bluuebunny/crossref_metadata_2025 huggingface dataset:
First insights into the archaeometric analysis of the Los Amores Mosaic in Cástulo (Linares, Spain): the Judgement of Paris
Authors: Sánchez Alberto , Tuñón José , Montejo Manuel , Amate Pilar , Ceprián Bautista , Rousaki Anastasia , Costa Mafalda , Saelens Delphine , Lycke Sylvia , Vandenabeele Peter
Published: January 2021

This paper discusses results obtained from in situ analysis of the tesserae of the Roman mosaic of Los Amores (Cástulo site, Linares, Spain) dating back to the turn of the 1st to the 2nd century AD. Specifically, it focuses on the scene The Judgment of Paris. In view of the exceptional state of preservation of the mosaic, from which very few tesserae had fallen off, non-invasive methods with portable Micro Raman Spectroscopy (MRS) and hand-held X-ray fluorescence (hXRF) and data assessment by use of principal component analysis and binary representations were selected. The results obtained allow to evaluate both the analytical method and the portable equipment used, as well as to classify the raw materials, the colouring agents and the opacifiers used. MRS analysis proved crucial for the identification of stone tesserae (ironstones, carbonate and siliciclastic rocks) and for the identification of the type of glasses used (soda-lime-silicate and lead type glasses) based on the analysis of two detached tesserae. hXRF analysis of the glass tesserae identified both colouring agents (Co, Cu, Pb, Zn) and opacifiers (calcium antimonate). The data obtained lend themselves to an assessment of the degradation process that threaten the integrity of the mosaic. The identification of tessera made of specific stone materials (especially ironstone) and of lead glass tesserae suggest the existence of a mosaic workshop in the Upper Guadalquivir (Eastern Andalusia, Spain).
Evaluation of the contribution of tropical cyclone seeds to changes in tropical cyclone frequency due to global warming in high-resolution multi-model ensemble simulations
Authors: Yamada Yohei , Kodama Chihiro , Satoh Masaki , Sugi Masato , Roberts Malcolm J. , Mizuta Ryo , Noda Akira T. , Nasuno Tomoe , Nakano Masuo , Vidale Pier Luigi
Published: January 2021

Previous projections of the frequency of tropical cyclone genesis due to global warming, even in terms of sign of the change, depends on the chosen model simulation. Here, we systematically examine projected changes in tropical cyclones using six global atmospheric models with medium-to-high horizontal resolutions included in the sixth phase of the Coupled Model Intercomparison Project/High-Resolution Model Intercomparison Project. Changes in the frequency of tropical cyclone genesis could be broken down into the contributions from (i) the tropical cyclone seed, a depression having a closed contour of sea level pressure with a warm core and (ii) the survival rate, the ratio of the frequency of tropical cyclone genesis to that of tropical cyclone seeds. The multi-model ensemble mean indicates that tropical cyclone genesis frequencies are significantly decreased during the period 1990–2049, which is attributable to changes in tropical cyclone seeds. Analysis of the individual models shows that although most models project a more or less decreasing trend in tropical cyclone genesis frequencies and seeds, the survival rate also contributes to the result in some models. The present study indicates the usefulness of decomposition into the frequency of the tropical cyclone seeds and the survival rate to understand the cause of uncertainty in projected frequencies of tropical cyclone genesis.
A hybrid metaheuristic for solving asymmetric distance-constrained vehicle routing problem
Authors: Ban Ha-Bang , Nguyen Phuong Khanh
Published: January 2021

The Asymmetric Distance-Constrained Vehicle Routing Problem (ADVRP) is NP-hard as it is a natural extension of the NP-hard Vehicle Routing Problem. In ADVRP problem, each customer is visited exactly once by a vehicle; every tour starts and ends at a depot; and the traveled distance by each vehicle is not allowed to exceed a predetermined limit. We propose a hybrid metaheuristic algorithm combining the Randomized Variable Neighborhood Search (RVNS) and the Tabu Search (TS) to solve the problem. The combination of multiple neighborhoods and tabu mechanism is used for their capacity to escape local optima while exploring the solution space. Furthermore, the intensification and diversification phases are also included to deliver optimized and diversified solutions. Extensive numerical experiments and comparisons with all the state-of-the-art algorithms show that the proposed method is highly competitive in terms of solution quality and computation time, providing new best solutions for a number of instances.
The aporia of refugee rights in a time of crises: the role of brokers in accessing refugee protection in transit and at the border
Authors: Riva Sara , Hoffstaedter Gerhard
Published: January 2021

Many refugees fleeing from persecution across borders, find navigating the refugee registration system extremely complicated. In many border spaces, destination or transit countries, the difficult registration processes and the lack of support services requires the intervention and support of many non-state actors. Over the past decades, neoliberal policies have increasingly relegated public responsibilities to the private sphere. In this vein, a range of organisations have been working with refugees to assist them access to their legal status. This paper seeks to critically examine on-the-ground practices of these individuals, international and local non-profit organisations—or brokers—in Malaysia and the United States of America. Using ethnographic fieldwork data from these two very disparate fieldsites—one a signatory of the Protocol to the Convention, the other a non-signatory country—we document shared difficulties, frustrations, opportunities and specific obstacles, strategies and tactics refugees and organisations deploy. Building on Hannah Arendt’s insights of an internal contradiction in the human rights framework, we point to a new aporia: Whilst there now exist international instruments to protect refugees, access to this framework and its protections is becoming ever more challenging. This means that those seeking asylum need the assistance and mediation of third-party organisations in order to access their rights. The struggle for recognition and protection thus is no longer about achieving universal rights, but rather on how vulnerable populations can access them.
Dynamics of dormancy regulation in ‘Sonata’ strawberry and its relation to flowering and runnering
Authors: Sønsteby Anita , Heide Ola M.
Published: January 2021

Background

Dormancy regulation in strawberry is a dynamic process that is causally interrelated with regulation of flowering. Interference between the two processes is therefore possible.

