bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiopoietin-2 early increase to predict benefit from regorafenib in metastatic colorectal cancer (mCRC) patients: The prospective REGOLAND study.
Authors: Marmorino Federica , Antoniotti Carlotta , Boccaccino Alessandra , Antista Maria , Zaffaroni Nadia , Zucchelli Gemma , Martinetti Antonia , Campi Elisa , Rossini Daniele , Sottotetti Elisa , Borelli Beatrice , Corti Francesca , Conca Veronica , Moretto Roberto , Germani Marco Maria , Falcone Alfredo , Giordano Mirella , Masi Gianluca , Pietrantonio Filippo , Cremolini Chiara
Published: June 2021

e15566

Background: Regorafenib is a treatment option for refractory mCRC patients with no validated predictors of benefit. We previously showed that, among several circulating angiogenic factors, low baseline Ang-2 and Tie-2 plasma levels were associated with good prognosis and that the early increase of Ang-2 during the treatment could predict benefit from regorafenib ( Antoniotti et al, J Clin Oncol 36:675-675, 2018). To prospectively validate these retrospective findings, we conducted the REGOLAND study. Methods: Ang-2 and Tie-2 were assessed by ELISA on plasma samples collected at baseline (d1) and after 15 days (d15) of treatment in a cohort of mCRC patients receiving regorafenib, as per indication. To detect a HR for PFS of 0.50 in favour of the early increase (Δd15-d1) of Ang-2 levels, setting two-sided α = 0.05 and β = 0.10, 87 events were required according to Schoenfeld design. Comparisons among concentrations of each marker at d1 and d15 were performed by Wilcoxon test. Median values at baseline were used as cut-off to discriminate patients with low versus high plasma levels and their correlation with outcome was analysed. Results: One hundred patients were included. Median PFS and OS were 2.5 and 6.7 months, respectively. The early increase of Ang-2 at d15 was reported in 42 patients and was associated with longer PFS (median 2.7 vs 2.4 months; HR for PFS: 0.72 [95%CI:0.48-1.08], P = 0.095). As compared to d1, an overall decrease of Tie-2 levels at d15 was observed ( P = 0.007), but it was not associated with clinical outcome. Low levels of Ang-2 at baseline were associated with longer PFS (HR: 0.59 [95%CI:0.39-0.89], P = 0.005) and OS (HR:0.62 [95%CI:0.41-0.94], P = 0.017), while Tie-2 levels were not. In the multivariate model, the association of Ang-2 levels with PFS was confirmed (HR:0.48 [95%CI:0.31-0.76], P = 0.001), but not with OS (HR: 0.80 [95%CI:0.49-1.28], P = 0.351). Conclusions: Ang-2 is a prognostic marker and its early modulation predicts clinical benefit among mCRC patients treated with regorafenib. We hypothesize that Ang-2 levels early increase as a consequence of the successful inhibition of Tie-2 by regorafenib that leads to a compensatory increase of the ligand and correlates with anti-tumour activity.
FORECAST-1: Feasibility of organoid response assessment to define effective treatments for patients with colorectal cancer after failure of standard therapy.
Authors: Gard Grace , Lee Margaret , Hirokawa Yumiko , Tie Jeanne , Clarke Jordan , Tebbutt Niall C. , Tan Tao , Jalali Azim , Mouradov Dmitri , Lee Belinda , Sieber Oliver , Gibbs Peter
Published: June 2021

e15571

Background: Many patients with metastatic colorectal cancer (mCRC) that have failed standard first- and second-line therapies remain fit and eager for further treatment. Therapeutic options include two agents with proven but modest survival benefit, a clinical trial of an investigational agent, rechallenge with agents successfully used in earlier lines of treatment, or agents that have shown some activity in non-randomised phase II studies. Patient derived tumouroid (PDT) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. They potentially represent a robust personalized model for real-time drug sensitivity testing to determine optimal anti-cancer therapies for individual patients. Methods: FORECAST-1 is an observational, non-randomized study to determine the feasibility of PDT based drug sensitivity screening for patients with mCRC that have failed at least two lines of therapy. Once established, PDTs undergo drug sensitivity screening including agents regorafenib, trifluridine/tipiracil (TAS102), oxaliplatin, irinotecan, 5-fluorouracil (5FU), erlotinib (a surrogate EGFR-inhibitor), gemcitabine, pemetrexed and temozolomide. Patients are treated at clinician discretion, with clinical response to be correlated with PDT response. Results: Since September 2020 we have enrolled 18 of a planned 30 patients, median age 55 years (range 44 – 81). 17 patients were ECOG 0-1. Four patients had received prior TAS102 treatment. Biopsies were obtained from liver (n = 6), soft tissue/peritoneal metastases (5), lung (2), lymph node (2), primary (1), brain (1) and bone (1). Drug sensitivity testing has been performed on seven PDTs at a median of 62 days from biopsy (range 42 – 128), one PDT culture has failed. A standardised reporting template has been developed. Treatments received by patients to date include TAS102 (n = 5), regorafenib (2), FOLFOX (3), FOLFIRI (1) FOLFIRI plus EGFR-inhibitor (1), capecitabine plus bevacizumab (1) and an immunotherapy-based clinical trial (1). Four patients did not receive further anti-cancer therapy post enrolment, and one patient is yet to commence further systemic therapy. Conclusions: Enrolment to this feasibility study has been rapid demonstrating this to be an area of clinical need. PDTs have been successfully established from a high proportion of patients, but with variable growth rates. Methods to accelerate PDT culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDT sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.
Association of TP53 mutation with decreased prevalence of MSI-high, RAS and PI3KCA mutations in metastatic colorectal cancer.
Authors: Pan Minggui , Jiang Chen , Tse Pamela , Solorzano-Pinto Aleyda V , Chung Elaine , Truong Thach-Giao , Arora Amit , Sundaresan Tilak Kumar , Suga Jennifer Marie Marie , Habel Laurel A. , Thomas Sachdev P.
Published: June 2021

