bluuebunny/crossref_metadata_2025 huggingface dataset:
18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) as a prognostic and predictive biomarker in metastatic colorectal cancer (mCRC)
Authors: Philip P. A. , Gupta S. , Heilbrun L. , Smith D. , El-Rayes B. , Shields A.
Published: August 2020

e15037

Background: Information on the prognostic and predictive role of FDG-PET in the management of patients (pts) with mCRC is limited. The growing complexity of current therapies and the increasing number of agents to be tested in this disease warrants better understanding of the role of FDG-PET in earlier treatment decisions. Methods: Consecutive pts with 2 or more serial FDG-PET scans at baseline and during the treatment course were studied. Tumor standardized uptake value (SUV) and its percentage change (%ΔSUV) were each studied for their potential association with time to progression (TTP) via univariate Cox models to estimate the hazard ratio (HR) for progression. Results: 27 pts (median age 58.2 yrs) with mCRC were studied. 85% of pts were treated in the first line setting. 44% had received prior adjuvant therapy. 63%, 26% and 11% received oxaliplatin based, irinotecan based and fluropyrimidine only regimens, respectively. 85% received concurrent bevacizumab. Median pretreatment SUV was 9.0 (range 1.7 - 46.0); Median post treatment SUV was 3.4 (0–13.5); median %ΔSUV was -77.2 (range -10% to -100%). Mean interval between scans was 4.1 months. Ten (37%) patients had no tumor uptake on post treatment scans. 56% and 37% of pts had partial response and stable disease (RECIST criteria), respectively. Median TTP was 13.0 months (90% CI: 10.9 - 16.3 mos), with a median follow-up time for progression of 7.8 months. The HRs for baseline SUV and %ΔSUV were 0.972 (90% CI: 0.901 - 1.048, p=0.534) and 1.018 (90% CI: 1.003 - 1.033, p=0.049), respectively. The median TTP of patients whose post-treatment SUV reached zero was 13.8 months vs. 10.9 months (p=0.17) for pts whose post-treatment SUV did not reach zero. Conclusions: Systemic therapy significantly decreased the SUV on follow up PET scans in pts treated for mCRC. However, no significant association was seen between either baseline SUV or %ΔSUV and TTP. There may be a very weak statistical association of decreasing SUV with decreasing risk of progression. Further work is needed to optimize and standardize evaluation of tumor response in mCRC patients with FDG-PET.

No significant financial relationships to disclose.
EGFR gene copy number, KRAS and BRAF status, PTEN and AKT expression analysis in patients with metastatic colon cancer treated with anti-EGFR monoclonal antibodies ± chemotherapy
Authors: Bengala C. , Bettelli S. , Fontana A. , Bertolini F. , Sartori G. , Malavasi N. , Losi L. , Del Giovane C. , Luppi G. , Conte P.
Published: August 2020

e15055

Background: Cetuximab and panitumumab have proven to be effective in metastatic colon cancer (mCRC). KRAS mutation has been demonstrated to be a biomarker of resistance to both monoclonal antibodies. However the status and expression of other biomarkers of the RAS-RAF-MAPK signalling pathway can have a crucial role in sensitivity to anti-EGFR monoclonal antibodies. Methods: We have retrospectively analyzed tumor tissue biomarkers including EGFR gene copy number (GCN) by FISH, KRAS and BRAF status by PCR-based sequencing, PTEN and AKT expression by IHC in patients with mCRC treated with cetuximab and panitumumab ±chemotherapy. Response to treatment, TTP and OS were evaluated. Results: Sixty-three patients (pts) have been analyzed. Median age was 59 years (34–80); 53 pts had received cetuximab and 10 pts panitunumab. Concomitatnt chemotherapy was FOLFIRI, CPT-11, FOLFOX4 and Xeliri in 35, 13, 6 and 4 pts respectively. Five pts had received monoclonal antibodies only. Twenty- one pts were treated in 1st-2nd line and 42 pts in 3rd-4th line. So far EGFR GCN is available on 55 pts, KRAS and BRAF on 63 pts, PTEN in primary tumor (PT) on 36 pts and in metastatic (MTS) site on 24 pts, AKT on 19 pts. EGFR/nuclei ratio was > 2.9 in 31 % of the pts, KRAS and BRAF were mutated in 36.5 % and 3 % of the pts respectively; PTEN was positive in 42 % and 79 % in PT and MTS respectively. Moreover 21.8 % of the pts had EGFR/nuclei > 2.9 and CEP7 Polisomy > 50 %. Four pts achieved a partial remission (6.3 %). Partial response rate was 17 % vs. 2.6 % in pts with high and low EGFR GCN respectively (p: 0.007) and 13 % vs. 2.5 % in pts with WT and mutated KRAS respectively (p: 0.048). Median TTP was 3 months (0.83–32.9). It was 4.2 vs. 2.3 mos in pts with WT and mutated KRAS respectively (p: 0.001). Median OS was 9.7 mos (2.03–49.0) and no statistically significant differences were observed according to the biomarkers status. However a trend was observed for pts with KRAS WT 10.6 vs. 7.8 mos and for PTEN positive in PT: 9.0 vs. 5.67 mos. Conclusions: Our data confirm the predictive role of EGFR gene copy number and KRAS status on the response and survival. Complete biomarker characterization is ongoing and an analysis for interaction will be performed.

