bluuebunny/crossref_metadata_2025 huggingface dataset:
Adherence with the multitarget stool DNA test for colorectal cancer screening in rural southeastern Kentucky.
Authors: Smith Forrest , Elsoueidi Joseph , Wisnieski Lauren , Kolagatla Sandhya , Moka Nagabhishek
Published: January 2022

64

Background: Colorectal cancer (CRC) screening has shown to improve early detection and reduce mortality. Despite, the availability of multiple screening tests for CRC, the current screening rates remains below the national goal. The multi-target stool (MTS) DNA test (commercially known as Cologuard) has contributed to an increase in population adherence to CRC screening and is currently recommended by multiple guidelines. Southeastern Kentucky (SE KY) has a high incidence of colorectal cancer and a low rate of CRC screening. The aim of this study is to assess the adherence to the MTSDNA test in rural SE KY. Methods: A retrospective review of all patients 45 and older with a MTSDNA test ordered between August 2020 and February 2021 at a large primary care group in SE KY. All patients had Tests ordered and kits delivered. Cross-sectional adherence was defined as completion and return of the kit within 180 days from test order and was assessed as overall adherence and by patient characteristics including age, sex and healthcare coverage. Results: 450 tests were ordered. 160 (35%) were male and 290 (65%) females. Mean age was 62 with age range (46-87). 207 tests were returned with a cross-sectional adherence of 46%. Adherence was significantly lower for age 45 - 55 at 35.2% (26.2-45.2) compared to age 55 - 65 at 48.9% (40.9-56.3), 65 and older at 50.0% (42.3-57.7) (P = 0.04). Highest adherence with Medicaid coverage 65.4% [44.3-82.8] and lowest in Managed Care Organization (MCO) coverage 34.0% [4.7-44.2] (P < 0.01). Gender was not associated with adherence (P = 0.75). Conclusions: This retrospective study showed that only 46% of patients were adherent to the MTS DNA test for colorectal screening which is significantly lower than previously reported in larger studies and further studies are needed to identify the barriers to non-adherence to this test, especially in the younger population with alarming increase in incidence of CRC. There is impending need to implement different strategies to improve screening adherence.
Biomarker testing in patients (pts) with metastatic colorectal cancer (mCRC): Perspectives from U.S. oncologists (ONC) in rural areas and urban clusters.
Authors: Lewis Mark Andrew , Stansfield Lindsay , Kelton John M. , Edwards Michelle L. , Lieu Christopher Hanyoung
Published: January 2022

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Background: In the US, pts living in rural areas have higher CRC mortality rates than urban areas. Clinical guidelines recommend testing for BRAF and RAS mutations and deficient mismatch repair/microsatellite instability in pts with mCRC. However, data on biomarker testing rates in rural communities compared with urban areas are limited. We surveyed ONC in the US who practice in rural areas or urban clusters to identify biomarker testing patterns and barriers (data previously reported) and conducted interviews with a select group of respondents to further understand key differences that may contribute to substandard biomarker testing rates in rural areas. Methods: A 2-part (quantitative and qualitative) survey was conducted with ONC who spend > 40% of their time providing direct care to pts in rural areas or urban clusters and who had treated ≥2 pts with stage IV mCRC in the month prior to the survey. After screening, a subset of those who completed the quantitative survey participated in the qualitative survey (a 30-minute, web-assisted, telephone interview). The interview questions targeted 6 areas: clinical practice description, biomarker and genomic testing patterns, pathology and molecular tumor board, tumor tissue journey, electronic health records, and training/educational opportunities. Results: Of the 99 ONC who responded to the quantitative survey, 17 were interviewed for the qualitative survey from June 16–29, 2021. A key finding of the quantitative survey was that although ONC reported being familiar with biomarkers relevant to mCRC, the reported rate of biomarker testing was suboptimal. The interviews probed reasons why testing does not align with current guidelines and found that challenges exist throughout the tumor tissue journey including insufficient tumor tissue available for testing (especially in the relapsed/refractory setting); lack of or limited protocols, clinical decision support systems, reflexive testing, and molecular tumor boards; lengthy and difficult-to-navigate next-generation sequencing reports; and financial toxicity surrounding biomarker tests (especially for underinsured pts), among other barriers. Despite these challenges, ONC reported easy access to third-party reference labs and electronic references, such as NCCN and UpToDate. Although telehealth visits have nearly quadrupled during the COVID pandemic, access to telehealth may be limited for pts living in rural areas or urban clusters. Conclusions: The ONC surveyed reported that practicing in rural/urban clusters poses unique challenges related to tissue acquisition, practice resources, pts’ ability to pay, and clinical knowledge gaps that may affect biomarker testing rates in pts with mCRC. Addressing these gaps is warranted if optimal utilization of precision medicine tools is to be realized.
Prevalence of information needs among emerging and young adult colorectal cancer survivors.
Authors: Yi Serena , Rodriguez Karli , Stal Julia , Cohen-Cutler Sally , Gallagher Phuong , Barzi Afsaneh , Freyer David R. , Milam Joel , Lenz Heinz-Josef , Miller Kimberly Ann
Published: January 2022

