bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential gene expression of tight-junction proteins and their correlation with PRSS8 and prognosis in colorectal cancer.
Authors: Yang Wancai , Guo Yongchen , Lu Jim , Bao Yonghua 
Published: June 2021

e15548 Background: Intestinal epithelia cells are made up of tight junctions, adheren junctions and desmosomes. As integral membrane proteins, the tight junction proteins (TJPs) claudins (CLDNs) and occludin (OCLN) are the most important TJPs that play a major role in maintaining the integrity of the intestinal epithelia and regulate several key signaling pathways in cancers. Dysregulation of tight junction and adheren junction has been shown to be associated with disruption of mucosa barriers, chronic colitis, early onset of colorectal carcinogenesis, epithelial mesenchymal transition and cancer metastasis. Our recent studies have shown that intestinal conditional knockout of the Press8 (protease serine 8) gene causes disruption of intestinal epithelial homeostasis, spontaneous inflammation and tumorigenesis in mouse intestine. Whether these pathogeneses are resulted from TJPs alterations and their correlation with PRSS8 are largely unknown. Methods: PRSS8 overexpression plasmid was transfected into colon cancer cell line HCT116 cells and proteomics was conducted. The Cancer Genome Atlas colorectal cancer (CRC) data set was deeply mined, and the correlation between TJPs’ alterations, PRSS8 and prognosis was analyzed. Results: In vitro proteomics assay showed that increasing expression of PRSS8 led to differential expression of cellular TJPs and adheren proteins, including upregulation of E-cadherin, TJP1 (ZO-1) and OCLN, and downregulation of RAC1, CDC42, RHOA, CLDND1, ARHGAP1, CTNNB1 and CTNNBL1. TCGA data mining showed differential gene expression of tight junction proteins. For instance, similar as PRSS8, most colonic mucosal TJPs, such as TJP1 (ZO-1), TJP3, OLCN, CLDN7, CLDN8 and PTPRJ, were significantly decreased in CRC tissues (n = 215), compared to normal mucosa (n = 22). Moreover, these reduced expression of TJPs were positively correlated with the reduction of PRSS8 and were inversely associated with prognosis. In contrast, another group of TJPs, such as TJP2, CLDN1, CLDN2 and CLDN12, was significantly increased in CRC tissues in comparison with the normal mucosa. These increases of expression were negatively correlated with PRSS8 expression and poor outcomes. More interestingly, the PTPRJ, a newly identified tumor suppressor, was dramatically reduced in metastatic CRC, compared to the primary CRC. Furthermore, the reduced expression of PTPRJ was linked to poor prognosis in the CRC patients. The underlying mechanisms of regulatory interaction between PRSS8 and TJPs are under investigation. Conclusions: TJPs are differentially expressed in CRC and the alterations were well correlated with PRSS8 and prognosis. Therefore, these two opposite groups of TJPs could be used as biomarkers for the monitoring of early onset colorectal carcinogenesis, progression and for the prediction of prognosis.
Early clinical experience with trifluridine/tipiracil for refractory metastatic colorectal cancer: The ROS study.
Authors: Garcia-Alfonso Pilar , Muñoz Martín Andres J. , Jimenez-Castro Jeronimo , Jiménez-Fonseca Paula , Pericay Carles , Longo Federico , Reyna Carmen , Argiles Guillem , Gonzalez Astorga Beatriz , Gomez-Reina Maria Jose , Ruíz Casado Ana , Rodriguez-Salas Nuria , Lopez-Lopez Rafael , Carmona Bayonas Alberto , Conde-Herrero Veronica , Aranda Enrique 
Published: June 2021

e15556 Background: Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. Methods: This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience program in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. Results: A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently favoured OS: ≤2 metastases, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropenia (23.2%), anaemia (12.1%), and thrombocytopenia (5.3%). Conclusions: This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.
A single-arm study on the efficacy and safety of regorafenib plus sintilimab as salvage-line treatments in non-MSI-H metastatic colorectal cancer.
Authors: Liu Rui , Wang Xia , Ji Zhi , Deng Ting , Zhang Le , Yang Yuchong , Ning Tao , Bai Ming , Ge Shaohua , Li Hongli , Duan Jingjing , Ba Yi 
Published: June 2021