e15578

Background: TP53 tumor suppressor gene is mutated in approximately 50% of colorectal cancer (CRC). How TP53 mutations are associated with the prevalence of the other common genomic alterations such as RAS (KRAS/NRAS), BRAF, PI3KCA, as well as microsatellite stability (MSI) is not clear. Methods: We investigated the impact of TP53 mutations on other common genomic alterations and survival in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC). Results: From November 2017 to January 2021, genomic profiling was performed on 1056 patients with metastatic CRC, of whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). We found that median overall survival (OS) was similar between the TP53wt and TP53mut patients (50.1 vs 47.5 months, p = 0.9), however, the percent with a Ras mutation was significantly higher in patients with TP53wt compared to TP53mut (63.2 vs 45.2%, p = 0.0001). Interestingly, the percent with MSI-high was also significantly higher in TP53wt than TP53mut patients (11.1 vs 1.4%, p = 0.0001), however, the response rate of the MSI-high patients to immune checkpoint inhibitor (ICI) was similar (40 vs 37.5%). In addition, a significantly higher percent of patients with TP53wt had PI3KCA mutations and a significantly lower percent had c-Myc amplifications compared to patients with TP53mut (PI3KCA, 32 vs 10.7%, p = 0.0001; c-Myc, 1.26 vs 4.6%, p = 0.008). There was no significant difference in the percent of BRAF mutations between the two patient populations (6.2 vs 9.8%). A significantly higher percent of patients with TP53wt and a PI3KCA mutation had a Ras mutation compared to patients with TP53mut and a PI3KCA mutation (81.2 vs 57%, p = 0.0004). However, TP53 mutation status was not significantly associated with the OS of patients with either a Ras, or BRAF, or PI3KCA mutation, or combination of Ras and PI3KCA mutations. Conclusions: TP53 mutation is associated with decreased prevalence of Ras, PI3KCA mutation and MSI-high in patients with metastatic CRC, however, without impacting the OS or response rate to ICI.
A novel outpatient regimen in management of fluoropyrimidine-induced cardiotoxicity.
Authors: Kasi Anup , Gaudel Pramod , Bennett Joseph , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Baranda Joaquina Celebre , Sun Weijing , Porter Charles B.
Published: June 2021

e15613

Background: Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are commonly used chemotherapies for solid tumors, and essential for curative intent treatment of colorectal cancer. But sometimes, their use may be limited by cardiac toxicity limiting the possibility of cure in some patients. Cardiotoxicity could be asymptomatic (EKG changes) or manifested as chest pain, arrhythmias, acute coronary syndrome or death. Rechallenging may be daunting and it may result in interruption or even discontinuation of planned chemo. Traditionally, nitrates and/or IV/oral calcium channel blockers (CCB) have been used for management of fluoropyrimidine-induced cardiotoxicity but without much benefit. Ranolazine, an oral antianginal drug approved for chronic angina, diminishes myocardial ischemia by reducing calcium overload caused by inhibition of late sodium current and it does not affect heart rate or blood pressure. Our objective was to evaluate the efficacy of our novel approach using ranolazine with other traditional drugs. Methods: 8 patients (median age 49.5 yrs) with fluoropyrimidine induced cardiotoxicity were retrospectively analyzed. They were rechallenged with the planned fluoropyrimidine regimen with our 3 drug cardioprotective regimen (KU protocol). This included oral Ranolazine 1000mg BID and Amlodipine 2.5 mg daily to start the day before starting 5FU infusion/oral capecitabine and to continue it until the day after completion of infusion/treatment, and Nitroglycerin paste 1 inch every 6 hours starting before infusion and continue until it was completed. These meds were discontinued upon completion of chemo. Results: 8 patients were rechallenged with fluoropyrimidine utilizing KU protocol, 6 patients (75%) were able to complete previously planned fluoropyrimidine regimen. One pt (*) discontinued capecitabine due to recurrent chest pain and treatment was switched to 5FU based regimen with KU protocol, which pt was able to complete without chest pain. Another pt (**), 5FU was stopped due to severe diarrhea, not due to cardiotoxicity. All pts tolerated KU protocol well. Conclusions: In our small, single center experience, we were able to safely and effectively rechallenge pts with fluoropyrimidines and complete curative intent treatment with our KU protocol. This protocol uses FDA approved oral and transcutaneous drugs without requiring a healthcare personnel to administer an IV CCB that can cause precipitous bradycardia and/or hypotension. Our results need validation in a larger cohort. [Table: see text]
Adjuvant chemotherapy for gastric cancer patients with mismatch repair deficiency or microsatellite instability.
Authors: Nie Run-Cong , Yuan Shu-Qiang , Kim Jin Won , Wang Yun , Chen Guoming , Zhou Jie , Chen Yingbo , Chen Yingbo , Zhou Zhiwei , Cai Muyan , Li Yuanfang
Published: June 2021