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Background: The information needs of young adult (YA) cancer survivors have been described, however, the specific needs of YA colorectal cancer (CRC) survivors are not well-documented. Characterizing the distinct unmet needs of YA CRC survivors is important given their unique cancer experience which may include an ostomy, chronic bowel symptoms, and functional deficits. The purpose of this study was to examine CRC survivors’ unmet needs across general, clinical, and psychosocial domains. Methods: An online, cross-sectional survey was administered via Facebook in collaboration with a national YA CRC patient advocacy organization. Respondents (diagnosed 18-39) endorsed areas in which they required more information on aspects of their lives that may have been affected by their cancer experience. Needs were stratified by life stage (emerging [18-29 years] and young [30-39] adulthood). Results: Respondents (n=189) were colon (40.2%) and rectal (59.8%) cancer survivors with a mean current age of 32.2 years (SD=4.6) and a mean age of 30.2 years (SD=4.3) at diagnosis. Most endorsed items per domain included: nutrition and diet (52.1%), complementary and alternative treatments (45.4%), and talking about your cancer experience with family, friends, and co-workers (36.1%). Survivors in emerging adulthood (n=80), compared with those in young adulthood (n=109), endorsed notably greater needs in: staying physically fit (57.5% versus 38.5%), complementary and alternative treatments (57.5% versus 36.7%), and advice/help about dating and intimate relationships (18.8% versus 6.4%). Conclusions: Overall, half of respondents endorsed a desire for information on nutrition and diet, staying physically fit, and complementary and alternative treatments. Differing endorsement rates by age group indicate the importance of tailored approaches. Optimal counseling, resources, and referrals specific to life stage can mitigate the unmet needs of YA CRC survivors to improve health outcomes and quality of life.[Table: see text]
Preventives for oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.
Authors: Hines Robert Brooks , Schoborg Christopher , Zhu Xiang , Elgin Elizabeth , Zhang Shunpu
Published: January 2022

83

Background: For colorectal cancer patients treated with the chemotherapy drug oxaliplatin, oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect. We conducted an observational comparative effectiveness study to evaluate whether several potential preventives reduced the rate of OIPN diagnosis in the two years following chemotherapy initiation. Methods: This was a retrospective cohort study that utilized the Surveillance, Epidemiology, and End Results database combined with Medicare claims (SEER-Medicare). Eligible patients were diagnosed with colorectal cancer between 2007-2015, 66 years of age or older, and received at least two cycles of oxaliplatin. We used two definitions to denote diagnosis of OIPN: OIPN 1 (diagnosis codes specific to CIPN) and OIPN 2 (additional codes for peripheral neuropathy). Multinomial propensity score weighting was used to balance potential confounders. The Fine-Gray subdistribution hazards model was used to perform a competing risk, time to event analysis for diagnosis of OIPN. Results: There were 4,482 subjects analyzed for the outcome of OIPN 1 (n = 477, 10.1%), and 4,561 for OIPN 2 (n = 1,191, 26.1%). Duloxetine, venlafaxine (marginally significant for OIPN 1), opioids, and minocycline were associated with a decreased rate of OIPN according to both definitions. In addition, memantine and neuromuscular therapy were associated with a decreased rate of OIPN 1 but not OIPN 2. Gabapentin and pregabalin exposure was associated with an increased rate of OIPN diagnosis according to both definitions. Mixed results were obtained for nortriptyline and cannabinoids. Conclusions: This study revealed several potentially effective preventive options for OIPN in colorectal cancer patients receiving oxaliplatin. A limitation of this study is the observational design which cannot directly inform treatment guidelines. However, evidence from this study may serve as preliminary data to support a future randomized clinical trial.[Table: see text]
Efficacy of bevacizumab-based treatment in early-onset treatment-naïve metastatic colorectal cancer patients: An ARCAD database analysis.
Authors: Jin Zhaohui , Dixon Jesse G. , Hubbard Joleen M. , Eng Cathy , Lieu Christopher Hanyoung , Fiskum Jack , Saltz Leonard B. , Hurwitz Herbert I. , Venook Alan P. , Schmoll Hans-Joachim , Fuchs Charles S. , Hecht J. Randolph Randolph , Cremolini Chiara , Diaz-Rubio Eduardo , Punt Cornelis J. A. , Tebbutt Niall C. , Heinemann Volker , Yoshino Takayuki , De Gramont Aimery , Shi Qian
Published: January 2022

101

Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p<0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p<0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p<0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p<0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]
Temsirolimus (T) in patients (pts) with colorectal cancer (CRC) with PIK3CA mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Grem Jean L. , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Khalil Maged F. , Rogosin Shane O. , Salmon John Stuart , Cannon Timothy Lewis , Grantham Gina N. , Halabi Susan , Schilsky Richard L.
Published: January 2022

