bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel patient derived orthotopic xenograft model of gastro-esophageal junction cancer: Key platform for translational discoveries.
Authors: Veeranki Omkara Lakshmi
Published: January 2019

64

Background: Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. Current GEJ models have limited applications in tumor microenvironment, immune oncology and metastatic studies. Methods: A novel patient derived tumor orthotopic xenograft (PDOX) was established from GEJ cancer via surgical implantation. Patient tumor was compared to subcutaneously implanted PDX and PDOX by H&E, IHC, and next generation sequencing (T200.1 panel). Drug efficacy studies of 5-flurouracil with and without radiotherapy are being performed. Results: Mechanical abrasion of mouse GEJ prior to implantation of patient derived tumor in situ promotes tumor engraftment (100%, n = 6). Complete PDOX engraftment was observed with rapid intra and extra luminal tumor growth as evidenced by MRI. Patient derived stroma co-engrafts with tumor cells in GEJ-PDOX. PDOXs contain fibroblasts, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature. GEJ-PDOXs is a clinically relevant model for metastases and immunological studies. Next generation sequencing with the T200.1 revealed that the loss of heterozygosity of NOTCH3, TGFβ1, EZH2, and MLL3 are maintained with similar allelic frequency between the patient tumor and the xenografts. Additional somatic SNVs such as ARID1A, NSD1 (CDS157-158), NSD1 (CDS158-159), KDM6A, XPO1, MAPK1 and EGFR were found to be acquired in xenograft tumor tissues that were not observed in patient tumor. Drug and radiation efficacy studies are ongoing, tumor response to radiation was observed. Conclusions: A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture facilitating it as a novel tool in translating to clinics. This model can be applied to address importance of tumor microenvironment in metastatic and immunological studies, and to develop novel therapeutic approaches for the treatment of GEJ cancer.
Implementing DPYD*2A genotyping in clinical practice, the Quebec experience.
Authors: Jolivet Catherine , Amireault Carl , Ayoub Jean-Pierre M. , Beauregard Patrice , Blais Normand , Carrier Christian , Cloutier Alexis-Simon , Desnoyers Alexandra , Jolivet Jacques , Lemay Anne-Sophie , Lemay Frederic , Letendre Francois , Loungnarath Rasmy , Soulieres Denis , Tehfe Mustapha , Viens Daniel , Weng Xiaoduan , Aubin Francine
Published: January 2019

650

Background: Fluoropyrimidines (FU) are part of chemotherapy combinations for multiple gastrointestinal cancers. Deficient dihydropyrimidine deshydrogenase (DPD) activity can lead to severe life-threatening toxicities in 3-5% of populations tested. The DPYD*2A polymorphism leading to deficient DPD activity is one of the most studied variants. Methods: We retrospectively performed chart reviews of all patients that tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec (Canada). The study objective was to document the impact of implementing this test in routine clinical practice, including the effects on treatment types, delays and toxicities. Results: 2,617 patients were tested by PCR for the presence of DPYD*2A in a period of 17 months: 25 patients tested positive. All were Caucasian. 24 of the 25 patients were heterozygous (0.92%) and one was homozygous (0.038%). A chart review was available for 20 patients: 15 were tested upfront while five were performed following severe toxicities on the first cycle of FU-based chemotherapy. Of the five patients identified following toxicities, all had grade 4 cytopenias, 80% grade ≥ 3 mucositis, 20% grade 3 rash and 20% grade 3 diarrhea, with an average of 15 days of hospitalisations due to febrile neutropenia. Seven of the 13 patients identified upfront received FU-based chemotherapy at reduced initial doses ranging from 25 to 50%. The average dose during the course of chemotherapy was 50% and two patients reached 100% dosage. No grade ≥ 3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation according to 99% of queried physicians. Conclusions: Upfront genotyping before FU-based treatment is feasible in clinical practice. It may prevent severe toxicities and hospitalisations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.
EXPERT study: Randomized phase III trial of radical surgery and postoperative mFOLFOX6 versus perioperative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases (CLMs).
Authors: Mise Yoshihiro , Hasegawa Kiyoshi , Oba Masaru , Yamaguchi Kensei , Uetake Hiroyuki , Yoshino Takayuki , Morita Satoshi , Takahashi Keiichi , Unno Michiaki , Shimada Yasuhiro , Muro Kei , Yoshida Kazuhiro , Mori Masaki , Baba Hideo , Shimada Mitsuo , Saiura Akio , Matsumura Masaru , Ishigure Kiyoshi , Sugihara Kenichi , Kokudo Norihiro
Published: January 2019

