bluuebunny/crossref_metadata_2025 huggingface dataset:
The effectiveness of colorectal cancer screening for cancer survivors.
Authors: Liu Chia-Jen , Lai Tzu-Yu , Yeh Chiu-Mei , Tsai Chun-Kuang , Chen Po-Min , Liu Jin-Hwang , Chiou Tzeon-Jye , Teng Chung-Jen
Published: May 2020

e16091

Background: Colorectal cancer (CRC) is one of the highest-incident neoplasms in many countries. Although the incidence of CRC is increasing gradually, the mortality rate has not increased due to early detection and multidisciplinary treatment. CRC screening programs, including colonoscopy and fecal occult blood tests, have been reducing CRC-related mortality worldwide. In Taiwan, the CRC screening program uses a biennial fecal immunochemical test (FIT) as the initial screening tool. FIT-positive participants receive a colonoscopy as a CRC confirmation examination. Cancer survivors have a higher incidence of secondary primary malignancies. Methods: We conducted a nationwide population-based study in Taiwan. The cancer survivors with FIT in the Nationwide Colorectal Cancer Screening (NCCS) Program between January 2010 and September 2014 were enrolled as the study group. The patients aged under 50, diagnosed with CRC before the FIT were excluded. The screening participants without a cancer history were served as the comparison group. The primary endpoint was CRC diagnosis within six months after a FIT. The cancer diagnosis was identified by using Taiwan Cancer Registry. The ratios of positive FIT, confirmatory colonoscopy, and CRC diagnosis in the cancer survivors and the comparison cohort were calculated and compared. Analyses were adjusted for participants’ characteristics by using multilevel logistic regression models. Results: We identified 288,919 cancer survivors who participated in the NCCS Program. Of them, 41.1% were male and the median age was 59 (interquartile ranges 54–64). There were 417,907 FITs performed in the study cohort. The FIT positive rates were 11.3% and 7.4% in the study and comparison groups, respectively (OR 1.59 95% CI 1.57–1.60). Of the FIT positive participants, 50.5% and 52.3% received confirmatory colonoscopy or the related examinations within six months, respectively (OR 0.93 95% CI 0.91–0.95). Then 3.0% and 4.4% of those receiving confirmatory colonoscopy were diagnosed with CRC in the study and comparison groups, respectively (OR 0.68 95% CI 0.63–0.74). After adjustment for age, sex, income, a family history of CRC, and comorbidities, the cancer survivors in this screening program had a similar rate of CRC diagnosis compared with those without antecedent malignancies (adjusted OR: 0.97, 95% CI 0.87–1.08). Conclusions: Although the cancer survivors had a higher rate of positive FIT, the CRC diagnosed by the screening did not increase. We further identified the risk factors associated with CRC in the cancer survivors.
Cell-free DNA and exoDNA analysis in metastatic colorectal cancer patients (mCRC).
Authors: Galvano Antonio , Castiglia Marta , Guarini Aurelia , Gristina Valerio , Cutaia Sofia , Bazan Viviana , Russo Antonio , Carreca Ignazio UGO
Published: May 2020

e16093

Background: Liquid biopsy is a growing field in translational cancer research. Two of the most studied liquid biopsy biomarkers are cell-free DNA (cfDNA) and exosomes, nano-sized vesicles that transport protein and nucleic acids including DNA (exoDNA). Therefore, both cfDNA and exoDNA are potentially useful to investigate the molecular landscape of tumor with a minimally invasive approach. Here we investigate the prognostic and predictive role of both cfDNA and exoDNA in mCRC using Next Generation Sequencing (NGS) analysis. Methods: From July 2017 to September 2018, samples of 40 mCRC patients were collected at the Medical Oncology of the AOUP Paolo Giaccone of Palermo. Blood samples were collected in EDTA-tubes before chemotherapy infusion (T1), at the first instrumental evaluation (T2) and every 2-3 months (T3). Plasma was used to isolate cfDNA and exosomes using the QIAamp Circulating Nucleic Acid and ExoEasy Maxi Kit respectively. ExoDNA was isolated through the QIAamp DNA micro kit. NGS analysis was conducted on IonS5 with AmpliSeq Cancer Hotspot Panel v2, which includes hotspot regions of 50 cancer-related genes. Results: Patients with cfDNA concentration > 0.47ng/μl have worse PFS compared with those with < 0.47 ng/μl cfDNA level. NGS analysis from 16 cfDNA samples showed a total of 292 mutations, with a median of 5 non-synonymous mutations in T1 vs. 8 non-synonymous mutations in T2 sample. We report an inverse and significant correlation between non-synonymous mutations count and disease-specific survival (DSS). Only 2 cfDNA samples carried KRAS mutations, despite it were previously reported in 5 paired tissue samples. An interesting result emerged from exoDNA sequencing of CRC20. KRAS mutation was identified in T1 exoDNA but not in the paired cfDNA samples, suggesting that exoDNA is able to intercept KRAS mutation earlier than cfDNA. Conclusions: cfDNA analysis could be a useful tool for better patients’ stratification. exoDNA could allow an early interception of disease recurrence that could be explained by the ability of exosomes to protect their cargo from degradation.
Bevacizumab associated calcifications might be a prognostic marker in patients with metastatic colorectal cancer.
Authors: Zhou Yuwen , Meng Qiu
Published: May 2020