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Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with PIK3CA mutation treated with T are reported. Methods: Eligible pts had advanced CRC with PIK3CA mutation reported by a genomic test performed in a CLIA-certified, CAP-accredited site selected lab, no standard treatment options, measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Use of T was approved by the TAPUR Molecular Tumor Board in each case. After antihistamine pre-treatment, T was administered at 25 mg IV over 30-60 minutes weekly until disease progression. Primary endpoint was disease control (DC), defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease at 16+ weeks (SD 16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, the study stops for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 10 pts (60% male) with CRC with PIK3CA mutation were enrolled from November 2017 to May 2020. All were eligible for efficacy and toxicity. Demographics and outcomes are summarized in Table. No objective responses (OR) were observed. 1 pt had SD of 16.1 wks duration for a DC rate of 10% (95% CI: 0%, 45%); the null DC rate of 15% was not rejected (p=0.80). 6 pts had at least one grade 3-4 adverse or serious adverse event (AE/SAE) at least possibly related to T, including acute kidney injury, dehydration, decreased platelet count hypertriglyceridemia, mucositis, neutropenia, and scrotal and penile edema. Conclusions: Monotherapy T does not have sufficient clinical activity in CRC pts with PIK3CA mutation for continued evaluation in this pt population. Other treatments should be considered for these pts, including treatments offered in clinical trials. Clinical trial information: NCT02693535. [Table: see text]
Modified FOLFIRINOX (mFOLFIRINOX) in high risk locally advanced rectal adenocarcinomas.
Authors: Prajapati Ramjas , Srinivas Sujay , Ostwal Vikas S , Bhargava Prabhat Ghanshyam , Engineer Reena , Krishnatry Rahul , Peelay Zoya , Desouza Ashwin Luis , Saklani Avanish , Ankathi Suman Kumar , Parulekar Manali , Ramaswamy Anant
Published: January 2022

108

Background: There is limited data with regard to the use of modified 5-fluoroural-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX) in enabling resection and increasing survival of locally advanced rectal adenocarcinomas (LARC) with high-risk characteristics (T4b status, signet ring histology, etc.) post standard neoadjuvant long course chemoradiation (NACTRT) or short course radiation (SCRT) and chemotherapy. Methods: Patients with LARC from January 2018 to December 2020 receiving mFOLFIRINOX (5-Fluorouracil - 1800mg/m2 over 46 hours, Leucovorin 300mg, Irinotecan 135mg/m2, oxaliplatin 65mg/m2) post NACTRT/SCRT to facilitate curative local resection were evaluated. The primary endpoint was event free survival (EFS), where event was defined as disease progression or recurrence post resection after mFOLFIRINOX. Survivals were calculated using Kaplan-Meier analysis. Results: Forty-seven patients were evaluated with a median age of 33 years (Range:18-59), 45% T4b status, 94% radiological circumferential margin (CRM) involved (79% CRM positive post NACTRT/SCRT), 43% extramural venous invasion (n=33) and 36% signet ring histology. 62% had received prior NACTRT and 38% had received SCRT with chemotherapy before receiving mFOLFIRINOX. The most common grade 3 and grade 4 treatment related side effects included diarrhoea (7%), anaemia (4%) and infections (4%). Intended duration of mFOLFIRINOX or beyond was completed in 94% of patients. 60% of patients underwent curative local resection with R0 resection rates of 100% (n=28) and pathological complete response rates of 21%. The most common surgeries done were exenterations and abdominoperineal resections in 22% and 17% patients respectively. With a median follow up of 19 months, 25 patients had recurred or progressed for a median EFS of 20 months [95% confidence interval (CI): 15-24] while median overall survival was 55 months (95% CI: 24-86). Conclusions: Locally advanced rectal cancers with high-risk characteristics are a niche group of cancers with less-than-optimal outcomes post standard neoadjuvant strategies. mFOLFIRINOX appears to be well tolerated in this cohort of patients and enables conversion to curative local resection and potentially improves survival as well.
Perioperative and oncologic outcomes of hepatic artery infusion pump therapy at an expanding HAI program.
Authors: Sharib Jeremy , Liu Annie , Creasy John , Wildman-Tobriner Benjamin , Uronis Hope Elizabeth , Strickler John H. , Hsu David S. , Zani Sabino , Allen Peter J , Lidsky Michael
Published: January 2022

