tbuckley/cabot-search huggingface dataset:
Comparing the mutation profiles of primary HER2-positive breast cancers in patients with and without brain metastases.
Authors: Tian Du, Peng Sun, Yuhong Chen, Rong Deng, Jun Tang
Journal: Journal of Clinical Oncology (2024)

e13018 Background: Brain metastasis is a frequent and devastating event of HER2-positive breast cancer. Identifying the driver genes of brain metastasis is important for the prevention and treatment of brain metastasis. In this study, we compared the gene mutation profiles of primary breast cancers between patients with and without brain metastases, aiming to identify new candidate genes associated with brain metastases. Methods: HER2-positive and lymph node-positive early breast cancers of 21 patients who eventually developed brain metastases (BM group) and 27 patients without any metastasis (NM group) at a minimum 5-year follow-up were retrieved from the Sun Yat-sen University Cancer Center. Whole-exome sequencing was performed on primary breast cancers (FFPE) and matched normal breast tissues or peripheral blood. Mutect2 was used to detect somatic mutations, and Fisher’s exact test was used to identify genes mutated at different frequencies in the BM and NM groups. The mRNA expression changes of genes mutated at higher frequencies in the BM group were further analyzed in 16-pair matched HER2-positive primary breast cancers and brain metastases using the public dataset (1). Results: The BM and NM groups exhibited similar TP53 (33.3% vs. 55.6%, p=0.15) and PIK3CA (23.8% vs. 25.9%, p=1) mutation rates. The mutation rates of AP3B1 (38.1% vs. 3.7%), DHTKD1 (23.8% vs. 0), ERCC6L2 (38.1% vs. 7.4%), DNAH5 (33.3% vs. 3.7%), ZNF207 (33.3% vs. 7.4%), SPATA31E1 (19.0% vs. 0), FAM111B (19.0% vs. 0), ATG3 (19.0% vs. 0), CDK14 (19.0% vs. 0), TUT4 (19.0% vs. 0), CCNB3 (19.0% vs. 0), MGA (19.0% vs. 0), CLCA1 (28.6% vs. 3.7%), BBS7 (28.5% vs. 3.7%) and GABRG1 (38.1% vs. 11.1%) were significantly (p&lt;0.05) higher in the BM group than in the NM group. Among these genes, CDK14 and TUT4 were significantly downregulated, and ZNF207 and FAM111B were significantly upregulated in brain metastases compared to their matched primary breast cancers. Conclusions: We identified several genes with higher mutation rates in primary breast cancer of patients who eventually developed brain metastases. These genes warrant further investigation in the development of brain metastases in HER2-positive breast cancer. 1. Cosgrove et al. NC 2022.
Translational history and hope of immunotherapy of canine tumors
Authors: Jeffrey N. Bryan, Charles A. Maitz
Journal: Clinical Cancer Research (2024)

Abstract Companion dogs have served an important role in cancer immunotherapy research. Sharing similar environments and diets with humans, dogs naturally develop many of the same cancers. These shared exposures, coupled with dogs’ diverse genetic makeup, make them ideal subjects for studying cancer therapies. Tumors like osteosarcoma, hemangiosarcoma, soft-tissue sarcoma, and non-Hodgkin lymphoma occur with greater frequency than their counterpart disease in humans. Canine brain tumors allow the study of therapy strategies with imaging, surgery, and radiotherapy equipment in veterinary patients with near-human geometry. Nonspecific immunostimulants, autologous and allogeneic vaccines, immune checkpoint inhibitors, and cellular therapies used in treating canine cancers have been tested in veterinary clinical trials. These treatments have not only improved outcomes for dogs but have also provided valuable insights for human cancer treatment. Advancements in radiation technology and the development of tools to characterize canine immune responses have further facilitated the ability to translate veterinary clinical trial results to human applications. Advancements in immunotherapy of canine tumors have directly supported translation to human clinical trials leading to approved therapies for patients with cancer around the world. The study of immunotherapy in dogs has been and will continue to be a promising avenue for advancing human cancer treatment.
Clinical guidelines for early hepatocellular carcinoma treatment options: a systematic review and bibliometric analysis
Authors: Chun-Ying Wu, Lee-Yuan Lin, Teng-Yu Lee, Yao-Chun Hsu, Chun-Chieh Yeh, Chiehfeng Chen, Yi-No Kang, Tsai-Wei Huang
Journal: International Journal of Surgery (2024)