e16108

Background: Cetuximab associated calcifications is a positive predictive factor in metastatic colorectal cancer (mCRC). In patients with glioblastoma, bevacizumab-induced calcifications are also related to a better prognosis. However, tumor calcifications are rarely recognized in mCRC patients treated with bevacizumab. This study was to investigate the correlation between clinical outcome and calcification in mCRC who received bevacizumab and chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy in our hospital from January 2016 to January 2019. Clinical variables were retrieved from medical records and tumor calcification were evaluated independently by radiologists on the basis of computed tomography scans. A univariate and multivariate COX regression analysis was performed to evaluate the association between calcification and outcome. Results: 159 patients with an average age of 59.0 years were included. Median follow-up was 29.6 months. Among all enrolled patients, 31 had tumor calcification [31/159 (19.5%)]. The median overall survival (OS) and progression-free survival (PFS) was significantly better in patients with calcification than those without calcification (28.0 vs. 24.9 months, p= 0.024; 12.0 vs. 10.0 months, p= 0.026). A higher objective response rate (61.3% vs. 50.0%) was also observed in calcification group. On multivariate analysis, tumor calcification was independently associated with OS (hazard ratio 1.799, 95% CI 1.002–3.230) and PFS (hazard ratio 1.609, 95% CI 1.013–2.557). Conclusions: Tumor calcification was independently associated with improved prognosis in colorectal cancer. It might be a potential prognostic marker.
Do irinotecan (IRI) dose reductions driven by UGT1A1*28 genotyping prevent IRI-related severe neutropenia? A real-world study.
Authors: Personeni Nicola , Mineri Rossana , Michelini Angelica , Bozzarelli Silvia , Pressiani Tiziana , Smiroldo Valeria , Sandri Maria Teresa , Giordano Laura , Santoro Armando , Rimassa Lorenza
Published: May 2020

e16116

Background: IRI is widely used in the treatment of gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach is still unclear. We assessed potential clinical variables that may predict grade ≥3 neutropenia and more specifically the upfront genotyping of UGT1A1 polymorphisms associated with IRI toxicity, according to predefined IRI dose reductions. Methods: We genotyped UGT1A1*28 polymorphisms in 247 patients with metastic colorectal, gastric and pancreatic cancers who received second or third-line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was undertaken in 179 patients receiving also fluoropyrimidines. We compared the incidence of severe neutropenia with full-dose IRI in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers who underwent initial IRI dose reductions by at least 30%. Results: The incidence of UGT1A1 7/7, 6/7, 6/6 genotypes was 11.3%, 51.4%, and 37.2%, respectively. IRI dose reductions were significantly more frequent with UGT1A 7/7 and 6/7 genotypes (odds ratio [OR] = 9.5; 95% confidence interval [CI]: 4.3-21.7), and combination chemotherapy (OR = 3.8; 95%CI: 1.3 – 11.1). Other clinical parameters, including sex, cancer type, baseline neutrophils levels, performance status were not significantly associated with IRI dose reductions. Despite initial IRI reductions driven by the UGT1A1 panel, patients with UGT1A1 7/7 genotype had an increased, albeit non-significant, risk of grade ≥3 neutropenia, compared to patients with UGT1A1 6/6 and 6/7 genotypes who received full dose IRI (incidence: 39% versus 21%; OR = 2.4; 95%CI: 0.85 – 7.03). Conclusions: UGT1A1 testing is a determinant of IRI dose reductions, however this strategy does not reduce the burden of grade ≥3 neutropenia in UGT1A1 7/7 carriers. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the increased risk of neutropenia in patients candidate to IRI-based chemotherapy.
Alterations of DNA damage repair genes in Chinese colorectal cancer patients.
Authors: Li Wenliang , Zhu Zhu , Xu Ning , Huang Wei , Shi Junping , Shi Jiaochun , Wang Weifeng , Klempner Samuel J , Zhao Juan , Gan Jialiang
Published: May 2020

e16121

Background: Colorectal cancer (CRC) is the second most common cancer in women and third in men. DNA damage repair (DDR) deficiency has emerged as a predictive biomarker for chemotherapy, PARP and immune checkpoint inhibitors. However, comprehensive molecular characteristics of DDR variants in Chinese CRC patients is lacking. Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay. The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Alterations of six functional gene sets involved in DDR pathways: homologous recombination (HR), mismatch repair (MMR), base excision repair (BER), nonhomologous end-joining (NHEJ), checkpoint factors (CPF) and Fanconi anemia (FA) were analyzed. The association of DDR gene mutations with TMB/MSI was assessed. Results: In total, 319 CRC patients were recruited, 127 female and 192 male with a median age of 59 (range 23-92). Over one third (36%,115/319) patients had at least one mutation in DDR genes. Mutation rates varied in different DDR pathway: HR (20.7%), CPF (15.1%), FA (11.3%), MMR (10.3%), BER (8.8%), and NHEJ (5.3%). The most frequently mutated DDR genes were ARID1A (13.4%), ATM (10.2%), BRCA2 (6.8%), MLH1 (5.6%), MSH6 (5.6%), POLE (5.0%). Germline mutations in MLH1 (2.5%), BRCA2 (1.2%), MSH2 (0.9%), MSH6 (0.9%), FANCA (0.9%), ATM (0.6%), BRCA1 (0.3%), and CHEK2 (0.3%) were detected in 24 patients. DDR variations were enriched in the right-side CRC compared to the left side CRC (50% vs. 32.8%, p= 0.024). Early stage (I-II) harbored more DDR variations. 20.1% of patients had high TMB (≥10 muts/Mb) with a median of 51 muts/Mb (10-326.7 mus/Mb). Patients with DDR mutations had a significantly higher TMB than patients with wild type DDR (8.5 vs. 4.6 muts/Mb, p< 0.001). All CRC tumors with high MSI harbored DDR mutations. Importantly, the mutations in “HM” (HR/MMR), but not BER/CPF/NHEJ/FA mutations, were significantly correlated with high MSI ( p< 0.001). Conclusions: DDR gene alterations occurred in 36% of Chinese CRC patients and were enriched in right sided tumors. DDR pathway alterations are relatively frequent in CRC and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.
Real-world outcomes for neoadjuvant capecitabine versus infusional 5-fluorouracil in the treatment of locally advanced rectal cancer.
Authors: Loft Matthew , Wong Hui-Li , Kosmider Suzanne , Lee Margaret , Tie Jeanne , Wong Rachel , Jones Ian , Croxford Matthew , Steel Malcolm , Faragher Ian , Guerrieri Mario , Christie Michael , Gibbs Peter
Published: May 2020

