bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between development of rash and efficacy of EGFR inhibitors: A meta-regression analysis.
Authors: Ortega-Parra Camilo A. , Donath Elie , Garcia Salvador Ricardo , Jacobson Robert J.
Published: March 2020

e13539

Background: Treatment with Epidermal Growth Factor (EGFR) inhibitors is frequently characterized by the presence of a rash. Previous research has suggested that developing this rash may be associated with improved outcomes. It has been difficult, however, to establish a direct link between occurrence of a rash and tumor response. Rashes are also likely to occur with greater drug exposure and it is possible that they exist as a confounder in the well established relationship between drug exposure/dosing and tumor response. The purpose of this meta-regression analysis is to define whether a correlation exists between the incidence of rash and clinical outcomes including response rate (RR), progression-free survival (PFS) and overall survival (OS) and then examine whether a similar relationship exists with other adverse events as that would suggest that rash occurrence is simply a function of drug dosing and not necessarily an indicator of tumor response. Methods: A literature search for RCT’s involving EGFR inhibitors in non-small cell lung cancer (NSCLC) identified 31 trials. This included 5 trials of Cetuximab, 13 trials of Gefitinib and 13 trials of Erlotinib. Multivariate meta-regression analysis was performed to evaluate whether all rashes (grades 1-5) and severe rashes (grades 3-5) as well as vomiting and neutropenia (two randomly chosen adverse events) may have influenced effect size (measured by RR, PFS and OS) across this cancer type. Results: The presence of severe rashes in the treatment arm was positively correlated with increased PFS (p<0.01) in NSCLC - a similar correlation was also found for risk of vomiting. Additionally, the presence of any rash in the treatment arm was positively correlated with increased OS (p=0.03) in NSCLC – a similar correlation was found for risk of vomiting and neutropenia. Conclusions: The presence of a rash seems to connote an increased likelihood of tumor response and/or survival in NSCLC. The fact that other adverse events (vomiting and neutropenia) are more evident in these responding patients suggests that rash occurrence may simply be a confounder in the EGFR inhibitors’ dose-response relationship as opposed to being independently associated with any tumor response.
Dose-efficacy relationship for molecularly targeted agents: A literature review of monotherapy phase I cancer clinical trials.
Authors: Arrondeau Jennifer , Paoletti Xavier , Sablin Marie-Paule , Pop Simona , Le Tourneau Christophe
Published: March 2020

e13553

Background: Data regarding the dose-efficacy relationship for molecularly targeted agents (MTAs) are conflicting and all based on institution data. We report the largest study evaluating this relationship based on an extensive literature review of phase I trials of MTAs administered as single agents over the last decade. Methods: Efficacy defined by the occurrence of partial or complete responses was recorded and related to the dose administered expressed as a percentage of the maximum tolerated dose (MTD) or the maximum administered dose (MAD) when the MTD was not reached. Association was estimated using logit model with random intercept to adjust for the study. Results: Hundred and sixty eight phase I trials evaluating 116 MTAs involving 5,668 patients were reviewed. Efficacy was present in 39% of trials, but in only 134 patients (2.3%). Among these 134 patients, the dose at which signs of efficacy occurred was known for 113 patients. Overall, the crude response rate slightly increased from 4% at doses <40% of the MTD/MAD to 6%, 7% and 7% at doses 40-80%, 80-120% and >120%, respectively. However, statistical significance was not reached (p=0.28), whether or not the MTD had been reached. Conclusions: Antitumor activity infrequently occurs in phase I trials of MTAs administered as single agents. Although efficacy seemed to increase with dose, statistical significance was not reached, possibly due to the low response rate and sample size.
Reversal of the Warburg effect in breast cancer cells by a novel agent.
Authors: Arora Ritu , Schmitt David , McClellan Steven , Tan Ming , Reed Eddie , Owen Laurie , Dean-Colomb Windy Marie
Published: March 2020

e13566

Background: It is well known that most cancer cells display a Warburg effect, a state of active glycolysis with lactate production under aerobic conditions. NF-κB has been shown to play a role in modulating cancer metabolism and control the balance between glycolysis and mitochondrial respiration. We have previously shown that panepoxydone (PP), a compound isolated from an edible mushroom, interferes with NF-κB mediated signal transduction. Additionally, we have shown that PP decreases cell viability and proliferation in breast cancer cells. To further characterize the antitumor effect of PP, here we have evaluated it ability to modulate cancer metabolism. Methods: The metabolic action of PP was evaluated in estrogen receptor positive (MCF-7) and triple negative (MDAMB-231) breast cancer cell lines. Cytotoxicity was determined by the cell titer glow assay and expressed as IC50. Metabolic activity, expressed as basal oxygen consumption rate (OCR, an indicator of oxidative phosphorylation) and extracellular acidification rate (ECAR, an indicator of lactate acid production), was measured in real-time using the XF24 Extracellular Flux Analyzer. Mitochondrial membrane potential (MMP) alteration was determined through flow cytometry and LDH-A expression was analyzed via western blot. Results: Significant antitumor activity with PP was seen in both MCF-7 (IC50 5 µM) and MDAMB-231 cells (IC50 15 µM). This correlated to a significant dose-dependent reduction in OCAR in MCF-7 (2-fold, p<0.05) and MDAMB-231 cells (3.5-fold, p<0.01). However, while a decrease in ECAR (1.5-fold, p<0.05), along with decreased LDHA expression was noted in the 231 cells (3.5-fold, p<0.01), this was not seen with the MCF-7 cells. A similar trend was noted with increased damaged mitochondria noted in 231-cells, but again no significant difference in MCF-7 cells. Conclusions: Taken together, these results indicate that PP has the potential to modulate metabolism in breast cancer cells, especially triple negative cells, as noted by its ability to inhibit glycolysis. The inhibition of glycolysis has become an important strategy in treating cancer and development of novel glycolytic inhibitors, such as PP, warrants its further investigation in breast cancer treatment.
Association of drug exposure with clinical response and toxicities in metastatic renal cell carcinoma patients (mRCC) receiving an alternative dosing (AD) regimen of sunitinib.
Authors: Teo Yi Ling , Chue Xiu Ping , Chau Noan-Minh , Tan Min-Han , Kanesvaran Ravindran , Wee Hwee Lin , Ho Han Kiat , Chan Alexandre
Published: March 2020