Methods

We studied dormancy control and its relation to flowering and runner formation in ‘Sonata’ strawberry under daylight phytotron conditions. Growth and flowering were observed in plants pretreated for 5 or 10 weeks at 10-h SD and 18-h LD at 6 and 18 ℃ and subsequently forced in a greenhouse in LD at 20 ℃ with and without previous chilling for 6 weeks at 2 ℃ in darkness.

Results

SD induced constrained leaf and inflorescence growth at both 6 and 18 ℃, while the typical strawberry semi-dormant condition was attained only by exposure to SD at 18 ℃ for 10 weeks, which also completely blocked runner formation. The constrained leaf and inflorescence growth observed in plants grown in SD at 18 ℃ were partially reversed by 6 weeks of chilling and gradually overcome in successively emerging leaves. While plants grown in LD at 18 ℃ for 10 weeks remained vegetative under subsequent forcing, they unexpectedly initiated flowers when subjected to chilling in darkness for 6 weeks before the forcing.

Conclusions

SD exposure at 18 ℃ constrained leaf and inflorescence growth in ‘Sonata’ strawberry, and when applied for 10 weeks, it induced the persistent semi-dormant state that is typical for strawberry. Transient growth constraints were also induced at 6 ℃ in both SD and LD, while the semi-dormant state was only attained by SD at the higher temperature. Flowering in complete darkness, which is known in both SD and LD plants, did also take place in ‘Sonata’ strawberry in response to chilling in the dark at 2 ℃ for 6 weeks. While the potential impact of the phenomenon seems limited for regulation of flowering in strawberry, we conclude that chilling in the dark at near-freezing temperature may substantially enhance flowering in marginally induced strawberry plants.
The case for cautious paternalism in the emergency management of patients with borderline personality disorder
Authors: Newton-Howes Giles
Published: January 2021

Principlism is the dominant ethical theory in modern medicine. Autonomy is ‘king’ of the principles espoused and operationalised in consent. Consent is the mechanism by which all medical interactions occur. In borderline personality disorder (BPD) there is often a diffuse sense of self, emotional instability and impulsivity that can lead to medically dangerous non-suicidal self-injury, acute medical intervention and then a withdrawal of consent while the potential threat to the person's well-being remains high. Claims of lack of capacity lack veracity, and simply acting against the patient's will may be illegal. Understanding the will and preferences of patients is a step forward, but it is not always possible in time-sensitive situations. A cautious paternalism is therefore warranted both to ensure the patient's well-being while being honest as to the reasons for this, and to possibly build epistemic trust between the medical system and the patient with BPD.
Chemoradiation-induced molecular alterations and associated outcomes in patients with rectal cancer.
Authors: Salem Mohamed E. , Yang Hsih-Te , Symanowski James Thomas , Puccini Alberto , Farhangfar Carol J. , El-Refai Sherif , King David , Kim Edward S.
Published: January 2021

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Background: Molecular changes and associated acquired resistance of rectal tumors following chemoradiotherapy (CRT) have not been well studied. We aimed to examine CRT-induced molecular changes and prognostic associations in rectal cancer patients (pts) undergoing preoperative CRT followed by surgery. Methods: A paired analysis using pre-CRT biopsies and the corresponding post-CRT resected tissues of rectal cancer patients undergoing preoperative CRT followed by surgery was performed. Pre- and post-CRT tumor samples underwent next-generation sequencing (NGS) by Tempus xT assay, which detects a panel of 596 gene mutations, including single nucleotide variants, insertions/deletions, copy number amplifications, and gene rearrangements. The cancer driver gene was detected based on positional clustering of gained mutations using OncodriveCLUST. The paired t-test was used to examine differences in tumor mutational burden (TMB) and microsatellite instability (MSI) between pre- and post-CRT samples. Results: In total, 61pts of median age 61yrs—75% white, 18% black, and 57% male—with localized rectal cancer were studied. NGS testing was performed in 57 pt tumor samples; 43 pts had pre-CRT samples, 48 pts had post-CRT samples, and 34 pts had paired samples. The most frequent genetic alterations seen in the 43 pre-CRT tumor samples were APC (37.2%), ARID1B (30.2%), KMT2C (30.2%), ZFXH3 (25.6%), FLT4 (20.9%), MLLT3 (20.9%), and TP53 (20.9%), whereas in the 48 post-CRT tumor samples, the most frequent mutations were APC (54.2%), TP53 (35.4%), KRAS (27.1%), MKI67 (25.0%), KMT2C (18.8%), APOB (14.6%), and CEBPA (12.5%). Comparing the pre- and post-CRT samples, no significant differences in TMB (median: 5.0 mut/MB vs. 3.3 mut/MB, p=0.922) or MSI status by NGS (p=0.069) were observed. Among the 34 pts with paired samples, 26.5% (9/34) relapsed, and 17.6% (6/34) died. When examining tumor mutation changes between pre- and post-CRT samples (table), the most common gained mutations were seen in APC (29.4% ), MKI67 (26.5% ), KTM2C (17.6%), and TP53 (17.67%); and most common losses were in ARID1B (26.5%), ZFHX3 (26.5%), FLT4 (21.0%) and GATA6 (21.0%). Of the gained mutations, OncodriveCLUST analysis showed that MKI67 potentially carries a driver mutation (pG866V) at exon 12 (p = 0.045), which exclusively existed in the two relapsed pts. Conclusions: Our data suggest that CRT did not alter MSI status nor the level of TMB. However, CRT did result in gained molecular alterations that could be responsible for treatment resistance and predict relapse. Gained MKI67 mutation may be a prognostic biomarker for relapse after CRT. Further prospective studies are needed to validate these findings. [Table: see text]
Tumor bulk as a prognostic biomarker and predictor of benefit from anti-EGFR therapy in patients with metastatic colorectal cancer: Analysis of 476 patients from the ARCAD Clinical Trials Program.
Authors: Weinberg Benjamin Adam , Rakez Manel , Chibaudel Benoist , Maughan Tim , Adams Richard , Zalcberg John Raymond , Grothey Axel , Yoshino Takayuki , Shi Qian , De Gramont Aimery , Deming Dustin A.
Published: January 2021

