bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Notch and tumor regression
Authors: Epenetos A. A. , Kousparou C. , Stylianou S.
Published: August 2020

e14623

Background: Notch signaling is an evolutionary-conserved pathway in vertebrates and invertebrates which is involved many developmental processes, including cell fate decisions, apoptosis, proliferation, and stem-cell self renewal. There is increasing evidence that the same molecular pathways regulating the self renewal of stem cells are also being employed in cancer progression. The Notch signal transduction pathway has been implicated in the self-renewal of stem cells in hematopoietic, skin, neural, germ and breast tissue. Increasing evidence suggests that the Notch signaling pathway is frequently up regulated in many forms of cancer including acute T-cell lymphoblastic leukemia, cervical, prostate, lung, breast and others. Thus,inhibition of the pathway could provide a novel treatment of cancer and cancer stem cells. Methods: We have genetically engineered a fusion protein, consisting of the Drosophila transcription factor Antennapedia (ANTP) and with the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits Notch activation (ANTP/DN MAML, TR4). This novel fusion protein has been tested for its ability to target tumor cells in vitro and in vivo. Results: Our data show that ANTP/DN MAML fusion protein, TR4 contains signals for proper cell targeting, internalization and nuclear transport. Furthermore, TR4 inhibits human mammary and colon xenograft tumor growth and metastases in immuno deficient mice.TR4 presence and activity was also detected in the brains of treated animals demonstrating that TR4 can cross the blood-brain barrier and potentially eliminate brain tumors and metastases, unlike other anticancer drugs and biological such as monoclonal antibodies that cannot cross the blood brain barrier. TR4 was found to be non- immunogenic following repeat administration in healthy animals. At very high doses (>10x therapeutic dose) it caused anorexia and weight loss in mice. Conclusions: The TR4 protein, a Notch inhibitor, can induce tumor regression and resolution of breast and colon cancer xenografts. It is non- immunogenic following repeat administration and has acceptable toxicity profile.

No significant financial relationships to disclose.
Additive/synergistic efficacy of zoledronic acid and LBH589 in the spheroid-based cellular angiogenesis assay
Authors: Soltau J. , Weber H. , Schächtele C. , Drevs J.
Published: August 2020

e14627

Background: The compounds Zoledronic acid (ZA) and LBH589 (histon deactetylase (HDAC) inhibitor) have shown in previous experiments antitumoral and antiangiogenic effects. Aim of this study was to determine their ability to inhibit VEGF-A induced endothelial cell (EC) sprouting and to observe potential additive/synergistic effects of the combination ZA and LBH589 in the spheroid-based cellular 3D angiogenesis assay. Methods: HUVEC spheroids were embedded in a 3D collagen gel, stimulated with VEGF-A [25 ng/ml] and treated for 24h with different concentrations of ZA alone or in combination with LBH589. Sprouting intensity of EC spheroids was quantitated by an image analysis system determining the cumulative sprout length per spheroid using an inverted microscope and digital imaging software. The mean of the cumulative sprout length of 10 randomly selected spheroids was analyzed as an individual data point. Results: Before testing the compounds in combination the single IC50 values for ZA (42 μM) and LBH589 (2.9 μM) were determined. The IC50 of ZA has to be considered with caution because of the low inhibitory effect which did not reach basal sprouting levels. In the first combination experiment a dilution series of ZA was tested in combination with a constant LBH589 concentration [2.9 μM, IC50 value as determined previously]. The combination of ZA with LBH589 was ∼330 fold more effective in the inhibition of EC sprouting than ZA alone [0.58 μM compared to 190 μM]. However, the sprouting intensity in the combination of LBH589 and ZA was very low. Therefore the experiment was repeated with a dilution series of ZA in combination with a constant LBH589 concentration that showed no inhibition of EC sprouting previously (1 μM). The second combination experiment revealed IC50 values of 1300 μM for ZA alone and 1.5 μM in combination with LBH589 [1 μM]. The combination LBH589 and ZA is again ∼870 fold more effective in the inhibition of EC sprouting than ZA alone. Conclusions: Our results indicate a very strong synergistic effect of the combination ZA and LBH589 in the spheroid-based angiogenesis assay.

No significant financial relationships to disclose.
Phase I study of sunitinib (SU) in combination with pemetrexed (Pem) in patients (pts) with advanced solid tumors (ST)
Authors: Nakagawa K. , Okamoto I. , Shimizu T. , Miyazaki M. , Tsurutani J. , Ichikawa Y. , Terashima M. , Takeda M. , Fumita S. , Kiriyama T.
Published: August 2020

e14630

Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSR-1, and shows antitumor activities in several types of solid malignancies. Non-small-cell lung cancer (NSCLC) xenograft data indicate SU enhanced the antitumor activity of Pem. This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of combination therapy with the oral SU and Pem for Japanese patients with advanced ST. Methods: Pts with ST refractory to standard therapy were randomly assigned to receive either oral SU 50 mg/day for 2 weeks followed by 1 week rest (Schedule 2/1, S-2/1) or SU 37.5 mg continuous daily dose (CDD). Fixed-dose Pem (500mg/m2 IV) was administered on day1 every 21 days. A standard “3+3” design was employed in both treatment schedules and treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results: A total of 12 pts (med. age 63 years, range 49–69; 10 Male/ 2 Female) have been enrolled (6 pts in the S-2/1 arm and 6 pts in the CDD arm). The most common cancer is NSCLC (9 pts, 75%). All patients completed their first cycle for DLT evaluation, and no DLTs were observed in either treatment arm. The most common toxicities were fatigue (n=8), anorexia (n=6), and thrombocytopenia (n=12). Treatment-related ≥ grade 3 adverse events (AEs) included fatigue (n=1), hypertension (n=1), neutropenia (n=4), leucopenia (n=3), thrombocytopenia (n=2), lymphopenia (n=2), and increased ALT (n=1). Three pts (S-2/1: 2, CDD: 1) required dose reduction of SU due to G3 toxicities. All toxicities were clinically manageable and reversible. One pt with NSCLC had a documented PR with cavity formation inside the tumor. Conclusions: SU 37.5 mg/day (CDD schedule) plus Pem 500mg/m2 every 21 days, and SU 50 mg/day (S-2/1 schedule) plus Pem 500mg/m2 every 21 days were well tolerated and associated with encouraging antitumor activity.

