bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment dependent improvements in survival of stage 2/3 rectal cancer patients treated with trimodality therapy between 2006-2016, an NCDB analysis.
Authors: Kennecke Hagen Fritz , Bahnson Henry T. , Lin Bruce Shih-Li , Kaplan Jennifer , Pham Huong , Suen Andrew , Simianu Val 
Published: June 2021

e15543 Background: Trimodality therapy (TT) with chemo/radiation (C/RT), chemotherapy and total mesorectal excision (TME) surgery remains the standard for patients with stage 2/3 rectal cancer. Use of pre-operative (pre-op) C/RT is an important Commission on Cancer (CoC) quality benchmark but has not previously been shown to improve overall survival when compared to post-op C/RT. The objective of this study was to document the impact on survival of peri-op C/RT in stage 2/3 rectal cancer in a broad population. Methods: The National Cancer Database was used to identify all patients diagnosed with stage 2/3 rectal cancer from 2006-16. Included patients received true TT and were classified into groups A, Total Neoadjuvant Therapy (TNT) with pre-op C/RT + pre-op multi-agent (MA) chemotherapy (CT); group B, pre-op C/RT+ post-op single-agent CT; group C, pre-op C/RT + post-op MA CT; and group D, post-op C/RT and MA CT. Cox multivariate survival analysis were performed including demographics, peri-op C/RT, surgery type, stage, lymph node count, year of diagnosis and facility type: academic (Acad), Comprehensive (Comp)/Community (Comm), Integrated (Integ) and unknown (Unkn). Results: Of 110,372 stage 2/3 patients, 32,467 received TT (mean age 58, 61% male) and were included. Of these, 8883 (27%, group A) received TNT, 5967 (18%) were in group B, 12,928 (40%) in group C, while 4,689 (14%) were in group D. A reduction in use of post-operative C/RT (group D) was observed between 2006 (28%) and 2016 (8%), p < .001, accompanied by a reciprocal increase in patients receiving pre-op C/RT and post-op MA CT (Group C) between 2006 and 2016 (24 to 45%, respectively, p<0.001). Increasing use of pre-op C/RT led to a migration to lower pathologic stages 0/1/2/3 from 0.60/10/31/57% in 2006, to 2.8/22/29/45% in 2016, respectively (p < .001), while clinical stage 2/3 distribution remained unchanged. Receipt of pre-operative C/RT (Groups A/B/C) was associated with improved survival compared to post-op C/RT (group D) (table). Conclusions: Between 2006-2016 the proportion of patients with stage 2/3 rectal cancer treated with post-op C/RT declined dramatically and in 2016 accounted for 8% of all patients treated with TT. Multivariate analysis documented superior overall survival among patients treated with pre-operative C/RT, justifying the introduction of the CoC quality benchmark.[Table: see text]
Real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in second line after failing irinotecan or oxaliplatin-based regimens.
Authors: Gathirua-Mwangi Wambui , Yang Tony , Khan Taha , Wu Yixun , Afable Manuel 
Published: June 2021