108

Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]
Epigenetic regulation of the Wnt-signaling pathway in CIMP-H BRAFV600E mCRC.
Authors: Lee Hey Min , Napolitano Stefania , Morris Van K. , Rai Kunal , Shen John Paul Y.C. , Davis Jennifer S. , Maru Dipen M. , Overman Michael J. , Wu Ji , Coker Oluwadara , Woods Melanie Nicole , Villarreal Oscar , Kopetz Scott
Published: January 2021

110

Background: BRAFV600E mutation identifies mCRC patients with poor prognosis with only little benefit from standard therapy. Analysis from TCGA revealed that 89% of BRAFV600E CRC tumors were associated with a high CpG island methylator phenotype (CIMP-H), which may result in epigenetic silencing of tumor suppressor genes, while only 29% of BRAF wild-type tumors are CIMP-H. In this study, we define key pathways regulated by global DNA hypermethylation in the context of BRAFV600E mutation. Methods: We analyzed the TCGA Illumina 450k array methylation datasets and RNA-sequencing datasets for 97 CIMP-H CRC tumors (27 BRAFV600E; 69 BRAF WT) identified by five universal CIMP annotations ( p14, p16, MLH1, MINT1, MINT2, MINT31). We defined differential methylation profile according to BRAF mutation status and calculated Spearman correlation between methylation and gene expression to identify CIMP-H BRAF-associated genes. Next, pathways enriched with CIMP-H BRAFV600E tumors were defined using PANTHER pathway analysis. Additionally, β-catenin IHC were conducted on 145 MD Anderson CRC patient samples and compared by CIMP and BRAF status. Results: BRAF mutation is associated with lower rates of APC mutation as has previously been shown (32%, 82%). We identified 6,097 differentially methylated probes by BRAF mutation status (FDR = 10-4), and as expected, our data suggests a higher methylation profile in BRAFV600E mutated tumors compared to BRAF WT. Intriguingly, CIMP-H BRAF-associated genes showed enrichment in the Wnt-signaling and cadherin signaling pathways ( p< 0.0001 (FDR < 0.0001)). Despite the epigenetic Wnt-signaling, nuclear β-catenin expression (as a measure of Wnt activity) in CIMP-H and BRAF tumors remains lower than for non-CIMP, and BRAF wild-type ( p= 0.0003 for comparison of CIMP). Conclusions: Genes under methylation regulation in the BRAF-mutant context showed enrichment in Wnt-signaling pathway. Since BRAFV600E CRC tumors have a low association with APC mutation, this data suggests role of epigenetic regulation of the Wnt-pathway activation. However, as measured by nuclear β-catenin, Wnt activation in these tumors is not as high as traditional APC-mutated CRC tumors. CIMP-H tumors with BRAFV600E mutation is a unique subset of CRC tumor that have Wnt-pathway activation regulated by epigenetic modifications more than a β-catenin activation.
Artificial intelligence-assisted immunohistochemical (IHC) evaluation of tumor amphiregulin (AREG) and epiregulin (EREG) expression as a combined predictive biomarker for panitumumab (Pan) therapy benefit in RAS wild-type (wt) metastatic colorectal cancer (mCRC): Analysis within the phase III PICCOLO trial.
Authors: Williams Christopher , Seligmann Jenny F. , Guetter Christoph , Zhang Liping , Yan Dongyao , Muranyi Andrea , Bai Isaac , Singh Shalini , Elliott Faye , Shires Mike , Richman Susan , West Nicholas , Barrett Jenny , Seymour Matthew T. , Quirke Philip , Shanmugam Kandavel
Published: January 2021

