluorouracil (5-FU; FOLFOX regimen) was demonstrated to improve the adjuvant treatment of stage III colon cancer. For patients with microsatellite instability (MSI) tumors, several studies suggested a lack of benefit from 5-FU adjuvant chemotherapy but very little data are available regarding FOLFOX adjuvant therapy. The aim of this study was to further assess the value of MSI status as a marker of clinical outcome from FOLFOX adjuvant chemotherapy in stage III colon cancer. Methods: This multicentric retrospective study included 223 unselected patients with stage III colon cancer treated by FOLFOX adjuvant chemotherapy between 2003 and 2007. MSI status was determined by immunohistochemistry as the absence of MLH1, MSH2 or MSH6 expression. Disease-free survival (DFS) and relapse-free survival (RFS) were analyzed according to the MSI status using Kaplan Meier method and compared by log-rank test. Results: Twenty three tumors (10.3%) were MSI. The rate of 3-year DFS was 88.6% and 76.6% for MSI and MSS groups, respectively (HR=0.64; 95% CI, 0.25 to 1.60; P=0.34). The rate of 3-year RFS was 88.6% and 76.7% for MSI and MSS groups, respectively (HR=0.52; 95% CI, 0.20 to 1.30; P=0.18). Conclusions: A trend toward longer survival was observed for patients with MSI tumors compared with those with MSS tumors but the differences in survival were not significant. Interestingly, DFS at 3-years of patients with stage III MSI tumors treated by FOLFOX was higher in our series (88.6%) than in the largest study published for patients treated by 5-FU-based adjuvant chemotherapy (around 67.5%) or surgery alone (around 62.5%) (Sargent et al, JCO 2010). These observations suggest that adding oxaliplatin to 5-FU re-establishes a benefit of adjuvant treatment in the stage III MSI population. These results should be confirmed by analyzing materials of previously completed trials comparing FOLFOX to 5-FU such as the MOSAIC study. [Table: see text]
Patterns of maintenance treatment (Tx) following first-line bevacizumab (bev) plus chemotherapy (CT) for metastatic colorectal cancer (mCRC): Results from a large German community-based cohort study.
Authors: Arnold D. , Petersen V. , Kindler M. , Schulze M. , Seraphin J. , Hinke A. , Srock S. , Kutscheidt A. 
Published: February 2017

502 Background: As a result of the long PFS with bev-containing combinations in first-line mCRC, discontinuation of at least one CT component after an “induction” period and continuation with “maintenance” Tx is common. It is anticipated that duration and patterns of maintenance Tx may affect PFS. Methods: We analysed induction and maintenance Tx in a large observational cohort study of bev + various first-line CT regimens. Results of the entire cohort were reported earlier [Arnold et al. ASCO GI 2010]. Results: From Jan 05 to Jun 08, 1620 patients (pts) were enrolled at 261 sites. 1,307 pts (81% of total) received bev + fluoropyrimidine-oxaliplatin (n=306, 23.5%) or fluoropyrimidine-irinotecan (n=1,001, 76.5%). While Tx reduction was not predefined, after induction 271 pts (21%) received de-escalated maintenance Tx: bev alone (n=106; 8%), or bev + CT (n=165; 13%). Median Tx duration for pts receiving bev alone was 8.7 mo for induction and 3.2 mo for maintenance. Pts receiving bev + CT maintenance had shorter induction (5.1 mo) but longer maintenance (4.4 mo). Median PFS (after induction) with bev maintenance was 10.8 mo vs. 13.5 mo for bev + CT maintenance. Data are available from 161 pts with bev + CT maintenance after induction with oxaliplatin (n=97) or irinotecan (n=64). Median total Tx duration was 9.6 mo for oxaliplatin-based induction and 10.9 mo for irinotecan-based induction; median induction duration was 4.1 and 5.5 mo, and maintenance duration was 4.3 and 4.4 mo, respectively. Median PFS (after induction) was 12.8 and 14.1 mo, respectively. Progressive disease (PD) has not yet occurred in 165 pts (62% of maintenance cohort). A high proportion of pts received Tx until PD (74% and 79%, respectively). Conclusions: Both de-escalation strategies led to long PFS and a high number of pts treated ′until PD′. A trend towards better PFS was observed in pts receiving bev + CT maintenance vs. single-agent bev. The ongoing randomized AIO KRK 0207 trial is prospectively evaluating three different maintenance strategies after induction with bev + fluoropyrimidine + oxaliplatin. [Table: see text]