bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology and survival of small cell carcinoma of gastrointestional tract: A Surveillance, Epidemiology, and End Results (SEER) database review.
Authors: Kumar Abhijeet , Sundararajan Srinath , Cui Haiyan , Patel Hitendra , Elquza Emad
Published: February 2017

518

Background: Small cell carcinoma of the gastrointestinal tract is an uncommon histology. Limited literature is available to clinicians about the incidence, distribution and prognosis of small cell carcinoma of the gastrointestinal tract (SCGIT). We reviewed the Survival, Epidemiology and End Result (SEER) database of National Cancer Institute to understand its epidemiology and prognosis. Methods: SEER database was reviewed for patients with histologically confirmed SCGIT (8041-45) and its variants in the GIT between 2002-2007 (all stages). Variables included were age, gender, race, primary site and disease specific survival. The incidence pattern across race, gender, and site of origin for SCGIT was investigated. Chi square test was used to assess the difference of incidence pattern. 5-yr survival rate across various sites was estimated using the Kaplan–Meier method and the difference in 5-yr survival was tested by log-rank test. If the significant difference is detected, the paired comparison was performed and the p-values were adjusted by Tukey multiple-comparison method. Results: A total of 645 patients were included. The distribution of SCGIT was: colorectal (30.08%), esophagus (22.17%), pancreas (20.16%), hepatobiliary (11.63%), stomach (9.61%) and NOS (6.63%). The incidence pattern of SCGIT in males and female was significantly different (p < 0.0008). Males had a higher incidence of esophagus; stomach and pancreas while females had a higher incidence of hepatobiliary, colorectal and NOS sites. Five-year survival of SCGIT was significantly associated with the primary site of disease (p = 0.03). Paired-comparison results showed that the 5-yr survival rate for patients with pancreas small cell cancer was significantly lower than patients with stomach or NOS(4.80% -pancreas vs 5.22 %-stomach and 12.81% - NOS) (p = 0.04 and p = 0.003 respectively). There was not a significant difference between other sites. Conclusions: Small cell carcinoma of the GI tract has difference in incidence patterns between genders. The 5-yr survival of patients with pancreatic small cell carcinoma is significantly lower as compared to stomach or NOS.
Case review for ramucirumab as a single agent in our hospital.
Authors: Murahashi Satoshi , Takahari Daisuke
Published: February 2017

52

Background: Ramucirumab is approved in the USA, EU, and Japan as second-line treatment in advanced gastric or gastroesophageal junction adenocarcinoma. This agent is often used with paclitaxel, but we can use it as a single agent in second-line treatment. Because REGARD trial has shown that Ramucirumab as a single agent prolongs overall survival and progression-free survival. However, this trial doesn’t include Japanese patients, and we have no trial concerning the efficacy of Ramucirumab as third or later-line treatment up to date. We reviewed retrospectively the efficacy and safety of Ramucirumab as a single agent in our hospital. Methods: We investigated 12 cases from June (when Ramucirumab has been approved) to September. Results: The median age was 61 years old, 6 male and 6 female patients. Performance status (0/1/2) = (1/10/1) cases. (second/third/fourth or later)-lines = (4/4/4) cases. Metastatic sites are lymph node, liver, lung, bone, and peritoneum. 7 patients had gastrectomy and 5 patients of them received adjuvant chemotherapy. Response rate is 50%, median progressive-free survival is 51 days, and median overall survival is 13 months. Some patients experienced grade 1or 2 adverse events: fatigue, loss of appetite, diarrhea, and hypertension. Conclusions: We cannot say that single agent administration of Ramucirumab demonstrates good response, some patients kept stable disease in this regimen. Ramucirumab as a single agent can be an option of treatments after paclitaxel fails or when it is difficult to administrate it.
The novel diagnostic method for colorectal cancer: Detection of methyl mercaptan from flatus.
Authors: Ishibe Atsushi , Ota Mitsuyoshi , Tsuboi Hiroshi , Takeshita Akemi , Suwa Yusuke , Suzuki Shinsuke , Suwa Hirokazu , Momiyama Masashi , Watanabe Jun , Kosaka Takashi , Watanabe Kazuteru , Akiyama Hirotoshi , Ichikawa Yasushi , Kunisaki Chikara , Endo Itaru
Published: February 2017

529

Background: Fecal occult blood test screening for colorectal cancer (CRC) reduces cancer specific mortality through the detection of early stage disease. However, medical examination rate is very low in Japan because of the inconvenience of sampling of stool. On the other hand, it is reported that dogs can be trained to distinguish breath samples of patients with lung and breast cancer from those of control. It is unclear that odour materials become effective tools in CRC screening. The aims of this study were to evaluate the gas components in the flatus of CRC patients and to compare with healthy controls. Methods: Thirty-two patient before elective colorectal surgery in Yokohama City University and 13 healthy controls were enrolled in this study.The apparatus for gas sampling was placed in the toilet. Defecation gas from a patient in a toilet stool was collected in a 25L sampling bag. A fan (50 L / min ) was arranged to aspirate air in the toilet stool. Defecation gas components were collected as follows: (1) Air in the toilet stool was aspirated with the fan and passed through a commercial gas sensor. (2) Gas sampling started after the gas sensor detecting gas components.Volatile sulfur-containing compounds in sampling bag were injected into the gas chromatography by Entech pre-concentrator and analyzed. Results: The amount of methyl mercaptan was significant higher compared with control. Methyl mercaptan and hydrogen sulfide were related to tumor size (r = 0.415，p = 0.018, r = 0.454，p = 0.009). Methyl mercaptan tended to increase as the stage advances (p = 0.022）．Based on an optimal cut-off value calculated by ROC curve analysis had accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 68.9%, 68.8%, 69.2%, 84.6%and 47.3%, respectively, for the diagnosis of CRC. Conclusions: The methyl mercaptan from the toilet stool during defecation was increasing in CRC patients. Measurements of methyl mercaptan suggests possibility of more easily and precise colorectal cancer screening.
Lynch Syndrome diagnosis in Ireland: The impact of universal mismatch repair protein testing.
Authors: Corrigan Lynda , Clabby Catherine , Green Andrew J. , Barton David , Gallagher David James
Published: February 2017