[Table: see text]
Detection of methylation in the CpG islands of the RASSF1A and RAR2b gene promoters in breast cancer (BC)
Authors: Desiris K. , Voyatzi S. , Stravoravdi P. , Boukovinas I. , Kiziridou A. , Paikos D. , Stergiou E. , Sibilidis G.
Published: August 2020

e14632

Background: Aberrant methylation of CpG islands of cancer-related genes has emerged as an important epigenetic mechanism during carcinogenesis. We examined the methylation of RASSF1A (Ras-association domain family 1, isoform A) and RAR2b (Retinoic Acid Receptor 2b) genes in BC. The knowledge of their role in BC is limited and confused to date. Methods: Promoter methylation was measured in 37 pts, 26 with BC and 11 with benign lesions. The specimens were obtained from archive formalin-fixed paraffin-embedded tumors. After DNA extraction, the methylation was determined by chemical modification of DNA with sodium bisulfite and subsequent double “hot start” Methylation-Specific PCR (MSP), followed by detection on agarose gel. Results: Methylation of at least one of the genes was observed in 18/26 pts (p<0.05). Methylation of RASSF1A gene was observed in 15/26 and RAR2b in 11/26 pts. Both genes were methylated in 8/26 pts. Correlation between methylation and clinicopathological features revealed an association of the RASSF1A gene with T2 tumors (12/15 pts, p<0.05) and ER (+) status (12/15 pts, p<0.05). T2 tumors and ER (+) status presented together in 9/15 pts. The methylation of RAR2b gene was not associated with any known clinicopathological features. In benign lesions methylation of at least one of the genes was observed in 8/11 pts (p<0.05). Methylation of RASSF1A gene was observed in 5/11 pts and RAR2b in 7/11 pts. Both genes were methylated in 4/11 pts. Conclusions: Both genes are frequently methylated in both benign and malignant breast lesions. The association of methylation of RASSF1A gene with tumor size and ER status is noteworthy. The small number of pts does not allow us to confirm the exact role of gene methylation in BC yet. Larger studies are required in order to assess if these epigenetic alterations point out new BC markers, which could be helpful for BC control.

No significant financial relationships to disclose.
Effect of a synthetic peroxisome proliferator-activated receptor-gamma (PPARγ) ligand on breast cancer cells
Authors: Youn H. , Lee B. , Jung S.
Published: August 2020

e14638

Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) ligands have been identified as a potential source of therapy for human cancers. And, it is reported that PPAR-γ ligands could serve as negative regulators of breast cancer development and progression, but their mechanism is still unknown. The purpose of this study was to determine whether the PPAR- γ ligand induces cell cycle arrest and apoptosis of MDA-MB-231(ERα-negative) and MCF-7(ERα-positive) breast cancer cell. Methods: The effect of PPAR-γ ligands on the cell viability of breast cancer cells was determined using mitochondrial tetrazolium(MTT) assay. The cell cycle distribution and apoptosis induction were evaluated by using the flow cytometry. The expression of apoptosis-related proteins were measured with Western blot analysis. Results: The treatment of MDA-MB- 231 cell with PPAR-γ ligand, troglitazone was shown to induce cell cycle G1 arrest and induction of apoptosis. Moreover, troglitazone treatment, applied in a dose-dependent manner, caused a marked decrease in phosphorylated retinoblastoma(pRb), cyclin D1, D2, D3, cyclin dependent kinase(Cdk) 2, 4, and 6 expression as well as a significant increase in Cdk inhibitor, p21 and p27. Troglitazone showed antiproliferative effect on MCF-7 cell with tamoxifen, respectively and synergically. Troglitazone and tamoxifen could induce G1 arrest and apoptosis of MCF-7 cell, through upregulation of Bax and downregulation of Bcl-2 and cyclin D1. Conclusions: PPAR-γ ligand, troglitazone induces cell cycle arrest and apoptosis of MDA-MB-231 cell and increases the sensitivity of anti-hormonal therapy in MCF-7 cell. These results suggest that troglitazone has anticancer effect on both ERα-negative and positive breast cancer cells.

No significant financial relationships to disclose.
Colorectal cancer risk prediction tool for men and women without known susceptibility
Authors: Freedman A. N. , Slattery M. L. , Ballard-Barbash R. , Willis G. , Cann B. J. , Pee D. , Gail M. H. , Pfeiffer R. M.
Published: August 2020

e15002

Background: Given the high incidence of colorectal cancer (CRC), and the availability of procedures that can detect disease and remove precancerous lesions, there is a need for a model that estimates the probability of developing CRC across various age intervals and risk factor profiles. Methods: The development of separate CRC absolute risk models for men and women included estimating relative risks and attributable risk parameters from population-based case-control data separately for proximal, distal, and rectal cancer and combining these estimates with baseline age-specific cancer hazard rates based on Surveillance, Epidemiology, and End Results (SEER) incidence rates and competing mortality risks. Results: For men, the model included a cancer- negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, history of CRC in first-degree relatives, aspirin and nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption. For women, the model included sigmoidoscopy/colonoscopy, polyp history, history of CRC in first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status. For men and women, relative risks differed slightly by tumor site. A validation study in independent data indicates that the models for men and women are well calibrated. Conclusions: We developed absolute risk prediction models for CRC from population-based data, and a simple questionnaire suitable for self-administration. This model is potentially useful for counseling, for designing research intervention studies, and for other applications.