e13582

Background: An AD regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for mRCC. This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients starting on sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and graded according to CTCAE and plasma AUCss was quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Statistical tests such as Mann-Whitney U were used to compare the levels between groups. Results: 24 patients with a mean age of 58.8 ± 11.2 years were recruited. Majority were males (75%) and Chinese (87.5%). Among the 17 and 14 analyzable cases for cycle 1 and 2, median total AUCsswere 2.2 and 2.1 µg•h/ml respectively. Fourteen patients completed 2 treatment cycles; 7 (50%) partial response, 4 (28.6%)stable disease and 3 (21.4%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical responseand among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]
Predictive value of VEGF gene polymorphisms in metastatic colorectal cancer patients treated with a bevacizumab-based chemotherapy.
Authors: Ulivi Paola , Marisi Giorgia , Scarpi Emanuela , Passardi Alessandro , Ragazzini Angela , Frassineti Giovanni Luca , Zoli Wainer , Valgiusti Martina , Nanni Oriana , Calistri Daniele , Casacci Fabio , Amadori Dino
Published: March 2020

e14512

Background: Bevacizumab (B) + chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of B efficacy have still not been identified. In this study we verified the role of specific VEGF polymorphisms as predictive markers of the efficacy of B in mCRC patients. Methods: One hundred and forty-nine patients enrolled onto the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were considered for this study. Seventy-four patients received FOLFIRI or FOLFOX plus B and 75 patients received only CT. A peripheral blood sample was collected from each patients and submitted to genomic DNA extraction. Five single nucleotide polymorphisms (SNPs) were analyzed by direct sequencing: VEGF -2578 C/A, -1498 C/T, -1154 G/A, -634 G/C, +936 C/T. All candidate genotypes were evaluated for a potential correlation with objective response rate (ORR) (Chi-square test). Results: In the B-treated group, the presence of VEGF -2578 AA, -634 GG or -1498 CC polymorphisms was associated with a better ORR compared to the other genotypes. In particular, of the 17 patients carrying the VEGF -2578 AA genotype, 14 (82.4%) showed a response, whereas only 30 (54.6%) of the 55 patients carrying -2578 CC or CA responded to therapy (p=0.05). Similarly, of 30 patients with VEGF -634 GG, 23 (76.7%) responded to therapy, whereas only 21 (50%) of the 42 patients with VEGF -634 GC or CC were responders (p=0.03). Moreover, 13 (81.3%) of the 16 patients carrying VEGF -1498 CC were responders, whereas of the 56 patients with VEGF -1498 CT or TT, only 31 (55.4%) showed a response (p=0.07). No differences in terms of ORR were observed in patients receiving only chemotherapy. However, as a result of the low power of the interaction test, the relation between ORR and treatment was very close to statistical significance for VEGF -2578 only (p=0.07). Conclusions: VEGF -2578 C/A seems to be a potential predictive marker for B-based CT in mCRC patients. Further studies on larger case series are now needed to confirm this finding.
Phase I/II trial of intraperitoneal implantation of agarose-agarose macrobeads (MB) containing mouse renal adenocarcinoma cells (RENCA) in patients (pts) with advanced colorectal cancer (CRC).
Authors: Ocean Allyson J. , Parikh Tapan , Berman Nathaniel , Escalon Juliet , Shah Manish A. , Andrada Zoe , Akahoho Eugene , Pogoda Janice M. , Stoms George B. , Escobia Verula B , Ruggiero Joseph T. , Fahey Thomas J. , Smith Barry H.
Published: March 2020

e14517

Background: RENCA tumor cells encapsulated in two concentric agarose layers which release signals to treat advanced cancers is a novel concept that has been substantiated in in vitro and in vivo models as reported in Cancer Research 71(3), 716-735, 2011.We report results of a phase I/II study in advanced CRC pts. Methods: Previously-treated advanced CRC pts (ECOG PS 0-2) were enrolled with informed consent obtained. Pts had intraperitoneal implantation up to 4 times via laparoscopy with 8 (37/40 pts- established dose) or 16 (3/40 pts) RENCA MB/kg. Serial exams, lab profiles, and imaging were done pre- and 3 months (mo.) post-implant to assess efficacy. Endpoints of safety, tumor marker decrease, response, and overall survival (OS) were evaluated. Results: 40 pts were implanted with RENCA MB (12 pts phase I; 28 pts phase II); 17M: 23F. Mean age 58.3. 14/40 pts had >1 implant (≥2: 14 pts; ≥3: 2 pts; =4: 2 pts). Response to MB is marked by a prominent initial rise in CRP, ESR, and IL-6, indicating a systemic inflammatory response (SIR) (100% of pts) and a parallel decrease in CEA and/or CA 19-9 in approximately 70%. SIR including its accompanying fatigue and anorexia lasts days to 3 wks. Overall, there was a statistically significant difference (p=0.009) in OS between the 70% of pts showing a decrease in tumor markers by at least 20% during the first 30 days post-implant (OS; 9.7 mo., C.I. 6.5-13.5) and those who did not (OS; 4.4 mo., C.I. 1.1-7.6). On PET-CT imaging, a striking feature of response, most often seen in pts with the longest OS, is tumor necrosis. MB were well-tolerated and no Grade ≥3 adverse events were treatment-related. Conclusions: For advanced, treatment-resistant CRC pts, early response to MB implantation characterized by tumor marker decrease in association with SIR correlates with a statistically significant increase in OS. RENCA MB represent a possible new therapeutic option for late-stage CRC. Clinical trial information: NCT01053013.
Reasons for delay in time to initiation of adjuvant chemotherapy (AC) for colon cancer (CC).
Authors: Wasserman David Warren , Boulos Majdi , Booth Christopher M. , Hopman Wilma , Goodwin Rachel Anne , Biagi James Joseph
Published: March 2020