e16124

Background: Neoadjuvant chemoradiation therapy (CRT) is a standard of care treatment for locally advanced rectal cancer (LARC). A pathologic complete response (pCR) following CRT is an early indicator of treatment benefit and associated with excellent survival outcomes. As capecitabine replaces infusional 5-fluorouracil (5-FU) as the fluoropyrimidine of choice in routine care of LARC, on the back of clinical trial data demonstrating equivalence, it is important to confirm that efficacy is maintained in the real-world setting. Methods: We analysed data from a prospectively maintained colorectal cancer database at 3 Australian hospitals including patients diagnosed January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5FU or capecitabine. Results: 657 patients were analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine treated patients and 118/380 (23.7%) that received 5-FU (p = < 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, p < 0.01). Two-year progression free survival was similar (84.9% vs 88.0%, p = 0.34). Conclusions: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with an oral therapy in the real-world setting is one possible explanation.
First-in-human (FIH) phase I study of GST-HG161, a potent and highly selective c-met inhibitor, in patients with advanced solid tumor.
Authors: Li Jin , Guo Ye , Xue Junli , Wu Wenqiang , Chen Shikui , Tang Yanan , Xu Xiongbin , Li Gang , Hu Lihong , Lin Yunfei , Shen Liang , Xia Yuanfeng , Chan Chi-Chung , Wang Zhouchong , Ni Dawen , Ding Charles , Chen Shuhui
Published: May 2020

e16126

Background: GST-HG161 is an orally bioavailable novel potent and highly selective c-Met inhibitor, which displayed significant antitumor activity in preclinical models as well as very desirable pharmaceutical properties for oral dosing. Preclinical studies demonstrated that GST-HG161 has the potential to be effective in HCC patients with active c-Met signaling. Methods: This is an open label, first-in-human, single center, dose-escalation study (NCT04228406) utilizing an accelerated dose escalation design using single patient cohorts for the first two dose levels (60 and 150 mg) followed by a conventional 3+3 design at the 3rd dose cohort (300 mg). Dose escalation is expected to continue to the proposed 7th dose cohort (900 mg). The objective of the study is to determine the maximum tolerated dose and/or recommended Phase II dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of GST-HG161 in patients with advanced solid tumors. Eligible patients are adults with advanced solid tumors refractory to standard therapies with confirmed c-Met positive. The definition of c-Met positive is a) IHC expression of c-Met (positive criteria: 1+ and above) and/or b) FISH amplification of c-Met and/or c) MET exon 14 (METex14) skipping. GST-HG161 is administered orally once-a-day starting on day 1 of each 21 days cycle. Results: To date, 6 patients (CRC 2, Gastric 1, NSCLC 1, HCC 1, Cholangiocarcinoma 1) were enrolled to 3 dose levels (60, 150, and 300 mg). Of these 6 patients, 4 had discontinued GST-HG161 treatment at the data cut-off date of Feb 1, 2020, due to progressive disease (3) and adverse event (1). Two patients at the 300 mg cohort are still on treatment. Overall, 4/6 patients showed no drug-related AEs > Grade 1. One patient reported a DLT: asymptomatic Grade 3 lipase elevation after a single dose of 60mg. To date, no other patients showed elevations of lipase and amylase. Bioanalysis of PK samples from study patients are currently ongoing. PK summary will be reported in the presentation. Conclusions: GST-HG161 has been well tolerated to date in study patients with a manageable safety profile. The dose escalation is expected to continue to the proposed 7th cohort at 900 mg. Clinical trial information: NCT04228406 .
Induction chemotherapy with mFOLFOXIRI in cT4N+ locally advanced rectal cancer: Subgroup analysis from a prospective trial.
Authors: Zhang Jianwei , Hu Huabin , Cai Yue , Xie Xiaoyu , Wu Zehua , Ling Jiayu , Deng Yanhong
Published: May 2020

