bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of deuterium-depleted water as a nutritive factor on the effectiveness of experimental chemotherapy in aging rats.
Authors: Shikhlyarova Alla I. , Zhukova Galina V. , Dzhimak Stepan S. , Baryshev Mikhail G. , Kit Oleg I. , Goncharova Anna S. , Shirnina Elena A. , Protasova Tatiana P. , Zhadobina Anastasia I. , Bragina Marina I. , Lukbanova Ekaterina A.
Published: May 2019

e14683

Background: The rates of physical and chemical interactions are associated with water isotopic composition. The ability of deuterium-depleted water (DDW) to influence free radical, metabolic and regulatory processes determines the need to change the drinking diet at aging, tumor growth antitumor chemotherapy (CT). Our purpose was to study the influence of DDW on the state of aging female rats, tumor growth and the CT effectiveness. Methods: The study included 37 aging outbred white female rats (250-280 g) with transplanted sarcoma 45 (S-45) receiving chemotherapy with cyclophosphamide (CF). DDW intake (46±2 ppm, 25-30 mL a day) was started 5 weeks before S-45 transplantation. CF was administered intraperitoneally on day 10 at a dose of 50 mg/kg twice with a 5-day interval. We determined tumor volume by Shrek, deuterium concentrations in the blood plasma (NMR spectrometer JEOL JNM-ECA 400MHz) and inner organs (mass spectrometer DELTAplus H/Device, Finnigan, Germany), estrous cycle stages and types of the nonspecific adaptational reactions of organism by Garkavi-Kvakina-Ukolova (1975). Results: DDW administration before the tumor transplantation significantly balanced the stages of the estrous cycle and increased the incidences of the antistress adaptational reactions development by 1.6 times (p < 0.05); external signs of rejuvenation were observed (changes in hair state and motor activity). After S-45 transplantation, its growth prior to CT was suppressed (tumor volume 0.25±0.07 cm3 vs. 0.47±0.10 cm3 in controls, p < 0.1). DDW increased the effect of CF by 4.8 times by day 15 (0.88±0.67 cm3 vs. 4.22±1.43 cm3 with CF alone, p < 0.05). Concentrations of deuterium in the blood plasma decreased by 33%, in the inner organs (liver, kidney and heart) – by 6-14% (p < 0.05). Conclusions: DDW has an antistress, geroprotective , antitumor and CT-optimizing effect.
Measuring parameters of the cancer ecosystem for cancer ecological staging.
Authors: Cunningham James R. , Rittenbach Jon , Clemens Mitch , Dodd Cheryl , Wilson Ashley , Roberson Kaikuihala
Published: May 2019

e14684

Background: Cancer progression through clonal evolution and emergent phenotypic heterogeneity is thought to reflect stochastic events such as genetic drift. This divergence over time in the character of a neoplasm might also reflect genetic selection, analogous to other populations in nature, to maximize niche resource utilization. We hypothesized that selection pressures operate in patients with cancer to drive cancer evolution, are clinically identifiable, their influence measurable. Methods: To develop a system for cancer ecology staging, a feasibility study recruited 15 patients with active cancer from any site, with expected survival of more than 6 months and providing informed consent. A set of clinical parameters obtained from a patient questionnaire, physical exam and laboratory testing was used to generate eight separate ecological profiles of tumor microenvironment, chronic inflammation, energy balance, psychosocial stress, GI microbiome, endocrine environment, skeletal remodeling and environmental mutagenesis. A scoring system, based on evidence of positive selection was designed to quantitate the individual profiles. Profile scores were then aggregated using a 2-D radar plot to generate a polygon, an ‘ecogram’, whose area, it is hypothesized, corresponds to the net level of selection pressure influencing tumor evolution. Results: Ecological profiles were obtained from each of 15 patients allowing determination of the ecogram area (EA) bounded by the polygon. EA determinations ranged widely among the 15 patient, from 0-12.7 arbitrary units (au, mean 5.01± 0.80). Ecograms from individual patients demonstrated unique shapes suggesting specificity for individual patient ecology. EA measurements were then used to inform an ecological staging system based on a simplified dichotomization, low/high, of ecosystem resources and threats. Of 15 patients, 6 were considered to have high resources (EA > 5au) available to support tumor evolution. High anti-tumor threat, measured by CD3 lymphocyte immunohistochemical scoring, was detected in 11 patients. Conclusions: An ecological assessment of patients with active cancer appears feasible. Inter-patient variation in ecogram area and morphology suggests there are potential important differences in genetic selection found between patients and should be correlated with survival outcomes in future studies, validation offering a target for ecosystem ‘restoration’.
Feasibility and clinical impact of next-generation sequencing (NGS) in patients with stage IV or recurrent malignancies.
Authors: Covut Fahrettin , Kewan Tariq Zuheir , Thapa Bicky , Haddad Abdo S. , Spiro Timothy Peter , Daw Hamed
Published: May 2019