e16004

Background: Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) serves as a predictor poor response to adjuvant chemotherapy in stage II colon cancer patients. Our objective was to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). Methods: We searched literatures through December, 2020 to identify clinical studies that reported survival comparing adjuvant chemotherapy with surgery alone in dMMR/MSI-H GCs. Two approaches were used to pool the hazard ratio (HR) of survival: (1) If Kaplan-Meier curves and number at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. Results: Six clinical studies were identified. For dMMR/MSI-H versus mismatch repair proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L), the estimated 5-years DFS were 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P < 0.001); the estimated 5-years OS were 60.8% versus 50.1% (HR, 0.72; 95% CI, 0.60-0.88; P = 0.001). At study-level data, the pooled HRs were 0.42 for DFS (95% CI, 0.31-0.57; P < 0.001) and 0.66 for OS (95% CI, 0.32-1.38; P = 0.268). For adjuvant chemotherapy versus observation in dMMR/MSI-H, the estimated 5-years DFS were 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171); the estimated 5-years OS were 74.9% versus 60.2% (HR, 0.60; 95% CI, 0.44-0.83; P = 0.001). Significant survival differences were also observed at study-level. Conclusions: This study further suggested adjuvant chemotherapy could be beneficial even in dMMR/MSI-H GC patients.
A phase 1b multicenter study of trifluridine/tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients (pts) with metastatic or unresectable gastric and gastroesophageal adenocarcinoma (mGEC) after at least one line of treatment with a fluoropyrimidine and platinum (FP) containing regimen.
Authors: Dayyani Farshid , Tam Kit Wah , Kim Edward Jae-Hoon , Ejadi Samuel , Lee Fa Chyi , Valerin Jennifer B. , Taylor Thomas H. , Cho May Thet
Published: June 2021

e16006

Background: FTD/TPI, an antimetabolite, is approved for treatment of refractory mGEC. This study sought to determine whether the combination of FTD/TPI with IRI (“TASIRI”) was safe and effective in mGEC previously treated with FP. Methods: This investigator‐initiated, multicenter, open‐label, single-dose level, single‐arm phase 1b study enrolled pts with mGEC previously treated with at least one line of FP containing regimen. FTD/TPI was given at 25 mg/m2 twice daily on days 1 to 5 with 180 mg/m2 IRI on day 1 of a 14‐day cycle. The primary endpoint was progression-free survival at six months (mo) (PFS-6). The aim was to show an improvement of PFS-6 from 15% to at least 30% based on historical controls. Results: At the time of data-cutoff (03Feb2021), 23 pts were screened and ultimately 20 pts were treated. The study met its primary endpoint. With a median follow-up of 9.8 mo (range 0.7 – 17), 8 pts are still on treatment and 4 pts have died. PFS-6 is 53.9% (lower limit of 95% CI: 28%). Median PFS and overall survival are 6.9 mo and not reached, respectively. At the time of data-cutoff, data were available for 13 pts with measurable disease by RECIST criteria and at least 1 on-treatment scan. Of those, 11 had stable disease and 2 had progressive disease as best response (5 pts had tumor shrinkage < 30%), therefore the disease control rate was 84.6%. The most common any grade (G) treatment related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (17%) and neutropenia (9%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. Conclusions: The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls. TASIRI was well tolerated and no new safety signals were seen. TASIRI warrants further investigation for patients with refractory mGEC and limited treatment options. Updated results with longer follow-up will be presented at the meeting. Clinical trial information: NCT04074343.
Preoperative chemotherapy combined with PD-1 inhibitor in locally advanced operable or potentially resectable esophageal squamous cell carcinoma: A real world study.
Authors: Wu Puyuan , Wang Tao , Chen Baojun , Shi Minke , Zhou Yong , Huang Bin , Wu Nandie , Qi Liang , Wang Lifeng , Wei Jia , Liu Baorui , Ren Wei
Published: June 2021

e16010

Background: Preoperative therapy of esophageal squamous cell carcinoma (ESCC) is stepping into the era of combined therapy with PD-1 inhibitor after the success of PD-1 antibodies in the first-line and second-line treatment for advanced ESCC. This single center study retrospectively analyzed the efficacy and safety of preoperative chemotherapy combined with PD-1 antibody in patients with locally advanced operable or potentially resectable ESCC in the real world. Methods: The study enrolled operable or potentially resectable locally advanced ESCC patients treated with preoperative chemotherapy combined with PD-1 inhibitor in our center from April 2020 to December 2020. The treatment regimen were 2 to 4 cycles of paclitaxel liposome (135̃175 mg/m2) or albumin paclitaxel (180mg/m2) plus nedaplatin (75mg/m2) or lobaplatin (30mg/m2) combined with PD-1 inhibitors (toripalimab 13/20, sintilimab 3/20, pembrolizumab 2/20, camrelizumab 1/20, tislelizumab 1/20) with standard therapeutic dose followed by tumor response assessment and surgery. The primary end point were safety, tumor response and complete pathological response (pCR) rate. Results: A total of 20 patients including 17 males and 3 females, of which median age was 65 and 85% were stage III-IVA (AJCC 8th), were included in the study. Of all the patients, 18 patients accomplished 2 cycles of therapy and had safety assessment, 13 patients underwent surgery, 2 patients were waiting for operations and 2 patients achieving partial response rejected surgery and were prepared for radical chemoradiotherapy. Treatment-related adverse events exceeding grade 3 levels included leukopenia 5.6% (1/18), neutropenia 16.7% (3/18), thrombocytopenia 5.6% (1/18), and immune hepatitis 5.6% (1/18). There was no severe surgery-related complication. Objective response rate (ORR) was 70.6% (12/17), and disease control rate (DCR) was 100% (17/17). R0 resection rate was 92.3% (12/13), the pCR rate was 15.4% (2/13), and 61.5% (8/13) of the patients had downstaged to the ypT1-2N0M0 I stage. One patient finally reached a pCR after switching to preoperative chemoradiotherapy because of progression after treatment of chemotherapy and PD-1 inhibitor. Conclusions: Preoperative chemotherapy combined PD-1 inhibitor treatment was well tolerated and had high efficacy in locally advanced operable and potential resectable ESCC. Since the study included some potentially resectable patients with late staging, the pCR rate may be lowered. The further study aims to find the efficient biomarker including PD-L1 expression and CD8+ T cell infiltration. Moreover, well-designed randomized prospective trials for better evidence are required.
The microbial characteristics of patients with esophageal squamous cell carcinoma before and after immunotherapy.
Authors: Zuo Jing , Lv Wenjing , Wang Yudong , Fan Zhisong , Feng Li , Wang Long , Zhang Xue , Han Jing , Jiang Da
Published: June 2021

