bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic significance of Musashi 2 (MSI2) RNA-binding protein expression in precancerous polyps and during colorectal cancer (CRC) progression.
Authors: Kharin Leonid , Karnaukhov Nikolay S. , Voloshin Mark , Milakin Anton G. , Bychkov Igor , Deneka Alexander , Frantsiyants Elena M. , Kit Oleg Ivanovich , Golemis Erica , Boumber Yanis
Published: May 2020

e16009

Background: The RNA-binding protein Musashi-2 (MSI2) controls the translation of proteins that support stem cell identity and lineage determination. Elevated expression of MSI2 plays an important role during progression, dissemination, and drug resistance in numerous solid and hematological malignancies. This study assessed MSI2 as potential clinical biomarker in colorectal cancer (CRC) and pre-malignant disorders of colon mucosa. Methods: This study included 125 patients, of whom 20 had tubulovillous adenomas (TAs) of the colon, and 105 had verified colorectal cancer. Of the 105 patients with CRC, 45 had locoregional invasion (stages I-III). The remaining 60 patients had liver metastases (mCRC), with 31 patients diagnosed with synchronous and 29 with metachronous metastases. We used immunohistochemical (IHC) approach to measure MSI2 expression in matching specimens of normal versus TA tissues, normal versus primary CRC tumor, and normal versus metastatic CRC, followed by correlative analysis in relation to clinical outcomes. In parallel, the biological effects of overexpressing or depleting MSI2 expression in human CRC cells were analyzed in vitro using qRT-PCR, western blot, proliferation and clonogenic assays. Results: MSI2 expression in patient samples was significantly elevated in TAs versus primary tissue (p < 0.002), and was further elevated in primary tumor, and in metastatic sites (p < 0.0001 versus normal tissue, p < 0.003 versus TAs). MSI2 expression positively correlated with decreased progression free survival (PFS) and overall survival (OS), lower tumor grade, and right-side localization (p = 0.004) of tumors. In vitro knockdown of MSI2 in CRC cells suppressed of proliferation, survival and clonogenic capacities of the cells. Conclusions: Elevated expression of MSI2 is associated with pre-cancerous polyps (TAs) in the colonic mucosa, indicating it is an early event in transformation. MSI2 is further elevated during, CRC progression, and associated with poor prognosis, and loss of MSI2 reduces multiple growth properties of CRC cell models. These data imply a causative role of MSI2 overexpression at multiple stages of CRC formation and progression.
18F-FDG PET scan and liquid biopsy as tools to assess the pace of tumor progression and to predict overall survival (OS) in refractory colorectal cancer (rCRC): The CORIOLAN trial.
Authors: Camera Silvia , Akin Telli Tugba , Woff Erwin , Kehagias Pashalina , Guiot Thomas , Critchi Gabriela , Bregni Giacomo , Trevisi Elena , Pretta Andrea , Deleruelle Amélie , Senti Chiara , Leduc Sophia , Shaza Leila , Hoerner Frédéric , Vandeputte Caroline , Sclafani Francesco , Flamen Patrick , Hendlisz Alain , Deleporte Amélie , Rothe Francoise
Published: May 2020

e16012

Background: Decision making in rCRC patients (pts) who have exhausted all available therapies is challenging. Clinical trials, treatment re-challenge and best supportive care are possible options. There are limited data, however, to predict pt outcome and guide treatment choices. Methods: CORIOLAN was a prospective, single-centre, single-arm trial. Eligible pts had to have an ECOG PS of ≤1, a life expectancy of ≥12 weeks (wks) and had to have received prior standard chemotherapy and targeted agents. No cancer treatment was allowed within 4 wks prior to study entry. 18F-FDG PET scan and blood sample collection were carried out at baseline and after 2 wks. No treatment was given between these timepoints, while further management was left to the treating physician. The primary objective was to evaluate the association between tumour metabolic progression index as defined by changes of the whole-body metabolically active tumour volume (WB-MATV) and OS. Exploratory objectives included evaluation of the prognostic value of circulating biomarkers such as cell-free DNA (cfDNA), circulating tumour cells (CTCs, CellTracks Analyzer II, CellSearch) and CEA. Validated cut-off values, Kaplan-Meier method, Cox proportional hazards model and logrank tests were used (R version 3.5.1). Results: From 2012 to 2018, 47 eligible pts were enrolled. Median age: 65 years (38-82). ECOG PS 1: 64%. Males: 53%. Left-sided tumours: 71%. Metastases: lung (83%), liver (66%), lymph-nodes (45%), peritoneum (30%), bone (21%). Known RAS/BRAF mutations: 57%/0%. Median number of prior treatments: 5 (2-8). At the time of analysis, 45 deaths had occurred, with 26% of pts dying within 12 wks. The median relative delta between WB-MATV at baseline and after 2 wks was +21%. Changes of WB-MATV, however, failed to predict OS (p≥0.383). Similarly, no association was observed between changes of any of the circulating biomarkers investigated and prognosis. By contrast, low WB-MATV (9.4 vs 4.2 months, HR 0.65, p = 0.003), low cfDNA (7.0 vs 4.7 months, HR 0.58, p = 0.015), low CTC count (7.5 vs 3.3 months, HR 0.67, p < 0.001) and low CEA (7.0 vs 4.4 months, HR 0.58, p = 0.053) at baseline were associated with longer OS. Conclusions: This study confirms the inaccuracy of life expectancy estimation for rCRC pts based on a physician judgement largely relying on conventional criteria. Baseline assessment of WB-MATV, cfDNA, CTCs and CEA, but not early change evaluation of the same, may help to refine pt prognostication and guide management decisions. Clinical trial information: NCT01591590 .
Association between gut microbiome and T lymphocytes among different primary tumor sites of patients with metastatic colorectal cancer.
Authors: Sun Lingyun , Yan Yunzi , Chen Dongmei , Mao Jun J. , Yang Yufei
Published: May 2020