111

Background: High tumor mRNA levels of the EGFR ligands, AREG and EREG are associated with anti-EGFR agent response in patients (pts) with RAS-wt mCRC, regardless of tumor location. However, ligand RNA assays have not been adopted into routine clinical practice due to issues with analytical precision and practicality. Here we test whether AREG and EREG expression assessed by IHC can predict benefit from Pan. Methods: A retrospective biomarker study within the PICCOLO trial (NCT00389870; irinotecan [Ir] ± Pan in fluoropyrimidine-resistant RAS-wt mCRC). AREG and EREG positive tumor cells were assessed by IHC in all RAS-wt patients with available tumor tissue. Pathologists annotated tumor areas on digital images of glass slides. Artificial intelligence (AI) algorithms calculated the percentage of tumor cells staining positive for AREG and EREG within the tumor areas. More than 50% AREG and/or EREG tumor cell positivity was regarded as high ligand expression. The primary endpoint was progression-free survival (PFS) and secondary endpoints were RECIST response rate (RR) and overall survival (OS). Results: 274 RAS-wt pts had available tumor tissue. High ligand expression (n = 132) was associated with significant PFS benefit from IrPan compared with Ir (8.0 vs 3.2 months; HR 0.54 [0.37-0.79]; p = 0.001); whereas low ligand expression (n = 142) was not (3.4 vs 4.4 months; HR 1.05 [95% CI, 0.74-1.49]; p = 0.78). The ligand-treatment interaction was significant (p = 0.02) and independent of BRAF-mutation status and primary tumor location. Likewise RR was significantly improved in pts with high ligand expression (IrPan vs Ir: 48% vs 6%; risk ratio, 7.8 [2.90-20.69]; p < 0.0001) but not those with low ligand expression (IrPan vs Ir: 25% vs 14%; risk ratio, 1.8 [95% CI, 0.89-3.65]; p = 0.10) (interaction p = 0.01). Lesser effect was seen on OS. Conclusions: IHC assessment of AREG and EREG identified pts who did or did not benefit from Pan, as has been previously demonstrated through mRNA quantification. IHC represents a more practicable technique as it can be provided at the point of care and is associated with shorter turn-around times. AREG and EREG IHC may be of use in routine practice to identify patients who would benefit from anti-EGFR therapy and those for whom alternative treatment strategies should be explored.
SCRUM-Japan genesis virtual sequencing (VSQ) project: A novel algorithm combining deep learning (DL) with pathological diagnostics to enable the prediction of BRAF mutations and microsatellite instability (MSI) in advanced colorectal cancer (CRC).
Authors: Fujii Satoshi , Kotani Daisuke , Hattori Masahiro , Masato Nishihara , Shikanai Toshihide , Hashimoto Junji , Hama Yuki , Nishino Takuya , Suzuki Mizuto , Yoshidumi Ayatoshi , Yamada Tomoyuki , Yoshino Takayuki
Published: January 2021

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Background: Numerous genetic and epigenetic abnormalities may lead to various morphologies of cancer. However, exactly which gene abnormality causes which morphology is unknown. The VSQ Project aims at investigating a novel algorithm by synergistically fusing DL technology and pathological diagnostics for the prediction of cancer genome abnormalities. This was achieved by elucidating the association between the morphological findings and genetic abnormalities, including BRAF V600E mutations and MSI status directly linked to the therapeutic strategies for advanced CRC patients (pts). Methods: Clinicopathological-genomic integrated DB derived from SCRUM-Japan GI-SCREEN, a nation-wide cancer genome screening project including CRC, were used. A total of 1,657 images of thin sections (one representative image per pt) cut from formalin-fixed and paraffin-embedded (FFPE) tissue specimens from primary or metastatic tumors with genetic abnormalities confirmed by next-generation sequencing (NGS) were investigated; 1,234 and 423 images (one per pt) were used for training and validation cohorts, respectively. First, we developed image-prediction models based on the morphological features precisely annotated by the single central pathologist, and then constructed the DL algorithms (gene-prediction models) that enabled the prediction of gene abnormalities by using images filtered by the image-prediction models. Results: We achieved high accuracy of AUC > 0.90 for 12 features among the 33 morphological features analyzed. Next, we created several DL algorithms that enabled the prediction of BRAF mutations and MSI. The prediction level reached a high accuracy of AUC = 0.955 for the BRAF mutations and AUC = 0.857 for MSI in the training cohort. We verified the AUCs in the validation cohort and achieved AUC = 0.831 and 0.883 for BRAF mutations and MSI, respectively. Conclusions: Our findings suggest that VSQ can appropriately predict BRAF mutation and MSI status in advanced CRC, potentially without performing NGS tests. VSQ may also enable prompt initiation of systemic treatments in CRC patients as well as establish an unprecedented next-generation pathology in the near future.
Real-world data evaluating immunotherapy markers and checkpoint inhibitor response among GI cancers in a large community-based oncology network.
Authors: Jones Carissa , Lachs Rebecca , Sturgill Emma , Misch Amanda , Lietman Caressa , Jones Suzanne Fields , Burris III Howard A. , Sen Shiraj , Bendell Johanna C. , Jones Carissa
Published: January 2021

