bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors for lymph node metastasis in submucosally invasive colorectal cancer.
Authors: Huang Liyong , Li Xinxiang , Cai Sanjun 
Published: February 2017

542 Background: The aim of this study was to identify risk factors for lymph node metastasis (LNM) in submucosally invasive colorectal cancer (SICC) that might be used in selecting patients for local excision. Methods: Records were reviewed from consecutive patients who had undergone curative resection of SICC at the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China, between 2006 and 2013. Clinical features such as age, gender, tumor size, and location were reviewed. Histopathologic examinations including tumor growth type, growth pattern at the invasive front, histopathological type, depth of tumor invasion, tumor budding, lymphovascular invasion, and neural invasion were performed. The expression of E-cadherin, p53, and Ki-67 were examined by immunohistochemistry. The association between the clinicopathologic factors and LNM was evaluated. Results: A total of 265 patients (140 men and 125 women) treated for SICC were included. The overall LNM rate was 12.8%. The incidence of LNM was significantly associated with growth pattern at the invasive front (p=0.028), tumor budding (p=0.006), histopathological type (p<0.001), and lymphovascular invasion (p<0.001). Other clinicopathologic and immunohistochemical factors were irrelevant to LNM. In multiple variable logistic analysis, histopathological type, and lymphovascular invasion were the two independent risk factors of LNM (p=0.015 and p=0.007, respectively). Conclusions: Histopathological type and lymphovascular invasion are significant independent risk factors for LNM in SICC. Careful selection for local excision in SICC should be considered.
Preoperative Chitinase 3-like-1, Galectin-3, and Activin Aplasma levels: A novel diagnostic panel for colorectal cancer.
Authors: Shantha Kumara Hmc , Miyagaki Hiromichi , Herath Sajith A , Gaita David , Yan Xiaohong , Njoh Linda , Cekic Vesna , Gandhi Nipa Dilip , Whelan Richard L 
Published: February 2017

546 Background: Colorectal cancers (CRC) expressChitinase 3-Like-1(Chi3L1), Galectin-3 (Gal-3) and Activin A (Act-A). Chi3L1, indirectly, via IL8 and MCP-1, promotes tumor angiogenesis and progression. Gal-3 promotes tumor cell invasion and angiogenesis while Act-A supports cancer cell migration. This study’s goal was to assess the diagnostic value of plasma levels of Chi3L1, Gal-3 and Act-A, alone or together, for CRC. Methods: PreOp plasma samples were obtained from consenting CRC and benign pathology (BP) patients (pts) undergoing elective resection (IRB approved tissue bank). Plasma levels of Chi3L1, Gal-3 (ng/ml), and Act-A (pg/ml) were determined via ELISA and reported as median + 95% CI. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the CRC diagnostic value of single and multiple plasma protein levels. The Mann-Whitney test was used for statistical analysis (significance p<0.05). Results: A total of 118 CRC (81% colon, 19% rectal) and 42 BP pts (adenoma 31%, diverticulitis 53%, other 16%) were studied. The CRC median plasma protein levels were significantly higher vs. the BP group results [Chi3L1: 120.1, CI: 95.0, 146.6 vs. 36.8, CI; 29.3, 44.4; Gal-3: 12.0, CI: 10.5, 13.3 vs. 7.7, CI: 7.2, 9.9; Act-A: 368.0 CI: 341.0, 421.6 vs. 272.1, CI: 196.0, 327.3 [p<0.001 for all]). The AUC value for the ROC curve for Chi3L1, Gal-3 and Act-A were 0.850, 0.724 and 0.734 respectively with 76%, 52% and 38% specificity. The AUC for the combination of these 3 proteins was 0.890 with 88% specificity. Conclusions: Themedian Chi3L1, Gal-3 and Act-1 values in CRC pts were significantly higher (226%, 55% and 35%) then BP levels. The 3 protein combination had improved AUC and specificity vs single protein results and may have value as a diagnostic panel. A larger study is needed.
Nightly dosing of regorafenib.
Authors: DeSimone Philip A. , Overley Colleen , Long Katie E 
Published: February 2017

