bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular analysis of advanced colorectal cancer in an ethnically diverse patient population at a single institution.
Authors: Ashai Nadia , Mejia Saldarriaga Mateo , Rao Devika , Stuart Matthew , Zhang Wei , Goel Sanjay , Halmos Balazs , Rajdev Lakshmi 
Published: January 2019

702 Background: CRC survival and treatment response differences have been noted across racial and ethnic groups, particularly between Hispanics (HA), non-Hispanic AA (AA), and non-Hispanic Caucasian (CA). We examined if there are differences in molecular drivers between these groups that could explain such differences in our diverse medical center. Methods: We retrospectively examined 361 HA, AA, CA patients at Montefiore Medical Center diagnosed with metastatic CRC (mCRC) from 2007 to 2018. Mismatch repair proficiency (MMR-P), deficiency (MMR-D) was determined by immunohistochemistry. KRAS, NRAS, BRAF were determined by polymerase chain reaction or next generation sequencing. Mutations were then correlated with overall survival (OS). Results: Across subgroups, there was no differences in MMR, KRAS, NRAS, BRAF incidence (Table). Using a univariate analysis, the median survival for RAS mutated (M) patients was 33 months (ms), compared to 69 ms for RAS wild-type (WT, p = 0.01). The median OS for RAS mutated HA patients was 41 ms, compared to 41 ms and 33 ms for CA and AA respectively (p = 0.14). There was also no statistically significant difference between median OS for RAS WT HA patients (69 ms), compared to AA patients (51 ms) and CA (not reached, p = 0.75). Conclusions: In our single institution study, we found no difference in incidence of RAS (KRAS and NRAS), BRAF, MMR amongst HA, AA, and CA. Delivery of uniform care may account for similar OS outcomes in our patient population. RAS WT and M disease had improved OS compared to previously established rates in the literature. Additional studies are needed to evaluate known differences in treatment response and survival in minority populations. [Table: see text]
Pharmacogenomics-guided chemotherapy and supportive care for patients with metastatic colorectal cancer.
Authors: Kasi Pashtoon Murtaza , Koep Tyler , Baldeo Candice , Schnettler Erica , Kamatham Saivaishnavi , Shahjehan Faisal , Hughes Caren 
Published: January 2019

703 Background: In metastatic colorectal cancer (CRC), pharmacogenomics (PGx) testing presents a unique opportunity to improve outcomes since the genes DPYD & UGT1A1 encoding the enzymes metabolizing the chemotherapy drugs, 5-fluorouracil and irinotecan, are already well known. In the TRIBE clinical trial, proportion of patients with serious adverse events (SAEs) was higher in those with DPYD/UGT1A1 aberrations and were dose dependent. Critical barrier has been integration into clinical practice. We aimed to report on the feasibility and results of incorporating PGx testing into clinical practice. Methods: As a quality improvement initiative, we integrated the use of OneOme RightMed comprehensive test through funding from our center of individualized medicine, which reports on 28 genes and over 350 medications of interest. Pharmacists provided dosage recommendations based on test results real-time. Results: 126 patients have had the PGx testing since November 2017. Results have been available within 3-5 days. The table outlines the analyzed results thus far of variants in UGT1A1 and the DPYD-genes alongside the CYP450 genes. Of these, 59% had a DPYD/UGT1A1 aberration and 100% had at least one actionable aberration related to supportive care medications from all possible medications listed on their PGx report. Conclusions: Preemptive comprehensive PGx testing can be integrated into clinical practice in real-time for cancer patients. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients. [Table: see text]
Comorbidity and systemic inflammation are independent prognostic factors in patients with colorectal cancer: A ScotScan collaborative study.
Authors: Park James Hugh , Fuglestad Anniken , Kostner Anne Helene , Roseweir Antonia K. , Edwards Joanne , Roxburgh Campbell SD , Horgan Paul G. , Kersten Christian , McMillan Donald C 
Published: January 2019