e16013

Background: Different primary tumor sites could impact colorectal cancer (CRC)’s survival outcomes and treatment effects. Previous studies had found that gut micro-biome distributions were different between left and right colon cancer(LCC, RCC). Out study aimed to further investigate the association between micro-biome and T lymphocytes among different tumor sites of patients with metastatic CRC. Methods: Between April 2018 and Mars 2019, we enrolled 40 metastatic CRC patients in Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China. We collected patients’ stool samples for micro-biome analysis by 16s rRNA sequencing approaches, as well as patients’ blood samples to analyses T lymphocyte subsets by flow cytometry methods. The study had been proved by ethics committee of Xiyuan Hospital (2016XLA122-1). All patients consented before enrollment. Results: Among 40 patients, 28% were female, with average age of 63±15 years old. There were 10 RCC, 9 LCC and 21 rectal cancer(RC) patients. Alpha diversity analysis showed that sobs index of the micro-biome of patients with RC and RC was significantly higher than whom were RCC(254.89±99, 247±89 versus.[vs.]101.17±51, p= 0.001). PCoA analysis on OTU level detected that first principal component[PC1] (26.24%) could be separated significantly between RCC and LCC( p= 0.048), as well as between RC and RCC (PC1,14.17%, p= 0.024). Community analysis showed that the proportion of Bacteroidetes was significantly higher in patients with RCC than whom with LCC and RC( p= 0.009). Conversely, the proportion of Firmicutes, Proteobacteria and Verrucomicrobia were higher in LCC patients than others( p= 0.37, 0.047 and 0.032 respectively). Canonical Correlation Analysis (CCA) analysis proved that the CD4+ and CD8+ T cells counts were environmental factors, which were significantly associated with certain micro-biome and samples from different tumor sites( p= 0.037 and 0.01 respectively). Trends showed that CD4+ T cells were positively related with samples of RC and bacteria parabacteroides and bifidobacterium, while CD8+ T cells were positively related with samples of RCC and bacteria Lachnospira, Sutterella and Bacteroides. Conclusions: In our study, we found that patients with LCC and RC had more beneficial gut micro-biome than whom with RCC. In addition, such difference might be associated with body T cell immunity.
A multicenter, open-label, phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of JMT-101 in patients (pts) with advanced colorectal cancer (ACC).
Authors: Li Jian , Shen Lin , Gong Jifang , Peng Zhi , Liu Dan , QI Changsong , Yuan Jiajia , Hu Rong , Yang Xiugao , Li Tao , Fu Dongxue , Yang Ruirui , Feng Li , Zhang Peng , Chen Xin , Yuan Jing , Liu Yuanyuan , Wu Zhufeng , Cao Ye , Zhong Shulin
Published: May 2020

e16025

Background: JMT101 is a fully human monoclonal IgG1 antibody targeting epidermal growth factor receptor (EGFR). This study aimed to evaluate the safety and tolerability of JMT101 alone or in combination with chemotherapy in ACC. Methods: This is an open label, dose-escalating, phase I clinical trial. The pts with ACC and naïve to systemic EGFR-targeted therapy were assigned to receive JMT101 monotherapy (JMT101 group, pts with wild-type RAS ACC and had experienced failure of at least one standard regimen) or JMT101 in combination with mFOLFOX6/FOLFIRI (combination group, pts with wild-type RAS/non-BRAF V600E mutant ACC). JMT101 was infused intravenously by accelerated titration and traditional "3+3" dose-escalation scheme. The initial dose of JMT101 monotherapy was 0.5 mg/kg (q1w), and sequentially escalated to 2.0, 4.0, 6.0, 8.0, and 10.0 mg/kg (q2w). Until the dose of JMT101 group was escalated to the higher dose and sufficient safety data were obtained, the dose of the combination group would be escalated sequentially from 6.0, 8.0, to 10.0 mg/kg (q2w). The primary endpoints were safety and tolerability. The secondary endpoints were clinical efficacy and pharmacokinetic parameters. Results: From April 2017 to December 2019, 16 enrolled pts in JMT101 group (13 males, 3 females, median age 59.5 [27-64] years) and 7 in combination group (4 males, 3 females, median age 49 [39-68] years) were evaluable. The dose of JMT101 was escalated to 10.0, 8.0, 6.0 mg/kg in JMT101 group, mFOLFOX6 group and FOLFIRI group, respectively. Dose-limiting toxicity was not observed, maximum tolerated dose was not reached, and treatment-related SAE was not reported so far. JMT101 monotherapy and combination therapy were associated with grade 1 (15 and 7 cases), grade 2 (10 and 7 cases), and grade 3 (5 and 5 cases) AEs. In all groups, the most common AEs were skin rash (81.3% [13/16] in JMT101 group, 100% [7/7] in combination group), proteinuria (62.5% [10/16] in JMT101 group, 28.6% [2/7] in combination group) and oral mucositis (86.0% [6/7] in combination group). JMT101 monotherapy and combination therapy resulted in partial response (2 and 4 pts), objective response rate (12.5% and 57.1%), disease control rate (56.2% and 100%), and disease control > 24 weeks (4 and 3 pts). Conclusions: JMT101 shows good safety, tolerability, and antitumor activity in pts with ACC. Clinical trial information: 20160904 .
The role of combined treatment of metastatic colorectal cancer inpatients with liver metastases.
Authors: Trandofilov Mikhail , Gridnev Danila , Popov Anatoly , Sizova Anna , Islamova Dina , Makarov Vladislav , Kostirev Semen
Published: May 2020