No significant financial relationships to disclose.
A prospective study of the interaction between p53 genotype and overall survival in patients with colorectal cancer liver metastases (CRCLM) with and without neoadjuvant therapy (oxaliplatin and capecitabine/5-FU): A p53 research group study
Authors: Kandioler D. , Pilat N. , Kappel S. , Gruenberger T. , Laengle F. , Mittlboeck M. , Herberger B. , Kuehrer I. , Jakesz R. , Muehlbacher F.
Published: August 2020

e15003

Background: Mutations in the p53 gene have been suggested as both a marker of tumour aggressiveness and a means of predicting response to chemotherapy. Unfortunately, there remains no clear evidence that p53 gene mutation affects cancer survival rates. Methods: We sought to evaluate whether mutation in the p53 gene is a marker of more aggressive tumours or of chemotherapeutic failure. Between 2001 and 2003 we collected data prospectively on 76 patients with CRCLM at a single institution. Patients considered to be technically operable were included. 51 patients received preoperative therapy with oxaliplatin plus 5-FU or capetcitabine and 25 were treated with surgery only. Treatment decision was based on the preference of the surgeon or the patient. The groups did not differ in age, chronicity of CRCLM, staging and grading of the primary colorectal cancer. The p53 gene was assessed in all tumours through complete direct gene sequencing (Exon 2–11 including splice sites). Results: For entire cohort the p53 gene mutation rate was 55%, and the median survival was 44.2 months. The overall death rate was 51%. There were 14 (41%) deaths in patients with a normal p53 gene compared to 25 (60%) deaths in patients with mutations in this gene (Logrank P=0.079). For patients that received only surgical treatment the overall death rate was 48% and was unaffected by the presence of p53 gene mutation (Logrank P=0.54). For patients who received neoadjuvant chemotherapy, median survival was 44 months if they had a normal p53 gene compared to only 20 months in patients with p53 gene mutations. The unadjusted hazard ratio for death was 3.24 in the p53 mutation group compared those with a normal p53 gene (95 percent confidence interval 1.5 to 7.0; P=0.045). The adjusted hazard ratio for death in patients with a p53 gene mutation receiving neoadjuvant chemotherapy was 5.5 (95% CI 2.3 to 13.2; P=0.0042). Conclusions: In CRCLM patients receiving neoadjuvant chemotherapy, the p53 gene mutation predicts overall survival. Our data suggests an interaction between the p53 gene and chemotherapy in patients with colorectal liver metastasis.

No significant financial relationships to disclose.
Receipt of chemotherapy among Medicaid-enrolled patients diagnosed with regional colon cancer
Authors: Foley K. L. , Tooze J. A. , Song E. Y. , Klepin H. D. , Geiger A. M.
Published: August 2020

e15016

Background: Although overall improvements in colon cancer mortality have been observed, persistent disparities marked by socioeconomic inequality remain. Inadequate treatment received by the poor leads to disparities in overall and disease-free survival. This paper evaluates the patient, health services, and community characteristics associated with receipt of chemotherapy among poor Medicaid beneficiaries diagnosed with SEER-staged regional colon cancer. Methods: A dataset was constructed from Medicaid-enrolled patients diagnosed with colon cancer from 1999 to 2002 (n=692). Using claims data, North Carolina Central Cancer Registry data, and U.S. Census data, multivariable models were constructed to evaluate the association between patient, health services, and community characteristics and adjuvant chemotherapy. Results: Characteristics of the study population include: 66% female; 25% ages 65–74 and 46% ages 75+; and 42% African American. 1 in 4 of individuals with regional stage colon cancer had a Medicaid or Medicare claim for chemotherapy within 12 months of diagnosis. Individuals under age 65 (OR 6.4, CI 3.6–11.1) and ages 65- 74 (OR 4.4, CI 2.6–7.7) were significantly more likely to receive chemotherapy than individuals 75 and older in the multivariable model. Although non-cancer related comorbidity, class of case, and poverty were significantly associated with received chemotherapy in unadjusted models, their effects were no longer significant after controlling for age. Conclusions: A substantial percentage of Medicaid enrollees do not receive recommended adjuvant chemotherapy. The poor elderly may be especially at risk for under treatment.

No significant financial relationships to disclose.
Extended TME- and MRI-assisted pathology show high incidence of pt4 after neoadjuvant treatment
Authors: Aamdal S. , Larsen S. G. , Hole K. H. , Grøholt K. K. , Dueland S. , Aamdal S. , Giercksky K.
Published: August 2020

e15033

Background: The clinical ability of pre- and post neoadjuvant MRI to predict the necessary extension of TME (ETME) in evaluation of the areas at risk in locally advanced rectal cancer (LARC). Evaluation of treatment response to chemo/ radiation in T4 tumours is difficult. MRI cannot discriminate between different tissue components within a voxel. Increasing rate of late local relapses are reported from different studies. Methods: Prospective registration of 92 MRI evaluated T4a cancers undergoing multimodal treatment for rectal cancer between 2002 and 2007 in a tertiary referral cancer centre. MRI was found to predict T- downstaging in 10% after neoadjuvant treatment. In 35% both MRI and histopathological examination staged the patients as T4 after treatment. 55% (n=51) of the patients were downstaged after the routine postoperative pathology work-up. A new technique with MRI- based sampling of areas of infiltration was introduced and dedicated histopathological evaluation of these threatened areas was performed. Results: ETME was performed in 95% of the patients, mostly as en-bloc resections. After MRI focused pathology 50% were reclassified and up scaled to have pT4. Accordingly, at least 2/3 of the MRI staged T4 tumours before treatment still were pT4 after multimodal treatment. Conclusions: The tumours were downsized, but to lesser amount downstaged. If cure is the goal of the treatment, extended TME as en-bloc resections has to be performed. It is necessary to remove tumour as shown in pre-treatment MRI, as well as tumour, fibrosis and mucus as shown in MRI after post neoadjuvant treatment. MRI assisted pathology is an important option for right T-stage classification and for planning the extent of surgical resection.