e14697

Background: Feasibility and outcomes of routine NGS in patients with stage IV or recurrent malignancies remain debatable. Methods: We reviewed patients who underwent Foundation One NGS between 9/2012 and 10/2018 after diagnosis of stage IV or recurrent solid cancer at Cleveland Clinic. Overall survival (OS) was estimated by the Kaplan-Meier method. Logistic and Cox regression analysis were performed to identify predictors of receiving targeted gene therapy (TGT) and OS, respectively. Results: We identified 1699 patients, 825 (49%) were female, 1634 (96%) had stage IV and 65 (4%) had recurrent cancer. At diagnosis of stage IV/recurrent cancer, median age was 61 (range: 18 – 94) and ECOG performance score was 0, 1, and ≥ 2 for 578 (34%), 859 (51%), and 258 (15%) patients, respectively. Most common primary cancers were lung (20%), colorectal (17%), urothelial/prostate (12%), and breast (10%). NGS revealed median of 4 mutated genes (range: 0 – 34), ≥ 1 FDA approved TGT was available in 505 (30%) and 1114 (66%) patients for the same and different primary cancer, respectively. Overall, 219 (13%) patients received 247 lines of TGT for median of 3 months (range: 0.1 – 62) based on NGS results. TGT use was via clinical trials for 49 (22%) and off-label for 83 (38%) patients. Best response was complete/partial response for 63 (29%) and stable disease for 40 (18%) patients. Commonly targeted genes were EGFR (12%), ERBB2/3 (11%), BRAF (10%), BRCA1/2 (8%), and PIK3CA (7%). Median follow-up after diagnosis of stage IV/recurrent cancer was 19 months. Two-year OS for TGT and no TGT cohorts were 70% (95% CI: 64 – 77) and 55% (95% CI: 53 – 58), respectively (p < 0.0001). On multivariable analysis, ECOG ( < 2vs ≥2), systemic therapy between diagnosis of stage IV/recurrent cancer and NGS (≥2 vs < 2 lines), and each 1 increase in number of mutated genes were predictors of receiving TGT (p < 0.05 for all). On multivariable analysis, age (≤65 vs > 65), ECOG ( < 2vs ≥2), stage (recurrent vs IV), and systemic therapy before NGS (≥2 vs < 2 lines) predicted longer OS (p < 0.01 for all). Conclusions: In this large cohort, NGS provided further therapeutic options including clinical trials for approximately 1 out of 10 patients with stage IV or recurrent cancer.
Impact of combined MRP1 inhibition and mutant p53-targeting compound APR-246.
Authors: Ceder Anna Sophia , Eriksson Sofi E. , Cheteh Emarndeena Haji , Bykov Vladimir J.N. , Abrahmsen Lars , Wiman Klas G.
Published: May 2019

e14712

Background: The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. Mutant p53 protein is often expressed at high levels and accompanied with gain-of-function activities that promote tumor development and resistance towards conventional treatment. APR-246 is a mutant p53-reactivating small molecule undergoing a Phase III clinical study in myelodysplastic syndrome (MDS), and several phase II studies. APR-246 is non-enzymatically converted to its active product methylene quinuclidinone (MQ) which binds to cysteine residues in p53. This stimulates proper folding of p53's DNA-binding core domain, leading to cell death. APR-246 also exhibits pro-oxidant activity as the electrophile MQ binds and inactivates important antioxidants such as glutathione and thioredoxin reductase, which both are essential for cellular defense against oxidative and electrophilic stress. Methods: All results are in vitro experiments by LC-MS as well as experiments in cultured cells, including 14C-APR-246/MQ detection, cell viability measurements, LC-MS analysis, enzyme recycling measurements and Western blotting. Results: We have utilized 14C-labelled APR-246 to investigate the effect of APR-246 and its active moiety MQ in tumor cell cultures upon inhibition of efflux transporter multidrug resistance protein 1 (MRP1) or cystine-glutamate transporter (xCT). Transient downregulation or small molecule inhibitors (MK-571, reversan, sulfasalazin) targeting MRP1 or xCT increased drug content and shifted intra- and extracellular thiol status. Missense mutant TP53-carrying cells exhibited higher sensitivity to APR-246 and combination therapies. MRP1 inhibition showed strong synergy with APR-246 and increased intracellular levels of MQ conjugated to glutathione (GS-MQ). We found that GS-MQ conjugate formation is reversible, and suggest that the intrinsic reversibility of MQ adduct formation is an important aspect of the mechanism of action of APR-246. This reversibility may also in part account for the benign safety profile reported from clinical studies with APR-246. Conclusions: Sensitivity to APR-246 is affected by MRP1 efflux activity and the redox status, reflected in ratios of cysteine/cystine and reduced/oxidized glutathione (GSH/GSSG).
CD205, a target antigen for a novel ADC: Evaluation of antigen expression on TNBC, pancreatic adenocarcinoma and bladder urothelial carcinoma.
Authors: Massa Simona , Collini Paola , Spagnuolo Rosalin Dolores , Bertolotti Alessia , Garzone Giovanna , Pruneri Giancarlo , Carcangiu Maria Luisa , Kaplan Angelo , Rohlff Christian , Buontempo Serena , Matera Mariagiuseppa , Bussolo Vanessa , Merlino Giuseppe , Binaschi Monica , Rossi Cristina , Tonini Giulia , Fedi Valentina , Simonelli Cecilia , Capriati Angela , Pellacani Andrea Ugo
Published: May 2019