707 Background: Although inextricably linked, both comorbidity and systemic inflammatory responses have been shown to determine survival in patients undergoing surgery for colorectal cancer (CRC). The present study examines the interrelationships between comorbidity (ASA grade) and systemic inflammation (modified Glasgow Prognostic Score (mGPS)) in patients from the ScotScan dataset. Methods: Clinicopathological characteristics and outcome of consecutive patients undergoing potentially curative resection of TNM I-III CRC in Glasgow Royal Infirmary (Scotland) and Sørlandet Hospital (Norway) were prospectively collected. ASA grade and mGPS (0-CRP ≤ 10mg/L, 1-CRP > 10mg/L, 2-CRP > 10mg/L and albumin < 35g/L) prior to surgery was recorded and relationship with overall survival (OS) examined. Results: 2,295 patients (Scotland: n = 1,234 , Norway: n = 1,061) were included. Patients from Norway were more likely to be older, female and have higher ASA grade (all P < 0.001), and more likely to have colon cancer (76% vs. 67%, P < 0.001). Patients from Norway were less likely to be systemically inflamed (mGPS = 0: 72% vs. 65%, P < 0.001), even after propensity score matching ( n = 736, OR 0.36 95%CI0.25-0.51, P < 0.001). ASA grade and mGPS were significantly associated; 21% of ASA 1 patients had mGPS ≥ 1 compared to 41% of ASA four patients ( P < 0.001). In the propensity-matched cohort, both increasing ASA (HR 1.98 95% CI1.57-2.49, P < 0.001) and mGPS (HR 1.20 95% CI1.02-1.41, P = 0.027) were associated with OS independent of age, N stage and adjuvant therapy use; results in the whole cohort were similar. The combination of ASA grade and mGPS was examined with respect to OS in patients with stage II-III CRC (Table 1). In patients with stage II disease, 3-year OS was stratified from 96% (ASA 1, mGPS0) to 67% (ASA 3, mGPS2) ( P < 0.001); in patients with stage II disease, 3-year OS was stratified from 84% to 44% ( P < 0.001). Conclusions: Using a large, prospectively collected dataset of patients undergoing resection of CRC in two countries, the results of the present study confirm the independent prognostic value of measures of comorbidity and systemic inflammation prior to surgery.
Racial effect of early stage colorectal cancer outcomes in a comprehensive cancer center.
Authors: Fangman Benjamin D , Beg Muhammad Shaalan , Sanjeevaiah Aravind , Araghizadeh Farshid , Scielzo Shannon , Kazmi Syed Mohammad Ali 
Published: January 2019

710 Background: Oncologic treatment at National Cancer Institute (NCI) designated comprehensive cancer centers improves outcomes in a variety of malignancies. Racial disparity plays an important role in cancer outcomes and prognosis. Racial outcomes were compared in early stage colorectal cancer patients that presented to a comprehensive cancer center. Methods: This is a retrospective analysis on patients diagnosed with AJCC stage II or stage III colorectal cancer and underwent surgery or adjuvant chemotherapy within the University of Texas Southwestern and Simmons Comprehensive Cancer Center. Pertinent data points were abstracted from EMR including demographic data and dates of initial diagnosis, surgery, adjuvant chemotherapy, progression, and death. Results: Between 4/2011 and 11/2015, 203 patients were identified and 167 patients had complete follow up data available. Median age of cohort was 62 (range 21-90) and most of the patients were men (52.7%). Stage II comprised 44.3% of patients while 55.7% were diagnosed at stage III. One hundred and twenty patients (71.9%) were white, while 34 patients (20.4%) identified as black and the rest belonged to other races. Hispanic ethnicity was identified in 10.4% of patients. There was no significant difference between white and black cohorts between variables age (median 62 vs. 64.5 years; p = 0.44), gender (p = 0.43), and stage (p = 0.99) of colorectal cancer. Similarly there was no significant difference between white and black race in regards to days to surgery (median 17 vs 32 days; p = 0.53), first medical oncology appointment (30 vs. 34 days; p = 0.23) and days to adjuvant chemotherapy (42 vs 52 days; p = 0.24). The rate of recurrence (10.9% vs. 26%; p = 0.09), rate of death (14.1% vs 14.7%; p = 1.0), median relapse free survival (41.7 vs. 36.2 months; p = 0.173) and median overall survival (42 vs. 38.5 months; p = 0.491) from colorectal cancer were also not significantly different between white and black races. Conclusions: Oncologic treatment at NCI designated comprehensive cancer centers may lead to racial parity in colorectal cancer outcomes. Further research should be completed to compare these results to those seen at safety net hospitals.
Endoscopic features of submucosal invasion in undifferentiated type early gastric cancer sized less than 2 cm without ulceration.
Authors: Kim Su Jin , Choi Cheol Woong , Kang Dae Hwan 
Published: January 2019