e14553

Background: AC improves survival among patients with colon cancer. Two meta-analyses have demonstrated a decrease in survival with increasing time to AC (TTAC). Here, we examine the predominant factors leading to delay in TTAC. Methods: Individual medical records of 565 patients with CC who initiated AC Aug 2005-Nov 2010 in Eastern Ontario were reviewed to capture patient and treatment characteristics including: medical comorbidities, post-operative complications, the reason if AC was not ordered after initial medical oncology (MO) consultation, dates of surgery, referral to MO, MO consult, central venous catheter (CVC) insertion, and first cycle of AC. Patients were then categorized into two groups: (i) medical/surgical reason for delay (MSRD), defined as post-operative complications or intercurrent illness, and (ii) No MSRD. No MSRD patients were further subcategorized as post-MO delay (PMOD), defined as AC deferred at time of consultation due to patient preference or further investigations required, vs. No PMOD. A multivariate logistic regression model was used to determine factors associated with TTAC > 8 weeks (w). Results: In the No MSRD group (n= 423), 25% (n=107) were subdivided into the PMOD subgroup. On multivariate analysis, TTAC >8w was significantly associated with the presence of a MSRD [OR = 2.4 (1.6-3.9), p = <0.001] or PMOD [OR = 3.3 (1.9-5.6), p = <0.001]. No other significant associations were found, including oral vs. IV AC. Proportion of cases with TTAC >8w in the subgroups were: MSRD 76.1% (n = 108); PMOD 80.4% (n = 86); No PMOD 57.6% (n = 182). Conclusions: MSRD and PMOD are strong predictors of increased TTAC; however, the majority of patients have no MSRD or PMOD. TTAC in this group is 9 weeks. This suggests that TTAC is modifiable, and likely reflects delays in referral, consultation, and chemotherapy booking. [Table: see text]
The "real life" impact of adding bevacizumab to first-line treatment of metastatic colorectal cancer: A retrospective large database study.
Authors: Hammerman Ariel , Greenberg-Dotan Sari , Battat Erez , Bitterman Haim , Brenner Baruch
Published: March 2020

e14571

Background: Bevacizumab is included in the Israeli National List of Reimbursed Drugs (NLRD) for 1st line treatment of all metastatic colorectal cancer (mCRC) patients since 7/2006. This study evaluates the "real life" impact of adding bevacizumab to 1st line treatment of mCRC by comparing patients' outcomes before and after the drug's availability in the NLRD. Methods: We conducted a retrospective database study ,using the computerized databases of Clalit Health Services' (CHS), Israel's largest health care provider, to compare two cohorts: (A) all CHS' patients diagnosed with mCRC between 1/2000-12/2004 that received 1st line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced), and (B) all CHS's patients that started 1st line treatment with irinotecan or oxaliplatin-based combination chemotherapy and bevacizumab between 7/2006 and 8/2009 (allowing a minimum follow-up of 3 years). The primary endpoint was overall survival (OS) and the secondary endpoints were 1st line progression free survival (PFS) and metastatectomy rates. Since data on actual progression status was unavailable, PFS was defined as the duration of 1st line treatment. As CHS covers more than 50% of the Israeli population, our study may represent the general care received by Israeli patients with mCRC. Results: The study population included 1,739 patients: 1,052 in cohort A and 687 in cohort B. Patient demographics were similar between the cohorts. Median OS was 15.0 months for cohort A (95% CI: 13.4–16.6) and 23.0 months for cohort B (95% CI: 21.7–24.3), with an unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.64-0.80, p<0.0001). Median PFS was 9.8 months (95% CI: 9.0–10.5) for cohort A and 14.0 months (95% CI: 13.0-15.0) for cohort B, with a HR of 0.80 (95% CI: 0.71-0.87, p<0.0001). The rate of metastatectomies was significantly higher in cohort B (8.1% vs. 3.9%; P = 0.001). Conclusions: In this retrospective database analysis, OS, PFS and metastatectomy rates of 1st line treatment of mCRC were significantly higher in the later period of the study. The addition of bevacizumab to standard treatment of mCRC may have had a major contribution to this improvement.
Survival outcome of ampullary and duodenal adenocarcinomas.
Authors: Shaib Walid Labib , Sharma Rahul , Kim Sungjin , Chen Zhengjia , Kauh John S. , Kooby David A. , Maithel Shishir K. , Landry Jerome Carl , El-Rayes Bassel F.
Published: March 2020