No significant financial relationships to disclose.
Involvement of ppGalNAc-T6, a new colon cancer marker, in the molecular basis of simple mucin-type O-glycosylated antigen expression
Authors: Ubillos L. , Berois N. , Mazal D. , Braña V. , Yacoel C. , Masllorens A. , Berriel E. , Rondan M. , Carriquiry L. , Osinaga E.
Published: August 2020

e15060

Background: Abnormal O-glycosylation is one of the most common changes during colon carcinogenesis, leading to the expression of short truncated O-glycan antigens (such as Tn, sialyl-Tn, Tk, and core 6). These structures which are related with the malignant behavior are actively investigated as immunotherapeutic targets. The ppGalNAc-T family enzymes regulate the initial step of mucin O-glycosylation and could be responsible for the altered glycosylation observed in cancer. The objective of this work was to describe the abnormal expression of ppGalNAc-Ts in colon cancer comparing its relationship with incomplete O- glycosylated antigens. Methods: We studied the gene expression of ppGalNAc-Ts in colon cell lines by RT-PCR assays. Using immunohistochemistry we determined ppGalNAc-T6, Tn, sialyl-Tn, Tk, and core 6 expression in 64 colon cancer samples and in 10 normal colon tissues. Results: We found that ppGalNAc-T6 (an enzyme usually restricted to normal placenta, trachea, brain, and pancreas) is expressed by colon cancer cell lines. Using immunohistochemistry we detected ppGalNAc-T6 in 70.3% of cancer samples with no staining in normal colon tissues. Staining pattern was predominantly cytoplasmatic. Staining of Tn, STn, core 6 and Tk antigens was observed in 87,5%, 79,6%, 76,5% and 68.7% of tumors, respectively. We observed a statistically significant relationship between the enzyme expression and Tn antigen (p=0.009) and core 6 (p=0.001). No relationship was observed between the enzyme expression and sialyl-Tn (p = 0.406) and Tk (p= 0.18) antigens. Conclusions: ppGalNac-T6 is a new tumor marker for colon cancer and its expression is related with the accumulation of two O-glycosylated antigens such as Tn and core 6. This is the first evidence in human tissues suggesting that the abnormal expression of a ppGalNac transferase could be in the molecular basis of aberrant O-glycosylated antigens accumulation in cancer.

No significant financial relationships to disclose.
Bi-weekly administration of capecitabine + oxaliplatin (Xelox-2) in first-line treatment of advanced colorectal cancer (ACRC): A phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM)
Authors: Fedele P. , Di Maggio G. , Leo S. , Nanni L. , Giuliani F. , Biglietto M. , Lorusso V. , Cinieri S. , Colucci G. , Maiello E.
Published: August 2020

e15066

Introduction: FOLFOX regimen represents a standard first-line therapy for ACRC pts. Oral capecitabine (XEL) has been shown to be a convenient and well tolerated alternative to intravenous 5-fluorouracil (5-FU) in the treatment of ACRC. Experimental data demonstrated the synergism of XEL with Oxaliplatin (OHP), but the questions about the most appropriate dosage and schedule of capecitabine have not yet been completely resolved. Taking into account these data the GOIM started a phase II study to evaluate the activity and the toxicity of biweekly administration of XEL plus OHP (XELOX-2) in ACRC pts. Methods: Previously untreated pts with histological diagnosis of metastatic colorectal cancer, measurable disease, ECOG PS<2, and age 18–75 yrs entered into this trial. The schedule of treatment was as follows: OHP at 100 mg/mq i.v. on days 1 and XEL at 2,000 mg/mq p.o. in two daily administrations from the 1 to the 7 day, every 2 weeks. RECIST and NCI criteria were employed to determine the activity and the toxicity of this regimen. Results: Fifty-one pts have been enrolled and up to now forty-seven are evaluable for activity and toxicity. The main characteristics of the entered pts were: sex (M/F) 38/13, median age 66,5 yrs (range 54–75 yrs), 28 (55%) single and 23 (45%) multiple site of disease. The main site of disease were liver in 38 pts (75%), lymph-nodes in 17 (33%), lung in 9 (18%). Two CR (4%) and 22 PR (47%), 13 SD (28%) and 10 PD (21%) were observed, with an overall response rate of 51% and a disease control rate (CR+PR+SD) of 79%. Median TTP was 5+ months (range 2–19). A total of 413 cycles were administered. In the evaluable pts the main toxicity rate (G1- 2 vs G3–4) were as follows: thrombocytopenia 51/6, anemia 42/0, neutropenia 15/0, nausea/vomiting 30/2, diarrhea 19/2, neurotoxicity 57/0 and asthenia 30/2. Only one pts presented G4 toxicity (diarrhea). Conclusions: These preliminary data show that the combination of XEL and OHP with a biweekly administration is active and well tolerated in ACRC pts.

No significant financial relationships to disclose.
Bevacizumab (Bev), irinotecan (IRI), folinic acid (FA), and 5-fluorouracil (FU) every 2 weeks (BIFF regimen) as first-line treatment for metastatic colorectal cancer (MCRC) patients (pts): The SICOG experience
Authors: Comella P. , Massidda B. , Natale D. , Filippelli G. , Farris A. , Condemi G. , Palmeri S. , Tafuto S. , Vessia G. , Barberis G.
Published: August 2020

