bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world analyses of BRAF alterations in patients with non-colorectal gastrointestinal cancers.
Authors: Mahipal Amit , Teslow Emily , Jaeger Ellen B. , Stoppler Melissa Conrad , Jin Zhaohui , MOHAMED AMR , Lumish Melissa Amy , Conces Madison , Chakrabarti Sakti 
Published: January 2024

759 Background: BRAF V600E mutations are present in 5-10% of patients with advanced colorectal cancer (CRC) and associated with poor prognosis. Recently, there was tumor agnostic FDA approval of dabrafenib + trametinib for BRAF V600E mutated solid tumors. However, the frequency of BRAF alterations ( BRAF alt), especially non-V600E, in other gastrointestinal (GI) cancers are not well described. This study characterizes BRAF alt in CRC vs other GI cancers (non-CRC). Methods: De-identified records from 51,560 patients diagnosed with GI cancers were retrospectively analyzed from the Tempus database. The molecular landscape including presence of pathogenic/likely pathogenic BRAF alt was evaluated by panel-based tissue DNA, RNA or ctDNA NGS sequencing (Tempus Labs, Inc.). The frequency of BRAF alt, co-mutations, MSI, TMB and MMR were compared between CRC and (non-CRC) by Chi-squared/Fisher’s Exact or Wilcoxon rank-sum tests. False-discovery rate correction was used for multiple testing. Results: BRAF alt were identified in 8.9% of CRC and 2.2% of non-CRC cohort. BRAF alt frequency varied by tumor type with the highest observed in colon (11%), jejunum (9.6%), intrahepatic bile duct (5.3%), rectal (4.5%), and ampulla of vater (4.5%) and lower in esophageal (0.9%) and gastric (1.6%). BRAF alt CRC had higher frequency of females (57% vs 45%, p <0.001) and older age at diagnosis (67 vs 66 yrs, p=0.029) compared to non-CRC group. Race was also significantly different, with white patients being more predominant in both groups (85% CRC,77% non-CRC). Among the BRAF alt, fusions (12% vs 2.2%, p <0.001) and amplifications (3.1% vs 0.3%, p <0.001) were higher in non-CRC vs CRC (Table). BRAF V600E was most common in all GI tumors, but higher in CRC vs non-CRC (75% vs 27%, q<0.001). Mutations higher in non-CRC vs CRC (q<0.009) included class II (G469A, K601E, BRAF-SND1, and BRAF amplification) and class III (D594N & N581S) BRAF alt. BRAF co-occurring mutations in CRC were TP53 (70%), APC (42%), RNF43 (30%), SMAD4 (22%), and PIK3CA (21%), and in non-CRC: TP53 (52%), CDKN2A (32%), CDKN2B (20%) SMAD4 (17%) and MTAP (16%). Among tissue samples, MSI-H (30% vs 4.%, p <0.001) and TMB-H ≥10 mut/MB (32% vs 6.7%, p <0.001) were more frequent in BRAF alt CRC vs non-CRC. Conclusions: Meaningful differences were found between the groups in terms of demographics, frequency, and type of BRAF alt and co-occurring mutations. In particular, certain BRAF fusions were present in a higher proportion of other GI cancers and could be an important therapeutic target for this patient population.[Table: see text]
Effect of laparoscopy-assisted vs open surgery on 3-year disease-free survival in patients with low rectal cancer: The LASRE randomized clinical trial.
Authors: Chi Pan , Su Xiangqian , Xu Jianmin , Qiu Huizhong , Wang Ziqiang , Kang Liang , Deng Haijun , Chen Weiping , Zhang Qingtong , Du Xiaohui , Yang Chunkang , Guo Yincong , Zhong Ming , Ye Kai , You Jun , Xu Dongbo , Li Xinxiang , Xiong Zhiguo , Tao Kaixiong , Ding Ke-Feng ,   LASRE Trial Investigators
Published: January 2024

