tbuckley/cabot-search huggingface dataset:
Impact of colorectal liver metastases (CRLM) in patients with metastatic colorectal cancer (mCRC) receiving trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) in the phase 3 SUNLIGHT trial.
Authors: Josep Tabernero, Gerald W. Prager, Julien Taieb, Elizabeth Martine Calleja, Mei Liu, Nadia Amellal, Marwan Fakih
Journal: Journal of Clinical Oncology (2024)

3584 Background: Many patients with CRC develop CRLM during their disease, which are associated with poor prognosis. In the phase 3 SUNLIGHT trial, the addition of BEV to FTD/TPI significantly improved overall survival (OS) compared with FTD/TPI alone in patients with refractory mCRC, irrespective of mutational status, tumor sidedness, and other factors associated with poor prognosis. Here, we assessed the impact of baseline CRLM on efficacy outcomes among patients treated in SUNLIGHT. Methods: In this post hoc analysis, OS, progression-free survival (PFS), and disease control rate (DCR) were assessed in patients with and without CRLM. Differences in survival between FTD/TPI + BEV and FTD/TPI alone were assessed in each subgroup. The Kaplan-Meier method and log-rank test were used to compare differences in OS and PFS; DCRs were compared using Fisher's exact tests. The hazard ratios (HRs) for OS and PFS were estimated using a Cox proportional hazards model. Results: Of the 492 patients enrolled in SUNLIGHT, 382 (77.6%) had CLRM, comprising 194 randomized to FTD/TPI + BEV and 188 randomized to FTD/TPI alone. Among patients randomized to FTD/TPI + BEV (n=246), median OS (95% confidence interval [CI]) was 10.4 (8.6, 11.0) months and not estimable (NE) (11.1–NE) for patients with and without CRLM, respectively (HR: 1.88; P=0.005). For patients randomized to FTD/TPI alone (n=246), median OS (95% CI) was 6.5 (5.9, 8.0) months and 10.9 (9.0, 13.8) months for patients with and without CRLM, respectively (HR: 1.75; P=0.002). Similar trends were observed for PFS and DCR. When comparing treatment effects across arms, FTD/TPI + BEV resulted in longer OS and PFS compared with FTD/TPI alone in patients with and without CRLM. In patients with CRLM, the HRs for OS and PFS were 0.61 (95% CI: 0.48, 0.77; P&lt;0.001) and 0.44 (95% CI: 0.35, 0.55; P&lt;0.001), respectively. In patients without CRLM, the HRs for OS and PFS were 0.60 (95% CI: 0.35, 1.0; P=0.052) and 0.38 (95% CI: 0.24, 0.58; P&lt;0.001), respectively. The DCR was also higher in patients treated with FTD/TPI + BEV compared with FTD/TPI alone (68.6% vs 38.3% in patients with CRLM and 73.1% vs 53.5% in patients without CRLM). Conclusions: The results of this analysis show that patients treated with the combination of FTD/TPI + BEV had numerically longer OS and PFS and a higher DCR than those treated with FTD/TPI alone, irrespective of whether or not patients had CRLM at baseline. Owing to the imbalance in numbers of patients with and without CRLM, the data need to be interpreted with caution. Clinical trial information: NCT04737187 .
Non-colorectal GI malignancies in the young: Incidence trends, demographic disparities, and survival analysis.
Authors: Deepak Vadehra, Shailesh M Advani, Anthony George, Kristopher Attwood, Timothy J Brown, Beas Siromoni, Sahithi Sonti, Sarbajit Mukherjee
Journal: Journal of Clinical Oncology (2024)