120

Background: Hepatic artery infusion (HAI) is a liver directed therapy to treat unresectable or resected colorectal liver metastases (CRLM) and unresectable intrahepatic cholangiocarcinoma (ICC). Historically, HAI has only been performed at few specialized centers; however, there is increasing expansion to new centers. We previously reported safety outcomes of our index year of HAI therapy. We now report safety, feasibility, efficacy and oncologic outcomes for an expanded cohort of 62 patients in an established HAI program. Methods: Patients selected for HAI by multidisciplinary review were evaluated for demographics and perioperative outcomes. Objective hepatic response was calculated according to RECIST 1.1. Overall, hepatic and extrahepatic progression-free survival (PFS) were calculated by the Kaplan-Meier method on an intent-to-treat basis. Results: 62 patients were treated with HAI from November 2018-September 2021: 46 for unresectable CRLM, 8 as adjuvant HAI for resected CRLM, and 8 for unresectable ICC. Median age was 54.5 years (range 32-80), 58% were male, and 97% received prior chemotherapy (median 12 cycles, range 0-66). Hepatectomy (18, 29%) and/or colectomy/proctectomy (27, 43.5%) was performed concurrently with pump placement, and 19 (30.6%) were performed robotically. Median operating time was 265 minutes (range 130-526), estimated blood loss was 100 mL (range 22-1000) and length of stay was 5 days (range 1-19). HAI-specific complications occurred in 14% (Table). Floxuridine (FUDR) was initiated in 95% of patients a median of 18.5 days after surgery. Of the 38 patients who received HAI for unresectable CRLM and had measurable disease on imaging, 3- and 6-month hepatic disease control was achieved in 86% (8 partial response [PR], 22 stable disease [SD], 5 progressed [PD]) and 89% (1 complete response, 8 PR, 8 SD, 2 PD), respectively. For patients with at least 3 months follow-up, median PFS, hepatic PFS and extrahepatic PFS were 13 months, 13 months, and 13 months, respectively. Conclusions: HAI can be safely and effectively delivered to well-selected patients with CRLM and ICC. Response rates, disease control and PFS in heavily treated patients with unresectable CRLM comparable to high-volume centers can be achieved at new programs with appropriate expertise. These data support the mission of the newly formed HAI Consortium to critically evaluate efficacy and innovation in HAI therapy through multi-institutional collaboration and contemporary prospective trials.[Table: see text]
Efficacy of retreatment with oxaliplatin-based regimens in metastatic colorectal cancer patients: The RETROX-CRC retrospective study.
Authors: Mauri Gianluca , Amatu Alessio , Tosi Federica , Bencardino Katia , Bonazzina Erica , Gori Viviana , Ruggieri Lorenzo , Arena Sabrina , Bardelli Alberto , Marsoni Silvia , Siena Salvatore , Sartore-Bianchi Andrea
Published: January 2022

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Background: Oxaliplatin in association with fluoropyrimidines is universally considered one of the most effective drugs for colorectal cancer and the mainstay of front-line treatment of metastatic patients. In contrast the efficacy and safety profile of oxaliplatin based regimens in the late-care treatment space have been poorly and conflictingly reported. Methods: We identified a real-world cohort of metastatic colorectal cancer (mCRC) patients undergoing repeated oxaliplatin treatments in a single institution and retrospectively analysed their clinicopathological features to identify potential efficacy-predictive determinants of oxaliplatin response at retreatment (RETROX-CRC Study). Results: Out of 2,606 consecutive mCRC patients referred to Niguarda Cancer Center, 119 fulfilled the eligibility criteria of the study. The response rate (RR) and the disease control rate (DCR) after oxaliplatin retreatments were respectively 21.6% (95% CI 14.4-31.0%), and 57.8% (95% CI 47.7-67.4). A trend towards better RR and DCR was observed among patients who were exposed to oxaliplatin in the adjuvant setting, while a significantly poorer outcome was observed when two or more intervening treatments were delivered in between oxaliplatin exposures. Median progression-free survival (PFS) was 5.1 months (95% CI 4.3-6.1), significantly lower if oxaliplatin was re-administered beyond the third line (HR 2.02; 1.25-3.25; p=0.004). Safety data were reliably retrieved in 65 patients (54,6%). Of these 18.5% (12/65) and 7.7% (5/65) of them had G3-4 toxicities. Overall, toxicity was the cause of treatment discontinuation in almost a third of cases (28.6%; 34/119), with hypersensitivity reactions as the most prevalent reason for stopping treatment (58.8%; 20/34). Conclusions: In this large real-world series of 2,606 mCRC patients, less than 5% were re-treated with oxaliplatin. A late-disease control was achieved in almost 60% of patients, with a clinically acceptable sustained PFS and safety. Given the low performance of current standard drugs in late care of mCRC, retreatment with oxaliplatin might be considered a viable alternative especially if hopefully biology-based predictive markers for improving patient selection could be found.
Improved organ preservation with dose escalation using contact X-ray brachytherapy for good responders following external beam chemoradiotherapy: Long-term outcomes from a single institution.
Authors: Sun Myint Arthur , Rao Christopher , Dhadda Amandeep Singh , Wong Helen , Hershman Michael , Sripadam Rajaram , Pritchard Mark
Published: January 2022

131

Background: We previously reported the benefit of Contact X-ray Brachytherapy boost (CXB) in achieving a higher clinical complete response (cCR) following partial response to external beam chemoradiotherapy (EBCRT). We now update our report on the organ preservation rate and long-term durability of the cCR in this cohort. Methods: Outcome data for rectal cancer patients referred to our institution from 2003 to 2012 were retrieved from an institutional database after an audit approval. These patients were referred after initial local multidisciplinary team discussion. All patients had EBCRT 45Gy/25/5 weeks with capecitabine 825mg/m2 (Mon-Fri). Those who respond well but has a small residual tumour were offered CXB boost of 90Gy in 3 fractions over 4-6 weeks as they were not suitable or unwilling to undergo completion surgery. Following treatment, patients had close 3 monthly follow-ups with DRE, endoscopy, and MRI in the first 2 years, then 6 monthly up to 5 years. Results: Of 345 consecutive patients with rectal cancer referred to us, 83 patients who responded well to EBCRT but with small suspicious residual disease (≤3 cm) were offered CXB boost. Median age was 72 years (range 36–87) and 58 (69.9%) were males. Initial MRI tumor stages were cT2 (n = 28), cT3 (n = 55) and 54.2% were node positive. The median follow up of surviving patients was 6.4 years (range 2-11 years). cCR was achieved after CXB boost in 53/83 (64%). After achieving cCR, 8/53 (15%) developed local regrowth. However, all patients successfully underwent curative surgery with R(0) resection rate of 24/30 (80%) and only 21/83 (25%) had stoma. Organ preservation was achieved in 62/83 (75%). 12/53 (14%) patients developed metastatic disease. At the end of the study period, 64/83(77%) were cancer free. Conclusions: Our long-term data suggests dose escalation with CXB boost following EBCRT can achieved high organ preservation rate with excellent long-term durable cCR. This approach can provide an alternative treatment option for elderly or comorbid patient patients who are not suitable for surgery. This can also be an option for some patients who wish to avoid surgery upfront after initial diagnosis. Those who needed surgery later for treatment failure can be salvage successfully. A phase 3 European randomised trial OPERA (Organ Preservation in Early Rectal Adenocarcinoma) was set up to evaluate this concept further.
Evaluation of efficacy and tolerance of radical radiotherapy and radiochemotherapy in treatment of locally advanced, unresectable rectal cancer.
Authors: Kraszkiewicz Małgorzata , Napieralska Aleksandra , Wydmanski Jerzy , Majewski Wojciech
Published: January 2022

