bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential expression of small ubiquitin-like modifier family of proteins in patients with colorectal adenocarcinoma.
Authors: Wiatrek R. , Duldulao M. P. , Chen Z. , Li W. , Kim J. , Li Y. , Chen Y. , Garcia-Aguilar J.
Published: February 2017

420

Background: The cytotoxic effects of radiation and chemotherapy are mediated in part by DNA damage. The small ubiquitin-like modifier (SUMO) family of proteins regulates DNA repair pathways by activating factors involved in homologous recombination (HR) or non- homologous end joining (NHEJ). Our objective was to determine the potential role of SUMO proteins in patients with colorectal cancer.

Methods: We first assessed two established colorectal cancer cell lines (HCT116 and HT29) and two normal colonic mucosa cell populations utilizing ultra high-throughput expression analysis (Solexa) to examine differential expression of genes involved in SUMOylation (SAE1, SAE2, PIAS-1, and DNAPKcs). To verify the clinical relevance of SUMOylation in colorectal cancer, we obtained archived specimens from patients with colorectal cancer (n=51) and examined the expression of these proteins in both benign and malignant tissue by immunohistochemistry (IHC).

Results: Ultra high-throughput expression analysis of cancer and normal cells revealed a 10 to 15-fold upregulation of SAE2 (heterodimer of the E1 activation enzyme in SUMOylation), a 10 to 11-fold upregulation of DNAPKcs (catalytic subunit in NHEJ repair pathway), and a 6-fold upregulation of SAE1 in cancer cells. In contrast, PIAS-1 showed similar expression levels between cancer and normal colonic cells. By IHC, SAE1 and SAE2 were highly expressed in 65% and 53% of tumor specimens, respectively; but only in 7% and 0% of normal tissues, respectively. DNAPKcs was also highly expressed in tumor tissues (63%) with corresponding low expression (0%) in normal tissues. Corroborating the cell line results, PIAS-1 was infrequently expressed in both tumor (10%) and normal tissues (0%).

Conclusions: We are the first to demonstrate the differential expression of SUMO proteins in colorectal cancer cell lines and in clinical specimens. SUMO proteins have a role in DNA repair and their expression in colorectal cancer may modify tumor response to chemoradiotherapy.

No significant financial relationships to disclose.
TP53 mutations in irinotecan-refractory KRAS wt-BRAF wt metastatic colorectal cancer patients treated with cetuximab-based chemotherapy.
Authors: Di Fiore F. , Lamy A. , Blanchard F. , Oden-Gangloff A. , Sesboüé R. , Sabourin J. , Frébourg T. , Michel P. , Laurent-Puig P.
Published: February 2017

426

Background: Anti-EGFR antibodies are more efficient when EGFR pathway is activated without mutations on downstream effectors such as KRAS and BRAF (Lievre et al. Cancer Res. 2008 and Khambata-Ford et al. J Clin Oncol. 2007). Moreover, tumor growth from EGFR activation may required inactivation of the molecular brake p53 suggesting that anti-EGFR therapy should be more efficient if p53 is inactivated (Oden-Gangloff et al. Br J Cancer. 2008). The aim of the study was to evaluate, in an independent series, the impact of p53 mutations in irinotecan-refractory KRAS wt-BRAF wt MCRC patients treated with anti- EGFR.

Methods: A total of 100 MCRC patients treated with cetuximab-based CT were included. KRAS and BRAF mutational status were determined using SNaPshot or allelic discrimination methods. TP53 mutations within exons 5 to 8 were detected using direct sequencing. Response to cetuximab, based on RECIST criteria, was evaluated according to molecular analysis using the Fischer exact test. Progression- free survivals (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared with log-rank test.

Results: Objective response (OR = partial and complete response) was observed in 40% and control disease (CD = OR+stable disease) in 74% of patients. Median PFS and OS was 12 weeks and 12 months, respectively. TP53 mutations were detected in 66% of patients and were not significantly associated with OR and CD. In contrast, patients with KRAS wt-BRAF wt and TP53 mutation had significantly longer PFS as compared to KRAS wt–BRAF wt and TP53 non mutated patients (32 weeks vs. 21 weeks, respectively; p = 0.01). There was a trend but not significant increased OS in patients with TP53 mutations (16 months vs. 13 months)

Conclusions: In this independent study, our results confirm that TP53 mutation was significantly associated with an increase PFS in irinotecan-refrcatory KRAS wt-BRAF wt MCRC patients treated with anti-EGFR.

[Table: see text]
Use of circulating endothelial cells to predict response to FOLFOX4 plus bevacizumab in metastatic colorectal cancer.
Authors: Matsusaka S. , Mizunuma N. , Suenaga M. , Chin K. , Shinozaki E. , Watanabe T. , Kawazoe Y. , Kuboki Y. , Terui Y. , Hatake K.
Published: February 2017

427

Background: The purpose of this study was to identify CEC threshold proposal for determining response to FOLFOX4 plus bevacizumab in metastatic colorectal cancer (mCRC).

Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital and provided informed consent. From July 2007 to June 2008, 33 patients treated with FOLFOX4 plus bevacizumab were enrolled in a prospective study. From January 2007 to June 2007, before bevacizumab was approved by the government in Japan, 31 patients treated with FOLFOX4 as a control were enrolled. The study population consisted of patients aged 18 years or older with histologically proven mCRC. Other inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function. CECs of whole blood at the baseline, day 4, 2 weeks after initiation of chemotherapy were isolated and counted using immunomagnetics.