Background: Hepatocellular carcinoma remains a major cause of cancer-related mortality worldwide, with treatment options including radiofrequency ablation (RFA) and surgical resection. This study evaluates the evolving guidelines for these treatments to identify the current consensus and divergences. Method: The authors conducted a systematic review following PRISMA 2020 guidelines of documents from 2017 to 2024 by major liver societies. The AGREE-II framework assessed guideline quality. This study is registered with PROSPERO (CRD42022342266). Results: The authors analyzed 23 guidelines and noted significant shifts in treatment recommendations over recent updates. This analysis reveals an increasing endorsement of RFA for certain patient groups and sustained strong support for surgical resection based on robust evidence levels. All demonstrated high quality, with the 2023 Japan Guidelines receiving the highest AGREE-II score. A significant finding was the low level of stakeholder involvement in the development of guidelines. Conclusion: The study highlights the dynamic nature of clinical guidelines for early-stage hepatocellular carcinoma, underscoring the need for ongoing updates and direct, high-quality comparative studies. The evolving recommendations for RFA, especially its role in managing small, localized tumors, reflect its emerging importance in the treatment paradigm.
Stem cell transplantation therapy for advanced liver damage -associated neurodegenerative disorders
Authors: Anjna Sharma, Ameya Sharma, Divya Dheer, Raghu Rai Sharma, Vivek Puri, Shabana Bibi, Amina Shamas, Sameeullah Memon, Rajat Goyal, None Priyanka, Hitesh Chopra
Journal: International Journal of Surgery (2024)

Hepatic encephalopathy and other neurodegenerative disorders have profound implications for extensive liver impairment, calling for new ways of treating the condition. The application of stem cell transplantation to treat these severe disorders is a new and encouraging technique. This review article digs deep into the subject of stem cell transplantation therapy, neurodegenerative disorders associated with advanced liver damage, and liver transplantation. It comprehensively analyses the background, rationale, scope, and objectives of using stem cells to treat such challenging conditions. The topic of discussion includes the subtleties of neurodegenerative disorders, the function of liver transplantation, and the possible advantages and disadvantages associated with it. The relevance of patient selection, intraoperative concerns and post-transplant care is discussed. Further, the article explores how stem cell-based therapies can benefit from nanotechnology, specifically how it can improve stem cell distribution, survival, and integration for better therapeutic results. This review aims to offer a thorough analysis of regenerative medicine's present and future possibilities in dealing with the intricate relationship between neurodegeneration and liver damage. It does this by examining the efficacy, safety, and long-term impacts of stem cell transplantation in treating neurodegenerative disorders associated with advanced liver damage. This will incorporate insights from ongoing clinical trials, the patent landscape, and future directions. The goal is to pave the way for innovative and personalized treatment approaches in this evolving research and clinical practice field. Therefore, these efforts represent a promising frontier in medical research that can alleviate the burden of HE and associated neurological complications combined with liver cirrhosis.
Lipid Screening in Children and Adolescents—A Missed Opportunity to Improve Lifelong Health
Authors: Stephen R. Daniels
Journal: JAMA Network Open (2024)

Angela M. Thompson-Paul, PhD, MSPH; Emily M. Kraus, PhD, MPH; Renee M. Porter, DNP; Samantha L. Pierce, MPH; Lyudmyla Kompaniyets, PhD; Ahlia Sekkarie, PhD, MPH; Alyson B. Goodman, MD, MPH; Sandra L. Jackson, PhD, MPH
Neoadjuvant docetaxel-cisplatin followed by concurrent chemoradiotherapy and adjuvant tislelizumab for locally advanced nasopharyngeal carcinoma: A multicenter, single-arm, phase II trial.
Authors: Yawei Yuan, Yunhong Tian, Huang Zhong, Ronghui Zheng, Lin Jie, Jian Zhang, Kai Liao, Jin Deng, Yi Yu, Wenze Qiu, Junguo Bu, Rong Zheng, Benhua Xu, Yong Chen
Journal: Journal of Clinical Oncology (2024)