652

Background: Up-front radical surgery and adjuvant chemotherapy were regarded as one of the standard-of-care (SOC) in patients with resectablecolorectal liver metastases (CLMs), while perioperative chemotherapy plus surgery is also accepted. We conducted a multicenter randomized phase III trial to compare radical surgery and post-operative mFOLFOX6 with peri-operative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable CLMs. Methods: Patients who had KRAS wild-type resectable CLMs having one to eight liver nodules without extrahepatic disease, were randomly assigned to groups: Group A (reference), hepatectomy and 12 cycles of post-operative mFOLFOX6: Group B (experimental), six cycles of preoperative mFOLFOX6 plus cetuximab (loading dose with 400mg/m2and thereafter 250mg/m2weekly), hepatectomy and six cycles of postoperative mFOLFOX6 plus cetuximab. Primary endpoint was progression-free survival (PFS). We hypothesized that 3-year PFS in Group B would be 25% with the hazard ratio (HR) being 0.75. Considering 3 year follow-up period with 5% of two-sided alpha error and 80% of power, target number were set as 500 (250 each). Study was registered in the University Hospital Medical Information Network (UMIN000007787). Results: This study was initiated since June 2012. However, the enrollment was terminated according to the recommendation from the monitoring committee on 2015 due to a slow accrual. A total of 77 patients (Group A 37 vs. Group B 40) were analyzed. Baseline characteristics were well-balanced between groups. Median numbers of liver mets were two each, ranging from one to eight. The HRs for PFS and overall survival (OS) showed no significant difference (PFS, HR = 1.18 [0.69-2.01], p = 0.54: OS, HR = 1.03 [0.46 – 2.29], p = 0.95). There were 3-year PFS of 35% in Group A vs. 30% in Group B, and 3-year OS: 86% vs. 74%, respectively. Conclusions: No additional survival benefits adding on peri-operative cetuximab were indicated, of which findings is consistent with the previous clinical studies, although there were small number of enrolled patients. Clinical trial information: UMIN000007787.
Clinical impact of D3 lymph node dissection preserving left colic artery (LCA) compared to D3 without preserving LCA: Exploratory subgroup analysis of data from randomized controlled trial of laparoscopic versus open surgery for colon cancer from Japan Clinical Oncology Group study JCOG0404.
Authors: Akagi Tomonori , Hara Takao , Inomata Masafumi , Mizusawa Junki , Katayama Hiroshi , Shida Dai , Ohue Masayuki , Hamaguchi Tetsuya , Ito Masaaki , Kinugasa Yusuke , Saida Yoshihisa , Masaki Tadahiko , Sato Takeo , Yamamoto Seiichiro , Hanai Tsunekazu , Otsuka Koki , Watanabe Masahiko , Fukuda Haruhiko , Kanemitsu Yukihide , Kitano Seigo
Published: January 2019

653

Background: In curative resection of sigmoid colon and rectal cancer, it is unclear whether D3 lymph node dissection preserving left colic artery (LCA) (Group A) is beneficial compared to D3 without preserving LCA (Group B) in terms of clinical outcomes. Preservation of LCA is expected to maintain blood supply which results in preventing anastomotic leakage, intestinal paralysis, and so on. Methods: The data of JCOG0404 (which is a randomized controlled trial comparing open to laparoscopic surgery for stage II/III colon cancer) were used. Eligibility criteria in JCOG0404 included histologically proven colon cancer; T3 or deeper lesion without involvement of other organs; N0-2 and M0. D3 lymph node dissection with or without preserving LCA was identified according to the photographs of the resected field collected for central surgical review in JCOG0404. The short and long-term outcomes were compared between each procedure. Results: Among all randomized 1057 patients in JCOG0404, 631 patients who received assigned sigmoid colectomy and anterior resection were included in the subgroup analysis. The number of patients were 135 in Group A and 496 in Group B. The patient backgrounds did not differ between groups. The median operative time, median blood loss, and the proportion of grade 1 or more anastomotic leakage and intestinal paralysis were not remarkably different (Group A vs. Group B: 185 min vs 186 min, 60 ml vs. 50 ml, 3.0% vs. 5.0%, and 2.2% vs. 3.8%). However, overall postoperative complication occurred more in Group B than in Group A (9.6% and 21.6%, p = 0.022). In terms of efficacy, 5-year relapse-free survival (RFS) and overall survival (OS) tended to be better in Group A than Group B (RFS: 83.7% and 80.5%, HR 1.25 (95% CI 0.79-1.96), OS: 96.3% and 91.1%, HR 2.47 (95% CI 1.13-5.40)). Conclusions: Short and long-term outcomes were better in Group A than Group B. It was considered that D3 lymph node dissection preserving LCA could be alternative treatment for D3 lymph node dissection. Clinical trial information: C000000105.
Long-term outcomes of surgical resection of lung metastases from colorectal cancer.
Authors: Mori Ryota , Kagawa Yoshinori , Yukawa Yoshiro , Toya Keisuke , Takase Kouki , Nose Yohei , Kawai Kenji , Sakamoto Takuya , Naito Atsushi , Murakami Kohei , Katsura Yoshiteru , Ohmura Yoshiaki , Masuzawa Toru , Takeno Atsushi , Takeda Yutaka , Kato Takeshi , Yamamoto Aya , Toda Michihito , Iwata Takashi , Murata Kohei
Published: January 2019