4023 Background: The incidence of gastrointestinal (GI) cancers is rising within the younger populations. Previously, we have detailed the increasing incidence of colorectal cancer (CRC) in the adolescent/young adult (AYA) population, defined as 15-39 years old. In this analysis, we seek to further describe incidence, mortality, and demographic differences in the AYA population for non-CRC GI malignancies compared to their older counterparts (≥50 years old). Methods: We queried the Surveillance, Epidemiology, and End Results Program (SEER) database from 2000-2020. The demographic, clinical, and secondary cancer characteristics were summarized in the overall sample (and within racial subgroups) by disease site. The summary statistics were reported for baseline covariates, with comparisons made using the Kruskal-Wallis or chi-square test. Overall survival (OS) and disease-specific survival (DSS) were reported using the Kaplan-Meier method and comparisons were made using the log-rank test. Univariate and multivariate Cox regressions assessed the association between baseline covariates and time-to-event. Changes over time were assessed by annual percentage change (APC). Results: We identified 21,677 AYA patients with non-CRC GI malignancies (esophageal, stomach, small intestine, anal, hepatobiliary, pancreas, and primary peritoneal) from 2000-2020. Most were male (58%), White (47%), and living in metro areas (90%). The median age of diagnosis was 38 years. The AYA population had a higher percentage of Black, Asian, and Hispanic patients (14%, 12%, and 25%, respectively) affected compared to the ≥50 group (11%, 10%, and 14%). The most common non-CRC GI malignancies in the AYA group were stomach, pancreas, and liver (27%, 20%, and 19 %, respectively). Stomach cancer was found to be much higher in the AYA group compared to the ≥50 group (27 vs 17%). More patients in the AYA group underwent surgery (46 vs 30%) and chemotherapy (54 vs 42%) compared to the ≥50 group. More patients in the AYA group began treatment within 1 month (35 vs 22%). OS and DSS were significantly better in the AYA group (Median OS 24 vs 9 months, Median DSS 52 vs 13 months, p&lt;0.001). Overall, the incidence of non-CRC GI cancers significantly increased from 2000-2019 based on APC (p &lt; 0.05). Specifically, the incidence of small bowel, anal, and liver cancer increased during this period. Univariate and multivariate analysis revealed that male sex, African American race, income &lt;$45k/year, no surgery, and delayed time to treatment were all predictors of worse OS and DSS (p&lt;0.01). Conclusions: Non-CRC GI malignancies are increasing within the AYA population, and specific socio-demographic disparities notably affect survival in this age group. Further study is needed to define the underlying mechanisms of these findings and to ultimately reverse these observed trends.
Unbiased transcriptome analysis of human cleft palate reveals evolutionally conserved molecular signatures of development: experimental study
Authors: Taehee Jo, Jeonghoon Kim, Jaehoon Choi, Junhyung Kim, Woonhyeok Jeong
Journal: International Journal of Surgery (2024)

The development of the secondary palate, an essential process for hard palate formation, involves intricate cellular processes. Here, we examined the expression patterns of palatal fusion-associated genes in postdevelopmental human palatal tissues.
Machine learning to predict lymph node metastasis in T1 esophageal squamous cell carcinoma：a multicenter study
Authors: Xu Huang, Qingle Wang, Wenyi Xu, Fangyi Liu, Liangwei Pan, Heng Jiao, Jun Yin, Hongbo Xu, Han Tang, Lijie Tan
Journal: International Journal of Surgery (2024)

Background: Existing models do poorly when it comes to quantifying the risk of Lymph node metastases (LNM). This study aimed to develop a machine learning model for LNM in patients with T1 esophageal squamous cell carcinoma (ESCC). Methods and Results: The study is multicenter, and population based. Elastic net regression (ELR), random forest (RF), extreme gradient boosting (XGB), and a combined (ensemble) model of these was generated. The contribution to the model of each factor was calculated. The models all exhibited potent discriminating power. The Elastic net regression performed best with externally validated AUC of 0.803, whereas the NCCN guidelines identified patients with LNM with an AUC of 0.576 and logistic model with an AUC of 0. 670. The most important features were lymphatic and vascular invasion and depth of tumor invasion. Conclusions: Models created utilizing machine learning approaches had excellent performance estimating the likelihood of LNM in T1 ESCC.
Staged resection versus simultaneous resection for conversion surgery for initially unresectable colorectal liver metastasis: A prospective cohort study.
Authors: Yijiao Chen, Dexiang Zhu, Jianmin Xu
Journal: Journal of Clinical Oncology (2024)