Results: There was no correlation between CEC levels and the outcome in the FOLFOX4. In the FOLFOX4 plus bevacizumab, CEC levels at the baseline were significantly associated with the outcome. Patients with 65 or more CECs at the baseline had shorter median PFS (9.2 months), than the median PFS of fewer than 65 CECs at the baseline (18.9 months) in the FOLFOX4 plus bevacizumab (p = 0.003). Patients with 65 or more CECs at the baseline had shorter median OS (23.3 months), than the median OS of fewer than 65 CEC s at the baseline in the FOLFOX4 plus bevacizumab (p = 0.027). In the univariate analysis, lung metastasis, lymph node metastasis, and CEC levels at the baseline predicted PFS. In the univariate Cox regression analyses, peritoneal metastasis, CEC levels at the baseline were associated with OS. In order to evaluate the independent predictive effect of FOLFOX4 plus bevacizumab, multivariate Cox regression analysis was carried out. CEC levels at the baseline were the strongest predictor.

Conclusions: A threshold of lower than 65 CEC/4mL at the baseline was a significant predictor of the outcome for colorectal cancer patients treated with FOLFOX4 plus bevacizumab.

No significant financial relationships to disclose.
Effect of miR-21 on resistance to 5-fluorouracil and regulation of MSH2.
Authors: Valeri N. , Gasparini P. , Braconi C. , Lovat F. , Paone A. , Fabbri M. , Nuovo G. , Fishel R. , Croce C. M.
Published: February 2017

431

Background: MicroRNAs are small non coding RNAs controlling cell homeostasis. Defects in mismatch repair (MMR) genes cause resistance to 5-fluorouracil (5FU). miR-21 is up-regulated in colorectal cancer (CRC) and is associated with poor benefit from adjuvant 5FU. We aimed at studying if miR-21 may induce 5FU resistance by down-regulating MSH2.

Methods: Fresh frozen (32) and paraffin-embedded (50) cases of CRC and matched normal tissues were studied for miR-21 expression (Northern Blotting and in situ Hybridization) and MSH2 expression (Western Blotting and Immunohistochemistry). CRC Colo-320DM, SW620 and isogenic Lovo cells with [Lovo(MSH2+)] and without MSH2 [Lovo(MSH2-)] were used. Pre-miR-21 was used for over-expression experiments. Luciferase vectors with MSH2 (Luc-MSH2) and MSH6 (Luc-MSH6) 3'UTRs downstream of the Luciferase gene were used. Cell cycle modifications after 5FU (10uM) were assessed by FACS analysis. Lentiviral vectors encoding for miR-21 or siRNA to MSH2 or empty vectors were used for stable infection. Stable clones were injected in the flank of nude mice. Mice were treated with 5FU i.p. for 2 weeks. Tumor volume was measured once a week and calculated according to the formula Volume=LxW2/2.

Results: A statistically significant inverse correlation between miR-21 and MSH2 expression was observed by Parson's test in the two CRC cohorts. miR-21 over-expression caused reduction in MSH2 and MSH6 protein expression and in Luciferase activity after transfection with Luc-MSH2 or Luc-MSH6 vectors confirming that miR-21 directly regulates MSH2 and MSH6. miR-21 up-regulation reduced 5FU induced apoptosis and G2/M arrest at the same extent of siRNA to MSH2 in all MMR proficient cells while no significant effect was observed in Lovo(MSH2-). Complementation experiments with plasmid encoding for MSH2 promoted 5FU induced apoptosis that was inhibited by co-transfection with miR-21. Xenograft tumors over-expressing miR-21 or siRNA anti MSH2 achieved the same response to 5FU and both showed to be less responsive to 5FU than controls.

Conclusions: miR-21 causes resistance to 5FU in a MSH2 dependent manner and might be a useful marker in predicting therapeutic outcome in CRC patients.

No significant financial relationships to disclose.
Identification of unique gene expression signatures in colon cancer stroma using microarray technology.
Authors: Wang S. X. , Wang J. , Ozhegov E. , Srinivasan R. , Olowokure O. O. , Qu A. X. , Aronow B. , Bogdanov V.
Published: February 2017

447

Background: Microarrays are widely used to study gene expression patterns in cancer. In colorectal cancer, it has proven useful to predict recurrence. The majority of expression profiles are generated from the cancer itself. Given the increasing evidence of importance of the microenvironment for tumor invasion, progression and metastasis, we explored tumor stroma gene signature using microarrays.

Methods: Four formalin-fixed paraffin embedded (FFPE) colon cancer specimen carrying a pathological stage of T3-4/N0-2 were retrieved. Tumor stroma and normal stroma were separated using microdissection technology. Random sampling was used to minimize sampling bias. Total RNA was extracted, amplified, and labeled using Nugene FFPE kit, with array analysis using Affymetrix Human Gene 1.0. Eight samples, four normal stroma and four tumor stroma, were analyzed and compared. Array data were balanced and analyzed using standard software. To identify gene signature differences in tumor vs normal stroma, ComparativeMarker analysis and unsupervised cluster analysis were carried out.

Results: We identified a 969 Affymetrix probe set as a signature that is highly expressed in tumor stroma. The top 117 genes were further analyzed to carry out a pathway analysis. We found a strong signature evident in tumor stroma, and much of this signature comprised the genes of the extracellular matrix. The pathway analysis revealed evidence of the generalized IGF1/TGFbeta/CTGF/activin mediated effect on the stroma, raising the possibility that some of this derives from, or is accompanied by, angiotensin receptor signaling. Through literature search, we found that several upregulated genes (e.g., FAP) were reported to be associated with stroma activation in vitro and in vivo.