e16016

Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Immune checkpoint–oriented immunotherapies have shown considerable promise and the advent of esophageal microbiome provides researchers with new ideas. Methods: DNA was extracted from blood, oral mucosal, saliva, urine, fecal samples from 20 ESCC patients before and after immunotherapy. Total microbial genomic DNA samples were extracted using an OMEGA Soil DNA Kit (D5625-01). The V3–V4 regions of bacterial 16S rRNA genes were amplified by PCR using the forward primer and the reverse primer and were sequenced with Illumina MiSeq platform. In order to comprehensively evaluate the α diversity of microbial communities, we used Chao1 and Observed Species indices to characterize the richness, Shannon and Simpson indices to characterize the diversity. PCoA were used to analyze differences in β diversity. Functions of 16S rRNA sequences were predicted using the PICRUSt2 and KEGG databases. Results: A comparison of blood, oral mucosal, saliva, urine, fecal samples of ESCC patients before and after immunotherapy showed that α diversity was not statistically significant. In terms of β diversity, no statistically significant differences were detected within blood, oral mucosal, saliva, urine, fecal samples of ESCC patients before and after immunotherapy. In ESCC patients treated before immunotherapy, the α diversity and β diversity of blood, oral mucosal, saliva, urine, fecal samples were different, and in ESCC patients treated after immunotherapy had the same rule. At the phylum level, the top 5 microbes in ESCC patients before and after immunotherapy were Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria. At the genus level, the top 5 microbes in ESCC patients before immunotherapy were Aquabacterium, Streptococcus, Prevotella, Veillonella, Bacteroides, and in ESCC patients after immunotherapy were Aquabacterium, Streptococcus, Prevotella, Faecalibacterium, Veillonella. In terms of the microbial functions in ESCC patients before and after immunotherapy, the metabolic pathways accounted for the most. Conclusions: This study is conducive to exploring new mechanisms for tumor cells to evade host immune surveillance, providing new ideas and new strategies for the microecology-based immunotherapy of ESCC.
Camrelizumab combined with SOX regimen in the first-line treatment of unresectable advanced or recurrent gastric cancer: A single-arm, prospective, open clinical study.
Authors: Han Zhengxiang
Published: June 2021

e16017

Camrelizumab combined with SOX regimen in the first-line treatment of unresectable advanced or recurrent gastric cancer£ºA single-arm, prospective, open clinical study. Background: Gastric cancer is one of the most common malignant tumors of the digestive system. In China, 80% of patients with gastric cancer are already in advanced or locally advanced stage at the time of detection. Even after receiving radical gastrectomy, more than half of patients will have local recurrence or distant metastasis, and the 5-year survival rate of patients with gastric cancer with metastasis is less than 10%.In recent years, more and more evidence supports the application of immune checkpoint inhibitors in advanced gastric cancer.In 2020, PD-1 was approved for advanced gastric cancer receiving second-line or above treatment in China, which is an affirming of the efficacy of PD-1 in the clinical treatment of gastric cancer. Immunotherapy combined with conventional chemotherapy, this study aims to explore the efficacy and safety of PD1 combined with chemotherapy in the treatment of first-line gastric cancer. Methods: This was a single center, prospective clinical study conducted at the Affiliated Hospital of Xuzhou Medical University, Jiangsu Province.Patients with newly treated unresectable advanced or recurrent gastric or gastroesophageal junction adenocarcinoma were enrolled.All enrolled subjects were treated with camrelizumab combined with SOX regimen every 3 weeks.The primary endpoint was progression-free survival (PFS).Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.This study was registered at Chictr.org.cn with the number Chictr2000029691. Results: The study plans to enroll 30 patients, and 16 patients have been included in the study from March 2020 to December 2020. Among them, 7 patients can be evaluated, 14 males, 2 females, ECOG score 0 or 1. Of the 7 patients who can be evaluated for efficacy, 1 achieved PR and 5 achieved SD, ORR was 14.29%, and DCR was 85.71 %. This is the early stage of data analysis, PFS has not yet reached, and the side effects are mild, mainly with grade 1 adverse reactions. The most common AEs are neutropenia (3/7) and decreased appetite (2/7). There were no treatment-related deaths. Conclusions: This study provides preliminary evidence for the first-line treatment of unresectable advanced or recurrent gastric or gastroesophageal junction adenocarcinoma with camrelizumab combined with chemotherapy. The current number of enrolled cases is small, but the preliminary effect of immunotherapy combined with chemotherapy in first-line patients with advanced gastric cancer can still be seen. This trial will further explore the clinical efficacy and safety of immunotherapy in the first-line gastric cancer. Clinical trial information: ChiCTR2000029691.
Molecular characterization of amplification of 11q13 region in patients with operable esophageal squamous cell carcinoma.
Authors: Liu Shuoyan , Wang Feng , Wang Peiyuan , Chen Yujie , Chen Peng , He Hao , Chen Xiaofeng , Zhang Derong , Shi Jialong
Published: June 2021