e15067

Background: The IRIFAFU regimen produced in MCRC pts a consistent activity (RR, 33% [95% CI, 27–39%], PFS, 7.4 [95% CI, 6.5–8.3] mo.) in 2 consecutive randomized SICOG trials . Bev was proven to significantly improve the efficacy of IFL regimen. Here we report the safety and activity results of the BIFF regimen as first-line treatment of MCRC. Patients: From Feb 2007 to Jul 2008, 95 pts with MCRC were treated: so far, 85 pts were evaluated for safety: M/F were 47/38, median age (range) was 64 (35–78) yrs. Fifty-six pts had a colon, and 29 pts a rectal carcinoma. ECOG PS was 0 (63 pts, 74%), or 1 (22 pts, 26%). Thirty-four (40%) pts had 1 site, 33 (39%) 2 sites, and 18 (21%) pts ≥3 sites of disease. Liver was involved in 66 (78%), lung in 23 (24%) pts. Twenty-one (25%) pts had an unresected primary (colon 13, rectum 8). Bev 5 mg/kg (1-h), and IRI 180 mg/sqm (1-h) were given IV on day 1, 6S-FA 250 mg/sqm (2-h), and FU 850 mg/sqm (bolus) were given IV on day 2 biweekly for a maximum of 12 cycles. Bev was continued until progression, severe toxicity, or refusal. Results: A median of 9 (range, 1–12) cycles of BIFF were delivered. G4 hematologic toxicity was: neutropenia (21%), and febrile neutropenia (10%). G≥3 non-hematologic toxicity was: diarrhea 15%, vomiting 7%, stomatitis 4%, hypertension 1%. No severe episodes of bleeding were registered. Among 81 assessable pts, 5 CRs (3 in liver, 1 in liver & nodes, 1 in liver & lung), and 41 PRs were registered, giving a RR of 57% (95% CI, 45–68%). Overall, 71/81 (88%, 95% CI, 77–93%) pts obtained a disease control. Liver mets resection, or primary resection, was safely performed in 3 pts and in 2 pts, respectively. After a median follow- up of 12 (range, 6–24) mo., median FFS was 8.4 (95% CI, 6.8–10.0), and median PFS was 14.1 (95% CI, 9.6–18.6) mo. With only 14 deaths, OS results are still immature. Conclusions: Unexpected side effects of the BIFF regimen were not registered. Addition of Bev increased the activity without worsening the tolerability of IRIFAFU combination as compared with our previous experience. Efficacy of BIFF was comparable with that reported with other Bev plus IRI-based combinations. Updated follow-up will be presented.

No significant financial relationships to disclose.
Predictors of adjuvant chemotherapy (AT) decision-making in referred patients (pts) with stage II and III colon cancer (CC)
Authors: Ksienski D. S. , Levesque M. , Gill S.
Published: August 2020

e15070

Background: Randomized clinical trials have demonstrated a robust survival benefit of AT for node positive (stage III) CC patients; similar evidence for node-negative (stage II) patients is lacking. While guidelines recommend AT for stage III colon cancer but AT is not a routine recommendation for stage II. Actual practice of the evidence varies and suggests the interplay of additional variables. We sought to identify factors associated with practice patterns which vary from conventional AT guidelines, ie no AT in stage III CC and receipt of AT in.stage II CC. Methods: Data pertaining to pt demographics, tumor characteristics, and treatment for pts with resected stage II (n=176) and III CC (n=235) referred to the British Columbia Cancer Agency in 2004 was collected by retrospective chart review. One-sided Fisher's exact test was used to assess statistical significance (p<0.05) by univariate analysis. Results: 28% (n=49) of stage II pts received AT. Compared to untreated pts, stage II pts who received AT were significantly more often younger than 66 years (57% vs 21%), lived in a city with a regional cancer center (71% vs 51%), had T4 disease (33% vs 9%), vascular invasion (22% vs 5%), perineural invasion (10% vs 2%) and high grade (26% vs 2%). Marital status, ethnicity, lymphatic invasion and high CEA were not associated with AT in stage II. 29% (n=69) of stage III pts did not receive AT. Compared to treated pts, stage III pts who did not receive AT were significantly more often older than 65 years (91% vs 51%), had low grade disease (96% vs 84%) and presented for oncology consultation greater than 42 days from surgery (29% vs 11%). Marital status, ethnicity, residence, T4 status or N2 status were not associated with no AT in stage III. Conclusions: For pts with stage II CC, subgroups associated with high risk for relapse were more likely to receive AT although the majority of stage II pts in this cohort remained untreated. For stage III disease, almost one-third of referred pts did not receive AT. Older age and delayed presentation were strongly associated with failure to receive AT. Within the limitations of a retrospective review, these data highlight the significant and commonly observed implications of factors other than stage in AT decision-making for high risk resected CC.

No significant financial relationships to disclose.
Palliative first-line treatment with weekly high-dose 5-fluorouracil and sodium folinic acid (s-FA) (AIO-schedule) as 24h-infusion plus biweekly oxaliplatin (ox) in patients with definitively non-resectable metastatic colorectal cancer (CRC) following secondary (sec.) metastatic resection: An interdisciplinary phase II trial
Authors: Albrecht H. , Boxberger F. , Wolff K. , Ostermeier N. , Reulbach U. , Maennlein G. , Meyer T. , Hohenberger W. , Hahn E. G. , Wein A.
Published: August 2020

e15073

Background: In an interdisciplinary phase II trial performed from 1995 to 1997 and based on a 5-FU monotherapy it was possible to achieve both a sec. metastatic resection after downsizing in 9 patients (17%) and a R0 resection offering curative option in 6 patients (11%) out of a total collective of 53 treated patients (Wein et al, Ann Oncol 2001). The objective of this phase II trial is to verify whether a combination therapy based on ox may improve the curative option in terms of a sec. metastatic resection in a patient cohort with identical inclusion - and exclusion criteria. Methods: Prospective evaluation of 50 patients.; palliative chemotherapy: ox (oxaliplatin, 85 mg/m2 i.v. as a 2h-infusion (inf.); d 1, 15, 29 qd 57) followed by 5-FU (2000 mg/m2 i.v. as a 24h- inf.; d 1, 8, 15, 22, 29, 36 qd 57) together with s-FA (Oncofolic, 500 mg/m2 i.v. as a 24h-inf.; d 1, 8, 15, 22, 29, 36 qd 57) via a miniature pump system. Results: Last date of evaluation: Sep/30/2008; median age: 63 years; chemoth. appl.: total number: 935; higher grade toxicity (grade 3+4): diarrhea 20,0 %, nausea 4,0 %; vomitus 6,0 %; hand-foot-syndrome 2,0 %; fever/infection 2,0 %; response: CR: 2,0 %; PR: 52,0 %; SD: 32,0 %; PD: 12,0 %; not evaluable: 2,0 %; tumor control (CR, PR, SD): 86,0 %; sec. metastatic resection: R0: 28,0 %; R1: 2,0 %; R2 8,0 %; TTP (n = 50): 9,8 months. Conclusion: Combination chemotherapy with weekly 5-FU and s-FA (AIO) plus bi-weekly ox on an outpatient basis is an effective palliative treatment schedule offering a high rate of curative metastatic resection with solely low grade toxicity and no higher grade neurotoxic side effects. Final results in terms of median survival remain to be seen whereas they are certainly influenced by the second line therapy.