e16026

Background: Combined treatment for patients with metastatic colorectal cancer (mCRC) offers better long-term outcomes and chemotherapy can increase the rate of hepatic resectability for patients with initially inoperable disease. Methods: The analysis included 132 patients diagnosed with mCRC having metastases in the liver treated from 2015 to 2020. Of these, 62 (47%) were men and 70 (53%) women. The average age of the patients was 63 years. At the beginning of the treatment, the overall condition of all patients met ECOG 0-1 points. Primary metastatic CRC had 93 (71%) patients. A total of 39 (29%) patients were diagnosed with advanced disease. Localization of the primary tumor in 25 patients (18.9%) was in the right part of the large intestine and 107 (81.1%) in the left part of the colon. At the time of the sample, metastases were detected only in the liver in 73 patients (55.3%). In the remaining 59 (44.7%) other organs were affected besides the liver. Various types of surgical treatment of metastases in the liver received 42 (31.8%) patients. The decision on the choice of chemotherapy was made by the attending physician on the basis of the recommendations of NCCN and RUSSCO, taking into account the molecular genetic characteristics of the tumor. The decision to apply and choose the method of surgical treatment was taken in conjunction with the surgeon. Results: From the general population of patients receiving complex therapy, 2 groups were identified, between which a comparison was made. The first group (group A) was 42 (31.8%) patients who received some surgical treatment of the liver. The second group (group B) included 90 (68.2%) patients, who for some reason or another, did not receive any surgical treatment. The groups are fairly homogeneous in their characteristics. The median overall survival (OS) in group A was 40.1 months, and in group B, 22.3 months. A similar trend continued in subgroup analysis. The calculation of the PFS was complicated by the fact that surgical operations were given at different stages of complex treatment. Three-year survival in group A was approximately 50%, and in group B, 28%. "Five-year" survival (In those patients who were observed from the start of the study for all 5 years) in group A was 15 %, and in group B, 5,5%. Conclusions: The inclusion of modern surgical techniques in the complex therapy of metastatic colorectal cancer, if possible, at any stage, can significantly increase the life expectancy of patients.
An open-label, single-arm, phase I study to assess the safety, efficacy, and biomarker effects of OMT-110 in patients with refractory colorectal cancer.
Authors: Park Soobong , Lee Haejun , Jeong Keun-Yeong , Baek Jeong-Heum , Chang Chong-Hwan
Published: May 2020

e16027

Background: A metabolism modulatory anticancer durg candidate, OMT-110, has been applied for phase I clinical trial to evaluate the effect of OMT-110 on safety, efficacy, and biomarker in patients with refractory colorectal cancer resistant to standard therapies. FDG PET-CT has been suggested to be a resonable biomarker for a metabolism modulator and tested as a possible biomarker for OMT-110 in the clinical trial. Methods: The study was composed of 4 cohorts with a specified dose of 12.5, 25, 50, and 100 mg, and each cycle consisted of daily subcutaneous injections for 3 consecutive weeks and had a resting period of 1 week. 3 subjects were enrolled in each cohort in a total of 12 patients. FDG-PET/CT was utilized as a biomarker and the SUVmax was evaluated according to European Organisation for Research and Treatment of Cancer (EORTC) criteria. Results: None of the subjects permanently discontinued or reduced the dose of the investigational drug due to dose-limiting toxicity. Serious drug adverse reactions that resulted in permanent discontinuation of investigational drugs were not reported. Biomarker evaluation using FDG-PET/CT revealed that the tumor responses of 9 from total 9 subjects who completed FDG-PET/CT evaluation by Cycle 2 (8 weeks) were stable metabolic disease (SMD) or higher . In particular, four subjects showed a clear tendency for a decrease in glucose transporting and were evaluated by partial metabolic response (PMR). The result was compatible with the response of Chest CT and APCT according to RECIST. Conclusions: In the study, the results of FDG/PET-CT show OMT-110 modulates the cancer-specific metabolism and thus reduces glucose transportation. Based on the study outcome, FDG PET-CT is possibly considered as a biomarker of OMT-110 and further study is warranted.
Efficacy and safety of fruquintinib in the treatment of poor patients with metastatic gastrointestinal cancer.
Authors: Cui Yanzhi , Jiang Da , Zhang Xue , Huang Fang , Fan Shaoshuang , Wang Long , Hou Ran
Published: May 2020

e16028

Background: To explore the efficacy and safety of fruquintinib in the treatment of poor PS patients with Metastatic colorectal cancer. Methods: The data of patients who were treated with fruquintinib in oncology department of our hospital from December 2018 to Janurary 2020 were analyzed retrospectively. Fruquintinib 5mg/ days, 3 weeks of withdrawal for 1 week, 4 weeks as a course of treatment, until the disease progression, death or voluntary cessation of treatment. When side effects occurred, the corresponding anti-symptomatic treatment can be given, if the drug side effects still intolerable, the drug was reduced to 4mg/ days or stop treatment. The adverse drug reactions were evaluated by CTCAE 4.0. The curative effects were evaluated by RECIST Version 1.1. All patients were followed up once every 28 days until the disease progression, death or voluntary cessation of treatment. Results: A total of 9 patients were included, including 2 patients with right metastatic colon cancer, 3 patients with advanced rectal cancer, the incidence of fruquintinib side effects was 100%, which occurred in the first 2 months of treatmentand was common in grade 1 and 2. The common symptoms were hypertension (100%),hand and foot skin reaction (50%), proteinuria (12.5%), dysphonia (31.4%), etc.Incidence of severe side effects was 12.5%, hypertension. Conclusions: The adverse reactions of fruquintinib often occurred within 2 months of treatment, most of which were grade 1 or 2; the patients can benefit from fruquintinib in physical state and organ function.
Evaluation of prognosis of rectal cancer patients with neoadjuvant chemoradiotherapy by clinical TNM stage: Is it suitable?
Authors: Chen Yue , Zhang Rui , Dong Xinxin , Liu Fang
Published: May 2020