e15560 Background: PD-1 blockade is particularly ineffective in patients with microsatellite stable (MSS) or mismatch repair (MMR)-proficient colorectal cancer (CRC). Regorafenib (R) has been shown to modulate anti-tumor immunity through different mechanisms, including the reduction of tumor-associated macrophages (TAMs) and lymphocyte activation or immunosuppressive cells, such as forkhead box P3 (Foxp3)+ CD25+ regulatory T cells (Tregs). Synergy between R and anti–PD-1/PD-L1 antibodies has been demonstrated in pre-clinical models compared to that of either treatment alone. Accordingly, this study attempted to evaluate the combined activity of regorafenib with an immune checkpoint inhibitor. Methods: This trial was a prospective, open-label, monocentric, nonrandomized, single arm study. This study included patients with non MSI-H mCRC who received R (80 mg QD 3weeks/4) and sintilimab (S)(200 mg every 3 weeks).The primary endpoint was the confirmed objective response rate (ORR).The secondary endpoints were progression free survival (PFS),overall survival (OS),disease control rate (DCR) and safety. Results: As of January 8, 2021, 24 patients (median age 59 years) with mCRC were enrolled and received treatment with R+S. RAS wild type was 50% of all patients. In addition, 83.3% of patients received two prior lines of treatment, while 58.3% had liver metastases at enrollment. Of the 24 patients, the best response was observed to be stable disease(SD) in six patients (25%) and progressive disease (PD)in four patients (16.7%). Another nine (37.5%) patients have yet to be evaluated. In the 15 evaluated patients, the ORR(RECIST version 1.1) was 33.3% , the DCR was 73.3%. Additionally, among the 10 evaluated patients with liver metastases, the ORR was 30% , the DCR was 80%. Among the nine evaluated patients with wild-type populations of k-ras, the ORR and DCR was found to be 44.4% and 66.7%, which was higher than the mutation patients. The median PFS was 4.2 (95% CI, 2.5, NA) months, the median OS was not reached. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (4.2%), erythra (4.2%). No death was related to the treatment. Moreover, four (16.7%) patients were subject to at least 1 dose modification or treatment interruption. Conclusions: In this study, the combination of R+S achieved a similar ORR with REGONIVO. Furthermore, this combination was well tolerated and had a manageable safety profile. However, due to the limited sample size, some biases may be present. As a result, we will continue to expand the sample size for future verification. Clinical trial information: NCT04745130.
DNA mismatch repair and microsatellite instability in colorectal tumors: An observational study in the Veterans Affairs Health Care System.
Authors: Klaassen Zachary William Abraham , Waller Justin , Gu Lin , De Hoedt Amanda M. , Wang Tongtong , Amonkar Mayur , Aurora-Garg Deepti , Liaw Kai-Li , Wehn Amy , Albo Daniel , Freedland Stephen J. 
Published: June 2021