No significant financial relationships to disclose.
RIPK1 gene polymorphism as a prognostic marker for survival in patients with colorectal cancer
Authors: Chae Y. , Kim J. , Sohn S. , Kim S. , Lee S. , Moon J. , Jeon S. , Cho Y. , Choi G. , Jun S.
Published: August 2020

e15078

Background: Since apoptosis plays a key role in cancer progression, we hypothesized that single nucleotide polymorphisms (SNPs) of apoptosis-related gene can affect survival after curative resection in patients with colorectal cancer. Patients and Methods: Three hundred and ninety seven patients with colorectal cancer who underwent surgery with curative intent were enrolled in the present study. The genomic DNA was extracted from fresh colorectal mucosal tissue, and the 19 SNPs of 15 apoptosis-related genes (CASP3, CASP6–10, FAS, FAS ligand [FASLG], TNSFR1A, TNSFR10B, RIPK1, BCL2, BCL2 ligand [BCL2L], TP53, and PTGS2) were determined using a PCR-RFLP assay. Results: The median age of the patients was 63 years (range, 21–85), and 218 (54.9%) patients had colon cancer and 179 (45.1%) patients rectal cancer. Pathologic stages after surgery were as follows: stage 0/I (n=86, 21.7%), stage II (n=146, 36.8%), stage III (n=145, 36.5%), and stage IV (n=20, 5.0%). Multivariate survival analysis including pathologic stage, differentiation, age, and CEA level showed that relapse-free survival for the patients with the GA+AA genotype of RIPK1 (Receptor interacting serine/threonine kinase 1) +83G>A (rs2272990) was worse than for the patients with the GG genotype (hazard ratio [HR]=1.66, 95% confidence interval [CI]=1.03–2.68, p=0.038). However, no associations were observed between the polymorphisms and overall survival (OS) in a multivariate analysis. Conclusions: RIPK1 gene polymorphism can be considered as a possible prognostic marker for survival after curative resection in patient with colorectal cancer.

No significant financial relationships to disclose.
A predictive test for therapeutic treatment outcomes of advanced gastrointestinal cancer patients (AGC)
Authors: Pandya N. B. , Tkaczuk K. R. , Tait N. , Ioffe O. , Tan M. , Van Echo D. A. , Sutula M. J. , Lesko S. A. , Deamond S. F. , Ts’o P. O.
Published: August 2020

e15079

Background: There are currently limited options for selecting an optimal treatment regimen for AGC patients. The Drug Response Indicator Test (DRIT) is a platform technology that provides a detailed profile of a patient's tumor response to commonly used chemotherapeutic drugs, as a basis for individualized treatment. Establishment of DRIT will allow physicians to choose effective drug treatments to improve the efficacy of cancer therapies on an individual basis. Methods: DRIT analysis is based on fluorescent dye-labeled monoclonal antibody staining followed by computer-assisted microscopy to measure expression levels in tumor sections. The interpretation of the Drug Response Indicator (DRI) expression levels result in classification of tumors as sensitive or resistant to treatment with a mechanistically related drug. Clinical outcomes are then analyzed with respect to the DRI data. This study utilized the following drug/DRI combinations: capecitabine, 5-flurouracil/thymidylate synthase; docetaxel, paclitaxel, abraxane/β-tubulin isoform III; gemcitabine/ribonucleotide reductase; platinum salts/ERCC-1; Irinotecan/Topoisomerase I. Results: DRIT retrospective studies were performed on a cohort of 33 consented patients (pts) receiving 55 treatments for AGC at UMGCC. This cohort included pts treated for rectal/colon, gastric, esophageal & pancreatic cancers. DRIT sensitivity was 0.96, positive predictive value 0.84, negative predictive value 0.67 and overall predictive accuracy 83 %. DRI expression level cut-off points indicating sensitivity or resistance to a specific treatment were derived from previous retrospective breast cancer studies using similar drug complements (abstract 6075 San Antonio Breast Conference 2008). Conclusions: This study indicates that DRIT can provide accurate prediction of treatment outcomes for individual AGC patients. DRI expression level cut-off points indicating sensitivity or resistance to a specific treatment may be applied to both breast cancer & AGC. DRIT will allow for tailoring of chemotherapy based on the specific biomarker expression within each patient's tumor tissue.

[Table: see text]
Association of integrin beta-3 polymorphism and chronic oxaliplatin-induced peripheral neuropathy: Preliminary results
Authors: Antonacopoulou A. , Argyriou A. , Kottorou A. E. , Scopa C. D. , Kalofonos H. P.
Published: August 2020

