scholarly journals A Biobank of Colorectal Cancer Patient-Derived Xenografts

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2340
Author(s):  
Suad M. Abdirahman ◽  
Michael Christie ◽  
Adele Preaudet ◽  
Marie C. U. Burstroem ◽  
Dmitri Mouradov ◽  
...  

Colorectal cancer (CRC) is a challenging disease, with a high mortality rate and limited effective treatment options, particularly for late-stage disease. Patient-derived xenografts (PDXs) have emerged as an informative, renewable experimental resource to model CRC architecture and biology. Here, we describe the generation of a biobank of CRC PDXs from stage I to stage IV patients. We demonstrate that PDXs within our biobank recapitulate the histopathological and mutation features of the original patient tumor. In addition, we demonstrate the utility of this resource in pre-clinical chemotherapy and targeted treatment studies, highlighting the translational potential of PDX models in the identification of new therapies that will improve the overall survival of CRC patients.

2021 ◽  
Vol 9-10 (219-220) ◽  
pp. 11-16
Author(s):  
Yerkezhan Zhadykova ◽  
◽  
Sauirbay Sakhanov ◽  
Dulat Turebayev ◽  
Dariyana Kulmirzayeva ◽  
...  

About 3.15 million new cases of colorectal cancer (CRC) are predicted and it is expected that about 1.62 million human will die from this pathology, according to the forecasts of the International Agency for Research on Cancer in 2040. To this aim, an analysis studying studying the indicators of the oncological service for CRC also makes it possible to evaluate the ongoing anti-cancer measures in East Kazakhstan region. Aim. Evaluate some indicators of the oncological service at CRC in East Kazakhstan region in 2009 to 2018. Materials and methods. The research material was data from the Ministry of Health of the Republic of Kazakhstan – annual form No. 7 and 35 regarding CRC (ICD 10 – C18-21) for 2009-2018 in East Kazakhstan region – incidence, mortality, early diagnosis, neglect, morphological verification. A retrospective study using descriptive and analytical methods of biomedical statistics was used as the main method. Results and discussion. For 2009-2018, 3,661 new cases of CRC were registered in East Kazakhstan region for the first time. The incidence of CRC was 25.30/0000 and in dynamics tended to increase from 21.90/0000 (2009) to 25.70/0000 in 2018, the difference was statistically significant (t=1.99 and p=0.047). The mortality rate from CRC tended to decrease from 15.50/0000 to 14.70/0000 (p=0.591), and the average annual mortality rate from CRC was 15.60/0000. The indicators of early diagnosis (the proportion of patients with stage I-II) improved from 58.8% (2009) to 62.3% in 2018, and, accordingly, the indicators of the proportion of neglected patients significantly decreased with stage III (from 25.5% to 20.8%), while with stage IV (from 15.7% to 16.9%) there is a slight increase. The indicators of morphological verification in CRC improved from 90.5% to 98.6% during the studied years. Conclusion. An improvement in the indicators of morphological verification and early diagnosis of CRC was found. The obtained results are recommended to be used for monitoring anti-cancer measures in the region. Keywords: colorectal cancer, incidence, mortality, early diagnosis, neglect, morphological verification.


2011 ◽  
Vol 29 (15_suppl) ◽  
pp. e14021-e14021 ◽  
Author(s):  
J. S. Yu ◽  
R. Woods ◽  
C. Speers ◽  
S. Gill ◽  
H. F. Kennecke

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14186-e14186
Author(s):  
Shivi Jain ◽  
Kireet Agrawal ◽  
Shinoj Pattali ◽  
Abhijai Singh ◽  
Kamal Agrawal ◽  
...  