549 Background: Fatigue and anorexia are major side effects in the use of regorafenib. These effects are compounded in patients with metastatic colon cancer to the liver. Finding a good fit for this agent has been difficult in patients when used in third and fourth line treatments. Our clinic has treated 21 patients with this agent. Methods: After the first four patients’s experienced extreme fatigue and anorexia at the recommended starting dose of 160mg daily, it was decided to start at a 21 day dose of 120mg. Even at this starting dose, it was necessary to dose deescalate. Ten patients were treated at the 120 mg daily dose and escalated 160 mg daily if tolerated. The agent was given at night to take advantage of the sleep period and the diurnal variation in adrenal gland function. No patient was treated with oral corticosteroids. Results: Two patients previously treated and responders were retreated after they decided they would give the agent a second opportunity. One of these patients, on day two of receiving the agent, developed a severe rash and the treatment was stopped. One patient received the agent for one week before he decided to stop, but was experiencing no side effects. Eight patients were eligible for evaluation. All patients had metastatic disease to the liver. Six were treated for at least two months and two were treated only for one month. All therapy was discontinued because of progression of disease. Fatigue and anorexia were evaluated by a change in their ECOG performance status, fatigue criteria and weight change. ECOG performance status of the patients was, ECOG 1, one patient, ECOG 2, six patients, ECOG 3, one patient. The evaluation was done before, during and after each monthly treatment. No patient had a greater than 5% weight loss. Four patients had Grade 1 fatigue, (fatigue relieved by resting). Six of the eight patients were escalated to 160mg daily after two weeks. Conclusions: Although this is a small sample study, it appears that night time dosing may be effective in helping a patient to achieve maximum benefit of regorafenib therapy. This study did not address the changes in absorption caused by a light fat free meal taken at night, and does not take into consideration the possible change in half-life of the agent when taken at night.
Therapeutic dual inhibition of HER2 pathway for metastatic colorectal cancer (mCRC): The HERACLES trial.
Authors: Siena Salvatore , Sartore-Bianchi Andrea , Trusolino Livio , Martino Cosimo , Bencardino Katia , Lonardi Sara , Leone Francesco , Zagonel Vittorina , Bertotti Andrea , Valtorta Emanuele , Siravegna Giulia , Amatu Alessio , Vanzulli Angelo , Regge Daniele , Ghezzi Silvia , Ciardiello Fortunato , Veronese Silvio , Comoglio Paolo Maria , Bardelli Alberto , Marsoni Silvia 
Published: February 2017

565 Background: HER2 amplification in mCRC associates with resistance to anti-EGFR moAbs and, based on studies in patient-derived xenografts (Bertotti et al, Cancer Discov 2011), predicts response to combined therapy with anti-HER2 moAbs and lapatinib (L). Accordingly, we conducted an independent proof-of-concept phase II study of trastuzumab (T) and L in HER2+ mCRC after failure of standard therapies (HERACLES Trial - EudraCT 2012-002128-33). Methods: mCRC patients (pts) progressing after fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab were eligible if tumors were HER2+ [IHC 3+ or 2+ and FISH positive (HER2:CEP17 >2) in >50% cells]. L was given po daily and T iv weekly at standard doses. Tumor response was assessed every 8 weeks. The primary end-point was objective response (OR, RECIST v1.1). To consider the study positive 6/27 ORs had to be observed (α=0.05; β=85%; H1=30%). Serial liquid biopsies for ctDNA (ddPCR), and HER2 ectodomain (ECD) plasma levels (ELISA) were collected until progression. Results: We screened 646 pts with KRAS exon 2 WT mCRC and found 28 (4.3%) HER2+; 18 (2.8%) were fully eligible and evaluable for response as of September 10, 2014. Pts had a median of 5 (r=3-8) prior therapies, median age 61 (r=41-86), ECOG PS ≤1, 2F/16M. Primary endpoint was met with 6/18 ORs (1 CR, 4 PR, 1 PRunc; ORR=33.3%, 95% CI 0.16-0.56). Stable disease (SD) lasting > 4 mos. was obtained in four further pts. Five of six ORs and the longest SD (10 mos.) were observed in pts with HER2 gene copy number variations (CNVs) ≥20 copies. Treatment was well tolerated with toxicities limited to grade 2 diarrhea, fatigue, and skin toxicities (one grade 3). HER2 CNV in ctDNA decreased in 2/3 ORs and 0/2 non responders. HER2 ECD plasma levels also decreased in 2/2 ORs but not in 6/6 pts with SD or progression. Exome analysis of index cases will be presented. Conclusions: As predicted by HER2+ mCRC xenografts, the combination of T and L was remarkably active in standard therapy refractory mCRCs with HER2 amplification. HERACLES represents the first precision medicine trial with positive results in mCRC. HERACLES is funded by Associazione Italiana Ricerca Cancro. Clinical trial information: 2012-002128-33.
Differences between colon cancer primaries and metastases utilizing a molecular assay for tumor radiosensitivity and implications for potential oligometastatic SBRT patient selection.
Authors: Ahmed Kamran A. , Fulp William J. , Berglund Anders E. , Hoffe Sarah E. , Dilling Thomas J. , Eschrich Steven A. , Shridhar Ravi , Torres-Roca Javier 
Published: February 2017

