bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of therapeutic GAS6/AXL inhibition of tumor and stromal cells on DNA damage and response to chemotherapy in ovarian cancer.
Authors: Mullen Mary M , Lomonosova Elena , Noia Hollie M , Guo Lei , Kuroki Lindsay Midori , Hagemann Andrea M , McCourt Carolyn K. , Thaker Premal H. , Mutch David Gardner , Powell Matthew A. , Fuh Katherine Cynthia
Published: May 2019

e14676

Background: Ovarian cancer is the leading cause of death due to gynecologic malignancy. Biomarkers to predict chemoresponse and novel therapies to target these proteins would be practice changing. We aim to establish serum and tissue GAS6 as a predictive biomarker of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Methods: AVB was supplied by Aravive Biologics. High grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor (OVCAR8, OVCAR5, COV62, and POV71-hTERT) and stromal cells (CAF86) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent assays targeting ɣH2AX were used to evaluate DNA damage. Results: Patients with high pretreatment tumor GAS6 expression ( > 85%, n = 7) or serum GAS6 concentrations ( > 25ng/mL, n = 13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression ( < 45%, n = 4) (P = 0.010) or low serum GAS6 concentrations ( < 15ng/mL, n = 5) (P = 0.002). Carboplatin plus AVB (2µM, 5µM) and paclitaxel plus AVB (1µM) resulted in decreased cell viability and clonogenic growth compared to chemotherapy alone (p < 0.05) in all tumor and stromal cell lines. Synergism was seen between carboplatin+AVB and paclitaxel+AVB with a weighted combination index < 1. In vivo tumor mouse models treated with chemotherapy+AVB had significantly smaller subcutaneous and intraperitoneal (IP) tumors than those treated with chemotherapy alone (3.1mg vs 64mg, P = 0.003 OVCAR8; 62mg vs 157mg, P = 0.0108 PDX subcutaneous model; 0.05mg vs 0.3669mg, P < 0.001 OVCAR5 IP model). Increased DNA damage was noted in tumor and stromal cells treated with carboplatin+AVB compared to carboplatin alone (OVCAR8, COV362, CAF86 P < 0.001). Conclusions: High GAS6 is associated with lack of neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability, tumor growth, and an increase in DNA damage response.
Clinical analysis of cancer associated venous thromboembolism in hospitalized patients with malignant solid tumors in real-world practices.
Authors: Jiang Da , Zhang Xue , Yang Haiying , Zuo Jing , Jin Hui , Li Ying , Huang Fang
Published: May 2019

e14686

Background: According to previous reports, 1% to 30% patients with malignant tumors developed venous thromboembolism (VTE) and an increased risk of VTE in hospitalized patients. However, real-world clinical analysis of VTE in Chinese hospitalized patients with malignant solid tumors is scarce. Methods: We utilized the collaborative Linkdoc database to retrospectively analyze hospitalized cancer patients in Department of Medical Oncology of the Fourth Hospital of Hebei Medical University from May 2014 to November 2018. Patients who were pathologically confirmed malignant solid tumor, ≥ 18 years of age, ECOG PS 0-4, median overall survival ≥ 1 months, and absence of serious diseases of vital organs such as heart, liver, kidney and blood system or the above chronic diseases in inactive period were included in this study. Results: A total of 3831 patients were enrolled, of whom 180 (4.70%) patients had VTE. The highest incidence of VTE in solid tumors was gynecological cancer (61/1288, 11.90%), followed by gastric cancer (42/701, 5.71%), other cancers (11/206, 5.33%), lung cancer (61/1288, 4.74%), colorectal cancer (18/399, 4.51%), breast cancer (34/903, 3.77%), and esophageal cancer (6/250, 2.40%). Of the enrolled patients, 21.11% (809/3831) underwent relevant imaging examinations to screen for VTE as required by the guidelines of cancer associated VTE. Based on the imaging examinations, the anticoagulant rates of patients with or without VTE were 100% (61/61) and 34.09% (255/748), respectively. Notably, only one patient received the anticoagulant therapy (both anticoagulant dose and time) in lines with the guidelines. Conclusions: This single-center real-world study showed the overall rates of VTE in hospitalized cancer patients was similar with the data previously reported. Referring to the guidelines of cancer associated VTE, the proportion of Chinese cancer patients receiving normative imaging examinations and anticoagulant therapy is seriously low currently, which should be paid more attention to in clinical practices by Chinese medical workers.
A novel CRISPR-directed gene editing method that catalyzes precise gene segment replacement in vitro enabling multiplex site-directed mutagenesis.
Authors: Tarcic Gabi , Sansbury Brett M , Wagner Amanda M , Barth Shaul , Paniri Ester , Kmiec Eric B
Published: May 2019

