bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting tumor metabolism: biguanides as anti-neoplastic agents
Authors: Knoblauch R. E. , Thompson C. B.
Published: August 2020

e14592

Background: During the process of malignant transformation, the tumor cell adopts a new form of metabolism, characterized by aerobic glycolysis and altered TCA cycle flux, that enable it to meet the energetic and biosynthetic demands of proliferation. This shift to anabolic metabolism results from oncogene-driven activation of signaling pathways, and therefore represents a potential therapeutic target that lies downstream of these genetic events. Methods: We have characterized the proliferative and metabolic effects of phenformin, a member of the biguanide family of compounds used in the treatment of diabetes, on the bcr-abl expressing K562 erythroleukemia cell line, and compared the resulting phenotype to those of imatinib and rapamycin, two targeted agents used in the treatment of malignant disease. Results: Phenformin induced the most profound growth inhibition of K562 cells, in a manner distinct from the targeted agents. Phenformin treatment eliminated the mitochondrial contribution to anabolic metabolism, through inhibition of Complex I of the Electron Transport Chain, as demonstrated by reduced oxygen consumption and intracellular ATP levels. Glutamine metabolism was also inhibited, consistent with TCA cycle inhibition as a secondary effect. The phenformin-induced mitochondrial dysfunction made K562 cells dependent upon glycolysis for survival. In contrast, the growth arrest resulting from imatinib treatment was associated with a complete reversion from the anabolic phenotype, as demonstrated by dramatically decreased glucose and glutamine consumption. Rapamycin, a poor inhibitor of K562 proliferation, decreased glycolysis but left mitochondrial function intact. Conclusions: Our results confirm the importance of metabolism to the proliferation of malignant cells, thereby validating anabolic metabolism's potential for therapeutic intervention. The direct inhibition of tumor cell metabolism by phenformin warrants further clinical study as a promising new approach to cancer therapy.

No significant financial relationships to disclose.
Susceptibility of head and neck cancer to an attenuated model of the oncolytic vesicular stomatitis virus expressing suicide genes
Authors: Porosnicu M. , Liu J. , Lyles D.
Published: August 2020

e14604

Background: The predominant loco-regional progression of head and neck squamous cell carcinoma (HNSCC) makes it suitable for testing oncolytic viruses. Recent work from several laboratories including ours has focused on developing vesicular stomatitis virus (VSV) as a replication-competent anticancer viral vector. Attenuated strains, such as M protein mutant VSV (M51R) are more likely to be promoted in clinical research. The major shortcoming of viral therapy is related to the large proportion of tumor cells remaining uninfected. We are addressing this limitation in two ways: the expression of the cytosine deaminase-uracil phosphoribosyltransferase (C:U) suicide gene by the rVSV vector, expected to produce a strong bystander effect and the exploitation of the radiosensitizing potential of the 5-FU chemo-drug produced intratumorally, as well as of the VSV virus itself. Methods: We determined the extent of defectiveness in interferon pathways and susceptibility to oncolytic VSV in a collection of HNSCC cell lines and in patient HN primary tumor cells. We employed gene array to screen for differences in gene expression in sensitive and resistant models. We have generated the rVSV-C:U and M51R-C:U viruses and we tested our collection of HNSCC cell models to infection with these viruses in the presence and absence of 5-FC. In vivo experiments were performed on a localized and on a metastatic SQ-20B model of HNSCC in nude mice. Results: 1) the primary patient HNC cells are more resistant than the HNC cell lines to the M51R-VSV; 2) the activation of IFN pathways and /or alterations of AKT pathway is contributing to resistance to VSVs. 3) Addition of the suicide gene to the attenuated VSV provided significantly more oncolytic effect in vitro and in vivo. The efficacy and the radiosensitizing potential of M51R- C:U on a nude mice model of HNSCC (SQ-20B) will be presented. Conclusions: M51R-VSV has increased efficiency and radiosensitizing effect on HNSCC models. We can define an optimal approach to testing VSV vectors for treatment of HNSCC, with a clinical trial in HNSCC patients as our next goal. Finally, we have important new information, both from cell lines and patient tissues, for proof-of-principle that cancers can down-regulate antiviral responses.

No significant financial relationships to disclose.
Genetic variability in DNA repair and clinical outcome in stage III non-small cell lung cancer (NSCLC) treated with concurrent platinum-based chemoradiation
Authors: Al Omari A. , Murry D. J. , Smith B. J. , Clamon G. , Bhatia S. , Vaena D.
Published: August 2020

e14621

Background: Concurrent platinum-based chemoradiation (CRT) is the standard of care for stage III NSCLC. CRT is associated with multiple toxicities and substantial interpatient variability in clinical outcomes, with a 20% cure rate. We evaluated the relationship of genetic polymorphisms in platinum metabolic and DNA repair pathways with clinical outcomes in patients treated for stage III NSCLC. Methods: This pilot study was IRB approved and all patients provided written informed consent. Patients with stage III NSCLC who completed CRT were eligible for enrollment. Genomic DNA was extracted from peripheral blood. Genotyping using Pyrosequencing™ was performed for 5 single nucleotide polymorphisms (SNPs): the detoxification enzyme GSTP1 I105V, and the DNA repair genes ERCC1 N118N, ERCC2 K751Q, ERCC2 R156R and XRCC1 R399Q. Pre-treatment variables, progression-free survival (PFS) and toxicity data were obtained from retrospective review of medical records. Results: 23 pts have been enrolled to date. Median age was 58 yrs (49–81). 5 pts received cisplatin and 18 carboplatin. Median radiation dose was 6480 cGy (5000–7020) and median V20 was 27%. 10 pts had grade 3/4 acute CRT toxicities and 7 pts required treatment breaks. Median duration of follow-up was 21 months (4–100). 14 pts recurred and median PFS was 12 months (4–100). 15 pts remain alive. Controlling for age, V20 and radiation dose and using multivariate cox proportional hazards regression, the ERCC2 K751Q and R156R genotypes were independent predictors of PFS (HRs= 0.404 & 2.184, p-values= 0.0172 & 0.0152, respectively, subjects with at least 1 variant allele being reference group). Using multiple logistic regression, the ERCC2 R156R variant showed a trend towards improved response (OR=2.98, p-value= 0.09). Overall survival data is limited by the majority of pts still being alive. Conclusions: Clinical and treatment variables were typical of a stage III NSCLC population. This pilot pharmacogenomic study indicates that outcomes were independently affected by genetic polymorphisms. Our findings, if validated prospectively, could have significant impact on optimizing treatment selection for stage III NSCLC pts, without need for additional tumor tissue.