e14186 Background: Overall survival in colorectal cancer is influenced by obesity, age, gender and stage at diagnosis. However, in minority based populations, effect of the above factors on overall survival has not been studied in any detail. Hence, we undertook this retrospective study to evaluate effect of above factors on overall survival in young colorectal cancer patients. Methods: 1,195 subjects with colorectal cancer treated at John H. Stroger Hospital of Cook County between 2000 and 2008 were retrospectively analyzed. 179 subjects with age 50 years and younger were identified. 146 of 179 subjects with available Body Mass Index (BMI) in kg/m2 were included in the study. Effect of BMI, age, sex, race, LDH and CEA levels, stage, site of tumor, smoking and family history on overall survival was evaluated using standard statistical multivariate analysis. Results: In our population, 22 of 146(15%) were underweight (BMI<20), 56 of 146(38.4%) were normal weight (BMI 20-24.9), 46 of 146(31.5%) were overweight (BMI 25-29.9) and 22 of 146(15%) were obese (BMI >30). Male: female ratio was 1.4:1. 75 of 146(51.7%) were African American, 23 of 146(15.9%) were Caucasians. 50 of 146(34.2%) were stage IV colorectal cancer at diagnosis. On univariate analysis, BMI<20(p=0.031, HR 2.1, 95% CI 1.15-3.82), CEA >4ng/ml (p=0.005, HR 1.93, 95% CI 1.21-3.08) and stage IV colorectal cancer (p<0.001, HR 6.1, 95% CI 2.42-15.53) were significantly associated with decreased overall survival. LDH<200 U/L was significantly associated with improved overall survival (p 0.029, HR 0.6, 95% CI 0.391-0.950). On multivariate analysis, stage IV colorectal cancer was a single significant independent predictor of overall survival (p=0.001, 95% CI 2.47-27.78). CEA>4ng/ml was marginally significant for decreased overall survival (p=0.06, 95% CI 0.978-3.015). On the contrary, no statistically significant difference was found on overall survival with age, BMI>20, gender, race, tumor location, smoking and family history. Conclusions: Advanced stage and CEA >4ng/ml are independent prognostic variables for decreased overall survival in minority based population of young colorectal cancer.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15007-e15007 ◽  
Author(s):  
Arkhjamil Angeles ◽  
Wayne Hung ◽  
Winson Y. Cheung

e15007 Background: The CORRECT trial demonstrated overall survival benefits of regorafenib monotherapy in patients with metastatic colorectal cancer (CRC) who were refractory to prior chemotherapy and biological therapy. However, stringent criteria used to determine treatment eligibility in the trial setting may limit its external validity in the real world. We aimed to examine treatment attrition rates and eligibility of regorafenib in routine clinical practice. Methods: All patients diagnosed with metastatic CRC between 2009 and 2014 who received 2 or more lines of systemic therapy at the British Columbia Cancer Agency were identified. During the study timeframe, cetuximab (cmab) and panitumumab (pmab) were only used in the chemo-refractory setting. Data on clinical factors, pathological variables and outcomes were ascertained and analyzed. Eligibility was defined based on criteria outlined in the CORRECT trial. Results: A total of 391 patients were included among whom only 39% were considered eligible for regorafenib. Median age was 61 (range 22-84) years. 247 (63%) were men, 305 (78%) were Caucasian, and 237 (60%) had a colonic primary. The disease burden at diagnosis was high: 267 (81%) had lymph node involvement, and 225 (59%) had distant metastases. In patients previously treated with cmab, main reasons for regorafenib ineligiblity were Eastern Cooperative Oncology Group performance status (ECOG PS) > 1 (26.9%), aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) (6.5%), and arterio-venous thrombotic or embolic events in the preceding 6 months (6.5%). In the group treated with pmab previously, main reasons for ineligibility were ECOG PS > 1 (46.6%), total bilirubin > 1.5 x ULN (14.1%), and thrombotic or embolic events in the past 6 months (5.7%). Additional analyses showed that regorafenib-eligible patients had increased median overall survival compared to ineligible patients (44.0 vs 37.1 months, P= 0.028). Conclusions: The strict trial eligibility criteria disqualified the majority of real world patients with metastatic CRC for regorfenib. As ineligibility predicts poorer outcomes, trials aimed at serving protocol-ineligible patients are warranted.


2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Dong Peng ◽  
Yu-Xi Cheng ◽  
Yong Cheng

Purpose. The purpose of the current meta-analysis was to evaluate whether multidisciplinary team improved overall survival of colorectal cancer. Methods. PubMed, EMBASE, and Cochrane Library database were searched from inception to October 25, 2020. The hazard ratio (HR) and 95% confidence (CI) of overall survival (OS) were calculated. Results. A total of 11 studies with 30814 patients were included in this meta-analysis. After pooling the HRs, the MDT group was associated with better OS compared with the non-MDT group ( HR = 0.81 , 95% CI 0.69-0.94, p = 0.005 ). In subgroup analysis of stage IV colorectal cancer, the MDT group was associated with better OS as well ( HR = 0.73 , 95% CI 0.59-0.90, p = 0.004 ). However, in terms of postoperative mortality, no significant difference was found between MDT and non-MDT groups ( OR = 0.84 , 95% CI 0.44-1.61, p = 0.60 ). Conclusion. MDT could improve OS of colorectal cancer patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Xinhui Fu ◽  
Hanjie Lin ◽  
Xinjuan Fan ◽  
Yaxi Zhu ◽  
Chao Wang ◽  
...  