133

Background: Evaluation of tolerance and efficacy of two schemes of neoadjuvant treatment in patients with unresectable rectal cancer: radiochemotherapy and radiotherapy, including conventional and accelerated hyperfractionation. Methods: 145 patients (pts) with unresectable, locally advanced rectal cancer. Schemes used: radiotherapy (RT) in 73 (50%) or radiochemotherapy (CRT) in 72 (50%). In RT group conventional fractionation (CFRT) and hyperfractionated accelerated radiotherapy (HART). In CRT 54 Gy in 1.8 Gy fractions was given with two cycles of 5 Fu-LV chemotherapy in three or five day cycles. Results: Objective response (OR) in RT and CRT group was 60% versus 75%. Resection rate (RR) in RT and CRT: 37% versus 65%. Tumor mobility and laparotomy-based unresectability were significant factors for OR. Performance status, tumor mobility, neoadjuvant treatment method were significant for RR. Five-year LC in CRT versus RT: 68% versus 37%. Five-year OS: 52% versus 27%. CRT was independent positive prognostic factor for resection rate, local control. Tumor volume did not reach significance for any of the end points. Lenght of chemotherapy cycles (three or five days) did not reach significance for any of the endpoints. Toxicity was acceptable in both groups. CRT had best outcome in LC: 68% versus 42% in HART; and 25% in CFRT. Five-year OS was much better in CRT than in CFRT: 52% versus 17%. Conclusions: The results of treatment depend on performance status, patients age, tumor mobility and unresectability based on earlier laparotomy. The lack of influence of the tumor volume on all endpoints indicates the need for radical neoadjuvant treatment independently of tumor volume and underlines the key role of a proper surgical treatment. In patients not suitable for CRT, HART is optimal strategy for its better efficacy than CFRT.
High-risk gene expression in colorectal liver metastasis: Potential for novel therapies.
Authors: Medin Caroline , Turgeon Michael K. , Keilson Jessica M. , Dwivedi Bhakti , Herting Cameron , Maithel Shishir K. , Lesinski Gregory B.
Published: January 2022

147

Background: Over half of patients with colorectal cancer (CRC) develop liver metastases. While immunotherapy is an emerging treatment of solid tumors, its use among CRC patients is limited. Furthermore, gene expression patterns of liver-specific CRC metastases remain unclear. The purpose of this study was to identify a high-risk gene expression profile for patients with colorectal liver metastasis (CRLM) to better inform prognosis and development of novel targeted therapies. Methods: Fifty-three FFPE CRLM samples from patients who underwent complete metastatectomy from 2009-2017 were examined. Expression profiling of extracted RNA was performed using NanoString Immuno-Oncology (IO360) 750-gene panel. Statistical analyses using cutoffs of absolute log 2-fold change≥1.5 and p-value≤0.05 were performed. Patients were analyzed by extremes of outcomes: survival time in the lowest quartile compared to those still alive at last follow-up. Results: Eight differentially expressed genes were associated with poor survival. Overexpressed genes included IL6R, CXCL2, C7, MGMT, PCK2, CSF1 and LILRB4 (Table). PLA2G2A was under-expressed. Conclusions: This study demonstrates differential gene expression associated with poor survival among patients with CRLM. Specific genes of interest include IL6R, MGMT, CSF1 and LILRB4. IL6R is a known effector in tumor proliferation via IL-6 signaling from tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs) and T-cells. MGMT repairs alkylating DNA damage and is implicated in carcinogenesis and response to chemotherapy. CSF1 promotes macrophage differentiation to M2 phenotype, suppressing inflammation and anti-tumor defense mechanisms. LILRB4 activation via MDSCs leads to T-cell inhibition. These overall suggest a myeloid-dominant tumor immune microenvironment and represent important potential therapeutic targets. Next steps include performing immunohistochemistry to validate findings at the protein level and investigate the tumor intrinsic role using human cell lines.[Table: see text]
The association between tumour sidedness, clinicopathological characteristics and outcomes in patients undergoing curative resection for colon cancer.
Authors: Golder Allan Matthew , Pennel Kathryn AF , Mansouri David , Horgan Paul G. , Roxburgh Campbell SD , Biankin Andrew V , Edwards Joanne , McMillan Donald C.
Published: January 2022