e14688

Background: Functional analysis of the multitude of mutations found in tumors is a major goal to better understand their role and to optimize patient treatment. PCR-based site-directed mutagenesis (SDM) techniques are often used to engineer these variants. While these tools are efficient, they are not without significant limitations, most notably off-site mutagenesis, limited scalability and lack of multiplexing capabilities. To overcome many of these limitations, we describe a novel, fast and simple method for the introduction of both simple and complex gene mutations in plasmid DNA by using in vitro CRISPR based DNA editing. Methods: For each mutation, a specifically designed pair of CRISPR/Cas12a ribonucleoprotein complexes are used to execute site-specific double-strand breaks on plasmid DNA enabling the excision of a defined DNA fragment. This is followed by donor DNA replacement and bacterial colony expansion. We term this method, CRISPR-directed DNA Mutagenesis (CDM). Results: Using CDM we have been able to synthesize known oncogenic mutations as well as novel variants in 8 different cancer genes. These mutations have been synthesized with over 60% success rate, compared to about 40% success rate in SDM. More importantly, we show that in the CDM method there were no off-site mutations eliminating the need to sequence large portions of the gene. Conclusions: We have developed a novel multiplex site-directed mutagenesis method that can generate multiple unique mutations simultaneously within plasmids. CDM has proven capable of precise, rapid and robust mutation synthesis, including single base point mutations, site-specific deletions, insertions and duplications within targeted plasmids.
Phenotypic and functional characteristics of patient derived murine xenograft models.
Authors: Kiver Verena Imke Isabel , Wulf-Goldenberg Annika , Schweiger Caroline , Jurmeister Philipp , Brzezicha Bernadette , Gorea Olga , Burock Susen , Kolberg-Liedtke Cornelia , Hoffmann Jens , Blohmer Jens Uwe , Keilholz Ulrich , Denkert Carsten
Published: May 2019

e14694

Background: Generation of patient-derived models for breast cancer has been difficult. In other histologies, success was higher in refractory disease. With the goal to develop a protean resource for testing novel compounds and combinations for treatment refractory breast cancer, we establish patient-derived murine xenograft models (PDX) from tumors clinically unresponsive to at least anthracyclin, platin and taxane. Here we report phenotypic and drug testing data of our established breast cancer models. Methods: On immunodeficient NOG mice, PDX were engrafted from breast cancer tissue samples. The tissues were obtained from patients with disease progression after chemotherapy with three to four drugs. The established PDX were characterized by immunohistochemistry and the PDX and primary tumor are currently undergoing exome and transcriptome sequencing. The PDX were tested for response to all standard chemotherapy agents. The drug testing included platin, taxane, anthracycline, 5-FU, Everolimus, Eribulin and depending on the subtype tamoxifen, olaparib, and a CDK4/6 Inhibitor. Results: Since May 2017 30 breast cancer samples have been processed under rapid and stringent conditions. Currently five models, three TNBC and two hormone receptor positive PDX, have been fully engrafted, phenotypically compared and drug tested. The immunohistochemistry (estrogen/progesterone/androgen/Her2 receptor, Ki-67, CK5/6) of original tumor and PDX were correlative. All patients had shown clinical resistance to platin, anthracyclines, and taxanes in the neoadjuvant or palliative setting. Concordant with the clinical resistance, the PDX models showed only limited or transient sensitivity to single agents. Six more PDX, three TNBC, two HR+ and one Her2+, are currently in various states of engraftment and testing. Conclusions: With our stringent approach, we successfully generated PDX models in 15%, which may rise to 30% with the ongoing models. Phenotype between patient tumors and PDX was consistent. The minor differences in responsiveness to chemotherapy may be due to differences in stromal factors. In summary, the PDX of refractory tumors are a versatile resource for preclinical studies of novel treatment approaches.
Sorafenib as a postoperative adjuvant therapy in patients with hepatocellular carcinoma and microvascular invasion: A propensity score matching analysis.
Authors: Zhang Xiu-Ping , Chai Zong-Tao , Gao Yu-Zhen , Ding Jin , Cong Wen-Ming , Lau Wan Yee , Cheng Shuqun
Published: May 2019

e14707

Background: There is an unmet need for the postoperative adjuvant therapy in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI), which is associated with early recurrence after curative resection. This study aimed to investigate the role of Sorafenib as a postoperative adjuvant therapy in HCC patients with MVI after R0 liver resection (LR). Methods: Consecutive HCC patients with pathologically confirmed MVI who underwent R0 LR between January 2009 and December 2016 at the Eastern Hepatobiliary Surgery Hospital were retrospectively reviewed. Patients in the LR+sorafenib group (n = 581) received oral sorafenib (400 mg/d) at 1 weeks after R0 LR, while patients in the LR group (n = 147) only underwent R0 LR. Propensity score matching (PSM) was performed to balance the baseline characteristics between the two groups. Overall survival (OS) and recurrence-free survival (RFS) were followed up, and multivariate Cox regression analysis was performed. Results: After PSM, there were 113 patients in each group. The LR+sorafenib group demonstrated improved OS (median, 43.3 vs. 34.9 months; 1-year, 85% vs. 65%; 3-year, 66% vs. 51%; 5-year, 57% vs. 37%; log-rank P = 0.007) and RFS (median, 32.0 vs. 15.0 months; 1-year, 72% vs. 55%; 3-year, 47% vs. 36%; 5-year, 39% vs. 19%; log-rank P = 0.001) compared with the LR group after PSM. Multivariate Cox regression analysis indicated that R0 LR with postoperative sorafenib therapy was associated with better OS and PFS ( P < 0.001). On subgroup analysis, similar survival benefits were observed for sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) 0-A, BCLC B and Child-Pugh A stages of disease. Conclusions: Sorafenib used as a postoperative adjuvant therapy in HCC patients with MVI after R0 LR was associated with significantly better survival outcomes than LR alone.
Multiplatform molecular profiling: Observational study to determine the effect of treatment selection in advanced or refractory metastatic solid tumors.
Authors: Khan Faraz A. , EL Khoury Maroun , Safar Thalia , Tareen Mona , Sayed Kadriya
Published: May 2019