Conclusions: In this study, we successfully applied microarrays to study reactive colon tumor stroma in FFPE samples. We identified a specific gene signature reflecting stromal reaction to tumor invasion. We further identified the potential pathway that was activated in the reactive tumor stroma. We provide evidence that microarrays are useful in stroma analysis and may help identify new stromal pathways with potential diagnostic and therapeutic value.

No significant financial relationships to disclose.
Can molecular markers help predict outcome in pseudomyxoma peritonei?
Authors: Beg M. S. , Wang J. , Ahmad S. A. , Wang X. , Olowokure O. O.
Published: February 2017

455

Background: Pseudomyxoma peritonei (PMP) is a rare malignancy characterized by mucinous ascites and peritoneal tumors. Cytoreductive surgery (CRS) with or without intraperitoneal hyperthermic perfusion (IPHP) is considered the mainstay of therapy, but prognosis is variable. Due to its rarity, data on molecular phenotype is lacking and the impact on outcome is unknown. The goal of our study is to correlate molecular markers with outcome in PMP.

Methods: A retrospective analysis of cases treated at the University of Cincinnati was performed and tumors analyzed. Medical records were reviewed for clinical, demographic and outcome data. Immunohistochemical studies were performed on formalin fixed paraffin embedded tissue using antibodies to Ki-67, cyclin D, and EGFR. Tumor cells were microdissected from H&E stained sections using laser capture microdissection and DNA was extracted. Exon 1 of K-ras gene was amplified by PCR and then directly sequenced. Data were analyzed using SPSS.

Results: Of 22 patients (pts) included in this study 16 (73%) had an appendix primary and 6 (27%) colon. There were 12 females (55%) and 20 (90%) pts were white. Mean age was 53 (29-74) years. Most pts had prior surgery (18, 82%). Complete resection (>99% of visible disease) was achieved in 15 (68%) pts while 17 pts (77%) underwent IPHP. Nine pts had known recurrence (41%) and median time to recurrence (TTR) was 21(+/- 0.398) months (mo). There was one confirmed death and median survival could not be calculated. K-ras mutation was seen in 13 (60%), cyclin-D1 in 9 (41%) and EGFR in 10 (45%) cases. High Ki-67 (>51%) was seen in 8 cases. On univariate analysis median TTR was 15 and 43 mo for pts with high and low Ki-67 (p=0.1); 21 and 43 mo for K-ras positive and negative mutation (p=0.16), 43 and 15 mo for EGFR positive and negative tumors (p=0.6). TTR was 21 mo for cyclin D1 positive as well as negative.

Conclusions: Pts with PMP who have undergone CRS and IPHP can have prolonged survival but relapses are common. Our study highlights the possible role of molecular markers such as EGFR and K-ras in tumorigenesis. A potential role in prognosis is being validated in a larger study. Future treatment strategies should incorporate molecular testing to enhance our understanding of PMP.

No significant financial relationships to disclose.
Systemic inflammatory response in predicting survival in patients with operable colorectal cancer.
Authors: Kwon K. A. , Oh S. , Kim S. , Lee S. , Han J. , Choi H. , Park K. , Roh M. , Kim H. , Kwon H.
Published: February 2017

456

Background: Several inflammatory response materials could be biomarkers for prediction of prognosis of cancer patients; elevated C-reactive protein (CRP), increased white cell, neutrophil, platelet, and decreased albumin. The Glasgow Prognostic Score (GPS) combines circulating CRP and albumin level, the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR) has been introduced for prognostic scoring system in colorectal cancer (CRC). Thus, in this study, we attempted to identify an more adequate prognostic model related with systemic inflammatory response for CRC.

Methods: Between Mar 2005 and Dec 2008, 200 patients who underwent curative resection for colorectal cancer were enrolled in this study. Systemic inflammatory parameters (CRP, albumin, neutrophil, lymphocyte, and platelet count) were checked for making 3 scoring systems. Based on clinical survival data, we then compared PFS and OS with GPS, NLR, and PLR.

Results: Male to female were 123:77. Median age of the patients was 64 years (range, 26-83 years). Median follow-up duration was 27.2 months (range 7.8-52.7 months). 36 patients were observed disease progression or death. 19 patients were passed away during follow-up duration. 3 year PFS and OS were 72% and 86%, respectively. Numbers of GPS 0,1, and 2 patients were 154 (77%), 44 (22%), and 2 (1%), respectively. Survival analysis according to GPS, PFS and OS could not be able to show the prognostic significance (P=0.313 and P=263). Cut-off value of NLR and PLR were determined 3 and 180 by ROC curve. Both of NLR and PLR were observed as a good prognostic biomarker of PFS and OS (P=0.009 and P<0.001 in PFS, P=0.006 and P=0.001 in OS).

Conclusions: Although GPS, NLR, and PLR were introduced as prognostic scoring systems for operable CRC, PLR which is constructed of platelet/lymphocyte count may represent a useful prognostic index for the prediction of PFS and OS in operable CRC.

No significant financial relationships to disclose.
Role of matrix metalloproteinase-8 in the modulation of systemic 5-fluorouracil pharmacokinetics by local irradiation.
Authors: Hsieh C. , Liu C. , Hsieh Y. , Tai H. , Wang L. , Tsai T. , Chen Y.
Published: February 2017

466

Background: Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats.

Methods: The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to the rats to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked.

Results: Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased the AUC in bile in a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma.