e16029

Background: In the Union for International Cancer Control /American Joint Committee on Cancer TNM classification system, the prognosis of rectal cancer patients with adjuvant treatment are based on pre-radiotherapy clinical TNM stage. However, the value of this classification system is still debated. Here, we find that neoadjuvant pathologic TNM stage may be better than clinical TNM stage in patients with rectal cancer. Furthermore, we propose a novel risk stratification which may be more accurate in the assessment of prognosis of these patients. Methods: Between 2010 and 2015, 316 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy followed by radical surgery were included for analysis. The clinicopathological factors for developing recurrences that affected prognosis were analyzed. Results: Our findings showed that the pathological complete response group had significantly better overall survival and recurrence-free survival than did the non-pCR group. Clinical N stage was not only an independent factor for developing recurrences but was also a significant prognostic factor in the pCR group, just as neoadjuvant pathologic TNM stage in the non-pCR group. Based on the independent prognostic factors, pCR patients were stratified into two recurrence risk categories: pCR with cN0 stage or pCR with cN+ stage. Non-pCR patients were stratified into three recurrence risk categories: non-pCR with ypTNM I stage, ypTNM II stage or ypTNM III stage, which might offer greater potential for the prognosis of patients with rectal cancer. Conclusions: Neoadjuvant pathologic TNM stage, rather than pre-radiotherapy clinical TNM stage, was an independent factor for developing recurrences in the non-pCR group. Furthermore, a novel risk stratification, which may be more accurate in the assessment of prognosis of rectal cancer patients, was proposed.
Phase I study (PAYLOAD) of RRx-001 + irinotecan in patients with advanced solid malignancies.
Authors: Kim Edward Jae-Hoon , Carter Corey Allan , Reid Tony R. , Caroen Scott , Oronsky Bryan , Abrouk Nacer D , Quinn Mary Flanagan , Poplin Elizabeth
Published: May 2020

e16031

Background: RRx-001 is a downregulator of CD-47 and SIRP-alpha, which demonstrated a clinically meaningful improvement in OS and PFS vs. regorafenib when dosed sequentially with irinotecan in a 3rd/4th line colorectal cancer randomized trial called ROCKET (NCT02096354). Recently, RRx-001 has been shown to downregulate PD-L1 on circulating tumor cells. This phase 1 trial named PAYLOAD (NCT02801097) was performed to assess the safety and tolerability of the combination of RRx-001 and irinotecan and to determine a recommended phase II dose (RP2D). Methods: Eligible patients (pts) had adequate organ and bone marrow functions and an ECOG of 0-2 and evaluable refractory advanced solid tumors. RRx-001 was administered once per week for 3 weeks and thereafter once every two weeks. RRx-001 was administered as a 10-15 min IV infusion with irinotecan, which began on Week 4 and which was also given every other week, staggered with RRx-001 . Dose escalation followed a standard 3 + 3 design with co-escalation of RRx-001 and irinotecan as follows: 1: Irinotecan 120 mg/m2 + RRx-001, 0.5 mg 2: Irinotecan 120 mg/m2 + RRx-001, 2 mg 3: Irinotecan 120 mg/m2 + RRx-001, 4 mg 4: Irinotecan 150 mg/m2 + RRx-001, 4 mg Radiological imaging was performed every 8 weeks. Results: 12 pts; 1 gallbladder, 1 ampullary carcinoma, 1 cholangiocarcinoma, 5 colon, 1 GE junction, 2 pancreatic and 2 rectal cancers were enrolled from January 2018 to November 2018. 1 and 18 doses (median: 6 doses) of the combination of RRx-001 and irinotecan were received. The median number of prior treatments was 4 (range 1-5). There were 2 Grade 3 events, leukopenia and anemia, judged not related to RRx-001 but related to irinotecan, 1 Grade 4 event, leukopenia, judged not related to RRx-001 but related to irinotecan and 1 Grade 5 event, neutropenic enterocolitis, also judged not related to RRx-001 but related to irinotecan. No dose-limiting toxicities were identified. The median overall survival was ~ 6.5 months. Conclusions: Alternating weekly infusions of 150 mg/m2 of irinotecan and 4 mg of RRx-001 were well tolerated. No Grade 2 or above diarrhea was observed with irinotecan treatment, which suggests that RRx-001 may protect against gastrointestinal (GI) toxicities, since RRx-001 has also demonstrated anti- oral mucositis and anti-diarrheal properties in other studies.This dose level is the recommended phase 2 dose for future trials. Clinical trial information: NCT02801097 .
Toxicity and tolerance profile of ANTI-EGFRS in metastatic colorectal cancer RAS wild type from the east of Algeria.
Authors: Abdelaziz Ammari , Djebnoune Linda , Khater Besma , Benmansour Aicha , Bensalem Assia
Published: May 2020