8 Background: Laparoscopic surgery has been increasingly used for low rectal cancer due to short-term benefits versus open surgery, but the long-term oncologic outcomes have not been fully established. Methods: This is a multicenter, noninferiority trial. Surgeons who had completed ≥100 laparoscopic TME surgeries from 22 high-volume centers in China participated in this trial. A total of 1070 patients scheduled for curative-intent resection of low rectal cancer (lower margin <5.0 cm dentate line) were randomized at a 2:1 ratio to undergo laparoscopic or open surgery from November 2013 to June 2018.The primary outcome was 3-year DFS; the noninferiority margin was 10% in the modified intent-to-treat population. Secondary outcomes included 3-year overall survival (OS) and locoregional recurrence. Results: The final analysis included 1039 patients (median age: 57 years, 620 men; 685 and 354 in laparoscopic and open groups, respectively). Clinical TNM stage was II/III in 659 patients, and I in the remaining 380 patients. The 3-year DFS rate was 81.4% in the laparoscopic group versus 79.8% in the open group (HR, 0.9 [95% CI, 0.7 to 1.2]; log-rank P = .558). The absolute difference was 1.6% (1-sided 97.5% CI, -3.34% to ∞), not exceeding the noninferiority . The 3-year OS rate was 91.7% in the laparoscopic group versus 93.7% in the open group (95% CI, -5.12% to1.54%, log-rank P = .243). The 3-year locoregional recurrence rate was 3.8% and 2.4%, respectively (95% CI, -1.07% to 3.45%, log-rank P = .209). Results of the per-protocol and as-treated analysis were consistent with the main analysis. Conclusions: Among patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons is not inferior to open surgery concerning 3-year disease-free survival. These results support laparoscopic surgery as a safe, minimally invasive approach for low rectal cancer. Clinical trial information: NCT01899547 .
Nivolumab in patients (pts) with advanced gastrointestinal (GI) cancers with high plasma tumor mutational burden (pTMB): Results from a SCRUM-Japan GOZILA phase II trial.
Authors: Nakamura Yoshiaki , Esaki Taito , Nishina Tomohiro , Komatsu Yoshito , Yuki Satoshi , Shinozaki Eiji , Taniguchi Hiroya , Kato Takeshi , Kato Ken , Nomura Shogo , Ikeno Takashi , Ishiguro Yukiko , Takahashi Koji , Higuchi Tsukiko , Sato Akihiro , Odegaard Justin Iver , Kuwata Takeshi , Matsushima Kouji , Nakatsura Tetsuya , Yoshino Takayuki 
Published: January 2024