e18047 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) have a high risk of distant metastasis or recurrence despite the current standard of neoadjuvant chemotherapy and concurrent chemoradiation (CCRT), indicating the need of more comprehensive treatment. Due to good compliance and convenient adverse event management, the TP (docetaxel and cisplatin) regimen is more widely accepted and commonly used as a neoadjuvant chemotherapy for LA-NPC in the real world. Immune checkpoint blockade therapy plus chemotherapy has been shown to improve the survival in recurrent or metastatic NPC. We investigated the efficacy and safety of tislelizumab, an anti-PD-1 monoclonal antibody, as adjuvant treatment in patients with LA-NPC that had the neoadjuvant TP chemotherapy and CCRT. Methods: This multicenter, open label, single arm, phase II clinical trial was done at four hospitals in China. Patients (aged 18-65 years) with histologically confirmed, LA-NPC (T4N1 and T1-4N2-3) were enrolled and treated with neoadjuvant chemotherapy for 3 cycles (docetaxel 75 mg/m 2 D1, cisplatin 75 mg/m 2 D1) followed by concurrent cisplatin (100mg/m 2 , D1 and D22) during intensity-modulated radiation (IMRT). Four weeks post-RT, tislelizumab (200 mg) was given intravenously once every 3 weeks for up to 12 cycles. By Fleming one-stage design (type I error 0.05, power 0.80, 10% drop out), planned sample size is 100. Primary endpoint is 3-year (yr) progression free survival (PFS). Secondary endpoints include safety and tolerability. Results: From June 2021 to January 2024, a total of 100 patients (median age 53y, 73.0% male) were recruited at four study sites. This protocol specified analysis included 78 subjects with &gt;12 months post-treatment follow up (median 26.2 months, 95% CI 21.3-30.1). Overall compliance rate: neoadjuvant cisplatin + docetaxel 97.5%, concurrent cisplatin 80.8%, adjuvant tislelizumab 78.2%, IMRT 99.7% (69.96 Gy). Treatment related adverse events (AEs, ≥grade 3, &gt;10%): dysphagia (30.5%), mucositis (26.2%), neutropenia(26.7%), radiation dermatitis (23.7%), anemia (16.2%). No ≥grade 4 mucositis/dermatitis. In addition, the incidence of immune-related adverse events (irAEs) of grade 3 or 4 was 5.2%, and all were thyroid toxicity and skin rash. The 2-yr PFS and 2-yr overall survival were 89.6% (95% CI 53.8 - 88.5%) and 100%, respectively. 3-yr PFS and long-term efficacy are awaited. Conclusions: Tislelizumab adjuvant therapy after neoadjuvant docetaxel -cisplatin followed by CCRT is safe with promising results for LA-NPC. However, further follow-up is needed to confirm the long-term efficacy. Clinical trial information: NCT04870905 .
Advancements in AI-driven Oncology: Assessing ChatGPT’s Impact from GPT-3.5 to GPT-4o
Authors: Lin-Jie Mu, Ting-Ting Wang, Yan-Dong Miao
Journal: International Journal of Surgery (2024)

aDepartment of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650000, China bCancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China Lin-Jie Mu, Ting-Ting Wang These authors contributed equally to this work. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ ⁎Corresponding author. Address: Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China. E-mail: [email protected] (Y. D. Miao). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Effect of RGT-61159 on inhibition of oncogene c-MYB synthesis and tumor growth inhibition in a broad range of ACC PDX models, at well tolerated doses in rodents and non-human primates.
Authors: Simon Xi, Patricia Soulard, Kai Li, Xiubin Gu, Ibrahim Kay, Sam Hasson, Chris Yates, Heather Sadlish, Jay Lee, Zhiping Weng, Simon Xu, Travis Wager
Journal: Journal of Clinical Oncology (2024)