e16032

Background: The results of the different studies showed that the use of anti-EGFRs (Epidermal Growth Factor Receptor) in the management of mCRCs, confront the healthcare team to a new toxicity which until then, were unknown before the era of anti EGFRs. knowing that there were no Algerian patients in these studies, reason for us to do this work. Methods: Between October 2015 and October 2018, our work consists of an epidemiological, observational, descriptive, longitudinal prospective study, including all patients with metastatic colorectal cancer RAS wild type, receiving specific medical treatment with anti EGFR (Panitumumab or Cetuximab) from Medical Oncology Department of Didouche Mourad Hospital of Constantine and the Medical Oncology Department of Batna’s Anti Cancer Center, performance status 0-2, and age 18-75 years. We have completed this work whose main objective is to evaluate the toxicity of anti EGFRs in patients with mCRC RAS wild-type from the east of Algeria. Results: 60 patients received an anti EGFR (Panitumumab or Cetuximab), in our study the most common toxicity was folliculitis with an average onset time of 3.36 weeks and a frequency of 83% of grade 2 and 3. Xerosis was observed in 71% of patients. Paronychia was observed in 50% of patients, in addition to the classical toxicities observed with the different chemotherapy regimens used in mCRCs. For secondary objectives, the median progression free survival in our study was 12 months, with a 95% confidence interval [10,787-13,213]. This median progression-free survival is comparable to those reported in the major anti-EGFR trials. Conclusions: Our results suggest that the Algerian patients with metastatic colorectal cancer RAS wild-type have the same profile of toxicity comparing to the results from different international trials studying anti EGFRs.
The role of continuity of systematic treatment and rehabilitation in patients with metastatic colorectal cancer in elderly and senile age.
Authors: Alekseeva Iuliia Vladimirovna , Semiglazova Tatiana , Tkachenko Elena , Kasparov Boris , Brish Nadezhda , Filatova Larisa Valentinovna , Semiglazov Vladislav , Belyaev Aleksey , Klimenko Veronika , Protsenko Svetlana , Teletaeva Gulfiya Midhatovna , Latipova Dilorom H.
Published: May 2020

e16041

Background: The concomitant pathology, cancer and geriatric status affect the organism of a sick elderly person. In routine clinical practice elderly patients require comprehensive geriatric assessment (CGO). Despite many treatment strategies for elderly patients with metastatic colorectal cancer (mCRC), there are no use of rehabilitation programs and the assessment of their impact on the treatment tolerability and survival. Methods: The study includes patients with newly diagnosed mCRC stage IV, receiving the first line of chemotherapy (FOLFOX). Patients are given CGO before starting chemotherapy and in dynamics.The following scales are used for geriatric examination: Cumulative Illness Rating Scale for Geriatrics (CIRS-G); Activities of Daily Living (ADL); Daily instrumental activity scale (IADL); Mini nutritional assessment (MNA); Clock Drawing Test (CDT); Geriatric depression scale (GDS). Results: At the moment 29 patients are included in the study. According the results of CGO we determined that elderly and middle-aged patients are similar in cognitive, mental, and nutritional status, but they have statistically significant differences on the MMSE scale (P=0,014). In both groups patients have a decrease in IADL and cognitive functions, the presence of depression. Elderly patients (> 60 years old) are more likely to experience chronic pain (P<0.05) and increased blood pressure (P<0.05) (Table). Conclusions: The management tactics of patients with mCRC in elderly age shouldn't be based only on chronological age, ECOG or the Karnovsky index, that don't reflect functional disorders in patients of the older age group. It is necessary to define algorithms for medical rehabilitation in cancer patients of the older age group. A CGO is aimed at developing a medical rehabilitation plan together with an elderly patient and his environment, and an algorithm for supporting his health status during and after specialized treatment. [Table: see text]
Impact of cetuximab sequence on progress-free survival (PFS) and overall survival (OS) in patients with RAS wild-type metastatic colorectal cancer (mCRC): A real-world study.
Authors: Geng Qirong , Cheng Wenxiu , Chen Zhiyu , Zhang Wen , Zhu Xiaodong , Guo Weijian
Published: May 2020

e16042

Background: Cetuximab provides a clear clinical benefit in the treatment in patients with RAS wild-type mCRC irrespective of treatment line, but the best sequence is still under investigation. Methods: Patients with RAS wild-type mCRC (2011-2019) who received cetuximab therapy were retrospectively analyzed. They were stratified based on the cetuximab treatment sequence, into the 1st, 2nd, 3rd or later-lines groups. The primary objective was to investigate the impact on Cetuximab sequence (2nd vs. 3rd and later-line) in PFS and OS. As for patients received the 3rd or later-line cetuximab with irinotecan therapy after refractory to the prior 1st and 2nd-line combined chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan, they will get another PFS of 2nd-line chemotherapy (PFSchemo) besides the PFS of 3rd or later-line cetuximab compared with the cetuximab 2nd-line used patients. We combined the PFSchemo to the PFS of 3rd or later-line cetuximab, then compared with PFS of 2nd -line cetuximab to evaluate the primary objective in PFS. As for the OS of primary objective, we calculated it from start of the 2nd-line of treatment. The secondary objective was to compare the efficacy of cetuximab sequence (1st vs. 2nd and later-lines) in OS calculated from start of the 1st-line of treatment. Results: In total, 193 patients were included: 106 in the 1st, 41 in the 2nd, and 46 in the 3rd-line groups. No difference was observed in baseline characteristics as sex,age,site of primary tumour,number of metastatic sites in the three groups. The median PFS of the 2nd-line and 3rd or later-line groups were 7.1 (95% CI 6.39-7.80) and 13.87 months(95% CI 11.44-16.29) respectively. PFS of the 3rd or later-line group was significantly longer than that of the 2nd-line group (hazard ratio[HR], 0.552; 95% CI, 0.349 to 0.871; P = 0.01). Median OS was 17.8 months (95% CI 13.5-22.1) in the 2nd-line and 27.4 months (95% CI 20.69-34.16) in the 3rd or later-line group (HR, 0.597; 95% CI 0.341 to 1.043; P = 0.07) from start of 2nd-line therapy. The median OS was 28.17 months (95% CI 22.11-34.22) in the 1st-line group and 33.10 months (95% CI 26.88-39.31) in the 2nd and later-lines group (HR, 0.724; 95% CI 0.507 to 1.304; P = 0.075) calculated from the 1st-line of therapy. Conclusions: In a real-world cohort we found that later-line especially 3rd or later-line therapy of cetuximab, may be more benefit for patients with RAS wild type mCRC, as 3rd or later-line use of cetuximab give one more line therapy chance.
Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status: Analysis of untreated RAS-wildtype mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109).
Authors: Kurreck Annika , Geissler Michael , Martens Uwe Marc , Riera-Knorrenschild Jorge , Greeve Jobst , Florschütz Axel , Wessendorf Swen , Ettrich Thomas Jens , Kanzler Stephan , Dominik Nörenberg , Seidensticker Max , Held Swantje , Buechner-Steudel Petra , Atzpodien Jens , Heinemann Volker , Stintzing Sebastian , Seufferlein Thomas , Tannapfel Andrea , Reinacher Anke , Modest Dominik Paul
Published: May 2020