e15568 Background: Anti-epidermal growth factor receptor agents are increasingly used in later lines of therapy for the treatment of metastatic colorectal cancer (mCRC). However, the real-world time on treatment (TOT) and overall survival (OS) of patients with mCRC receiving cetuximab in second-line (2L) setting have not been described. Therefore, we sought to evaluate TOT, OS and identify factors associated with longer TOT and OS based on retrospective observational data. Methods: A total of 1,011 patients were selected from the nationwide Flatiron electronic health record database (January 2013-August 2020) who were: 1) diagnosed with mCRC, 2) received 2L treatment with cetuximab containing regimens, and 3) had failed oxaliplatin/irinotecan-based regimens in first-line (1L). TOT was defined as the time from initiation of cetuximab in 2L (index date), to the last date showing evidence of cetuximab administration. End of therapy was defined if patients progressed to third-line of therapy, or having a death record. OS was calculated from the index date to the date of death or censored to last visit date available. The Kaplan-Meier estimates, and stepwise Cox models were adapted to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associated factors. Results: Majority of patients receiving 2L treatment with cetuximab containing regimens were: less than 65 years old (58%), male (60%), had a median body mass index (BMI) of 26.6 kg/m², received FOLFOX regimens in 1L (61%) and were treated in the community setting (96%). The most common 2L regimens were cetuximab+FOLFIRI (46%) and cetuximab+Irinotecan (29%). Overall, the median TOT (mTOT) for patients receiving 2L cetuximab was 3.94 months (median Interquartile range (mIQR) 3.51-4.40), and median OS (mOS) was 14.36 months (mIQR 13.01-15.70). Of all cetuximab containing regimens, receiving cetuximab+FOLFIRI in 2L (mTOT = 4.43 months, mIQR 3.71-5.36), KRAS wild-type (vs. KRAS+), and receiving 2L cetuximab after prior therapy with 1L CapeOX (vs. FOLFOX) were associated with a longer mTOT. Living in the South region (vs. Midwest) was associated with a shorter mTOT. Having a higher BMI (obese vs. underweight HR = 0.46, 95% CI 0.32-0.66) was associated with a longer mOS, while receiving cetuximab+FOLFOX in 2L (mOS = 10.97 months, mIQR 5.55-14.06) or being older (≥65 vs. < 65 years; HR = 1.24, 95% CI 1.05-1.46) were associated with a shorter mOS. Conclusions: In this real-world retrospective analysis we show TOT and OS overall in mCRC patients who received cetuximab containing regimens in 2L. These patients were mostly male, < 65 years, and majority received FOLFOX regimens in 1L therapy. Key factors associated with TOT and OS were treatment regimens received in 1L and 2L. In addition, KRAS status and region were associated with TOT, while BMI and age were associated with OS only.
Trop-2 inactivates E-cadherin and drives colon cancer metastasis.
Authors: Alberti Saverio , Guerra Emanuela , Altomare Donato F. , Depalo Raffaella , Trerotola Marco 
Published: June 2021

e15576 Background: Metastatic diffusion is the biggest hurdle for colon cancer (CRC) cure and the identification of decisive drivers of CRC metastasis is an urgent need in CRC care. Methods: The expression of target molecules in primary tumors and metastases was systematically assessed by DNA array and IHC analysis. Cell-cell adhesion capacity was quantified in 2D cell cultures and in HCT116 CRC cell spheroids. Pro-metastatic impact of wtTrop-2 and activated, tail-less Trop-2 (Δcyto) was assessed in vivo in orthotopic diffusion models of KM12SM CRC cells. Primary CRC and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of CRC patients. Results: Trop-2 was identified as uniquely upregulated in CRC models by transcriptome analysis. wtTrop-2 and ΔcytoTrop-2 were shown to induce cell migration, wound-healing and resistance to apoptosis induction . wtTrop-2 increased the metastatic capacity of KM12SM cells, raising metastasis diffusion from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Constitutive high expression of E-cadherin was revealed in cancer metastases. No evidence was obtained for transcriptional down-regulation of epithelial differentiation biomarkers. No induction of EMT transcription factors was observed in Trop-2-activated cells. Trop-2 tightly bound E-cadherin and caused its release from the cytoskeleton, for loss of cell-cell adhesion and activation of β-catenin. The Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in CRC patients and was shown to impact on CRC metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a key driver of metastatic diffusion in CRC. These findings may pave the way for novel multi-marker personalized diagnostics and anti-cancer therapies. [Table: see text]
Responsibility of immune microenvironment for poor response to immune checkpoint inhibitors in CRC patients with KRAS mutation.
Authors: Liu Qiyu , Zhang Hushan , Cai Shenggang , Xu Lin , Zhao Rong , Zhang Xiaolong , Yin Jianhui , Zhang Lijun , Liu Leyang , Gong Xiaolei , Huang Depei , Shen Xudong , Luo Shibi 
Published: June 2021

