bluuebunny/crossref_metadata_2025_split huggingface dataset:
The imprecise promise of the Precision Medicine Initiative (PMI): Where we got it wrong and how can we fix it?
Authors: Clinton Natasha , Patel Kashyap B. 
Published: June 2021

e15102 Background: Over the last several years, science has taken strides in how we understand and treat cancer. We have learned that each person’s cancer is unique, in part because it is influenced by a patient’s biological characteristics, environmental exposures, lifestyle and epigenetic influence. There is excitement about the potential of PMI to transform healthcare delivery and improve population health. Targeted therapies developed based on specific mutations can result in improved outcomes and reduced toxicities. Limited knowledge of cancer biology and the genomic underpinnings of cancer in racial and ethnic minorities diminishes the potential of PMI. Previous efforts of obtaining biospecimens from institutional or local biobanks presents a challenge of inadequate representation of racial and ethnic diversity. This can result in exacerbation in the therapies efficaciousness. Methods: Numerous research studies have surfaced indicating that PMI has resulted in widening racial and ethnic health care disparities since state-of-the art diagnostic and treatment options are unequally distributed across the entire cancer population. A literature review highlighted the racial inequalities and disparities. Results: A report examining the racial diversity of samples in TCGA found that whites were overrepresented in the U.S. population while Asian and Hispanic patients were underrepresented at a 5 percent frequency. In the BATTLE study, 82 percent of participants were white, and only 6% were African American (AA). The NCI-MATCH trial preliminary numbers show that AAs accounted for about 10 percent of patients. Therefore, it should not be assumed that the response rates or clinical effectiveness of the therapeutics tested in these trials will generalize to all racial and ethnic groups. The underrepresentation of racial and ethnic minorities in cancer clinical trials and prevention research, along with the documented challenges to enrolling these individuals into studies pose a barrier for the implementation of precision medicine in these populations. Collectively, these challenges can slow the pace of medical innovation, decrease the generalizability of research findings, lead to incorrect interpretations, and limit our full understanding of precision medicine. Conclusions: It is imperative we develop solutions to solve for issues identified related to precision medicine testing and treatment development. We have developed a framework to address disparities in PMI through community-based initiatives. A two-step solution could be considered to address this unmet need. Through the development of a registry and biospecimen banking as well as just in time trials that include pharmacogenomics, we can follow the patient journey to identify unique characteristics by race and/or socioeconomic status to begin solving for the disparities across the population.
Association of the anorectal microbiome and patient-reported gastrointestinal outcomes in patients with anal cancer.
Authors: Kouzy Ramez , Lin Daniel , El Alam Molly Blue , Abi Jaoude Joseph , Smith Grace L. , Koay Eugene Jon , Minsky Bruce D. , Das Prajnan , Holliday Emma B. , Klopp Ann , Taniguchi Cullen M. , Colbert Lauren Elizabeth 
Published: June 2021

e15504 Background: Among patients with anal cancer undergoing chemoradiotherapy, the association between the microbiome and toxicity is not well documented. We sought to quantify the gastrointestinal-related patient-reported outcomes (PROs) and local microbiome profiles of patients with anal cancer receiving chemoradiotherapy in order to check for potential profiles that can help in predicting toxicity during treatment. Methods: We prospectively followed patients with non-metastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Anorectal swab samples were collected before treatment initiation and at 4 subsequent timepoints. Consequently, PROs were collected using the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC). Samples were sequenced using 16S rRNA of the V4 region. Sequence reads were grouped by amplicon sequence variants (ASV’s) representative of unique bacterial species. We then used Linear discriminant analysis Effect Size (LEfSe) with an effect size of 4 to identify taxa at baseline that were differentially enriched in patients with high vs. low toxicity by end of treatment. We compared the EPIC scores with the relative abundance of species identified in the LEfSe using a paired Wilcoxon test. Results: The study included 22 patients (18 women and 4 men), whose median age was 59 years. Most patients were Stage III (59%) with negative HIV status (94%). The majority of patients (91%) received standard of care chemoradiotherapy. Overall toxicity was the highest at week 5 of treatment. At all individual time points, alpha diversity of the microbiome did not correlate with patient-reported GI function, additionally overall baseline diversity was not predictive of eventual GI outcomes. The LEfSe identified that patients with low patient reported toxicity at week 5 had higher of abundance of Selenomonas at baseline, while patients with higher toxicity had high abundance of baseline Actinobacteria, Peptoniphilus, Clostridiales , and Clostridia. When comparing the relative abundance of bacterial species among patients with high and low toxicities, patients with higher relative abundance of Clostridia and Actinobacteria had significantly higher toxicity (p = 0.03). Conclusions: Certain microbiome profiles at baseline are associated with anal cancer patients’ gastrointestinal-related PROs during chemoradiation. Our data provide novel avenues to study the potential uses of the local microbiome as a biomarker in predicting treatment toxicities in anal cancer.