e14726

Background: CD205 is a type I transmembrane surface protein belonging to the mannose receptor family with propensity for antigen uptake/internalization. CD205 is expressed in different cancer histotypes and seems to have a role in migration and invasion. For these features CD205 is an ideal candidate to be exploited as an ADC target. MEN1309/OBT076 (herein as MEN1309) is a humanized IgG1 antibody against CD205, conjugated through a cleavable linker to DM4. It has shown impressive anti-tumor activity when tested in high/low CD205 expressing xenografts for solid tumours and NHL. MEN1309 is under assessment in Phase I trials in EU (NCT03403725) and as OBT076 in USA. Methods: A retrospective evaluation of CD205 expression in 103 triple negative breast carcinomas (TNBC), 50 pancreatic adenocarcinomas (PAC) and 100 bladder urothelial carcinomas (UC) was performed at INT in Milan, Italy. Immunohistochemistry was performed on one FFPE representative sample per case, using a commercial anti-CD205 antibody. A semiquantitative score was applied to measure CD205 expression. Absence of staining tumor cells was scored as negative. Positivity was scored based on the percentages of neoplastic cells (NCs), with intensity of cytoplasmic staining ranging from 1 (weak) to 3 (strong). Membrane staining in NCs, immunoreactivity of the intratumoral/peritumoral inflammatory component and of normal tissue were scored as absent or present. Results: TNBC: 85% were positive, 70% in > 5% of NCs; 14% showed 2+/3+ staining intensity in > 50% of NCs. 57% of cases showed a membrane positivity. PAC: 100% were positive in > 5% of NCs; 50% showed 2+/3+ staining intensity in > 50% of NCs. 98% of cases showed a membrane positivity. UC: 67% were positive, 60% in > 5% of NCs; 10% showed 2+/3+ staining intensity in > 50% of NCs. 29% of cases showed a membrane positivity. Inflammatory component and normal tissue were positive in almost all cases. Conclusions: CD205 is heterogeneously expressed in the majority of TNBC and UC and in all PAC cases. The results of this study support the clinical investigation of MEN1309 in these tumor types.
IDH1 polymorphism G105G (rs11554137) as a prognostic factor in gliomas.
Authors: Franceschi Enrico , De Biase Dario , Tosoni Alicia , Paccapelo Alexandro , Acquaviva Giorgia , Pession Annalisa , Tallini Giovanni , Argento Chiara Maria , Bartolini Stefania , Brandes Alba Ariela
Published: May 2019

e14734

Background: IDH mutational status is required for diagnosis according to the 2016 WHO criteria. The single nucleotide polymorphism (SNP) rs11554137 ( IDH1105GGT) at codon 105 of IDH1 has been reported in patients with several tumor types, including glioma. The aim of this study is to investigate the prognostic role of IDH1105GGT Methods: We analyzed our institutional data warehouse for consecutive patients (pts) with newly diagnosed, histologically proven grade II or Grade III gliomas. IDH sequencing was performed using the 454 GS-Junior next generation sequencer (NGS) (Roche Diagnostic, Mannheim, Germany). All analyses were performed on DNA from formalin fixed and paraffin embedded (FFPE) specimens. Results: The analysis included 77 pts with grade II (n = 51, 66.2%) or grade III glioma (n = 26, 33.8%). Median follow up of this study was 91 months. Patients received biopsy/partial resection/complete resection in 7.8%, 70.1% and 22.1%, respectively. Postsurgical RT and/or chemotherapy was delivered in 64.9% of pts. IDH mutations affecting codons 132 (for IDH1) and 172 (for IDH2) were found in 71 pts (92.2%). IDH1105GGTwas found in 11 pts (14.3%), mainly harboring also IDH mutations (81.8%), and was more frequent in grade 3 (30.8%) than in grade 2 gliomas (5.9%, P = 0.006). Pts harboring both IDH mutations and IDH1105GGTshowed a significantly longer progression-free survival compared with pts with IDH mutation alone (78.7 months vs 49.9 months, p = 0.041). Conclusions: IDH1105GGT represents a promising novel biomarker in IDH mutated grade 2 and 3 gliomas and warrants further investigations.
Receptor status conversion between primary and recurrent/metastatic breast cancer: A single institutional study.
Authors: Ramadas Poornima , Leibovitch Jennifer , Ramakrishna Karan , Krishnan Prathik , Wang Dongliang , Benjamin Sam
Published: May 2019

e14735

Background: Hormone receptor and HER2 status have both predictive and prognostic implications in breast cancer (BC). Studies report differences of 3% to 54% for Estrogen receptor (ER), 5% to 78% for Progesterone receptor (PR), and 0% to 34% for HER2 between primary (P) and recurrent/metastatic breast cancer (RMBC). To evaluate this difference, we conducted an observational single institution study in adult patients (pts) ≥ 18 years with RMBC. Methods: After IRB approval, we conducted a retrospective chart review of pts diagnosed with RMBC between January 1st, 2010 and October 31st, 2018, with history of PBC. We recorded age at PBC diagnosis, stage, tumor type, receptor status, initial treatment, age at RMBC diagnosis, if biopsy performed, receptor status and survival. We studied the differences in ER, PR and HER2 receptors between P and RMBC. Descriptive statistics was used for analysis. Results: We found a total of 179 pts in the time interval. Median age was 54 ± 13.2 years at PBC diagnosis, 98.9% females, 1.1% males. 187 events were recorded. At PBC diagnosis, 27.4% had Stage I, 37.4% had Stage II and 31.8% had Stage III disease. Tumor type was ductal in 83.8% and lobular in 12.2%. 78.8% was ER+, 68.7% was PR+ and 14% was HER2+. 70.9% received chemotherapy, 12.8% received HER2 therapy and 67% received hormonal therapy. Age at RMBC was median of 61 ± 13.1 years. Biopsy was done in 93.3%. Time between PBC and RMBC ranged from 7 and 324 months. 31.3% had local recurrence and 68.7% had distant disease. In RMBC, 59.2% was ER+, 41.9% was PR + and 13.4% was HER2 +. 58.7% are alive and 38% deceased. With RMBC, 19.2% who were ER+ became ER-, 4.9% who were ER- became ER+, 37.5% who were PR+ became PR-, 8.6% who were PR- became PR+, 23.1% who were HER2+ became HER2-, 4.5% who were HER2 - became HER2+. In pts who became ER-/PR-, 88.5% received hormonal therapy and 61.5% received chemotherapy at the time of PBC. In pts who became HER2-, 83.3% received HER2 therapy at the time of PBC. Conclusions: In our study, we found a difference of 24.1% in ER, 46.1% in PR and 27.6% in HER2 between PBC and RMBC. It is recommended that patients with RMBC should have a biopsy to evaluate the receptor status as it would impact treatment and survival.
Analysis of lipid metabolism genes in advanced small cell lung cancer.
Authors: Merino Maria , Fernández Lara , Sereno Maria , Ramirez de Molina Ana , Moreno Juan , Colmenarejo Gonzalo , Gómez César , Lopez-Gomez Miriam , Falagan Sandra , Aguayo Cristina , Zambrana Francisco , Jimenez Gordo Ana Maria , Casado Enrique
Published: May 2019