Conclusions: Local irradiation may modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. This unexpected influence is worthy of further investigation and for consideration in clinical practice of radiotherapy for cancer.

No significant financial relationships to disclose.
Patient-reported toxicity after colorectal cancer (CRC) treatment.
Authors: Hill-Kayser C. E. , Vachani C. , Hampshire M. K. , Di Lullo G. A. , Metz J. M.
Published: February 2017

484

Background: Colorectal cancer patients may be at risk for myriad late effects after multimodality therapy, the impact of which may difficult to evaluate using conventional methods. This Internet-based study evaluates patient perceptions of toxicity after treatment for CRC.

Methods: Patient-reported data was gathered via a convenience sample frame from CRC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLink website, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, CRC survivors are queried regarding late effects associated with specific treatments, and asked to answer “yes,” “no,” or “I don't know.” They are also asked to score GI toxicity using WHO criteria. All data have been maintained with IRB approval.

Results: 148 CRC survivors answered queries regarding late effects; 64% were female and 82% Caucasian. Median diagnosis age was 50 (24-76) and median current age 54 (24-77). Most reported having had multimodality therapy - 97% surgery, 89% chemotherapy, and 37% radiation. When queried regarding GI toxicity, 51% reported chronic changes in bowel patterns, 34% chronic diarrhea, 12% bowel obstruction, 18% hernia development, 8% radiation colitis, and 2% fistula formation. Of 18 survivors who graded GI toxicity, 27% reported 4-6 stools per day, and 22% > 6 stools per day or incontinence. When queried regarding sexual function, 31% of men reported worse erectile function than pre-treatment, and 39% of women reported sexual changes such as vaginal dryness. Perceived cognitive decline since diagnosis of cancer was reported by 57%.

Conclusions: Survivors using this tool anonymously and voluntarily report significant GI toxicity after cancer treatment. Approximately 1/3 of male and female survivors report impact on sexual function, and more than 50% report perceived cognitive decline. This tool offers a unique way for survivors to report their experiences; the data reported here may be of significant impact in future study of quality of life, as well as patient counseling and survivor care.

No significant financial relationships to disclose.
Analysis of oxaliplatin-induced sensory neurotoxicity (sNT) in patients receiving FIREFOX, alternating regimen of mFOLFOX-6 and FOLFIRI, with metastatic colorectal cancer (MCRC): Results from combined analysis of KSCC0501 and KSCC0701.
Authors: Kusumoto T. , Emi Y. , Kakeji Y. , Akagi Y. , Samura H. , Baba H. , Natsugoe S. , Tokunaga S. , Maehara Y. ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: February 2017

492

Background: The Kyushu Study Group of Clinical Cancer (KSCC) conducted two phase II trials (KSCC0501 and KSCC0701, Akagi et al. J Clin Oncol. 28:15s, 2010, UMIN ID: 000001342) to evaluate the efficacy and safety of first-line oxaliplatin-based chemotherapy for MCRC. This combined analysis was performed to compare the incidence of oxaliplatin-induced sNT between the two trials.

Methods: Patients (pts) were accrued from 2005 to 2007 in KSCC0501 and from 2007 to 2008 in KSCC0701. Sixty pts received FOLFOX-4 in KSCC0501 and 47 pts received FIREFOX(4 cycles of mFOLFOX-6 alternating with 4 cycles of FOLFIRI) in KSCC0701. All pts were reviewed for efficacy and toxicity (NCI-CTCAEv3.0). Kaplan-Meier analysis was performed to assess the incidence of sNT.

Results: The incidence of sNT was 71.4% with FOLFOX-4 and 36.2% with FIREFOX (Table). The ORR was 34.5% (95% CI F22.5-48.1%) for FOLFOX4 and 58.7% (43.9-73.5%) for FIREFOX. Median PFS was 7.0 M (5.1-9.8 M) with FOLFOX-4 and 10.3 M (7.5-11.9 M) with FIREFOX. MST and 2-year survival were respectively 31.5 M (18.1-40.1 M) and 58.0% for FOLFOX4, versus not determined and 57.1% for FIREFOX. The median no. of treatment cycles was 9 for FOLFOX-4 and 12 for FIREFOX. After 4, 8, and 12 cumulative treatment cycles, the incidence of grade 2+sNT was respectively 24.0%, 30.7%, and 60.5% with FOLFOX-4 versus 6.5%, 6.5%, and 16.0% with FIREFOX.

Conclusions: As first-line oxaliplatin-based chemotherapy for MCRC, FIREFOX caused less oxaliplatin-induced sNT and prolonged the duration of treatment. We have now finished enrollment for study KSCC 0801 (KSCC 0701+bevacizumab) and are following the pts.

[Table: see text]

[Table: see text]
A randomized pilot study comparing safety and efficacy of irinotecan plus S-1 (IRIS) plus bevacizumab (BV) and modified (m) FOLFIRI plus BV in patients (pts) with metastatic colorectal cancer (mCRC): First report of T-CORE0702.
Authors: Kato S. , Andoh H. , Gamoh M. , Yamaguchi T. , Murakawa Y. , Sasaki Y. , Takahashi S. , Shimodaira H. , Yoshioka T. , Ishioka C. ,   Tohoku Clinical Oncology Research and Education Society (T-CORE)
Published: February 2017

496

Background: Sequential combination with irinotecan (CPT-11) and S-1 (IRIS) is active and safe regimen against mCRC (ASCO2008, abstract #4107, T. Yoshioka et al. Br J Cancer 101: 1972-77, 2009). The aim of this prospective randomized pilot study was to compare safety (CTCAE v3.0, primary endpoint) and efficacy (RR and PFS, secondary endpoint) of IRIS with mFOLFIRI when these were used with BV.