98 Background: TMB is a biomarker for immune checkpoint inhibitors (ICIs). Analysis of circulating tumor DNA (ctDNA) has the potential to non-invasively identify pts likely to benefit from ICIs by assessing pTMB. We conducted a phase II basket trial as part of the SCRUM-Japan GOZILA umbrella/basket trial to evaluate the efficacy and safety of nivolumab monotherapy in pts with advanced GI cancers with high pTMB. Methods: Eligibility criteria included histologically confirmed unresectable or recurrent GI cancers; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high pTMB identified by Guardant360 CDx, a 74-gene ctDNA assay. Pts received intravenous nivolumab monotherapy of 360 mg every 3 weeks until progressive disease. The primary endpoint was objective response rate (ORR) per investigator assessment. The pTMB score was calculated by adjustment of mutation count by tumor fraction, and initial pTMB thresholds were determined based on previously reported ORR for ICI treatment for each GI cancer in the cohort. The cohort 2 proceeded only for esophageal cancer, and an ultra-high TMB cohort was created to include pts in the top 2% for pTMB scores. Results: Fifty-one pts with high pTMB in the cohort 1/2 (n=32) and the ultra-high TMB cohort (n=19) were enrolled. The median duration of follow-up was 7.5 months (range, 0.9–51.3). Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) was observed in 1 pt in cohort 1/2 and 2 in ultra-high TMB cohort. The ORR was 12.5% and 21.1%, with median duration of response of 14.0 months and not reached, respectively. In an exploratory analysis of the overall population, pts with esophageal cancer had the highest ORR of 33.3% (4/12), followed by pancreatic (1/6, 16.7%) and colorectal cancer (3/27, 11.1%). Of 2 pts with proficient MMR/non-MSI-H colorectal cancer who had a response, 1 had a POLE mutation. Pts with response tended to have higher pTMB score (median, 26 vs. 8). dMMR/MSI-H (HR=0.16; 95% CI, 0.02–1.18), PD-L1 CPS ≥1 (HR=0.55; 95% CI, 0.29–1.01), and absence of liver metastasis (HR=0.36; 95% CI, 1.48–5.14) were significantly associated with longer progression-free survival. Treatment-related grade 3–4 adverse events occurred in 3 pts (9%) in the cohort 1/2 and 3 (16%) in the ultra-high TMB cohort, with no treatment death in either cohort. Conclusions: Nivolumab demonstrated antitumor activity in pretreated pts with advanced GI cancer and high pTMB. These results suggest that the use of pTMB potentially identify patients who may benefit from ICI treatment. Clinical trial information: UMIN000033182 .
A randomized controlled trial of CAPEOX vs observation in patients with early-stage colorectal cancer with positive MRD after curative surgery (CAREME).
Authors: Ding Ke-Feng , Xiao Qian , Xiang Jianbin , Zhou Yiming , Song Jun , Xu Yixin , Huang Xue-Feng , Chen Min , Du Jinlin , Jin Ketao , Dai Xiaoyu , Shen Zhonglei , Li Taiyuan , Ye Shanping , Cui Wei , Zhao Yibin , Chen Wenbin , Cheng Xiaofei , Ju Haixing , Zhang Qian ,   Genecast Medical Group
Published: January 2024

TPS225 Background: Most patients (pts) with early-stage colorectal cancer (CRC) have a good prognosis, but some still relapse shortly after surgery. Effective methods to assess the risk of recurrence in these pts and guide adjuvant chemotherapy (ACT) decision-making are lacking. Increasing studies have shown that circulating tumor DNA (ctDNA) can detect minimal residual disease (MRD) and identify pts with a high risk of recurrence. ACT could improve survival of MRD-positive pts with stage Ⅱ CRC suggested by recent studies, whether it is appropriate for those with stage Ⅰ or clinically low-risk stage Ⅱ CRC remains unknown. Methods: CAREME is a multicenter randomized controlled clinical trial aimed at investigating the benefit of chemotherapy for MRD-positive pts with early-stage CRC. Pts with resected stage Ⅰ or Ⅱ CRC will be evaluated by oncologists. Those who did not receive neoadjuvant therapy and are deemed suitable for active surveillance (i.e., ACT is not needed) will undergo a postoperative ctDNA test using MinerVa MRD assay (a tumor-informed assay covering 769 cancer-related genes). Pts with mismatch repair-deficient tumors will be excluded and stage Ⅱ pts should have no traditional high-risk features according to clinical practice guidelines. Pts with positive ctDNA (N = 38) will be equally randomized into two groups: treatment group (Arm A) or surveillance group (Arm B). Arm A will receive 8 cycles of CAPEOX therapy while pts in Arm B will not receive any ACT; both groups will undergo ctDNA tests at 6 months after randomization and be followed up every 3 months. The primary endpoint is 18-month recurrence-free survival, and a key secondary endpoint is ctDNA clearance at 6 months after randomization. Tumor samples from the pts will be collected for MRD assay and exploratory research. Accrual started in February 2023. Support: Genecast Biotechnology Company. Clinical trial information: NCT05699746 .
SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer.
Authors: Morris Van K. , Guthrie Katherine A. , Kopetz Scott , Breakstone Rimini , Karasic Thomas Benjamin , Hu Zishuo Ian , Colby Sarah , Fakih Marwan , Gholami Sepideh , Gold Philip Jordan , Philip Philip A. 
Published: January 2024