e16136

Background: FOLFOXIRI had been recommended as induction treatment for patients with T4N+ rectal cancer in the latest NCCN guideline. However, no prospective study to support this recommendation in his population. Here, we tried to analyze the efficacy of FOLFOXIRI as induction chemotherapy in the subgroup of rectal cancer patients with T4N+ from a prospective trial. Methods: A phase II trial exploring the efficacy of mFOLFOXIRI as neoadjuvant chemotherapy in locally advanced rectal cancer had been conducted in our center recently. The subgroups of patients with clinical T4N+ rectal cancer were extracted for further analysis. All candidates were to receive 4 to 6 cycles of mFOLFOXIRI. MRI will be performed every two cycles to assess clinical responses. And then the patients would receive total mesorectal excision directly or proceed to chemoradiotherapy according to the result of restaging evaluation. Postoperative FOLFOX chemotherapy was recommended. The primary endpoint is the ratio of tumor downstaging to ypT0-2N0M0. Results: There were 27 patients with cT4N+. There were twenty male and 7 female, with the median age of 46 years old. MRF involved was observed in 14 patients. Neoadjuvant chemotherapy with mFOLFOXIRI was performed for at least 4 cycles. Six patients received radiotherapy before total mesorectal excision, including short-term radiation in 1 patient. R0 resection was achieved in all the patients (100%) and 24 (88.9%) of patients had received sphincter-saving operation. According to the pathologic result, all patients showed regression in the primary tumor (ypT0-3). The pCR rate was 22.2% (6/27) and the tumor downstaging (ypStage 0-I) rate was 29.6%. Another 13 (48.1%) patients showed downstaging to ypStage II. The main grade 3/4 adverse event was neutropenia (35.7%). With a median follow-up of 25 months, no local recurrence was observed. Only 3 patients developed distant metastasis. The 2-year survival rate for this group of population was 85.0%. Conclusions: mFOLFOXIRI showed high tumor downstaging rate in locally advanced rectal cancer. It could be reasonable to use mFOLFOXIRI as induction chemotherapy for cT4N+ rectal cancer patients. Clinical trial information: NCT02217020 . [Table: see text]
Clinicopathologic features and survival outcomes of signet cell carcinoma of the appendix: Analysis of the SEER database.
Authors: Abushalha Kamelah , Tuqan Wa'el , Albagoush Sara , Abulaimoun Sawsan , Silberstein Peter T.
Published: May 2020

e16147

Background: Signet ring cell carcinoma of the appendix (SRCCA) is an exceedingly rare tumor, and limited data are available on the characteristics and survival probabilities of this tumor. Methods: Surveillance, Epidemiology, and End Results (SEER) database was used to identify 527 patients diagnosed with SRCCA between 2000 and 2015. The database was used to examine demographic information. Survival analysis was made by Kaplan-Meier and compared by log-rank test. Cox proportional hazards model was adopted for prognostic variable evaluation. Results: The majority of SRCCA patients were female (63.9%) and white (83.8%), with a mean age at diagnosis of 56 years. Histologically; 60% of the tumors were of high grade (poorly-differentiated and undifferentiated). The majority of patients were diagnosed with metastatic disease (61.3%) and received surgical treatment (86.5%), with sub-total colectomy was the most common surgery performed (45.6%). Median overall survival was 26 months, with a cancer-specific survival at three-year and five-years of 39% and 18.4%, respectively. There was a 10-year difference in median survival time based on sex (females vs males; 23 vs 33 months respectively). On bivariate analysis; factors associated with significantly increased mortality (p < 0.05), include increased age (HR 1.02), female gender (HR 1.33), AJCC T category (T4 compared to T0; HR 1.96), AJCC N category (N1 compared to N0; HR 1.9) and AJCC M category (M1 compared to M0: HR 2.62). Factors associated with improved survival (p < 0.05) included treatment by surgical resection; total colectomy (HR 0.47) and sub-total colectomy (HR 0.45) . Conclusions: This is the largest study to date on SRCCA. Older white females are most commonly affected and often diagnosed at advanced stage and grade.
Outcome of locally advanced carcinoma of oesophagus: A single institution experience.
Authors: S Thianeshwaran , Bj Sriniivas , Sanghavi Niyati Prakash , Sarathy Vinu , Lalkota Bhanu Prakash , PK Kiran , Byas Nitin , Shah Mansi , N Madhusudhan , Varayathu Hrishi , Puii Lalnun , Hazarika Diganta , Mufti Suhail Sayeed , Ajaikumar Basavalinga Sadasivaiah , Radheshyam Naik
Published: May 2020

e16507

Background: Oesophageal cancer is the twelfth most common cancer worldwide and seventh leading cause of cancer related death. Neoadjuvant treatment in addition to surgery has shown improved overall survival compared to surgery alone in resectable oesophageal cancer. We aimed to analyse the survival outcome among locally advanced oesophageal carcinoma patients in neoadjuvant setting. Methods: We analysed 37 patients with locally advanced carcinoma of oesophagus from 2015 to 2019 who underwent neoadjuvant chemoradiotherapy followed by surgical excision of tumour. Descriptive analysis was used for demographic data. overall survival and disease free survival was analysed using Kaplan-Meier survival analysis. Results: Our study includes 20 males (54%) and 17 females (45%). Over all consumption of Tobacco and alcohol consumption was found to be 64% and 18% respectively. The most common tumour site in this study was middle oesophagus (56%) followed by lower (37%) and upper (5%). Histopathologically, moderately differentiated squamous cell carcinoma constituted the highest (62%), followed by well differentiated squamous cell carcinoma (21%) and poorly differentiated carcinoma (16%). The pathological stage post chemoradiotherapy was 80%, 50% and 57% for stage I, II and III respectively. Median over all survival is 60 months and no statistical difference in stage I and stage II. Median over all survival for poorly differentiated squamous cell carcinoma is 16 months and lower one third of squamous cell carcinoma is 37 months. Complete pathological response is 42 %. Conclusions: Our study concluded that patients with tobacco and alcohol consumption have poorer survival. Prognosis was worst for patients with lower end oesophagus and poorly differentiated type. Disease free survival was better for patients who achieved complete pathological response when compared to partial responders.
Effects of removing heat and phlegm prescription on the proliferation and autoantigens expression of esophageal carcinoma cell.
Authors: Si Fuchun
Published: May 2020