No significant financial relationships to disclose.
Final safety results from the post-marketing survey (PMS) of bevacizumab (BV) in Japanese colorectal cancer patients
Authors: Doi T. , Shirao K. , Uetake H. , Hatake K. , Takahashi Y. , Nihira S.
Published: August 2020

e15035

Background: BV was approved in Apr. 2007 in Japan in patients (pts) with advanced colorectal cancer. The number of pts in Japanese clinical trials were extremely limited. Therefore, the Japanese MHLW (Ministry of Health Labor and Welfare) required Chugai to initiate a PMS in all pts after the launch as a post-approval commitment to evaluate the incidence of adverse drug reactions (ADRs) in Japanese pts. This is the first safety well controlled large cohort PMS in Asian pts. Objectives: To assess the use of BV in clinical practice and to evaluate the incidence of ADRs in Japanese pts. Methods: All pts who were treated by BV were registered before initial administration since the launch of BV in Jun. 2007. Follow-up period was 6 months. Results: Between Jun. and Nov. 2007, 2712 pts were registered from 574 institutions, and 2699 pts were eligible for the safety analysis. Pts characteristics were colon/rectum/colon and rectum cancer; 1580/1105/14, M/F; 1632/1067, median age; 61 (15–86), ECOG P.S.0/1/2/3; 2192/477/28/2, combination chemotherapy regimens with BV (FOLFOX / FOLFIRI /5-FU LV /IFL/Other); 1716/778/141/54/10, treatment lines (1st, 2nd, 3rd and more); 1238/1418/43. Of 2699 pts, ADRs were reported in 1589 pts (58.9%) with serious ADRs in 381 pts (14.1%). The common BV ADRs of interest were hypertension; 13.0%, hemorrhage; 11.3% (epitaxis;7.3%), proteinuria; 4.1%. Other ADRs were wound healing complications 1.2%, GI Perforation 0.9%, and thromboembolism (arterial/venous); 0.4 /1.3%. No Japanese-specific ADRs were observed. Conclusions: These safety results are consistent with those reported in International observational studies (BRiTE, Hedrick et al. JCO 2006;24(Jun 20 Suppl.):abstr 3536; First BEAT, Berry et al. JCO 2008;26(May 20 Suppl):abstr 4025).

[Table: see text]
Correlation of bone marrow micrometastasis to TNM stage of colorectal tumors
Authors: Soni M. , Saha S. , Korant A. , Chakravarty B. , Arora S. , Iddings D. , Sirop S. , Bisnoi R. , Wiese D. , Singh T.
Published: August 2020

e15039

Background: Bone marrow (BM) micrometastasis(M) has been shown to be an important prognostic factor in Breast Cancer. However, there is paucity of data for BMM in Colorectal Cancer(CrCa). Hence a study was undertaken to find any correlation between TNM staging with BMM in CrCa patients(pts). Methods: A total of 155 consecutive patients(pts) from March 2004-October 2008 with CrCa were included in the study. Prior to resection of the primary tumor, pts underwent bilateral posterior-superior-iliac spine BM aspiration and samples were examined for presence of micrometastasis by Automated Cellular Imaging System using Chroma Vision Cytokeratin Detection Kit to detect cells expressing CK 8 as defined by CAM 5.2 monoclonal antibody. BMM and TNM staging were recorded and analyzed for correlations. Results: Of 155 CrCa pts, 11.6%(18/155) were found to have BMM. BMM was positive(+ve) in 50%(9/18) bilaterally and 50%(9/18) unilaterally. BMM was +ve in 11.5%(13/113) of colon pts and 12%(5/42) of rectal pts. When analyzed by T stage in colon pts, BMM was present in 10.5%(2/19) of T1 pts, 16.6%(2/12) of T2 pts, 14% (6/42) of T3 pts, 37.5%(3/8) of T4 pts, and 16%(5/31) of M1 pts. Upon analyzing rectal cancer pts data, BMM was found in 8.3%(1/12) of T1 pts, 16.6%(3/18) of T3 pts and 16.6% (3/18) of M1 pts. Of 113 total Colon pts, 27%(31/113) had nodal disease without distant metastasis(stage III); 13%(4/31) of these pts had BMM with 60% (3/5) unilaterally and 40%(2/5) bilaterally. In the Rectal group, 16%(7/42) had stage 3 disease; 14% (1/7) of stage 3 rectal pts had BMM. Conclusions: BMM did not correlate with tumor size, nodal status or distant metastasis. This discrepancy between tumor stage and BMM suggests BMM to operate independently of TNM staging. Further studies correlating prognosis and disease free survival in +ve BMM pts are needed to examine the significance of BMM in CrCa.