113

Background: Checkpoint inhibitor (CPI) therapies have shown prolonged survival in patients (pts) with microsatellite instability (MSI). Tumor mutation burden (TMB) has also been associated with benefit from CPIs, with pembrolizumab recently approved for solid tumors with a TMB of ≥10 muts/mb. However, the validity of a tissue-agnostic approach has been debated given the high degree of TMB variation across tumor types. We sought to evaluate the impact of TMB and MSI on CPI response in pts with advanced gastrointestinal (GI) cancers who received NGS profiling. Methods: Patients within the Sarah Cannon network with GI cancer and comprehensive next generation sequencing (NGS) data were identified through Genospace, Sarah Cannon’s clinico-genomic analytics platform. Microsatellite (MS) status [high (MSI-H) vs. stable (MSS)] was defined by NGS. TMB-high (TMB-H) was defined as ≥10 muts/mb. Kaplan-Meier estimates were used to examine time to treatment failure (TTF), defined as the time from therapy start to start of next therapy, death, or loss to follow-up. Results: We identified 5,788 pts with GI cancers who received NGS, of which 48% (N=3,603) had colorectal cancer (CRC). MS status was evaluated on 4,219 (66%) NGS reports, TMB on 2,922 (46%) reports, and both on 2,863 (45%) reports. MSI-H and TMB-H co-occurred on 127 reports (4%), MSS/TMB-H occurred on 312 reports (11%), and MSS/TMB-Low (TMB-L) occurred on 2,424 reports (85%). No reports were MSI-H/TMB-L. Overall, 580 pts (14%) received CPI therapy (N=52 MSI-H/TMB-H, N=41 MSS/TMB-H, N=215 MSS/TMB-L). Independent of line of therapy or tumor type, TTF was significantly shorter for CPI vs. non-CPI therapies [median TTF (mTTF)=151 vs. 238 days, respectively, p=3.4x10-9]. As expected, MSI-H was also associated with longer CPI TTF compared to MSS (mTTF=727 vs. 124 days, p=3.1x10-11). Due to small sample sizes, further analyses were focused on pts with CRC (Table). TMB-H was independently associated with longer CPI TTF compared to TMB-L (Table, p=9.2x10-10). Similarly, the co-occurrence of MSI-H/TMB-H was also associated with longer CPI TTF (Table). However, there was no difference in CPI TTF for MSS/TMB-H and MSS/TMB-L (Table, p=0.45). All pts who received non-CPI therapies, regardless of MS/TMB group, had longer TTF than MSS/TMB-H and MSS/TMB-L pts who received CPI (Table). mTTF [days (N)] for pts with CRC by biomarker. Conclusions: Despite recent tissue-agnostic approvals, TMB does not appear to be a good biomarker of CPI response in pts with CRC. Rather, time to CPI failure is associated with the co-occurrence of TMB-H with MSI-H. Continued research is needed to identify better biomarkers of response to immunotherapy in GI cancers. [Table: see text]
Impact of primary tumor size/horizontal extent on survival in colorectal cancer.
Authors: Alese Olatunji B. , Zhou Wei , Jiang Renjian , Zakka Katerina Mary , Shaib Walid Labib , Wu Christina , Diab Maria , Akce Mehmet , El-Rayes Bassel F.
Published: January 2021

125

Background: Pathologic staging in colorectal cancer (CRC) is crucial in patient management. Data regarding the impact of size/horizontal tumor extent is limited, contradictory and currently excluded from the American Joint Committee on Cancer (AJCC) staging model. However, a previously published SEER analysis showed that AJCC stages I and IIIA have similar 2- and 5- year survival rates, and worse rates for stage II. Using the largest cohort to date, we report the impact of primary tumor size on CRC survival. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2010 and 2015. Univariate and multivariate analyses were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics and overall survival (OS). Results: A total of 61,145 patients were identified with a similar gender distribution (M/F:50.9%/49.1%). The mean age was 62.7years (SD+/-14.1) and 82% were non-Hispanic Whites. Majority had colon primary (82.7%) and 82.4% had microsatellite stable (MSS) disease. Distribution across stages I-IV was 20.1%, 32.1%, 34.7% and 13.2% respectively. Among the total study population, AJCC stage correlated closely with OS on multivariate analysis (HR 1.49, 2.29, 8.38 for stages II to IV compared to stage I), while the distinguishing power for tumor size was relatively mild (HR 1.19 and 1.33 for 5-10 cm and >5cm compared to <5cm). Among patients with stage II disease, tumors >10cm were associated with worse survival compared to those <5cm (HR 1.2; 1.03-1.39; p=0.22). Stage III disease also had differential survival rates; patients with tumors 5-10cm (HR 1.21; 1.14-1.28; p<0.001) and >10cm (HR 1.57; 1.37-1.80; p<0.001) had worse survival than those <5cm. Patients with stage II who did not receive adjuvant chemotherapy (CTX) had worse survival outcomes (HR 1.29; 1.08-1.55; p=0.005) compared to stage III disease who did. Accounting for tumor size, there was no statistically significant survival differences between stage I patients and stages II and III patients who received adjuvant chemotherapy. Conclusions: Tumors larger than 10cm have inferior outcomes among patients in the same AJCC stages. Stage II patients without adjuvant CTX did worse than stage III with CTX. Further studies are needed to clarify the role of tumor size in staging models. [Table: see text]
Circulating tumor DNA in identifying resistant subclones post EGFR blockade: Implications for EGFR rechallenge.
Authors: Chennamadhavuni Adithya , Kasi Pashtoon Murtaza
Published: January 2021

131

Background: For patients with metastatic RAS/RAF wild-type refractory colorectal cancer anti-EGFR therapy can be reused in subsequent lines of therapy. However, it is not entirely clear if all patients derive benefit. Increasingly it is been recognized that these patients acquire mechanisms of resistance which can be detected on circulating tumor DNA-based testing. We present a series of patients who had serial testing post EGFR therapy showing its feasibility and value. This would have implications for EGFR rechallenge. Methods: We reviewed records for patients who initially were noted to have tissue RAS/RAF Wild type who received prior anti-EGFR therapy and then subsequently had at least 1 circulating tumor DNA-based testing. Included a result of patients who had comprehensive NGS based profiling for both tissue as well as ctDNA. Results: Median duration of initial prior anti EGFR therapy was around 10 months. Table shows results of patient's tissue based genomic testing in parallel with the serial circulating tumor DNA-based testing that was done later when subsequent lines of therapy were being decided. As noted, known acquired mechanisms of resistance were noted in 100% of the cases. These included KRAS, NRAS, extracellular domain mutations in EGFR and BRAF mutations. Interestingly the levels of the sub-clones expressed as variant allele fraction percentage varied and decreased over time in relation to timing of the prior EGFR exposure. Additionally, these were noted to be polyclonal and the number of clones also varied including some disappearing over time during non-EGFR based therapy (EGFR holiday). Conclusions: Patient's post EGFR blockade may have multiple mechanisms of acquired resistance that can be easily detected on noninvasive liquid biopsies. These patients likely will not benefit from EGFR rechallenge based on the results of the recently reported CRICKET (NCT02296203) and CAVE (EudraCT number: 2017-004392-32) clinical trials. Rechecking liquid biopsy plasma RAS/RAF status is one thing that may be incorporated into practice with EGFR rechallenge only if acquired mechanisms of resistance are absent. [Table: see text]
Cost-effectiveness of cetuximab + FOLFIRI versus bevacizumab + FOLFIRI in the first-line treatment of RAS wild-type metastatic colorectal cancer in China.
Authors: Van Oostrum Ilse , Hu Yannan , Yuan Zijiao , Schlichting Michael , Tao Libo , Pescott Chris P.
Published: January 2021