e16510

Background: o explore the effects of removing heat and phlegm prescription (RHPP) on the proliferation and autoantigens expression of esophageal carcinoma(EC) cell, so as to provide basis for the molecular pathogenesis and clinical medication of EC. Methods: RHPP was developed by us for treating EC, EC autoantigens CK13, CK16, CaD, ACTG2 were identified in our previous studies. The effects of RHPP and and its ethanol extraction on the proliferation, cell cycle and autoantigen protein expression of Eca109 cell, EC9706 cell and TE-1 cell were investigated by MTT assay, flow cytometry and western blot analysis. Results: RHPP and its removing heat (RH) and removing phlegm (RP) separated prescriptions all have inhibitory effects on the proliferation of EC9706, EC109 and TE-1 cells in dose-dependent and time-dependent manner, changed morphology of four esophageal carcinoma cells, which appeared as round with rough edges, karyopyknosis, and karyorrhexis. Ic50 values of RHPP for Ec9706, Eca109 and TE1 cell were 33.31 ug·ml−1, 20.70 ug·ml−1, 21.93 ug·ml−1 respectively, while Ic50 values of RHPP’s ethanol extraction for Ec9706, Eca109, TE1 were 0.653 ug·ml−1, 0.082 ug·ml−1, 0.172 ug·ml−1 respectively. RHPP and RP induced G2/M phase arrest in EC109 and TE-1 cells, while RH induced G0/G1 phase arrest in EC109 and TE-1 cells; RHPP and RP induced G0/G1 phase arrest in EC9706 cells, while RH induced S phase arrest in EC9706 cells. RHPP and its two separated prescription could downregulate CK16, CaD, ACTG2 expression and upregulate CK13 expression. Conclusions: Autoantigens CK13, CK16, CaD and ACTG2 were expressed in EC cell, RHPP could regulate these four autoantigens expression. This study provides new basis for the EC mlecular mechanism and development of anti-esophageal carcinoma drugs in traditional Chinese medicine.
Observation on the clinical effect and survival period of patients with esophageal cancer treated with UMIPIC combined with low dose radiotherapy.
Authors: Liu Jian , Jing Peng , Gao Feng , Shang Wei , Zhang Peicheng , Zhang Xiaomin , Feng Jianbin , He Guangyong , Zhang Gequn , Li Wenli , Wu Yanfei , Yu Baofa
Published: May 2020

e16517

Background: To observe the clinical effect and survival period of UMIPIC (ultra-minimum incision personalized intratuoral chemoimmunotherapy) combined with radiotherapy in the treatment of esophageal cancer. Methods: 712 patients with esophageal cancer who received UMIPIC treatment in our hospital from January 2011 to December 2015 were selected for the study subjects, 540 cases were treated by UMIPIC combination with radiotherapy in group A and 172 cases were treated by UMIPIC without radiotherapy in group B. All patients were diagnosed with esophageal cancer, and signed the consent for treatment. The patients were treated according to the UMIPIC treatment guidelines. This study was to observe the adverse reactions, clinical efficacy, survival and survival rate of esophageal cancer patients treated with UMIPIC combined with low-dose radiotherapy. Results: The common adverse reactions in group A were fever (18.06%), pain (8.89%), hemoglobin reduction (5.59%), leucopenia (5.40%), nausea (1.48%) and thrombocytopenia (1.12%);The common adverse reactions in group B were fever (26.16%), hemoglobin reduction (17.16%), pain (16.86%), leucopenia (3.55%), thrombocytopenia (2.35%), nausea (1.74%), liver function damage (2.42%), renal function damage (1.21%) and vomiting (1.16%). The other adverse reactions were all lower than 1.00%; The fever, pain and hemoglobin decrease in group A were significantly lower than those in group B (P < 0.05). There were 522 patients whose clinical efficacy could be evaluated in 712 patients. The benefit rate of group A was 95.28%, higher than that of group B 91.84%.The mean and median survival time of group A was 28.412 and 15.670 months, significantly higher than that of group B at 22.103 and 7.070 months. The 1-year survival rate of group A was significantly higher than that of group B (P < 0.05). The 1-year, 2-year and 5-year survival rates of group A were 60.05%, 35.61% and 28.26% while the 1-year, 2-year and 5-year survival rates of group B were 36.94%, 26.44% and 25.00%. Conclusions: The main adverse reactions of UMIPIC in the treatment of esophageal cancer are fever and pain, and other adverse reactions are relatively low. Combined radiotherapy can improve the clinical benefit rate, prolong the survival time and the clinical treatment effect is good, it is encouraged to treat esophageal cancer using local therapy of UMPIC with radiotherapy at low dose.
Changing HER2-status of the primary gastric tumor after neoadjuvant trastuzumab-based therapy.
Authors: Orlova Rashida , Beliak Natalia P. , Kutukova Svetlana , Zhukova Natalia V. , Avramenko Inna , Popova Natalia V. , Ivanova Anastasia , Androsova Alexandra , Zorina Ekaterina
Published: May 2020