e14730

Background: To assess the clinical benefit of treatment in advanced and refractory solid tumors utilizing evidence-guided molecular profiling (MP) of tumors in routine clinical practice. Methods: This retrospective observational study was conducted on patients with advanced or refractory metastatic solid tumors, whose tumor biopsy samples were referred for profiling using a multi-platform tumor profiling service (Caris Molecular Intelligence) between January 2014 and April 2017. Specific testing was performed per physician’s request and included a combination of next-generation sequencing (NGS), protein expression (IHC), gene amplification (CISH or FISH), and/or RNA fusion analysis. Results: Data of twenty five patients with solid tumors was analyzed (median age of 58 years, range 25-82 years). Patients had received a median of 2 prior lines of therapy (range 0-6). In evaluable patients, 1 (4%) patient had a complete response, 10 (46%) patients had a partial response, 5 (23%) had stable disease and 6 (27%) had progressive disease, giving a disease control rate of 73%. The majority of patients received chemotherapy (CT) alone (13; 56%). Five patients received CT combined with targeted therapy (TT), 2 received TT alone, 2 received TT combined with hormone therapy (HT), 2 have received immunotherapy and 1 received HT alone. Two patients were not evaluable for response. In responding patients, median duration of response was 7 months (3-18 months). Conclusions: The result of this study show that treatment based on Broad tumor profiling in a select group of advanced and refractory solid tumors was associated with a high disease control rate.
The impact of androgen receptor (AR) expression on the prognosis of ductal carcinoma in situ (DCIS).
Authors: Lee Choong Man , Kim Jisun , Jo Hwi Gyeong , Park Hye Jin , Lee Sae Byul , Chung Il Yong , Yu Jong Han , Kim Hee Jeong , Ko Beom Seok , Lee Jong Won , Sohn Byung Ho , Ahn Sei-Hyun
Published: May 2019

e14731

Background: Ductal carcinoma in situ (DCIS) display favorable outcome while little is known about the factors associated with invasive recurrence. To identify better prognostic biomarkers we performed gene expression analysis followed by immunohistochemistry (IHC) staining validation. Methods: Differential gene expression analysis of 29 pure DCIS patients was performed using nanostring platform. RNA was extracted from paraffin blocks from age/size matched 11 recurrence-free and 18 invasive-recurrence cases (disease free interval > 5 years). Gene annotation enrichment analysis was done for differentially expressed genes (DEG) using DAVID. Eighty-two pure DCIS cases were selected for external validation by IHC staining. Allred score cutoff 1 was used for survival analysis. Results: Ninety-nine differentially expressed genes were found statistically significant (p-value < 0.05). Androgen receptor (AR) gene, which encodes a transcription factor AR, has recently been highlighted as a favorable prognostic marker and a therapeutic target in invasive tumor (fold change = - 1.35, p < 0.001). AR protein expression was externally validated by IHC staining of 82 pure DCIS cases (24 invasive-recurrence versus 58 recurrence-free). Similar to gene expression analysis result, patients with invasive recurrence showed lower AR staining score than recurrence-free patients (p = 0.007). Cox regression analysis showed lower AR level as an independent risk factor of long-term invasive recurrence (HR 7.43, 95%CI 1.50 – 36.62). Gene enrichment analysis revealed enrichment of kinase pathway and cell cycle pathway in recurred cases (Enrichment Score = 2.43, 2.41 respectively). Conclusions: DEG pattern was observed among pure DCIS cases. AR may serve as a prognostic biomarker and targeting kinase, cell proliferation may be effective for higher risk DCIS patients.
Changes in TROP2 expression in lung cancer patients receiving anticancer treatments.
Authors: Omori Shota , Kenmotsu Hirotsugu , Muramatsu Koji , Kawata Takuya , Kobayashi Haruki , Nakashima Kazuhisa , Wakuda Kazushige , Ono Akira , Naito Tateaki , Murakami Haruyasu , Sugino Takashi , Takahashi Toshiaki
Published: May 2019

e14732

Background: Human trophoblast cell surface glycoprotein (TROP2) is expressed on the cell surface of trophoblasts and various solid cancer cells. Recently, an antibody-drug conjugate (ADC) targeting TROP2 has been developed. The objective of this retrospective study is to evaluate the prevalence of TROP2 expression in the specimen of lung cancer and its changes during anticancer treatments. Methods: TROP2 expression was evaluated prior to and following anticancer treatment by immunohistochemical (IHC) analysis using an anti-TROP2 antibody (SP295). IHC scores were graded from 0 to 3 and grade ≥2 was considered to be positive. Pre- and post-treatment IHC scores of TROP2 expression were compared by Wilcoxon signed rank test. Results: Among 160 patients with evaluable tissue samples, median age was 65 (range, 39-89) years with 69% in stage III-IV. Histological diagnosis included 81% adenocarcinoma (Ad), 12% squamous cell carcinoma (Sq), 5% neuroendocrine carcinoma (NEC), and others. Among 130 Ad patients, 59% had EGFR mutations. Anticancer treatments included cytotoxic chemotherapy (77%), targeted therapy (42%), and radiotherapy (19%). TROP2 was expressed in 143 (89%) and 139 (87%) in pre- and post-treatment samples, respectively. Pre-treatment TROP2 positive expression were more frequently observed in Ad (92%) or Sq (100%) than NEC histology (25%, p < 0.001). There was no significant change in TROP2 expression after treatment (p = 0.509). Conclusions: TROP2 was commonly observed in the specimen of lung cancer especially in non-NEC histology regardless of anticancer treatments. TROP2-targeted ADC might have a therapeutic potential to be tested in TROP2-expressing lung cancer. [Table: see text]
Morphologic and genomic characterization of circulating tumor cells in patients with metastatic colorectal cancer treated with combinational treatment of andecaliximab, bevacizumab and chemotherapy.
Authors: Shishido Stephanie , Kuhn Peter
Published: May 2019