Methods: Sixty pts with mCRC were randomized to compare 30 pts for IRIS+BV (CPT-11 150 mg/m2 infusion on day 1, S-1 80 mg/m2 orally on day 3-16, q3w) with 30 pts for mFOLFIRI+BV (CPT-11 150mg/m2). 57 pts (IRIS arm 29, mFOLFIRI arm 28) were evaluable. Most of them were treated as first-line therapy.

Results: Background of pts was well balanced among two arms. Although G3/4 hematological AEs profiles were similar between two arms, G2-4 neutropenia was significantly lower in IRIS arm than mFOLFIRI arm (56.6%, vs. 88.9%, p=0.01, χ2test). Among G3/4 nonhematological AEs, gastrointestinal toxicities were lower in IRIS arm than mFOLFIRI arm (anorexia: 3.5% vs. 17.9%, nausea: 0% vs. 7.1%, diarrhea: 6.9% vs. 14.3%, stomatitis: 0% vs. 3.6%). By χ2 test, nausea, vomiting and hair loss were significantly lower in IRIS arm than mFOLFIRI arm (p<0.05). GI-perforation, a BV-related severe AE, occurred in 2 pts only from mFOLFIRI arm and one of them was died as TRD. RRs (institutional evaluation) were 58.6% in IRIS (CR 2, PR 15, SD 11, and PD 1) and 55.1% in mFOLFIRI arm (CR 0, PR 16, SD 10, PD 2, and not evaluable 1). Our independent review committee will clarified definite RR and median PFS near future.

Conclusions: Our IRIS+BV regimen is well tolerated, effective and appears to be a promising choice for pts with mCRC.

[Table: see text]
Detection of aberrant drainage after sentinel lymph node mapping and its impact on staging and change of operation in colon cancer.
Authors: Saha S. , Sirop S. , Korant A. , Nalluri S. , Machek O. L. , Desai D. , Kaushal S. , Ganatra B. , Badin J. , Wiese D.
Published: February 2017

500

Background: Sentinel lymph node mapping in colon cancer leads to the detection of micrometastasis in 15- 20% of patients leading to upstaging to stage III disease.

Methods: Between 1996-2010, patients diagnosed with colon cancer were enrolled in our study and underwent SLNM at the tim of surgery plus standard oncological resection including regional LN resection. After initial years of experience, exact locations of the SLNs were mapped in relation to the primary tumor. Aberrant drainage was observed when a SLN was detected outside the standard lymph node basin. The primary objective of this analysis is to identify the frequency of detection of such aberrant drainage and the rates of positive aberrant SLNs leading to change of operation and staging.

Results: Between 1996-2010, 304 patients were included in the study. The overall success rates of SLNM was 99.7%. The average number of resected LNs was 15.4. SLNM had a sensitivity, negative predictive value, accuracy and false negative rates of 85.3%, 91.7%, 94.4% and 14.6% respectively. Micrometastatic disease was detected in 15.1% of patients with node positive disease. Since 2001, 150 patients were evaluated for the presence of aberrant drainage and potential change of planned surgery. In 27 patients (18%), extended surgery was performed due to aberrant drainage. The nodal positivity in these 27 patients was 59.5%, compared to 46% in the whole group. The average number of lymph nodes in this group was 16 and the average number of SLNs was 4.3. The most common location of the primary tumor was the right colon in 55.6% of patients with aberrant drainage. In 13 patients (8.7% of case), change of operation led to the detection of positive SLNs leading to upstaging to stage IIIA/B diseases. All of these 13 patients had T3 or T4 disease. All node positive patients underwent adjuvant chemotherapy.

Conclusions: SLNM in colon cancer is highly successful, sensitive and overall accurate staging procedure. It leads to detection of SLNs outside the regional lymphatic basin and change of surgery in 18% of patients. This results in higher nodal positivity and significant change of planned surgery in 8.7% of cases.

No significant financial relationships to disclose.
Dasatinib (D) in previously treated metastatic colorectal cancer (mCRC) patients: A phase II trial of the University of Chicago phase II consortium.
Authors: Sharma M. , Wroblewski K. , Kozloff M. , Modi S. S. , Sleckman B. G. , Taber D. , Vokes E. E. , Stadler W. M. , Polite B. N. , Kindler H. L.
Published: February 2017

506

Background: Dasatinib (Sprycel, Bristol-Myers Squibb), an oral inhibitor of SRC family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. Since treatment options for mCRC are limited after a fluoropyrimidine (F), oxaliplatin (O), and irinotecan (I), novel agents need to be explored in this setting.

Methods: We conducted a phase II trial of D in unresectable, previously treated mCRC patients (pts) at 9 centers. No more than 2 prior chemotherapy regimens were permitted, which must have contained F, O and I. Disease progression on or after treatment was required. Eligible patients also had to have measurable disease per RECIST criteria; normal organ function; PS 0-2. Pts received D 70 mg PO BID continuously. CT scans were obtained every 8 weeks. The primary endpoint was progression-free survival (PFS) at 4 months. We employed a Simon, two-stage design with 19 pts enrolled in the first stage, and a second stage planned if ≥ 5 were progression-free at 4 months. 19 pts enrolled 10/07-11/08. Pt characteristics: male 58%; median age 64 (range 38-83); PS 0: 47%, 1: 53%.