e16053

Background: The efficacy of programmed cell death 1 (PD-1) targeted therapy had showed effective treatment in patients (pts) with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). Meanwhile some studies have shown that PD-1 as neoadjuvant therapy showed promising anti-tumor activity with acceptable tolerance for locally advanced ESCC. Previous studies have shown genomic amplification of 11q13 region may serve as a negative predictive marker for ESCC patients receiving anti-PD-1 based immunotherapy. However, related molecular characterization study of amplification of 11q13 region in patients with operable ESCC is rare reported. Methods: The study recruited pts with operable ESCC whose tissues were send to perform target-capture deep sequencing with the pan-cancer panel and immunohistochemistry of PD-L1 with 22C3 assay. Pair-wise comparison of TMB and PD-L1 was analyzed in pts with 11q13 amplification and pts without 11q13 amplification. Results: 58 operable ESCC pts (cT1-T3N0) were enrolled, median age at diagnosis was 63 years(yrs) (45-73). Copy number analysis identified 30 out of 58 (52%) patients with amplifications of four genes located in chromosome 11q13 region, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Among the 11q13 amplification cohort, four genes amplified together were occurred in 27(90%) pts, 1(3%) patient had amplification of three genes ( CCND1 and FGF3/4), 2 (7%) pts had amplification of one gene that are FGF3 and CCND1 respectively. The prevalence rate of 11q13 amplification was not significantly different between older age (≥ 63 yrs) and young age ( < 63 yrs). Among 58 pts with TMB evaluated, median TMB was 5.76 muts/Mb (range: 0 - 20.16 muts/Mb). The prevalence of TMB-H and microsatellite instability was 12% (7/58) and 0% (0/58). TMB and expression of PD-L1 showed no significantly difference between 11q13 amplification cohort and 11q13 wild cohort. The most frequently mutated genes were TP53 (96.7%, 29/30 pts), NOTCH1 (33.3%, 10/30 pts), CDKN2A (23.3%, 7/30 pts) and MLL2 (20%, 6/30 pts) in 11q13 amplification cohort, while TP53 (89.3%, 25/28), NOTCH1 (39.3%,11/28), MLL2 (28.6%, 8/28), FAT1 (25%,7/28) were the most frequently mutated genes in 11q13 wild cohort. Conclusions: Amplification of 11q13 region was a high prevalence event in operable ESCC and there was show no age bias. Molecular characterization of amplification of 11q13 region in patients receiving PD-1 as neoadjuvant therapy before surgery may be meaningful.
Prevalence-adjusted trends in U.S. healthcare spending on upper gastrointestinal cancers, 1996 to 2016.
Authors: Stukalin Igor , Ahmed Newaz Shubidito , Fundytus Adam Michael , Singh Siddharth , Ma Christopher
Published: June 2021

e16064

Background: Upper gastrointestinal cancers are rising in prevalence and associated with high healthcare costs. We estimated trends in the US healthcare spending in patients with esophageal and stomach cancer between 1996 and 2016. Methods: We used data on national healthcare spending developed by the Institute for Health Metrics and Evaluations Disease Expenditure Project. Corresponding prevalence of esophageal and stomach cancer was estimated from the Global Burden of Diseases Study. Prevalence-adjusted, temporal trends in the US healthcare spending in patients with upper gastrointestinal cancer, stratified by age and setting of care (ambulatory, inpatient, emergency department, pharmaceutical prescriptions, nursing care and government administration) were calculated using joinpoint regression, expressed as annual percent change (APC) with 95% confidence intervals. Results: Overall, annual US healthcare spending on esophageal cancer increased from $0.76 billion (95% CI 0.68-0.86) in 1996 to $1.06 billion (95% CI 0.88-1.29) in 2016, although after adjusting for increasing prevalence, there was a significant decrease in per capita spending of -0.4%/year (95% CI -0.7%, -0.1%). Annual US healthcare spending on stomach cancer increased from $1.23 billion (95% CI $1.14 billion - $1.34 billion) in 1996 to $1.49 billion (95% CI $1.20 billion - $2.03 billion) in 2016. Per capita spending increased by 1.8%/year (95% CI 1.4%, 2.1%) between 1996 and 2011, followed by a decrease in gastric cancer-related per capita spending after 2011 (APC -4.4%/year [95% CI -5.8%, -2.9%]). Inpatient care was the largest contributor to total cost of both cancers between 1996-2016: 61.9% for esophageal cancer and 73.1% in gastric cancer in 2016. The rising price and intensity of care (defined as the cost per encounter) was the largest driver of change from 1996-2016 for both cancers, accounting for $0.28 billion (95% CI 0.12-0.41) for esophageal cancer and $0.95 billion (95% CI 0.41-1.39) for stomach cancer. Conclusions: After adjusting for rising prevalence, US per capita healthcare spending on esophageal cancer has decreased significantly since 1996, while per capita spending on gastric cancer has remained stable. Inpatient care was the most significant contributor to costs for both cancers over the time period studied.
Prognostic value of subclassification of pT2 stage in patients with gastric cancer.
Authors: He Kang , Wang Xiaohua , Chen Cheng , Jiang Yingying , Shi Yue , Chen Qianying , Zhu Jingni , Sun Yan , Zhou Guoren , Lu Jianwei
Published: June 2021