3582 Background: Patients with initially unresectable colorectal liver metastasis (CRLM) who undergo successful conversion therapy have two treatment options to consider for surgery: simultaneous resection or staged resection. Numerous studies have conducted comparisons between both strategies in cases of initially resectable CRLM. However, almost were retrospective and conclusions were contradictory. Moreover, there have been no research studies that have directly compared the safety and effectiveness of these two approaches in patients with initially unresectable CRLM who are undergoing conversion surgery. Methods: We recruited prospectively patients undergoing conversion surgery for initially unresectable CRLM on the basis of completed randomized controlled trials (RCT) and ongoing multicenter RCT studies. The major outcomes included the rate of perioperative complications within 60 days following surgery, overall survival (OS), and relapse-free survival (RFS). Results: A total of 351 CRLM patients were recruited. Three-hundred-ten eligible patients (203 and 107 in the staged- and simultaneous-resection groups, respectively) were analyzed. In comparison to the staged-resection group, the simultaneous-resection group exhibited a significantly higher percentage of perioperative complications (37.4% VS. 50.5%, P=0.027). The start of adjuvant chemotherapy was significantly later in simultaneous-resection group (the percentage of time to start adjuvant chemotherapy &gt;4 weeks: 14.8% VS. 28.0%, P=0.010). In the staged-resection group, two (1.0%) patients did not reach the liver resection stage, and this was due to disease progression. As compared with simultaneous-resection group, the staged-resection group showed a significantly improved RFS (HR=0.762, 95%CI 0.600-0.969, P=0.024) and liver-specific RFS (HR=0.709, 95%CI 0.554-0.908, P=0.005). The OS analysis did not differ between groups after a median follow-up of 49.7 months (HR=0.798, 95%CI 0.580-1.098, P=0.163). Conclusions: Among patients undergoing conversion surgery for initially unresectable CRLM, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications and impaired relapse-free survival.
Analysis of toxicity and mechanisms of DEHP in prostate cancer with network toxicology and molecular docking strategy
Authors: Zhaofa Yin, Xi Jin, Congling Mao, Le Kang, Can Gong, Shijian Feng, Jijun Yang
Journal: International Journal of Surgery (2024)

Yin, Zhaofa; Jin, Xi; Mao, Congling; Kang, Le; Gong, Can; Feng, Shijian; Yang, Jijun Author Information
When I use a word . . . The languages of medicines—street drugs
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

The term "street drug" is hard to define. Various features have been proposed to be unique determinants of a street drug: recreational use, illicit use, the use of street slang to label a drug, unprofessional manufacture, the presence of impurities or adulterants, use by people "on the street," and the use of dangerous drugs. However, none of these uniquely defines a street drug. Here I propose a practical definition of a street drug, while recognising its limitations: "a medicinal product supplied or sold by one who is not legally permitted to do so." Recognising that perhaps no single dictionary-style definition is totally satisfactory, I also suggest that, to circumvent its limitations, this definition could be afforced by an extensional list of the types of products that are likely to be subsumed by the definition, and the circumstances in which that would be the case. This is an approach that others have also suggested.
Dynamic changes of serum α-fetoprotein predict the prognosis of bevacizumab plus immunotherapy in hepatocellular carcinoma
Authors: Zhenyun Yang, Yizhen Fu, Qianyu Wang, Yangxun Pan, Juncheng Wang, Jinbin Chen, Dandan Hu, Zhongguo Zhou, Minshan Chen, Yaojun Zhang
Journal: International Journal of Surgery (2024)

Alpha-fetoprotein (AFP) has been established as a biomarker for hepatocellular carcinoma (HCC); however, whether its dynamic changes could predict the response to systemic therapy remains elusive. This study explored the AFP trajectory and the association with survival in patients received bevacizumab plus immunotherapy. We retrospectively enrolled 536 HCC patients received bevacizumab plus immunotherapy between February 2021 and February 2023. Patients were divided into two groups according to AFP values before treatment (400 ng/ml). Dynamic changes of AFP were fitted using a latent class model to generate the AFP trajectories. Multivariable Cox models were utilized to compute hazard ratios (HRs) for survival. Inverse-probability-of-treatment weighted analyses were conducted to mitigate the influence of unmeasured confounding variables. The primary endpoint is progression free survival (PFS). The second endpoint is overall survival (OS). Three distinct trajectories were identified for AFP-low and AFP-high patients, respectively. In AFP-low group, compared with the high-rising class (25%; n=69), HRs of PFS were 0.39 and 0.2 for the low-stable class (59.1%; n=163) and sharp-falling class (15.9%; n=44), after adjusting by tumor diameter, tumor number, and extra-hepatic metastasis. In AFP-high group, compared with the high-stable class (18.5%; n=48), HRs of PFS were 0.3 and 0.04 for the middle-stable class (56.5%; n=147) and sharp-falling class (25%; n=65), after adjusting by tumor diameter, tumor number, and extra-hepatic metastasis. Furthermore, the AFP trajectories exhibited the utmost relative importance among all covariates regarding PFS and OS in the multivariable regression models. The AFP trajectories in HCC patients receiving bevacizumab and immunotherapy, constituted an independent biomarker indicative of clinical outcomes. Findings from this study hold potential clinical utility in dynamically forecasting the prognosis of systemic therapy in HCC patients and facilitating clinical decision-making. Rapid reduction of AFP post-treatment can lead to favorable patient prognoses.
Clinical impact of oncogenic <i>KRAS</i>dosage variation in pancreatic cancer.
Authors: Kwangrok Jung, Jong-Chan Lee, Jaihwan Kim, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2024)