[Table: see text]

No significant financial relationships to disclose.
Analysis of pharmacogenetic biomarkers in rectal patients trated with chemoradiotherapy
Authors: Lamas M. J. , Balboa E. , Duran G. , Rana P. , Gomez A. , Bernardez B. , Lopez R. , Carracedo A. , Barros F.
Published: August 2020

e15051

Background: 5FU-based chemoradiotherapy before total mesorectal excision (TME) is currently the gold standard treatment for stage II and III rectal cancer patients. Pathological complete response (pCR) is related with a longer survival. We have used known predictive pharmacogenetics biomarkers to identify in our series responders and non responders to preoperative RQ. Methods: 77 stage II/III rectal patients were genotyped using direct sequencing (TS VNTR) and SNAPshot (DPYD, EGFR) techniques. DNA was obtained from peripheral blood samples. We have studied Thymidylate synthetase (TS VNTR; high expression haplotypes: TSER 2R/3R, 3C/3G, 3G/3G and low expression: TSER 2R/2R, 2R/3C, 3C/3C; TS 1494del6: associated to a better efficay of 5Fu), dihydropyrimidine dehydrogenase (DPYD; DPYD*2 associated to worse toxicity), EGFR (CA repeats in intron 1: 16/16 associated to worse efficacy) polymorphisms. Median age of our study cohort was 65 years old (37–85). There were 24 female and 53 male patients. All of them were Caucasian. 21 patients (27.3%) had stage II and 56 (72.7%) stage III. They were staged by TC, colonoscopy and endorectal ultrasonography. The patients received 5fu 325 mg/m2/day continuous infusion along the hyperfractionated accelerated radiotherapy schedule (50,4 Gy). All were submitted to TME. Outcomes after surgery are measured by tumour regression grade (from TRG1= complete pathological response, to TRG5=no regression). Data were studied by univariate and multivariate analysis. Results: The sample was in Hardy-Weinberg equilibrium for all polymorphisms, irrespectively of the response status. 50 patients (64.9%) and 27 (35.1%) had low and high expression genotype for TS respectively. pCR (TRG1) was obtained in 24 patients (31,6%) and microscopic foci (TRG2) in 14 (18,2%), TRG 3–4 in 38 (49,3%), and 1 patient had no response (TRG5). We haven’t found a statistically significant relationship between TRG1 and TS status, or any other biomarker studied. There's no relationship also with initial clinical stage. Conclusions: Biomarkers EGFR (intron 1 CA repeats), TS (TS 1494del6, TS VNTR) and DPYD in blood samples, are not good enough to predict response to RQ in rectal cancer.

No significant financial relationships to disclose.
Impact of a simple intervention that improves colon cancer lymph node yield and assessement
Authors: Kowalczyk L. , Shah P. , George T. , Lu L. , Sarosi G. , Beyth R. , Sultan S.
Published: August 2020

e15058

Background: The National Quality Forum has endorsed the 12 lymph node (LN) benchmark as a quality metric. Currently, less than 40% of institutions meet this requirement. The purpose of this study was to determine whether implementation of a simple pathology template with dedicated fields for LN reporting led to an increase in the number of colon cancer resections where >12 LNs were reported. Methods: A simple pathology template, derived from the College of American Pathology, using standardized terminology and dedicated fields for LN reporting was implemented in August 2007. Using a pre and post- test design, all consecutive pathology cases were retrospectively reviewed. Inclusion criteria consisted of all stage 0-IV colon cancer patients who underwent surgical resection at a single Veterans Affairs Medical Center. The primary outcome was the percentage of cases in which >12 LNs were assessed between the pre and post-template group. Age, gender, anatomic location, and stage were also collected. Statistical comparisons were made using chi-square and Fisher's exact t-test. Results: 111 pre-template and 71 post-template cases were analyzed. The majority of patients were Caucasian (74%) males (97%). There were no significant differences between the two groups (see Table 1 ), however there was a trend towards more right-sided colon cancers in the pre-template group. 51% of all pre-template pathology reports evaluated >12 LNs compared to 68% of post-template reports (33% improvement in LN yield; p=0.03). Conclusions: Examination of >12 LNs has important therapeutic and prognostic implications in colon cancer patients. Use of a standardized pathology template with dedicated fields for LN reporting is a simple intervention that can increase yield of LN reporting. This can have a significant impact for institutions striving to reach the 12 LN quality metric.

[Table: see text]

No significant financial relationships to disclose.
Primary adenocarcinoma of the anus: a 22-year SEER population database analysis
Authors: Yap J. C. , Yang G. Y. , Fakih M. , Mashtare T. , Bullard Dunn K. , Kuvshinoff B. W. , Smith J. , Khushalani N. I. , Gibbs J. F.
Published: August 2020