e14579

Background: Adenocarcinomas of the duodenum are divided into two locations: ampullary (AMP) and duodenal (DA). AMP represents 2% of all gastrointestinal (GI) malignancies and commonly present with tumor related obstruction of the common bile duct. DA is rare, and constitutes 0.4% of GI but 45% of small bowel malignancies. The literature regarding treatment and outcome of DA and AMP is very limited. The objective of this project is to evaluate the outcome for these cancers. Methods: After IRB approval, AMP and DA patients were identified from Emory University database. A chart review from July 1995 to July 2012 was conducted. Data was collected for demographic characteristics, pathology, treatment and survival.Survival rates were estimated by Kaplan Meier method and compared with Log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP versus DA on overall survival (OS). Results: A total of 162 patients with AMP (94) and DA (68) were identified. Median age at diagnosis for AMP was 62 and for DA was 63 years. Equal distribution of males and females was found in both locations. No difference was found comparing grade of the tumors. There was a difference in race. DA presented with larger primary tumor compared to AMP. DA presented with advanced stage. Treatment was driven by stage and included surgery, surgery followed by adjuvant chemotherapy (5-FU based) +/- radiation or chemotherapy alone. Median OS of 27.5 for AMP and 19.3 months for DA, not statistically significant difference. Adjusting for stage, no significant survival difference was observed (HR=0.88 95%CI=0.54 – 1.46, p=0.63). Conclusions: Race, size, stage and treatment were different comparing AMP to DA. Majority of AMP had early stage and were treated with surgery; DA tends to present at a late stage. When accounting for stage and location, the OS was not significantly different. [Table: see text]
Retrospective analysis of dose intensity, toxicity, and clinical outcomes in 5-fluorouracil based regimens in the treatment of metastatic colorectal cancer.
Authors: Mulder Karen E. , Loree Jonathan , Ghosh Sunita , Spratlin Jennifer L.
Published: March 2020

e14595

Background: Metastatic colorectal cancer (mCRC) chemotherapy utilizes either sequential monotherapy followed by combination therapy or early combination therapies. Patients receive therapy consisting of oxaliplatin with 5-FU as an intravenous formulation (FOLFOX6) or capecitabine (CAPOX). A retrospective analysis was performed comparing average relative dose intensity (ARDI), overall survival (OS), progression free survival (PFS), and toxicity profiles of these 2 regimens in mCRC patients. Methods: 122 mCRC patients identified between January 1, 2006 and December 31, 2011 received either FOLFOX6 (n= 46) or CAPOX (n=76) in Edmonton, Alberta. ARDI was compared by calculating a percent of target dose achieved in the average cycle for each patient. Data on OS, PFS, baseline demographics, and toxicities was gathered. Survival data was plotted using the Kaplan-Meier method and compared using the log-rank test. Variable comparisons were performed with the Student’s t-test or the Fisher’s Exact test. Follow up was complete until November 1, 2012. Results: Oxaliplatin ARDI trended towards being lower in those treated with CAPOX compared to FOLFOX6 (84.01 vs 89.52 p=0.0553), and 5-FU component was significantly lower (81.28 vs 95.76, p<0.0001). More patients treated with CAPOX had dose limiting toxicities (DLTs), although not statistically significant (68.42% vs 54.35%, p=0.1268), while toxicities of grade 2 and higher were increased with CAPOX (38.16% of patients vs 15.22%, p=0.0079). Neuropathy rates were similar between regimens as were cycle numbers were completed between CAPOX and FOLFOX6 (5.329 vs 6.174, p=0.2796). Survival analysis demonstrated trends towards improved median OS (300 vs 227 days, p=0.1183) and median PFS (132 vs 101.5 days, p=0.1674) with CAPOX. The groups had similar age, gender, and ECOG at diagnosis. Conclusions: Patients treated with CAPOX had significantly more DLTs resulting in lower doses of oxaliplatin and capecitabine compared to FOLFOX6. This does not seem to impact clinical outcomes as mCRC patients on CAPOX showed a trend toward improved outcomes compared to FOLFOX6.
Methylated miR-124, -137, and -34b/c as predictive biomarkers for ulcerative colitis-associated colorectal neoplasia.
Authors: Toiyama Yuji , Hur Keun , Tanaka Koji , Inoue Yasuhiro , Tabata Tsutomu , Kusunoki Masato , Boland C. Richard , Goel Ajay
Published: March 2020

e14631

Background: Accumulating evidence suggests that microRNAs (miRNAs) can be targets of methylation-induced silencing in colorectal cancer, which can occur in an age-dependent manner, and constitutes an epigenetic “field defect”. We hypothesized whether methylation of miR-124, -137 and -34b/c can predict colorectal neoplasia in patients with ulcerative colitis (UC). Methods: We examined 185 samples from 70 UC patients (45 patients without neoplasia, 12 with dysplasia and 13 with cancers) for the methylation status of miR-124, -137 and -34b/c by quantitative bisulfite pyrosequencing analysis. In addition, expression levels of these 3 miRNAs in dysplastic (n=12), cancerous (n=13) and non-neoplastic UC mucosa (n=20) were quantified by TaqMan qRT-PCR. Results: MiR-124 and -137 methylation levels were significantly higher in rectal tissues than in proximal mucosa from non-neoplastic UC tissues, and were significantly associated with age and disease duration in rectal tissues. Methylation levels of all 3 miRNAs were significantly higher in dysplasia and cancer compared to mucosa without neoplasia, and showed a “field defect” in the non-neoplastic rectal tissues from patients with cancer . Receiver operating characteristic (ROC) analysis revealed that methylation levels of all 3 miRNAs in non-neoplastic rectal tissues could discriminate patients with cancer from those without (miR-124 AUC value = 0.74; miR-137 AUC = 0.79; miR-34b/c AUC=0.72). Furthermore, methylated miR-137 in non-neoplastic rectal tissues allowed discrimination of UC patients with neoplasia from those without (AUC = 0.76), and independently predicted neoplasia (OR= 5.55; 95% CI: 1.40–22.05; P = 0.0148). Expression levels of all 3 miRNAs were significantly downregulated in dysplasia or cancer compared to non-neoplastic UC mucosa, and the expression and methylation were negatively correlated. Conclusions: Methylation of miR-124, -137 and -34b/c in rectal biopsies, particularly miR-137, may serve as novel predictive biomarkers for neoplasia in UC patients. Restoration of expression by reversing their methylation status could be an attractive strategy to slow or reverse age-related UC-associated neoplasia.
Heterogeneity of colorectal cancer (CRC) in reference to KRAS proto-oncogene utilizing wave technology.
Authors: Perez Kimberly , Walsh Robert , Brilliant Kate E. , Nobel Leila , Yakirevich Evgeny , Breese Virginia , Jackson Cynthia , Chatterjee Devasis , Pricolo Victor , Roth Leslie , Shah Nishit , Cataldo Thomas , Safran Howard , Hixson Douglas , Quesenberry Peter J.
Published: March 2020