532

Background: It is estimated that approximately 2-4% of colorectal cancers (CRCs) are attributable to Lynch Syndrome (LS). Immunohistochemical testing for mismatch repair proteins is increasingly being performed on CRC specimens. In some centres all incident cases undergo this testing. An abnormal result should initiate a cascade of testing to determine if the loss of mismatch repair protein expression is sporadic or hereditary. We examined the pattern of cancer genetics referral for hereditary CRC diagnosed in Ireland under the age of 70 years. Methods: The number of patients with CRC diagnosed under the age of 70 between 2005 and 2013 was obtained from the National Cancer Registry of Ireland. The number of patients referred for cancer genetics work-up with a diagnosis of CRC < 70 years of age was ascertained from the Department of Clinical Genetics, Our Lady’s Hospital, Crumlin (DCG), the only genetics laboratory in Ireland which processes such samples. The database of the DCG was searched for referrals for hereditary CRC syndromes; and the clinical reason for referral recorded. Results: Between 2005 and 2013, 10,334 patients were diagnosed with CRC less than 70 years of age. 85% were between 50 and 69 years of age (n = 8,736). 229 people under the age of 70 years were referred for cancer genetics work-up for LS with a diagnosis of CRC. Those referred for a non-CRC LS phenotypic manifestation and for predictive testing were excluded. For 41 individuals the reason for referral was not specified. Individuals with CRC were referred for one of the following reasons: diagnosis of CRC < 70 years in 76 patients (33%), diagnosis of CRC < 70 with a family history of LS-associated malignancy in 137 patients (60%), and diagnosis of CRC < 70 with known familial genetic mutation in 16 patients (7%).This represents a referral rate of approximately 0.02% for CRC diagnosed under 70 years of age. Conclusions: 0.2% of colorectal cancer cases diagnosed at < 70 years of age in Ireland over a nine year period were referred for cancer genetics opinion. Increased immunohistochemical testing for mismatch repair proteins should result in increased cancer genetics referral, which will require appropriate service provision within oncology management pathways.
Tumor marker CA 11-19 as a new serum blood test for monitoring colorectal cancer.
Authors: Costanzi John J. , Jordan Tommye Ann , Jensen-long Lisa
Published: February 2017

536

Background: Colorectal cancer remains the third most frequent cause of cancer deaths globally. The FOBT (fecal occult blood test) and FIT (fecal immunochemical test) as well as CEA are increasingly being used to screen or monitor patients at increased risk for colorectal cancer (CRC), however none has optimal performance in terms of both sensitivity and specificity. Data was recently published* on the new serum blood test colorectal tumor marker CA11-19. This data showed a sensitivity of 98% (95% CI, 93.1%-99.5%) and specificity of 84% (95% CI, 80.0%-87.9%) at a cut-off value of 6.5 U/mL with a high sensitivity for detection of early stage CRC as opposed to CEA whose values are reported ~40% and ~30–80%** respectively for sensitivity and specificity. This study will look at case studies that show an array of long-term monitoring outcomes which suggest possible use of CA 11-19 instead of CEA. Methods: Using a sandwich ELISA assay, a new colon cancer antigen, CA 11-19, (100 kDa glycoprotein) was measured in samples of 7 patients with a variety of conditions in normal, benign GI diseases, polyps and colon cancer. This long-term follow up is recorded from 8 to 20 years. Results: Serum samples previously frozen were used to measure the CA11-19 antigen. An average follow up time of 15 years (range 8 to 20 years) was recorded. Elevated levels of CA11-19 were detected in patients with polyps and CRC prior to treatment and decreased levels were measured after the removal of the polyps or cancer. Importantly, rising rates of CA11-19 were seen in patients with cancer recurrences of colorectal cancers. Conclusions: CA 11-19 is a serologic tumor marker for colorectal cancer with a published sensitivity of 97.7% and a specificity of 84.4%*. Preliminary reports from 7 cases show long-term data which could be more helpful in monitoring and or follow-up of high risk patients for CRC than the current CEA testing method. Additional studies are needed to further validate the use of CA 11-19 in these patient groups.
Tumor genomic profiling (TGP) in metastatic colorectal cancer (CRC): Bridging the community and the tertiary cancer center through genomic consultation (GC).
Authors: Kaczmar John M. , Gustafson Karen S. , Wong Yu Ning , Minniti Carl J. , Sandilya Vijay Krishna , Sprandio John David , Chertock Yana , Hart Caitlin , Hall Michael J.
Published: February 2017