569 Background: We have previously identified a multigene expression model of tumor radiosensitivity with validation in four independent cohorts (breast, rectal, esophageal, and head and neck). This model predicts a radiosensitivity index (RSI) that is directly proportional to tumor radioresistance, (RSI, high index = radioresistance). The purpose of this study was to assess differences in RSI between primary colon cancer and metastases. Methods: Patients were identified from our institutional IRB-approved prospective observational protocol. A total of 704 metastatic and 1,362 primary lesions were obtained from a de-identified meta-data pool. Gene expression was obtained from Affymetrix Hu-RSTA-2a520709 microarrays. RSI was calculated using the previously published ranked based algorithm. An independent cohort of 38 lung and liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiotherapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors compared with 54% of primaries were in the RSI-radioresistant (RSI-RR) peak, suggesting that metastatic tumors may be slightly more radioresistant than primaries (p=0.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radioresistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31), p<0.0001. These findings were confirmed when the analysis was restricted to lesions from the same patient (n=69). In our independent cohort of lung and liver metastases, lung metastases had an improved outcome over patients with liver metastases (2 yr local control, lung vs. liver metastases; 100% vs. 74.0%, p=0.027). Conclusions: Assessment of radiosensitivity between primary and metastatic tissues of colon cancer histology, reveals significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.
Cetuximab-induced skin rash: A molecular map relating polymorphisms, cell-adhesion, and autoimmunity.
Authors: Schaaf Sebastian , Froelich Matthias , Kirchner Thomas , Heinemann Volker , Jung Andreas , Stintzing Sebastian , Mansmann Ulrich Robert 
Published: February 2017

570 Background: Colorectal cancer (CRC) treatment with the EGFR-inhibitory antibody Cetuximab (CTX) is known to cause skin rashes (SR) of varying degree in most patients. Severity of SR is positively associated with tumor response. The underlying molecular mechanism linking both effects is still unknown. Detangling its genetic background would allow a simultaneous understanding of SR and response. Stratification of patients based on the related polymorphisms (PMs) is of clinical relevance. Methods: A systematic literature review was performed to develop a molecular map which incorporates specific pathways related to cancer, CTX specific mechanisms of action, skin rash, and autoimmunity. Exome data was generated from blood samples of 23 KRAS wild type patients taken prior to CTX treatment. Under CTX, eleven of the 23 patients showed SR of grades 3-4, twelve reacted with a grade 1 SR. Differential somatic PMs were analyzed between both groups. A gene set enrichment analysis for the imbalanced PMs was performed against gene sets of our molecular map. Imbalance was stated if at least seven patients more in the one group compared to the other carried this specific PM. Results: A total of 591 genes containing imbalanced PMs were found. Bioinformatic validation focused on the following findings of potential clinical interest: (1) PMs in genes specifically related to cell adhesion (CDH1, LAMC1, FBN2, NCAM1) or its regulation (WNT9B), (2) to autoimmunity (CXCL16, ADAM12, OS9, DOCK2), (3) in the central regulator TP53, (4) in genes playing a role in immunity and cell adhesion (DOCK2 and THBS2). PMs in the mentioned genes enabled to discriminate patients with and without severe skin rash. Validation of these findings is needed based on new independent CTX treated patients. Conclusions: Our findings suggest that genomic predisposition may exist which interact with CTX treatment by inducing alteration of cell adhesion. Altering adhesion between tumor cells makes them more accessible to the EGFR-inhibitory effect of CTX. Altering cell adhesion between epithelial cells introduces the acne like phenotypes of skin rash, presumably via the mechanism of epithelial activation. This will be the starting point for further research.
Multiple independent methods fail to confirm MET amplification rate reported in literature for metastatic colorectal cancer (mCRC).
Authors: Raghav Kanwal Pratap Singh , Tang Chad , Morelli M. Pia , Amin Hesham M. , Chen Ken , Manyam Ganiraju C. , Broom Bradley McIntosh , Talasaz AmirAli , Overman Michael J. , Shaw Kenna Rael , Meric-Bernstam Funda , Maru Dipen M. , Eng Cathy , Hong David S. , Kopetz Scott 
Published: February 2017