Results: The study was terminated after the first stage due to lack of efficacy. A median of two 4 week cycles were administered (range <1-8). 2 pts discontinued due to adverse events, 2 others withdrew, and 2 had early deaths before the first CT scan. Grade 3/4 toxicities (% pts): anemia 11%; fatigue 16%; anorexia 11%; dyspnea 11%; nausea/vomiting 11%; pleural effusion 5%; diarrhea 5%; pneumonitis 5%; dehydration 5%. There were no objective responses; 1 pt (5%) had stable disease for 7 months. PFS rate at 4 months was 5% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3).

Conclusions: Dasatinib is inactive in previously treated mCRC pts. Novel agents are still needed for this patient population. Supported by NCI grant N01-CM-62201.

[Table: see text]
Population pharmacokinetic (PPK) analysis for 5-FU, tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo) in the eight clinical studies of S-1 in Western patients with advanced solid tumors.
Authors: Yoshida K. , Ikeda K. , Yoshisue K. , Rodriguez W. , Bodoky G. , Moiseyenko V. , Lichinitser M. , Saito K. , Benedetti F. M. , Ajani J. A. ,   The FLAGS Trial Investigators Group
Published: February 2017

53

Background: This analysis was performed to establish the PPK model of S-1, and to identify the intrinsic or extrinsic factors that influence S-1 exposure in the Western patients with advanced solid tumor.

Methods: PK data obtained in seven phase I and one phase III (FLAGS) studies were combined for PPK analysis. The total number of patients was 315, and the number of data points for FT, CDHP, 5-FU and Oxo were 2,860, 2,625, 2,492, and 2,484, respectively. The two-compartment model was used for FT, CDHP and Oxo, whereas for 5-FU, inhibitory effect of CDHP on 5-FU clearance was incorporated into a two-compartment model to describe its non-linear PK. The final models were validated by visual predictive check and bootstrapping.

Results: The individual fit and the stability of four models were acceptable. The predicted daily AUCs (at steady state) were calculated to evaluate the effect of covariates. The daily AUC of 5-FU strongly correlated with oral clearance (CL/F) of CDHP, but not with that of FT. The ethnic difference in exposure to 5-FU was not apparent despite the significantly lower CL/F of FT observed in the Asian patients. Co-administration with food delayed the absorption of S-1 but exhibited no or limited effect on the AUC of FT, CDHP and 5-FU, whereas the bioavailability of Oxo decreased to approximately 30%. Renal function primarily influenced CDHP exposure and, in turn, 5-FU. The model simulation suggested that the S-1 dosages of 30, 25 and 20 mg/m2 BID could achieve similar daily AUC of 5-FU in the Western patients with normal renal function (CLcr>80 mL/min), mild (50-80 mL/min) and moderate (30-50 mL/min) renal impairment, respectively. Other factors such as age, gender, liver function, serum albumin, PS, gastric cancer, gastrectomy, combination with cisplatin and liver metastasis, had little or minimal impact on the daily AUC of 5-FU.

Conclusions: This analysis suggests that the daily AUC of 5-FU after S-1 administration is primarily affected by the CDHP levels, and hence renal function remains the primary factor for 5-FU PK in patients. Other factors as well as CL/F of FT had little impact on 5-FU.

[Table: see text]
Modeling 5-FU AUC-dose relationship to develop a PK dosing algorithm.
Authors: Haregewoin A. , Kaldate R. R. , Hamilton S. A. , Saam J. R. , Wenstrup R. J.
Published: February 2017

547

Background: 5-fluorouracil (5-FU) is an ideal candidate for pharmacokinetic (PK) dosing. 5-FU is administered based on standard BSA dosing. BSA administration results in highly variable PK and exposure, and potential underdosing in about 50% of patients. Patients with higher 5-FU AUC levels derive greater clinical benefit but with increased risk of toxicity. An immunoassay (OnDose) that measures 5-FU concentration in plasma and reports a computed AUC in mg·h/L has been developed to aid optimization of therapy using PK dosing. The results of an analysis to model the 5-FU AUC-dose change relationship from our clinical database are presented.

Methods: A set of 585 sequential patients from our database receiving FOLFOX6 regimen with 5-FU continuous infusion (CI) over 41-48 hours, with or without bevacizumab, for the adjuvant and metastatic treatment of CRC was used for the preliminary analyses. A subset restricted to include only patients that had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 at the initial test cycle, and had blood sample collection times ≥ 18 hours was used to conduct regression modeling of change in AUC versus change in dose. Outliers such as AUC values < 5 mg·h/L and > 50 mg·h/L were excluded from the analysis.

Results: Our analysis corroborates previous findings that large variability in 5-FU PK measurements exists during the early part of the infusion cycle. The following simple regression model with an R2=0.51 developed over N=307 cycle-pair observations characterizes the AUC-dose relationship as: change in AUC (mg·h/L) = 0.02063 * dose change (mg/m2).

Conclusions: The above model suggests that dose changes ranging from 145 to 720 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg·h/L for most patients. Assuming a 2,400 mg/m2 baseline dose, a maximum 720 mg/m2 dose increase would correspond to a 30% increase, but would likely be needed only by 10% of the patient population with low AUC readings. Our data from the US clinical setting indicate that it is possible to optimize 5-FU therapy by adjusting the dose based on AUC measurement.