538

Background: TGP of cancers is increasingly accessible to oncologists (MDs) and patients (pts). Despite efforts to provide clinical interpretation and decision support within TGP reports, results are complex and their interpretation remains fraught with uncertainty. In an ongoing pilot, we provide community MDs access to a 50-gene next generation sequencing (NGS)-based TGP assay and expert guidance through remote access to genomic tumor board (GTB) resources via telephone-based GC. Our goal is to explore how access to GTB expertise impacts community patterns of care. In parallel, we examine MDs and pts perceptions of TGP with a focus on awareness and expectations. Methods: MDs from 4 community practices participated. Participating MDs and their pts with metastatic unresectable CRC receiving 2nd line or beyond chemotherapy provide informed consent and complete baseline and follow-up surveys. Adequate tumor samples are tested with the Fox Chase 50-gene NGS-based TGP assay. All results are presented at a bi-monthly GTB or are reviewed with the GTB chair. MDs have a ~10 min GC by telephone with the PI to summarize findings and convey GTB recommendations. Results: 9 MDs have enrolled 22 pts and TGP has been completed on 15 samples (4 additional in process and 3 insufficient for TGP). Pts report diverse ancestry (24% Hispanic or non-White) and SES (33% income < $25K). To date, all completed TGPs have reported > 1 mutation. Of 11 pts who have received TGP results, 1 has sought consultation at a tertiary center for a clinical trial. Pts with higher education were more aware of TGP (p = 0.05). Most (80%) pts felt TGP would improve their MD’s ability to treat their cancer. Male sex and higher education were associated with stronger belief that TGP will improve life expectancy. Conclusions: A partnership with community MDs to provide TGP and GTB expertise through GC is feasible. Pts exhibit high expectations of TGP, despite limited data to support improved outcomes from TGP-guided treatment. Further research into optimizing partnership between community MDs and tertiary centers is valuable to guide treatment and clinical trial participation based on TGP results.
Post-treatment surveillance in locally advanced squamous cell carcinoma (SCCA) of the anal canal: A global subspecialist survey.
Authors: Eng Cathy , Adams Richard A. , Kachnic Lisa A. , Das Prajnan , Ernst Randy Devereux , Rodriguez-Bigas Miguel A. , Dupont Elisabeth , Benson Al Bowen ,   on behalf of the International Rare Cancer Initiative (IRCI) Working Group
Published: February 2017

573

Background: Squamous cell carcinoma of the anal canal will be diagnosed in 28,000 individuals globally. Considered a rare cancer, the incidence of anal carcinoma continues to rise annually. Majority of patients present with locally advanced disease in which concurrent chemoradiation (CRT) will be provided with curative intent. The Anal Cancer IRCI Working Group was created to pursue novel approaches to the diagnosis, treatment, and surveillance of patients. Yet, surveillance following completion of CRT is not well established and varies as per NCCN (v2.2015) and ESMO guidelines. Methods: A 22-question survey provided to anonymous international GI subspecialists in various fields. Questions pertained to timing and type of diagnostic imaging, surveillance interval, approach to detection of complete response (CR), and prevention of sexual dysfunction. Results: Survey distribution was initiated in March 2015 and still ongoing. Thus far, 96 physicians responded. Conclusions: Carcinoma of the anal canal continues to rise in incidence annually. Surveillance following completion of CRT is warranted; however, global variability in practice patterns for surveillance exists. As such, the IRCI Anal Cancer Working Group intends to provide an international consensus surveillance statement. [Table: see text]
Emerging transcriptional landscape and putative therapeutic targets in young patients with metastatic colorectal cancer (CRC).
Authors: Lieu Christopher Hanyoung , Pitts Todd M. , Kim Jihye , Tan Aik-Choon , Messersmith Wells A. , You Y. Nancy , Eng Cathy , Eckhardt S. Gail
Published: February 2017

605

Background: Patients younger than 50 yrs of age comprise roughly 10% of the total incidence of CRC, but the incidence in the younger population is increasing. Recent data suggest that younger patients are at higher risk of progression of disease and death from CRC. The purpose of this pilot study was to investigate genomic differences between younger and older CRC tumors to generate hypotheses regarding potential differences in tumor biology that may explain worse outcome in young patients. Methods: To determine genomic differences in tumors from younger and older patients with CRC, a cohort of metastatic microsatellite stable CRC tumors was selected using tumors from 9 younger patients (< 35 yrs) and 7 older patients (> 70 yrs). Total RNA was extracted from tumor tissues and sequenced with Illumina HiSeq 2000. On average, 45 million reads were obtained from individual tumor samples. Sequencing reads were mapped to the reference genome using Bowtie; exon junctions were mapped using TopHat and transcript assembly was performed using Cufflinks. Results: The median ages for the younger and older cohorts were 31 and 73, respectively. From the RNA-seq analysis, gene expression profiles from younger patients were enriched for pathways involved in cell proliferation. Specifically ERBB2, NOTCH3, CAV1 were upregulated in multiple pathways in young patients (p < 0.00001). The expression pattern was noted to be different in older patients with enrichment for CDX2, HMGB3, and EPHB2 within pathways involved in regulation of cell differentiation (p = 0.07). In total 77 genes were noted to be enriched in younger patients compared with older patients and 23 genes were enriched in older patients compared with young patients (FDR < 0.05). These data, although preliminary, may provide support to explore ERBB2, NOTCH, and downstream signaling pathways as therapeutic targets for younger patients. Conclusions: In this pilot study, patients < 35 yrs with metastatic CRC exhibited gene sets enriched for several cellular proliferation pathways, including significant upregulation of ERRB2, NOTCH3, and CAV1. These results are hypothesis generating and are being investigated further in a larger validation cohort.
Micro-RNAs as positive biomarkers of pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal carcinoma.
Authors: Ruiz Garcia Erika B. , Lopez-Rosas Gilberto , Lopez-Camarillo Cesar , Namendys-Silva Silvio , Lino-Silva Leonardo , Lopez-Yañez Alicia , Ortega Alette , Caderillo-Ruiz German , Diaz Dr. Consuelo , Herrera MaryTere , Marchat Laurence , Moreno Jesus Zamora , Sarmiento Itzel Vela , Meneses-Garcia Abelardo , Astudillo Horacio
Published: February 2017