e15082

Background: Peripheral neuropathy (PN) is widely recognised among the major non-haematological dose- limiting toxicities of oxaliplatin (OXL) which is used to treat advanced or metastatic colorectal cancer (CRC). OXL induces two clinically distinct forms of PN. The acute transient syndrome and the chronic OXL-induced peripheral neuropathy (OXLIPN). The integrin beta-3 (ITGB3) polymorphism at residue 33 (L33P) has been previously associated with altered adhesion ability and ERK2 activation. Thus it may affect neuronal survival. The aim of the current study was to investigate the role of the ITGB3 polymorphism at residue 33 in the development of chronic OXLIPN. Methods: Thirty four patients with advanced CRC were genotyped. All patients, 22 males and 12 females had received adjuvant chemotherapy consisting of 12 courses of the formal FOLFOX-4 regimen. Following the discontinuation of treatment, 20 of the patients (58.8 %), developed OXLIPN, whereas the remaining 14 (41.2%) patients remained unaffected with normal peripheral nerve function. The grading of the OXLIPN severity was defined by Total Neuropathy scores, corresponding to the WHO grading scales 1–3 for chemotherapy-induced PN. Genotyping was performed using allele specific primers and sybr green in real time polymerase chain reactions. Statistics were performed using the SPSS for Windows (release 16.0). Results: Patients with normal peripheral nerve function OXLIPN were 14.3% homozygous for C, 28.6% heterozygous and 57.1% homozygous for T. The corresponding percentages for patients who developed OXLIPN did not differ significantly and were 5%, 25% and 70%, respectively. The majority of patients with mild OXLIPN were heterozygotes (50%, with 16.7% CC and 33.3% TT), whereas the majority of patients with moderate OXLIPN were homozygous for TT (85.7% with the remaining 14.3% being CT). Notably, the TT genotype was associated with increased OXLIPN compared to the genotypes containing the C allele (p= 0.046). Conclusions: The ITGB3 polymorphism at residue 33 appears to be unrelated to the development of OXLIPN but related to the grade of OXLIPN.Further study on this important clinical issue is warranted.

No significant financial relationships to disclose.
Correlation between K-ras mutations status and benefit from cetuximab treatment in advanced colorectal cancer
Authors: Xie L. , Lai R. , Wu X. , Zhang S. , Tang X. , Chen T.
Published: August 2020

e15084

Background: Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We follow -up study the efficacy and toxicity of cetuximab with chemotherapy in the treatment of advanced colorectal cancer from Chinese in East China. Methods: We analyzed tumor samples from 120 patients with advanced colorectal cancer by direct sequencing, to observe the mutations status in exon 2,3 of K-ras gene. And 30 patients were followed up according the RECIST standard for their treatment outcome of cetuximab plus chemotherapy at 2 -12 months. Results: K-ras mutations were identified in 48 of 120(40%) patients with colorectal cancer in exon2, which including 8 mutation types; 38/48(79.2%) mutations in 12 codon(G12D 43.7%,G12V 25%,G12C 10.4%,G12R 6%,G12S 4%,G12A 2%) and 10/48(18.7%) in 13 codon(G13D 18.7%,G13C 2%). None mutation was found in 61codon of exon3. we observed the clinical efficacy of 30 patients treated by cetuximab plus chemotherapy, of 21 patients with wild-type K-ras tumors as compared with 9 patients with mutated K-ras significantly improved the response rate (5/21 21.8% vs 1/9 11.1%,P<0.01)and the disease control rate (19/21 90.4% vs,2/9 22.2%,P<0.01). There were a few patients with mutated K-ras tumors benefit from cetuximab, in which the fluorescence intensity of mutation cells of all detected tumor tissue approach to 1:3 status by sequencing analysis. The major toxicities of treatment were acne-like rash, which were found in 14/21(66.6%)of patients with wild-type K- ras, and 5/9(55.5%)of patients with mutated K-ras . Conclusions: The East-China patients share the same (40%) mutation frequency and type of k-ras gene with other races . Patients with wild type K-ras mutation have significantly higher Response rate and disease control rate on cetuximab plus chemotherapy treatment .Our results once again show that somatic mutations status of k-ras is a major determinant of cetuximab response in advanced colorectal cancer. There was no statistical correlation between acne-like rash of the major toxicities and mutations status of k-ras. There were a few patients bearing mutated k-ras did benefit from cetuximab, that would need to be validation between Chinese or Ethnicity association phenotype by a large numbers of samples.

No significant financial relationships to disclose.
Nfy-c expression in colorectal cancer
Authors: Kottorou A. E. , Antonacopoulou A. G. , Skarlas L. , Grivas P. D. , Scopa C. D. , Makatsoris T. , Kalofonos H. P.
Published: August 2020

e15086

Background: Nuclear factor Y- C (NFY-C) gene encodes one of the three subunits of nuclear factor Y, a highly conserved transcription factor which binds to the promoters of a variety of genes, which are implicated in cell cycle progression, drug metabolism and antigen presentation. The purpose of the current study was to investigate the role of NFY-C in colorectal cancer by evaluating its mRNA expression in both malignant and normal colonic tissue from patients with colorectal carcinomas with and without disease relapse. Methods: Publicly available expression microarray data were analyzed to reveal elevated levels of NFY-C in patients with colorectal carcinoma who relapsed compared to patients who remained disease free. The mRNA levels of NFY-C were evaluated by quantitative RT-PCR in 81 neoplastic colorectal tissue specimens and 23 normal tissue specimens from patients with colorectal cancer who had undergone curative resections at the University Hospital of Patras, Greece, between 1995 and 2005. The mRNA levels were analysed in relation to clinicopathological parameters. Results: No significant difference was found in the expression levels of NFY-C between normal and malignant tissues. The expression levels of NFY-C were not related to age, gender, grade, stage or primary site of the disease. However, a statistically significant difference (p=0.02) was observed in NFY-C levels between patients with and without disease recurrence. More specifically, patients with low NFY-C levels relapsed more often than patients who overexpressed NFY-C. Nevertheless, the expression was not related to time to disease progression. Finally, patients with higher NFY-C expression levels seem to have improved survival, compared to patients with low NFY-C expression levels although the difference was not statistically significant. Conclusions: Expression levels of NFY-C seem to be associated with disease recurrence. The role of NFY-C in colorectal cancer warrants further investigation.