6107 Background: RGT-61159 is a first in-class oral inhibitor of the oncogenic transcription factor c-MYB via selective alteration of its RNA splicing machinery. RGT-61159 selectively induces the inclusion of the cryptic “poison” exon into the c-MYB RNA transcripts, resulting in the robust elimination of c-MYB canonical mRNA transcript and consequently of its protein in cells. Overactivation of the c-MYB oncogene, primarily due to chromosome rearrangements, is a hallmark of adenoid cystic carcinoma. (ACC). ACC is a rare and aggressive type of cancer for which effective treatment does not exist. By inhibiting oncogenic MYB protein production, RGT-61159 has the potential to efficiently and selectively inhibit proliferation or induce cell death of cancer cells overexpressing MYB protein. Methods: RGT-61159 cell killing activity was measured against a broad panel of cancer cell lines in a CellTiter-Glo assay. MYB RNA and MYB protein levels were assessed after drug treatment by RT-qPCR and JESS assay respectively. Anti-tumor activity of RGT-61159 as single agent or in combination was evaluated in a panel of ACC PDX mouse models harboring different molecular alterations in c-MYB, including ACCX6, ACCX11, ACCx5M1 and ST105B2. Results: Here, we showed that RGT-61159 has potent cancer cell killing activity (EC50 – 100nM -200nM) against a large panel of cancer cell lines overexpressing c-MYB, while sparing normal cells. Robust c-MYB RNA and c-MYB protein depletion (&gt;80%) was observed in treated cells confirming RGT-61159 on-target cell killing effect. In addition, RGT-61159 single agent showed a remarkable anti-tumor activity (up to 90% TGI) at tolerated doses in the four ACC PDX models evaluated: ACCX6, ACCx11, ACCx5M1 and STB105B2. Importantly, we confirmed that RGT-61159 anti-tumor activity correlated with c-MYB target modulation. RGT-61159 efficacious doses reduced c-MYB transcript and c-MYB protein levels (by &gt;80%) in all ACC PDx models evaluated. In addition, RNAseq analysis of ACC tumor after treatment showed that RGT-61159 drug treatment reversed the published ACC overexpression gene signature. Notably, the optimal RGT-61159 regimen was well tolerated, as assessed by changes in animal body weight and clinical signs in rodents and non-human primate. Finally, we showed that the combination of RGT-M001, an analog of RGT-61159, with the NOTCH Inhibitor AL-101 resulted in significant tumor regression at well tolerated doses. Conclusions: Altogether, these data demonstrated that RGT-61159 efficiently and safely targets the undruggable oncogenic transcription factor c-MYB. Down-regulation of c-MYB by the RGT-61159 RNA-targeting small molecule is a very promising therapeutic strategy to treat ACC and other cancers driven by c-MYB dysregulation.
Pyrotinib in HER2-altered advanced salivary gland carcinomas: Analysis of two cohorts from an exploratory study.
Authors: Shengjin Dou, Lin Zhang, Wen Jiang, Lulu Ye, Rongrong Li, Guopei Zhu
Journal: Journal of Clinical Oncology (2024)

6108 Background: The HER2 altered in a subset of salivary gland cancers (SGCs). Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting HER1, HER2, and HER4. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-amplified/overexpressed/mutated advanced SGCs, including recurrent/metastatic(R/M) and locally advanced (LA) patients with high-risk of recurrence. Methods: R/M and high-risk LA SGCs with HER2-alteration were enrolled. Pyrotinib (400 mg) was given orally once daily. In LA cohort, pyrotinib were given as adjuvant therapy after standard surgery and postoperative radiation. Results: Between August 2019 and August 2023, 18 patients were enrolled (10 in R/M cohort and 8 in LA cohort). In R/M cohort, the median age was 58.5 years, and all patients were grade III. The ORR was 90%, including 2 CRs, 7 PRs and 1PD; median DOR was 5.7 months (range: 3.1-13.7) and median PFS was 7.6 months (range: 2.7-16.8). In LA cohort, the median age was 59.0 years, and all patients but one were grade III. All patients but one had T4 disease; 5 patients had N3 and 2 had N2b disease; 5 patients had ENE and 5 patients had positive margin. With a median follow up 21.3 months, only 3 patients experienced recurrence, and one patient died due to non-tumor reasons. The estimated 2-years PFS and 2-years OS were 75% and 100%. The most common adverse event was diarrhea, which occurred in 11/18 (61.1%) patients and 3/18 (16.7%) were grade III. Conclusions: Pyrotinib showed promising antitumor activity in recurrent/metastatic HER2-altered SGCs, and had a potential to prolong survival outcome as adjuvant treatment in LA patients setting, which needs further randomized studies. Clinical trial information: NCT05087706 .
Phase II trial of regorafenib in metastatic medullary thyroid carcinoma (MTC) and radioactive iodine refractory differentiated thyroid carcinoma (RAIR DTC).
Authors: Kartik Sehgal, Ruichao Shi, Theodora Pappa, Judy K Min, Liam B Oakley, Anne ONeill, Michael J. Dennis, Hari Anant Deshpande, Robert I. Haddad, Jochen H. Lorch
Journal: Journal of Clinical Oncology (2024)