148

Background: Right-sided colon cancer is associated with worse outcomes than left-sided disease, likely due to an association between tumour/host factors and tumour sidedness. The present study analyses the association between tumour sidedness, clinicopathological features and common mutations to better understand this discrepancy in outcomes. Methods: The association between tumour sidedness, clinicopathological characteristics and survival was examined within a cohort of patients undergoing curative surgery for TNM I-III colon cancer. Results: 3,419 patients were identified. 54% of cases were right-sided and associated with worse 3-year OS/CSS. On multivariate analysis for clinical factors: sex (OR 0.63), Systemic Inflammatory Grade (SIG), anaemia and differentiation (OR 0.80/0.31/0.57) were associated with T3 cancer sidedness and: sex, anaemia and differentiation (OR 0.61/0.46/0.57) were associated with T4 cancer sidedness. On further MVA including mutational factors anaemia/BRAF status remained significant in T3/T4 cancer respectively (OR 0.08/0.09). BRAF mutant status was associated with SIG in all patients/T3 disease (p=0.046/0.016). Conclusions: Worse outcomes seen in right-sided colon cancer are likely explained predominantly by factors including tumour stage, SIG, anaemia and BRAF mutational status. BRAF mutations are associated with the Systemic Inflammatory Response and further research is required to better understand this relationship taking into the tumour microenvironment, microsatellite instability.[Table: see text]
Analysis of 16S rRNA sequencing in advanced colorectal cancer tissue samples.
Authors: An Hojung , Partha Mira A. , Lee Hojoon , Lau Billy , Shin Giwon , Almeda Alison Figueroa , Ji Hanlee P.
Published: January 2022

163

Background: Changes in the colon’s microbiota composition are contributors to the pathogenesis of colorectal cancer (CRC). Features of this microbiome may have prognostic significance. For this study, we analyzed 16S rRNA sequencing data from tumor tissue samples of advanced CRC patients and determined if there were potential correlations between microbiome composition and clinical outcomes. Methods: One hundred and thirty three advanced CRC patients in St. Vincent’s Hospital in Korea were enrolled. DNA was extracted from collected tissue samples, the V3-V4 regions were amplified, and a 16S rRNA gene amplicon library was prepared using an Illumina protocol. DNA was sequenced on an Illumina MiSeq instrument. We used three different bioinformatic packages to process the sequence data and evaluate the microbiome composition of each tumor. Results: The classification performances of three different analytic pipelines (Kraken2, QIIME2, and DADA2) were compared in a microbiome control sample. Among these, DADA2 and QIIME2 were chosen for use in subsequent analysis, due to their lower Chi-square (χ2) test statistic values on the control data. After excluding samples that retained less than 5% of total reads after merging, 120 samples were analyzed. The median age of the cohort was 63 years, 63.3% were male, and all were Korean. The distribution over primary sites was 27.5% from the right-side colon, 30.8% from the left-side colon, and 41.7% from the rectum. All subjects received the first line of systemic treatment. The median progression-free survival time was 8.9 months. Twenty-nine patients (24.2%) survived more than 24 months. When examining the results from the two bioinformatic packages, pairwise comparisons showed positive correlations in the relative abundances of the top 20 genera. Fusobacterium, a microbe known to relate to pathogenesis and prognosis of CRC, was not detected by QIIME2. Stratifying by primary site, rectal cancers showed higher alpha diversity than left- or right-side colon cancers. Separately, a higher serum CEA level (≥8) at diagnosis, and the presence of lung metastasis were both found to be related to higher alpha-diversity, a global indicator of microbiome composition. When excluding minimally abundant (< 1% per patient) genera, beta-diversity was found to be differentiable by T stage, the presence of lung metastasis, and the presence of liver metastasis. Most notably, beta-diversity differed between patients who survived more than two years and patients who died within 2 years. Using the DADA2 results, we confirmed that the presence of Fusobacterium nucleatum in CRC tissue was found to be a strong predictor of poor overall survival (OS), along with old age and liver metastasis. Conclusions: This study suggests potential associations between microbiome composition and clinical parameters of advanced CRC. Microbial biomarkers may be a valuable prognostic tool in this population.
Use of ascites CEA as a predictive value for distant metastasis in high-risk stage II and III colorectal cancer.
Authors: Lee Chul Seung , Lee In Kyu
Published: January 2022