e14737

Background: Lung cancer is the leading cause of cancer death worldwide. Although most of the knowledge about metabolic dysregulation in cancer focuses on carbohydrates, the importance of alterations related to lipid metabolism is starting to be recognized. There is increasing data on lipid metabolism and non-small lung cancer, but much less is known about this in small cell lung cancer (SCLC). In order to improve our knowledge of these alterations we evaluated a genetic profile related to lipid metabolism and studied clinical outcomes. Methods: We performed a retrospective analysis of 22 genes related to lipid metabolism in 37 tumoral tissue samples of SCLC patients and evaluated clinical features and outcomes. Advanced SCLC patients enrolled from November 1, 2008 through December 31, 2015 were included in this analysis. Clinical data were collected from medical records at the time of enrollment. The study was approved by an Ethics Comittee and all patients signed an Informed Consent form. We used formalin-fixed, paraffin- embedded tumor tissue. Samples were deparaffinated and total RNA was extracted. A Taq-Man Low Density Array (Applied Biosystems) was specifically designed and gene-expression assays were performed in a HT-7900 Fast Real time PCR. RT-StatMiner software was used to detect and determine the quality control and differential expression analyses of data. Results: We included 37 patients, 73 % males and 27 % women, with a median age of 62. 29 patients (78%) had stage IV tumor and nearly all of them (92%) were treated with platinum- based chemotherapy. 11 % (4/37) received thoracic radiotherapy and 5% (2/37) received whole brain radiotherapy. 6 patients (16%) were on chronic treatment with metformin and 15 (40%) on statins. We performed a multivariable analysis and found that overexpression of two metabolic genes (a mitochondrial enzyme and a lipid metabolism regulator) led to longer overall survival. (HR 0.13 (0.04-0.42), p 0.0019, padjusted 0.04 and HR 0.11 (0.03-0.35) p 0.0006, padjusted 0.01, respectively). Conclusions: These genes contribute to normal functioning and regulation of lipid metabolism and could be considered as potential prognostic biomarkers. There is no previous evidence of association between levels of expression of these genes and overall survival in SCLC. Validation in a larger series of patients is ongoing.
Therapy alteration of solid tumors based on FoundationOne comprehensive genome profiling assay.
Authors: Karlin Kirill , Kahraman Abdullah , Curioni Fontecedro Alessandra , Moch Holger , Zoche Martin , Siebenhuener Alexander Rheinhard
Published: May 2019

e14742

Background: Molecular profiling assays are becoming widely available and provide valuable information on tumor characteristics, which can identify targeted therapies or immunotherapies for cancer patients. However, the clinical utility of such tests remains unclear. Within our institution, we analyzed the clinical utility and subsequent treatment alterations of the FoundationOne Comprehensive Genome Profiling Test (FOne). Methods: We conducted a retrospective cohort review (2017 - 2018) of patients with solid tumors under standard diagnostic care who received FOne testing. We reviewed the therapies that were proposed by FOne and studied whether they led to a therapeutic alteration. Results: 71 patients were identified, of which the majority presented a progressive disease state (80%). Among the cancer types most frequently tested were adenocarcinoma of the colon (14%), prostate (8%), lung (4%), intrahepatic cholangiocarcinoma (8%) and breast invasive ductal carcinoma (4%). In 16 cases (22%), therapies suggested by FOne were approved in patient’s tumor type while in 30 cases (42%) therapies were approved in another tumor type. For an additional 13 cases (18%) only therapies tested in clinical trials were reported. 4 patients (6%) received a new therapy based on the FOne result: cancer of unknown primary (Everolimus due to a TSC1 mutation), cutaneous angiosarcoma (Pembrolizumab due to a high tumor mutational burden (TMB)), gastrointestinal neuroendocrine carcinoma (Ipilimumab and Nivolumab due to an intermediate TMB) and mucinous adenocarcinoma of the appendix (Talazoparib due to an ATM mutation). For 11 cases (15%), a new therapy option was identified by FOne, which due to the current treatment plan might be considered for later use. 3 cases (4%) were evaluated for potential clinical trial enrollment. Note that for an additional 6 patients (8%), the therapies proposed by FOne were already established on the basis of previous testing (e.g. smaller genomic panels, IHC, FISH). Conclusions: Overall, 18 (25%) patients received a new therapy option by FOne after standard of care diagnostics. Therapeutic alterations were observed particularly in patients with a rare or unknown tumor type.
p53 expression and clinical outcomes in untreated and treated breast cancer patients after long-term follow-up.
Authors: Yang Sherry X. , Huang Erich , Nguyen Dat
Published: May 2019