e16055

Background: In patients with mCRC, dynamics of response and disease progression may play a critical role in the understanding of long-term outcome. Depth of response (DpR), time to DpR and post-DpR survival represent innovative endpoints to evaluate response and disease dynamics. Methods: We evaluated DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR image to tumor progression or death), and post-DpR overall survival (pOS = DpR image to death) with special focus on BRAF mutational status in 66 patients. Results: BRAF wildtype (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (-57.6% vs. -40.8%, p = 0.013) with a comparable time to DpR (BRAF-WT 4.0 (95% CI 3.1-4.4) months vs. BRAF-MT 3.9 months (95% CI 2.5-5.5), p = 0.8852). pPFS was 6.5 (95% CI 4.7-8.4) versus 2.6 (95% CI 1.0-3.9) months in favor of BRAF-WT patients (HR: 0.24 (95% CI 0.11-0.53; p < 0.001). This also transferred into a significant difference in pOS (33.6 (95% CI 30.0-42.1) versus 5.4 (95% CI 4.7-16.1) months, HR: 0.27 (95% CI 0.13- 0.55); p < 0.001). Further data including primary tumor site will be presented at the meeting. Conclusions: BRAF-MT patients treated within the VOLFI-trial derive a less profound response to treatment as compared to BRAF-WT patients. The substantial difference in outcome according to BRAF status is evident after achievement of deepest response with BRAF-MT patients hardly deriving any further disease control beyond DpR. This is reflected by pPFS and pOS. Our observations hint towards aggressive tumor evolution in patients with BRAF-MT-tumors which may already be molecularly detectable at time of DpR. These findings somehow challenge the currently practiced aggressive treatment strategy of FOLFOXIRI-based 1st-line regimens as they may stimulate treatment resistance and suggest that close monitoring of BRAF-MT patients may include the continuous monitoring of clonal evolution.
A precision medicine drug discovery pipeline to identify dual CDK2/9 inhibition as a novel treatment for colorectal cancer.
Authors: Salman Roghani Roham , Sanjari moghaddam Ali , Rupprecht Gabrielle , Altunel Erdem , Kim So Young , McCall Shannon , Thomas Beatrice , Ware Katie , Somarelli Jason , Hsu David S.
Published: May 2020

e16056

Background: Colorectal cancer (CRC) is the 3rdmost common form of cancer in the US, responsible for over 50,000 death each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new therapies to treat this deadly disease. To address this need, we have developed a precision medicine pipeline that integrates high throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDXs) to identify new treatments for CRC. Methods: We used high-throughput chemical screens of 2,100 compounds across five low-passage, patient-derived CRC cell lines. These results were validated using dose-response IC50curves for CDK1, CDK2, CDK9 or CDK1/2/9 inhibitors and by siRNA-mediated knockdown of CDK9 with or without CDK2 inhibition. Cell cycle arrest analysis was performed by flow cytometry and anaphase catastrophe was analyzed by immunofluorescence staining. For in vivo studies, matched PDXs were treated with either CDK2, CDK9 or dual CDK2/9 inhibitors. Results: We identified the CDK inhibitor drug class as among the most effective cytotoxic compounds across all five CRC lines. Further analysis of the CDK inhibitor class revealed that combined targeting of CDK1, 2, and 9 was the most effective, with IC50 in the range of 110 nM to 1.2 μM. We further validated the efficacy of combined CDK2/9 inhibition using siRNA-mediated knockdown of CDK9 in the presence of a CDK2 inhibitor(CVT-313), and showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Dual CDK2/9 inhibition led to significant G2/M cell cycle arrest and anaphase catastrophe. Finally, combined CDK2/9 inhibition in vivo synergistically inhibited PDX tumor growth as compared to single-agent CDK inhibitors. Conclusions: Our precision medicine pipeline revealed CDK2/9 dual inhibition as a combinatorial therapy to treat CRC and can also be used to identify new and novel therapies
Gender disparities in anal cancer incidence and mortality: A long-term US population-based analysis.
Authors: Baidoun Firas , Saad Anas M , Gad Mohamed , Asfari Mohammad Maysara , Sarmini Muhammad Talal , Elkeraie Yasmine , Alkehef Yazan , Al-Husseini Muneer J. , Alhaj Moustafa Muhamad
Published: May 2020

