bluuebunny/crossref_metadata_2025_split huggingface dataset:
The case for cautious paternalism in the emergency management of patients with borderline personality disorder
Authors: Newton-Howes Giles 
Published: January 2021

SummaryPrinciplism 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

104 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

112 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]