e14753

Background: The liquid biopsy is a noninvasive route to evaluate circulating tumor cells (CTCs) during the course of treatment to gain understanding of tumor biology, with potential prognostic utility. CTCs could serve as a predictive biomarker while aiding in the identification of resistance mechanisms to treatment through single cell genomic and proteomic analysis providing a longitudinal snapshots of tumor heterogeneity. Methods: Through the use of the high definition single cell assay (HD-SCA) workflow, we characterized the rare circulating cells to determine prognostic value of the liquid biopsy in monitoring the efficacy of andecaliximab in a combinational treatment as 1st or 2nd line therapy in patients with metastatic colorectal cancer (mCRC). 174 samples from 95 patients were analyzed to determine the significance of CTCs during treatment. Results: HD-CTCs were detected in 31% of samples, with 41 (43%) patients being CTC positive in at least 1 timepoint during the study. Patients receiving 1st line therapy presented with a median of 0 (range 0-346.04) and a mean of 9.49 (±14.06) HD-CTC/mL at baseline (BL). At initiation of 2nd line therapy, patients presented with a median of 0 HD-CTC/mL (range 0-277.37) and a mean of 10.94 (±15.32). There was no association between BL HD-CTC/mL and response, but for the 20 patients with > 1 HD-CTC at BL, there was a trend toward response for higher HD-CTC/mL (non-response: mean 2.8, n = 12; response: mean 89.7, n = 8; p = .04). The 3 patients with > 10 HD-CTC/mL at BL had undetectable HD-CTC on-treatment, which accompanied radiologic partial response; however, the 2 patients with complete radiological response had no HD-CTC detected at BL. In case studies, treatment pressure led to an observable change in HD-CTC morphology and genomic instability (single cell CNV analysis), suggesting these parameters may inform prognosis. Conclusions: Characterization of CTCs from patients with mCRC is feasible and may provide prognostic information to guide clinical decision making. Further evaluation of CTCs for pharmacodynamics and clinical monitoring in patients with mCRC is warranted.
Association of co-occuring mutations in exosomal DNA and clinical outcomes of patients with metastatic colorectal cancer.
Authors: Zhao Chuanhua , Chang Lianpeng , Cui Cong , Tan Zhaoli , Jia Ru , Wang Yan , Liu Rongrui , Zhang Yun , Liu Jianzhi , Xu Jian-Ming
Published: May 2019

e15001

Background: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Compared with cell-free DNA (cfDNA) derived from apoptotic cells, exosomal nucleic acids (exoNAs) released from living cells, which include more complete DNA, RNA and protein component, can better reflect underlying cancer biology. However, little evidence supports the clinical relevance of such a biomarker in metastatic colorectal cancer (mCRC). Methods: From May 2013 to July 2016, patients with mCRC received chemotherapy with or without molecular targeted drugs were enrolled in the Fifth Medical Center, General Hospital of PLA. Clinical response was evaluated using RECIST 1.1. Serial blood samples were collected and used to extract exosomal DNA. Targeted amplicon ultradeep sequencing was employed to analyze mutations in exosomal DNA with a customized-designed 10-genes panel including prognostic-related and cetuximab-resistant genes of CRC. Results: 91 patients were enrolled in this study, and median follow-up time was 11.7 months. In total of 82 pretreatment samples, 58% were detected to harboring mutations in designed targeted regions. The most frequent mutant genes were TP53 (56%), KRAS (54%), and PIK3CA (33%). Co-occuring genes were detected in 25 (31%) patients, including 16 patients with mutation in both KRAS and TP53 gene. Patients with co-occurring TP53/KRAS mutations showed significantly poor outcome (median OS=9.23m ), than those without co-occuring in these two genes (median OS=18.75m; P=.0141). Further analysis showed progress disease with new metastasis was enriched in patients with co-occurring KRAS/TP53-mutant patients (p=.0016). Of 23 samples from progressed patients received cetuximab, 39% were detected with acquired cetuximab-resistance related mutations in KRAS (26%), PIK3CA (17%), NRAS (4%) and BRAF (4%). In addition, exosomal DNA abundance increased was observed at or before disease progression (mean leading time = 8.90 weeks). Conclusions: This study provided clinical evidence for exosomal DNA as a potential biomarker of prognosis and cetuximab-resistant mechanism of mCRC.
Clinical significance of ZHX2 in colitis and colorectal carcinogenesis.
Authors: Bao Yonghua , Guo Yongchen , Yang Wancai
Published: May 2019