76 Background: The prediction of invasion depth is important to decide the treatment modality for the undifferentiated type early gastric cancer (EGC) when size is less than 2 cm and had no ulceration. We aimed to identify the endoscopic features associated with submucosal invasion in the undifferentiated type EGC that meet the criteria of size and status of ulcer in the endoscopic submucosal dissection (ESD). Methods: A total of 120 patients with undifferentiated type EGC who received ESD or operation from August 2008 to December 2017 were enrolled in this study. All lesions met the ESD criteria except the invasion depth. We retrospectively reviewed endoscopic features of tumor before the resection and depth of invasion after resection. Results: In 120 undifferentiated EGCs, the mucosal and submucosal cancer were 97 and 23 lesions, respectively, In univariable analysis, discolor change, upper third location, the presence of deep/wide erosion were associated with submucosal invasion. Multivariable analysis revealed that upper/middle third location (odds ratio [OR] 8.0, 95% confidence interval [CI] 1.2-55.0; OR 7.9, 95% CI 1.8-35.1), erosion or polypoid (OR 41.8, 95% CI 4.1-427.9), and elevated type (OR 20.9, 95% CI 2.5-173.8) were significant risk factors. In 112 patients received gastrectomy with lymph nodes dissection, lymph node metastases were found in four cases (three mucosal cancer and one submucosal cancer). However, there was no lymph node metastasis in the lesions meeting the expanded ESD indication. Conclusions: The careful decision of treatment modality is needed for undifferentiated type EGC with erosion or elevated gross type located on the upper/middle third, although the tumor size and ulcer status meet the ESD indication.
A phase II study of M6620 and irinotecan in TP53 mutant gastric and gastroesophageal junction (GEJ) adenocarcinoma patients (pts) [NCT03641313].
Authors: Das Satya , Whisenant Jennifer , Doyle Austin , Allegra Carmen Joseph , Berlin Jordan 
Published: January 2019

TPS175 Background: Progressive metastatic or unresectable gastric/GEJ adenocarcinoma pts carry dismal prognoses with a significant need for novel systemic therapies. One avenue for drug development in this disease is targeting salvage DNA repair pathways. TP53, a central gene to DNA damage repair (DDR), is mutated in 50% of gastric/GEJ cancer pts. Pre-clinical models from multiple cancer types demonstrate that cancer cells with TP53 mutations rely on the ataxia telangiectasia and Rad-3 related protein kinase (ATR) axis as a primary pathway of salvage DDR in the face of cytotoxic stress. The ATR pathway is typically triggered by single strand DNA breaks such as those generated by topoisomerase I inhibitors. Irinotecan is already known to be active in later line gastric/GEJ pts, thus, there appears to be an opportunity to combine the agent with the ATR inhibitor M6620 in TP53 mutant pts with the disease. Methods: Our trial is a single arm phase II study of M6620 plus irinotecan in progressive gastric/GEJ adenocarcinoma pts. Only pts with TP53 mutations in exon 2 and exons 4-11, as determined by next-generation sequencing from archived tissue, will be eligible. Pts will receive 180 mg/m^2 of irinotecan immediately followed by M6620 every 2 weeks; the M6620 dose will be determined based on the recommended phase 2 dose from the ongoing phase I trial. CT scans will be repeated every 2 months to assess response. The primary endpoint of the study is overall response rate (ORR), with a pre-specified target of 35%. Correlative studies will be performed on fresh tumor tissue from the first 9 pts, obtained by biopsies on day 1 of cycle 1 post-irinotecan and day 2 of cycle 2, to assess dynamic changes in the biomarkers Y-H2AX, KAP1 p-Ser 824, and p-ATR. Our study employs a Simon’s two-stage design (α = 0.1, power = 0.8) where an initial analysis will be performed after 9 pts are enrolled. If < 2 pts demonstrate objective response, the trial will stop for futility. If > 2 pts demonstrate response, the study will enroll 14 more pts. If ≥ 6 pts experience an objective response, the trial will achieve its efficacy threshold. Accrual will be ensuing in the near future. Clinical trial information: NCT03641313.
Phase II multicenter pilot study of safety, efficacy, and immune cell profiling in advanced hepatocellular carcinoma (HCC) on combination of sorafenib (SOR) plus nivolumab (NIVO).
Authors: Keenan Bridget , Griffith Madeline J , Bauer Kelly , Bracci Paige M. , Behr Spencer , Umetsu Sarah E , Gordan John Dozier , Ngo Zoe , Iqbal Syma , Hanna Diana L. , Venook Alan P. , El-Khoueiry Anthony B. , Fong Lawrence , Kelley Robin Kate 
Published: January 2019