e16070

Background: The data about prognosis difference of patients with pT2 stage gastric cancer (GC) after radical surgery is diverse. The latest TNM staging system does not define details for the pT2 stage subclassification. The purpose of this study is to investigate the survival difference according to depth of tumor muscularis propria involvement and find biomarker to reinforce the prognostic and therapy-guided ability of TNM staging system. Methods: A total of 380 patients with pT2 GC after radical surgery were retrospectively analyzed, including 185 in sMP (superficial muscularis propria) group and 195 in dMP (deep muscularis propria) group. The log-rank test was used to identify survival outcomes. Independent factors were identified by multivariable Cox proportional hazard model for OS. Results: The overall survival (OS) of patients in sMP group was significantly better than patients in dMP group (P = 0.007). On multivariate analysis, age (＜60 vs ≥60: P = 0.004, HR, 2.075(95%CI: 1.261-3.414)), primary location (P = 0.002, U vs M: 0.985(0.509-1.909); U vs L: 0.400(0.235-0.680)), depth of tumor invasion (sMP vs dMP: P = 0.050, 1.584(1.261-3.414), pN stage (P = 0.000, N0 vs N1: 2.304(1.364-3.890); N0 vs N2: 1.879(0.967-3.652); N0 vs N3: 5.335(2.533-11.237)), expression of p53 (negative vs positive: P = 0.016, 1.793(1.117-2.879)) were independent prognostic factors for the OS. In pN0 stage tumor, the sMP group had a significantly better OS than the dMP group (P = 0.014). When classified as N+, there was no obviously difference of OS between two groups (P = 0.384). When patients were stratified according to the depth of tumor invasion and pN stage, the OS was not significant difference between dMPN0 group and sMPN1-2 group (P = 0.100), the OS of patients with adjuvant chemotherapy were statistically better than those without in dMPN0 group (P = 0.045), but not significance in sMPN1-2 group (P = 0.486). After further grouping according to adjuvant chemotherapy status, in comparison to sMPN1-2 patients, dMPN0 patients with adjuvant chemotherapy had better OS (P = 0.015), but not significance in patients without (P = 0.599). Upon stratification according to the expression of p53, in p53-positive group, greater OS could be observed in patients with sMPN0 than patients with dMPN0 (P = 0.002). Similar OS could be seen between dMPN0 patients with p53-positive and T2N1-2 patients (P = 0.872). Conclusions: For pT2 gastric cancer patients, there were differences in survival outcomes for sMP and dMP invasion. The prognosis of dMPN0 patients were similar to patients with sMPN1-2, and dMPN0 patients who accepted adjuvant chemotherapy had an improved prognosis than those without. Appropriate adjuvant chemotherapy should be considered for patients with dMPN0 stage. In addition, positive expression of p53 could be potential factors to identify the different prognoses for patients with pT2 gastric cancers.
Cost-effectiveness analysis of gastric cancer management using perioperative chemotherapy versus adjuvant chemoradiation therapy.
Authors: Prasath Vishnu , Quinn Patrick L. , Oliver Joseph B. , Mahmoud Omar , Jaloudi Mohammed , Akkaraju Vikas , Arjani Simran , Ahlawat Sushil , Chokshi Ravi
Published: June 2021

e16079

Background: The most commonly used treatment options for gastric cancer include complete resection with adequate margins with either perioperative chemotherapy (PCT) or adjuvant chemoradiotherapy (CRT). While both treatment strategies have shown superiority over surgical resection alone, it is not clear which treatment strategy is more optimal. Methods: Our decision tree model was built to analyze the survival and costs associated with the two major management methods: perioperative chemotherapy and adjuvant chemoradiation therapy. Costs were obtained from Medicare reimbursement rates using a third-party payer perspective. Our model’s effectiveness was represented using quality-adjusted life years (QALYs). Our analysis tested the robustness of our conclusions by utilizing one-way, two-way, and probabilistic sensitivity analyses. Results: PCT was the preferred treatment strategy for diagnosed gastric cancer over CRT, with a cost of $54,326.10 and 4.08 QALYs. CRT was the costliest economic strategy with a cost of $77,987.52 and 4.28 QALYs and an ICER of 115,907.48. We set a threshold of $100,000 per QALYs gained which CRT surpassed making PCT the preferred treatment modality. Over 100,000 simulations, 51.4% of simulations favored PCT. CRT became favored when CRT non-curative procedure rates rose 3% higher than PCT non-curative procedure rates and when PCT complication rates rose 15% higher than CRT complication rates. Conclusions: In our simulated patients with diagnosed gastric cancer, the most cost-effective treatment strategy was PCT. We see cost-effectiveness alternating to favor CRT with changes in non-curative procedure rates and adjuvant therapy complication rates.[Table: see text]
Contemporary trends and survival outcomes of females with esophageal cancer in the United States.
Authors: Baumrucker Camille , Remer Lindsay , Franceschi Dido , Livingstone Alan S , Macedo Francis Igor
Published: June 2021

e16100

Background: Esophageal cancer (EC) is historically a male dominant disease. Current evidence on the impact of gender on clinical presentation and survival outcomes of EC is limited by small sample size or single institution series. Methods: Patients with EC (stage I-III) were identified in the NCDB (2004-2016). Clinicopathologic and treatment characteristics of male and female patients were compared using Chi-square analysis. Kaplan-Meier and Cox multivariable regression were used to estimate overall survival (OS). Results: Of 62,893 patients included, most patients were male (77.7%). Adenocarcinoma was the most common subtype (66.7%). Squamous cell carcinoma was more predominant in females (57.1% vs. 26.5%, p<0.001). Females were older (68.5 vs. 66.1 yrs; p<0.001) and more likely African American (AA, 14% vs. 8.1%; p<0.001). Females presented with more local disease (stage I, 19.6% vs. 18.2%; p<0.001) while males presented with more locoregional disease (LRD, stage II/III, 80.4% vs 81.8%, p<0.001). Of those with LRD, females less frequently received chemotherapy (CT, 75.4% vs. 82.9%, p<0.001), radiation therapy (RT, 78.9% vs. 82.6%, p<0.001), and esophagectomy (EG, 28% vs. 40.5%, p<0.001). White females with LRD received less CT (76.2% vs. 83.9%, p<0.001), RT (79.5% vs. 83.3%, p<0.001), and EG (30.6% vs. 43.5%, p<0.001). AA females with LRD received less CT (71.9% vs. 75.2%, p=0.013) and RT (77.4% vs. 80.5%, p=0.013) but had similar rates of EG as AA males (p=0.476). Females had worse OS than males (18.1 vs. 19.7mo, p=0.001; cI: 23.5 vs. 31.9mo, p<0.001; LRD: 17.2 vs 18.3mo, p=0.473). White females had worse OS than white males (18.6 vs. 20.4mo, p<0.001) while AA females had better OS (13.5 vs. 12.6mo, p=0.001). White females who underwent EG had improved OS over white males (47.6 vs 38mo, p<0.001) while AA males and females who underwent EG had similar OS (p=0.473). Female gender, older age, AA race, high comorbidity score and clinical stage, and lack of access to CT, RT, and EG were independent predictors of mortality (Table 1). Conclusions: Females with EC seem to have less access to CT, RT, and EG with worse OS than males. Healthcare policies should focus on increasing access to standard treatments for female patients with EC.[Table: see text]
Liver regeneration after radiotherapy in patients with hepatocellular carcinoma: A simple-to-use model and nomogram.
Authors: Su Ting-Shi , Li Li-Qing , Liang Shi-Xiong
Published: June 2021