No significant financial relationships to disclose.
In vivo activity of R1530 (R) alone and in combination with bevacizumab (B) and peginterferon alfa-2a (P) in a renal cell carcinoma (RCC) xenograft model
Authors: Higgins B. , Packman K. , Zhang Y. , Char H. , Simcox M. , Kolinsky K.
Published: August 2020

e14629

Background: R1530 is a multikinase inhibitor currently in clinical phase I testing. Its inhibitory profile includes several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. These properties translate into a potent cytotoxicity in a wide range of cancer cell lines in vitro and tumor growth inhibition in human tumor xenografts. Preclinical studies were conducted to evaluate the effects of R alone and in combination with B and P in the Caki-1 RCC xenograft model. Methods: We initially evaluated the antitumor activity of optimal dose (OD) and 1/2 OD R alone and with OD B. This was followed up with testing of OD & 1/2 OD P ± OD B, along with triplets of 1/2 OD P + OD B + 1/2 OD R and OD P + OD B + 1/2 OD R. A final study compared 1/2 OD R to OD R triplets to attempt to increase tumor growth inhibition (TGI) and increase life span (ILS). Results: No doublets or triplets tested showed antagonism or enhanced toxicity. Antitumor activity and survival results are listed below (Table). Conclusions: 1/2 OD R + OD B or OD R + OD B doublets gave better TGI and ILS than monotherapy. Comparing these two doublets, TGI is better in the high dose combination but ILS is equivalent. All TGI and ILS are better in doublet P + B combinations over respective single agent arms except for TGI (but not ILS) for 1/2 OD P vs its correlative doublet with B. The OD P + B doublet gave better TGI and ILS than 1/2 OD P + B doublet. TGI and ILS do not differ between triplets containing OD R + 1/2 OD or OD P or for triplets containing the OD P + 1/2 OD or OD R. Therefore, either agent can be alternatively dose reduced without a loss of tumor response or detriment to survival in this preclinical model of RCC. [Table: see text]

[Table: see text]
Evaluation of thymoquinone (TQ) as an antiproliferative, proapoptotic, and immunomodulatory agent in a non-small cell lung cancer cell (NSCLC) line
Authors: Jafri S. H. , Glass J. , Shi R. , Kleiner H.
Published: August 2020

e14644

Background: NSCLC is the most common cause of cancer death worldwide. We performed in vitro testing of Thymoquinone (TQ), a derivative of black caraway seed against NSCLC cell line NCI-H460 Methods: Cells were grown in RPMI and were plated at a density of 5,000 cells per well in a 96 well plate and cell growth determined in the presence of 80 and 100μM of TQ dissolved in DMSO with appropriate solvent only as control. Cell proliferation was determined at 24, 48 and 72 hrs intervals using 3-(4,5-dimethyltiazol 2-yl)-2,5-diphenyltetraolium bromide (MTT) assay. Factorial analyses of variance (ANOVA) were used to determine the effect of TQ and control with the time. Student-Newman-Keuls test was used to determine statistical significance with P value <0.05 considered significant. Apoptosis was detected using Annexin V-FITC Aptosis Detection Kit analyzing the effects of TQ at 24 hrs after treatment by flow cytometry. The immunomodulatory effects of TQ were tested using RayBio Human Cytokine Antibody Array C series 200. NCI-H460 cells (50,000 cells per well in duplicate 6 well plates) were grown in serum free RPMI media. 24 hrs after treatment with TQ or DMSO media was collected and analyzed for expression of various cytokines. Results: The MTT assay showed that TQ at 80 and 100 μM significantly inhibited cell growth as compared to control and at 24 hrs for example, 100 μM TQ inhibited cell growth by 78%. Apoptosis occurred rapidly after treatment with TQ with 73.5% of cells being positive for expression of Annexin-V as detected by flow cytometry after 24 hrs of exposure to TQ as compared to 2.6% of controls. The cytokine array revealed that TQ significantly decreased expression of ENA-78(Epithelial neutrophil activating peptide), and GRO (Growth related oncogene).ENA-78 is correlated with vascularity and tumor growth in NSCLC tumor, whereas GRO is associated with neoangiogenesis. Conclusions: TQ is shown to be a powerful anti-proliferative, pro-apoptotic and anti- angiogenic agent in a NSCLC cell line.

No significant financial relationships to disclose.
Cure rate in early colorectal cancer estimated from disease-free survival curves from phase III comparative clinical trials: Necessity of long follow-up
Authors: Barrajon E. , Lopez A. , Esquerdo G. , Cervera J. M.
Published: August 2020