e14745

Background: p53 alteration represents one of the hallmarks of malignant transformation. However, its role on treatment outcome remains controversial and is unknown in untreated patients in breast cancer. This study aims to evaluate p53 expression in association with clinical outcomes in untreated patients relative to those undergoing homogeneous therapy. Methods: p53 protein was examined by immunohistochemistry in 956 patients with stage I, II and III breast cancer. Overall survival (OS) and relapse-free survival (RFS) between p53-positive and -negative tumors in chemotherapy, radiation or endocrine therapy alone and no treatment groups were estimated by Kaplan-Meier method. OS and RFS were further assessed by multivariable Cox model that incorporates p53, age, tumor size and grade, estrogen receptor, and HER2 in specific treatment group(s). Results: p53 expression was detected in 22.7% of breast cancer. Median follow-up time was 115.5 months, with a range of 5 to 282 months. Expression of p53 was associated with younger age at diagnosis, higher tumor grade, ER/PR negativity, and HER2 positivity ( P< 0.001). Without any treatment including systemic and radiation therapy (n = 227), OS and RFS curves were overlapped from the beginning until the end of follow-up between p53-positive and -negative patients, respectively. In contrast, p53 was significantly associated with worse OS and RFS with univariate analysis and multivariate statistics of OS (HR 4.07, 95% CI 1.95-8.50; P< 0.001) and risk of relapse (HR 2.23, 95% CI 1.11-4.48; P= 0.025) by endocrine therapy alone (n = 130). Moreover, apparent trends for p53 toward unfavorable OS and RFS were observed in those undergoing homogeneous radiation therapy and chemotherapy, only within 150 months of follow-up. Conclusions: p53 is not associated with clinical outcomes in the absence of conventional therapy, and independently predicts worse survival and increased risk of recurrence after endocrine therapy.
Rectal cancer and pathologic complete response after preoperative chemoradiotherapy: Romanian single-center experience.
Authors: Bonci Eduard-Alexandru , Bobeş Valentin Ioan , Kirsch Timea , Ţîţu Ştefan , Adam Teodora-Irina , Vlad Ioan-Cătălin , Irimie Alexandru , Muntean Alina , Achimaş-Cadariu Patriciu
Published: May 2019

e15002

Background: Current guidelines recommend neoadjuvant chemoradiation followed by total mesorectal excision for patients with locally advanced rectal cancer (LARC). After neoadjuvant chemoradiation, some of these patients achieve a pathologic complete response (pCR) of the primary tumor (ypT0) and seem to have improved oncologic outcomes. In the last years, a "wait-and-watch"/active surveillance or less radical surgery was proposed for these patients. The aim of this study was to analyze the overall survival (OS), disease-free survival (DFS), various clinicopathological factors and treatment factors in patients with LARC and ypT0 treated in our institution. Methods: Patients with LARC who received neoadjuvant chemoradiotherapy and achieved ypT0 on the surgical specimen were included in the present study. Clinical, pathological and surgical data from 51 patients was retrospectively collected between 1st of January 2012 and 31st of December 2017. Kaplan-Meier method and multivariate analysis were used to investigate the role of various clinicopathological factors and treatment characteristics in modulating the outcome for the patients included in the present study. Results: The study group included 18 females and 33 males having a mean age (+/- standard deviation) of 61 years (+/- 11,48) and 59 years (+/- 12,04), respectively. After a median follow-up of 19 months, OS was 88,24% and DFS was 98,03%. Classic open surgery was performed in all patients, low anterior resection and Miles resection was performed in 36 and 15 patients, respectively. Adjuvant chemotherapy was administered to 5 patients. Nodal status was ypT0N0 in 50 patients, ypT0N1 in one patient. Two of the recorded factors, stenosis and circumferential resection margin (CRM), appeared to play a significant role in modifying OS. Conclusions: Most of the patients with LARC treated with neoadjuvant chemoradiation and radical surgery seem to have a favorable long-term outcome but the stenosis and the involvement of CRM appears to predict the postoperative OS. Further studies are needed to determine the role of other factors in predicting OS and DFS in patients with LARC and ypT0.
Cost-effectiveness for metastatic colorectal cancer.
Authors: Yao Linli , Han Jiaqi , She Longjiang , Ding Dong , Liao Mengting , Hu Huabin , Zeng Shan , Shen Liangfang , Huang Jin
Published: May 2019

e15003

Background: As standard third-line treatments for metastatic colorectal cancer, regorafenib and fruquintinib, compared with placebo, increase median overall survival by 2.5 months and 2.7 months, respectively. Given the incremental clinical benefit, we aim to estimate the cost effectiveness of regorafenib versus fruquintinib in the third-line treatment for patients with metastatic colorectal cancer from Chinese payer perspective. Methods: A mathematical Markov model was established to project the cost-effectiveness of regorafenib versus fruquintinib from the CONCUR and FRESCO clinical trials. Quality-adjusted-life-years (QALYs) were analyzed with extracted data from the trials. Willingness to pay (WTP) of $26508 was used. Drug costs were estimated from the perspectives of the health care system in the People’s Republic of China. One way sensitivity and scenario analyses were performed by varying potentially modifiable parameters of the model. Results: Fruquintinib, compared with regorafenib, provided an additional 0.028 QALYs (0.274 QALYs versus 0.246 QALYs) at less cost ($33536 versus $35607). Conclusions: Fruquintinib is more cost-effective than regorafenib as the third-line management for patients with metastatic colorectal cancer when WTP is $26508.
Cetuximab maintenance therapy in unresectable metastatic colorectal cancer patients with wild-type RAS and BRAF: A single-center retrospective study.
Authors: Jiang Tao , Lin Xiaoyan , Chen Hao , Zhen Jianwei , Du Bin , Liu Qing , Zhong Dongta , Yang Baoyu , Wang Xinli
Published: May 2019