e16115

Background: In the past clinical practice of radiotherapy for liver cancer, liver regeneration (LR) which is beneficial to the prevention or recovery of radiation-induced liver injury, has not received enough attention. In current study, we aimed to build and validate multivariate model for liver regeneration after radiation therapy for hepatocellular carcinoma (HCC) based on data from 2 prospective studies. Methods: Thirty patients treated with preoperative downstaging radiotherapy were prospectively included in the training cohort, and 21 patients treated with postoperative adjuvant radiotherapy were included in the validation cohort. Liver regeneration was defined as an increase of more than 10% of normal liver volume in the areas of the protected hepatic segment or lobe, without Child-Pugh class decreased and tumor progression compared to pre-radiotherapy. Model and nomogram of liver regeneration after radiotherapy were developed and validated. The cut-off points of each optimal predictors were obtained using receiver-operating characteristic analysis. Risk stratification based on the cut-off point was conducted to compare the proportion of patients with liver regeneration between subgroups. Results: After radiotherapy, 12 (40%) cases in the training cohort and 13 (61.9%) cases in the validation cohort experienced liver regeneration. The model and nomogram of liver regeneration based on SVs20 (standard residual liver volume spared from at least 20 Gy) and alanine aminotransferase (ALT) showed good prediction performance (AUC = 0.759) in training cohort and performed well (AUC = 0.808) in the validation cohort. The risk stratification according to the cutoffs of SVs20 with 303.4 mL and ALT with 43 U/L demonstrated clear differentiation in risk of liver regeneration between the training(P = 0.049) and entire cohort (P = 0.032). The proportion of patients with liver regeneration decrease progressively with 88.9% in high-probability group (ALT＜43 U/L and SVs20＜303.4 mL), 60% in high-intermediate probability group (ALT ≥43 U/L and SVs20＜303.4 mL), 43.75% in low-intermediate probability group (ALT＜43 U/L and SVs20≥303.4 mL) and 33% in low- probability group (ALT≥43 U/L and SVs20≥303.4 mL). Conclusions: SVs20 and ALT are optimal predictors for liver regeneration. This simple-to-use nomogram is beneficial to the constraints of normal liver outside the radiotherapy target area and make prognosis-based decision without complex calculations. Clinical trial information: ChiCTR1800015350. [Table: see text]
Sintilimab plus anlotinib as first-line therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: Chen Xiaofeng , Li Wei , Wu Xiaofeng , Zhao Fengjiao , Wang Deqiang , Wu Hao , Gu Yanhong , Li Xiao , Qian Xiaofeng , Hu Jun , Li Changxian , Xia Yongxiang , Rao Jianhua , Yao Aihua , Seesaha Poshita kumari , Shao Qianwen , Dong XiaoWei , Li Xiangcheng , Shu Yongqian
Published: June 2021

e16146

Background: The synergic combination of anti-PD-1/PD-L1 and antiangiogenic agents has exhibited as an encourage treatment pattern in aHCC. Multi-targeted antiangiogenic TKIs, such as lenvatinib and sorafenib, are approved for 1st-line treatment of aHCC. Sintilimab, a novel selective anti-PD-1 monoclonal antibody, has demonstrated encouraging clinical activities in aHCC. The trial aims to explore the safety and efficacy of sintilimab plus anlotinib (a TKI against angiogenesis) in aHCC. Methods: This is a single-arm phase 2 study. Eligible Pts with aHCC, BCLC stage C or B (not amenable for surgery and chemoembolization), Child-Pugh scores≤7 and ECOG PS ≤ 1 received 1st-line treatment of sintilimab (200mg, iv, D1) plus anlotinib (12mg, po, QD, D1-14) every 3 wks until disease progression or unacceptable toxicity. Primary endpoints were safety and objective response rate (ORR, per RECIST 1.1), and secondary endpoints included disease control rate (DCR), progression free survival (PFS), duration of response (DOR) and overall survival (OS). Results: As of January 15, 2021, 20 pts were enrolled (males 18 ; median age 56 yrs [range 41-70] ; BCLCB/C: 5/15 ; Child-Pugh A/B7: 19/1 ; HBV infection 20). All pts received at least two cycles of treatments with median cycles 7.5 [range 2-22]. Median follow-up was 12 months [range 3-19]. The most common treatment-related adverse events (TRAEs) were grade 1-2 with thrombocytopenia (45.0%), hand-foot syndrome (40.0%), hypertension (35.0%), increased AST (35.0%), ALT (30.0%), decreased neutrophil count (25.0%), leukopenia (25.0%). 8 pts experienced manageable grade 3 TRAEs, and no grade 4/5. 12 pts required dose reduction of anlotinib (9 pts to 10 mg and 3 to 8 mg). No treatment withdraw caused by TRAEs. ORR was 40.0% (8/20) with 1 CR and 7 PR, 11 pts were SD, and DCR was 95.0% (19/20). Median DoR was not reached. 6m-PFS rate was 66.4% (95%CI: 47.7%-92.5%), immature median PFS was 14.65 months (95%CI: 5.06 -not reached) with 8 events. Conclusions: The combination of sintilimab and anlotinib showed promising clinical activities with manageable toxicity for first line treatment of aHCC. Clinical trial information: NCT04052152. Research Sponsor: Innovent Biologics, Inc., Chia-Tai Tianqing Pharmaceutical Group Co Ltd. Clinical trial information: NCT04052152.
177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with somatostatin-expressing neuroendocrine tumors: A real-world retrospective review of efficacy and safety from an Australian tertiary cancer Center.
Authors: Nalder Mark , Ladwa Rahul , Raina Anant , Burge Matthew E. , Love Amanda , Pattison David A. , Ramsay Stuart , Wyld David
Published: June 2021