655

Background: The lungs are one of the most frequent sites of metastases from colorectal cancer(CRC). Surgical resection has been widely performed on patients with pulmonary metastases from CRC with favorable outcomes. Surgical treatment is considered an effective option, but the surgical indications of lung resection have institutional bias. In our hospital, we aggressively perform surgery for lung metastases when the primary tumor and other metastases are controlled and all lung metastases are resectable. In this study, the aim is to investigate the long-term outcomes of resections of lung metastases from CRC in our institute. Methods: Between April 2009 and November 2017, patients who underwent lung resections for metastases from CRC with curative intent in our hospital were investigated retrospectively. Kaplan-Meier survival curves, log-rank tests, chi-squared test and T-test were used to analyze the survival rates and the factors predicting recurrence. Results: Sixty-seven patients underwent lung resection of metastases from CRC. The median follow-up period was 25.3 (6-60) months. Five-year disease free survival was 33.6 % and 5-year overall survival was 63.9%. Because of pulmonary recurrence, second surgery was performed in 16 patients and a third surgery in three patients. 5-year overall survival rate after first lung resection in patients who underwent repeated lung resection was 49.2%. There was no significant difference between the number of patients with pulmonary recurrence and those with no recurrence after lung resection (p = 0.38). Twenty-one patients had experienced prior liver resection; the 5-year overall survival rate after lung resection in these patients was 57.9 %. Factors predicting recurrence were vascular invasion (v ≥ 2) of primary tumor (p = 0.02), pre-operative serum CEA (p = 0.03) and CA-19-9 (p = 0.04). Conclusions: The outcome of lung resection of metastases from CRC in our hospital was satisfactory. Aggressive lung resection for cases even after liver resection and repeated pulmonary recurrence may improve long-term outcomes.Vascular invasion of primary tumor and the pre-operative serum CEA and CA 19-9 level can be predictive markers for recurrence.
Safety of bevacizumab in cancer patients with inflammatory bowel disease.
Authors: Herrera Gomez Ruth Gabriela , Gallois Claire , Adler Marcel , Malka David , Planchard David , Pistilli Barbara , Ducreux Michel , Mir Olivier
Published: January 2019

664

Background: Digestive and non-digestive cancers in patients with inflammatory bowel disease (IBD) are potentially sensitive to bevacizumab-based chemotherapy. Previous reports have suggested an increased toxicity in IBD patients receiving anti-VEGF agents. The safety of bevacizumab in this population is poorly documented. Methods: A retrospective review of records of patients with IBD treated with bevacizumab-containing chemotherapy for metastatic solid tumors in Gustave Roussy hospital between 2007 and 2016. Results: Twenty eight patients (median age 43, range: 23-73) with a past history of IBD (6 ulcerative colitis, 22 Crohn’s disease) were identified. IBD was considered severe in four pts (13%). Patients presented a good control of IBD symptoms with a median number of 0 (range: 0-2) disease flares during the two years before bevacizumab initiation. Three patients were receiving corticosteroids, and another four were receiving mesalazine for IBD. No patient had abscess, fistula or hemorrhage at the time of bevacizumab initiation. The treated cancer was: colon (n = 8), rectum (n = 5), small bowel (n = 5), NSCLC (n = 4), ovary (n = 1), breast (n = 3) and other (n = 2). Patients received chemotherapy [5-FU-based (LV5FU2, FOLFOX or FOLFIRI) in 17, oxaliplatin in 7, irinotecan in 8, taxanes in 7] with bevacizumab given at the approved dose-intensities of 2.5 mg/kg/week (19 pts) or 5 mg/kg/week (7 pts). Records of chemotherapy from 2 patients were missing. A median number of 8 cycles of bevacizumab(range: 2-39) was given concomitantly to chemotherapy and then as maintenance therapy, with the following grade ≥2 toxicities: hypertension in 6 cases (20%) and proteinuria in 3 cases (10%). No dose-limiting toxicity was observed. No change in IBD treatment was required. One patient developed grade 2 rectorragia (identified as Crohn’s disease flare-up) after 6 months of bevacizumab+ FOLFIRI. After withdrawal of irinotecan, the patient was re-challenged with bevacizumab for another 6 cycles without recurrence of bleeding. Conclusions: In our experience, bevacizumab can be given to cancer patients with quiescent IBD at conventional doses with good clinical tolerance.
Examining the effects of BET, HDAC2, and EZH2 inhibition on esophageal adenocarcinoma (EAC) cell line proliferation.
Authors: Kofonikolas Kleovoulos , Frankell Alex M , Smyth Elizabeth Catherine , Fitzgerald Rebecca C.
Published: January 2019