e16059

Background: Anal cancer is an uncommon malignancy accounting for less than 3% of gastrointestinal malignancies in the US. In this large database study, we aimed to re-evaluate the difference in the incidence and mortality trend in both genders. Methods: We used SEER 18 database to study anal cancer cases in the US during 2000-2016. Incidence and mortality rates of anal cancer were calculated by gender and were expressed by 1,000,000 person-years. Annual percent change (APC) was calculated using join point regression software. Results: We reviewed 25,418 patients with anal cancer, of which 61.4% were females. Incidence of anal cancers was 14.375 and 19.427 per 1,000,000 person-years, in males and females, respectively. Incidence rates of anal cancer significantly increased over the study period, but this increase was sharper in females (APC = 2.220%, 95%CI [1.924-2.517], P < .001) when compared to males (APC = 0.915%, 95%CI [0.303-1.531], P = .006). Mortality rates from anal cancer over the study period were 7.425 and 7.532 per 1,000,000 person-years, in males and females, respectively. Overall anal cancer mortality rates did not change between 2000-2009 but started to decrease starting from 2010 and this decrease became sharpest between 2014-2016; APC = -44.905%, 95%CI [-57.572- -28.457], P = .001). Mortality rates followed the same trend in both genders. Conclusions: Anal cancer incidence is increasing with significant increase in the incidence trend is noticed in females compared to males which is a change from the previous trend that was seen from 1973-2000. On the other hand, anal cancer mortality has started to decrease for the first time starting from 2010 with no difference in the mortality trend between males and females. This improvement in mortality rate can be explained by the improvement in early detection rate and possibly improvement in the treatment approach for these high-risk patients.
Immune tolerance to colon cancer is mediated by colon dysbiosis: Human results and experimental In Vivo validation.
Authors: Bergsten Emma , Mestivier Denis , Amiot Aurelien , DeAngelis Nicola , Khazaie Khashayarsha , Sobhani Iradj
Published: May 2020

e16062

Background: Lynch syndrome (Ly) but not Sporadic (Sp) CRC patients are responsive to immunotherapies. We have shown micorbiota from CRC patients induces precancerous colonic lesions in germ-free mice. The aim was to investigate microbiota linked compromised anti tumor immune response. Methods: We compared 1) Whole metagenomic fecal microbiotas of CRC patients [Sp, n = 53+Ly, n = 19] to controls (n = 90) or being first degree relatives of Ly patients (n = 14), respectively; 2) Tumoral to normal mucosa-adherent microbiota (16sRNA sequences); 3) Normal to tumoral tissues’ mRNA RT-PCRs of IL1b, IL4, IL6, IL8, IL17, TNFa, TGFb, FasL, Granzyme A&B, Thy1; 4) CD3, CD4, CD8, Granzym, KL1, FoxP3, RORgT, MastCell, cells in tumor tissues quantified by immunohistochemistry (IHC), between subgroups. Associations between bacteria, tissue immune cell infiltrates and clinical data (3-yrs follow up or death) were established by using unsupervised Systems Biology and Bioinformatics analyses (Institut Pasteur Shaman platform and Qlucor program). Anti tumoral immune response links with bacteria were based on differences between Ly and Sp CRC patients. Tumor tolerance links with bacteria were identified using germ-free mice (n = 185) who orally received microbiota (9 Sp CRC patients vs 9 controls) with colonic mucosa examined 3 months after human fecal transfer (whole exome sequencing, methylchips, IHC for CD3, CD11b, FoxP3, RORgT, ILC3). Results: Enrichment in Peptostreptococcus, Thermodesulfovibrio and diminution in Ruminococcus, Eubacterium, Coprococcus were linked with FoxP3 and IL-17 over expressions in tumor tissues. Enrichment in Escherichia, Enterobacter, Thioalkalimicrobium, and diminution in Eubacterium, Faecalibacterium and Butyrovibrio were associated with higher FoxP3, FasL, Granzyms A&B, Perforin, Thy1 mRNAs/mRNACD3. Diminution of Eubacterium, Dorea, Faecalibacterium genera and enrichment in Fusobacterium, E. Coli/Shigella were associated with higher CD3, FoxP3, GranzymA and B and FOXP3-RORgT cells in tumor tissues. Higher fecal enrichments in oral bacteria (parvimonas micra) and lack of Thermodesulfovibrio enrichment were associated with higher FoxP3-RORgt cells and short survival; in mice ILC3 and FoxP3-RORgT cells were linked with Sp CRC dysbiosis. Species linked with immunotolerance are identified. Conclusions: Fecal and tissue microbiota can impact failure of anti tumoral immune response in sporadic CRC patients by enhancing overexpression of IL-17 and reducing cytotoxic T-cell infiltration in tumors. Clinical trial information: NCT01270360 .
Mutation profile of colon cancer in hispanic population of central California.
Authors: Hinduja Sanjay , Ali Mir , Bukari Mohammed SANI , Chaudhary Uzair Bashir , Mortenson Tanner , Mahmood Omar , Lee Matthew , Chaudhary Fihr
Published: May 2020