e15072

Background: Most anal canal cancers consist of squamous cell carcinoma (SCCA). Adenocarcinoma (AdenoCa) is rare and accounts for approximately 10% of anal cancers. A search of the SEER database (1973 to 2005) was carried out to evaluate the pattern of radiation (RT) and surgical treatment. Impact of the treatment on overall survival (OS) was evaluated. Methods: The search of the SEER database revealed 1,008 pts who had pathologically confirmed anal cancers with either SCCA or AdenoCa. All pts had single diagnosis of anal cancer with localized disease without nodal involvement. Excluded were pts with unknown use of surgery or radiation. Kaplan-Meier estimates and Cox-Mantel model were used to calculate and compare survival rates. Results: Median age of all pts was 57 years (range 29 to 99). For the SCCA group, median age was 57 years (range 29 to 99), which was younger than the AdenoCa group with median age of 74 years (range 37 to 92). Among the 1,008 pts, 954 had SCCA (94.6%), and 54 had AdenoCa (5.4%). Within the SCCA group, 14 (1.5%) had abdominoperineal resection (APR) in combination with external beam RT, and 795 (83.3%) had RT only with non-APR local surgical treatment inclusive of excision. Remaining 145 SCCA pts (15.2%) had non-APR local surgical treatment only without RT or had no treatment. Within the AdenoCa group, 10 (18.5%) had APR in combination with external beam RT, and 21 (38.9%) had RT only with non-APR local surgical treatment inclusive of excision. Remaining 23 AdenoCa pts (42.6%) had non-APR local surgical treatment only without RT. None of the adenoCa pt had no treatment. OS at 10 years was superior for pts with SCCA vs. AdenoCa (64.9% vs. 25.8%, p<0.05). Among the SCCA subset, there was no signficant difference in the 10-yr OS between the APR versus the RT pts (71% vs. 65%, p=0.78). On the other hand, among the AdenoCa subset, pts who had APR had better 10-yr OS than RT pts (53.8% vs. 0%, p=0.03) Conclusions: For localized anal SCCA, RT yielded equivalent overall survival as compared to APR. On the other hand, pts with localized anal adenoCa appeared to do worse when APR was omitted. RT only without APR might not be sufficient treatment in these patients. This database lacks information on use of chemotherapy and local disease control. Omission of APR in pts with anal canal adenoCa should be cautiously weighed.

No significant financial relationships to disclose.
Phase II study of capecitabine and gemcitabine in patients with metastatic colorectal cancer (mCRC)
Authors: Iqbal S. , Yang D. , Cole S. , El-Khoueiry A. B. , Boswell W. , Agafitei R. , Lujan R. , Lenz H. J.
Published: August 2020

e15077

Background: Failing standard chemotherapy, many mCRC patients (pts) maintain an adequate performance status necessitating therapeutic options. Preclinical data in CRC cell lines shows that 5-FU and gemcitabine have synergistic cytotoxicity by stabilization of thymidylate synthase resulting in stronger inhibition of DNA synthesis. Methods: The primary objective was to assess time to progression (TTP) in mCRC pts who had progressed on irinotecan and oxaliplatin therapy. Secondary objectives included response rate (RR), overall survival (OS), toxicity and correlates to assess genes in the 5-FU, gemcitabine pathways. This single center study was a two stage minimax design. A ≤ 30% chance of progressing within the first 6 weeks would be promising. 27 pts were enrolled in the first stage, if ≥ 13 progressed (or had unacceptable toxicity) prior to 6 weeks then the study would be terminated. The planned sample size was 53 pts. A cycle was defined as capecitabine 650 mg/m2 BID days 1–14 and gemcitabine 1,000 mg/m2 i.v. over 100 minutes days 1, 8. Results: The study met its first stage goal and continued to accrue 54 eligible pts (male 24/female 30), median age 58 years (range 31–78). Pts received a median of 2 cycles (range 1–19), with 22% of pts receiving 6 + cycles. Three pts that withdrew shortly after start were excluded from toxicity analysis. Of 51 pts, 23 had Grade 3/4 drug related toxicity, commonly 9 pts ANC/AGC; 4 pts pain. The probability of progressing at 6 weeks was .46 + .07, with 23 pts progressing or dying within that time. Median OS was 5.9 months (95% CI 4.3, 8.7), PFS was 8.1 weeks (95% CI 5.6, 11.6). Of 48 pts evaluable for response, 17 had stable disease, for these pts, the median PFS was 4.3 months (95%CI: 3.9–8.8) and OS 10 months (95%CI: 7.9–16.6); 31 had progressive disease or symptomatic deterioration. Conclusions: The combination of gemcitabine and capecitabine in refractory mCRC was well tolerated. Unfortunately, the study did not meet the primary endpoint, but there appears to be a subset of pts with stable disease who may benefit from therapy. Correlatives are pending.

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Evaluation of plasma total and cleaved cytokeratin 18 as predictive markers of chemotherapy in colorectal cancer
Authors: Moore M. M. , Chua W. , Zhao J. , Clarke S. J. , Horvath L.
Published: August 2020

e15091

Background: Cytokeratin 18 (CK18) is a cytoskeletal protein present in the circulation of cancer patients. Caspase-cleaved CK18 fragments are released from apoptotic cells and may be a simple non-invasive tool for measuring response to chemotherapy. This study aims to assess the associations between levels of CK18 with clinical parameters in patients with metastatic colorectal cancer (mCRC) receiving palliative chemotherapy. Methods: Prospectively collected plasma from 23 mCRC patients were analysed for the presence of total CK18 (M65, Peviva) and cleaved CK18 (M30-Apoptosense, Peviva) using an ELISA assay. 8 patients received 2nd-line chemotherapy (irinotecan) and 15 patients received 1st-line 5FU-based chemotherapy. Levels of both total and cleaved CK18 were determined at day 0 prior to chemotherapy and +24 hours for 2nd-line patients or +72 hours for 1st-line patients post-chemotherapy. Patients were grouped as responders (CR + PR) or non-responders (SD + PD) and results were analysed by non-parametric tests (Mann- Whitney and Wilcoxon Signed Rank Tests). Results: The median age of patients was 62 (range 24–79) with 9 patients (39%) responding to chemotherapy. Pre-chemotherapy, both total and cleaved CK18 levels were significantly lower in patients that responded to chemotherapy compared to non-responders [mean total CK18 responders 447.8U/L (95%CI 286.6–609.0 U/L ) versus mean total CK18 non-responders 999.4U/L (95%CI 602.7–1396.1 U/L), p=0.033; mean cleaved CK18 responders 174.7 U/L (95% CI 26.4–323.0) versus mean cleaved CK18 non-responders 331.4 U/L (95%CI 185.3–477.6), p=0.046]. There was a statistically significant increase in the concentration of total CK18 in the post-chemotherapy samples compared to baseline (p=0.003) however there was no association with response (p=0.12). The mean ratio of cleaved: total CK18 was significantly lower after chemotherapy [baseline 0.33 (95% CI 0.28–0.38) versus post-chemotherapy 0.29 (95%CI 0.24–0.34), p=0.01]. The mean ratio of cleaved: total CK18 at baseline was unable to discriminate between responders and non responders (p=0.83). Conclusions: These data suggest that pre-chemotherapy total and cleaved CK18 plasma levels are potential predictors of chemotherapeutic response for patients with mCRC.