e15010

Background: Colorectal cancer (CRC) is one of the most common malignancies. Mechanistic studies have revealed that the malignant transformation of chronic colitis is one of the major causes besides the activation of Wnt/beta-catenin signaling. Our preliminary data have shown that ZHX2 is a common target of the miRNAs and is associated with colitis malignant transformation. This study aimed to explore the changes of ZHX2 in colitis-CRC tissues and their clinical significance, and to reveal the underlying mechanism. Methods: ZHX2 protein expression levels were analyzed by immunohistochemical staining in a CRC tissue microarray containing 400 cases of CRC and matched normal mucosa; mRNA levels were analyzed in fresh tissues by qRT-PCR. ZHX2 functional studies were conducted in ZHX2 transgenic mouse model and in vitro; Protein regulation was assayed by proteomic analysis using iTRAQ and RNA changes were assayed by RNA-sequence. Results: Protein and mRNA levels of ZHX2 were significantly increased in CRC and was associated with poor outcomes and recurrence, the copy numbers were also elevated in CRC. Intestine-specific transgenic Zhx2 mouse model showed chronic inflammation in the intestine at early age and intestinal carcinogenesis at late ages. Intestinal epithelial cell RNA sequence assay showed differential expression of genes and signaling pathways, compared to the wild-type mice. Biological functional studied showed that increasing ZHX2 in CRC cells enhanced cell proliferation, motility and migration, and suppressed cell apoptosis. Proteomic analysis showed that ZHX2 and HMGA1 were synergistic during tumorigenesis; mi-RNA regulatory study showed that miR-150 targeted ZHX2 and suppressed ZHX2 expression, but ZHX2 could regulate Wnt/beta-catenin and Serine family member PRSS8. Conclusions: This study has revealed the critical roles of ZHX2 in chronic colitis and its malignant transformation and underlying molecular mechanism, identifying a novel target for CRC prevention and therapy.
Phase I/II study of oxaliplatin dose escalation via a laparoscopic approach using pressurized aerosol intraperitoneal chemotherapy (PIPOX trial) for nonresectable peritoneal metastases of digestive cancers (stomach, small bowel and colorectal).
Authors: Dumont Frederic , Boisdron-Celle Michele , Hiret Sandrine , Senellart Helene , Raimbourg Judith , Campion Loic , Pein Francois J. L. , Bakrin Naoual , Raoul Jean-Luc , Glehen Olivier , Thibaudeau Emilie
Published: May 2019

e15027

Background: The pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new route of intraperironeal drug administration that enhances the absorption of oxaliplatin. The objectives were to determine the MTD and PK of Oxaliplatin administred via the PIPAC technic. Methods: This was a phase I two center study with standard 3 x 3 design for pts with extended peritoneal carcinomatosis from gastrointestinal cancer (gastric PCI>4, small bowell PCI>13, colorectal PCI>15), ECOG PS≤1 and no organ dysfunction. The primary endpoint are dose determining dose limiting toxicity (DLT), maximum tolerable dose (MTD), recommandation dose for the phase 2 (RD2P) and PK of oxaliplatin. The dose escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m² and starting with 90 mg/m². Pts were monitored for DLT from the first PIPAC up to 4-6 weeks after the second PIPAC. Each patient who experiences good tolerance will be invited to receive two to five PIPAC procedures at 4–6 week intervals. A systemic chemotherapy was allowed between the PIPAC session. Adverse event (AEs) were defined according NCI-CTCAE toxicity scale version 4. Results: To date, 10 patients received 31 PIPACs procedures and were treated in 2 differents dl. Two DLTs (grade 4 allergic reaction and grade 3 neutropenia) occurred at second level dose of 140 mg/m2 and no one at 90mg2. Frequent treatment related AE (TRAE) grade ≤ 2 during PIPACs sessions were nausea (9/31), abdominal pain (8/31) and fatigue (7/31). Nine patients were evaluable for response after at least 2 PIPACs. The histologic peritoneal regression grading score (PRGS) were 4 (no response), 3 (minor response), 2 (major response), and 1 (complete response) in respectively 0, 5, 2 and 2 pts. Pts with PRGS 1 underwent complete cytoreductive surgery and HIPEC. In this ongoing study, the PK profile is currently investigated. Conclusions: The RP2D of oxaliplatin during PIPAC was 90mg/m2 with correct tolerance and some patient have experienced of major histological response allowing a secondary complete resection. The study was opened for phase II enrollement. Clinical trials informations: NCT03294252 .
Analysis of age, tumor-sidedness, and mismatch repair (MMR) genes with response to immune checkpoint inhibitors (ICIs) in MMR-deficient (dMMR) colorectal cancer (CRC) patients (pts): A multi-institutional study.
Authors: Sahin Ibrahim Halil , Chen Wanqi , Sonbol Mohamad Bassam , Das Satya , Chen Zhengjia , Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Ahn Daniel H. , Ciombor Kristen Keon , Borad Mitesh J. , Berlin Jordan , Bekaii-Saab Tanios S. , Draper Amber , El-Rayes Bassel F. , Wu Christina
Published: May 2019

e15029

Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age < 50 and 50-65 years old had better ORRs compared to pts with age >65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts > 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]
A phase I clinical trial of fluorouracil (5-FU) + devimistat (CPI-613) combination in previously treated patients (pts) with metastatic colorectal cancer (MCR).
Authors: Rocha Lima Caio Max Sao Pedro , Alistar Angela Tatiana , Desnoyers Rodwige J. , Sorscher Steven , Yacoub George Hosni , Dressler Emily Van Meter , Pardee Timothy S. , Grant Stefan C. , Luther Sanjeev , Butler Destini , Ogburn Olivia , Strickland Kristin , Pasche Boris
Published: May 2019