624

Background: Neoadjuvant chemoradiotherapy (nCRT) follow by surgery, as treatment for locally advanced rectal carcinoma (LARC), has improve local disease control, increase of complete pathological response (cPR) and preserve anal sphincter. cPR is associated with better prognosis. CRT act mainly through induction of DNA damage. MicroRNAs (miRNAs) are small non-coding RNAs able to regulate gene expression at post-transcriptional level. miRNAs are involved in the regulation of DNA damage/repair mechanism. Our goal was to measure expression of miRNAs involved in DNA damage/repair genes and correlated with cPR. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 20 Mexican patients with LARC treated with nCRT at National Cancer Institute of Mexico between 2010-2013. Treatment response was evaluated with Ryan Classification. Ten patients had cPR (Ryan Grade 0) meanwhile other 10 poor response (Ryan Grade 3). RNA extraction was done with RNeasy FFPE (Qiagen) Kit. RNA concentration and purity was assessed using NanoDrop 2000 Spectrophotometer. miRNAs expression were evaluated by real-time polymerase chain reaction (PCR) analysis with TaqMan Probes from Applied Biosystems. Statistical analysis was carried out with IBM SPSS Statistics 22.0. Differential expression between the two groups was performed with Chi square test. Results: There wasn’tsignificant difference betweenclinical/demographic features between the 2 groups. All patients received CRT at a total dose of 4500 cGy of pelvic irradiation, concomitantly with fluoropyrimidine. Surgical treatment was performed 14 weeks after completion of nCRT. The 2 miRNAs (188-5p and 590-5p) was overexpressed in the cPR group vs poor response group (p = 0.011 and p = 0.057, respectively). Conclusions: We evaluated the expression of miR590-5p and miR188-5p because they are related to DNA repair genes such as: MSH2, ERCC3, BRCC3 and XRCC5. We found overexpression in both miRNAs. Even though miR590 5p didn't reach statistical significance this maybe because of simple size.Our results now are been analyzed with a biological and functional genes network platform: Ingenuity Pathway Analysis.
Suppressive signals in colorectal cancer: RasGRP1 a new marker for anti-EGFR therapy?
Authors: Roose Jeroen , Depeille Philippe , Warren Robert S.
Published: February 2017

625

Background: Treatment of metastatic colorectal cancer (mCRC) is largely palliative, making potentially curative therapy via molecular inhibition of specific cellular targets in CRC is a highly sought-after goal. One target of considerable focus in both basic and clinical investigation in CRC is the Epidermal Growth Factor Receptor (EGFR). Despite widespread EGFR expression in CRC, clinical trials have shown modest benefit from the use of anti-EGFR blocking antibodies and tumors with activating mutations in KRAS (KRASMUT) do not benefit from EGFR blockade. Given the ubiquitous expression of EGFR in CRC, why does such a large subset of patients fail to benefit from anti-EGFR antibodies? Methods: We combine the analysis of genetic mouse models, CRC cell line, and CRC patient database information and tumor samples. Results: We recently reported that two structurally distinct types of RasGEFs, SOS1 and RasGRP1, are co-expressed in both normal intestinal epithelial cells and in CRC cells. We observed that EGFR signals in CRC cells with KRASMUT result in even more RAS activation, arguing that RasGEFs load more RAS molecules with GTP following EGF stimulation. Indeed, we found that both SOS1 and RasGRP1 are activated downstream of the EGFR. Quite surprisingly, SOS1 and RasGRP1 have opposing functions here. Biochemically, RasGRP1 limits the amount of EGFR-SOS1-RAS signals. Biologically, knockdown of RasGRP1 expression in KRASMUT CRC cells leads to increased tumor growth in a xenograft mouse model. Conclusions: We hypothesize that anti-EGFR therapy may lead to unwanted inhibition of the inhibitory EGFR signals when CRC tumor express significant levels of RasGRP1 protein. We will discuss our current research that focuses on RasGRP1 as a prognostic marker of CRC outcome but also as a diagnostic indicator for EGFR therapy.
Sorafenib and irinotecan combination for pre-treated RAS-mutated metastatic colorectal cancer patients: A multicentre randomized phase II trial (NEXIRI 2).
Authors: Samalin Emmanuelle , De La Fouchardiere Christelle , Thezenas Simon , Boige Valérie , Senellart Hélène , Guimbaud Rosine , Taïeb Julien , Francois Eric , Galais Marie-Pierre , Adenis Antoine , Lievre Astrid , Seitz Jean-François , Metges Jean-Philippe , Bouche Olivier , Fonck Marianne , Di Fiore Frédéric , Artru Pascal , Aparicio Thomas , Mazard Thibault , Ychou Marc
Published: February 2017