e16198

Background: There is relatively limited data guiding optimal treatment algorithms for inoperable or metastatic neuroendocrine tumours (NETs). The randomised NETTER 1 study established PRRT as a standard of care in midgut NET. The aim of this study was to retrospectively review the efficacy and safety of patients treated with 177Lu-DOTATATE at Royal Brisbane and Women’s Hospital. Methods: Consecutive patients with unresectable or metastatic NET who received their first 177Lu-DOTATATE therapy between 2010 and 2017 were identified. Paragangliomas were excluded. Response rates, progression free survival (PFS) and overall survival (OS) were assessed via a combination of chart review, post-therapeutic 68Ga DOTATATE PET/CT and multi-disciplinary meeting decisions. Gr3/4 haematological and renal safety data was analysed via chart review. Progression free survival (PFS) and overall survival (OS) were assessed via the Kaplan-Meier method. Results: 123 consecutive patients were included in the analysis (57% male, median age 61). Primary site: 41% gastroenteric, 34% pancreatic, 10% lung, 6% colon/rectum, 9% other. Grade 1 (42%), Grade 2 (31%) Grade 3 (6%), unknown (21%). 76% of patients had previously received somatostatin analogues. 80% received four cycles (with persistent myelosuppression the most common cause of ceasing therapy early). 20% of patients received concurrent chemotherapy (10% capecitabine, 10% capecitabine and temozolomide). For the entire cohort, median follow up was 51 months. Median PFS, 34.2 months (95% CI, 30.3 – 38.17) and median OS, 61 months (95% CI, 54.2– 67.8). There was no significant difference in PFS or OS between small bowel and pancreatic patients. Response rates to PRRT included complete response (n = 4, 3%), stable or responding disease (n = 96, 78%), progressive disease (n = 22, 18%), not assessable (1, 1%). Grade 3 or 4 thrombocytopenia, neutropenia or anaemia occurred in less than 1% of patients. Confirmed acute leukaemia occurred in three patients. One patient had grade 3 renal toxicity secondary to treatment. 26 patients received retreatment with 177Lu-DOTATATE at progression with median time to re-treatment of 35 months. Conclusions: This single centre, retrospective audit confirms the efficacy of 177Lu-DOTATATE in the treatment of unresectable and metastatic NETs. Treatment was associated with low rates of severe haematological or renal adverse events. Our results are comparable to similar published reviews.
Correlation of NFE2L2 mutation with higher tumor mutation burden (TMB), microsatellite instability (MSI) and PD-L1 expression in 3,716 cases of Chinese pan-cancer.
Authors: Wu Bin , Li Aijun , Chen Keji , Chen Lin , Zhang Qin , Duan Qianqian , Xiao Mingzhe , Li Mengmeng
Published: June 2021

e16211

Background: Nuclear factor E2-related factor-2 (NFE2L2) gene encodes a transcription factor which is a member of basic leucine zipper (bZIP) proteins family. Overexpression of NFE2L2 lead to cell proliferation and promoted tumor metastasis. Previous report indicated that NFE2L2 mutation (NFE2L2-MT) was an independent poor prognostic factor in esophageal squamous cell carcinoma (ESCC). However, the correlation between NFE2L2 mutation and pan-cancer types of TMB, MSI, and PD-L1 expression is unclear. Methods: TMB analysis was performed in 3,716 Chinese pan-cancer patients who underwent NGS sequencing using a 539 gene panel. The TMB calculation included synonymous and nonsynonymous mutations and InDels. MSI analysis was performed in 3,110 patients. MSI-H was defined as above 10% positive of the 195 tested microsatellites sites. The PD-L1 expression analysis was performed in 3,415 patients with immunohistochemistry staining (IHC) by antibody SP263. PD-L1 positive was defined as greater than or equal to 1%. The statistical correlation was investigated using Chi-square analysis. TMB value was compared using Wilcoxon Rank Sum test. We used TCGA public database to verify the result. Results: The mutation frequency of NFE2L2 mutation was 2.66% (99/3716). The TOP 5 cancer types were liver cancer 3.53% (14/397), lung cancer 2.97% (42/1416), colorectal cancer 2.02% (7/347), gastric cancer 1.36% (3/221), soft tissue sarcoma 0.53% (1/189). NFE2L2-MT had a significant correlation with higher TMB (p = 2.2e-16), compared with NFE2L2 wild-type (NFE2L2-WT). Among 3110 samples with MSI status, the MSI-H percentage of NFE2L2-MT and NFE2L2-WT were 8.60% (8/93) and 1.33% (40/3017), respectively (p = 1.29e-7). In 3,415 patients with PD-L1 protein expression information, the PD-L1 positive percentage of NFE2L2-MT and NFE2L2-WT were 51.52% (51/99) and 61.9% (1,268/2,048), respectively. NFE2L2-WT has higher PD-L1 positive percentage than NFE2L2-MT (p = 0.01). NFE2L2-MT was significantly correlated with higher TMB and MSI when we used TCGA data to verify, p<0.0001. However, the survival analysis of 1661 MSKCC immunotherapy cohort showed that the median OS of NFE2L2-MT vs NFE2L2-WT was 21 months vs 18 months (p=0.858), but the difference was not significant. Conclusions: NFE2L2 mutation has a very significant correlation with higher TMB and MSI, but not related to PD-L1 expression. However, whether NFE2L2-MT is related to the efficacy of immunotherapy was still unclear and more clinical data were needed.