e15004

Background: Cetuximab plus FOLFIRI (leucovorin, fluorouracil and irinotecan) is preferred first line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC) patients. However, the side effects often require dose-reductions or discontinuation calling for maintenance strategies to reduce toxicity and preserve efficacy. Therefore, we evaluated efficacy and safety of cetuximab maintenance therapy after first-line treatment in unresectable mCRC patients with RBWT. Methods: This single center, retrospective study enrolled patients (aged 18-71 years) with untreated mCRC with RBWT, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, with at least one measurable lesion according to response evaluation criteria in solid tumor (RECIST). All patients received first line cetuximab plus FOLFIRI every two weeks for 9-12 cycles, after which, patients with treatment response chose to either enter observation (stop treatment) or maintenance 1 (cetuximab plus irinotecan) group. After 6-12 cycles of maintenance 1, patients with treatment response entered maintenance 2 (cetuximab only). If patients progressed on maintenance 2, reintroduction of cetuximab plus FOLFIRI was suggested. Primary endpoint was failure-free survival (FFS); while secondary endpoints included disease control rate (DCR), objective remission rate (ORR) and progression free survival (PFS). Safety events were also evaluated. Results: Among 62 enrolled patients, 56 patients completed first-line treatment (DCR: 90.3%, ORR: 62.9%) and 30 patients entered maintenance 1 [median PFS1 (mPFS) =6.1 months, 95%CI: 6.0-6.2, DCR=60%, ORR=30%]. Of these, 18 entered maintenance 2 [mPFS2=6.6 months, 95%CI: 5.1-8.1, DCR=27.8%, ORR=5.6%]. The mFFS was significantly longer in maintenance 1 (12.8 months, 95%CI: 10.8-14.8) compared to observation group (3.0 months; hazard ratio [HR]: 0.21, 95%CI: 2.6-3.4, P<0.001). Overall mFFS was 19.0 (95%CI: 11.0-27.0) in maintenance and 9.5 months in observation group (HR: 0.195, 95%CI: 7.4-11.6; P<0.001). Rash acneiform, mucositis and asthenia were the common adverse events observed during maintenance treatment. Conclusions: Maintenance treatment with cetuximab after first line therapy significantly improved FFS, with acceptable safety profile in untreated mCRC RBWT patients.
Efficacy of quxie capsule in metastatic colorectal cancer: Update of a double-blind, randomized, placebo controlled trial.
Authors: Zhang Tong , He Wenting , Xu Yun , He Bin , Yang Yufei
Published: May 2019

e15030

Background: To verify the efficacy of Quxie Capsule in patients with metastatic colorectal cancer (mCRC). Methods: This is a update of a randomized, double-blind, placebo-controlled trial. Between April 2014 and July 2015, 121 patients were enrolled in the study. Sixty patients were eligible and randomized to the two groups at a 1:1 ratio. Treatment group received conventional therapy and Chinese herbal medicine combined with Quxie Capsule for 3 months. Control group received conventional therapy and Chinese herbal medicine combined with placebo for 3 months. Main outcome measures were overall survival (OS) and progression-free survival (PFS). As of Dec 31st 2018, one patient in the control group was still alive, and all the other patients reached the main clinical endpoint. Median follow-up time was 19.4 months. Bo Ao Tong (Beijing) Medical Technology Co. Ltd. was responsible for the protocols of blind and block randomization. Results: The median OS were 23.9 months in the treatment group [95% confidence interval (CI) 15.9–28.5] vs. 14.3 months in the control group (95% CI 11.3–21.4) (Kaplan–Meier, Log-rank P=0.032), hazard ratio (95%CI)= 0.55 (0.31, 0.95), P=0.04. In the subgroups of left-sided colon, RAS wild type, non-targeted therapy, colon cancer and ≥second-line therapy, the median OS of the treatment group and the control group were respectively: 20.9 vs 12.2m, 17.4 vs 14.4m, 20.8 vs 12.0m, 25.1 vs 18.5m, 25.1 vs 12.0m ( P=0.037, 0.019, 0.022, 0.018, 0.007). There were no significant differences between the two groups in PFS. Conclusions: Quxie Capsule showed good efficacy, can reduce the risk of death and prolong the OS of patients with mCRC. Clinical trial information: ChiCTR-IOR-16009733.
Evaluation of Dworak grading system as a prognostic indicator after neoadjuvant chemoradiotherapy in rectal cancer patients.
Authors: Buecker Rebecca , Torsten Hansen , Hartmann Frank , Schafer Ulrich
Published: May 2019

e15053

Background: The objective of this study was to assess the prognostic role of Tumor Regression Grading (TRG) according to the Dworak system on progression free survival (PFS) after chemoradiotherapy (CRT) in locally advanced rectal cancer. Methods: In total, 159 patients with locally advanced rectal cancer who underwent neoadjuvant CRT from January 2007 and December 2016 were enrolled. PFS (any relapse after surgery) was tested against TRG (Dworak grade 1+2 versus Dworak grade 3+4) and other potential risk factors (age, gender, pre- and postoperative T-stage, pre- and postoperative N-stage, grading, lymph invasion, vessel invasion, chemotherapy regime, resection margin, treatment delay). Risk factors with a highly significant influence (p < 0.01) in the univariate Kaplan-Meier (KM) estimation were tested for independence using the multivariate cox regression model. Results: With a mean follow-up of 42.5 months, 5 years and 10 years estimated PFS for all patients was 60.1% and 49.1% respectively. Estimation of 5 years and 10 years PFS was 49.7% and 45.5% for TRG Dworak grade 1+2 (n = 109) and 83.8% and 67% respectively for TRG Dworak grade 3+4 (n = 50). This difference was highly significant (p < 0.001). Other highly significant risk factors were postoperative N-stage (negative versus positive), lymph invasion (L0 versus L1), and resection margin (R0 versus R1/2). In the multivariate analysis, only TRG and post-op N-stage were identified as independent risk factors for PFS. Conclusions: In this analysis, Dworak Tumor Regression Grading appears to be a prognostic marker for oncologic outcomes in locally advanced rectal carcinoma patients treated with neoadjuvant CRT.
Effect of acid-reducing agents on the efficacy of capecitabine in metastatic gastrointestinal cancers.
Authors: Bah Tonjeh Mary Stella , Comeau Jill , Clarke Andrea , Robinson Arelis , Storer Amanda , Shi Runhua , Kavanaugh Mindie Michelle
Published: May 2019