e15054

Background: MCR that failed standard lines of therapy have a poor outcome. Inhibition of glutamine metabolism potentially can synergize with chemotherapy and reverse resistance. Devimistat is a novel anti-mitochondrial agent that alters energy metabolism and redox processes, leading to apoptosis, necrosis, and autophagy. Methods: Phase Ib dose escalation (3+3 design) to determine the MTD of devimistat, when used in combination with fixed doses of bolus and infusional 5-FU, in non-resectable MCR, ECOG PS 0-3, and good organ function who have failed, or could not tolerate, prior standard therapies. A cycle was 2 weeks. Escalating doses of devimistat were given IV over 2 hrs via central line on days 1-4. On Day 2 when both devimistat and bolus 5-FU were given, devimistat was given first, followed by 5-FU bolus (400 mg/m2) followed by infusional 5-FU over 46 hrs (2,400 mg/m2) on Days 2-4. Plasma samples to measure devimistat and metabolites were collected before and after the first and last dose of devimistat on cycle 1. Results: 19 pts enrolled from 1/20/2015 to 1/16/2019. One was never treated with devimistat and was excluded from analyses. Median age was 63 (range 32-83). 10 males and 8 females. Median devimistat cycles were 4 (range 1-8). Dose levels of devimistat: 1 pt treated at 2,000 mg/m2, 1 pt treated at 2,250 mg/m2, 7 pts treated at 2,500 mg/m2, then dose was de-escalated for an additional 9 pts treated at 2,250 mg/m2. Two of 7 pts had a DLT at the devimistat 2,500 mg/m2 dose level; a grade 3 and a grade 4 creatinine level. The dose of devimistat was de-escalated to 2,250 mg/m2 with a total of 10 pts being treated without DLTs observed (2 still on treatment). Other G1-2 non-hematologic and G1-3 hematologic toxicities were observed but related to 5FU except for two episodes of G1 intravascular hemolysis. No radiologic responses were observed. Four pts had SD and two pts at 2,250 mg/m2 of devimistat continue on therapy. Median PFS and OS are currently 2.73 and 5.75 months respectively. Conclusions: Devimistat and 5FU combination demonstrated a tolerable safety profile in heavily pretreated MCR pts. Durable SDs observed at the MTD suggest antitumor activity at the 2,250 mg/m2 devimistat dose level. Clinical trial information: NCT02232152.
Characteristics and outcomes of patients with colorectal cancer and bone metastasis.
Authors: Shahjehan Faisal , Kamatham Saivaishnavi , Cochuyt Jordan , Li Zhuo , Colibaseanu Dorin , Merchea Amit , Kasi Pashtoon Murtaza
Published: May 2019

e15063

Background: Bone metastasis from colorectal cancer is a relatively rare phenomenon. The aim of this study is to identify the risk factors and survival patterns of bone metastasis after colorectal cancer diagnosis. Methods: A total of 23,846 colorectal cancer patients who were diagnosed between 1972 and 2017 at Mayo Clinic were included in the analysis. Freedom from bone metastasis since diagnosis at 5, 10, 15, 25 and 35-years were estimated using Kaplan-Meier method. Multivariable Cox regression models were used to assess the differences in overall survival rate for patients with different cancer sides and cancer locations. All tests were two-sided with alpha level set at 0.05. Results: A total of 798 (3.3%) patients had a diagnosis of bone metastasis after colorectal cancer diagnosis over a median follow up of 3.2 years. Thirty-five year freedom from bone metastasis was 83% (95%CI: 80%-86%) for all patients, and were 87.13%, 82.29% and 77.26% for left colon, right colon and rectal cancer patients. Male gender, recent surgical years, and higher cancer stage were associated with higher risk of developing bone metastasis after colorectal cancer diagnosis. Rectal cancer patients had higher hazard of developing bone metastases compared to left and right colon cancer patients. Conclusions: We were able to identify several patient and tumor-related factors associated with the development of bone metastasis in patients with colorectal cancer. The proportion and factors identified are similar to other studies. Future directions would be to analyze other molecular determinants within this subset of patients.[Table: see text]
Clinicopathologic predictors of worse outcome in early onset colorectal cancer (EO-CRC): A single-institution experience.
Authors: Rao Devika , Acuna Villaorduna Ana , Kaumaya Meghan , Ashai Nadia , Tolu Seda , Chergui Adel , Rajdev Lakshmi , Goel Sanjay
Published: May 2019

e15064

Background: A growing body of evidence indicates an increasing incidence of CRC diagnosis prior to age 50 years. Despite improvements in morbidity and mortality in metastatic CRC (mCRC), racial disparities persist. Limited data is available on the influence of clinical and pathologic factors on outcomes in EO-CRC. We aim to analyze variables which may serve as prognostic markers in a racially diverse, under-served EO-CRC population. Methods: All mCRC patients (n=321) diagnosed between 2004-12 were identified through the institutional tumor registry and charts were reviewed for age at diagnosis, gender, race, site of primary and metastatic tumors and histologic grade. Clinical outcome was measured in terms of overall survival (OS). Clinicopathologic characteristics were compared with a t test between EO and standard onset (SO) groups. Multivariate analyses were performed to assess influence on EO-CRC. Results: Of the 321 patients, 60 (18.7%) had EO-CRC, with median age at diagnosis 42 years. Both groups showed a female preponderance (Table), with colon being the prevalent primary site (~70%). On analysis of racial distribution, non-Hispanic whites (NHW) and non-Hispanic blacks (NHB) had a lower incidence of EO-CRC compared with Hispanic (H) and Asian (A) patients (12.7% v 17.6% v 26.7% v 40%, p= 0.07). Additionally, EO-CRC had a higher incidence of high-grade histology (42.6% v 25.8%, p=0.09), which on multivariate analysis had a significant influence on clinical outcome (p<0.01). Median OS in the EO group was 2.1 years compared to 2.7 years in the SO group. Conclusions: EO-CRC is an aggressive malignancy with distinct pattern of racial distribution. Histologic grade has the potential to serve as a negative prognostic marker. Further analysis of patients diagnosed between 2013-18 is underway. [Table: see text]
BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.
Authors: Kasi Pashtoon Murtaza , Kamatham Saivaishnavi , Colibaseanu Dorin , Shahjehan Faisal , Merchea Amit
Published: May 2019