e14637

Background: The use of Epidermal growth factor receptor (EGFR) inhibitor monotherapy in patients that have KRAS wild type has produced response rates of only 10-20%. We propose two possible explanations to explain these low response rates; 1) levels of resistant CRC cells carrying mutated KRAS are below the sensitivity of standard direct sequencing modalities (<5%) or 2) the standard practice of analyzing a single area within a heterogeneous tumor is a practice that can overlook areas with mutated KRAS. Methods: In a collaborative effort with Lifespan Pathology Department and the Molecular Pathology Core of the COBRE for Cancer Research Development, 3 FFPE tissue blocks of human CRC were obtained. The three specimens previously demonstrated KRAS mutations detected by the Applied Biosystems Kit. The Wave system 4500 (High performance ion-pairing liquid chromatography (IP-HPLC)) was utilized to evaluate tissue for presence of KRAS proto-oncogene mutations at codon 12 and 13. Results: Initially, sensitivity of WAVE technology was compared with direct sequencing by evaluating a dilutional series. WAVE detected mutant alleles at levels of 2.5% compared to 20% performed with standard direct sequencing. Samples from 3 patients were evaluated by WAVE technology. 8 samples from patient 1 were analyzed. In 2 of 8 samples, no mutations were detected at concentrations as low as 5%. In one sample a mutation was noted by WAVE and not by direct sequencing. All 4 samples from patient 2 tested positive for Exon 12/13 mutations. Of the 7 samples from patient 3, 5 were positive for Exon 12/13 mutations and 2 were negative for Exon 12/13 mutations. Conclusions: Results demonstrated a greater degree of sensitivity in mutation detection when compared to standard sequencing. These studies also demonstrated heterogeneity of expression of KRAS mutations between areas of the tissue samples at a genomic level. The low clinical response rates to EGFR inhibition might be explained by the variation in mutation presence, which was dependent upon the region examined. The heterogeneity demonstrated in these studies provides another phenotypic variant that will impact clinical care.
Association between smoking and tumor grade in colorectal cancer: A retrospective analysis from a single institution.
Authors: Elsoueidi Raymond , Tom Sabrina , Adane Eyob , Dignan Mark
Published: March 2020

e14673

Background: Colorectal cancer is the third most common cancer worldwide. Smoking has been increasingly reported as a risk factor. Poorly differentiated adenocarcinoma in colorectal cancer has been reported to have a worse outcome. Poorly and moderately differentiated adenocarcinomas in Non Small Cell Lung cancer were more strongly correlated with smoking than well differentiated adenocarcinoma. This study was designed to evaluate the association between cigarette smoking and tumor grade in colorectal cancer. Methods: The medical records of patients diagnosed with colorectal cancer between 2001 and 2011 at the Appalachian Regional Healthcare in Hazard, KY were retrospectively reviewed. Age, gender, pathology and smoking history were obtained. The association between smoking and tumor grade was evaluated by the χ2 test. Results: Three hundred seventeen patients were diagnosed with colorectal cancer between 2001 and 2011. The percentage of male and female patients was 53.3% and 46.7%, respectively. Among these patients, 49.5% (n=157) were smokers and 38.8% were nonsmokers (n=138), while for 11.7% (n=35) of patients smoking history was unknown. In smokers, 17.1% had high grade adenocarcinoma (poorly differentiated) and 82.9% had low grade adenocarcinoma (moderately differentiated + well differentiated) whereas in non-smokers, 13.8% had high grade adenocarcinoma and 86.2% had low grade adenocarcinoma. Although the percentage of high grade adenocarcinoma was higher among smokers this was not statistically significantly (p=0.55). Moreover, tumor grade was not significantly associated with age and gender. Conclusions: Based on these results, there was no association between degree of differentiation of tumor in colorectal cancer and smoking history, age and gender. Although to be noted that the pathologic grading may vary from one pathologist to another.
Immunihistochemical detection of galNAc-T6 to predict survival in patients with colon cancer.
Authors: Ubillos Luis , Rondan Mariela , Berriel Edgardo , Mazal Daniel , Barrios Enrique , Berois Nora , Osinaga Eduardo
Published: March 2020

e14682

Background: Alterations in the O-glycosylation is one of the most common changes during colon carcinogenesis, which leads to the expression of short O-glycan antigens (Tn, sialyl-Tn, Tk, and core 6). These structures are associated with malignant behavior being actively investigated as targets for immunotherapy. The enzymes of GalNAc-T family regulate the initial step in mucins O-glycosylation and could be responsible for the altered glycosylation observed in cancer. The aim of this work was to evaluate the expression of GalNAc-T6 in colon cancer, and to determine its role as prognostic marker. Methods: We evaluated GalNAc-T6 expression in colon cell lines by immunocytochemistry, and in colon cancer tissue samples by immunohistochemistry using the monoclonal antibody T6.3 developed by us (Berois et al. J Histochem Cytochem. 2006). We analyzed 103 colon cancer samples and 10 normal colon tissues. Results: We found that GalNAc-T6 (usually expressed in normal placenta, trachea, pancreas and brain) is detected in colon cancer cell lines. GalNAc-T6 was also detected by immunohistochemistry in 50.5% of samples with cancer and no expression was found in normal colon tissue. The staining pattern was predominantly cytoplasmic. Multivariate analysis showed that GalNAc-T6 expression is an independent prognostic marker predicting improved survival in patients with positive tumors (p 0.014). Conclusions: GalNAc-T6 could be a new independent prognostic marker to predict better outcome in colon cancer patients.
Prognosis factors and colorectal cancer survival at Oncologos del Occidente from Colombia, South America.
Authors: Chacon Cardona Jose Arnoby , Villegas Mejia Carlos Raul , Sanchez Villegas Tomas
Published: March 2020