e15058

Background: Recent retrospective and subgroup analyses have evaluated the effects of capecitabine with acid-reducing agents both in the adjuvant setting for colon cancer and in the palliative setting for stage IV gastroesophageal malignancies. Efficacy outcomes in these studies are contradictory. Acid-reducing agents are thought to reduce the absorption of capecitabine by increasing gastric pH leading to a concern of decreased efficacy. Studies thus far have not included stage IV colorectal cancers, a common population who receives capecitabine-based regimens. Methods: We conducted a retrospective chart review of patients diagnosed with stage IV Gastro Intestinal (GI) cancers treated with capecitabine-based therapies between 2012 and 2018. Electronic health records were used for data collection. Descriptive statistics and COX regression model were utilized for data analysis. Results: Of the 249 charts that were screened for inclusion, 58 were included in this review. Thirty-eight (65.5%) had a diagnosis of colon cancer, 11 (19%) had rectal cancer, and 9 (15.5%) had other GI malignancies. The most common capecitabine-based regimens included XELOX alone (29%) or with bevacizumab (36%). During capecitabine treatment, 20 (34.5%) patients received concomitant acid-reducing therapy. This included 19 patients taking a PPI and 1 patient taking a H2 Inhibitor. Patients who did not receive acid-reducing therapy had a 1-year PFS of 23.7% compared to 25% in patients who did not, (HR 0.55, p = 0.46). The 1-year OS was 68.4% in the non-acid-reducing agent group and 60% in the patients who did receive acid-reducing agents during capecitabine treatment, respectively (HR 0.17, p = 0.68). Conclusions: Receiving acid-reducing agents concomitantly with capecitabine-based regimens appears to not have an effect on 1-year PFS or OS in patients with Stage IV GI cancers. These outcomes may have been affected by the sample size, incomplete home medication lists, and compliance issues with capecitabine. Larger population studies are needed to validate these findings and identify the significance of utilization of acid-reducing agents in patients with Stage IV GI cancers receiving capecitabine.
Comprehensive immune transcriptomic subtypes of colorectal cancer for development of precision immunotherapy.
Authors: Jing Zhou , Guo Xueguang , Zhao Jing , Zhao Xiaochen , Zhang Yuzi , Huang Mengli , Cai Shangli , Zhu Haitao
Published: May 2019

e15078

Background: Immune checkpoint blockades (ICBs) have been approved for colorectal cancer (CRC) with microsatellite instability high (MSI-H). However, 50% to 60% MSI-H and almost 100% microsatellite stability (MSS) CRC patients can’t benefit from ICBs treatment. How to warm these “cold tumor” for boosting response to ICBs is still a problem. We aimed to integrate the expression signatures of T cell activation, exclusion and dysfunction to generate immune microenvironment subtypes which may guide precision immunotherapy. Methods: RNA-Seq of 596 CRC patients from The Cancer Genome Atlas were analyzed. T cell activation, dysfunction and exclusion signatures were calculated from TIDE model algorithm. Unsupervised clustering was used to classify CRC into various immune subtypes. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. COX regression multivariate analysis was applied to analyze the association of subtypes with overall survival (OS). Results: Compared with 543 patients with MSS, 83 patients had significantly higher expression of T cell activation related genes (including CD8A, CXCL9, CXCL10, GZMB, IFNG et al) and immune checkpoint genes (including PD-L1, PD-1, LAG3 et al.), but lower signatures scores of M2-like tumor-associated macrophage (TAM) and T cell exclusion ( all P value<0.001). Based on expression signatures of myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF), M2-like TAM, cytotoxic T-lymphocytes (CTL) and PD-L1, all the patients were clustered into four subtypes. Cluster 4 was enriched by MSI-H and characterized with high T cell activation and moderate T cell dysfunction and exclusion. Comparatively, another MSI-H enriched Cluster 1 had both high CTL and T cell dysfunction which indicated that activated T cell might be escaped by tumor cell. Cluster 2 and Cluster 3 were enriched by MSS and characterized with moderate T cell activation and high T cell exclusion. In survival analysis, Cluster 4 had prolonged OS (HR [95% CI]=0.46 [0.27-0.80]) compared with Cluster 1, 2 and 3, after adjusted for age, pathological stage, tumor residue, MSI status, BRAF and PIK3CA mutations. In MSS, Cluster 4 also had better prognosis than the other three clusters (HR [95% CI]=0.38 [0.20-0.73]). Conclusions: Our findings provide evidence to guide further patient stratification in ICBs treatment. The distinct immune subtypes of CRC also paved the way of combination immunotherapy based on immune microenviroment to turn “cold tumor” into “hot tumor”.
Detection of KRAS mutations in colon adenocarcinoma by droplet digital PCR.
Authors: Enin Yaroslav S. , Kit Oleg I. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kharagezov Dmitry A. , Milakin Anton G. , Sustretov Vyacheslav A. , Dashkov Andrey , Vladimirova Liubov Yu
Published: May 2019