TPS234 Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repairs genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 participants with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve PFS for participants with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N=75), participants with previously treated MSS, BRAFV600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All participants will receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and participants in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α= .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional participants specimens will be collected for exploratory correlative research. As of 9/2023, 37 of 75 planned participants have been enrolled. Clinical trial information: NCT05308446 .
Surgeon fatigue in robot-assisted and laparoscopic gastrectomy for gastric cancer: Exploratory prospective observational study ancillary to JCOG1907 randomized controlled trial (JCOG1907A1).
Authors: Fujiya Keiichi , Terashima Masanori , Kita Ryosuke , Mizusawa Junki , Makuuchi Rie , Omori Takeshi , Yanagimoto Yoshitomo , Isobe Taro , Ojima Toshiyasu , Kawashima Yoshiyuki , Fukuda Haruhiko , Kurokawa Yukinori , Boku Narikazu , Yoshikawa Takaki 
Published: January 2024

TPS422 Background: Fatigue is being increasingly recognized as an important factor in surgical procedures, because it leads to errors in surgeons' decisions and reduced operating efficiency. In comparison to laparoscopic surgery, robot-assisted surgery is expected to reduce surgeon fatigue due to ergonomic adjustments, comfortable sitting positions, minimal restriction of instrument movement, and stable visualization. The aim of this study is to assess surgeon fatigue and explore the superiority of robot-assisted gastrectomy over laparoscopic gastrectomy in surgeon fatigue. Methods: This study is conducted as a prospective observational study ancillary to a randomized controlled phase III trial investigating the superiority in safety of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer (JCOG1907: UMIN000039825). The lead surgeon and the first assistant performing surgeries as protocol treatment in JCOG1907 were included. Surgeon fatigue is quantitatively assessed using multiple assessment tools. The primary endpoint is the average NASA-Task Load Index (NASA-TLX) value for the lead surgeons. Secondary endpoints include six individual parameters of NASA-TLX, visual analog scale assessments for fatigue, advanced trail-making tests, and continuous heart rate variability measurements for lead surgeons and first assistants. The primary analysis compares surgeon fatigue between robot-assisted and laparoscopic surgery. Secondary analyses examine the association between surgeon fatigue and various factors, such as surgeon and patient background, and surgical findings, as well as cross-correlations among measures of surgical fatigue. In addition, the association between surgeon fatigue and postoperative complications and its impact on long-term survival outcomes is also evaluated. The sample size is 500 surgical cases, with a planned accrual period of 2 years. This study was initiated in April 2023 and registered at the University Hospital Medical Information Network as UMIN000052120. As of August 2023, 52 cases (10.4% of the planned accrual) have been enrolled in the study. Clinical trial information: UMIN000052120 .
Phase 1b/2, open-label dose-escalation and -expansion study evaluating trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with HER2+ and HER2-low gastric cancer (GC): DESTINY-Gastric03 (DG-03).
Authors: Janjigian Yelena Y. , Raoufmoghaddam Saeed , Sztachelska Magdalena , Winter Megan , Das Satya (Nanu) 
Published: January 2024