6109 Background: Multi-kinase inhibitors show activity in both MTC &amp; RAIR DTC. However, therapeutic options are limited after disease becomes refractory to one or two lines of standard of care therapies. We report here results of an investigator-initiated phase II clinical trial evaluating regorafenib in this population (NCT02657551). Methods: Patients with MTC (disease progression within 6-12 months, mo, prior to study registration) and RAIR DTC (progression within 12 mo) were enrolled regardless of prior lines of therapy. Regorafenib (each cycle 3 weeks ON/1 week OFF) was started at 80 mg daily, with planned escalation after 1 &amp; 2 weeks to 120 mg daily &amp; 160 mg daily, respectively, in absence of significant treatment-related adverse events (TRAEs). The highest tolerated dose was continued from cycle 2 onwards until progression. The primary endpoints were proportion progression-free at 10 months in MTC &amp; overall response rate (ORR) by RECIST v1.1 in RAIR DTC. Simon two-stage design was utilized; MTC: &lt;2 in 8 progression-free in first stage stops for futility, stage 2: enroll 13, &gt;6/21 provides 81% power for proportion &gt;20%; DTC: &lt;3 in 9 in response in first stage stops for futility; stage 2: enroll 11, &gt;7/20 provides 81% power for ORR &gt;25%. Results: 17 patients (8 MTC, 9 DTC) were enrolled between April 2016 and October 2022. Among MTC, median (range) age was 54.7y (48.1, 62.8), 25% female. Among DTC, median age (range) was 62.8y (44.3, 75.8), 55.6% female. In MTC group, the proportion progression-free at 10 months was 12.5% (95% CI 0.3%, 52.7%) &amp; did not meet the criteria to continue into 2 nd stage. ORR in MTC group was 12.5% (95% CI 0.3%, 52.7%). In DTC group, ORR was 11.1% (95% CI 0.3%, 48.2%), &amp; did not meet the criteria to continue into 2 nd stage. No patients were receiving treatment at cutoff. Patients with MTC and DTC with objective responses (1 each) had received one (vandetanib) &amp; no prior systemic therapy, respectively. The most common reason for discontinuation was disease progression in MTC (4, 50%) &amp; DTC (5, 55.6%). Grade 3-4 TRAEs were observed in 8/17 (47.1%), most frequent were diarrhea, hypophosphatemia, &amp; hypertension (each grade 3: 2, 11.7%). There were no treatment-related deaths. Median progression-free survival (PFS) in MTC &amp; DTC were 5.3 (95% CI 3.6, 20.1) &amp; 11.0 (95% CI 1.2, 24.0) mo, respectively. Median overall survival (OS) in MTC &amp; DTC were 16.1 (95% CI 5.2, NA) and 20.1 (95% CI 1.6, NA) mo, respectively. Conclusions: Regorafenib clinical trial did not reach its primary endpoints in MTC and DTC. Analyses are planned to investigate impact of prior VEGFR inhibitor exposure, biomarkers and resistance mechanisms. Clinical trial information: NCT02657551 . [Table: see text]
Prostate cancers with distinct transcriptional programs in Black and White men
Authors: Minhyung Kim, Patrick Tamukong, Gloria Cecilia Galvan, Qian Yang, Amanda De Hoedt, Michael R. Freeman, Sungyong You, Stephen Freedland
Journal: Genome Medicine (2024)

Abstract Background Black men are at a higher risk of prostate cancer (PC) diagnosis and present with more high-grade PC than White men in an equal access setting. This study aimed to identify differential transcriptional regulation between Black and White men with PC. Methods We performed microarray of radical prostatectomy tissue blocks from 305 Black and 238 White men treated at the Durham Veterans Affairs Medical Center. Differential expression, gene set enrichment analysis, master regulator analysis, and network modeling were conducted to compare gene expression by race. Findings were validated using external datasets that are available in the Gene Expression Omnibus (GEO) database. The first was a multi-institutional cohort of 1152 prostate cancer patients (596 Black, 556 White) with microarray data (GEO ID: GSE169038). The second was an Emory cohort of 106 patients (22 Black, 48 White, 36 men of unknown race) with RNA-seq data (GEO ID: GSE54460). Additionally, we analyzed androgen receptor (AR) chromatin binding profiles using paired AR ChIP-Seq datasets from Black and White men (GEO IDs: GSE18440 and GSE18441). Results We identified 871 differentially expressed genes between Black and White men. White men had higher activity of MYC-related pathways, while Black men showed increased activity of inflammation, steroid hormone responses, and cancer progression-related pathways. We further identified the top 10 transcription factors (TFs) in Black patients, which formed a transcriptional regulatory network centered on the AR . The activities of this network and the pathways were significantly different in Black vs. White men across multiple cohorts and PC molecular subtypes. Conclusions These findings suggest PC in Black and White men have distinct tumor transcriptional profiles. Furthermore, a highly interactive TF network centered on AR drives differential gene expression in Black men. Additional study is needed to understand the degree to which these differences in transcriptional regulatory elements contribute to PC health disparities.