TPS464 Background: The antiangiogenic tyrosine kinase inhibitor (TKI) SOR prolongs survival in advanced HCC, but responses occur in fewer than 5% of patients (pts) and median progression-free survival (PFS) is less than 6 months. Immune checkpoint inhibition (CPI) with the PD-1 inhibitor, NIVO, achieved an overall response rate (ORR) of approximately 20% in sorafenib-naïve pts enrolled on CheckMate 040 trial though most pts had progression. In preclinical studies, TKI can inhibit regulatory T cells and myeloid derived suppressor cells, immune cell subsets which may contribute to CPI resistance. CD8+ T cells in sorafenib-resistant tumors are characterized by PD-1 expression, providing rationale for a combined approach. The combination of TKI or the anti-angiogenic bevacizumab with CPI improves anti-tumor activity in HCC mouse models and in preliminary clinical studies. This study will examine the safety, maximum tolerated dose (MTD), and ORR of the combination of SOR plus NIVO in advanced HCC pts, along with correlative analyses of tumor and circulating immune cells. Methods: Eligible pts must have Child-Pugh A liver function and advanced HCC, without prior systemic therapy and measurable by RECIST 1.1. In Part 1 (3+3 dose escalation), SOR dose will be 400 mg QD or BID plus NIVO 240 mg IV Q2 weeks. In Part 2, Arm 1, pts will start NIVO Cycle 1, Day 1 (C1D1), with addition of SOR at MTD on C1D15; in Part 2, Arm 2, SOR is given at MTD on C1D1 with addition of NIVO on C1D15. Primary endpoints are MTD of SOR (Part 1) and ORR by RECIST 1.1 with H0 7.5% vs. H1 25% (Part 2). For expected sample size of 24 evaluable pts in Part 2, the power is 83% with 1-sided alpha 5% to determine ORR >25% by Chi-square tests. Secondary endpoints are safety, duration of response, PFS, and overall survival. Exploratory endpoints include peripheral and tumor immune cell profiling, PD-L1 expression, and alpha-fetoprotein (AFP) response. An interim safety analysis will be performed after 50% enrollment in Part 2. Optional paired biopsies in Part 2 will allow for investigation of the tumor microenvironment on SOR, NIVO, and combination. Clinical trial information: NCT03439891.
Phase Ib trial of cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with advanced hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer (GC/GEJC), or colorectal cancer (CRC).
Authors: Spencer Kristen Renee , Ramsingh Giridharan , Mohamed Nehal , Pal Sumanta K. , Rimassa Lorenza 
Published: January 2019

TPS478 Background: C is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM family kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that C promotes an immune-permissive tumor environment which may enhance response to checkpoint inhibitors such as the anti-PD-L1 mAb A. C significantly improved overall survival vs placebo in previously treated advanced HCC, and the combination of A and bevacizumab has shown synergistic activity in advanced HCC. Checkpoint inhibitors have shown clinical activity in advanced CRC primarily in pts with high microsatellite instability (MSI); combination with immune-modulating agents may enhance activity in pts with stable or low MSI. Likewise, combination therapy may improve response in pts with GC/GEJC resistant to standard chemotherapy. Here, we present the study design of an ongoing phase 1b trial which includes cohorts with advanced HCC, GC/GEJC, or CRC. Methods: This global, phase 1b, open-label trial will assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of C in combination with A (NCT03170960). The study consists of a dose-escalation stage and an expansion stage. In the dose-escalation stage (3+3 design), a recommended C dose for combination with a standard dose of A will be established. In the expansion stage, 18 cohorts will be enrolled at the recommended dose of C + A including 3 cohorts with gastrointestinal cancers: (1) advanced HCC not previously treated with systemic therapy; (2) advanced GC/GEJC after progression on platinum- or fluoropyrimidine-containing therapy; and (3) advanced CRC after progression on fluoropyrimidine combined with oxaliplatin or irinotecan. Pts will continue treatment as long as they experience clinical benefit as judged by the investigator or until unacceptable toxicity. The primary objective of the expansion stage is the objective response rate for each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, immune cell profiles, and MSI status with clinical outcome. Clinical trial information: NCT03170960.
NuTide:302: A phase Ib study to assess the safety, pharmacokinetics and clinical activity of the ProTide NUC-3373 when combined with standard agents used in colorectal cancer.
Authors: Evans T.R. Jeffry , Blagden Sarah Patricia , Graham Janet Shirley , Ciombor Kristen Keon , De Gramont Aimery , Tabernero Josep , Berlin Jordan 
Published: January 2019