TPS424 Background: T-DXd is approved for treatment of advanced/metastatic HER2+ GC after a trastuzumab-based regimen. The efficacy of T-DXd in advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC has been shown (confirmed objective response rate [ORR], 43% vs 12% with standard chemotherapy) in previously treated Japanese or South Korean pts (DG-01) and in Western pts with progression on a trastuzumab-containing regimen (confirmed ORR, 42%; DG-02). Also, antitumor activity was shown in pts with HER2-low GC (confirmed ORR, 26.3% [IHC 2+/ISH−], 9.5% [IHC 1+]) in DG-01. Other studies have shown benefits of immunotherapies combined with trastuzumab and other chemotherapies for treatment of HER2+ GC. The DG-03 trial is evaluating the safety and efficacy of T-DXd in combination with chemotherapy and/or immunotherapy in HER2-expressing GC. Previously, confirmed ORRs of 50% and 43% were reported with T-DXd + 5-fluorouracil (5-FU) and T-DXd + capecitabine (Cap), respectively, in the second-line or later setting in part 1 of DG-03. The protocol was amended to add an additional arm in part 2 and a new part 3, which will investigate T-DXd in combination with a fluoropyrimidine and volrustomig (MEDI5752), a PD-1/CTLA-4 bispecific antibody, in pts with HER2+ and HER2-low (IHC 2+/ISH− or IHC 1+) GC. Methods: DG-03 (NCT04379596)is a multicenter, dose-escalation (part 1) and -expansion (parts 2 and 3) study in HER2-expressing, locally advanced or metastatic, unresectable gastric, gastroesophageal junction, or esophageal adenocarcinoma. In arm F of part 2, pts with previously untreated HER2+ GC will be treated with T-DXd + investigator’s choice of 5-FU or Cap + pembrolizumab. In part 3, pts with previously untreated HER2+ (arm 3A) or HER2-low (arm 3B) GC will receive T-DXd + investigator’s choice of 5-FU or Cap + volrustomig. The primary endpoint in parts 2 and 3 is investigator-assessed confirmed ORR per RECIST v 1.1. Secondary endpoints include safety, duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596 .
Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor–Mutated Metastatic Non–Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722
Authors: Mok Tony , Nakagawa Kazuhiko , Park Keunchil , Ohe Yuichiro , Girard Nicolas , Kim Hye Ryun , Wu Yi-Long , Gainor Justin , Lee Se-Hoon , Chiu Chao-Hua , Kim Sang-We , Yang Cheng-Ta , Wu Chien Liang , Wu Lin , Lin Meng-Chih , Samol Jens , Ichikado Kazuya , Wang Mengzhao , Zhang Xiaoqing , Sylvester Judi , Li Sunney , Forslund Ann , Yang James Chih-Hsin 
Published: January 2024

PURPOSE The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251 ) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor ( EGFR)–mutated metastatic non–small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs). METHODS Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR). RESULTS Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively. CONCLUSION Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.
Training Performance Assessment for Intracranial Aneurysm Clipping Surgery Using a Patient-Specific Mixed-Reality Simulator: A Learning Curve Study
Authors: Cuba Miguel , Vanluchene Hanne , Murek Michael , Goldberg Johannes , Müller Mandy D. , Montalbetti Matteo , Janosovits Katharina , Rhomberg Thomas , Zhang David , Raabe Andreas , Joseph Fredrick J. , Bervini David 
Published: January 2024

BACKGROUND AND OBJECTIVES:
The value of simulation-based training in medicine and surgery has been widely demonstrated. This study investigates the introduction and use of a new mixed-reality neurosurgical simulator in aneurysm clipping surgery, focusing on the learning curve and performance improvement.

METHODS:
Five true-scale craniotomy head models replicating patient-specific neuroanatomy, along with a mixed-reality simulator, a neurosurgical microscope, and a set of microsurgical instruments and clips, were used in the operation theater to simulate aneurysm microsurgery. Six neurosurgical residents participated in five video-recorded simulation sessions over 4 months. Complementary learning modalities were implemented between sessions. Thereafter, three blinded analysts reported on residents' use of the microscope, quality of manipulation, aneurysm occlusion, clipping techniques, and aneurysm rupture. Data were also captured regarding training time and clipping attempts.

RESULTS:
Over the course of training, clipping time and number of clipping attempts decreased significantly (P = .018, P = .032) and the microscopic skills improved (P = .027). Quality of manipulation and aneurysm occlusion scoring improved initially although the trend was interrupted because the spacing between sessions increased. Significant differences in clipping time and attempts were observed between the most and least challenging patient models (P = .005, P = .0125). The least challenging models presented higher rates of occlusion based on indocyanine green angiography evaluation from the simulator.

CONCLUSION:
The intracranial aneurysm clipping learning curve can be improved by implementing a new mixed-reality simulator in dedicated training programs. The simulator and the models enable comprehensive training under the guidance of a mentor.