No significant financial relationships to disclose.
Treatment of cetuximab-associated cutaneous side effects using topical aplication oh vitamin K1 cream
Authors: Ocvirk J. , Rebersek M.
Published: August 2020

e15087

Background: The EGFR-targeting monoclonal antibody cetuximab has been licensed by the EMEA in combination with chemotherapy for the treatment of 1st line metastatic colorectal cancer (mCRC) patients (pts) whose tumors have KRAS wild type status. The major side effects of cetuximab are cutaneous reactions (approx. 80% of pts.) predominantly consisting of an acne- like rash 60–100%, but also including pruritus, dry skin (35%), desquamation, hypertrichosis and nail disorders (10–40%). If not properly managed, they have the potential to cause dose reductions and delays, which may in turn impact on treatment efficacy. The aim of our study was to determine the efficacy of topical vitamin K1 cream in pts with cutaneus side effects caused by cetuximab therapy. Methods: Between January 2007 and August 2008, 79 pts with mCRC were treated with weekly cetuximab in combination with chemotherapy. Topical use of a cream containing urea and 0.1% vitamin K1 was applied when an acne-like rash (NCI CTCAE version 3) appeared . Pts were monitored weekly for at least 12 weeks. Results: Sixty nine patients developed an acne-like rash after a median of 1.2 weeks after first cetuximab administration (range 1- 4), 20 pts grade 3, 38 grade 2 and 11 grade 1. Twice-daily application of vitamin K1 cream resulted in a gradual decrease in cutaneous toxicity. Median time to improvement (all toxicity grades) was 1.2 weeks and 2.3 weeks to a down-staging of the rash by at least 1 grade. Dose reduction of cetuximab was necessary for only 5 of the 20 pts with grade 3 toxicity. No dose reductions or treatment delays were needed for any patient with grade 1 or 2 cutaneous toxicity. Topical clindamycin was used concomitantly in 12/20 and 2/38 pts with grade 3 and grade 2 reactions respectively. No toxicity was associated with the topical use of vitamin K1cream. Conclusions: This study demonstrated the efficacy of topically applied vitamin K1 containing cream in the management of cetuximab-induced acne-like skin rash.

No significant financial relationships to disclose.
Colorectal cancer survival following adjuvant chemotherapy with weekly i.v. fluorouracil 425 mg/m2 and folinic acid 50mg
Authors: Jameson M. B. , Head M. , Deva S.
Published: August 2020

e15089

Background: Adjuvant chemotherapy for colorectal cancer (CRC) using fluorouracil (5FU) and folinic acid (FA) has been proven effective and the QUASAR trial showed that a weekly administration schedule was as effective as, and less toxic than, the same daily doses delivered over 5 days every 4 weeks (the “Mayo regimen”). However the 5FU dose used (370 mg/m2) was lower than in some trials and a higher 5FU dose was considered desirable if tolerated. We therefore implemented a weekly regimen using 5FU 425 mg/m2 and DL-folinic acid 50mg in 2001 and retrospectively evaluated its efficacy and tolerability. Methods: Patients with non-metastatic CRC at assessment by medical oncologists in this institution between 2001 and 2004 were included in the analysis. Data was gathered on patient characteristics, duration of adjuvant chemotherapy and survival. Actuarial survival was calculated using the Kaplan-Meier method. Results: 417 patients (pts) were seen: 181 females, 236 males; median age 67 yrs (24–89); 291 with colon cancer, 126 with rectal cancer; 1 stage 1; 100 stage 2, 316 stage 3. Median follow-up was 6.2 years. 210 pts with colon cancer received adjuvant weekly 5FU/FA (32 stage 2, 178 stage 3) as did 58 pts with rectal cancer (50 of whom also received concurrent chemoradiation). 75% of pts with colon cancer received all 30 planned doses and 59% of rectal cancer pts received all 20 planned doses. 3 year survival for all pts treated with this regimen was 83.0% and for the subgroups with colon and rectal cancer it was 82.4% and 84.5% respectively. For stage 2 and 3 colon cancer pts treated with this regimen 3 year survival was 87.9% and 76.0% respectively; for stage III rectal cancer pts it was 84.1%. Conclusions: These outcomes compare favorably on indirect comparison with results from the QUASAR trial (which reported 3 year survival of 70.6%) and suggest that using a higher 5FU dose in this regimen is tolerable and may be advantageous.

No significant financial relationships to disclose.
Preoperative transcatheter arterial chemoembolization (TACE) and chemotherapy for hepatic colorectal metastases: Impact on hepatic histology and postoperative outcome
Authors: Lu Q. , Zhao A. , Shen L.
Published: August 2020

e15090

Background: The objective was to evaluate the effect of preoperative administration of TACE and chemotherapy on hepatic injury and on postoperative outcome in patients with colorectal liver metastases (CRM) Methods: Seventy seven patients underwent hepatic resection for CRM between January 1999 and December 2007 were evaluated. Pathologic review of the non-tumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal dilation. The effect of two different treatment and hepatotoxicity on postoperative outcome was analyzed. Results: 40 patients (51.9%) received no preoperative treatment, where 27 patients (35.0%) received preoperative chemotherapy, 10 patients (12.9%) performed TACE before resection. The median duration of TACE group was 4.5 months (range, 1–6 months), where the median duration of chemotherapy group was 5 cycles (range, 2–9 cycles). Chemotherapy regimen consisted of oxalipaltin plus FU (29.9%), or irinotecan plus FU (5.2%). On pathologic analysis, 36 patients (46.7%) had steatosis, 24 (31.1%) had sinusoidal dilation, and 8 (10.3%) had steatohepatitis. TACE was associated with steatosis, steatohepatosis and postoperative complication, when compared with no chemotherapy (all p<0.05).Among chemotherapy group,Oxaliplatin was associated with steatohepatitis compared with no preoperative treatment (13.0% v 0%, respectively; p<0.05). Irinotecan was associated with steatohepatitis compared with no preoperative treatment (50% v 0%, respectively; p=0.0006). Patients with preoperative chemotherapy had increased steatohepatitis compared with no treatment group (18.5% v 0%, respectively, p=0.0008), the postoperative morbility rate in preoperative chemotherapy (25.9%) was double that of the no-chemotherapy (12.5%), but this difference was not statistically significant (p=0.20). Preoperative chemotherapy was also not associated with 90-day mortality. Conclusions: Preoperative TACE treatment may cause pathological liver injury, and increase postoperative morbility after hepatic surgery. The standard preoperative chemotherapy regimen with Oxaliplatin or Irinotecan may increase steatohepatis.