e15588 Background: The clinical trial Keynote 177 is a breakthrough research in colon rectal cancer (CRC), however, the results of subgroups revealed that immunotherapy did not benefit more than chemotherapy in patients with KRAS mutation. Here we assessed characteristics of tumor immune microenvironment in patients with or without KRAS mutation, to find out the underlying mechanisms that prevent KRAS-mutated CRC patients from benefiting from immunotherapy. Methods: Tumor tissue samples of 77 CRC patients were collected from Janary 2019, several kinds of immune cells including CD8+ T cells, M1/M2 tumor associated macrophages (TAM), CD56bright NK cells and CD56dim NK cells in the tumor tissue were evaluated by multiple fluorescence immunohistochemistry (mIHC), and expression of PD-L1 were detected by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. In addition, gene mutation was detected by means of next generation squesing (NGS). All these detections were performed in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: According to whether KRAS is mutated, these 77 patients were divided into two groups, KRAS wild type (WT) (n = 49) and KRAS mutation group (n = 28). There was no significant difference in the CD8+T cells infiltrated in tumor tissue of KRAS WT and KRAS mutation samples, however, less CD8+ T cells were found in stroma of tumor tissue of KRAS WT samples than in KRAS mutation. What’s more, both the ratio of M1:M2 and CD56dim NK: CD56bright NK cells in the tumor tissues of KRAS WT were significantly higher than in KRAS mutation samples(p < 0.05). No significant difference was found between two groups, while higher MSI-H proportion was found in KRAS mutation group than in KRAS WT (33.4% and 12.5%, respectively). The proportion of positive PD-L1expression (TPS≥1) in both groups is very low, especially, proportion of strong positive (TPS≥50). Conclusions: The different response to immune checkpoint inhibitors therapy for CRC patient with or without KRAS mutation mainly associated with factors of TIME, not only CD8+T cells, but tumor associated macrophages and different sub-population of NK cells should be put into consideration.
Mutation profile of DNA damage response genes in Chinese colorectal cancer patients and its association with TMB and MSI.
Authors: Yang Meiling , Yao Jianfei , Liu Danni , Huang Tanxiao , Wang Zhizheng , Chen Shifu , Huang Haifu 
Published: June 2021

e15608 Background: DNA damage response (DDR) genes are essential to maintain genomic integrity. Increasing evidence showed that mutations in DDR genes were related to tumor mutation load (TMB), microsatellite instability (MSI) and clinical benefit from immunotherapy. TMB and MSI are predictive biomarkers for immunotherapy. However, the mutation spectrum of genes involved in the DDR pathways and its association with TMB and MSI in Chinese colorectal cancer patients are still ambiguous. Methods: The genomic information of 728 Chinese colorectal cancer patients without germline mutation of Lynch syndrome related genes was obtained from HapLab database. HaploX WESPlus gene panel (an upgraded version of the standard WES) was performed to analyze the genomic data of patients. Results: 630 out of 728 patients (86.54%) had at least one mutation of the DDR genes. The frequently mutated DDR genes included TP53 (54.95%), BRCA2 (18.27%), PARP4 (13.46%), MSH2 (9.62%), XPC (7.55%), RAD54L2 (7.28%), ATM (6.73%), HMGB1 (5.77%), REV3L (5.49%) and POLD3 (5.36%). The TMB in patients with one, two, three and more than three mutations of DDR genes increased sequentially. The proportion of MSI-H in patients with more than three mutations of DDR genes (20.9%) was significantly higher than that in patients with less than 3 mutations of DDR genes (0.38%). Among the frequently mutated DDR genes, mutations of BRCA2, PARP4, MSH2, XPC, RAD54L2, ATM, REV3L or POLD3 were associated with higher TMB, mutations of MSH2, RAD54L2, ATM, REV3L or POLD3 were associated with higher proportion of MSI-H. The patients with mutation in each of eight DDR pathways showed significantly higher TMB and proportion of MSI-H than who without mutation of DDR genes. Conclusions: This study revealed the mutation profile of DDR genes in Chinese colorectal cancer patients. The mutation of DDR genes was closely related to TMB and MSI status. This result indicated the mutation of DDR genes may be a promising biomarker for immunotherapy in Chinese colorectal cancer patients.
Association of antibiotic exposure with the mortality in bevacizumab-treated metastatic colorectal cancer: A secondary analysis from Dryad database.
Authors: Sun Chenyu , Guo Xianwei , Kozma Kelly , Bhan Chandur , Kim Na Hyun 
Published: June 2021