133

Background: Adding cetuximab to FOLFIRI chemotherapy (cet+CT) as first-line (1L) treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC) has been reported as cost-effective vs bevacizumab + FOLFIRI (bev+CT) in multiple jurisdictions. This study determined the cost-effectiveness (CE) of cet+CT for patients with mCRC in China. Methods: A published 3–health-state (nonprogressive, progressive, death) CE model was adapted to reflect Chinese patient characteristics, health state utilities, unit costs, and discounting rates, applying FIRE-3 trial–based resource utilization and adverse event rates. Progression-free and overall survival estimates were based on published FIRE-3 trial simulations to statistically adjust for available later-line treatment modalities in China vs those observed in FIRE-3. [1] Cetuximab and bevacizumab costs were based on up-to-date prices after the 2019 national reimbursement drug listing negotiations. Incremental CE ratios (ICERs) are given as cost (Chinese Yuan [¥]) per life-year (LY) and quality-adjusted LY (QALY) gained. The willingness-to-pay (WTP) threshold was ¥193,931, equivalent to 3 times the gross domestic product per capita, following WHO guidance. Results: Overall costs/costs restricted to 1L treatment were ¥483,771/¥249,619 (cet+CT) and ¥366,036/¥156,802 (bev+CT). Health effects were 3.32/2.68 (cet+CT) and 2.39/1.94 (bev+CT) LYs/QALYs gained. Discounted ICERs for cet+CT vs bev+CT were ¥148,311 and ¥186,517 per LY and QALY gained in deterministic analysis. cet+CT had a 71.8% (LY) and 52.5% (QALY) probability of being cost-effective. Treatment duration with a biologic in 1L, utilities in 3L treatment, and duration of 2L treatment were the main outcome drivers. Conclusions: Projections suggest that cet+CT is cost-effective vs bev+CT for 1L treatment of patients with RAS wt mCRC in China, with ICERs below the current WTP threshold in deterministic and probabilistic sensitivity analyses. [1] Van Oostrum I, et al. Value Health. 2020;23(Suppl 1): S8.
Impact of preoperative therapy for locally advanced thoracic esophageal cancer on the risk of perioperative complications: Results from multicenter phase III trial JCOG 1109.
Authors: Koyanagi Kazuo , Kato Ken , Ito Yoshinori , Daiko Hiroyuki , Ozawa Soji , Ogata Takashi , Hara Hiroki , Kojima Takashi , Abe Tetsuya , Bamba Takeo , Watanabe Masaya , Kawakubo Hirofumi , Shibuya Yuichi , Tsubosa Yasuhiro , Tsuda Masahiro , Nozaki Isao , Baba Hideo , Machida Ryunosuke , Fukuda Haruhiko , Kitagawa Yuko ,   The Japan Esophageal Oncology Group/Japan Clinical Oncology Group
Published: January 2021

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Background: We have conducted randomized three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel plus CF (DCF) versus radiation with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer, which is on-follow-up for primary analysis planned in 2023 (JCOG 1109). This study aimed to evaluate the influence of preoperative therapies on perioperative complications and risk factors for perioperative complications after three-arm preoperative therapies. Methods: Patients with potentially resectable advanced thoracic esophageal cancer were randomly assigned to three preoperative therapies and followed by open or thoracoscopic esophagectomy with regional lymphadenectomy. Clinical data, surgical results, and perioperative complications in the patients received DCF and CF-RT were compared with those in the patients received CF. Univariate and multivariate analyses were performed to explore the risk factors of perioperative complications. Results: Between December 2012 and July 2018, 601 patients were randomized (CF/DCF/CF-RT; 199/202/200). Of 589 eligible patients, 546 patients underwent surgery (185/183/178). Patients` characteristics were not different between arms. Median number of harvested lymph node in patients received CF-RT was significantly lower than that in patients received CF (49 vs. 58; P < 0.0001). Incidence of ≥ Grade 2 perioperative complications in patients received DCF was lower than that in patients received CF (44.8% vs. 56.2%; P = 0.036). Incidence of ≥ Grade 2 chylothorax in patients received CF-RT was higher than that in patients received CF (5.1% vs. 1.1%; P = 0.032). Incidence of reoperation and intra-hospital death in patients received DCF and CF-RT did not differ from that in patients received CF. Multivariate analysis showed that operation time (≥ median) and open esophagectomy were independently associated with an increase in ≥ Grade 2 perioperative complications. CF-RT was associated with an increase in occurrence of ≥ Grade 2 chylothorax (Relative Risk 4.84; P = 0.043). Conclusions: Preoperative DCF and CF-RT does not increase the risk of perioperative complications and mortality when compared with standard preoperative CF therapy, but CF-RT increases the risk of chylothorax after esophagectomy for advanced thoracic esophageal cancer.
Outcomes of a phase II study of intraperitoneal paclitaxel plus systemic capecitabine and oxaliplatin (XELOX) for gastric cancer with peritoneal metastases.
Authors: Chia Daryl , Sundar Raghav , Kim Guo Wei , Ang Jiajun , Lum Jeffrey , Nga Min En , Cheng Ean Chee , Tan Hon Lyn , Ho Jingshan , Ngoi Natalie , Lee Matilda , Muthu Vaishnavi , Chan Gloria , Pang Angela , Ang Yvonne , Choo Joan , Lim Joline Si Jing , Shabbir Asim , Yong Wei-Peng , So Jimmy Bok Yan
Published: January 2021