572 Background: MET inhibition is emerging as a potent therapeutic strategy and MET gene amplification has shown predictive significance. MET amplification rate in mCRC, as previously reported in literature, varies from 9% in primary to 18% in metastases but intermixes increased copy number from chromosomal level aberrations with focal gene amplification. Validation of MET amplification rate in mCRC is needed. Methods: We performed analyses of MET amplification in mCRC patients (pts) (n = 636) across multiple cohorts. Cohort 1 (n = 103) included tissue microarray from liver metastases analysed using fluorescence in situ hybridization (FISH) [cMET and CEP7 probes, MET/CEP7 ratio > 2]. Cohort 2 (n = 205) included pts referred for phase I trials who had MET amplification testing using FISH. Cohort 3 (n = 279) included cases sequenced with HiSeq (Illumina) with full exome coverage for 202 genes including MET (average depth 800) with focal gene amplification (≥ 4 copies) identified by an in-house algorithm. Cohort 4 (n = 49) included pts refractory to EGFR monoclonal antibodies enrolled in the ATTACC (a prospective molecular screening) program for mCRC, in whom plasma circulating-free DNA (cfDNA) was analyzed by Guardant sequencing technology. Results: In tissue based analyses, focal MET amplification rate was 1.7% and was higher in primary tumors compared to metastases [3.1% (9/291) vs. 0.4% (1/288), p = 0.02] [Table]. In cohorts 2 & 3 MET amplification was found in 4 [MET/CEP7: 2.1 – 7.7; primary (4/130), metastases (0/75)] and 6 [copy number: 4.0 – 6.7; primary (5/161), metastases (1/110)] cases, respectively. MET amplification rate in pts who had progressed on anti-EGFR therapy was 14.3% (Table). Conclusions: Contrary to prior reports, in this large cohort, MET amplification was a rare event in mCRC pts and the rate was not higher in metastatic sites. However, MET amplification occurred in a sizable subset of pts refractory to anti-EGFR therapy as identified by cfDNA analysis. MET amplification appears to play a minor role in de novo colorectal carcinogenesis but may play an important role in acquired resistance to anti-EGFR therapy. [Table: see text]
Efficacy of Goshajinkigan for prophylaxis against oxaliplatin-induced peripheral neuropathy.
Authors: Kono Toru , Suzuki Yasuyuki , Mizuno Keita , Miyagi Chika , Omiya Yuji , Sekine Hitomi , Mizuhara Yasuharu , Miyano Kanako , Kase Yoshio , Uezono Yasuhito 
Published: February 2017

576 Background: Oxaliplatin-induced peripheral neuropathy (OPN) is often observed and is the most frequent dose-limiting toxicity. However, there is no effective therapeutic option for preventing OPN. Goshajinkigan (GJG), a traditional Japanese herbal medicine, has widely been used for disease-assessed neuropathy in Japan. Recently, the preventive effect of GJG against OPN in a placebo-controlled double-blind randomized phase II study was reported (Kono T et al., Cancer Chemother Pharmacol. 2013, 72,1283-90). However, the precise mechanisms underlying preventive effect of GJG are unknown. Methods: To be established the OPN rat model, oxaliplatin (4 mg/kg) was injected intraperitoneally twice weekly for 8 weeks in rats. Animals were treated with oral administration of GJG (0.3, 1.0 g/kg) five times a week for 8 weeks. We performed behavioral tests (acetone test and hot plate test) and pathological examination of neuronal tissue using the OPN rat model. We carried out pharmacokinetic study of GJG and searched for active ingredients in GJG in order to explore the mechanism of GJG. Results: The rats injected with oxaliplatin for a long-term showed both cold hypersensitivity and heat hyposensitivity. Co-administration of GJG ameliorated OPN in the rat. In light and electron microscopic study, scattered axonal damages in sciatic nerve of oxaliplatin groups were observed, which were substantially suppressed by GJG. Pharmacokinetic study revealed that considerable neuroprotective and analgesic ingredients were detected after oral administration of GJG in rat plasma. Some ingredients in GJG significantly suppressed oxidative stress caused by oxaliplatin in the experiment using neuronal cells. Conclusions: Oxaliplatin-induced chronic neuropathy symptoms are similar to human symptoms caused by long-term oxaliplatin administration. Oral administration of GJG in rat substantially diminished OPN, and promises to provide an effective and convenient treatment at risk of developing peripheral neuropathy in oxaliplatin-treated patients.
Molecularly-guided therapeutic options beyond tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST).
Authors: Feldman Rebecca , Gatalica Zoran , Reddy Sandeep K. , Chawla Sant P. , Sankhala Kamalesh Kumar 
Published: February 2017