164

Background: Adjuvant chemotherapy in patients with high-risk stage II and III colorectal cancer prevents recurrence by eliminating minimal residual disease. However, patients who are at high risk of recurrence after completing standard adjuvant therapy are currently unknown. Although ascites CEA level has been associated with long-term oncologic outcomes, the clinical significance of ascites CEA in high-risk stage II and stage III colorectal cancer (CRC) has not yet been described. The present study aimed to determine the long-term oncologic impacts of ascites CEA level after curative colorectal cancer. Methods: A total of 191 patients with stage II/III CRC were included in this study, between January 2015 and December 2018. CEA of peritoneal fluid sampled at the beginning of each operation was analyzed. long-term oncologic outcomes were analyzed with the known risk factors for recurrence in CRC. Results: Multivariate analysis of recurrence revealed that lymphatic invasion (HR 6.0, 95% CI 1.1–32.0, p = 0.04), vascular invasion (HR 2.9, 95%CI 1.0–8.0, p = 0.04), mucinous cancer (HR 5.5, 95% CI 1.6–18.4, p = 0.006), and peritoneal fluid CEA above 5 ng/dl (OR 4.2, 95% CI 1.2–15.0, p = 0.008) were significant risk factors (Table). Peritoneal fluid cytology, microsatellite instability, cancer obstruction did not significantly impact DFS in stage II/III CRC. There were 14 patients with liver metastasis, among them, 11 patients without peritoneal metastasis; they had high ascites CEA level. While 8 patients had lung metastasis, 7 of them confirmed high ascites CEA levels. Conclusions: Our results indicate that the ascites CEA may predict as an important biomarker to identify those at risk of distant metastasis in high-risk stage II and stage III CRC patients. We suggest ascites CEA analysis might be included in patient risk assessments and oncologic prediction tools.
Circulating nucleosomes for detection of colorectal cancer and high-risk advanced adenomas.
Authors: Chang Li-Chun , Herzog Marielle , Hardat Nathalie , Pamart Dorian , Chiu Han Mo
Published: January 2022

169

Background: Detection and treatment of early colorectal cancer (CRC) or advanced adenomas (AA) is the key for superior outcomes and fecal immunochemical testing (FIT)-based screening has proven effective in reducing CRC death and the risk of advanced-stage CRC but the discrepancy in the effectiveness was observed between proximal and distal cancers. On the other hand, false-positive results of FIT with 60 % of negative colonoscopy is another concern, considering the burden to the screening participants and the healthcare providers. A blood-based test as an alternative or supplement to FIT has the potential to concurrently enhance the detection of high-risk neoplasms and identify individuals at risk who should then be referred to colonoscopy. We investigated the levels of circulating free nucleosomes containing different epigenetic modifications in patients referred for colonoscopy. Methods: 10mls whole blood was obtained from 520 asymptomatic patients prior to colonoscopy at National Taiwan University Hospital. Patients were classified into 5 groups based on their colonoscopy reports: (i) patient with CRC (n = 33), (ii) patients with AA (n = 123, including 18 with AA > 2cm); (iii) patients with non-AA (n = 168); (iv) patients with non-neoplastic polyps (n = 30); (vi) healthy controls with no endoscopic lesion (n = 166). Plasma samples were analyzed for nucleosome levels using 7 different quantitative immunoassays (Nu.Q assays; Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K27Me3-, H3K36Me3-, H3K9Me3-, H3K14Ac-, H3K27Ac- or H3R8Cit-nucleosomes). All study subjects were asked to collect a stool sample at home within 48-hours before the colonoscopy. The fecal samples were assayed with the Eiken OC-SENSOR FIT kit (Eiken Chemical Co., Ltd., Tokyo, Japan) for all study subjects. Results: At a cut-off of 20µg/g feces, the FIT test showed a sensitivity of 92,9% at 17.5% specificity for CRC +AA vs. Controls. All the CRC patients and 83.3% of the high-risk AA (> 2cm) patients were FIT positive. A combination of 2 Nu.Q biomarkers: H3K27Me3 and H3R8Cit with FIT in a logistic regression model showed improved sensitivity of 95% at 20.6% specificity allowing the detection of all CRC patients and 94.3% of AA patients including all the high-risk adenomas. The FIT test detected 46 out of 55 proximal adenomas whereas the combined model could detect 50 proximal adenomas including 3 proximal AA > 2cm not being detected by FIT (p < 0.05). The same combination would reduce unnecessary colonoscopies by 21.8% of the control and 23.3% of the non-neoplastic polyps subgroups compared to 17.5% and 6.7%, respectively with the FIT test alone. Conclusions: Our results indicate that H3K27Me3 and H3R8Cit-nucleosome levels in combination with FIT could improve the detection of proximal high-risk AA and could also provide a non-invasive method to reduce unnecessary colonoscopy.
The prevalence of common KRAS variants and associated outcomes in patients with metastatic colorectal cancer (mCRC).
Authors: Musselwhite Laura W. , Trufan Sally J. , Kadakia Kunal C. , Hwang Jimmy J. , Salem Mohamed E.
Published: January 2022