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Background: The addition of intraperitoneal (IP) paclitaxel (PTX) to systemic chemotherapy comprising taxane/fluoropyrimidine doublet has shown promising results for patients with gastric cancer (GC) and peritoneal metastases (PM). However, this has not been studied in combination with platinum/fluoropyrimidine doublet which is the current standard-of-care for metastatic GC. We conducted a prospective phase 2 trial of IP PTX with capecitabine and oxaliplatin (XELOX) in patients with GCPM. Methods: The trial enrolled 44 patients with GCPM who received treatment comprising IP PTX (40mg/m2 on day 1,8), PO capecitabine (1000mg/m2 twice daily from day 1-14) and IV oxaliplatin (100mg/m2 on day 1) in 21-day cycles. Patients with synchronous GCPM were eligible for conversion surgery comprising radical gastrectomy if they had good response after chemotherapy, negative cytology on 2 consecutive peritoneal fluid assessments, no extraperitoneal metastasis and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were also compared with a retrospective cohort of 39 patients with GCPM who received identical systemic chemotherapy (SC) comprising platinum/fluoropyrimidine agents alone. Results: The median OS for the IP and SC groups was 14.6 and 10.6 months (HR 0.44; 95% CI, 0.26-0.74; P=0.002). The 1-year OS was 67.8% in the IP group and 32.3% in the SC group (Logrank p<0.001). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI, 0.25-0.66; P<0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p=0.021) and had better baseline performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p=0.007) compared to the IP cohort. In the IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95%CI 13.1 – 35.3) months and 1-year OS of 84.6%. Wound-related complications requiring the port to be explanted or re-sited occurred in 9% (4/44) of patients. Conclusions: IP PTX with XELOX is a promising treatment option for GCPM patients. For patients with good response, conversion surgery was feasible with favourable outcomes. Clinical trial information: NCT01739894. [Table: see text]
Esophagectomies for malignancy among general and thoracic surgeons: A propensity score-matched NSQIP analysis stratified by surgical approach.
Authors: Leonard-Murali Shravan , Ivanics Tommy , Nasser Hassan , Tang Amy , Hammoud Zane T.
Published: January 2021

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Background: Training of general and thoracic surgeons continues to diverge, especially with the increasing role for minimally invasive surgical (MIS) approaches. Previous studies of esophagectomy outcomes by specialty do not adequately address malignancy or surgical approach. We sought to evaluate perioperative outcomes of esophagectomy for malignancy stratified by surgical specialty and approach using a national database. Methods: The National Surgical Quality Improvement Program (NSQIP) Targeted Esophagectomy Dataset was queried for esophagectomies for malignancy and grouped by surgeon specialty: thoracic surgery (TS) or general surgery (GS). Those with missing data were excluded (n = 6). To account for confounding due to specialty selection bias, we performed propensity score matching (PSM) by age, body mass index, ethnicity, American Society of Anesthesiologists class ³ 3, and surgical approach in a 1:1 ratio. An absolute standardized difference of ≤ 0.1 was considered an appropriate balance. The primary outcome was mortality and secondary outcomes were anastomotic leak, Clavien-Dindo grade ≥ 3 and positive margin rate. Univariate logistic regression analysis was performed for these outcomes on the matched cohort, with stratification by surgical approach (open vs. MIS). Results: A total of 1463 patients met inclusion criteria (512 GS, 951 TS). After PSM each group was comprised of 512 patients with similar demographics, neoadjuvant chemotherapy and radiation rates, and preoperative stage. The TS group consisted of 169 (33.0%) open and 343 (67.0%) MIS cases, while the GS group consisted of 177 (34.6%) open and 335 (65.4%) MIS cases. Postoperative complications, including surgical site infection, pneumonia, pulmonary embolism, stroke, and myocardial infarction were similar between matched groups, and remained similar when stratified by surgical approach. Mortality rates were similar between the TS and GS groups, both overall (14 (2.7%) vs. 10 (2.0%)) and when stratified by surgical approach (MIS: 11 (3.2%) vs. 10 (3.0%), open: 3 (1.8%) vs. 0 (0%)). By univariate analysis of the matched cohort stratified by surgical approach, TS patients had similar odds as GS patients of anastomotic leak (open: adjusted odds ratio (AOR) = 1.11, 95% confidence interval (95%CI) = 0.58 – 2.15, p = 0.75; MIS: AOR = 0.70, 95%CI = 0.47 – 1.04, p = 0.08), Clavien-Dindo grade ≥ 3 (open: AOR = 1.27, 95%CI = 0.79 – 2.06, p = 0.32; MIS: AOR = 1.01, 95%CI = 0.73 – 1.39, p = 0.97), positive surgical margins (open: AOR = 0.75, 95%CI = 0.33 – 1.68, p = 0.49; MIS: AOR = 0.62, 95%CI = 0.35 – 1.07, p = 0.09), and mortality (open: unable to be calculated due to 0 deaths in the GS group; MIS: AOR = 1.08, 95%CI = 0.45 – 2.62, p = 0.87). Conclusions: Esophagectomy for malignancy had a similar perioperative safety profile and positive margin rate among general and thoracic surgeons, regardless of surgical approach.
The effect of gender on outcomes in esophageal cancer.
Authors: McDonald Jordan , Saeed Sabrina , Hoffe Sarah E. , Mehta Rutika , Frakes Jessica M. , Fontaine Jacques-Pierre , Dineen Sean P. , Pimiento Jose Mario
Published: January 2021