e16529

Background: Aproximetly 16 % of patients with metastatic gastric cancer (GC) have HER2+ tumors. With localized stages, the detection rate of HER2+ is known to be lower. Addition of trastuzumab (T) to chemotherapy (CT) improved survival in metastatic, HER2+ GC. Unlike the metastatic disease, Her-2 did not represent an independent prognostic biomarker for early stages during exploratory analysis of MAGIC trial. The aim of the study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer, to evaluate the contribution of trastuzumab to the effectiveness of neoadjuvant treatment in this rare patient population. Methods: We assessed HER2 expression using immunohistochemistry in pre-treatment biopsied specimens and post-treatment resected specimens obtained from 10 patients with locally advanced HER2-positive (3+) gastric cancer receiving trastuzumab-based neoadjuvant chemotherapy: 8 men (80%) and 2 women (20%), from 30 to 80 years old, the median age was 63,5 years. Included 7 patients with resectable adenocarcinoma of the stomach and 3 patients with adenocarcinoma of the esophageal-gastric junction. All patients received neoadjuvant therapy with trastuzumab (100%) + chemotherapy: FLOT (2 patients), FOLFOX (7 patients), XELOX (1 patient). All patients underwent R0 gastrectomy. Tumor regression grading (TRG) after treatment were determined according to Mandard system. Results: Two patients showed a complete pathomorphological response of the tumor (20%,TRG1), therefore, the determination of postoperative HER2 status was not possible. Two patients (20%) maintained the HER2-positive status and six patients (60%) had a change in HER2 expression from positive to negative. Three patients had a (y)pT3 and 5 had a (y)pN+ tumor. Basing on histological changes the tumor regression TRG3 ( < 10% residual tumor cells) was observed in 5 patients (50%). TRG 4-5(preponderance of tumor cells/tumors without changes of regression) observed in 3 patients (30%). The follow-up period is too short for disease-free survival or overall survival to be assessed. Conclusions: HER2 expression can change after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after neoadjuvant treatments may be utilized to determine whether the continued use of trastuzumab is advisable.
Clinicopathological features and outcomes of patients with esophageal cancer undergoing neoadjuvant chemoradiation (chemoRT) in Southern Brazil: A comparison to the Worldwide Esophageal Cancer Collaboration.
Authors: Gössling Gustavo Cartaxo de Lima , Pinto Bruno Siliprandi , Martins Eduardo Ferreira , Silva Rafaela Kathrine da , Peruzzo Nicolas , Schwartsmann Gilberto , Parikh Aparna Raj
Published: May 2020

e16535

Background: Despite low- and middle-income countries representing 80% of esophageal cancer global burden, TNM staging is based on data from the Worldwide Esophageal Cancer Collaboration (WECC) that is mainly composed of patients from developed countries. Notably, 87.8% of patients staged after neoadjuvant chemoRT in the WECC were from North America or Europe and only 0.09% (N = 7) from Latin America (LA), raising questions about its applicability. We wanted to see if the characteristics of patients undergoing neoadjuvant chemoradiation in LA were representative of patients in the WECC. Methods: We retrospectively identified patients with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) who underwent chemoRT at Hospital de Clínicas de Porto Alegre (HCPA), an academic hospital in southern Brazil, and compared their clinicopathological features, treatments and outcomes data with WECC patients. WECC data were extracted from previous publications. Results: Compared to WECC, there were no differences in age (ESCC: 61±7.7 vs. 61±9.4, P = 0.91; EAC: 62±7.2 vs. 61±9.8, P = 0.67) and sex (female: 30.0% vs. 33.2%, P = 0.64; 30.8% vs. 11.6%, P = 0.06). However, we found statistically significant differences in histology (ESCC: 79.4% vs. 26.5%, P < 0.001), PS 0/1/≥2 (ESCC: 24/70/6% vs. 50.6/41.7/7.7%, P = 0.002; EAC: 38.5/61.5/0% vs. 34.9/61.5/3.6%, P = 0.91), active tobacco use (62% vs 27.8%, P < 0.001; 38.5% vs. 15.7%, P < 0.001), weight loss (8.4±5.8Kg vs. 2.6±6Kg, P < 0.001; 14.0±11.6Kg vs. 3,6±7,1Kg, P < 0.001), location (upper/middle/lower: 0/30/70% vs. 16.3/46.6/37.1%, P < 0.001; 0/0/100% vs. 0.7/3/96.3%, P = 0.63) and lymphadenectomy extension ( > 20 resected lymph nodes: 8.6% vs. 38.1%, P < 0.001; 0% vs. 37.9%, P = 0.027). There were no statistically significant differences in pathologic stage (Table) or overall survival in 30 days and 1 year from treatment decision (97.7% vs 98%, P = 0.69; 74.7% vs 75%, P = 0.78). Conclusions: Despite clinically significant differences in presentation were found, they did not implicate worse prognosis in this analysis. [Table: see text]
Novel target discovery in pembrolizumab-resistant gastric cancer using a comprehensive RNA-seq analysis pipeline.
Authors: Lee Jeeyun , Kim Seung Tae , Kim Kyoung-Mee , Schultz Eric , Skrzypczak Stan , Patro Rob , Kingsford Carl
Published: May 2020

e16541

Background: Immune checkpoint inhibition (ICI) has made significant breakthroughs in several tumor types including gastric cancer (GC) in recent years. We recently showed that single agent pembrolizumab demonstrated remarkable and durable response in MSI and EBV GC. However, the response to ICI remains low in MSS and most patients progress after initial response. We explore novel targets in ICI-resistant GC patients by analyzing pre- and post-resistant expression. Methods: Of the 61 patients who were enrolled onto our previously reported phase II pembrolizumab trial (NCT#02589496), whole transcriptome RNA-seq analysis of 10 paired freshly collected tissue samples (all from primary gastric tumors) was performed using TruSeq. All biopsies were performed at progression following stable disease (SD) or partial response (PR) to pembrolizumab. All patients had a MSI status of MSS and EBV negative. Molecular features were extracted using the validated Ocean Genomics, Inc. gene expression analysis pipeline, which trims reads, computes transcript- and gene-level expression, predicts structural variants, assembles novel isoforms, and computes per-sample quality control metrics, among other analyses. Samples that passed quality control, with mapping rates > 88%, were selected for analysis. Differentially expressed (DE) genes between resistant and pre-resistant samples were identified using a statistical test with a study design that accounted for the pairing of samples for each patient. Results: 16 genes (GENCODE v31) had absolute log2-fold expression changes (L2FC) > 2, P-value < 10−5 and FDR-adjusted P-value < 0.05. Because sex was only partially controlled for, we excluded genes on the X and Y chromosomes. We also excluded non-protein encoding genes and pseudogenes. The 7 remaining genes are in the table. PDL-1 (CD274) was not identified as significantly DE (FDR-adjusted P-value > 0.9999). Conclusions: This is the first study to identify novel targets in pembrolizumab-resistant GC using RNA-seq algorithms beyond PDL-1. [Table: see text]
The association between hyperfibrinogenemia and clinicopathological factors, and the survival analysis of gastric cancer.
Authors: Su Yu , Zhu Xuecong , Zuo Jing , Liu Fengling , Wang Yudong , Fan Zhisong , Wang Long , Liu Feiran , Jiang Da
Published: May 2020