e15006

Background: The traditional end point for adjuvant clinical trials is overall survival (OS). Short-term disease-free survival (DFS) has been accepted as a surrogate of 5-year OS in colorectal cancer trials. Nevertheless, recent adjuvant trials have not shown a consistent improvement in OS despite a significant improvement in DFS. Two reasons may explain this effect: 1) a delay in relapse produced by treatment, not affecting the cure rate, or 2) more effective treatments in relapsing patients which delay death, hiding a real difference in cure rates. The aim of this project is to study the relationship between DFS and OS in trials of early colorectal cancer. Methods: Phase III comparative trials in colorectal cancer were searched in databases and cancer meetings. Trials were split to build and validate the model. United States 2000 population life table data were obtained from Berkeley Mortality Database. Survival curves were modelled according to a cured fraction following a Weibull distribution and a relapsing fraction following a binomial distribution. DFS was modelled as time to a single event and OS was modelled as time to two events. Cured fraction was estimated and odds ratio (OR) with 95% confidence interval was calculated for experimental arms. Time to achieve a plateau in DFS was estimated as the curve point with a risk of relapse below 1%. Regression analysis between DFS and OS was performed for different intervals of follow up. Results: Thirty six study arms reporting DFS were analyzed to build the model. The model is consistent with an annual event rate of 0.33. DFS curves with this event rate predict a mean cure rate of 0.58 (range: 0.11–0.73). Estimated time to achieve a plateau in DFS is 9.3 years (range: 8.3–11.2 years). Significance of OR is coherent with hazard ratio reported in the studies. Trials finished after 1999 show more OS related to DFS. Regression analysis between DFS and OS show changing parameters at different intervals of follow up and some non-linearities. Trial validation, and analysis with trials reporting relapse free survival will be presented. Conclusions: Follow up of up to 10 years in colon adjuvant trials appears to be appropriate to reliably detect benefit in OS instead of a delay effect on relapse.

No significant financial relationships to disclose.
Presurgical comparative imaging evaluation in patients with colorectal cancer liver metastasis (PROMETEO Study)
Authors: Rojas Llimpe F. , Di Fabio F. , Ercolani G. , Giampalma E. , Serra C. , Castellucci P. , Pini S. , Mutri V. , Golfieri R. , Pinto C. , Martoni A.
Published: August 2020

e15010

Background: The aim of the study was to define the specific diagnostic accuracy of different imaging techniques in patients (pts) with resectable colorectal cancer liver metastasis (CLMs). Methods: Consecutive pts with, potentially resectable CLMs afferent to the Multidisciplinary Liver Team of Bologna Sant’Orsola Malpighi Hospital performed, in the 3 weeks prior to liver surgery, computed tomography scan (CT), magnetic resonance diffusion-weighted (MR-DW), and liver contrast-enhanced ultrasonography (CEUS1). Liver contrast-enhanced ultrasonography was also performed intra-operatively (CEUS2). All the imaging exams were performed according to the standard operative procedures. Results: From December 2007 to December 2008, twenty-nine out of 50 pts enrolled in the PROMETEO study underwent liver resection. The pt characteristics were: 18 (62%) males, 11 (38%) females; 18 (62%) synchronous metastasis, 11 (38%) metachronous metastasis; 15 (51.7%) neoadjuvant chemotherapy; 7 (24.1%) previous liver surgery; 3 (10.3%) previous loco-regional treatment. Ninety-three liver lesions were resected; the median number lesions per patient was 2 (range 1- 10). All lesions were studied with CT and CEUS1, 90 (96.8%) with CEUS2, 83 (89.2%) with PET and 85 (91.4%) with MR-DW. Five lesions at pathological examination were non-metastasis (1 hamartoma, 1 steatosis, 1 giant-cell reaction, 2 necrosis). Only 3 lesions were not detected by all imaging techniques (in one pt. previously treated with chemotherapy and radiofrequency). Conclusions: These results show that CT, CEUS1 and MR-DW have a good accuracy in the detection of liver metastasis in patients who are candidates for resection. CEUS2 presents the best pathological predictive value.

[Table: see text]

No significant financial relationships to disclose.
Addition of bevacizumab or sunitinib to biweekly cetuximab and irinotecan as salvage therapy in patients with metastatic colorectal cancer after failure to CetIri
Authors: Pfeiffer P. , Joergensen T. L. , Jensen B. V. , Qvortrup C. , Skougaard K. , Bjerregaard J. K. , Hansen T. P. , Høgdal E. , Nielsen D.
Published: August 2020

e15011

Background: The combination of cetuximab and irinotecan (CetIri) given biweekly has shown remarkable efficacy in patients with chemo-resistent metastatic colorectal cancer (mCRC). At the time of PD to CetIri many patients are still in an excellent performance status and they are often requesting further therapy. Preclinical and clinical studies have shown an additive effect of inhibiting both the EGFR and the VEGF pathways. The Danish National Board of Health (DNBH) launched a national programme for experimental cancer therapy in 2004. According to this programme, non-proven therapy may be offered after approval by an expert panel appointed by DNBH that subsequently finances the cost of treatment. Inspired by BOND-2, we have offered dual-modulated therapy with a combination of biweekly CetIri with either bevacizumab 5 mg/kg (CIB) or sunitinib 25 mg/day continuously (CIS). Methods: Observational study designed to evaluate the toxicity and safety of CIB or CIS. From January 2007 to April 2008, 51 patients received either CIB (n=24) or CIS (n=27) at two oncologic departments. Therapy was approved by DNBH in each case. All patients had mCRC resistant to 5-FU, oxaliplatin, irinotecan and CetIri. CIB or CIS was offered independently of KRAS status and EGFR expression. Results: Results were updated December 1st 2008. Median duration of therapy was 30 weeks/10 weeks, response rate was 8%/0%, median PFS was 8.7/3.2 months and median OS was 12.1/8.7 months, respectively for CIB/CIS. Toxicity was comparable except for patients receiving CIS where fatigue and diarrhea were more common. Conclusions: Modulation of the VEGF pathway in combination with biweekly CetIri is a promising and tolerable treatment option for patients with mCRC refractory to CetIri. Some patients had extraordinary long PFS and OS. We are currently performing translation research into predictive markers.