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Background: Few epidemiological studies address differences in outcomes by gender in locoregional esophageal cancer (LEC) for which the current standard of care is chemoradiation followed by surgical resection. Although male gender is associated with the majority of LEC cases, we sought to determine if gender could impact clinical presentation as well as surgical and oncologic outcomes in our single institution 20 year experience. Methods: A retrospective query of our institution’s IRB-approved database of patients that had surgical therapy between 2008 and 2019 for esophageal cancer (EC) was performed. Patients were stratified by gender and analyzed based on characteristics such as tumor histology, tumor location, clinical stage at presentation, age at diagnosis, receipt of neoadjuvant therapy, surgical intent, surgical complications, length of post-operative hospital stay, response to neoadjuvant therapy, final pathology, and recurrence. Chi-square, ANOVA and Kaplan Meier survival analysis were performed on the previously defined groups. Results: The cohort studied included 1180 patients with resection for EC. Of those, 1005 (85.2%) had adenocarcinoma, 145 (12.3%) had squamous cell cancer (SCC), 10 (0.8%) had adenosquamous carcinoma, and 20 (1.7%) had other histological variants. There were 985 (83.5%) male patients and 195 (16.5%) female patients. SCC was more common in females (29.2% in females vs. 8.9% in males, p = 0.000) and females tended to have tumor location in the upper thoracic esophagus more often (4.7% in females vs. 0.9% of males, p = 0.000). Additionally, females developed surgical complications more often than males (72.2% vs. 64.7%, p = 0.045). Staging at diagnosis (p = 0.508), receipt of neoadjuvant treatment (p = 0.676), and age at diagnosis (65.3 years in males vs. 66.3 years in females, p = 0.934) had no association with gender. Response to neoadjuvant therapy (p = 0.157) and cancer recurrence (p = 0.434) did not have significant associations with gender. The median overall survival was not statistically significantly different but trended to be longer for females (73.4 months in females [95% CI: 51.5-95.4] vs. 47.0 months in males [95% CI: 39.6-54.5], p = 0.160). Conclusions: Based on our high-volume cancer center study, female patients were more likely to have SCC, upper thoracic esophageal lesions, and surgical complications following resection. While univariate analysis did not demonstrate significant differences in overall survival between genders, there are plans to report additional data after controlling for other variables. Further studies are warranted to validate these findings, given the potential for higher prioritization of an organ preservation approach for this patient population.
Factors associated with treatment duration from start of second-line ramucirumab plus paclitaxel or nab-PTX for advanced gastric cancer: real-world evidence from Japanese Claim Database.
Authors: Hironaka Shuichi , Komatsu Yoshito , Tanizawa Yoshinori , Cai Zhihong , Piao Yongzhe , Boku Narikazu
Published: January 2021

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Background: Recently, the value of RWE has been recognized to be important. We investigated the first line(1L)-2L therapy(Tx) sequence for AGC and factors associated with whole treatment period after RAM plus(+) (nab-)PTX therapy using RWE in Japan. Methods: This study used a hospital-based claims database in Japan. Patients who were diagnosed with GC and started 1L Tx between Jun 2015 and Jul 2019 were selected. The 1L Tx was defined as fluoropyrimidine(FP)+platinum (with or without trastuzumab[Tmab]), and defined to be discontinued when it was suspended for >90 days or switched to different antitumor drugs (2L Tx). In patients who started RAM+(nab-)PTX as 2L Tx, factors associated with overall Tx duration (from start of 2L Tx to the last dose of chemotherapy including subsequent Tx) were explored by Cox regression analysis. Results: 10581 patients (mean age 67.9 years, male 73.9%) received 1L Tx (9024 patients without Tmab and 1557 patients with Tmab). In patients who discontinued 1L Tx, the proportion of 1L-2L Tx transition was 61% (4509/7443) without Tmab and 68% (849/1245) with Tmab. Among 5358 patients who received 2L Tx, 3650 patients (68%) received RAM+(nab-)PTX. The median overall Tx duration was 6.7 months after initiation of 2L Tx with RAM+(nab-)PTX. Factors positively associated with the overall Tx duration from initiation of 2L Tx with RAM+(nab-)PTX were Tmab use before data cutoff (Sep 2019; hazard ratio [95% CI] 0.9 [0.79-1.00]), previous oral FP (0.7 [0.54-0.89]), duration of 1L Tx >150 days (0.8 [0.74-0.87]). Factors negatively associated were peritoneal metastasis or ascites (1.3 [1.17-1.40]), comorbidities e.g., edema (1.3 [1.07-1.45]), renal disease (1.1 [1.01-1.30]), diabetes (1.1 [1.01-1.22]), previous oxaliplatin (1.2 [1.09-1.30]), and rehabilitation (1.9 [1.67-2.24]) or nutritional intervention (1.5 [1.34-1.68]) within 1 month before and after starting 2L Tx. Conclusions: Many of the patients received RAM+(nab-)PTX as 2L Tx regardless of Tmab. This large-scale RWE demonstrated that Tmab use, oral FP, and long 1L Tx duration were associated with longer treatment course from start of 2L RAM+(nab-)PTX therapy.