e16547

Background: It is reported that hyperfibrinogenemia is commonly seen in gastric cancer. This study aim to discuss the association between fibrinogen level and preoperative clinicopathological factors and to evaluate the value as a predictor of prognosis. Methods: Retrospectively reviewed the medical records and follow-up data of patients with gastric cancer who underwent curative resection from January 2011 to December 2014 at Surgery Department of the Fourth Hospital of Hebei Medical University. Fibrinogen was measured a week before the surgery. Results: A total of 248 cases were enrolled. The means±SD of fibrinogen was 3.28±1.06g/L. Fibrinogen level was higher in older adults(≥60y), advanced tumor, poorly differentiated, deep invasion, lymph node metastasis, large tumor size and in those with high CEA, platelet count, albumin, NLR and PLR,( P< 0.05). All the people were divided by the TNM staging system and found that the plasma fibrinogen was higher in stageⅡand Ⅲ (stageⅠvs. stageⅡ: 2.84±0.72g/L vs. 3.36±1.18g/L, P= 0.009;stageⅠvs. stage Ⅲ: 2.84±0.72g/L vs. 3.43±1.07g/L, P< 0.001), however, there was no difference between stageⅡand Ⅲ( P= 0.662)(our study did not enrolled stage IV patients).When patients were classified into 4 groups according to the T classification, the plasma fibrinogen level gradually increased with increasing depth of cancer invasion (one way ANOVA; P= 0.002). Yet, when the patients who have lymph nodes metastasis classified according to the N classification, the differences among them did not have statistically significance ( P= 0.333). Multivariate analysis revealed that hyperfibrinogenemia had an independent association with advanced cancer (odds ratio,2.686(1.012-7.125); P= 0.047), lymph node metastasis (odds ratio,2.012 (1.012-3.125); P= 0.035) and tumor size(odds ratio,1.949 (1.099-3.454); P= 0.022). Our study aslo suggested that the patients with hyperfibrinogenemia before surgery showed a significantly lower survival rate (Log-Rank test; P< 0.001), hyperfibrinogenemia was a independent predictor on the overall survival, which could predict worse clinical outcome. Conclusions: Hyperfibrinogenemia may be considered a useful biomarker to predict advanced tumor, lymph node metastasis and large tumor size and can be a good predictor of worse clinical outcome.
Clinical and molecular features of responders to PD-1 blockade for patients with microsatellite instability high or mismatch repair deficient advanced gastrointestinal tumors.
Authors: Chida Keigo , Kawazoe Akihito , Kawazu Masahito , Nakamura Yoshiaki , Suzuki Toshihiro , Kitano Shigehisa , Nakatsura Tetsuya , Kuwata Takeshi , Shitara Kohei , Ikeda Masafumi , Yoshino Takayuki
Published: May 2020

e16550

Background: An anti-PD-1 inhibitor pembrolizumab showed a durable response for patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors. However, clinical and molecular features of responders to PD-1 blockade for MSI-H/dMMR advanced gastrointestinal (GI) tumors are not well understood. Methods: Patients with MSI-H/dMMR GI tumors who received anti‒PD-1 monotherapy were enrolled in this study. PD-L1 expression in tumor cells or immune cells as well as combined positive score (CPS) were assessed using the PDL1 IHC 22C3 pharmDx assay. Cancer genome alterations were evaluated by a next generation sequencing-based panel with Oncomine Comprehensive Assay for tumor tissue samples or Guardant360 ctDNA Assay for plasma samples. Results: A total of 43 patients with gastric cancer (n = 19), colorectal cancer (n = 16), cholangiocarcinoma (n = 4), small intestine cancer (n = 2) and pancreatic cancer (n = 2) were analyzed in this study. All patients had measurable lesions and objective response was observed in 20 patients (46%). Objective response rate (ORR) was significantly higher in patients with ECOG PS of 0 than in those with PS of 1 or 2 (64% vs. 22%, p = 0.01) and PD-L1+ in tumor cells than in those with PD-L1- in tumor cells (67% vs. 32%, p = 0.03). ORR was similar according to PD-L1 CPS; 45% in CPS < 1, 47% in CPS ≥1 and 56% in CPS ≥10, respectively. ORR was numerically lower in patients with PTEN mutation than in those with PTEN wild type (29% vs. 56%). Also, durable response rate (objective response lasting continuously ≥6 months) was significantly lower in patients with PTEN mutation than in those with PTEN wild type (0% vs. 52%, p = 0.03). In the overall population, median progression-free survival (PFS) was 10.0 months (95% CI, 4.0-not reached). In univariate analysis, PS (1 or 2 vs. 0) was the strongest clinical factor associated with PFS (3.9 months vs. not reached, HR 3.9; 95% CI 1.7-9.2, p = 0.002). After adjusted by PS, PTEN mutation was only molecular factor associated with shorter PFS (3.4 vs. 24.5 months, HR 3.0; 95% CI 1.1-8.4, p = 0.03). Conclusions: Some clinical and molecular factors were associated with response to PD-1 blockade for MSI-H/dMMR advanced GI tumors. Updated biomarker analysis with whole exome sequencing and multiplex IHC will be presented.
Association of HLA class I genotype with outcomes of gastrointestinal cancer patients with immunotherapy.
Authors: Lu Zhihao , Shen Lin , Zhang Henghui , Jiao Xi , Wang Yujiao , Zhang Lei , Qian Juanjuan , Chen Huan , Yang Ying , Wu Lijia , Liu Chang , Gong Jifang , Li Jian , Zhang Xiaotian , Wang Xicheng , Peng Zhi , QI Changsong , Wang Zhenghang , Li Yanyan
Published: May 2020