e15609 Background: Colorectal cancer (CRC) is one of the most diagnosed cancers and the second leading cause of cancer-related death worldwide. Globally, more than 1.8 million people are diagnosed of colorectal cancer (CRC) in 2018. In advanced CRC patients, bevacizumab plus 5-fluorouracil-based or platinum-based therapy has become one of the standard first-line chemotherapy regimen. A recent study also found that antibiotic exposure could be inversely associated with the mortality in metastatic colorectal cancer (mCRC) patients treated with bevacizumab. However, subgroup analysis of this study was no sufficient. Therefore, we conducted a secondary analysis based on the data of this study from Dryad database. Methods: In this retrospective cohort study, 147 mCRC patients treated with bevacizumab were included. All data was obtained from Dryad database (https://doi.org/10.5061/dryad.ft5sk66). Patients were divided into follow subgroups: (1) left colon vs right colon; (2) BMI < 18.5 vs BMI 18.5-24 vs BMI≥24;(3) Age < 45 vs Age≥45, (4) no surgery vs palliative surgery vs radical surgery, (5) bevacizumab plus FOLFIRI vs bevacizumab plus capeOX/FOLFOX vs bevacizumab plus other chemotherapy regimen. Specific survival of each subgroup was analyzed through the Kaplan-Meier curve, and the survival curves of the variables were compared using the log-rank test. Results: Survival analysis found no statistically significant differences of the cumulative survival rates between left colon cancer and right colon cancer, (58.9% vs 62.5%, respectively; χ2 = 0.043, P = 0.836), groups of different BMI (57.9% of BMI < 18.5 vs 55.2% of 18.5≤BMI < 24 vs 70.7% of BMI ≥24，χ2 = 3.026, P = 0.220), Age < 45 group and Age≥45 group (54.8% vs 61.2%, respectively; χ2 = 0.001, P = 0.976), surgical treatments (No surgery 59.0% vs Palliative surgery 57.6% vs Radical Surgery 61.3%; χ2 = 1.885, P = 0.390), as well as groups of different chemotherapy regimens (66.7% of FLOFIRI vs 52.0% of CapeOX/FOLFOX vs 59.9% of others; χ2 = 1.572, P = 0.456). Conclusions: Based on the data from this study, we found that different sites of colon cancer, age, BMI, different surgical treatments, and different chemotherapy regimens did not affect the survival outcome of patients with mCRC treated with bevacizumab after antibiotic exposure. Subsequent studies with larger sample size are still needed to further elaborate the effects of different antibiotics on survival outcomes.
Safety and efficacy of apatinib as third or later line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma: A post-marketing phase IV study.
Authors: Li Jin , Qin Shukui , Wen Lu , Wang Junsheng , Deng Wenying , Guo Weijian , Jia Tongfu , Jiang Da , Zhang Guifang , He Yifu , Zhong Haijun , Ba Yi , Lin Xiaoyan , Yang Jianwei , Zhao Jun , Bai Yuxian , Wu Xiangyuan , Gao Feng , Sun Ying , Hou Zhiguo 
Published: June 2021

e16034 Background: Apatinib, a small molecule multi-target tyrosine kinase inhibitor with high selectivity for VEGFR-2, has been approved for the treatment of advanced gastric cancer or gastroesophageal adenocarcinoma in China by significantly improving progression-free survival (PFS) and overall survival (OS). Here, we report safety and efficacy data from an open-label, single-arm, multicenter, phase IV trial of apatinib as a third-line or later line treatment for advanced gastric cancer. Methods: Eligible patients had histologically or cytologically confirmed advanced gastric cancer or gastroesophageal junction adenocarcinoma; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and adequate haematological and hepatic function; and failure of at least two lines of chemotherapy. Patients received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety, and secondary endpoints included PFS and OS. Results: The intention-to-treat population (ITT) included 2004 patients. At baseline, the median age was 59 (range, 19-85) years, ECOG performance status of 0/1/2 (%) was 15.4/68.8/15.1, and stage III/IV was 3.5/96.4; 98.8% had metastases, and among which metastatic foci≤2/ > 2 was 64.5/34.2 (%), respectively. 89.6% of the patients were given apatinib 500mg as the initial does and the median treatment duration was 56 days. After a median follow-up of 126.5 days, adverse events (AEs) occurred in 95.1% of the patients and 70.3% were grade ≥3. 87.9% of the patients experienced treatment-related AEs (TRAEs), of which 51% had grade ≥3, 12.3% and 16.8% reduced dose and discontinued the treatment, respectively. 57 (2.9%) TRAEs-related deaths were reported, mainly because of gastrointestinal bleeding (16 cases), upper gastrointestinal haemorrhage (7), cerebral haemorrhage (2), and gastric perforation (1). The incidence of TRAEs of special interest was 74.3%; 38.1% of patients developed grade≥3, mainly including hypertension (26.3%), bleeding (5.1%), proteinuria (4.5%), and hand-foot syndrome (3.1%). In an ITT population, median PFS was 2.7 months (95%CI 2.23-2.79) and median OS was 5.8 months (95% CI 5.42-6.11). Conclusions: This study confirms that apatinib has a well-established and manageable safety profile and survival benefit as third or later line therapy for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma. Clinical trial information: NCT02426034.
Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell cancer.
Authors: Bai Ming , Deng Ting , Ba Yi 
Published: June 2021