58 Background: GISTs are characterized by KIT/PDGFRA mutations. A range of multi-targeted tyrosine kinase inhibitors (TKIs) are available for treatment, however, resistance mechanisms inevitably emerge. Recent data (Boichuk, et al 2014) suggests the potential efficacy of various cytotoxic therapies that were identified as being able to effectively kill TKI-responsive and -resistant GIST cells. We sought to investigate the theranostic markers associated with non-TKI therapy options for their potential role in treatment of GIST. Methods: 147 GIST cases were evaluated. A multiplatform approach of biomarker testing was used and included a combination of sequencing (NGS, Sanger), protein expression (IHC) and gene amplification (ISH). Results: Multidrug resistance phenotype was found in 52-68% (PGP, MRP1). Tubulin-binding agents (taxanes, vinca alkaloids) may be of potential use due to the high frequency of low TUBB3 expression (72% or 39/54). Anthracyclines and topoisomerase inhibitors may be of potential benefit in 1/3 of patients based on expression of TOPO2A (32% or 32/99) and TOPO1 (34% or 37/110). Cytotoxic agents used in non-GIST solid tumors, may also be considered, based on high frequency of low expressin of MGMT (47% or 57/122), TS (70% or 76/109) and RRM1 (79% or 88/111). PTEN was intact (positive expression) in the majority of GIST (87%). Nine patients were examined for PD1/PDL1: 56% exhibited positive tumor infiltrating lymphocytes and 33% exhibited PDL1 tumor expression. Only one amplification event was observed: cMET (0/53), HER2 (0/69), EGFR (0/16), PIK3CA (0/1) and TOP2A (1/11). Mutational screening using a hot spot cancer panel (and Sanger sequencing for some genes) resulted in the detection of variants in only 10 genes, excluding KIT (97/132) and PDGFRA (5/55). Variants were detected in the following genes, in decreasing order of frequency: RB1, APC and JAK3 (2/55; 2/55; 2/57), PIK3CA (2/69) and ABL1, cMET, EGFR, KDR, VHL and BRAF (1/55, 1/57, 1/57, 1/57, 1/52, 1/78). Conclusions: A multi-platform approach of theranostic biomarkers identified therapies beyond TKIs for GIST. Various cytotoxics and non-KIT/PDGFRA targeted therapies were identified based on protein expression or gene variations.
Association of EGFR CA simple sequence repeat 1 (CA-SSR1) variant with cetuximab (cet)-induced skin toxicity (ST) in Japanese metastatic colorectal cancer (mCRC) patients (pts) with overexpressed EGFR and KRAS exon 2 wild-type (KRAS wt) (JACCRO CC-05/06 AR).
Authors: Ichikawa Wataru , Sunakawa Yu , Tsuji Akihito , Takahashi Takehiro , Denda Tadamichi , Shimada Ken , Kochi Mitsugu , Nakamura Masato , Kotaka Masahito , Segawa Yoshihiko , Tanioka Hiroaki , Negoro Yuji , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Masuishi Toshiki , Takeuchi Masahiro , Lenz Heinz-Josef , Fujii Masashi , Nakajima Toshifusa 
Published: February 2017

582 Background: Associations of EGFR gene copy number (GCN) and EGFR CA-SSR1 polymorphism with clinical outcome still remain controversial in mCRC pts treated with cet. Interethnic differences in the repeat number of EGFRCA-SSR1 have been reported between Caucasian and Asians, however, there have been few reports about the associations with clinical outcome in Japanese pts. The aim of this study was to evaluate the predictive value of two biomarkers in Japanese mCRC pts treated with cet. Methods: This study enrolled 77 pts with tumor available from two prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in mCRC pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Genomic DNA isolated by macro-dissection from tissue was screened for the EGFR GCN determined by FISH on FFPE tumor specimens with the cut-off value of 2.9, adopted as previously reported (Cappuzzo F, et al., 2008), and the EGFR CA-SSR1 short (S; ≤19) / long (L; ≥20) determined by PCR amplification and fragment length analysis using capillary electrophoresis. Associations of the biomarkers with efficacy, including response, progression-free survival, and overall survival, were evaluated. Additional analysis was addressed at a possible association between the EGFRCA-SSR1 and ST. Results: The frequency of the L alleles of the EGFR CA-SSR1 was 64%. There was no significant association between two biomarkers and efficacy. However, the EGFR CA-SSR1 variant significantly correlated with ST evaluated on 8 weeks after initial administration. The rate of ST with grade 2 or 3 was 33% (10/30), 19% (5/26), and 64% (7/11) in LL, SL, and SS genotype, respectively (fisher's exact test p=0.03). Conclusions: Our study provides first evidence that the EGFR CA-SSR1 variant was associated with cet-induced ST in Japanese mCRC pts. No predictive value for cet treatment could be identified in our screened biomarkers, however, extended RAS mutations analysis is warranted (UMIN000010635).