[Table: see text]
POCHER (preoperative chemotherapy for hepatic resection) with cetuximab (Cmab) plus CPT-11/5-fluorouracil (5-FU)/leucovorin(FA)/oxaliplatin (L-OHP) (CPT-11-FFL) in unresectable colorectal liver metastases (CLM)
Authors: Garufi C. , Torsello A. , Tumolo S. , Mottolese M. , Campanella C. , Zeuli M. , Lo Re G. , Sperduti I. , Pizzi G. , Ettorre G. M.
Published: August 2020

e15020

Background: We have previously shown preliminary data with Cmab+ all active drugs, CPT-FFL, with primary end- point CLM resectability (Garufi C. et al ASCO GI 2008). Here we report definitive clinical results. Methods: Unresectability criteria: size>5 cm (a), multinodular (b), ilar location (c), extrahepatic disease (d), >3 stable mets after chemotherapy before surgery (e). Aim of the study was to have at least 30% liver resection rate (power of 80% for p0=10% and p1=25%). Pts received weekly Cmab 400 then 250 mg/m2/wk plus CPT-11, 130 mg/m2/d1, 6 h infusion, (peak at 13:00) and a 12-h, days 2–5, infusion of L-OHP 20 mg/m2/day (peak at 16:00), FA 150 mg/m2/day plus 5-FU 600 mg/m2/d (peak at 4:00), q 2 wks; after the first 17 pts 5-FU and L-OHP were reduced to 550 and 15 mg/m2 respectively. Results: Since 07/20/2006 we enrolled 43 pts, irrespective of EGFR, K-ras and gene copy number (gcn): M/F 27/16, median age 60,7 y (33–76), median PS 0. Primary tumor: colon/rectum 34/9, primary tumor resected 39 pts (79%), synchronous metastases: 35 pts (81%), liver <25%/25%: 9/34 ((21/79%); median CEA/CA19–9: 55 ng/ml (1–6,600)/91.8 U/L (2.66440); unresectability: (a): 9 (21%), (b):14 (33%), (c) 1, (d): 4 (9%), (e): 15 (35%). We had 34 partial responses (79%, CI 79.1–87.0), 5 SD (11.6%) and 4 patients not evaluable becouse of toxicity. Complete Resection of CLM was obtained in 27 pts (63%) with 4 pts still to be resected. Median number (n.) of courses (c) was 10 (2–18), median n. of c before surgery (s) was 5 (3–10) and after s was 6 (1–6); median time from last c to s was 2 wks (2–4), from s to recovery chemo was 10 wks (2–16). Median follow-up was12 months, median PFS 13 months (7–19), median OS not reached with 2-y survival of 61%, 8 pts alive without recurrence (19%), 11 deaths (25%).Major limiting toxicity was diarrhea, with no difference after dose reduction: Grade 0–1: 6% of pts, G2 6%, G3 76%, G4 12%; neutropenia G3 6% with no febrile neutropenia. Conclusions: This is the first phase II study with CPT-FFL + Cmab in pts with unresectable CLM. Complete resection was obtained in 63% of pts with diarrhea being limiting toxicity. Analysis of EGFR status, K-ras and gcn will be further presented.

No significant financial relationships to disclose.
A phase Ib/2, dose-escalating, safety, and efficacy study of imprime PGG, cetuximab and irinotecan in patients with advanced colorectal cancer (CRC)
Authors: Tamayo M. E. , Cornelio G. H. , Bautista J. B. , Flores M. L. , Kurman M. R. , Paul M. M. , Gargano M. A. , Patchen M. L.
Published: August 2020

e15062

Background: Imprime PGG (Imprime PGG Injection) is a ß-glucan polymer being developed for treatment of cancer in combination with complement-activating monoclonal antibodies. This trial evaluates the safety and efficacy of Imprime PGG in combination with cetuximab and irinotecan in CRC patients (pts). Methods: Pts with recurrent/progressive CRC (Karnofsky > 70%) previously treated with 5-FU (alone or combined with other therapies) were treated with Imprime PGG (weekly), cetuximab (weekly; loading dose 400 mg/m2, then 250 mg/m2), and irinotecan (wks 1–4 of each 6-wk cycle; 125 mg/m2). In a 3 + 3 design, Imprime PGG dosing started at 2 mg/kg and escalated to 4 and 6 mg/kg after safety review. Safety (primary endpoint) was assessed by adverse events (AEs) and efficacy (secondary endpoint) by RECIST. Results: Imprime PGG was dosed in 3 pts at 2 mg/kg, 6 pts at 4 mg/kg and 1 pt at 6 mg/kg. Median age was 56. One pt remains on therapy at wk 49; other pts exited due to progressive disease (5 pts), irinotecan intolerance (2 pts), investigator discretion (1 pt), and withdrawn consent (1 pt). Median duration of treatment was 17.5 wks. No protocol-defined dose-limiting toxicities were observed. AEs experienced by > 50% of pts included diarrhea (90%), hypokalemia, neutropenia (80%), weight loss (70%), anemia, anorexia, leucopenia (60%), alopecia, dry skin, hypomagnesemia, increased amylase, vomiting (50%). Grade 4 SAEs included increased amylase, increased lipase, and neutropenia. Partial response (PR) occurred in 3 pts (30%) and stable disease (SD) in 7 pts (70%), yielding a disease control rate (PR + SD) of 100%. The median time to progression was 22.3 wks. Conclusions: Imprime PGG combined with cetuximab and irinotecan in CRC pts was safe and efficacy warrants further investigation.