e14692

Background: Colorectal cancer is the fourth cause of cancer in the United States and the third cause of mortality in the same country. In Colombia, it is the fourth most common cancer and the fifth cause of death. Methods: 5,500 medical records of patients suffering from colorectal cancer were analyzed in a study of a retrospective phase in Oncologos del Occidente a Private Cancer Center from January 1995 to September 2005. 771 out of these patients correspond to gastrointestinal tumours, and 351 out of them with a diagnosis of colorectal cancer in order to identify the main prognosis factors described on the medical literature and to illustrate their behaviour regarding the survival of the patients suffering from colorectal cancer in our region. Results: Obstruction was observed on 33.7%; ulceration on 20.3%; lympho-neuro-vascular invasion on 7.5%; perforation on 2.1%; clinical state T4 on 2.3%; positive surgical margins on 1.8% and poor differentiation on 4.6%. The survival to 5 years to those patients showing perforation was 66.7% (IC95%: 28.9-100); 79.9 on tumours T4 (IC95%: 52.3-100); 62.5% on positive margins (IC95%:20-100); 42.4% on poor differentiated tumours (IC95%:0-85), 50% out of this correspond to colon cancer and 34% to rectal cancer; 51.2% on obstruction (IC95%:38.9-63.4); 71,9% on lympho-neuro-vascular invasion (IC95%:52.6-91.1) and 63% on ulcerated tumour (IC 95%:49-76.9). Conclusions: Survival calculated in months can be correlated with number of adverse prognostic factors present (Table). [Table: see text]
A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.
Authors: Janjigian Yelena Yuriy , Capanu Marinela , Gromisch Christopher M. , Kelsen David Paul , Ku Geoffrey Y. , Brown Karen T. , Schattner Mark , Ilson David H. , Solit David B. , Berger Michael F. , Vakiani Efsevia
Published: March 2020

e15017

Background: Trastuzumab, approved by the FDA, has been the standard of care for pts with HER2-positive EG cancer. Resistance to trastuzumab is now emerging in this population. Afatinib, an oral inhibitor of EGFR, HER2, and HER4 has potent single agent activity in HER2-positive EG cancer NCI-N87 and MSKCC patient derived xenografts (Janjigian JNM 2013). We report the initial results of a phase II study of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2 positive (IHC 3+ or FISH>2.0) metastatic EG adenocarcinoma, following failure of at least one trastuzumab/chemotherapy regimen received afatinib 40 mg daily. Archival tissue from pre-trastuzumab biopsy, a new biopsy prior to the start of therapy and after 1 wk of afatinib are mandated. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD), complete response (CR), or partial response (PR) by RECIST 1.1. Results: Nine patients treated with afatinib; median follow up 2.7mos (0.5 to 5.3mos). Median age 62, KPS 80, 6 males, 56% IHC3+; 44% IHC1+/2+/FISH>2.0. Number of prior trastuzumab containing regimens: median 2 (1 to 4). The following treatment emergent adverse events were observed: nausea/vomiting (Grade 1/2: 22%), diarrhea (Grade 1/2:67%), fatigue (Grade1/2: 33%), rash (Grade 1/2:44%), anorexia (Grade 1/2:33%,Grade 3:11%), mucositis (Grade1/2: 11%), paronychia/nail loss (Grade 1/2:11%). To date, 7 pts evaluable for response, 3 of 7 patients (43%) derived clinical benefit; 1 pt (14%) with ongoing RECIST 1.1 confirmed PR - a durable 50% regression of biopsy proven metastases in lung and lymph nodes at 5.3 mo. A second patient had 20% tumor regression in biopsy proven liver metastasis, 3.6 mos disease stabilization. A third patient experienced 4.7 mos disease stabilization and regression of biopsy proven skin metastasis. Conclusions: Single agent afatinib shows clinical efficacy in patients with trastuzumab refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of trastuzumab resistance in EG cancer are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.
A phase IIb trial of coix seed injection for advanced pancreatic cancer.
Authors: Tagliaferri Mary Ann , Schwartzberg Lee Steven , Chen Michael M. , Camacho Luis H. , Kaplan Edward H. , Arena Francis P. , Bienvenu Bryan J. , North Susan E. , Patel Hermant , Li Dapeng
Published: March 2020

e15023

Background: Kanglaite injection (KLTi) is a purified botanical extract injection tested for pancreatic cancer. KLTi is derived from Coix seed of the plant Coix lacrama-jobi. KLTi demonstrated growth inhibitory effects in vitro. In xenograft models with PANC-1 cell lines in BALB/C mice, KLTi combined with gemcitabine had synergistic tumor inhibitory activity greater than gemcitabine alone. KLTi is approved and widely used in China to treat non-small cell lung cancer and primary liver cancer. We report final cohort 1 results from a US phase 2b clinical trial. Methods: Eligible patients with histologically confirmed unresectable pancreatic cancer were randomized to a regimen of either KLTi 30g/day plus a standard course of gemcitabine or a standard course of gemcitabine only. The two groups were compared in efficacy, measure by progression-free survival (PFS), and safety. Results: Forty-one patients were randomized to cohort 1 and 38 patients received treatment: 26 received KLTi plus gemcitabine, 12 received gemcitabine only, and 3 received no treatment. The KLTi plus gemcitabine group had a median PFS of 114 days, significantly longer than the median PFS of 57.5 days in the gemcitabine only group (HR 0.338, 95% CI: 0.145, 0.788, p=0.008). The overall response rates were 15.5% (4/26) and 8.3% (1/12) for KLTi plus gemcitabine and gemcitabine only, respectively. Two serious adverse events were possibly related to KLTi; one subject had a pulmonary embolism and the other experienced transient confusion. The adverse events were similar between the groups and consistent with gemcitabine toxicities. Conclusions: Combined with gemcitabine, KLTi injection showed favorable tolerability and encouraging clinical activity for the treatment of advanced pancreatic cancer. Clinical trial information: NCT00733850.
Neoadjuvant chemotherapy using concurrent docetaxel/CDDP/5-FU (DCF) in esophageal squamous cell carcinoma and its excellent short-term prognosis.
Authors: Yamashita Keishi , Katada Natsuya , Katada Chikatoshi , Hosoda Kei , Moriya Hiomitsu , Higuchi Katsuhiko , Koizumi Wasaburo , Watanabe Masahiko
Published: March 2020