635

Background: Sorafenib and irinotecan (NEXIRI regimen) showed promising activity with a disease control rate (DCR) of 65% in heavily pretreated mutated (mt) KRAS metastatic colorectal cancer (mCRC) patients in a phase I/II trial (Samalin et al. 2014).This multicentre randomized phase II trial aimed to determine the 2-month progression-free survival rate (2-PFS) of NEXIRI versus irinotecan or sorafenib monotherapy in mtRAS mCRC patients after failure of all approved active drugs at the time of the study. Methods: Patients PS ≤ 1 with progressive measurable and non-resectable mtKRAS (then RAS) mCRC pre-treated with irinotecan, oxaliplatin, fluoropyrimidines and bevacizumab (none regorafenib), were randomized in 3 arms: NEXIRI (irinotecan IV 120 (C1), 150 (C2) and 180mg/m² (C3) if diarrhea grade < 1 in a biweekly regimen combined with a fixed dose of sorafenib, 400mg twice daily) versus irinotecan alone (180mg/m²) versus sorafenib alone until progression or toxicity, with cross over to NEXIRI at progression for the monotherapy arms. The primary endpoint was the 2-PFS (RECIST v1.1). Pharmacokinetic, pharmacogenetics and pathologic translational studies were undertaken. Results: We included 173 patients (median age 62 [31-82]; PS 0/1: 38/61%) between 2012/09 and 2014/07 in 17 French centres. Main results are shown below (median follow-up 17.5 months). Conclusions: We confirmed the NEXIRI regimen efficacy in a randomized study for refractory mtRAS mCRC patients. These results justify comparing this combination to regorafenib or TAS 102 monotherapies in this population. Ancillary studies are ongoing to identify biomarkers. Clinical trial information: NCT01715441. [Table: see text]
SIRFLOX: Differences in site of first progression between mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 ± bev + selective internal radiation therapy (SIRT) in first-line patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Gibbs Peter , Heinemann Volker , Sharma Navesh K. , Findlay Michael P. N. , Ricke Jens , Peeters Marc , Perez David , Robinson Bridget Anne , Strickland Andrew , Ferguson Tom , Rodriguez Javier , Kroening Hendrik , Wolf Ido , Ganju Vinod , Walpole Euan Thomas , Boucher Eveline , Tichler Thomas E. , Gebski Val , Van Buskirk Mark , Van Hazel Guy A.
Published: February 2017

637

Background: SIRFLOX, an international multi-centre open-label RCT in first-line pts with non-resectable, liver-only or liver-dominant mCRC, showed that compared to FOLFOX (± bev) chemotherapy alone [arm A] FOLFOX (± bev) plus SIRT using Y-90 resin microspheres [arm B] did not improve overall PFS (median 10.2 v 10.7 months arm A v B, HR: 0.93; 95% CI 0.77–1.12; p = 0.429). However, liver PFS by competing risk analysis was improved with the addition of SIRT (median 12.6 v 20.5 months in arm A v B, HR: 0.69; 95% CI 0.55–0.90; p = 0.002). The current analysis examines patterns of disease progression and potential impact on the primary study endpoint. Methods: Site and pattern (intra/extra-hepatic) of first progression, and whether progression was due to growth of existing lesions or the appearance of new lesions, was judged by an independent reader blinded to study arm. Results: From Oct 2006 to Apr 2013, 530 pts were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases at study entry; 292 (55%) were stratified to receive bev. As of 31 Jan 2015, the total number of patients with disease progression in arm A v B were 178 and 166, respectively. The site of first progression was more frequently in the liver (± other sites) in arm A v B (92.1% v 72.3%; p < 0.001). Conversely, site of first progression was less frequent in the lung (± other sites) in arm A v B (19.1% v 42.8%; p < 0.001). A higher proportion of first progression occurred in the liver alone in arm A v B (77.0% v 52.4%; p < 0.001). Conversely, a lower proportion of first progression occurred only in non-liver sites, primarily lung, in arm A v B (7.9% v 47.7%; p < 0.001). Of patients with first progression in the liver, a higher proportion occurred in existing liver lesions (± extrahepatic sites) in arm A v B (72.5% v48.2%; p < 0.001). Conclusions: The addition of SIRT to FOLFOX chemotherapy alone (± bev) reduced the frequency at which first disease progression occurred in the liver. Where first progression did occur in the liver, the addition of SIRT led to this more frequently being due to the appearance of lesions not evident on baseline imaging. Clinical trial information: NCT00724503.
TAS-102 versus placebo (PBO) in patients (pts) ≥65 years (y) with metastatic colorectal cancer (mCRC): An age-based analysis of the recourse trial.
Authors: Van Cutsem Eric , Benedetti Fabio M. , Mizuguchi Hirokazu , Mayer Robert J. , Falcone Alfredo , Garcia-Carbonero Rocio , Tabernero Josep , Sobrero Alberto F. , Peeters Marc , Zaniboni Alberto , Yoshino Takayuki , Shimada Yasuhiro , Yamazaki Kentaro , Komatsu Yoshito , Hochster Howard S. , Lenz Heinz-Josef , Tran Ben , Ohtsu Atsushi ,   on behalf of the RECOURSE Study Group
Published: February 2017

638

Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5 (weight ratio, 1:0.471). Efficacy and safety of TAS-102 in pts with mCRC refractory to standard therapies were evaluated in the RECOURSE trial; enrollment criteria included ≥2 prior lines of standard chemotherapy. Primary results of RECOURSE demonstrated a significant improvement in overall survival (OS) (TAS-102 7.1 mo vs PBO 5.3 mo; HR=0.68; P<0.0001) and progression-free survival (PFS) (HR=0.48; P<0.0001). Methods: This prespecified analysis compared the efficacy and safety of TAS-102 vs PBO in pts ≥65 y and <65 y with mCRC. A retrospective analysis of pts ≥75 y was also performed. Results: Of 800 randomized pts, 352 (44.0%) were ≥65 y and 60 (7.5%) were ≥75 y. Median OS in pts ≥65 y was 7.0 mo with TAS-102 vs 4.6 mo with PBO (HR=0.62, 95% CI: 0.48-0.80, P=0.0002). PFS HR was 0.41 (95% CI: 0.32-0.52, P<0.0001) for pts ≥65 y, also favoring TAS-102. In pts ≥65 y, disease control rate (complete or partial response or stable disease) was 48.7% with TAS-102 vs 15.5% with PBO. An age-related difference in overall incidence of adverse events (AEs) was not observed in either treatment arm. Treatment-related AEs, ≥ Grade 3 AEs, and severe AEs were generally more common in pts ≥65 y than in pts <65 y (Table). Mean drug exposure was similar among pts ≥65 y and ≥75 y, as was overall safety profile. Conclusions: Significant improvements in OS and PFS were observed in pts ≥65 y who received TAS-102 vs PBO, with a mild increase in toxicity. Pts ≥65 y and <65 y showed a generally favorable safety profile. A significant increase in toxicity in pts ≥75 y was not apparent vs the overall ≥65 y population. Clinical trial information: NCT01607957. [Table: see text]
An open label, randomized phase III trial evaluating the treatment (tx) effects of panitumumab (pmab) + best supportive care (BSC) versus BSC in chemorefractory wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and in WT RAS mCRC.
Authors: Kim Tae Won , Elme Anneli , Kusic Zvonko , Park Joon Oh , Udrea Anghel Adrian , Kim Sun Young , Ahn Joong Bae , Villalobos Valencia Ricardo , Srinivasan Krishnan , Bilic Ante , Manojlovic Nebojsa , Dong Jun , Guan Xuesong , Lofton-Day Catherine , Jung A. Scott , Vrdoljak Eduard
Published: February 2017