[Table: see text]
Updated phase II study results of capecitabine (X) + irinotecan (I) + bevacizumab (A) as first-line therapy for metastatic colorectal cancer (MCRC)
Authors: Beslija S. , Banjin M. , Jungic S. , Obralic N. , Kecman-Malcic G. , Rakita I. , Salkic B. , Pasic A. , Tinjic L. , Smoljanovic V.
Published: August 2020

e15064

Background: The oral fluoropyrimidine X has improved efficacy, safety, and convenience vs. 5-FU/LV in MCRC [Van Cutsem et al. Br J Cancer 2004] and early-stage colon cancer [Twelves et al. NEJM 2005]. A recent study showed that I + X q2w is active and well tolerated [Garcia-Alfonso et al. ESMO 2006]. The humanized monoclonal antibody A targets VEGF and limits tumor angiogenesis. The addition of A to 5-FU/LV/I (IFL regimen) improves survival significantly in patients (pts) with MCRC [Hurwitz et al. NEJM 2004]. Replacing 5-FU/LV with X in this combination is a logical step forward. Here we report data from an open-label phase II trial of XIA in MCRC. Methods: Pts with untreated, histologically confirmed MCRC received I 175mg/m2 i.v. d1, X 1,000 mg/m2 orally bid d2–8, and A 5 mg/m2 d1. Treatment was repeated q2w x 12 cycles in the absence of progressive disease (PD) or unacceptable toxicity. Pts without PD after 12 cycles of XIA continued on the same dose of A + X 1,500 mg/m2 bid d2–8, q2w. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rate (ORR, RECIST), overall survival (OS), safety, and quality of life. Results: 57 pts have been enrolled. Baseline characteristics: M/F 44%/56%; median age 52 years (range 30–70); disease stage at initial diagnosis II/III/IV 16%/9%/75%; no. of metastatic sites 1/>1 47%/53%; most common metastatic site liver. Pts received a median 12 cycles (range 1–12) of XIA. All 57 pts are evaluable for safety and 56 for efficacy. ORR is 46% (3 CR, 13 PR); 5 pts (22%) have stable disease and 35 have PD. Median PFS and OS are 14.9 months (range 1.7–39.2) and 18.3 months (range 2.9–39.2), respectively. Grade 3 adverse events occurring in more than 1 pt are diarrhea (9%), hypertension (9%), hand-foot syndrome (7%), ileus (4%), and hypertriglyceridemia (4%); there is one report of grade 4 leucopenia. Conclusions: The XIA combination appears to be highly active and well tolerated as first-line treatment for MCRC; further studies of XIA are warranted.

[Table: see text]
Incidence and significance of K-RAS mutation in first line treatment of colorectal cancer (cc): Experience of a single institution (Hospital Universitario Central de Asturias (HUCA))
Authors: Vieitez J. , Jiménez Fonseca P. , Fernandez de Sanmamed M. , Pitiot A. S. , Crespo G. , Berros J. , Muriel C. , Izquierdo M. , Pardo P. , Lacave A.
Published: August 2020

e15081

Background: Although the significance of K-RAS mutation and cetuximab/panitumumab has been established in first line (ASCO 08 abstract 2# and 4000#) and in previously treated patients (pts) (NEJM 2008; 359: 1757. JCO 2008; 26: 374. JCO 2008; 26: 1626), data of the significance of this mutation in relation to bevacizumab is scarcer (JNCI 2005; 97: 981). Methods: Sample tissue of alive patients diagnosed of stage IV colorectal cancer were analyzed for the presence of K-RAS mutation by PCR amplification and direct sequencing. Data regarding presence of K-RAS mutation were retrospectively analyzed in relation to clinical data. Results: From IV to XII 08 122 paraffin embedded samples were analyzed. The percentage of mutant cases were 41% (95% CI 32–51%). The most frequent mutant type was Gly12Asp (37%) followed by Gly12Val (25%) and Gly13Asp (19%). We have clinical data of 94 pts. 62 were men and 32 female. 25 pts had received previous complementary treatment; in 80 pts primary tumor was previously resected (85%); median number of affected organs was 1 (1–4); in first line 76 pts received bevacizumab and 18 did not received any biological agent. Response Rate (RR) between mutant and no mutant pts was 48% (95% CI 37–59%) vs 47.8% (95% CI 32–63%) (p=0.92). Median follow up was 15.4 months. Progression free survival was 15 months for mutant and native K-RAS. There were no differences in response or PFS in any subgroup studied. Multivariable Cox analysis did not find any significant difference between sex (p=0.78), primary resected organ (p=0.28), liver metastases (p=0.37), LDH value at diagnosis (p=0.0.43), employ of biological agents in first line (p=0.37) or mutation in K-RAS gene (p=0.68). Conclusions: The percentage of K-RAS mutants is coherent with the results of the literature; mutations Gly12Asp, Gly12Val, and Gly13Asp represents the majority of the cases (81%); no significant relation was found between responses or DFS and mutations in the gene.

No significant financial relationships to disclose.
BNIP3L (Nix) expression in colon cancer
Authors: Littlejohn J. E. , Jupiter D. , Cao X. , Zhang L. , Shabahang M. , Smythe W. R.
Published: August 2020

e15097

Background: Microenvironmental adaptation to hypoxic conditions is critical for a cell to survive in a growing solid tumor. BNIP3L (Nix) mediates apoptosis during hypoxia in cancer cell lines, and Nix knockdown promotes tumor growth in-vivo through decreased apoptosis and increased proliferation, suggesting a means by which cells can adapt. Little is known specifically about Nix expression and its importance in human colon cancer. To gain insight into expression of this gene in colon tumors, the present study analyzed mRNA microarray data from 227 colon tumors and 22 normal colon tissue samples and queried differential expression of Nix. These results were compared to the protein levels present in human colon tumors. Methods: mRNA expression of 227 human colon tumors (made available by the Expression Project for Oncology (expO)) and 22 normal colon samples (retrieved from the Gene Expression Omnibus (GEO)) was analyzed. These samples were hybridized to the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array, assaying 17,726 NCBI Entrez genes. Immunohistochemistry was performed on human tissue microarray CO701 (US Biomax, Inc.) containing 62 tumor samples. Results: Nix mRNA levels were shown to increase from normal to cancer (log-fold change of 0.961, Benjamini-Hochberg FDR adjusted p < 0.001). IHC demonstrated variable levels of Nix present in colon tumors: 38/62 (61.3%) of tumors stained positive for Nix while 24/62 (38.7%) were negative. Conclusions: We have shown that mRNA levels of Nix are upregulated in the transition from normal colon tissue to cancer but that protein levels in tumors demonstrate variable expression. This suggests that silencing of Nix occurs at various stages of tumorigenic progression and results in isolated populations of cells within a growing tumor that are uniquely resistant to apoptosis. Better understanding of Nix in the context of a growing colon tumor is needed and could lead to development of more successful therapeutics.