e16551

Background: Chowell et al. showed that HLA (human leukocyte antigen) class I (HLA-I) heterozygosity may avail to survival benefit from immune checkpoint blockade (ICB) in advanced cancer patients. Among their cohorts of melanoma patients, patients with the HLA-B44 supertype had improved survival, while the individuals with HLA-B62 supertype had worse outcome. However, these observations were not supported by another study of NSCLC patients treated with immune checkpoint inhibitors (ICIs). Now whether HLA-I genotype can serve as predictive marker for ICB treatment of other malignancies such as gastrointestinal cancer remains unclear. Methods: Tumor tissue samples before immunotherapy as well as related clinical data were collected from 91 Chinese gastrointestinal cancer patients receiving anti-PD-1/PD-L1 inhibitors and/or anti-CTLA-4 antibodies. Genomic features of tumor specimens were characterized by whole exome sequencing (WES) and HLA-I genotyping of normal DNA from peripheral blood cells were performed using WES data. Tumor immune microenvironment signatures were examined by RNA-sequencing targeting 395 immune related genes. Results: We observed that the individuals with HLA-B62 supertype (n = 15) had a significantly shorter PFS (median PFS, 1.83 months versus 3.53 months; HR, 2.3; 95% CI, 1.03-5.0; p= 0.009) than that of those without HLA-B62 supertype (n = 35) in a subgroup of patients with microsatellite stability (MSS, n = 50) and it was not so in other patients with microsatellite instability-high (MSI-H, n = 17) or unknown MSI status (n = 24). Moreover, the patients with B62 supertype and TP53 mutations (n = 15) exhibited more markedly shortened PFS (mPFS, 1.8 months versus 5.57 months; HR, 3.9; 95% CI, 1.5-9.6; p< 0.0001) and OS (mOS, 4.2 months versus 17.3 months; HR, 4.5; 95% CI, 1.5-13.2; p< 0.0001) compared to those patients with non-B62 supertype and TP53 wildtype (n = 26). Furthermore, gene expression levels of certain immune activation related pathways or markers (IFN-γ signature, cytolytic marker, etc.) in the patients with B62 supertype and without B44 supertype (n = 23) were statistically lower ( p< 0.05) than in those patients without B62 supertype (n = 62). Chi-square test revealed no correlation between HLA-B62 supertype and TP53 mutation, MSI status, tumor mutation burden (TMB) or PD-L1 expression. Conclusions: HLA-B62 supertype in combination with TP53 mutations may define a subset of gastrointestinal cancer patients who probably fail to benefit from ICIs, especially in MSS patients.
The dynamic change of cancer genome and T-cell receptor repertoire of an early gastric cancer cohort.
Authors: Li Zhuoran , Bai Jing , Wu Xi , Zhou Weixun , Xu Yaping , Yang Ling , Yang Aiming
Published: May 2020

e16553

Background: The dynamics of the cancer genome and T-cell receptor (TCR) repertoire are largely unclear during the development of gastric cancer, especially in the early stage. In this study, we studied the characteristics of genome and tumor microenvironment changes chronologically in 15 early gastric cancer (EGC) patients and illustrated their influence on carcinogenesis. Methods: 75 gastric tissues including precancerous lesions, cancer lesions and paired reference gastric samples, and 29 peripheral blood samples were obtained chronologically from 15 patients. All the lesions were categorized into 3 groups according to its pathology type (group1: inflammation or intestinal metaplasia, group 2: low-grade dysplasia (LGD), group 3: EGC). Deep sequencing of whole-exome and CDR3 chain of TCR of each sample was performed. Tumor mutation burden (TMB), TCR repertoire diversity and clonality were evaluated based on the sequencing data. Results: Heterogeneity existed in cancer genome and TCR repertoire among different patients. During carcinogenesis, TMB increased at first and then decreased, reaching its peak at LGD, which was different from what we have known from other advanced cancer. A detailed analysis showed that only part of the driver gene mutations maintained in this process. Compared with T cells infiltrated in reference samples, tumor-infiltrating T cells shared more clones with peripheral blood T cells. Diversity and clonality of TCR repertoire didn’t show significant change with the development of cancer (Shannon index: group 1 = 6.32, group 2 = 6.06, group 3 = 6.09, p = 0.836; Clonality: group 1 = 0.19, group 2 = 0.19, group 3 = 0.17, p = 0.374). Some CDR3 clones appeared in early-stage and maintained during the carcinogenesis process. Conclusions: Our research is the first to analyze the cancer genome and TCR repertoire changes from both the spatial and temporal perspectives during the development of early gastric cancer. Somatic mutations appeared in the very early stage of gastric cancer and may induce the immune microenvironment changes in gastric mucosa.