e15122

Background: Neoadjuvant chemotherapy (NAC) using 5-FU/CDDP (FP) followed by surgery is a standard treatment for esophageal squamous cell carcinoma (ESCC). However, this therapy often encountered progression during the early course of treatment. We are developing the novel NAC using Docetaxel/CDDP/5-FU (DCF). Methods: Thirty eight patients who underwent DCF NAC in cStage II/III ESCC was compared with the 41 counterparts treated by FP NAC. Docetaxel and CDDP were both given to 70-75 mg/ m2 with concurrent 5-FU at 750 mg/m2in 3 cycles. Median follow-up term of DCF NAC reached 18 months. Results: In DCF NAC, grade 3 adverse effects (AEs) were recognized in 97% (37/38), however non-hematological AEs exhibited 8% in stomatitis and 5% in anorexia, and completion rate of the DCF NAC was 86 %. In terms of PR+CR rate, DCF NAC was remarkably more excellent (33/38: 86.8%) than FP NAC (24/41: 58.5%)(P=0.0050). In DCF NAC therapy, 30 patients underwent surgery including 24 R0 esophagectomy, whereas another 8 patients selected definitive chemoradiation therapy. We experienced 3 patients with a pathologic complete response (ypCR)(10%) in DCF NAC. The 1st univariate prognostic analysis for progression free survival (PFS) among all the cases with NAC revealed that significant factors were R0 resection (P<0.0001), cT factor (P=0.0098), and NAC modality (P=0.1), and multivariate proportional hazard model identified these 3 factors as independent prognostic factors (IPFs). We then performed the 2nd stage multivariate prognostic analysis limited to R0 cases including pathologic factors for PFS. The univariate negative prognostic factors were FP NAC (P=0.0064), ypT3 (P=0.032), ypN3 (P=0.0017), ypv2/3 (P=0.0072), as well as cT3 (P=0.033), and multivariate analysis identified only NAC modality. DCF NAC was significantly associated with less frequency of ypT3 (P=0.019) and ypv2/3(P=0.013). Conclusions: Novel DCF NAC for ESCC demonstrated high response rates, and is promising for excellent survival in R0 cases, with acceptable feasibility. It improved the patient survival through downstage of the significant prognostic factors.
Phase II randomized study comparing concurrent chemoradiation versus neoadjuvant chemotherapy followed by chemoradiation in locally advanced unresectable squamous cell carcinoma of esophagus.
Authors: Chaudhari Pritee Baburao , Chander Subhash , Mohanti B. K. , Sharma Atul , Kaur Jaspreet , Pathy Sushmita , Deo S. V. S.
Published: March 2020

e15138

Background: A significant number of patients diagnosed with esophageal cancer (EC) presents with locally advanced disease. Nonsurgical curative therapy for unresectable EC has limited outcome. Methods: Phase II randomized control trial to assess early locoregional response (LRR) to neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiation (CRT) versus definitive CRT in surgically unresectable squamous cell carcinoma of esophagus (ESCC). A total of 30 patients were randomly assigned to two arms. Arm 1: 2 cycles NACT regimen of 5-fluorouracil (750mg/m2 D1-4) and cisplatin (80mg D1-2) followed by CRT, radiation of 56Gy/ 28 Fr concurrent with weekly paclitaxel 50mg/m2 and carboplatin AUC2. Arm2: CRT; consisting of radiation 56Gy/28Fr and weekly paclitaxel 50mg/m2 and carboplatin AUC2. All the patients were followed till 6 months post treatment. LRR assessment was done at 1, 3 and 6 months post treatment. Wilcoxon multivariate analysis was carried out and difference of the factors were assessed by chi square test (x2 p<0.05). Results: Mean age in two arms were 52 and 54 years respectively. The study had median follow up of 6.6 months. Conclusions: In unresectable EC, CRT showed higher LRR, treatment completion and lesser toxicity compared to NACT combined with CRT. In this pilot cohort of locally advanced unresectable EC paclitaxel and carboplatin combined with radiotherapy has good tolerance and compliance. [Table: see text]
Results of observational study of docetaxel, platinum compounds, 5-fluorouracil and leucovorin as first-line therapy in advanced gastric cancer (AGC).
Authors: Trusilova Elena , Besova Nataliya , Gorbunova Vera A.
Published: March 2020