e15080

Background: The screening of mutations in the KRAS gene is a traditional marker of the effectiveness of targeted therapy for colorectal cancer. Mutations in the 12 codon of the second exon of the KRAS gene are present in 40% of colorectal tumors, and monitoring of the mutational status together with the level of mutant DNA is of particular clinical interest. However, the sensitivity level of the traditionally used real-time polymerase chain reaction (RT-PCR) method is insufficient in some cases. Recently, Droplet Digital PCR (DD-PCR) has been considered as an alternative method, which is more sensitive. The purpose of this study was to compare the methods of detection of somatic mutations in the second exon of the KRAS gene using DD-PCR versus RT-PCR. Methods: This study included 134 patients with colon adenocarcinoma. The presence or absence of activating mutations in the second exon of the KRAS gene in samples of FFPE blocks was detected by RT-PCR using the “Real-time-PCR-KRAS-7M reagent kit” (Biolink, Russia) and Digital Droplet PCR using the “KRAS Screening Multiplex kit” (Bio-Rad, USA). Results: For all 134 samples, selected for the study, the WT status of the KRAS gene was identified by the RT-PCR method. According to the results of DD-PCR for 131 samples (96.2%), a positive amplification response of mutant DNA with more than 200 events was obtained. The number of amplicons varied from 312 to 117917 per sample, the median was 2940 copies. According to recent trials, a clinically significant level of mutational events must exceed 5% of the total number of amplicons in a sample. In our study, 12.9% of cases (17 patients) met this criterion. Conclusions: The DD-PCR method demonstrated a much higher analytical sensitivity for the detection of SNP mutations in comparison with RT-PCR that may be of critical importance in the therapeutic decision.
Frequency of somatic mutations in the KRAS gene in patients of the South Russia diagnosed with colorectal cancer.
Authors: Gvaldin Dmitry Yu. , Kit Oleg I. , Omelchuk Ekaterina P. , Kaymakchi Dmitry O. , Poluektov Sergey I. , Petrov Dmitry Sergeevich , Kolesnikov Vladimir E. , Vladimirova Liubov Yu
Published: May 2019

e15081

Background: Colorectal cancer (CRC) is a common pathology in the world; the annual incidence rate reaches 1 million cases, and the annual mortality rate exceeds 500,000. The target therapy of EGFR with monoclonal drugs improves the survival of patients with this pathology. However, the effectiveness of therapy depends on the presence of mutations in genes involved in the EGFR signaling cascade, in particular KRAS. The purpose of this study was to determine the frequency of somatic mutations in the KRAS gene in tumor samples of patients from the South Russia diagnosed with colorectal cancer, as well as to analyze the effect of point mutations G12A, G12C, G12D, G12R, G12S, G12V and G13D on tumor metastasis. Methods: 744 patients diagnosed with colorectal adenocarcinoma were examined for mutations in 12th and 13th codons of KRAS. Somatic mutations in the KRAS gene were detected with reagent kit Biolink (Russia) using FFPE DNA samples of tumor tissues. Statistical analysis was performed using the method of binary logistic multiple regression and χ2-test. Results: Mutations in the KRAS gene were found in 32% of patients in the pooled sample; the most common mutation was the replacement of G12D in the KRAS gene (36%). Less common detectable mutations in the KRAS gene were G13D (18%), G12V (16%), G12A (10%), G12C (8%), G12S (10%), G12R (2%). Metastatic CRC was found in 86% of carriers of the wild-type allele and in 88% of carriers of the mutant allele. The presence of a G12V substitution almost 6 times increased the risk of metastasis in patients with CRC (OR = 5.89; 95% CI: 0.8-43.45; p = 0.049). Conclusions: Mutations in the KRAS gene were found in 32% of patients with CRC in the South of Russia. A significant association of G12V replacement with a high risk of metastasis was established. Further study of somatic mutations in the KRAS gene will allow to choose the most effective therapeutic strategies in the presence of one or another of the studied mutations.
Clonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer.
Authors: Wang Beili , Huang Fei , Shen Minna , Wu Shengchao , Yu Qian , Jiang Huiqin , Yu Yiyi , Yang Yihui , Zhao Ying , Zhou Yiwen , Pan Baishen , Liu Tianshu , Guo Wei
Published: May 2019

e15083

Background: Clonal hematopoiesis (CH) leads to blood-derived somatic mutations in KRAS, NRAS and BRAF. Our aim is to identify the prevalence of CH-derived mutations in these three genes in metastatic colorectal cancer (mCRC) patients and reveal the practical clinical implication of these mutations on plasma genotyping. Methods: We analyzed KRAS, NRAS and BRAF genotypes in plasma and matched tumor tissues of 236 mCRC patients through next-generation sequencing (NGS) and polymerase chain reaction. Suspected CH mutations were defined as those only detected in plasma with variant allelic frequencies (AFs) of <5% and were confirmed by paired peripheral blood cells (PBCs) using droplet digital PCR (ddPCR). The hemopoietic lineage harboring a CH-derived mutation was analyzed through flow cytometry. Results: We identified suspected CH mutations in twenty patients (8.4%, 20/236). Three of these patients (1.27%, 3/236) had a CH-derived KRAS mutation, which was confirmed present in paired PBCs. Two of them had a KRAS G12X and the third had a KRAS Q61H. We did not detect CH-derived NRAS or BRAF mutations in our cohort. All three patients harboring a CH-derived mutation previously received chemotherapy treatment. In a selected CH-derived KRAS G12X case, the mutation was enriched in lymphocytes and persisted in plasma cell-free DNA (cfDNA) over the course of 4 months of therapy. Conclusions: In summary, we confirmed the existence of CH-derived KRAS mutations in a small proportion of mCRC patients. This should be noted to prevent misclassification as tumor somatic mutations when performing cfDNA sequencing in the absence of genotyping matched PBCs.