[Table: see text]

[Table: see text]
Biomolecular, biochemical, and radiologic evaluation of patients on anti-VEGF treatment for mCRC.
Authors: Rossi L. , Veltri E. , Di Seri M. , Vari S. , Colonna M. , Adua D. , Longo F. , Zoratto F. , Mottolese M. , Tomao S.
Published: February 2017

556

Background: K-ras mutation is a negative predictor of clinical benefit (CB) from anti-EGFR treatment in mCRC. Bevacizumab combined with chemotherapy prolongs both PFS and OS in first-line treatment of mCRC. Previously data suggested that this results are independent of K-ras status. We conducted a study to investigate the CB of Bevacizumab in treatment of mCRC according to K-ras status and to evaluate timing of response to treatment trough the correlation between tumor markers values and clinical responses. Finally we evaluated CB in patients affected by mCRC with only hepatic metastases vs patients with multiple metastasis sites.

Methods: 82 patients were enrolled and underwent first-line chemotherapy with Folfiri or FolFoX and bevacizumab. Tissue samples were analyzed for DNA sequencing in order to identify K-ras mutations in codons 12 and 13. Before therapy all patients were investigated with CT scan and with a blood sample to define tumor markers values; a new evaluation of tumor markers after 2 months of chemotherapy was performed and a CT scan after 3 months.

Results: An overall objective response rate (RR) of 40% and a CB of 79% were obtained, with a correlation between tumor markers values and clinical response of 89%. 49% of population presented only hepatic metastases while other 51% showed multiple metastatic sites. RR in exclusive hepatic metastatic group was 45% vs 33% multiple metastatic sites group, CB was 90% vs 66% respectively. No grade 3 or 4 bevacizumab associated toxicity was showed in patients. K-ras mutations were investigated in 75 of 82 patients. 49 patients were wild-type (wt 65%) while 26 patients were mutated (mut 35%). RR in wt group was 45% vs 35% in mut group, while CB was 82% vs 81% respectively. Correlation between tumor markers values and clinical response was 90% in wt group vs 93% in mut group.

Conclusions: RR in two K-ras groups was different with an advantage in K-ras wt group, but this difference does not observe in CB. Bevacizumab provides significant RR and CB after a short time of treatment and tumor markers values could be an optimal correlative parameters of early clinical response. Bevacizumab provides significant CB in patients with only hepatic metastases vs patients with multiple metastatic sites.

No significant financial relationships to disclose.
A randomized cross-over trial comparing single-agents capecitabine (C) and UFT plus leucovorin (LV) in patients (Pts) with advanced colorectal cancer (CRC): Preliminary data of a patient preference study.
Authors: Peugniez C. , Fournier C. , Guerin-Meyer V. , Berger S. , Gasnault L. , Girault C. , Rad E. , Lam Y. , Maes P. , Adenis A. ,   Noroncomed Network - France
Published: February 2017

558

Background: Oral fluoropyrimidines such as C and UFT plus LV (U) are widely used pro-drugs dedicated to the care of CRC. Although their toxicity profile may slightly differ, no direct comparison between these treatments has been done as both molecules are converted into fluorouracil. To help the physicians to choose between C and U, we initiated this randomized cross-over trial aimed to assess patient's preference.

Methods: Pts with advanced CRC received either a first cycle of C (1,250mg/m2 x 2/d for 14 days, q3 wks) or a first cycle of U (UFT 300mg/m2/d plus LV 75 mg/d in 3 divided doses every 8 hrs for 28 days, repeated at 35-day intervals). Patients were randomized to receive C at cycle 1 followed by U (arm A) or U at cycle 1 followed by C (arm B). After 2 cycles, pts were asked which treatment they preferred. Treatment was then continued with the chosen regimen. Preferences rates are presented with 95% confidence intervals and the two groups are compared with the chi-squared test.

Results: 89 pts were enrolled from 10/2005 to 6/2010. Treatment arms were well balanced for baseline characteristics: male 57%; median age 66 years; PS 0-1 81%. Most of the pts were heavily pretreated (0/1/2/ and >2 previous chemotherapy lines: 6/2/15/66). 64 (arm A: 35, arm B: 29)/89 pts received at least 2 cycles of chemotherapy and were evaluable for preference. At cycle 1, 21% and 43% of the pts presented at least 1 severe toxic event with C and U, respectively. Pts with U at cycle 1 presented more likely with severe fatigue and anorexia. There was 1 toxic death under C (gr. 3 diarrhea, gr.4 neutropenia) at cycle 1. Overall, 66% (95%CI: 52-77%) of evaluable pts expressed preference for C, and there was a statistically significant difference between arms A and B (p<0.02) with more pts preferring C in arm A: 79% (95%CI: 61-91%), as compared to arm B: 50% (95%CI: 31-79%).

Conclusions: Pts with advanced CRC preferred C over U, especially when given during the first cycle.

No significant financial relationships to disclose.
The role of postoperative PET-CT in the evaluation of patients with high-risk stage III colorectal cancer (CRC).
Authors: Purim O. , Asman Y. , Bard S. , Kundel Y. , Wasserberg N. , Gordon N. , Brenner B.
Published: February 2017

566

Background: Routine PET-CT evaluation is still not indicated for stage III CRC patients; however accumulating data suggest that it may modify these patients' staging and treatment. We hence evaluated the role of PET-CT in high risk stage III CRC patients and to characterize positive predictors.

Methods: Retrospective chart review of stage III CRC patients who underwent PET-CT for being at high risk for systemic disease attributable to: early T stage (T < 3), grade > 3, < 12 lymph-nodes examined, > 3 involved lymph-nodes, elevated postoperative CEA and/or CA-19.9. The demographic and clinicopathological characteristics of patients found to have metastatic disease were compared to those who were negative.