Peripheral blood levels of tumor-infiltrating lymphocytes (TILs) and circulating tumor cells (CTCs) in patients with colorectal cancer.
Authors: Novikova Inna A. , Kit Oleg I. , Zlatnik Elena Yu. , Sitkovskaya Anastasia O. , Shulgina Oksana G. , Ulianova Elena P. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kolesnikov Vladimir E. , Aleksandrovich Maksim K. , Dashkov Andrey V. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Mirzoyan Ellada A. , Pavlov Vladislav K. , Dzhenkova Elena A. , Shaposhnikov Aleksandr V. , Vereshchak Maksim A. , Katelnitskaya Oksana V. , Savchenko Dmitriy A. 
Published: June 2021

e15510 Background: Tumor is a structure where malignant cells interact, among others, with cells of the adaptive and innate immune systems largely determining the tumor microenvironment. The role of TILs in the disease prognosis has been shown. The amount of CTCs is one of the factors that significantly affect the risk and rate of metastasis. The purpose of the study was to assess an association between TILs and CTCs in the peripheral blood of patients with various stages of colorectal cancer (CRC). Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1. TILs were identified in tumor material after standard histological processing. Lymphocytes were counted per 100 epithelial cells in 5 fields of view at a magnification of x400; the result was expressed as a percentage ( < 5% weak, 5-30% moderate, >30% strong). The numbers of CTCs were measured in the peripheral blood using the Veridex CellSearch system (Janssen), taking into account the expression of epithelial cell adhesion markers EpCAM, cytokeratins 8,18,19 and absence of the CD45 expression. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: Weak lymphocytic infiltration was detected in 32.8%, moderate - in 48.1%, strong - in 19.1% of cases. CTCs were detected in 62.9% cases (in 188 of 299 patients). The percentages of patients with 1-3 CTCs and with >3 CTCs were equal - 50% (94 of 188). CTCs were not registered in 37.1% cases (111 of 299). The absence of CTCs was noted equally often in moderate and strong lymphocytic infiltration – 43.7% and 43.8%. The presence of tumor cells in the peripheral blood was most often detected in weak lymphocytic infiltration, being 1.4 times more frequent than in moderate and strong infiltration (76.5% vs. 56.3% and 56.2%) (p = 0.019, c2= 11.890). Conclusions: The study demonstrated a significant relationship between the level of CTCs and the intensity of lymphocytic infiltration in the tumor (p≤0.05), which can be used as a new prognostic approach.
A retrospective study of local hepatic artery infusion chemotherapy combined with regorafenib in the treatment of advanced colorectal cancer with predominant liver metastases.