4027 Background: Some studies have reported that KRAS oncogenic dosage variation plays a critical role in the biology and phenotype diversification of pancreatic ductal adenocarcinoma (PDA). However, this has not been confirmed in large-scale data. Therefore, this study aims to validate the clinical impact of oncogenic KRAS dosage variation using a large Korean clinico-genomic dataset. Methods: We conducted whole exome sequencing (WES) in 205 human PDA tissues. Tumor cellularity, ploidy, and allele-specific copy number (CN) were derived from WES data using the SEQUENZA software. Subsequently, allele-specific CN for both of mutant and wild-type KRAS was assigned based on tumor cellularity and variant allele fraction (VAF) of mutant KRAS. Finally, we defined mutant KRAS allelic imbalance as a condition where the mutant KRASCN exceeded that of the wild-type KRAS and assessed its clinical significance. Results: Out of 205 PDA patients, 183 (89.3%) patients harbored KRAS mutation and 166 (81.0%) patients were evaluable for mutant KRAS allelic imbalance. Among 166 patients, mutant KRAS allelic imbalance was identified in 62 (37.3%) patients. There was no significant difference in the proportion of stage IV PDA between the imbalance and balance group (59.7% vs. 51.0%, p = 0.353). Nevertheless, a significant disparity was noted in the metastatic pattern, indicating a higher incidence of liver metastasis in the imbalanced group compared to the balanced group (81.1% vs. 52.8%, p = 0.011). In the survival analysis, the imbalance group exhibited significantly shorter progression-free survival and overall survival compared to the balance group (4.6m vs 8.0m, p = 0.009 and 12.5m vs. 17.9m, p = 0.002, respectively). This statistical significance persisted even after adjusting for several variables such as age, sex, stage, and treatment course. Conclusions: Our findings underscore the role of oncogenic KRAS dosage variation, as assessed by mutant KRAS allelic imbalance, in shaping clinical phenotypes and prognosis in PDA. [Table: see text]
Combined impact of primary tumor molecular profile and location in the relapse pattern of early-stage, microsatellite stable colorectal cancer.
Authors: Paolo Manca, Ayush Kris, Henry S. Walch, Christopher Fong, Justin Jee, Karl Pichotta, Nikolaus Schultz, Walid Khaled Chatila, Francisco Sanchez-Vega, Rona Yaeger
Journal: Journal of Clinical Oncology (2024)