TPS719 Background: Although 5-fluorouracil-based chemotherapies (5-FU, capecitabine, and floxuridine) remain the cornerstone of combination therapies for colorectal cancer (CRC), their clinical utility is limited by key cancer resistance mechanisms associated with breakdown, transport, and activation. These agents require intracellular conversion to the active metabolite fluorodeoxyuridine-monophosphate (FUDR-MP) before they can exert their core anti-cancer activity through inhibition of the enzyme thymidylate synthase (TS). NUC-3373 is a phosphoramidate transformation of FUDR-MP designed to bypass the key resistance mechanisms associated with 5-FU. Results from the first-in-human study of NUC-3373 (NuTide:301) in patients with advanced solid tumours demonstrated a favourable PK/PD profile for NUC-3373, with a longer plasma t1/2 (9.7 hours) than 5-FU (8-14 minutes) and much higher levels of the active anti-cancer metabolite, FUDR-MP (Ghazaly et alESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes (TS-T), depleting the pool of dTMP within 2-4 hours. Methods: NuTide:302 is a two-part, Phase Ib study in patients with CRC who have relapsed after ≥ 2 prior lines of 5-FU-containing therapies. The primary objective is to identify a recommended NUC-3373 dose when administered every 2 weeks in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD, and anti‐tumour activity. In Part 1, approximately 12 patients will be administered NUC-3373 with leucovorin (LV) to determine if LV is beneficial in augmenting the formation of TS-T. If so, it will be administered in Part 2. In Part 2, the following combination agents will be administered with NUC-3373 (±LV): oxaliplatin; oxaliplatin + bevacizumab; oxaliplatin + panitumumab; irinotecan; and irinotecan + cetuximab. Up to 62 patients will be enrolled in cohorts of 3-6, in a modified 3+3 design. Enrollment to Part 1 initiated in September 2018. Clinical trial information: NCT03428958.
BMP signaling is required for amphioxus tail regeneration
Authors: Liang Yujun , Rathnayake Delima , Huang Shibo , Pathirana Anjalika , Xu Qiyu , Zhang Shicui 
Published: January 2019

ABSTRACT
Amphioxus, a cephalochordate, is an ideal animal in which to address questions about the evolution of regenerative ability and the mechanisms behind the invertebrate to vertebrate transition in chordates. However, the cellular and molecular basis of tail regeneration in amphioxus remains largely ill-defined. We confirmed that the tail regeneration of amphioxus Branchiostoma japonicum is a vertebrate-like epimorphosis process. We performed transcriptome analysis of tail regenerates, which provided many clues for exploring the mechanism of tail regeneration. Importantly, we showed that BMP2/4 and its related signaling pathway components are essential for the process of tail regeneration, revealing an evolutionarily conserved genetic regulatory system involved in regeneration in many metazoans. We serendipitously discovered that bmp2/4 expression is immediately inducible by general wounds and that expression of bmp2/4 can be regarded as a biomarker of wounds in amphioxus. Collectively, our results provide a framework for understanding the evolution and diversity of cellular and molecular events of tail regeneration in vertebrates.
An integrated transcriptional analysis of the developing human retina
Authors: Mellough Carla B. , Bauer Roman , Collin Joseph , Dorgau Birthe , Zerti Darin , Dolan David W. P. , Jones Carl M. , Izuogu Osagie G. , Yu Min , Hallam Dean , Steyn Jannetta S. , White Kathryn , Steel David H. , Santibanez-Koref Mauro , Elliott David J. , Jackson Michael S. , Lindsay Susan , Grellscheid Sushma , Lako Majlinda 
Published: January 2019

ABSTRACT
The scarcity of embryonic/foetal material as a resource for direct study means that there is still limited understanding of human retina development. Here, we present an integrated transcriptome analysis combined with immunohistochemistry in human eye and retinal samples from 4 to 19 post-conception weeks. This analysis reveals three developmental windows with specific gene expression patterns that informed the sequential emergence of retinal cell types and enabled identification of stage-specific cellular and biological processes, and transcriptional regulators. Each stage is characterised by a specific set of alternatively spliced transcripts that code for proteins involved in the formation of the photoreceptor connecting cilium, pre-mRNA splicing and epigenetic modifiers. Importantly, our data show that the transition from foetal to adult retina is characterised by a large increase in the percentage of mutually exclusive exons that code for proteins involved in photoreceptor maintenance. The circular RNA population is also defined and shown to increase during retinal development. Collectively, these data increase our understanding of human retinal development and the pre-mRNA splicing process, and help to identify new candidate disease genes.