e15156

Background: AGC is relatively chemosensitive, but a standard chemotherapy (CT) regimen has yet to emerge, and responses are of short duration. Docetaxel-containing scheme are new option for pts with AGC. The V325 trial demonstrated the efficacy benefit of adding docetaxel to CF (cisplatin + 5-FU) (DCF). DCF is associated with significant toxicity, making it less tolerable to pts. We modified the original DCF regimen to reduce its toxicity without decreasing efficacy. Methods: AGC pts received docetaxel 75mg/m2 and cisplatin 75mg/m2 (n=42) or oxaliplatin 100mg/m2 (n=39) in day2 with leucovorin 50mg and 5-FU 500mg/m2 (3-hour infusion) in day1-3 every 3w (TPFL or TOFL) instead of original DCF (docetaxel 75mg/m2, cisplatin 75mg/m2 in day1 and fluorouracil 750 mg/m2in day 1-5 continuous infusion). Results: 81 CT-naïve pts with AGC were included in our observational study from Feb 2008 to Dec 2012 (42 female, 39 male). ECOG 0/1/2 were 9.9/85.2/4.9% pts. ORR was 41% (32/79), SD – 37% (29/79), PD – 23% (18/79). Median PFS and median OS were evaluated in 80pts and were 5.6m and 12.4m, respectively. ORR, PFS, and OS comparable TOFL and TPFL results were: 49 and 34%, 5.4 and 6.5m, 11 and 12.8m respectively. Toxicity of both regimens was moderate. Grade 3+4 toxicities for TPFL/TOFL included leucopenia – 23/5%, neutropenia –50/61%pts, febrile neutropenia -7pts (9%) - 1pt from TPFL and 6pts from TOFL, thrombocytopenia – 2/0% pts. Nonhematologic toxicities were max grade 3: asthenia –2 /20%, stomatitis – 2/0%, diarrhea – 7/5%, vomiting – 0/2,5% pts. There were 2 pts experienced 3grade neurotoxicity in TOFL. We didn’t use G-CSF prophylaxis. There were no deaths and treatment discontinuation due to toxicity. At present 13 pts are still alive, 4 of them were operated on due to distant mts resolution after 4-17 CT courses. Their survival is 41m without PD, 43m, 52m and 22m with PD over 10m,12m and 7m after surgery. Conclusions: Our data suggest that docetaxel and platinum-contain regimens has the similar efficacy and better tolerability than the standard DCF. Both regimens can be safely given in an ambulant setting. Febrile neutropenia and neurotoxicity were more common in TOFL.
Concurrent chemoradiotherapy with S-1 plus cisplatin for advanced cervical esophageal carcinoma: Long-term results of a phase II trial.
Authors: Iwase Hiroaki , Shimada Masaaki , Tsuzuki Tomoyuki , Hirashima Noboru , Okeya Masayuki , Ryuge Nobumitsu , Kida Yuichi , Kuno Takeshi , Tanaka Yusaku , Kato Eriko
Published: March 2020

e15159

Background: Carcinoma of the advanced cervical esophagus is a highly virulent disease. Although surgery is considered the standard therapy, the results of surgery alone remain poor. The present study analyzes the efficacy of concurrent chemoradiotherapy (CCRT) with S-1 and cisplatin for advanced cervical esophageal carcinoma (ACEC). Methods: CCRT comprised two courses, 30-Gy radiotherapy over 3 weeks (2 Gy per fraction, 5 times a week) accompanied by daily oral S-1 powder (80 mg/m2/day) for 2 weeks and a 24-hr cisplatin infusion (70 mg/m2) on Day 8. An identical course was administered after a 2-week break. Responders received a 5-week cycle of chemotherapy with S-1 and cisplatin. Results: Twenty-one subjects, 3 with Stage II, 14 with Stage III, and 4 with Stage IV ACEC participated, and all completed the CCRT courses. Eighteen subjects received a total of 59 cycles of chemotherapy after CCRT and a median of 3 cycles per subject was administered (range: 1 to 9 cycles). Complete response rates in subjects with Stage II, Stage III, and Stage IV diseases were 100%, 85.7%, and 25%, respectively, and a dysphagia-free status was found in 80.9%. The most serious toxicity was myelosuppression; Grades 3 and 4 neutropenia occurred in 33.3% and 9.5%, of subjects, respectively. Non-hematologic toxicities were moderate. The most common were Grade 2 nausea (38.0%), esophageal pain, and oral mucositis (19.0% each) and renal dysfunction (9.5%). Adverse events from the first course of CCRT resolved during the 2-week treatment break. Overall median progression-free survival was 1.5 years and the median survival time was 2.5 years. The 1- and 5-year survival rates were 75.0 and 27.7%, respectively. Conclusions: This regimen showed favorable antitumor activity, improving survival and quality of life with tolerable toxicity, and could become an alternative to conventional surgery for the treatment of ACEC.
The vascular endothelial growth factor as a predictive and prognostic factor in patients with advanced gastric cancer treated with docetaxel, cisplatin, and 5-florouracil (DCF) regimen.
Authors: Aktas Sedef H. , Akbulut Hakan , Yazici Ozan , Zengin Nurullah , Akgun Nalan , Ustuner Zeki , Icli Fikri
Published: March 2020

e15191

Background: Vascular endothelial growth factor (VEGF) is a key element stimulating the angiogenesis in solid tumors. In the current study, we aimed to assess the role of plasma VEGF levels as a prognostic and predictive marker for advanced gastric cancer patients treated with a modified docetaxel, cisplatinum and 5-florouracil (DCF) regimen. Methods: Thirty consecutive patients treated with a modified DCF regimen were included in the study. The plasma VEGF levels of the patients before treatment and following two cycles of chemotherapy were assayed. Results: The modified DCF regimen was well tolerated and yielded a median overall survival (OS) time of 9,0 months and 2-year OS rate of 20%. Good performance status, lower pre-treatment VEGF levels,and decrease in VEGF levels following chemotherapy were found to be independent prognostic factors for OS. Conclusions: The results of the current study suggest that the corrected plasma levels of VEGF could be used as a prognostic factor for advanced gastric cancer patients and a decrease in VEGF levels following 2 cycles of chemotherapy as a predictive marker for patients receiving DCF chemotherapy regimen.