642

Background: An overall survival (OS) benefit in WT KRAS exon 2 mCRC was not seen with pmab monotherapy in study 20020408 possibly due to crossover of patients (pts) in the BSC arm. Retrospective analyses have indicated that other KRAS and NRAS mutations beyond KRAS exon 2 are predictive of anti-EGFR tx effects. Study 20100007 assesses the OS benefit of pmab in chemorefractory WT KRAS exon 2 mCRC and is the first phase 3 trial to prospectively evaluate pmab tx effects in WT RAS (exons 2, 3, and 4 of KRAS and NRAS) mCRC. Methods: Anti-EGFR naive pts were randomized 1:1 to receive pmab (6 mg/kg Q2W) + BSC or BSC. KRAS exon 2 and RAS mutation status of tumors were determined centrally. The primary endpoint was OS in WT KRAS exon 2 mCRC. Secondary endpoints were OS in WT RAS mCRC and progression-free survival (PFS), objective response rate (ORR), and safety in both WT KRAS exon 2 and WT RAS groups. Crossover was not permitted. Results: 377 pts with WT KRAS exon 2 mCRC were enrolled. RAS ascertainment rate was 86%. OS was significantly improved with pmab + BSC vs BSC in both WT KRAS exon 2 (HR=0.73, 95% CI=0.57-0.93, P=0.0096) and WT RAS (HR=0.70, 95% CI=0.53-0.93, P=0.0135) mCRC (results in table). Pts with mutant RAS mCRC did not benefit from pmab tx (OS HR=0.99, 95% CI=0.49-2.00). No new safety signals were seen. Conclusions: Pmabsignificantly improved OS in chemorefractory WT KRAS exon 2 mCRC. The tx effects in OS and PFS were more pronounced in those with WT RAS mCRC, further substantiating the importance of RAS testing at diagnosis to best inform the use of pmab to treat mCRC. Clinical trial information: NCT01412957. [Table: see text]
TOPO1 expression in primary and metastatic GI cancers.
Authors: Castro Michael , Feldman Rebecca , Reddy Sandeep K.
Published: February 2017

643

Background: Irinotecan failed in Stage III colon cancer, but succeeds in Stage IV, to prolong survival. We propose that TOPO1 over-expression is a phenomenon of metastatic disease, and perhaps part of the epithelial-mesenchymal-transition (EMT) associated with metastatic phenotypes. Methods: 5029 colorectal (CRC), 3016 pancreatic, 848 gastric and 309 small bowel adenocarcinoma (SBA) patients were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). A threshold of ≥ 2+ and ≥ 30% (intensity and percent staining) and TOPO1 (1D6) clone was utilized. TOPO1 was examined in primary and metastatic specimens. Two-tailed Fisher’s exact test was performed to test where proportions of positive results were different by subgroup (p ≤ 0.05). Results: See table below. Conclusions: The EMT associated with the transition from primary to invasive metastatic disease appears to include upregulation of TOPO1, in some GI cancers, including CRC, pancreatic and gastric cancer. The paradoxical failure of adjuvant irinotecan in stage III, the epithelial phase of the cancer, may be due to a smaller fraction of patient's whose cancers express this biomarker of response in that setting. A re-examination of irinotecan makes sense for a portion of stage III patients whose cancer expresses high levels of TOPO1 in the primary lesion. The recent superiority with regard to response rate and survival or FOLFOXIRI over FOLFOX alone in the stage IV setting raises renewed interest in whether patients with non-metastatic disease could derive a superior cure rate if suitably selected for FOLFOXIRI with a biomarker approach. At the same time, a large number of patients fail to express TOPO1 in the metastatic setting and perhaps should be spared irinotecan-based approaches including the use of FOLFOXIRI. [Table: see text]
Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity.
Authors: Ma Wen Wee , Saif Wasif M. , El-Rayes Bassel F. , Fakih Marwan , Cartwright Thomas H. , Posey James , von Borstel Reid , Bamat Michael K.
Published: February 2017