173

Background: KRAS is the most common driver oncogene in mCRC. Comprehensive analysis of KRAS variants prevalence and the relationship between variants and outcomes are lacking. Herein, we aimed to examine the impact of KRAS variants on outcomes in patients (pts) with mCRC. Methods: A retrospective review of pts with mCRC with known KRAS mutation status was performed. Fisher’s exact test was used to analyze the association between KRAS variants. Cox Proportional Hazard modeling was used to study the relationship between KRAS variants and overall survival (OS). Kaplan-Meier method was used to assess OS. Results: A total of 423 pts diagnosed with mCRC from 2014-2020 with available extended KRAS status were evaluated. Median age at diagnosis was 59.8 yrs (22.3-92 range), 57% were male, 22% were Black, and 75% presented with de novo metastatic disease. A majority (56%) of tumors harbored KRAS mutations. The most frequent KRAS variants were G12D 47% (111), G12V 12% (28), G12C 13% (31), G13D 9% (21), and 20% (47) were other variants. In univariate analyses, the presence of a KRAS mutation, Black race, de novo metastatic disease, age, receipt of chemotherapy, and receipt of surgery were associated with OS. Tumor location was not associated with OS. In multivariable analyses, mutation type was a significant predictor of death and the presence of G12D was associated with an increased risk of death compared to G12V and KRAS wildtype. There was no increased risk of death in pairwise comparisons of G12D and G13D or other KRAS variants. Black race, de novo metastatic disease, and no receipt of surgery were additional independent predictors of death (Table). With a median follow-up of 25.7 months (mo.), median OS was 35.5 mo. (95% CI 10.5-50.9) with G12C, Not Reached (NR) (95% CI 21-NR) with G12V, 36.2 mo. (95%CI 14.9-58.5) with G13D, 26.2 mo. (95% CI 21.8-37) with G12D, 39.6 mo. (95% CI 22.4-47.9) for other KRAS mutations, and 59.6 mo. (95%CI 48.2-NA) for KRAS wildtype, respectively (p=0.0003). Conclusions: Our findings highlight differences in unadjusted overall survival when comparing G12D to some other KRAS variants. Codon and amino acid-specific mutations of KRAS should be considered when evaluating prognosis and further study on treatment effects and sequencing is warranted. [Table: see text]
Association of BRAF V600E mutation with survival in patients with metastatic mismatch repair-deficient colorectal cancer.
Authors: Tan Elaine , Whiting Junmin , Xie Hao , Imanirad Iman , Carballido Estrella M. , Felder Seth , Frakes Jessica M. , Mo Qianxing , Walko Christine Marie , Permuth Jennifer , Kim Richard D. , Anaya Daniel A. , Fleming Jason B. , Sahin Ibrahim Halil Halil
Published: January 2022

174

Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p<0.001). Pts older than 50 had a lower median OS vs. those who were ≤50 at 21.4 months vs. 38.7 months (HR 1.66, 95% CI: 1.33-2.07, p<0.001). When comparing MSH2/MSH6 mutations to MLH1/PMS2, a trend towards improved OS was seen with median survival of 35.2 months vs. 22.7 months, respectively (HR 0.79, 95% CI: 0.61-1.02, p=0.067). On multivariate analysis, BRAF mutation and older age continued to be associated with differences in survival, while KRAS mutation and specific MMR gene loss did not. Conclusions: BRAF V600E mutation and age greater than 50 are associated with decreased survival for pts with MMR-D mCRC. KRAS mutations and specific MMR alterations are not associated with differences in survival.
ENDOV upregulation and outcomes in females with colorectal adenocarcinoma.
Authors: Bhan Chandur , Sun Chenyu , Bheesham Nimarta , Shakuntulla Fnu , Siddiqui Zain I. , Tuason John Pocholo W. , Paudel Arpana , Ahmed Marwan K. , Kim Na Hyun , Memon Burhan , Mohammed Abdul Humaed , Gerais Yasmin A. , Prasad Apurwa , Abid Qurrat-ul-ain
Published: January 2022

175

Background: Colorectal adenocarcinoma (COAD) is a common cancer in gastrointestinal tract. Endonuclease V (ENDOV), an enzyme with specificity for deaminated adenosine (inosine) in nucleic acids, was found to be involved in the development of certain cancers. Thus, this study was performed to explore the effects of ENDOV on the prognosis of COAD. Methods: RNA-sequencing FPKM data and corresponding clinical information of 41 normal tissues and 480 tumor tissues of COAD were acquired from The Cancer Genome Atlas (TCGA). Then ENDOV expression differences between the normal and cancer tissues were compared with Wilcoxon rank-sum test via ‘limma’ package. Overall survival (OS) and disease specific survival (DSS) analyses were conducted by Kaplan–Meier (K–M) method via ‘survminer’ package. Subgroup analyses of different genders were also performed. Results: The expression of ENDOV was downregulated in tumors compared with normal tissues (p < 0.001). However, higher expression of ENDOV is associated with worse OS (HR: 1.83, 95%CI: 1.23-2.73, P = 0.003) and DSS (HR: 1.75, 95%CI 1.06-2.91, P = 0.03). Subgroup analysis found that higher expression of ENDOV was associated with worse OS (HR: 2.17, 95%CI 1.18-3.98, P = 0.012) in females, but not in males (HR: 1.48, 95%CI 0.86-2.53, P = 0.158). As for DSS, higher expression of ENDOV was also correlated with worse outcome (HR: 2.36, 95%CI 1.07-5.19, P = 0.033) in females, but not in males (HR: 1.45, 95%CI 0.73-2.86, P = 0.287). Conclusions: ENDOV is overall downregulated in COAD tumor samples. However, higher expression of ENDOV in certain COAD patients is associated worse OS and DSS in females but not in males. This indicates the potential role of ENDOV in predicating the prognosis of COAD in female patients.