No significant financial relationships to disclose.
AVASTERB OUEST: A prospective cohort study of unresectable metastatic colon cancer treated successively by FOLFIRI bevacizumab and cetuximab irinotecan
Authors: Metges J. , Gamelin E. , Faroux R. , Klein V. , Ganem G. , Douillard J. , Stampfli C. , Corbinais S. , Riche C. , Grude F.
Published: August 2020

e15103

Background: Bevacizumab and cetuximab regimen are approuved since 2005 in Europe for Metastatic Colorectal Cancer Patients (MCCP). Very few studies have reported data concerning the sequence (FOLFIRI BEVA and after failure CETUXIMAB- CAMPTO) in MCCP from the real world. Methods: Since 2003, in west of France, (Bretagne-Pays de Loire),a network called OMIT(Observatoire des Médicaments et Innovations Thérapeutiques) directed by Regional Health Agencies has been created. This structure gathered prospectively data from MCCP treated with targeted therapies. Since 2006, a cohort of MCCP treated successively by FOLFIRI BEVACIZUMAB (same protocol : same dose) as first line to progression or unacceptable toxicity and CETUXIMAB- CAMPTO after the first line failure was constitued (AVASTERB cohort). Criteria for initial unresectability of metastic lesions was based on investigator's evaluations during local comitee (surgeons and oncologists). In order to have a large follow up, the 35 first patients of the cohort were studied in this abstract.Age, sex, response rate to the different regimens,secondary metastatic lesion resection, time to progression to the different regimens, follow up and overall survival are the criterias studied. Results: Median age 60 years (49–83), Males : 60%, colon 71%,rectum: 17%, colorectal jonction :12%.Response rate(OR+SD)with Folfiri Bevacizumab : 45.7%. 17% of the patients underwent hepatic surgery with curative intent (all during Folfiri bevacizumab) Time to progression with Bevacizumab : 6 months. Fifty eight percent of the patients are still alive with a median follow up of 25 months (11–29)Median overall survival was not reached.The 12 months and 24 months overall survival rates are respectively 71.4% and 45.7% (date of point: 01/01/2009). Actualisation of the data will be provided during the meeting Conclusions: The results from this prospective unselected cohort of MCCP treated with the sequence FOLFIRI BEVA and after failure CETUX-CAMPTO from the real world show promising TTP, and overall survival. The study of the Kras mutation and others biomarkers could improve these results by personalization of the treatment. This part of our study is actually ongoing.

No significant financial relationships to disclose.
Preoperative concomitant chemoradiotherapy with oxaliplatin and 5-fluorouracil in locally advanced rectal carcinoma
Authors: Djellali L. , Larbaoui B. , Boukerche A. , Ghazi S. , Chaiba I. , Meziane N. , Yekrou D. , Youcef D. F.
Published: August 2020

e15108

Background: Preoperative concomitant chemoradiotherapy has shown to improve local control and sphincter preservation with decreased acute toxicity compared with postoperative treatment in locally advanced rectal carcinoma. The primary endpoint of this phase II trial was pathologic tumor response. Secondary endpoint was sphincter preservation and toxicity Methods: Inclusion criteria: rectal adenocarcinoma <12 cms from anal verge, clinical stage T3–4, adequate renal, hematological and liver function. Planned sample for this trial was 40 patients. Treatment schedule: Pelvic radiotherapy (25 Gy/ 5 fractions: 5 Gy on day 1 to day 5) and chemotherapy: Oxaliplatin 85 mg/m2 on 2 hours, day 1 and 15, folinic acid 20 mg/m2 and 5 fluoro-uracil bolus 500 mg/m2 on day 1, 8 and 15 (cycle repeated every 4 weeks). Surgery with TME was performed after the end of the second cycle of chemotherapy. Adjuvant chemotherapy with 5FULV2 was administered after surgery Results: 15 patients have been recruited between January and October 2006: 10 males/5 females. Median age: 45 years (range 26–62). Clinical stage (determined by CT or RMI): T3: 66.6% and T4: 33.3%. Tumor location (from anal verge): < 6 cm in 10pts, >6 cm in 5pts. Surgery (performed in 14 patients) consisted of low anterior resection in 5pts and abdominal-perineal resection in 10p. Tumor down-staging was observed in 10pts (66.6%), including 5pts with complete pathological response (33.3%). Main adverse effects (NCI-CTC): diarrhea G3–4: 14.2%, sensitive peripheral neurotoxicity G1: 26.6%, nausea/vomiting G3–4: 11%, Anemia G3–4: 7.1%, neutropenia G3–4: 14.2% Conclusions: Preliminary results show that preoperative concomitant chemoradiotherapy with oxaliplatin and 5FU-folinic acid is an effective regimen with an acceptable safety profile for locally advanced rectal cancer, leading to a high probability of tumor downstaging. This interim analysis has to be confirmed by the final analysis.