e16067

Background: The clinical and mutational profile of Hispanic patients with metastatic colon cancer is not well documented. In this retrospective study, we aim to describe the clinical and mutational profile of Hispanic patients with metastatic colon cancer in central California. Methods: We retrospectively evaluated the clinical and mutational profile of colon cancer at a single institution in Fresno, California from 2010-2019. We selected 136 patients out of which 70 patients self-identified as Hispanic and 66 self-identified as non-Hispanic. We studied clinical parameters and next-generation sequencing via Foundation one testing for these patients. Results: Among Hispanics, there were 43(61%) males and 27(38%) females. The median age at diagnosis was similar in both groups at 57. Right sided colon cancer accounted for 52% of Hispanic patients versus 40% in non-Hispanics. Fifty two percent of Hispanic patients presented with metastatic disease versus 45% in non-Hispanics. The frequency of commonly mutated genes in colon cancer in Hispanics versus non-Hispanics are as follows. KRAS (35.7% vs 37%), NRAS (11% vs 4%) BRAF (8% vs 7%), Her2/neu 0% in both groups. The frequency of other mutations such as TP53, APC, ATM, PTEN, CDKN2A, Myc amplification were also noted to be similar in both groups. PIK3CA mutation was seen in 18.6% of Hispanic patients versus 34% in non-Hispanic population which was statistically significant with a p value = 0.032. Microsatellite instability (MSI) was seen at 3.3% in Hispanics versus 10.6% in non-Hispanics. Tumor mutational burden was similar in both groups. Conclusions: The frequency of actionable mutations was similar in both Hispanic and non-Hispanic patients. Hispanics were noted to have lower PIK3CA and microsatellite instability. Metastatic disease and right sided colon cancer were seen at higher frequency in Hispanic population. Our results were similar to another population-based study which analyzed KRAS mutation with colon cancer patients in Puerto Rico[1]. Larger population based studies would be needed to further assess the differences in this patient population. Ruiz-Candelaria, Y., C. Miranda-Diaz, and R.F. Hunter-Mellado, K-RAS mutation profile in Puerto Rican patients with colorectal cancer: trends from April 2009 to January 2011. Int J Biol Markers, 2013. 28(4): p. e393-7.
Do differences in the microbiome explain early onset in colon cancer?
Authors: Keshinro Ajaratu , Vanderbilt Chad , Stadler Zsofia Kinga , Shia Jinru , Gonen Mithat , Chen Ching-Tung , Cercek Andrea , Mendelsohn Robin B , Yaeger Rona , Zehir Ahmet , Bowman Anita , Weiser Martin R.
Published: May 2020

e16070

Background: Intestinal dysbiosis has been hypothesized as a possible etiology of the increasing incidence of early-onset colon cancer (EO-CC). Here, we compare the microbiome signature in nonmetastatic, microsatellite stable (MSS) EO-CC to average-onset colon cancer (AO-CC). Methods: Specimens from patients with resected stage I-III MSS colon cancer from 2014-2019 were sequenced by MSK-IMPACT, a large panel next generation sequencing (NGS) assay. A validated technique using non-human read sequences from NGS analysis was used to identify the microbial species in tumor tissue. The tumor microbial alpha diversity and differentially abundant microbiome were compared between patients younger than 40 years (EO-CC) with those older than 60 years (AO-CC). Results: Of 275 patients with MSS, 24 (mean 33.6, range 24-39) and 114 patients (mean 70, range 61-90) had EO-CC and AO-CC, respectively. There was no significant difference in clinicopathological features including gender, tumor stage and neoadjuvant treatment between the two groups. EO-CC was more likely to present with left sided disease compared to AO-CC (81% vs. 45%, p = 0.001). There was no significant difference in the tumor microbial diversity (alpha diversity) between the EO-CC and AO-CC (pShannon= 0.95). Although there was a relative abundance of microbial species from bacterial phylum such as Actinobacteria, Deinococcus-Thermus, α-proteobacteria, γ-proteobacteria and δ-proteobacteria in EO-CC compared to AO-CC, this difference was not significant after controlling for multiple comparisons (Table). Conclusions: Our analysis did not reveal a significant difference between EO-CC and AO-CC in both the abundance and diversity of tumor microbial species, suggesting intestinal dysbiosis may not be a major driver in early onset colorectal cancer pathogenesis. However, additional studies with a larger sample size are warranted for further analysis and subgroup comparison. [Table: see text]
A multi-institution analysis of molecular biomarkers in patients with metastatic colorectal cancer in ethnically diverse populations.
Authors: Choudhary Zunaira H , Advani Shailesh M , Ashai Nadia , Tariq Sara , Grothey Axel , Kopetz Scott , Rajdev Lakshmi
Published: May 2020

e16074

Background: Differences in clinical outcomes for metastatic CRC (mCRC) have been reported across racial-ethnic groups, particularly between Hispanics (HA), non-Hispanic Blacks (NHB), and non-Hispanic Whites (NHW), with limited information available among Asian Americans (AA). We examined if there were differences in clinical outcomes by molecular drivers between these groups in a pooled analysis of two institutions serving ethnically diverse patient populations. Methods: We retrospectively examined 1927 mCRC patients from Montefiore Medical Center and the University of Texas MD Anderson Cancer Center. Mutations in KRAS, NRAS, and BRAF were determined by polymerase chain reaction or next generation sequencing. Mutations were then correlated with overall survival (OS). Results: Our patient population consisted of 1153 (61%) NHW, 314 (17%) HA, 320 (17%) NHB and 59 (3.1%) AA. Across subgroups, borderline significant difference in prevalence of BRAF mutation was observed (p = 0.04), with higher prevalence observed among NHW as compared to other groups. No differences were observed for KRAS and NRAS mutation prevalence. In univariate analysis, the median survival for BRAF MT tumors was 18.5 months vs 32 months for BRAF WT tumors (p < 0.0001). Similarly, median OS for KRAS WT, KRAS MT, NRAS WT and NRAS MT was 29.3, 27.4, 31 and 31.5 months respectively, with no differences between groups. In subgroup analysis by race/ethnicity, median OS in BRAF MT NHW was 19.98 months vs 33.48 in BRAF WT NHW (p < 0.0001). Similar trends were observed in HA and NHB. No differences in median OS were observed by KRAS or NRAS mutation status across racial-ethnic groups. Conclusions: This multi-institution study found no meaningful difference in the prevalence of molecular drivers across racial-ethnic groups. Additionally, in our subgroup analyses, OS based on the presence of a specific molecular driver mutation did not seem to vary by race. For example, RAS mutated and BRAF mutated patients showed similar OS across racial-ethnic groups. Our study demonstrates that reported differences in clinical outcomes by race and ethnicity in the literature are unlikely to be dependent on the difference in the presence of certain molecular drivers.