655

Background: Life-threatening or lethal 5-FU toxicity occurs due to infusion pump/reservoir errors and 5-FU dosage miscalculations. Additionally, DPD-deficient patients often experience serious or lethal toxicity. Regardless of DPD status, some patients demonstrate severe, early-onset toxicities (as early as during 5-FU infusion) such as encephalopathy or cardiotoxicity. Uridine triacetate is an orally bioavailable prodrug of uridine, a direct antagonist of 5-FU, that competitively inhibits 5-FU incorporation in normal tissues and can counter 5-FU toxicity, reducing morbidity and mortality due to toxicity. Methods: 135 patients at excess risk of 5-FU toxicity due to overdose or accidental capecitabine ingestion (n = 111); or DPD deficiency and/or who showed rapid onset of severe toxicities (n = 24) have been treated with uridine triacetate under emergency IND or expanded access protocols. Patients were to receive uridine triacetate granules (10g q6h for 20 doses) up to 96h after the termination of 5-FU therapy. Clinical endpoints included survival compared with historical controls, time to resumption of chemotherapy, and safety. Results: A total of 130/135 (96%) patients treated with uridine triacetate recovered fully (within 30 days after receiving uridine triacetate), including rapid reversal of cardiotoxicity (EKG abnormalities, chest pain, etc) and neurotoxicity (altered mental status, ataxia, etc). Of the 111 overdose patients, 24 had a pump malfunction; 49 dose error; 5 had accidental capecitabine ingestion (2 adults/3 peds); 33 unknown. No patient who received uridine triacetate within 96 h after stopping 5-FU died. Comparatively, 38 of the 47 historical controls (81%) with 5-FU overexposure died. Of the 106 overdose patients with a diagnosis of cancer, 40 (37.7%) resumed chemotherapy within 30 days (median 20.0 days post-5-FU), highly indicative of rapid recovery from toxicity. Overall compliance was 92.5% (mean 18.3/20 doses). Mild, infrequent adverse events (diarrhea/nausea/vomiting) were attributed to uridine triacetate. Conclusions: In this study, uridine triacetate was a safe and effective life-saving antidote for 5-FU overexposure, and facilitated rapid resumption of chemotherapy. Clinical trial information: NCT01432301.
Oncologic outcome of lateral pelvic lymph node metastasis in locally advanced rectal cancer.
Authors: Kim HyungJin , Kim Gun , Yoo Ri Na , Kye Bong-Hyeon , Cho Hyeon-Min
Published: February 2017

661

Background: Lateral pelvic lymph node (LPLN) metastasis is a major cause of recurrence in patients with rectal cancer. This study investigates the oncologic outcome based on LPLN status after neoadjuvant chemoradiotherapy (nCRT). Methods: Between January 2009 and February 2013, 141 patients with rectal cancer received nCRT followed by curative radical surgery in our hospital. 16 patients were identified with LPLN before nCRT. These patients were categorized to two groups according to nCRT response evidenced by post-nCRT imaging studies with 5mm criteria. Group 1 included 7 patients who showed disappearance of LPLN after nCRT. Group 2 consisted of the patients identified with LPLN after nCRT. Results: The mean follow-up period was 35.6 ± 12.8 months. The mean overall survival (OS) period and 3-year OS rate for the patient with LPLN before nCRT was 56.0 ± 2.6 months and 93.3%, respectively. The mean relapse free survival period and 3-year RFS rate for the patient with LPLN before nCRT was 32.6 ± 5.7 months and 47.1%, respectively. The risk factors associated with RFS were ypN stage (P = 0.031), tumor location (P = 0.002), and postoperative CEA level (P = 0.022). Comparing RFS between Group 1 and 2, Group 1 tended to demonstrate longer RFS (P = 0.058). Analyzing oncologic outcome of two groups compared to the cohort population, group 1 showed similar oncologic outcome with ypTNM stage II. Group 2 demonstrated a tendency of worse oncologic outcome than ypTNM stage III (Group 1 vs. ypII P = 0.761 and Group 2 vs. ypIII P = 0.135). Conclusions: Preoperative LPLN status after nCRT seems to influence oncologic outcome in rectal cancer patient. If patients with LPLN metastasis before nCRT exhibit persistent LPLN metastasis after nCRT, they may require additional treatment.
Resection of non-regional lymph node metastasis in patients with colorectal cancer.
Authors: Bailey Christina Edwards , Idrees Kamran , Parikh Alexander A.
Published: February 2017

664

Background: Approximately 20% of patients with colorectal cancer (CRC) present with metastatic disease-most commonly to the liver or lungs. Successful resection of these metastatic foci leads to significant long-term survival. Less commonly, patients present with isolated metastasis to non-regional lymph nodes (NRLN) and little is known regarding the role of resection in these patients. The primary aim of this study is to evaluate the outcomes of patients with CRC who undergo resection of NRLN metastasis. Methods: A retrospective cohort study of patients diagnosed with CRC and NRLN metastasis was performed using the Surveillance, Epidemiology, and End Results database (2004-2012). Demographic and clinical factors were compared for patients who underwent resection of NRLN metastasis and those who had not. Kaplan-Meier and log-rank analysis was used for survival analysis. Logistic regression analysis was used to assess factors associated with resection of NRLN metastasis. Results: A total of 22,848 patients presented with metastatic CRC and underwent primary tumor resection. Of these, 786 (3.4%) presented with isolated NRLN metastasis and 78 (9.9%) underwent NRLN resection. Patients who underwent resection were more likely to be male, have rectal cancers, and poorly or undifferentiated grade tumors. Median overall survival (OS) was significantly improved for patients who underwent resection compared to those who did not (36 vs. 28 months, p = 0.036). In patients with colon cancer (N = 602), median OS was 33 vs. 21 months (p = 0.042) for those who underwent resection compared to those who did not, whereas in patients with rectal cancer (N = 184), the median OS was 45 vs. 38 months (p = 0.977), respectively. In multivariate analysis, rectal cancer (OR 1.84, 95% CI 1.08 to 3.13) and poorly or undifferentiated grade tumors (OR 1.64, 95% CI 1.01 to 2.66) were associated with increased resection of NRLN. Conclusions: Resection of NRLN metastasis in patients with CRC is associated with an overall survival benefit, particularly among patients with colon cancer. Further studies are needed to identify which specific patient subgroups would best benefit from this resection strategy.
Characterization of a novel regulator of AKT/mTOR signaling in gastric cancer.
Authors: Singh Shikha Satendra
Published: February 2017