Authors: Cao Guang , Zhu Xu , Yang Renjie , Chen Hui , Wang Xiaodong , Liang Xu 
Published: June 2021

e15563 Background: The hepatic arterial infusion chemotherapy (HAIC) as a second/third-line therapy has resulted in promising clinical outcomes for unresectable liver metastatic colorectal cancer (CRC). HAIC combined with regorafenib has not been reported for advanced CRC patients with predominant liver metastases. This retrospective study explored the benefits and tolerability in advanced hepatic metastatic CRC patients who received HAIC combined with regorafenib after failure of standard systemic chemotherapy. Methods: This retrospective study collected and analyzed 47 patients treated with HAIC in combination with regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with Bevacizumab or Cetuximab between Jan 2017 and Jun 2020 at the Beijing cancer hospitals in China. Regorafenib was taken for 3 weeks every 4-week cycles and mostly taken 5-7 days before or after the first HAIC. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were observed. Results: Among these 47 patients, 32(68%) were males. The median age was 61 (range: 29-75) . The median follow-up was 22.2 months (range:3.7-50.7 months). Before receiving HAIC in combination with regorafenib, 34 (72.3%) patients had previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%) patients had previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both).These patients underwent HAIC for a median of 4 sessions (range2--8,). The starting doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%). The median OS was 22.2 months. The median PFS was 10.8 (95% CI: 9.0-13.7) months. The ORR was 51.3% and DCR was 100% among 39 patients whose tumor responses were evaluated in the liver. The ORR was 13.8% and DCR was 48.3% among 29 patients whose tumor responses were evaluated outside the liver. Toxicity profile of regorafenib was as expected, with common AE were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). The most common grade 3 and 4 adverse events were hand-foot skin reaction (4.26%), hypertension (2.13%), diarrhea (2.13%), and stomachache (2.13%). Only 2 patients stopped regorafenib due to AEs. Conclusions: This real-world study demonstrated that regorafenib combined with HAIC was beneficial and tolerable in advanced CRC patients with liver metastases whose disease had progressed after standard systemic therapy. It also indicated a new promising treatment strategy for late stage CRC. Additional prospective and large-scale studies are required for further confirmation. Key words: hepatic artery infusion chemotherapy; regorafenib; colorectal cancer
Angiopoietin-2 early increase to predict benefit from regorafenib in metastatic colorectal cancer (mCRC) patients: The prospective REGOLAND study.
Authors: Marmorino Federica , Antoniotti Carlotta , Boccaccino Alessandra , Antista Maria , Zaffaroni Nadia , Zucchelli Gemma , Martinetti Antonia , Campi Elisa , Rossini Daniele , Sottotetti Elisa , Borelli Beatrice , Corti Francesca , Conca Veronica , Moretto Roberto , Germani Marco Maria , Falcone Alfredo , Giordano Mirella , Masi Gianluca , Pietrantonio Filippo , Cremolini Chiara 
Published: June 2021

e15566 Background: Regorafenib is a treatment option for refractory mCRC patients with no validated predictors of benefit. We previously showed that, among several circulating angiogenic factors, low baseline Ang-2 and Tie-2 plasma levels were associated with good prognosis and that the early increase of Ang-2 during the treatment could predict benefit from regorafenib ( Antoniotti et al, J Clin Oncol 36:675-675, 2018). To prospectively validate these retrospective findings, we conducted the REGOLAND study. Methods: Ang-2 and Tie-2 were assessed by ELISA on plasma samples collected at baseline (d1) and after 15 days (d15) of treatment in a cohort of mCRC patients receiving regorafenib, as per indication. To detect a HR for PFS of 0.50 in favour of the early increase (Δd15-d1) of Ang-2 levels, setting two-sided α = 0.05 and β = 0.10, 87 events were required according to Schoenfeld design. Comparisons among concentrations of each marker at d1 and d15 were performed by Wilcoxon test. Median values at baseline were used as cut-off to discriminate patients with low versus high plasma levels and their correlation with outcome was analysed. Results: One hundred patients were included. Median PFS and OS were 2.5 and 6.7 months, respectively. The early increase of Ang-2 at d15 was reported in 42 patients and was associated with longer PFS (median 2.7 vs 2.4 months; HR for PFS: 0.72 [95%CI:0.48-1.08], P = 0.095). As compared to d1, an overall decrease of Tie-2 levels at d15 was observed ( P = 0.007), but it was not associated with clinical outcome. Low levels of Ang-2 at baseline were associated with longer PFS (HR: 0.59 [95%CI:0.39-0.89], P = 0.005) and OS (HR:0.62 [95%CI:0.41-0.94], P = 0.017), while Tie-2 levels were not. In the multivariate model, the association of Ang-2 levels with PFS was confirmed (HR:0.48 [95%CI:0.31-0.76], P = 0.001), but not with OS (HR: 0.80 [95%CI:0.49-1.28], P = 0.351). Conclusions: Ang-2 is a prognostic marker and its early modulation predicts clinical benefit among mCRC patients treated with regorafenib. We hypothesize that Ang-2 levels early increase as a consequence of the successful inhibition of Tie-2 by regorafenib that leads to a compensatory increase of the ligand and correlates with anti-tumour activity.