68

Background: EACs often carry amplifications in MYC (19%) and mutations in the SWI/SNF complex (13%) which act as oncogenic drivers. Targeting of MYC-amplified tumors via BET inhibition, as well as HDAC2 or EZH2 inhibition in SWI/SNF-mutated tumors, show promise in hematological cancers, and solid tumors, respectively. Herein, we investigate the effects of BET, HDAC2, and EZH2 inhibition on EAC cell line proliferation. Methods: MYC-wild type (n = 5), MYC-amplified (n = 2), SWI/SNF-wild type (n = 6) and SWI/SNF-mutant (n = 1) EAC cell lines that have undergone whole genome sequencing (WGS) were plated at 10% confluency and treated with BET (JQ1), pan-HDAC (SAHA), and EZH2 (EPZ-6438) inhibitors at various concentrations. The CellTiter-Glo cell proliferation assay was used to compare the effects of drug treatment on proliferation between different cell lines and drug concentrations before and after treatment. Results: MYC-amplified EAC cell lines were more sensitive to BET inhibition (Table); GI50 concentrations for JQ1 are comparable to those achieved in melanoma and lymphoma cell lines, cancer types in which clinical activity has been demonstrated. ERBB2 amplified or ERBB2 mutant EAC cells were also sensitive to BET inhibition. HDAC2 inhibition reduced proliferation of both SWI/SNF-wild type and mutant cell lines at high concentrations, whilst all cell lines were resistant to EZH2 inhibition, even at the highest concentrations used. Conclusions: MYC amplified EAC tumors appear to be sensitive to BET inhibition; these results warrant further evaluation in pre-clinical models and clinical trials. HDAC2 and EZH2 inhibition were ineffective in both the SWI/SNF-wild type and mutant type EAC cell lines; these therapies are less likely to provide benefit for EAC patients. [Table: see text]
A phase Ib study of pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver metastatic colorectal cancer (CRC).
Authors: Turk Anita Ahmed , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , LoConte Noelle K. , Mulkerin Daniel , Kim David H. , Matkowskyj Kristina , Weber Sharon M. , Abbott Daniel , Eickhoff Jens C. , Bassetti Michael F. , Deming Dustin A.
Published: January 2019

680

Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intratumoral and a rapid influx of responding immune cells. We hypothesize that radiation enhances immunogenicity of MSS CRC and potentiates effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety of this regimen and the recurrence rate at one year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: Nine patients (median age 61.5 [range 39-69]) have completed the intended neoadjuvant therapy, operative management and at least one adjuvant cycle of Pem. All patients received prior FOLFOX. Any-grade AEs (> 20%) through cycle 2 of Pem attributable to SBRT include fatigue (44%) and nausea (22%). Any-grade AEs related to Pem include lymphopenia (25%). Postoperative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. One patient developed a rash following SBRT and Pem which may be an immunotherapy-related toxicity. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT, Pem, and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity. Clinical trial information: NCT02837263.
Wait times for colorectal cancer patients in a universal healthcare system over a decade: Is it sustainable?
Authors: Delisle Megan E , Helewa Ramzi , Park Jason , Hochman David J , McKay Andrew
Published: January 2019