No significant financial relationships to disclose.
Neoadjuvant chemoradiotherapy in rectal cancer patients (pt) with oxaliplatin (Ox) and capecitabine (Cp): Results of a phase II trial
Authors: Gasent Blesa J. , Alberola Candel V. , Juan O. , Provencio Pulla M. , Giner Marco V. , Gravalos C. , Fernandez I. , Llorca C.
Published: August 2020

e15101

Background: Between April 2006 and May 2008, 27 rectal adenocarcinoma pt were included (cT3: 25 pt, T4: 2 pt, N0: 11 Pt, N+: 16 pt), stages II-III, RMN staged, 14 male and 13 female. Mehtod: Neoadjuvant treatment was: Ox: 50 mg/m2 weekly, oral Cp: 825 mg/m2 tid the days of the Rt, and a Rt of 50.4 Gy. 9 pt had a lower third tumor, 9 middle, 9 upper. Surgery was planned 6–8 weeks after treatment´s end. 4 adjuvant chemotherapy cycles with Xelox were planned. Results: 7 pt had pCR (26%), 2 pt progression disease 18 pt tumor downstaging(dwst). Percentages of dwst were: T 85%, N 37%. Sphincter preservation (sp) was 81.9%, for tumors of the lower third sp was 44.4%. Presurgical (prsrg) RMN did not predict the pathological result in 21 pt. Main side effects: Dermatitis G1 in 21 pt, and G2 in 4 pt. Diarrhea 12 pt G1, 11 pt G2, and 4 pt G3. Hand and foot G1 5 Pt and G2 4 pt. Paresthesias G1 10 pt, G2 7 pt. Leucopenia 6 pt G1. 4 Pt did not complete treatment because of toxicity. Median Rt dose was 49.7 Gy (47.5–50.4 Gy).At a mean follow up of 22.5 months (7–31) 4 pt presented metastatic disease (15% ), none in the pCR group. Mean pre-neoadjuvant (preneo) CEA was 6.8 ng/ml (2.1–17.0). There was difference statistically significant when compared preneo CEA vs prsrg CEA: 2.72 ng/ml inferior with the second outcome (p<0.001). Mean prsurg CEA was 4.1 (0.1–12.0). In the subgroup with pCR the mean prsrg CEA was 1.1 (0.5–1.5), and in non-pCR it was 5.1 (0.1–12.0). Comparing the prsrg CEA between pCR and the non-pCR subgroups, the mean difference was 4.0 ng/ml greater in the non pCR. This difference was statistically significant (p=0.002, 95% CI: 1.68–6.3).We found a nadir of <5ng/ml as significantly associated with pCR (p=0.036). Conclusions: Preoperative chemoradiotherapy with Ox and Cp, is safe and well tolerated. Offers an interesting ratio of pCR, and of tumor downstaging. Prsrg CEA level and CEA nadir should be studied as predictors of pCR. It is possible that with more patients, the significant nadir level could be lower. We consider this combination and the CEA nadir interesting to be included in further studies.

No significant financial relationships to disclose.
Serum IGFBP3, IGF-I, and MMP7 changes in advanced colorectal cancer (ACRC) patients (pts) treated with anti-EGFR therapy: A GEMCAD study
Authors: Pineda E. , Pericay C. , García-Albéniz X. , Augé J. , Alonso V. , Escudero P. , Fernández-Martos C. , Gallego R. , Maurel J.
Published: August 2020

e15109

Background: Insulin-like growth factor-I (IGF-I) is a potent mitotic and anti-apoptotic peptide, whereas IGF binding protein-3 (IGFBP3) seems to have pro-apoptotic effects. Matrix metalloproteinase-7 (MMP7), an enzyme with in vitro ability to degrade IGFBP3, has been shown to be a prognostic factor in ACRC. Methods: This is a prospective single cohort traslational study. Pts undergoing second/third line with irinotecan plus anti-EGFR therapy were eligible as cases. Patients with ACRC not undergoing therapy were eligible as controls. IGFBP3 and MMP7 were measured in serum with immunoassays at baseline and at 48h after treatment start. KRAS mutation status in codons 12/13 was determined by sequencing in 53 pts. The primary endpoint is to define the IGFBP3 and MMP7 variation under anti-EGFR therapy. IGFBP3 was used as a continuous variable and MMP7 was used to create two groups by its third quartile. Results: Eighty-five cases and 25 controls were recruited. No significant changes at 48h in IGF-I and IGFBP3 were found, but a significant decrease in MMP7 from 10.8 (95%IC 8.3–13.3) to 8.4 ng/ml (95%IC 6–10.9) was observed in cases (p<0.001) in contrast with controls, where no changes were found. Splitting the sample by the third quartile of MMP7 interesting changes in IGFBP3 variations were found. In the group with low levels of MMP7, IGFBP3 increases from 1,859 to 1,959 ng/ml (p=0.043) 48h after treatment initiation; on the contrary, in the group with high levels of MMP7, IGFBP3 decreases from 1,811 to 1,757 ng/ml (p=0.741). We found no association with IGFBP3 and neither response rate, time to progression nor overall survival. This latter analysis was also done only in pts with wild-type KRAS, without any change in the results. Conclusions: In pts with ACRC treated with anti-EGFR therapy, serum levels of IGFBP3 variations depend on basal MMP7 levels. IGFBP3 failed to be a predictive/prognostic factor in our sample although the limited number of KRAS pts analyzed can influence our results. [Table: see text]