FORECAST-1: Feasibility of organoid response assessment to define effective treatments for patients with colorectal cancer after failure of standard therapy.
Authors: Gard Grace , Lee Margaret , Hirokawa Yumiko , Tie Jeanne , Clarke Jordan , Tebbutt Niall C. , Tan Tao , Jalali Azim , Mouradov Dmitri , Lee Belinda , Sieber Oliver , Gibbs Peter 
Published: June 2021

e15571 Background: Many patients with metastatic colorectal cancer (mCRC) that have failed standard first- and second-line therapies remain fit and eager for further treatment. Therapeutic options include two agents with proven but modest survival benefit, a clinical trial of an investigational agent, rechallenge with agents successfully used in earlier lines of treatment, or agents that have shown some activity in non-randomised phase II studies. Patient derived tumouroid (PDT) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. They potentially represent a robust personalized model for real-time drug sensitivity testing to determine optimal anti-cancer therapies for individual patients. Methods: FORECAST-1 is an observational, non-randomized study to determine the feasibility of PDT based drug sensitivity screening for patients with mCRC that have failed at least two lines of therapy. Once established, PDTs undergo drug sensitivity screening including agents regorafenib, trifluridine/tipiracil (TAS102), oxaliplatin, irinotecan, 5-fluorouracil (5FU), erlotinib (a surrogate EGFR-inhibitor), gemcitabine, pemetrexed and temozolomide. Patients are treated at clinician discretion, with clinical response to be correlated with PDT response. Results: Since September 2020 we have enrolled 18 of a planned 30 patients, median age 55 years (range 44 – 81). 17 patients were ECOG 0-1. Four patients had received prior TAS102 treatment. Biopsies were obtained from liver (n = 6), soft tissue/peritoneal metastases (5), lung (2), lymph node (2), primary (1), brain (1) and bone (1). Drug sensitivity testing has been performed on seven PDTs at a median of 62 days from biopsy (range 42 – 128), one PDT culture has failed. A standardised reporting template has been developed. Treatments received by patients to date include TAS102 (n = 5), regorafenib (2), FOLFOX (3), FOLFIRI (1) FOLFIRI plus EGFR-inhibitor (1), capecitabine plus bevacizumab (1) and an immunotherapy-based clinical trial (1). Four patients did not receive further anti-cancer therapy post enrolment, and one patient is yet to commence further systemic therapy. Conclusions: Enrolment to this feasibility study has been rapid demonstrating this to be an area of clinical need. PDTs have been successfully established from a high proportion of patients, but with variable growth rates. Methods to accelerate PDT culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDT sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.
Association of TP53 mutation with decreased prevalence of MSI-high, RAS and PI3KCA mutations in metastatic colorectal cancer.
Authors: Pan Minggui , Jiang Chen , Tse Pamela , Solorzano-Pinto Aleyda V , Chung Elaine , Truong Thach-Giao , Arora Amit , Sundaresan Tilak Kumar , Suga Jennifer Marie Marie , Habel Laurel A. , Thomas Sachdev P. 