697

Background: Delays in treatment for colorectal cancer (CRC) may worsen prognosis and increase patient anxiety. This study aims to understand population-based trends and variations in wait times (WTs) for CRC in a universal healthcare system over a decade. Methods: Patients diagnosed with stage I-IV CRC in Manitoba, Canada between 2004 and 2014 were included. Data were obtained through province-wide administrative claims and cancer registry. WTs were defined as time from index contact to pathological diagnosis (diagnosis WT), time from pathological diagnosis to first treatment (treatment WT) and total (diagnosis + treatment WT). Index contact was the consult preceding the first gastrointestinal investigation in the year preceding the date of diagnosis. First treatment was radiation, chemotherapy or surgery. The association between WTs and year of diagnosis was estimated using Negative Binomial regression and reported as incidence rate ratio (IRR). Variability in WTs by year were estimated using the Coefficient of Variation (CV) and average annual percent change (AAPC). A CV > 100 indicates high-variability and < 100 indicates low-variaability. Results: A total of 5359 patients were diagnosed with CRC (1802 rectal vs 3557 colon). WTs increased overall. Total WTs for rectal cancer increased by 6% (IRR 1.06, 95% CI 1.04-1.07, p < 0.01) per year from a median of 90 days in 2004 to 147 days in 2014. This was due increases in time to diagnosis (IRR 1.07, 95% CI 1.06-1.09, p < 0.01) and treatment (IRR 1.04, 95% CI 1.03-1.06, p < 0.01). Total colon cancer WTs increased an estimated 5% (IRR 1.05, 95% CI 1.04-1.06, p < 0.01) per year from a median of 89 days in 2004 to 110 days in 2014. This was due to both time to diagnosis (IRR 1.05, 95% CI 1.04-1.07, p < 0.01) and treatment (IRR 1.03, 95% CI 1.02-1.04, p < 0.01). There was increasing variability in total WTs. The CV increased from 87 in 2004 to 102 in 2014 in rectal cancer (AAPC +3.85%) and from 86 in 2004 to 128 in 2014 in colon cancer (AAPC + 5.04%). Conclusions: Total WTs for CRC in Manitoba have increased from 2004 and 2014. This may reflect the growing challenges in providing increasingly complex cancer care to geographically dispersed populations in a universal healthcare system.
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

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

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.
Wnt/Fgf crosstalk is required for the specification of basal cells in the mouse trachea
Authors: Hou Zhili , Wu Qi , Sun Xin , Chen Huaiyong , Li Yu , Zhang Yongchun , Mori Munemasa , Yang Ying , Que Jianwen , Jiang Ming
Published: January 2019

Basal progenitor cells are crucial for the establishment and maintenance of the tracheal epithelium. However, it remains unclear how these progenitor cells are specified during foregut development. Here, we found that ablation of the Wnt chaperone protein Gpr177 (also known as Wntless) in mouse tracheal epithelium causes a significant reduction in the number of basal progenitor cells accompanied by cartilage loss in Shh-Cre;Gpr177loxp/loxp mutants. Consistent with the association between cartilage and basal cell development, Nkx2.1+p63+ basal cells are co-present with cartilage nodules in Shh-Cre;Ctnnb1DM/loxp mutants, which maintain partial cell-cell adhesion but not the transcription regulation function of β-catenin. More importantly, deletion of Ctnnb1 in the mesenchyme leads to the loss of basal cells and cartilage, concomitant with reduced transcript levels of Fgf10 in Dermo1-Cre;Ctnnb1loxp/loxp mutants. Furthermore, deletion of Fgf receptor 2 (Fgfr2) in the epithelium also leads to significantly reduced numbers of basal cells, supporting the importance of Wnt/Fgf crosstalk in early tracheal development.
Recent developments in non-coplanar radiotherapy
Authors: Smyth Gregory , Evans Philip M , Bamber Jeffrey C , Bedford James L
Published: January 2019

This paper gives an overview of recent developments in non-coplanar intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Modern linear accelerators are capable of automating motion around multiple axes, allowing efficient delivery of highly non-coplanar radiotherapy techniques. Novel techniques developed for C-arm and non-standard linac geometries, methods of optimization, and clinical applications are reviewed. The additional degrees of freedom are shown to increase the therapeutic ratio, either through dose escalation to the target or dose reduction to functionally important organs at risk, by multiple research groups. Although significant work is still needed to translate these new non-coplanar radiotherapy techniques into the clinic, clinical implementation should be prioritized. Recent developments in non-coplanar radiotherapy demonstrate that it continues to have a place in modern cancer treatment.