e15065

Background: Colorectal cancer (CRC) is a heterogeneous disease. Specifically for patients with BRAF-V600E mutations and/or mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-High), there have been significant advances in terms of treatment options. Early identification of these subsets of patients has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests i.e. carbohydrate cancer antigen 19-9 and carcinoembryonic antigen tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients. Methods: We included and analyzed the ratio of CA-19-9/CEA levels in patients with metastatic CRC at Mayo Clinic from December 2016 to February 2019, where both the results were available. Non-parametric tests were done to compare and contrast the differences in the median ratio and tumor marker levels. Results: BRAF-V600E mutant CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. The median CA-19-9/CEA ratio was 20 (range: 0.3-167.3) in BRAF-V600E MSS patients as opposed to 4.40 (range: 0.003-216.2) in all other patients, p-value of 0.007 (Table). Similarly, the mean CA-19-9/CEA ratio for BRAF V600E MSS tumors was 57.15 (S.D.± 62.76) versus 10.5 (S.D.± 33.90) for all other types. Furthermore, this discordant elevation is not seen in BRAF-mutant MSI-High or any MSI-High patients (median CA-19-9/CEA ratio - 0.46). Conclusions: To date, this is the first report utilizing the ratio of tumor markers CA-19-9/CEA as predictive rather than just prognostic markers. It clearly identifies BRAF-V600E MSS and the MSI-High CRC patients from other subsets.[Table: see text]
Simultaneous resection of colorectal cancer with synchronous liver metastases: A survey-based analysis.
Authors: Serrano Aybar Pablo Emilio , Griffiths Christopher , Bogach Jessica , Ruo Leyo , Hallet Julie , Simunovic Marko
Published: May 2019

e15073

Background: Patients with colorectal cancer and synchronous liver metastases may undergo simultaneous or staged resection. Methods: We electronically surveyed members of the Society of Surgical Oncology, Canadian Hepato-Pancreato-Biliary Association and the College of Physicians and Surgeons of Ontario with a pilot-tested questionnaire. Four clinical scenarios were presented. Perceived outcomes of and barriers to simultaneous resection were assessed on a Likert scale using Mann-Whitney U and Chi-square tests for ordinal and categorical variables, respectively. We compared results between general and hepatobiliary surgeons. We sought to determine surgeons’ attitudes and perceived barriers to simultaneous resection and compare them between general and hepatobiliary surgeons. Results: The response rate of 20% (234/1166) included 50 general and 134 hepatobiliary surgeons. A high likelihood score (Likert ≥5-7) for support of simultaneous resection among general and hepatobiliary surgeons, respectively, included the following: for minor liver and low complexity colon, 83% and 98% (p < 0.001); for minor liver and rectal resection, 57% and 73% (p = 0.042); for complex liver and low complexity colon resection, 26% and 24% (p = 0.858); and, for complex liver and rectal resection, 11% and 7.0% (p = 0.436). Among hepatobiliary surgeons, the most common barriers for simultaneous resections were patient comorbidities and extrahepatic disease, whereas general surgeons additionally identified transferring care to another facility. Lack of information regarding non-responders is relevant given our relatively low response rate. Our respondents mostly worked in academic settings, which may not be representative of the majority of surgeons who manage colorectal cancer. Conclusions: Surgeon support for simultaneous resection increased with less complex surgery and was similar among hepatobiliary and general surgeons. Surgeons’ perceived practice patterns and barriers to simultaneous resection should inform clinical trials and disease care pathways.
Radiomics features on CT scans to predict response to HER2-targeted therapy of hepatic metastases from colorectal cancer.
Authors: Giannini Valentina , Mazzetti Simone , Defeudis Arianna , Cappello Giovanni , Vassallo Lorenzo , Vanzulli Angelo , De Mattia Cristina , Torresin Alberto , Siena Salvatore , Sartore-Bianchi Andrea , Leone Francesco , Martino Cosimo , Zagonel Vittorina , Marsoni Silvia , Regge Daniele
Published: May 2019