Results: Seventy-three patients (33 males [45%], median age 67 years [range: 29-88 years]) were included. Pathologic FDG-uptake was observed in 33 (45%) patients. Of them, 16 (22%) were upstaged with altered treatment protocol, 13 (18%) required further work-up and 4 (5%) were found to have post operative changes. Elevated post-operative CEA and CA-19.9 levels correlated with positive PET-CT (p = 0.002 and p = 0.015, respectively). None of the other examined parameters differed between the groups. With a median follow-up of 26 months (range:1-63 months), overall survival was 88% in patients with positive PET-CT and 92% in patients with negative PET-CT. Eight patients in the positive group were disease free following metastectomy, five were alive with disease, two patients died of disease and one patient died of other cause.

Conclusions: Selective postoperative PET-CT influenced staging/therapy in 22% of high risk stage III CRC patients. Postoperative CEA and CA-19.9 levels may play a role in selecting eligible patients. Failure to identify other parameters may be related to the preexisting selection bias and the small cohort.

No significant financial relationships to disclose.
Phase I/II study of transcatheter arterial chemoembolization with cisplatin powder and degradable starch microspheres for unresectable hepatic metastases from colorectal cancer refractory to systemic standard chemotherapy.
Authors: Nishiofuku H. , Tanaka T. , Anai H. , Sueyoshi S. , Matsuoka M. , Otsuji T. , Yamamoto K. , Inaba Y. , Sakaguchi H. , Kichikawa K. ,   Nara 1
Published: February 2017

577

Background: We conducted a phase I/II study of novel transcatheter arterial chemoembolization with cisplatin powder and degradable starch microspheres (DSM) to determine the recommended dose (RD) and to assess the efficacy and safety.

Methods: Cisplatin powder and DSM mixing solution was administered followed by the injection of DSM alone via hepatic artery every 4 weeks. In phase I, cohorts of 3 patients received escalating dose of cisplatin (50, 65 and 80mg/m2), and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response, toxicity, hepatic progression free survival (H-PFS) and 6-month overall survival (OS) rate.

Results: A total of 24 patients (male 16, female 8; mean age 63.0, range 45-79; colon 15, rectal 9) were enrolled in this study. FOLFOX had previously been administered to all patients, irinotecan-containing regimen to 12 and bevacizumab and/or cetuximab to 14. During phase I (n= 9 patients), maximum tolerated dose was not reached and cisplatin 80 mg/m2 was recommended for a phase II. Phase II enrolled 15 patients. The following grade 3 toxicities were observed: platelets reduction 16.6%, aspartate transaminase elevation 38.8%, alanine transaminase elevation 16.6%, hyponatremia 11.1%, cholecystitis 5.5%. The tumor response rate was 53.3% (CR 0, PR 8, SD 6, and PD 1). The median H-PFS was 6.3 months (95% CI; 2.71 to 9.88) and 6 -month OS rate was 86.7%.

Conclusions: This phase I/II study demonstrates that novel transcatheter arterial chemoembolization with 80 mg/m2 cisplatin powder and DSM is well tolerable, and can produce a high response rate with encouraging survival duration. Further clinical trials are warranted.

No significant financial relationships to disclose.
Patients' perspective on palliative chemotherapy of colorectal and non-colorectal tumors.
Authors: Rehm M. , Rentsch A. , Trautmann K. , Hornemann B. , Schuler U. , Ehninger G. , Folprecht G.
Published: February 2017

581

Background: In contrast to trials investigating treatment efficacy, patients perspective on given chemotherapy is less studied. Known surveys indicate that patients accept therapy for very limited benefit.

Methods: Patients who had received 3 or more months of systemic, palliative therapy for colorectal (CRC) or non-colorectal (upper GI, NSCLC, SCCHN) cancer were eligible. They completed a questionnaire including their retrospective report on symptomatic toxicity (according to NCI-CTC) and using numeric ranking scales their burden from the toxicity and the comparison to the informed consent. Depression and anxiety was measured by HADS. Finally, the patients were asked for the minimal gain in life expectancy they would feel it worth to repeat the therapy for.

Results: Between August 2008 and December 2009, 134 patients were enrolled. Median age was 63 (32-86); 71% of patients were male. Colorectal cancer patients would repeat their therapy for a minimal gain of life expectancy of 36.0 mo (14.0-57.0 mo), non-CRC patients for 15.9 [12.3-19.5] months (p = 0.01). Considering additional time with best supportive care, the minimal expectation from treatment trended to be longer than the actual survival of the same patients (39.3 [33.6-45.0] and 19.9 [16.3- 23.5] months for CRC and non-CRC patients, respectively), p = 0.08. Depression, diarrhea and tumor entity (CRC vs. non-CRC) were an independent factors for the minimal expected life expectancy in a multivariate analysis. Most frequent self reported toxicity (grade 3/4) was fatigue (9.0%), nausea (8.1%), diarrhea (8.5%) and stomatitis (8.3%), severe burden was felt from fatigue (14.3%) followed by neuropathy (12.0%), diarrhea (11.1%), nausea (9.8%) and stomatitis (8.8%). Fatigue was felt ′a little bit more′ or ′much more′ than in the patient information in 29.9%, followed by neuropathy (20.5%), acne (18.4%) and diarrhea (17.6%).

Conclusions: Patients' expectations of life-prolonging systemic therapy are higher than expected from previous studies or the median survival in phase III studies. Compared to their actual survival it may be regarded as realistic. Fatigue might deserve more attention when toxicity of treatment and symptoms of disease are explained.

[Table: see text]