68

Background: Gastric cancer (GC) is a leading cause of cancer-related death with poor prognosis and “one-size fits all approach”. Dysregulation of PI3K/Akt/mTOR pathway is a common event in GC with PIK3CAmutations reported to correlate with poor prognosis. With prognosis far from satisfactory, we aimed to identify novel surrogate biomarkers. We hypothesize the role of DP103, a DEAD-box RNA helicase, as a novel surrogate biomarker for GC by regulating the PI3K/Akt/mTOR pathway. Additionally, we shed light on high DP103 GC cells responding to Akt/mTOR dual inhibitor treatment, indicating its potential role as a surrogate biomarker for GC treatment. Methods: Tissue microarray data from GC cohorts were used in correlation analysis between DP103 and PIK3CA expression. Effect of DP103 knockdown was assessed on functions downstream of PI3K/Akt/mTOR pathway including apoptosis, autophagy and cell invasion. Next, DP103 depletion studies were done and PI3K/Akt/mTOR pathway proteins were assessed. Further, immunoprecipitation studies assessed for DP103 interacting partners from PI3K/Akt/mTOR pathway in GC. Results: Herein, we provide clinical evidence of DP103 upregulation in GC patients’ tissues compared to normal gastric tissues. Additionally, we showed a positive correlation between DP103 and PIK3CA expression in GC patients’. DP103 knockdown resulted in decrease in cell invasion and an increase in apoptosis and autophagy. Further, decrease in phosphorylation of PI3K/Akt/mTOR pathway proteins was observed with DP103 depletion. Mechanistically, we discovered a novel physical interaction between DP103 and PI3K in GC. Conclusions: Here we summarized, current understanding of DP103 regulating PI3K/Akt/mTOR pathway in GC and discuss potential use as a new surrogate biomarker for better clinical application.
Quality of life (QoL) and therapy management in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI and aflibercept in Germany, Switzerland, and Austria (GSA): Interim results of the noninterventional QoLiTrap-study.
Authors: Hofheinz Ralf , Thaler Josef , Von Moos Roger
Published: February 2017

681

Background: QoLiTrap (AIO-LQ-0113) is a non-interventional study to assess the QoL and clinical outcomes of mCRC patients treated with Aflibercept and Folfiri in Germany, Austria and Switzerland. This interim analysis shows the first results of the study. Methods: QoL is assessed by EORTC-QLQ C30 questionnaires that are filled in by the patients at baseline and before every therapy cycle. Clinical data (overall survival, progression-free survival (PFS), response to treatment, therapeutic sequences) are reported by participating physicians. Results: The first 277 patients who completed at least baseline and 2 additional EORTC questionnaires were included in this analysis. Median cycle number at the time of analysis was 6 (including patients still on therapy). Therapeutic sequences comprised treatment with Bevacizumab (B) (48%), anti-EGFR (13%), both (13%) or no biological (14%) before Aflibercept (A) (n.d.: 12%). Median PFS was similar in B (PFS: 6.6 months, CI[5.4;8.9]) and anti-EGFR (PFS: 7 months, CI[4.7,12.1]) pre-treated patients. Complete or partial remission was observed in 22%, Stable Disease in 52% and Progressive Disease in 26% of all patients with evaluated response (n=144). Main grade 3-5 adverse events were hypertension (15.9%) and diarrhea (6%). Only minor changes in EORTC global health score were observed from baseline (57.50; sd: 20.39; n=277) to cycle 6 (52.27; sd: 20.6; n=114). Conclusions: In clinical practice A is used in various therapeutic sequences in GSA. This interim analysis provides encouraging results with a tumor control rate of 74% in patients with response documentation and similar median PFS values for B and anti-EGFR pretreated patients. The decline in global health status was moderate. No unexpected safety signals were observed. This study is supported by Sanofi. Clinical trial information: AIO-LQ-0113.
Bevacizumab effectiveness and primary tumor location in metastatic colorectal cancer patients.
Authors: He Wen-zhuo , Yang Qiong , Jiang Chang , Liao Fang-xin , Liu Shou-sheng , Xia Liang-ping
Published: February 2017

683

Background: There is currently no consensus about whether bevacizumab effectiveness is associated with the primary tumor location of metastatic colorectal cancer (mCRC). The aim of this study was to assess whether the primary tumor location was a predictor for bevacizumab treatment. Methods: From 2004 to 2013, 740 patients with mCRC treated with oxaliplatin / 5-FU / leucovorin (mFOLFOX6) or irinotecan / 5-FU / leucovorin (FOLFIRI) (CT group) and 244 patients treated with bevacizumab plus mFOLFOX6 or FOLFIRI (CT + B group) as first-line setting were included from Sun yat-sen university cancer center. Right-side colon cancers included those occurring in the cecum, ascending colon or transverse colon. Left-side colon cancers included those from descending or sigmoid colon. The primary outcome was overall survival (OS). Kaplan-Meier curves with log-rank tests were used to detect difference. All statistical tests were two sided. Results: 222 right-side colon, 259 left-side colon and 259 rectal cancer patients were included in CT group while 78 right-side colon, 86 left-side colon and 80 rectal cancer patients were included in CT + B group. Patients in CT + B group had similar OS compare with CT group only when the primary tumor located at right-side colon (median OS was 19.6 months for CT + B group versus 19.5 months for CT group, P = 0.269). For left-side colon cancer, significantly longer OS were observed in CT + B than CT group (22.3 months versus 21.9 months, P = 0.014). For rectal cancer patients, those in CT + B group also had longer OS than CT group (25.9 months versus 21.1 months, P = 0.005). Conclusions: Our data suggested that patients with right-side colon cancer could not get survival benefit from the addition of bevacizumab to first-line chemotherapy. Further data from randomized trials are needed to test our hypothesis. [Table: see text]