e15562 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) cancers exhibit high mutational load and are observed in colorectal carcinomas (CRC). The objectives of this study were to determine the proportion of MSI-H/dMMR in CRC and to describe clinical and demographic characteristics among MSI-H/dMMR and non-MSI-H/dMMR CRC patients receiving standard of care in an equal access health care system. Methods: Using the Veteran Affairs (VA) Healthcare system data, we conducted a retrospective study of patients, aged ≥18 years old, diagnosed with CRC who underwent MSI/MMR testing from January 1, 2010 to December 31, 2018. MSI/MMR testing was defined as having received an MSI status determined by polymerase chain reaction and/or next-generation sequencing test or an MMR status determined by immunohistochemistry test. Median and interquartile range (IQR) were calculated for continuous variables while frequencies and percentages were calculated for categorical variables. Results: A total of 291 patients diagnosed with CRC who underwent MSI/MMR testing between 2010-2018 were identified from VA centers. The majority of patients were white (69.8%) and male (95.5%), with median (IQR) age of 65 (56-70) years at diagnosis. Sixty-four (22.0%) patients had stage I CRC at diagnosis, 84 (28.9%) stage II, 87 (29.9%) stage III, and 45 (15.5%) stage IV; 11 (3.7%) had no stage information. Fifty-four (18.6%) patients were reported to have MSI-H and/or dMMR CRC, with rates similar for MSI-H [17.4% (21/121)] vs. dMMR [19.7% (44/223)] alone. The proportion of MSI-H/dMMR varied by CRC stage, and was more common in stage II (26%) and stage III (23%) than in stage IV (6%). Patients were similar between MSI-H/dMMR and non-MSI-H/dMMR with regards to age at diagnosis, gender, race, and ethnicity. Of 54 patients with MSI-H/dMMR CRC, three had metastatic CRC (mCRC) at diagnosis and seven progressed to mCRC. Among 51 MSI-H/dMMR patients without metastatic disease at diagnosis, 18 (35%) underwent chemotherapy and 44 (86%) underwent curative surgery. A similar pattern was also observed among non-MSI-H/dMMR CRC patients. Conclusions: In this real-world observational study in a VA population, we found MSI-H/dMMR was present in 18.6% of CRC patients who received MSI testing, highest in stage II (26%) and stage III (23%) and lowest in stage IV (6%) disease. Results are consistent with published estimates seen across other populations and geographies. Additional research is needed in larger cohorts of patients to further assess utilization patterns and real-world clinical outcomes of newer treatments (immunotherapies) approved for MSI-H/dMMR CRC.
Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.
Authors: Bouchahda Mohamed , Saffroy Raphael , Karaboué Abdoulaye , Hamelin Jocelyne , Innominato Pasquale , Saliba Faouzi , Levi Francis , Bosselut Nelly , Lemoine Antoinette 
Published: June 2021

e15574 Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p < 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.
Landscape of COVID-19 vaccine uptake in the colorectal cancer community: Responding to community needs.
Authors: Dwyer Andrea , Marosits Michael , Weltzien Elsa , Garcia Reese , Davis Anjee 
Published: June 2021

e15577 Background: The novel coronavirus (COVID-19) has caused numerous disruptions across the cancer prevention and treatment landscape. A model released by the National Cancer Institute (NCI) predicts that delays in care will cause 10,000 excess breast and colorectal cancer deaths over the next 10 years due to the pandemic. Vaccines will play an integral role in colorectal cancer patients and their support systems to return to care and resume ‘normal activities’; but based on anecdotal reports from the oncology and prevention community, there are questions about patients’ willingness to receive vaccines when available. The goal of this analysis was to better understand general uptake of vaccines at various time points, intention to vaccinate when available and what questions and concerns patients have about getting a vaccine. Methods: In January, 2021 Fight Colorectal Cancer (Fight CRC) distributed an online survey to the colorectal cancer community asking about vaccine related questions. The survey was a convenience sample approach distributed through social media channels and targeted emails from mid-January to early February 2021. Virtual focus groups and repeat surveys will be administered in spring of 2021 to further gather detail about the uptake of the vaccine, including barriers and facilitators to care. Results: In total, 201 individuals responded to the survey (survivor = 77%, family member = 11%, caregiver/friend = 8% other = 3%). The colorectal cancer patient sample was composed mostly of later stage patients (stage III and IV = 77%). Approximately 30% of patients reported vaccine uptake, 81% noted they would likely get vaccinated when a vaccine became available to them. Of all the patients, 16% noted they would need more information about the vaccine before deciding if they would be vaccinated. The majority indicated needing tips to discuss receiving the vaccine with their doctor, including impact on treatment, and the top questions patients have are: 1) Is the vaccine safe? 2) Will the vaccine interrupt my cancer treatment care? Conclusions: People with cancer face unique challenges since the pandemic, including treatment disruptions. Even with a vaccine, not all patients have access or are convinced they will receive the vaccine when it becomes available to them. Understanding patient needs and how to respond to ensure patients receive the most credible information to make informed decisions is critical.
Apatinib plus paclitaxel versus placebo plus paclitaxel as second-line therapy in patients with gastric cancer with peritoneal carcinomatosis: A double-blind, randomized phase II trial.
Authors: Wang Fenghua , Ren Chao , Xu Jianying , Wang Zhiqiang , He Ming-ming , Qiu Miaozhen , Jin Ying , Luo Huiyan , Wang Feng , Li Yuhong , Tan Qiong , Zhang Rong , Xu Ruihua 
Published: June 2021