BackgroundPIK3CA is a high-frequency mutation gene in colorectal cancer, while its prognostic value remains unclear. This study evaluated the mutation tendency, spectrum, prognosis power and predictive power in cetuximab treatment of PIK3CA in Chinese CRC cohort.MethodsThe PIK3CA exon 9 and 20 status of 5763 CRC patients was detected with Sanger sequencing and a high-resolution melting test. Clinicopathological characteristics of 5733 patients were analyzed. Kaplan-Meier method and nomogram were used to evaluate the overall survival curve and disease recurrence, respectively.ResultsFifty-eight types of mutations in 13.4% (771/5733) of the patients were detected. From 2014 to 2018, the mutation rate of PIK3CA increased from 11.0% to 13.5%. At stage IV, exon 20 mutated patients suffered shorter overall survival time than wild-type patients (multivariate COX regression analysis, HR = 2.72, 95% CIs = 1.47-5.09; p-value = 0.012). At stage III, PIK3CA mutated patients were more likely to relapse (multivariate Logistic regression analysis, exon 9: OR = 2.54, 95% CI = 1.34-4.73, p = 0.003; exon 20: OR = 3.89, 95% CI = 1.66-9.10, p = 0.002). The concordance index of the nomogram for predicting the recurrence risk of stage III patients was 0.685. After cetuximab treatment, the median PFS of PIK3CA exon 9 wild-type patients (n = 9) and mutant patients (n = 5) did not reach a significant difference (3.6 months vs. 2.3 months, Log-rank test, p-value = 0.513).ConclusionsWe found that PIK3CA mutation was an adverse predictive marker for the overall survival of stage IV patients and recurrence of stage III patients, respectively. Further more, we suggested that PIK3CA exon 9 mutations are not negative predictors of cetuximab treatment in KRAS, NRAS, and BRAF wild-type mCRC patients.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 977-977
Author(s):  
Elysia Alvarez ◽  
Helen Parsons ◽  
Frances Maguire ◽  
Yi Chen ◽  
Cyllene Morris ◽  
...  