No significant financial relationships to disclose.
Use of anti-neuropilin 1, 2 antibodies to predict colorectal cancer prognosis
Authors: Takeda A.
Published: August 2020

e15111

Background: Neuropilin (NRP) was initially described as non-tyrosine kinase receptors for neuron guidance factor belonging to the Semaphorin family. Two subtypes, NRP-1 and NRP-2 have been isolated. Neuropilins are widely expressed not only normal developing tissues but also several types of tumor cells. It was reported that the expression of NRP-1 is increased by VEGF, mediated through VEGFR-2, which correlates with tumor growth and invasiveness in colorectal cancer. NRP-2 knockout mice studies showed marked deficits in the development of small lymphatic vessels and its function was associated with the formation of lymphatic network, but the role of NRP-2 in colorectal cancer remains unknown. Methods: We have newly established two useful anti- Neuropilin antibodies against CUB domains of NRP-1 and cytoplasmic domains of NRP-2. In recent study, we have analyzed the expression of NRP-1 and NRP-2 in some cultured cell lines by western blot and the clinicopathological significance in colorectal cancer. Tissues samples were obtained from 72 primary colorectal adenocarcinomas (colon:39 cases, rectum:33 cases). The pathologic stage were as follows; stageI:10 patients, II:25 patients, III:26 patients and IV:11 patients. NRP-1 and NRP-2 gene expression was evaluated by RT- PCR, which was compared with immunohistochemical examination of colorectal cancer tissues. Constitutive expression of NRP-1 was detected in PC3, HT29, PC9 and PC13 cell lines and NRP-2 in HT29, PC3 and PC9. Results: There was significant correlation between NRP-1 and -2 protein expression and both of mRNA expression. The expression of NRP-1 showed apparent correlation with liver metastasis (p=0.027) and venous invasion (p=0.0025), while NRP-2 expression was correlated with lymph node metastasis (0.001) and lymphatic invasion (0.039) by immunohistochemical analysis. The post-surgical treatment observation revealed that patients with co- expression of NRP-1 and NRP-2 were significantly correlated with poorer prognosis than both NRP-1 and NRP-2 negative patients (p=0.035). Conclusions: These results suggest that NRP-1 acts as angiogenesis factor and NRP-2 acts lymphangiogenesis factor, both of them are useful predictive marker in colorectal cancer.

No significant financial relationships to disclose.
Overexpression of EphA4 gene and reduced expression of EphB2 gene: Correlation with liver metastasis in colorectal cancer
Authors: Oshima T. , Yamamoto N. , Sato T. , Nagano Y. , Fujii S. , Kunisaki C. , Shiozawa M. , Akaike M. , Rino Y. , Masuda M. , Imada T.
Published: August 2020

e15129

The Eph receptors, members of a large family of transmembrane receptor tyrosine kinases, play important roles in a variety of biologic functions. Recent studies have suggested that EphA4 and EphB2 participate in the growth and development of various carcinomas. This study examined the relations of EphA4 and EphB2 gene expression to clinicopathological factors, especially metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal cancer. The relative expression levels of EphA4 and EphB2 mRNA in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of EphA4 mRNA was higher in the presence than in the absence of liver metastasis, whereas the relative expression levels of EphB2 mRNA were similar. Analysis of the relations between clinicopathological features and gene expression showed that high expression of the EphA4 gene and low expression of the EphB2 gene correlated with liver metastasis. There was no correlation between EphA4 and EphB2 gene expression. Our results suggest that over-expression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer. Over-expression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer.

No significant financial relationships to disclose.
The use of panitumumab (Pan) in patients (pts) with metastatic colorectal carcinoma (CRC) whose disease has progressed through treatment (Rx) with cetuximab (Cet)
Authors: Martel C. L. , McNamara M. V.
Published: August 2020

e15142

Background: Both Pan and Cet have activity in the Rx of metastatic CRC. As they each target the epidermal growth factor receptor, and are believed to have the same mechanism of action, pts who fail Rx with one of these agents are generally not treated with the other. Methods: A retrospective chart review was performed of pts in our practice with metastatic CRC. The response to Pan of pts whose disease had progressed despite use of a Cet containing regimen was assessed. Results: We identified three pts who received Pan after failing Rx with Cet. Pt 1 was an 81 year old female who had discontinued Rx with 5- fluorouracil (5-FU) and leucovorin (Lcv) plus bevacizumab (bev); capecitabine; and irinotecan due to intolerance. She received Cet for 6 months with initial stable disease (SD) and subsequent progressive disease (PD). She was later treated with Pan for 6 months with slight shrinkage of her metastatic disease (SD by response evaluation criteria in solid tumors) and marked improvement of her performance status (PS) before eventual PD. Pt 2 was a 43 year old female who had eventual PD after Rx with oxaliplatin and capecitabine plus bev; irinotecan plus bev; and an experimental vaccine. She was treated with Cet for 6 months with a PR, followed by PD. She received Pan for 3 months, with improvement in her PS, decreased pain and a 45% decline in her carcinoembryonic antigen level, before eventual PD (no radiologic studies were obtained during Rx with Pan). Pt 3 was a 64 year old female whose prior Rx had included oxaliplatin plus infusional 5-FU and Lcv (FOLFOX), as well as irinotecan plus infusional 5-FU and Lcv (FOLFIRI) with Cet; the latter was continued for 3.5 months, with a best response of SD. She then received 4 doses of Pan, but had PD. Conclusions: Pan led to clinical improvement with objective evidence of disease stabilization or response in 2 of 3 pts in our practice who had previously failed Cet. Pan has meaningful, although modest, activity in pts with metastatic CRC whose disease has progressed through Cet. The use of Pan should be considered in pts who have failed Cet and who do not have other viable Rx options.

No significant financial relationships to disclose.