e15086

Background: Metastatic Colorectal cancer (mCRC) is the 2nd cause of cancer death worldwide. Repeated cycles of therapies, combined with surgery in oligo-metastatic cases, are the therapeutic standard in mCRC. However, this strategy is seldom resolutive. Different lesions in in the same patient could have different responses to systemic therapy. Recently, CT texture analysis (CTTA) had been shown to potentially provide with prognostic and predictive markers, overcoming the limitations of biopsy sampling in defining tumor heterogeneity. The aim of this study is to use CT texture analysis (CTTA) to identify imaging biomarkers of HER2+ mCRC able to predict lesion response to therapy. Methods: The dataset is composed of 39 extended RAS wild type patients with amplified HER2 mCRC enrolled in the HERACLES trial (NCT03225937) that received either a lapatinib+trastuzumab treatment (n = 23) or a pertuzumab+ trastuzumab-emtansine treatment (n = 16). All patients underwent CT examination every 8 weeks, until disease progression. All mCRC on baseline CT were semi-automatically segmented and quantitative features extracted: size, mean, percentiles, 28 texture features. A logistic regression model was created using: (i) the whole dataset of mCRC as training and test set and (ii) 100 randomly generated training sets (with 70% of responder (R+) mCRC and an equal number of non-responder (R-) mCRC), and 100 test sets including the remaining mCRC. A mCRC was classified as R+ if size decreased (-10%) or was stable (±10%); as R- if size increased (+10%), during subsequent CT scans. Results: A total of 199 metastases were included (75R+ and 124R-). The training set was composed of 53R+ and 53R- mCRC and the test set of 22R+ and 71R- mCRC. Using the whole dataset, the model reached an AUC = 0.82 (sensitivity = 84%, specificity = 70%), while it reached a mean AUC of 0.70 (sensitivity = 68%, specificity = 67%) within the 100 repetitions. Conclusions: CTTA might help in stratifying different behaviors of mCRC, opening the way for lesion-specific therapies, with conceivable cost and life savings. Further extended analysis is needed to better characterize and validate predictive value of these biomarkers.
Genetic characteristics of lung metastasis and liver metastasis from left-sided colorectal cancer with microsatellite stability.
Authors: Wang Zhenghang , Zheng Xue , Li Jian , Wang Xicheng , Gao Jing , Li Zhongwu , Yu Jianing , Yang Wanning , Mao Beibei , Zhang Henghui , Shen Lin
Published: May 2019

e15097

Background: Metastases from colorectal cancer (CRC) are common and develop in 40 to 60% of the patients. The liver and lung are the most frequently metastatic sites. Although lung metastasis (LuM) is characterized with slower growth rate and longer survival duration compared to liver metastasis (LiM). Little is known about the genetic differences between LuM and LiM CRC patients. Methods: The LuM cohort was composed of 18 patients with isolated lung metastasis and LiM cohorts was composed of 18 patients with liver metastasis. All the 36 patients were left-sided CRC and all lesions were microsatellite stability (MSS). The two cohorts were matched case by case according to age, gender, primary location, T stage and N stage. The Control cohort involved 10 patients who had locally advanced tumors, received R0 resection and suffered no relapse in at least five years. Based on a 1408 cancer-related gene panel (covering 967010 bases), the next-generation sequencing (NGS) of primary tumors and metastases was performed on the primary and metastatic lesions of these patients. Results: For primary tumors, results showed that the frequency of BRD4 amplification in the LuM cohort (n = 16 ) was 50%, which was much higher than that in the LiM (n = 16) and Control cohorts (n = 10) ( p < 0.05). U2AF1 amplification in the LuM (30%) was more common than that in LiM (0%) patients ( p= 0.043). For metastatic lesions, amplification of MET and SDHC and Hippo pathway activation were more frequently observed in LuM cohort (n = 15) than that in LiM (n = 18). Median TMB of the primary tumors and metastases in the LuM cohort were 9.518 and 6.022 mutations/Mb, respectively, which were both much higher than that in the LiM and Control cohorts ( p< 0.05). Conclusions: Amplification of BRD4 and U2AF1 was the characteristic feature of primary tumors which metastasized to the lungs, indicating this genetic alteration might be used in identifying patients at risk of developing LuM. MET amplification and Hippo pathway activation were promising therapeutic targets of left-sided CRC-LuM with MSS. Patients with LuM might respond well to immunotherapies due to relatively high level of TMB. Expanded prospective cohorts are warranted to further elucidate these findings.
Effect of JAG2 on migration and invasion in colorectal cancer cell by PRAF2, independent of epithelial-mesenchymal transition.
Authors: He Wan , Wu Han , Liu Dongcheng , Li Wenwen , Xu Ruilian , Zou Chang
Published: May 2019

e15107

Background: Our previous studies revealed the increased expression of Jagged 2 (JAG2) in most intestinal cancer tissues. In colon cancer cell lines, JAG2 involved in the regulation of migration and invasion without affecting cell proliferation. This study further explored the mechanisms of how JAG2 promotes migration and invasion of colorectal cancer cells. Methods: We analyzed the expression of JAG2 mRNA and protein in normal human colon tissue cells and colorectal cancer cells. The promotive role of JAG2 in migration and invasion was tested by JAG2 siRNA and JAG2 overexpression in various colon cancer cell lines. To understand the mechanisms, we first treated HT29 cells with LY2157299, a TGF-β signaling pathway inhibitor, and Slug siRNA, to identify the cross-talk between JAG2 and EMT pathway. In addition, co-expression status of JAG2 and TGF-β-induced epithelial-mesenchymal transition (EMT) markers was analyzed. Finally, by using siRNA and proteomics technology, co-expressed proteins of JAG2 in colorectal cancer cells were identified. Results: JAG2 was abnormally expressed in colorectal cancer tissues and directly related with clinical stages. Similar to the findings in human tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. Interestingly, the promotion of JAG2 in migration and invasion was independent of EMT pathway. Furthermore, we found that the expression of JAG2 was correlated with PRAF2 (PRA1 Domain Family Member 2), a protein involved in the formation of exosome-like vesicles. In the presence of PRAF2, JAG2-rich exosome promoted migration and invasion. JAG2 might regulate the migration and invasion of colon cell through PRAF2. Conclusions: This is the evidence supporting the biological function of JAG2 in migration and invasion through non-EMT-dependent pathways and also the first exploration of the role of PRAF2 in colorectal cancer cells. These findings provide the theoretical basis for potential targeted therapy against JAG2/PRAF2.