No significant financial relationships to disclose.
Phase I study of RAD001 (everolimus), cetuximab, and irinotecan as second-line therapy in metastatic colorectal cancer (mCRC)
Authors: Sharma S. , Reid T. , Hoosen S. , Garrett C. , Beck J. , Davidson S. , MacKenzie M. , Brandt U. , Hecht J.
Published: August 2020

e15115

Background: The PI3K/AKT/mTOR pathway is frequently dysregulated in colorectal cancer (Cancer Res 2005;65:11227). In a phase I study in patients with advanced solid tumors, everolimus an oral mTOR inhibitor demonstrated clinical benefit including a partial response in pts with colorectal cancer (J Clin Oncol 2008;26:1603–10; J Clin Oncol 2008; 26:1588–95). Methods: This open-label, multicenter phase I study uses a Bayesian logistic model to identify feasible doses of everolimus + irinotecan + cetuximab. Adult pts with mCRC progressing despite prior 5-FU/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (XELOX) plus bevacizumab (if standard practice) were treated using a sequential dose escalation scheme (Table). Dose decisions were driven by the probability of dose-limiting toxicity (DLT) in the first 2 cycles. Dose level decisions were based on maximizing the probability that end-of-cycle-2 DLT rate would be within the targeted toxicity interval (20% to <35%) and minimizing the risk of over-dosing (< 5% risk of unacceptable toxicity and < 25% risk of excessive/unacceptable toxicity). Results: 18 pts were treated from April ‘07 to August ‘08, 5 pts at dose level A1 and 13 pts at dose level B1. Two DLTs (G3 rash on cycle 2 day 1 lasting > 7 days and G3 mucositis on cycle 1 day 14 lasting > 7 days, 1 pt each) were reported in 4 evaluable pts at dose level A1. No DLTs were reported in 7 evaluable patients at dose level B1. Conclusions: At dose level B1 everolimus in combination with irinotecan and cetuximab was generally well tolerated. The study was stopped due to changes in clinical practice based on emerging data indicating that cetuximab has limited efficacy in mCRC patients with KRAS mutations and that efficacy data favors daily RAD001 over weekly dosing. Patients in this study were treated with cetuximab irrespective of KRAS status.

[Table: see text]

[Table: see text]
Phase II study of capecitabine plus oxaliplatin for the first-line treatment of patients with metastatic colorectal carcinoma
Authors: Xu none R. , Li Y. , Luo H. , Wang F.
Published: August 2020

e15125

Background: The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients responding to XELOX is able to maintain the response and improve the duration of disease control (DDC). Methods: Patients with mCRC were treated with a 3-weekly regimen of oxaliplatin at a dose of 130 mg/m2 intravenously on Day 1 plus capecitabine 1000 mg/m2 orally twice daily from Days 2 to 15. Patients who did not progress after finished the XELOX therapy were choice to stop or receive oral capecitabine until disease progression or unacceptable toxicity. Results: 124 patients received a total of 637 cycles (median, 6) of treatment. Responses rate was 49.1%. Median overall and median progression-free survival was 20.0 months and 8.0 months, respectively. Main grade 3–4 drug-related toxicities included neutrapenia (5.6%), nausea/vomiting (4%), thrombocytopenia (2.4%), and hand-foot syndrome (2.4%). 23 of 101 patients responding to XELOX received oral capecitabine as maintenance therapy.The median DDC was 8 months for patients in the group of not using maintenance therapy, versus 12 months in the group of using capecitabine as maintenance therapy. Conclusions: XELOX is a highly effective first-line treatment for mCRC and provides a more convenient regimen, likely to be preferred by both patients and healthcare providers. Furthermore, these results support the feasibility of maintaining good response and improving DDC with oral Capecitabine after combination chemotherapy in mCRC.

No significant financial relationships to disclose.
Positive expression and correlation of chemokine receptor CXCR4 with nodal metastasis and prognosis in colorectal cancer
Authors: Iqbal K.
Published: August 2020

e15128

Background: Colorectal cancer is one of the leading causes of cancer related deaths,with recurrence and metastasis as the primary reasons for mortality. New evidence hasimplicated Chemokines as the likely cause. We studied the positive expression of CXCR4 chemokine receptors in colorectal carcinoma and investigated its correlations to clinicpathologic characteristics and prognosis. Methods: Tumor tissue specimens of patients with colorectalcarcinoma (n = 67) who underwent surgery from January 2003 to December 2004 at the Department of Surgery, Tongji Hospital were collected. CXCR4 expression levels and tumor micro vessel density were evaluated by immunohistochemistry. Specimens were immunostained using formalin-fixed, paraffin-embedded tissues. The correlation between the CXCR4 expression and clinicopathological factors was evaluated Results: In 67 cancer tissue specimens, CXCR4 was positively expressed in 38 cases; positive rate being 56.7%. Positive expression of CXCR4 is associated with an increase incidence of nodal involvement, higher clinic stage, higher tumor micro vessel density and a lower 3-year disease free survival rate as compared to those with negative CXCR4 expression (P<0.05). Conclusions: Positive CXCR4 expression and high tumor micro vessel density are associated with poor prognosis and could be a potential predictive factor for recurrence or metastasis of colorectal cancer patients. So CXCR4 may be a potential target for specific therapeutic interventions in the future.