Abstract Introduction: Adolescent and young adult (AYAs: 15-39) patients with cancer have not had the same relative improvement in survival as other age groups over the last decades. Studies have shown that having public insurance or being uninsured at diagnosis is associated with more advanced disease at presentation and worse overall survival. However, previous studies have not differentiated patients who joined Medicaid at diagnosis from those with continuous enrollment which may have different implications for access to care prior to diagnosis. Therefore, we examined the impact of insurance status, including Medicaid enrollment at diagnosis, on stage at diagnosis for AYAs with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) only] and on survival for AYAs with NHL, HL, acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL). Methods: Using Medicaid enrollment data linked to the California Cancer Registry, we identified AYAs with NHL, HL, ALL, and AML diagnosed from 2005 to 2014. Insurance type was classified as: continuous Medicaid, discontinuous Medicaid prior to diagnosis, Medicaid at diagnosis, other public (Medicare, Indian/Public Health Service, county), private/military, and uninsured. Multivariable logistic regression and Cox proportional hazards regression were used to determine the impact of insurance type on stage at diagnosis (for NHL and HL) and overall survival, respectively. Results are represented as adjusted odds ratios (OR) and hazard ratios (HR) with associated 95% confidence intervals (CI). Results: Of the 11,667 AYA patients in our study, 4,435 had NHL, 4,161 had HL, 1,522 had AML and 1,549 had ALL. Patients with HL had the highest proportion of private insurance (66%) followed by those with NHL (60%), AML (50%) and ALL (37%). Of the 4,059 patients enrolled in Medicaid, 41% had continuous Medicaid, 15% had discontinuous Medicaid and 43% received Medicaid at diagnosis. Only 2-4% of patients, depending on primary diagnosis, remained uninsured after cancer diagnosis. The majority of AYAs with HL and NHL were diagnosed with stage I/II disease (59% and 52% respectively). Compared to AYAs with private insurance, NHL and HL patients with discontinuous Medicaid and Medicaid at diagnosis had a higher likelihood of later stage disease (III-IV vs I/II) at diagnosis (NHL: discontinuous OR 1.45, CI 1.10-1.92; at diagnosis OR 1.69, CI 1.38-2.06; HL: discontinuous OR 1.63, CI 1.19-2.23; at diagnosis OR 1.68, CI 1.35-2.09) after adjusting for sociodemographic factors, baseline comorbidities and type of facility. In addition, NHL patients with continuous Medicaid (OR 1.23, CI 1.01, 1.51) and HL patients with other public insurance (OR 1.56, CI 1.05-2.32) had a higher odds of late stage disease. Type of health insurance was associated with overall survival in multivariable models (Table). NHL patients with Medicaid (continuous HR 1.74, CI 1.39-2.17; discontinuous HR 2.52, CI 1.94-3.27; at diagnosis HR 1.88, CI 1.53-2.31), other public (HR 1.83, CI 1.16-2.87) and no insurance (HR 1.87, CI 1.09-3.20) had worse survival than NHL patients with private insurance. Similarly, HL patients with Medicaid (continuous HR 2.10, CI 1.42-3.12; discontinuous HR 1.89, CI 1.08-3.29; at diagnosis HR 2.43, CI 1.699-3.48) and no insurance (HR 1.87, CI 1.09-3.20) experienced worse survival. For AML, health insurance was not significantly associated with survival. For ALL, only continuous Medicaid (HR 1.32, CI 1.05-1.67) and other public (HR 1.32, CI 1.05-1.67) insurance were associated with worse survival, though discontinuous Medicaid trended toward significance (p=0.06). Conclusion: Our study demonstrates that a significant proportion of patients previously thought to have public insurance were discontinuously insured with Medicaid or uninsured at time of diagnosis, only receiving Medicaid after diagnosis. While important, insurance enrollment at diagnosis does not provide the same pre-diagnosis access to services as those with continuous enrollment. Indeed, for NHL and HL, we observed the strongest associations between discontinuous Medicaid and Medicaid at diagnosis and late stage disease. However, Medicaid, regardless of type of enrollment, was associated with worse survival in AYAs with NHL, HL and ALL relative to private insurance. Therefore, future studies should focus on factors influencing worse outcomes for AYA patients with public insurance. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Author(s):  
Xiaohui Zhou ◽  
Yeqing Gong ◽  
Xiaorong Liu ◽  
Jiaqi Mao ◽  
Zhen Chen ◽  
...  

Abstract Background: The heterogenetic nature of colorectal cancer (CRC) constitutes a major challenge for drug development. Simultaneous targeting multiple molecules by combination therapy provides a promising strategy, but it requires identification of more potentially useful targeted agents. Palbociclib, a selective CDK4/6 inhibitor approved for the treatment of HR/ER-positive and HER2-negative breast cancer, exhibited anti-cancer versatility in several types of cancer. In this study, we evaluated its usefulness in the treatment of CRC either by single-agent or combined with a small molecule EGFR inhibitor erlotinib. Methods: The impacts of palbociclib, erlotinib, and their combination on cell proliferation, colony formation, cell cycle, apoptosis, senescence, and ROS accumulation in CRC cells were assessed. Their efficacies were evaluated in CRC patient-derived organoids (PDO) and xenograft (PDX) models.Results: Single-agent palbociclib efficiently inhibited proliferation, suppressed the RB phosphorylation, and caused G1-phase arrest in KRAS/BRAF mutated CRC cell lines. IC50 of all cell lines were below 1 µM. Moreover, it induced ROS accumulation and consequently caused apoptosis and senescence of CRC cells. The addition of erlotinib further aggravated palbociclib-induced anti-proliferation, cell cycle arrest, ROS accumulation, apoptosis, and senescence via blocking multiple critical effectors on RB/PI3K/RAS pathways and such interaction between two agents are synergistic. Finally, both palbociclib and erlotinib demonstrated anti-CRC activities, but only their combination caused statistically meaningful inhibition of tumor growth and prolonged survival with tolerable toxicity in KRAS wildtype/mutated PDX models. Conclusion: Our work demonstrated that the palbociclib and erlotinib combination treatment is a promising therapy for CRC and worthy of further clinical evaluation.


2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 3630-3630
Author(s):  
Michael Hayden Rosenthal ◽  
Stephanie Anne Holler Howard ◽  
Kyung Won Kim ◽  
Jeffrey A. Meyerhardt ◽  
Charles S. Fuchs ◽  
...  

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