No significant financial relationships to disclose.
Association of upregulated GATA-4 transcription factor colorectal adenocarcinoma with metastatic and primary tumors
Authors: Marginean E. C. , Torlakovic G. , Neufeld H. , Torlakovic E.
Published: August 2020

e15093

Background: GATA-4 zinc finger transcription factor is involved in regulation of cellular development, proliferation, and differentiation and is important in embryonic development of gastrointestinal tract. However, GATA-4 is not expressed in normal adult colonic mucosa. Its protein expression in colonic adenocarcinoma has not been systematically evaluated and small number of samples was previously reported as negative. Nuclear factor-B (NF-B) activation was shown to promote the growth of the colon tumors in experimental models and was correlated with tumor angiogenesis and progression in human colorectal cancer. Methods: Forty cases of colorectal adenocarcinoma were evaluated. The benign colonic mucosa and the matching metastatic tumors of the same patients were also included in the study. TMAs which included 139 samples were evaluated by immunohistochemistry and nuclear and cytoplasmic GATA-4 expression was scored (0–3+). NF-B activation was detected as nuclear reactivity for p65. Results: GATA-4 was expressed in 32% of colorectal adenocarcinoma, but not in benign colonic mucosa (p=0.0001, Chi-Square). GATA-4 was also significantly more expressed in metastatic (41%) than in primary (21%) colorectal adenocarcinoma (p<0.0001, Chi-Square). NF-B activation was not present in any of the samples of benign colonic mucosa, but it was detected in 64% adenocarcinomas (p<0.0001, Chi-Square). While there was no difference in NF-B activation between primary vs. metastatic adenocarcinoma, a strong positive association between GATA-4 expression and NF-B activation (p<0.0001, Linear-by- Linear) was found. Conclusions: GATA-4, a developmental transcription factor is not expressed by normal colonic mucosa, but is present in 1/5 of primary tumors that gave rise to distant metastases and in almost 1/2 of their respective metastases. GATA- 4 is also strongly positively associated with NF-B activation previously described to have a role in human cancer progression. GATA-4 may have a role in colorectal adenocarcinoma development and progression and it should be further evaluated in prospective studies as a putative adverse prognostic factor in colorectal adenocarcinoma.

No significant financial relationships to disclose.
The role of oophorectomy for colon cancer with ovarian metastasis
Authors: Lee S. , Lee J. , Ahn H. , Park J. , Kim J. , Park K. , Lim H. , Kang W. , Kim B. , Park Y.
Published: August 2020

e15113

Background: A recent study demonstrated that colorectal cancer with ovarian metastases were less responsive to chemotherapy compared to extraovarian metastases. Hence, the ovary may actually represent a “sanctuary” for metastatic cells from CRC. The aim of the study was to investigate the impact of oophorectomy on survival of colorectal cancer patients with ovarian metastasis. Methods: Between 1996 and 2008, 83 colorectal cancer patients underwent oophorectomy. For the historical control, 47 colorectal cancer patients without oophorectomy were included in the analysis. Survival and its associated factors were analyzed using Kaplan-Meier method, log-rank test and Cox-regression analysis. Results: The median age was younger (48 years) in the oophorectomy group when compared to the historical control (54 years) (P =.012). The proportion of synchronous metastasis was higher in the oophorectomy than the control group (57% vs 30%, respectively; P=.003). After a median follow-up duration of 60.8 months (range, 7.4 - 169.7 months), the median OS was significantly longer in the oophorectomy group (28.1 vs 21.2 months, oophorectomy vs non-oophoreectomy; P=.038). For ovary-specific survival (date of ovarian metastasis diagnosis to death), colorectal cancer patients with oophorectomy showed significantly favorable survival than the control group (20.8 vs 10.9 months, respectively; P<.001). At univariate analyses, no oophorectomy (P=.038), bilaterality of ovarian metastasis (P=0.032), the presence of extraovarian metastasis (P<0.001), elevated CEA (p<0.001), poor performance status (p=0.001), no palliative chemotherapy(p=0.001), no primary disease resection(p=0.005) were identified as significantly poor prognostic factors for overall survival. The no oophorectomy, no chemotherapy, extraovarian metastasis, elevated CEA, poor performance status retained statistical significance at multivariate level. (p=0.003, p=0.004, p=0.005, p=0.015, p=0.029, respectively). Conclusions: Based on this retrospective analysis, the oophorectomy significantly prolonged survival in colorectal cancer patients with ovarian metastases. A potential role of oophorectomy in the management of colorectal cancer should be prospectively studied.

No significant financial relationships to disclose.
Use of an in vitro chemoresponse assay to define a subset of colorectal carcinomas responsive to cetuximab
Authors: Rice S. D. , Ervin P. R. , Brower S. L.
Published: August 2020