No significant financial relationships to disclose.
A phase II clinical trial utilizing maximum medical and surgical cytoredutive treatments for patients with metastatic colorectal cancer to the liver
Authors: Glisson S. D. , LaRocca R. V. , Hargis J. B. , Cervera A. , Goldsmith G. , Cornell B. , Repishti D. D. , Sunderland J. E.
Published: August 2020

e15130

Background: The median overall survival (‘OS‘) for patients with mCRC treated with chemotherapy is about 20.4 months. Combination chemotherapy with surgical cytoreduction for patients with liver metastases are evaluated in a phase II clinical trial. Methods: Patients with newly diagnosed mCRC to the liver or recurrent CRC after 5FU failure were consented to receive further chemotherapy with at least irinotecan-based chemotherapy, oxaliplatin-based chemotherapy, and with the intention to treat the liver metastases with either RFA and/or liver resection between chemotherapy regimens whenever possible. Bevacizamab and cetuximab were considered options for treatment after their respective FDA approvals. Chemotherapy was given until there was treatment failure. The primary endpoint was OS. Results: Between 2001 and 2004 thirty-seven patients aged 41 to 79 were consented. One remained alive by December 2008. Only patients with an ECOG performance status of 0–1 were consented. Twenty had been treated with 5FU for a stage III CRC befored developing mCRC. All patients received irinotecan in the form of FOLFIRI, IFL, or as a single agent. Thirty-six also received oxaliplatin in the form of either FOLFOX4 or 6. Twenty-two patients received cetuximab as a single agent. Some regimens were augmented with bevacizumab. Fourteen patients could not undergo resection or RFA because of performance status or progression. Three required radiation to the CNS or distant bone. There were eleven patients who underwent RFA of at least one liver metastasis. There were ten patients who underwent liver resection. One patient underwent both RFA and liver resection at two different times. Another patient underwent RFA, adrenalectomy and wedge resection of the lung at three different times. He remained alive at 78 months at the time of submission. Median OS was 34.5+ months at the time of submission. Patient survival ranged from 15 to 86 months. There were no deaths associated with any surgical intervention. Conclusions: OS was improved in mCRC patients or recurrent CRC patients who had potentially ablatable or resectable liver lesions at the time of their diagnosis and who were treated with available aggressive medical and surgical therapies.

[Table: see text]
A review of the outcomes of patients with anal cancer enrolled in the Hurley Cancer Registry: 1987-2004
Authors: Subramonia Iyer S. , Akl A.
Published: August 2020

e15131

Background: This paper describes the outcomes of patients with anal cancer enrolled in the Hurley Cancer Registry. Methods: Retrospective registry and chart review study. The Hurley cancer registry was searched using diagnosis codes for anal cancer. The records retrieved, were reviewed for demographic and pathologic details,cancer recurrence, and vital status at last follow up. Relative survival was calculated for the patient cohort. Results: Over a period of 18 years (1987 - 2004), there were 36 patients enrolled in the registry, with a diagnosis of anal cancer. There were 18 males and 18 females. Mean age at diagnosis was 59.3 (SD 17.6) years for males, and 64.6 (SD 13.8) years for females. Squamous cell cancers were the most common: 27 / 36 (75%). The median survival of these 36 patients was 6 years. The median disease free survival was 5.3 years. Five patients (14%) developed recurrent disease during follow up, after a median of 1.8 years (range: 0.67- 4.2 years). Four of these patients had local recurrence only. One patient had local, regional recurrence with distant metastases. Three of the five (60%) recurrent cancers were associated with HIV infection. For all patients without recurrence, the median survival is 7.1 years. Relative survival is the observed survival adjusted for expected mortality. The expected survival probabilities for 3-yr and 5-yr intervals were calculated using the age, sex and race- matched survivorship information U.S. population life tables for 1989–91 and 1999–2001. Cumulative survival functions for the cohort were derived for the time points of 3-yrs and 5-yrs after diagnosis. The relative survival for the cohort was 84.6% at 3 years and 79.8% at the end of five years of follow up. These results appear superior when compared to the overall 5-year relative survival rate for 1996–2004 from 17 SEER geographic areas, which was 66.5%. Conclusions: Among patients in the Hurley Cancer Registry, 1. Squamous cell carcinoma is the commonest (75%) anal cancer. 2. The risk of recurrence of anal cancer was 14% over 6-years, and 80% of recurrence was localised to the anal canal. 3. The relative survival for the cohort was 79.8% at the end of five years of follow up. This was 78.9% for the subgroup of patients without recurrence, and 86.1% for the subgroup with recurrent disease.

No significant financial relationships to disclose.
Polymorphism detection of K-Ras mutations using high-resolution melting analysis in Mexican patients with metastatic colorectal cancer (mCRC)
Authors: Astudillo H. , Sanchez-Guillen J. , Romero-Garcia P. , Bastarrachea-ortiz J. , Morgan-Villela G. , Salazar J. M. , Vazquez-Rivera V. M. , Ruiz-Calzada H. , Cortes-Esteban P.
Published: August 2020

e15135

Background: Metastatic carcinoma of the colorectum remains a major problem. Nowadays the mutational polymorphism detection of K-ras gene is useful for patients with diagnosis of mCRC especially when an anti-EGFR biological therapy is considered to be used. The purpose of this study was to analyze and establish a molecular method to detect the mutational polymorphism of K-Ras gene in paraffin-embedded biopsies from Mexican patients with mCRC. Methods: The presence and polymorphism of K-ras gene mutations were analyzed in paraffin-embedded biopsies from 156 patients using a real time PCR technique with target specific oligomer competitor shifting the PCR amplification towards the mutated target, thus yielding an enriched PCR product containing variations. Results: K-ras mutations were detected in 89 of 156 patients (59%). There was not evaluated a relationship between the presence of a K-ras mutations and clinicopathological features. 39 of the 89 (42.85%) biopsies with a positive K- ras mutation had a 12G mutation polymorphism, 11 of the 89 (12.08%) biopsies had a 12D mutation polymorphism and 10 of the 89 (10.98%) biopsies had a 12S mutation polymorphism. Of the 64 biopsies without K-ras mutation (wild type), none clinicopathological correlation was determine in this group. The rate of the K-ras mutation was higher than that of the K-ras mutation negative group (wild type). Conclusions: This study demonstrates that the determination of mutational polymorphism of k-ras gene is possible and could be implemented as a predictor response in patients with mCRC to benefit from antibody based anti-EGFR therapies.

No significant financial relationships to disclose.