3603 Background: The primary tumor location (PTL) and the genetic profile of colorectal cancer (CRC) impact the risk, localization and timing of metastases. We investigated the PTL-specific impact of genomic alterations in a large cohort of patients (pts) with localized, MSS CRC through the automatic data mining of radiology reports and comprehensive genome profiling (CGP). Methods: Eligible CRC cases consisted of consecutive early-stage primary tumor samples from pts seen at a single institution (Memorial Sloan Kettering, MSK). All tumors were MSS, without pathogenic POLE mutations, and diagnosed after Jan 1st 2015, when MSK-IMPACT testing was standard in the clinic. MSK-IMPACT sequencing provided CGP of 341-505 genes. All pts underwent at least 1 surveillance scan at MSK comprising at least chest, abdomen and pelvis, had a minimum follow-up (FUP) of 1 year and developed metastatic disease at least 6 months after initial diagnosis. Time to metastasis (TTM) for each anatomic site was retrieved from radiology reports using validated natural language processing methods. TTM was defined for each organ as the interval from the diagnosis until the first radiologic evidence of metastasis or last scan. TTMs and OS were modeled with univariate cox regression, using competitive risk of death for TTMs. FDR was used to account for multiple comparisons, with a threshold of &lt;0.1. Results: The final cohort comprised 1442 pts, with a median FUP of 42.3 months (IQR 39.5-44.5) and a median number of 6 scans (IQR 4-10) per pt. The PTL was right colon, left colon and rectum in 305, 498 and 639 pts. Expected PTL-specific metastatic patterns were observed, comprising higher risk of peritoneal metastases for right-sided PTL (HR=1.41, p=0.050) and higher risk of lung metastases for rectal tumors (HR=1.45; p=0.004); rectal cancer had the highest risk of metastatic relapse (HR=1.42, p&lt;0.001). The impact of genetic alterations on the risk of developing metastatic disease varied by PTL and the metastatic site. Ten, eight and one pathway-metastatic site significant associations were observed, respectively, in the left-sided, right-sided and rectal PTL cohorts; the most relevant are reported in the table. Conclusions: The metastatic patterns and prognostic stratification of pts with early-stage MSS CRC are affected by the interplay of PTL and genetic profile. Genomic alterations are less impactful on outcomes of pts with rectal cancers. [Table: see text]
Real-world ctDNA testing patterns, associated biomarkers and sites of metastasis in early stage colorectal cancer.
Authors: Erin Fidyk, Laurynas Kalesinskas, Konstantin Krismer, Auriane Blarre, Lilia Bouzit, John James Ritten, Jessica Gao, Anca Marinescu, Jonathan Kelly, Katherine Harrison, Aaron B. Cohen
Journal: Journal of Clinical Oncology (2024)

3610 Background: There is a growing body of evidence to support the prognostic and predictive relevance of ctDNA in patients (pts) with early stage colorectal cancer (CRC). Relatively little is known about the real-world (rw) utilization of tumor-informed, personalized ctDNA assays in this population. We described the uptake of ctDNA testing over time as well as how results correlate with other biomarkers and the development of specific sites of metastasis (SOM). Methods: Pts with stage I-III CRC diagnosed after 1/1/2018 and a commercial ctDNA test in the early stage setting were selected using machine learning models from the Flatiron Health nationwide EHR-derived, de-identified database with a data cutoff of 10/31/23. Pts were considered ctDNA positive (ctDNA+) if they had at least one positive test. Odds ratios (OR) were calculated using logistic regression, adjusting for age, race, stage, practice type, insurance, and adjuvant treatment. Median time to metastasis (mets) for the ctDNA+ cohort (indexed to first positive test) was estimated using the Kaplan Meier estimator. Differences in minimal residual disease (MRD) in MTM/mL were compared using a Wilcox rank-sum test using maximum MRD. Results: In a cohort of 78,046 pts with stage I-III disease, 17,209 ctDNA tests were performed in 5,005 pts (median 3 per pt) with the majority in stage III pts (54.2%). 11% of pts (1652 / 14803) diagnosed between 1/1/21 and 4/1/22 received ctDNA testing compared to 14% of pts (1610 / 11412) diagnosed between 4/1/22 and 4/1/23. Among tested pts, 1,729 (34.5%) had at least one positive test. Pts with ctDNA+ tests were more likely to have tumor mutations in TP53 (OR: 1.69 [95% CI: 1.37, 2.08]) and KRAS (OR: 1.78 [95% CI: 1.10, 1.72]) than pts with ctDNA- tests. No differences were found in NRAS, BRAF or HER2. Progression to metastatic disease was observed in 365 (21.1%) pts with ctDNA+ tests vs 93 (2.8%) pts with ctDNA- tests (OR: 8.84 [95% CI: 6.95, 11.26]). The median time from first ctDNA+ to mets was 24.2 [95% CI: 21.7, NR] months. In those who developed mets, pts with ctDNA+ tests were significantly more likely to have liver mets compared to pts with ctDNA- tests (OR: 1.89 [95% CI: 1.12, 3.19]). Pts with liver mets had higher levels of MRD compared to non-liver SOM. (p &lt;0.001). Conclusions: This is the largest study to date of early stage CRC ctDNA testing in routine practice. Results suggest that pairing ctDNA and NGS testing has the potential to predict risk for liver mets and other pt outcomes. Future work is needed to translate these findings into clinically actionable insights and treatment strategies. [Table: see text]