Published: June 2021

e15578 Background: TP53 tumor suppressor gene is mutated in approximately 50% of colorectal cancer (CRC). How TP53 mutations are associated with the prevalence of the other common genomic alterations such as RAS (KRAS/NRAS), BRAF, PI3KCA, as well as microsatellite stability (MSI) is not clear. Methods: We investigated the impact of TP53 mutations on other common genomic alterations and survival in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC). Results: From November 2017 to January 2021, genomic profiling was performed on 1056 patients with metastatic CRC, of whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). We found that median overall survival (OS) was similar between the TP53wt and TP53mut patients (50.1 vs 47.5 months, p = 0.9), however, the percent with a Ras mutation was significantly higher in patients with TP53wt compared to TP53mut (63.2 vs 45.2%, p = 0.0001). Interestingly, the percent with MSI-high was also significantly higher in TP53wt than TP53mut patients (11.1 vs 1.4%, p = 0.0001), however, the response rate of the MSI-high patients to immune checkpoint inhibitor (ICI) was similar (40 vs 37.5%). In addition, a significantly higher percent of patients with TP53wt had PI3KCA mutations and a significantly lower percent had c-Myc amplifications compared to patients with TP53mut (PI3KCA, 32 vs 10.7%, p = 0.0001; c-Myc, 1.26 vs 4.6%, p = 0.008). There was no significant difference in the percent of BRAF mutations between the two patient populations (6.2 vs 9.8%). A significantly higher percent of patients with TP53wt and a PI3KCA mutation had a Ras mutation compared to patients with TP53mut and a PI3KCA mutation (81.2 vs 57%, p = 0.0004). However, TP53 mutation status was not significantly associated with the OS of patients with either a Ras, or BRAF, or PI3KCA mutation, or combination of Ras and PI3KCA mutations. Conclusions: TP53 mutation is associated with decreased prevalence of Ras, PI3KCA mutation and MSI-high in patients with metastatic CRC, however, without impacting the OS or response rate to ICI.
A novel outpatient regimen in management of fluoropyrimidine-induced cardiotoxicity.
Authors: Kasi Anup , Gaudel Pramod , Bennett Joseph , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Baranda Joaquina Celebre , Sun Weijing , Porter Charles B. 
Published: June 2021

e15613 Background: Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are commonly used chemotherapies for solid tumors, and essential for curative intent treatment of colorectal cancer. But sometimes, their use may be limited by cardiac toxicity limiting the possibility of cure in some patients. Cardiotoxicity could be asymptomatic (EKG changes) or manifested as chest pain, arrhythmias, acute coronary syndrome or death. Rechallenging may be daunting and it may result in interruption or even discontinuation of planned chemo. Traditionally, nitrates and/or IV/oral calcium channel blockers (CCB) have been used for management of fluoropyrimidine-induced cardiotoxicity but without much benefit. Ranolazine, an oral antianginal drug approved for chronic angina, diminishes myocardial ischemia by reducing calcium overload caused by inhibition of late sodium current and it does not affect heart rate or blood pressure. Our objective was to evaluate the efficacy of our novel approach using ranolazine with other traditional drugs. Methods: 8 patients (median age 49.5 yrs) with fluoropyrimidine induced cardiotoxicity were retrospectively analyzed. They were rechallenged with the planned fluoropyrimidine regimen with our 3 drug cardioprotective regimen (KU protocol). This included oral Ranolazine 1000mg BID and Amlodipine 2.5 mg daily to start the day before starting 5FU infusion/oral capecitabine and to continue it until the day after completion of infusion/treatment, and Nitroglycerin paste 1 inch every 6 hours starting before infusion and continue until it was completed. These meds were discontinued upon completion of chemo. Results: 8 patients were rechallenged with fluoropyrimidine utilizing KU protocol, 6 patients (75%) were able to complete previously planned fluoropyrimidine regimen. One pt (*) discontinued capecitabine due to recurrent chest pain and treatment was switched to 5FU based regimen with KU protocol, which pt was able to complete without chest pain. Another pt (**), 5FU was stopped due to severe diarrhea, not due to cardiotoxicity. All pts tolerated KU protocol well. Conclusions: In our small, single center experience, we were able to safely and effectively rechallenge pts with fluoropyrimidines and complete curative intent treatment with our KU protocol. This protocol uses FDA approved oral and transcutaneous drugs without requiring a healthcare personnel to administer an IV CCB that can cause precipitous bradycardia and/or hypotension. Our results need validation in a larger cohort. [Table: see text]