e16022 Background: Individuals with gastric cancer who present with peritoneal metastasis (PM) have poor prognosis. VEGF and VEGFR-2-mediated angiogenesis can increase vascular permeability, mesothelial cell permeability and promote peritoneal metastasis and ascites formation. This study assessed whether apatinib, a small-molecule VEGFR-2 tyrosine kinase inhibitor, in combination with paclitaxel would improve survival in patients with gastric cancer with PM as second-line therapy. Methods: This was a randomized, placebo-controlled, double-blind phase 2 trial. Recruitment of the trial was stopped after 44 patients due to poor accrual. Patients aged 18 years or older with gastric adenocarcinoma with PM and disease progression after first-line chemotherapy (platinum plus fluoropyrimidine) were randomly assigned in a 1:1 ratio to receive apatinib or placebo 500 mg oral once daily plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR) and safety profiles. Results: Between January 2017 and January 2019, 44 patients were randomly assigned to treatment (21 in Paclitaxel/apatinib group while 23 in Paclitaxel/placebo group). Median PFS was significantly longer in apatinib plus paclitaxel group than in placebo plus paclitaxel group (4.67 months [95% CI, 3.90 to 9.13 months] vs 4.07 months [95% CI, 1.93 to 5.00 months]; hazard ratio 0.46 [95% CI, 0.22 to 0.97]; P=0.037). There was no significant difference between the two groups in median OS (8.57 months vs. 9.03 months; P=0.85), ORR (19.0% vs. 4.3%; P=0.290) and DCR (76.2% vs. 52.2%, P=0.098). Apatinib group showed a higher incidence of proteinuria (38.1% vs. 4.3%; P=0.016), while no significant difference was found in the incidence of grade 3 or higher drug-related adverse events. Conclusions: Compared with placebo plus paclitaxel, the combination of apatinib with paclitaxel as second-line therapy significantly improved median PFS with an acceptable safety profile in patients with gastric cancer with peritoneal metastasis. Clinical trial information: NCT03144843. [Table: see text]
A nutritional management algorithm in older patients with locally advanced esophageal cancer.
Authors: Moy Ryan H. , Sabwa Shalom , Maron Steven Brad , Shcherba Marina , Apollo Arlyn J. , Janjigian Yelena Y. , Ku Geoffrey Yuyat , Tew William P. , Ilson David H. , Won Elizabeth 
Published: June 2021