e15127

Background: Cetuximab (Erbitux) is a chimeric monoclonal antibody that binds to the extracellular domain of the epidermal growth factor receptor. This interaction interferes with ligand binding and activation of the receptor blocking the downstream signaling of EGFR and impairing cell growth and proliferation. Cetuximab also has been shown to mediate antibody dependent cellular cytotoxicity. Thus, a singular approach to drug mechanism likely would not capture the true effects of cetuximab. Cetuximab is FDA-approved to treat head and neck cancer and colorectal carcinomas and is being evaluated for use in non-small cell lung and endometrial cancer. Due to the low population response rate of cetuximab, an integrated biomarker that can identify patients with an increased likelihood for response would be of great clinical utility. The current study describes an in vitro chemoresponse assay to predict response of primary cultures of human colorectal tumor specimens to cetuximab. Methods: The chemoresponse assay (ChemoFx) was developed using four different immortalized carcinoma cell lines (NCI-H292, NCI-H522, NCI-H1666, Calu3). The chemoresponse assay was also performed on 54 first passage primary cultures of human colorectal tumor specimens. Cell lines and specimens were treated with a 10 dose concentration range of cetuximab for 72 hours, stained with a nuclear dye, and remaining post-treatment live cells were counted. Resulting dose-response curves were analyzed. Results: Two of the examined cell lines showed response to cetuximab treatment; EC50 values for NCI-H292 and NCI-H1666 were 825nM and 13nM, respectively. NCI-H522 and Calu3 were deemed non-responsive to cetuximab. Dose-response curves of the 54 primary colorectal cultures revealed that 8% of the cultures tested were responsive to cetuximab, 22% had an intermediate response, and 70% were deemed non-responsive. These results are consistent with a reported clinical response rate of 11% for cetuximab in colorectal carcinoma patients. Conclusions: Initial results demonstrate that in vitro chemoresponse testing may be useful in predicting patient response to cetuximab. This could increase the efficacy of the current chemotherapy decision-making process for oncologists and their patients.

No significant financial relationships to disclose.
New “sutureless” technique of ileostomy and colostomy
Authors: Phadke M. V. , Stocks L. H. , Phadke Y. G.
Published: August 2020

e15132

Purpose: Purpose is to prevent infection and subsequent complications following construction of either an Ileostomy or a colostomy in an elective or emergency operation. Technique is based on delayed-primary wound healing and established principles of basic sciences. Methods: Discovered by serendipity in 1986 during an Ileostomy, procedure was used for all stomata. Stomal (proximal) end of bowel (small/large) was left obstructed with staples and brought out at proposed site of stoma. Mesenteric corner was brought above skin opening. A cone was formed by lifting anti-mesenteric corner of bowel as apex of the stoma by pulling anti-mesenteric surface of bowel. Length of the stoma was determined by thickness of the abdominal wall. Serosa was sutured circumferentially to a round opening in rectus sheath starting below the mesenteric corner leaving an arc to accommodate the mesenteric vessels. This neutralized pulling effect of peristalsis on mesenteric corner of stoma and protects mesentery under skin reducing the chances of thrombosis of mesenteric vessels. Stoma was covered in OR using an appliance with transparent pouch. Obstructed stoma prevented immediate contamination of stomal and main wounds by feces. Postoperatively, serosal surface was covered by angiogenesis, making the stomal wound refractory to infection. When peristalsis returned, bulging stoma was opened using electro-cautery as a bedside procedure. Mucosal cuff protrudes and everts on angiogenesis over a single layer of serosa. Cuff progresses with peristalsis and grafts over a bed of granulation tissue. Margins of cuff adhere with dermis of skin opening completing self-maturation of stoma. Absence of sutures reduced tissue trauma and eliminated foreign body reaction resulting in better wound healing. This new scientific technique was named “DELAYED-PRIMARY SELF-MATURATION (DPSM)”. Results: 63 Colostomies and 17 Ileostomies were performed using DPSM. Infection in stomal and/or main wound was prevented. Subsequent complications were prevented. Conclusions: DPSM prevents infection and complications associated with Ileostomy and Colostomy operations. It is technically easier and more scientific than a conventional stoma. This technique is recommended for all cases requiring end/loop, temporary/permanent types of intestinal stomas.

No significant financial relationships to disclose.
Safety profile of first-line bevacizumab and chemotherapy in patients with unresected primary colorectal cancer and synchronous metastases
Authors: Mello C. , Oliveira T. B. , Paiva T. F. , Silva M. J. , Sanches S. M. , Cruz M. R. , Nicolau U. R. , Fanelli M. F.
Published: August 2020

e15133

Background: The role of palliative resection of the primary tumour in patients who present with metastatic colorectal cancer (mCRC) is unclear. Most recently bevacizumab has been used as first line treatment for mCRC showing improvement in survival with a slight increase in the risk of bleeding and rarely gastrointestinal (GI) perforation. These side effects would cause concern in patients with unresected colorectal cancers (CRC). Methods: Retrospective analysis of twelve patients treated straightaway by chemotherapy (CT) and bevacizumab without primary tumour resection, between January 2007 and August 2008. The aim of the study was to evaluate the rate of complications related to the unresected colorectal tumour and to determine the safety of bevacizumab use in this situation. All of these patients had none or minimal symptoms related to the primary tumour. Results: Mean age 54.6 years (range 28–75), 5 males and 7 females, all patients ECOG 0. The sites of the primary lesion were the rectum in 8 patients (66.6%), the left sigmoid colon in 3 (25%), and the transverse colon in 1 (8.3%). Eight patients (66.6%) presented with rectal bleeding at diagnosis (mild). The mean interval between diagnosis and start of CT was 40,8 days (range 6–125). The total number of bevacizumab cycles was 151 (mean 12,5 cycles, range 4–37). First line CT was FOLFOX-6 in 66% and FOLFIRI in 33% of patients. Only 3 patients (25%) developed low GI bleeding, all grade 1, without bevacizumab interruption. None of them developed intestinal perforation or obstruction. Two patients (16.6%) developed grade 1 epistaxis and 1 (8.3%) grade 2 hypertension. No other complications were observed in a mean follow up of 9.3 months. Conclusions: Our data show that upfront chemotherapy with bevacizumab in patients with unresected primary CRC and synchronous metastases is safe. No major complications related to the primary tumour were observed. Although our data comes from a limited number of patients there is a lack of prospective controlled trials in the literature on this topic. Therefore, in select cases, a non-operative management of asymptomatic or minimal symptomatic mCRC could be advised, even with the use of anti-angiogenic therapy.

No significant financial relationships to disclose.