e16046 Background: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy. However, alternative therapies are required for patients refractory or intolerant to the existing therapies. Methods: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for six weeks, followed by 8.0 mg/kg once every two weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95%CI: 5.6%–34.7%). The median PFS and OS was 3.1 months (95%CI: 1.5–4.3) and 6.8 months (95%CI: 4.7–10.1) respectively. Numerical difference without a statistical significance in ORR was observed in patients with different EGFR expression (≥50%: 25.0% vs. < 50%: 0%, P = 0.140) or TP53 mutation abundance ( < 10%: 23.8% vs. ≥10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) and OS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of < 10%. The most common treatment-related adverse events of grade 3 or 4 (occurring in ≥2 patients) were hypomagnesemia (7 [23.3%]) and rash (2 [6.7%]). No treatment-related death occurred. Conclusions: SCT200 monotherapy as second- or further-line for advanced ESCC showed favorable efficacy, with an acceptable safety profile. TP53 mutation abundance might serve as potential predictive biomarkers. Clinical trial information: NCT03817567. [Table: see text]
Predictors of survival after metastasectomy of oligometastatic recurrence following gastroesophageal cancer treatment.
Authors: MacKenzie Malcolm , Ma Lucy Xiaolu , Epsin-Garcia Osvaldo , Suzuki Chihiro , Bach Yvonne , Allen Michael J , Darling Gail Elizabeth , Swallow Carol Jane , Brar Savtaj Singh , Yeung Jonathan , Kalimuthu Sangeetha , Wong Rebecca , Panov Elan David , Veit-Haibach Patrick , Chen Eric Xueyu , Elimova Elena , Jang Raymond Woo-Jun 
Published: June 2021

e16060 Background: Recurrent gastroesophageal (GE) carcinomas carry a poor prognosis and are usually treated with palliative chemotherapy (CTX). However, recent studies suggest that certain patients with oligometastatic recurrence can have long term survival after metastasectomy. Appropriate patient selection for metastasectomy remains a challenge, as few predictors of overall survival (OS) after metastasectomy have been identified. Our primary aim was to identify predictors of OS following metastasectomy in GE cancers. Methods: We conducted a retrospective study of GE cancer patients treated from 2007 to 2015 using the Princess Margaret Hospital Cancer Registry. We included patients who underwent curative-intent surgery or definitive chemoradiation (CRT) for localized GE cancer who then had single organ recurrence treated with metastasectomy. The probability of OS from date of recurrence was estimated with the Kaplan Meier method. Predictors of OS after metastasectomy for isolated recurrence were determined using Cox proportional hazards analysis. Covariates included time to recurrence (interval from curative-intent surgery or completion of definitive CRT), site of recurrence (lung/non-lung), sex, age and race (Asian/Non-Asian). Within the multivariable model, predictors with a p-value less than 0.05 were deemed significant. Results: Of 44 patients, median age was 58 years (28-78), and 59% were male. Primary sites were: esophagus 25%, GE junction 41% and gastric 34%. Treatment of the primary was: surgery alone 13%, surgery and (neo)adjuvant CTX 76%, and CRT 11%. Recurrent sites were brain 22%, ovary 20%, lung 18%, bone 7%, adrenals 7%, liver 7%, distant lymph node 6%, and other 13%. The median follow up time was 38.9 months. The 1, 3 and 5-year (yr) OS following metastasectomy were 79% (95% CI 68-92%), 40% (27-58%) and 28% (16-49%). Univariable analysis revealed that time to recurrence greater than 1 yr (HR=0.45 95% CI 0.21-0.93, p=0.032) and lung site recurrence (HR=0.16 95% CI 0.04-0.67, p=0.012) were associated with longer OS. On multivariable analysis, only lung site recurrence was significant (HR=0.12 95% CI 0.03-0.54, p=0.0056). The 1, 3 and 5-yr OS for patients after resection of isolated lung recurrence were 100% (95% CI 100-100%), 86% (63-100%) and 69% (40-100%). Conclusions: In our study, patients with isolated pulmonary recurrences demonstrated prolonged overall survival following metastasectomy. These patients could be considered for resection following recurrence of GE cancer. [Table: see text]