e16038 Background: Esophageal cancer primarily affects older adults, who are at highest risk for poor nutritional status due to medical comorbidities, physiological changes of aging and geriatric issues such as altered cognition and mobility. Malnutrition is correlated with poor outcomes in patients with esophageal cancer; however, standardized nutritional interventions are not commonly utilized. Therefore, we performed a feasibility study of a nutritional management algorithm with risk-based guidelines for older patients with esophageal cancer receiving chemoradiation (CRT). Methods: Elderly patients (age ≥ 65 years old) with locally advanced esophageal or gastroesophageal junction (GEJ) cancer receiving induction chemotherapy and preoperative or definitive CRT were eligible for enrollment on this single center study. Patients completed baseline nutritional assessment using the Mini Nutritional Assessment (MNA) screening scale, and patients who were at risk for malnutrition or malnourished were referred to a clinical dietician for evaluation and counseling. Nutritional status was reassessed after induction chemotherapy, and patients with severe malnutrition were to be referred for enteral feeding tube placement prior to CRT. The primary objective was to determine the feasibility of the nutritional management algorithm based on completion rates of nutritional assessment, clinical dietician referral and enteral feeding. Secondary endpoints included toxicity, functional status and quality of life assessment. Results: Twenty elderly patients with locally advanced esophageal cancer were enrolled, and fourteen patients met criteria for clinical dietitian referral based on poor baseline nutritional status. Induction chemotherapy was associated with improved dysphagia, with 92% of patients reporting improvement or resolution of symptoms. There were no patients who met criteria for enteral feeding prior to CRT based on the guidelines, and only one patient (5%) required feeding tube placement during CRT. In total, 17 patients (85%) completed the nutritional management algorithm and finished the planned treatment course. Rates of hospitalization, grade ≥2 esophagitis, grade ≥3 toxicity and early CRT discontinuation were similar between patients with normal and abnormal baseline nutrition. Conclusions: This study demonstrates that a risk-based nutritional management algorithm is feasible in elderly patients with esophageal cancer. The induction chemotherapy approach may ameliorate dysphagia, reduce the need for enteral feeding and facilitate CRT completion in this nutritionally vulnerable population. Clinical trial information: NCT02027948.
The efficacy and safety of toripalimab combined with definitive chemoradiotherapy for patients with locally advanced esophageal squamous cell carcinoma.
Authors: Xi Mian , Zhu Yujia , Li Qiao-Qiao , Zhao Lei , Yang Yadi , Hu Yonghong , Liu Mengzhong 
Published: June 2021

e16043 Background: Definitive chemoradiotherapy (CRT) is the standard treatment option for unresectable locally advanced esophageal cancer. However, the loco-regional and distant recurrences after definitive CRT were as high as 50%. Immunotherapy targeting the PD-1/PD-L1 axis has demonstrated antitumor activity in advanced esophageal cancer. With the potential benefit of combining PD-1 blockade to CRT, we performed a phase II trial to evaluate the efficacy and safety of the combination of toripalimab (an anti-PD-1 antibody) and definitive CRT in locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with previously untreated, unresectable, stage II–IVA ESCC were enrolled. Patients received concurrent radiotherapy (50.4 Gy in 28 fractions), chemotherapy (weekly paclitaxel 50 mg/m2 and cisplatin 25 mg/m2 for 5 cycles), and toripalimab (240 mg, every 3 weeks until 12 months or disease progression). The primary endpoint was clinical complete response (cCR) rate at 3 months after CRT according to PET-CT scan and esophagogastroduodenoscopy with biopsies. Second endpoints were overall survival (OS), progression-free survival (PFS), adverse events (AEs). Exploratory endpoints included PD-L1 expression, tumor mutational burden, and genetic biomarkers as potential efficacy predictors. Results: Between November 2019 and December 2020, 42 eligible patients (2 stage II, 19 stage III, and 21 stage IVA) were included. Of them, 39 completed CRT and 3 remained under treatment. Twenty-eight patients were included for efficacy analysis (median follow-up: 7.2 months) and 42 for safety analysis (median follow-up: 5.8 months). The cCR rate was 60.7% (17/28) and the median OS and PFS were not reached. Thirty-nine patients (92.9%) had AEs, 20 patients (47.6%) experienced grade ≥3 AEs, and 1 patient (2.4%) suffered grade 5 esophageal fistula. The most common grade ≥3 AEs were lymphopenia (45.2%), neutropenia (33.3%), and anemia (28.6%), respectively. Conclusions: The addition of toripalimab to definitive CRT for locally advanced ESCC demonstrated encouraging efficacy and acceptable toxicity. The exploratory endpoints including PD-L1 expression and genetic biomarkers analyses are ongoing. Clinical trial information: NCT04005170.