tbuckley/cabot-search huggingface dataset:
Treatment of HER2 positive stage 4 breast cancer: When to stop anti-HER2 agents.
Authors: Yoshihiko Kamada, Naoko Takigami, Kanou Uehara, Kentaro Tamaki, Nobumitsu Tamaki
Journal: Journal of Clinical Oncology (2024)

e13027 Background: The goal of treatment of stage 4 breast cancer has been prolongation of live without compromising the quality of life of the patient and family. However, with the incorporation of anti-HER2 agents in the treatment of HER2 positive primary breast cancer, stage 4 disease of this subtype has become potentially curable. The issue is when or by what criteria anti-HER2 drugs can be discontinued, since continuation of expensive medication post cure could be considered to be financial toxicity, but then premature discontinuation might jeopardize a previously unattainable condition of cure. We endeavor to address this issue. Methods: The treatment and survival of 110 cases of Stage 4 primary breast cancer treated between April 2011 to December 2023 (i.e. 12-year period) in our institution was evaluated retrospectively. Results: The subtype by immuno-histiochemistry of the 110 cases is as follows; Luminal A - 17 cases, Luminal B - 23 cases, HER2-enriched - 13 cases, Luminal-HER2 - 17 cases, Triple negative - 6 cases. The 5 and 10 year survival rates according to subtype is as shown in the table. Of the surviving 25 HER2 positive (Luminal and Enriched) cases, 16 cases are still on anti-HER2 therapy, while 6 cases have discontinued. 3 cases have been lost to follow-up. The metastatic site/duration (months) of anti-HER2 therapy/observation time (months) post anti-HER2 therapy of the 6 cases are, ..... case 1: bone &amp; distant lymph-nodes / 19.0 / 11.2, ..... case 2: bone / 52.7 / 6.8, ..... case 3: bone / 76.2 / 2.1, ..... case 4: liver &amp; distant lymph-nodes / 80.8 / 19.3, ..... case 5: liver 6 bone / 103.8 / 24.9, and ..... case 6: lung / 120.0 / 11.4. The cCR status by imaging modalities of all 6 cases were confirmed by 6 months after initiation of anti-HER2 therapy. Case 5, who continued hormonal therapy (i.e. tamoxifen) for an additional 22 months, terminated anti-HER2 therapy after testing negative for ERBB2 related genes on liquid biopsy. Conclusions: This observational study suggests that in stage 4 HER2 positive primary breast cancer patients in which cCR is achieved within 6 months of initiation of anti-HER2 therapy, the treatment might safety be concluded after an additional 2 to 3 years of anti-HER2 therapy. Liquid biopsy for tumor related genes (e.g. ctDNA, miRNA) might facilitate decision making. Subtype Luminal A Luminal B Her2-enriched Luminal HER2 Triple Negative 5 year survival rate 74.0% 52.4% 53.5% 76.0% 0% 10 year survival rate not assessable 52.4% 53.5% 60.8% not assessable
Novel oleanolic acid derivative ZQL-4c as a target for SCD to modulate lipid metabolism reprogramming to overcome trastuzumab resistance in HER2 positive breast cancer.
Authors: Yiwen Ma, Shisheng Wang, Xiaorui Li, Xiangyu Guo, Cui Jiang, Tao Sun
Journal: Journal of Clinical Oncology (2024)

e13009 Background: Approximately 15% to 20% of patients with breast cancer are characterized as Human epidermal growth factor2 (HER2) positive with a high recurrence rate and a poor survival outcome. With the development and application of anti-HER2 drugs such as trastuzumab, the prognosis of patients with HER2-positive breast cancer has improved significantly. However, more than 30% of patients still experience treatment failure, recurrence, and distant metastasis due to drug resistance. It is therefore important to develop new drugs to overcome trastuzumab resistance and investigate the precise mechanism. Oleanolic acid (OA), one of the most common pentacyclic triterpenoids, has been shown to have significant benefits in treating tumors. Still, its clinical application is limited due to its poor bioavailability and target uncertainty. Methods: We synthesized ZQL-4c, a novel derivative of oleanolic acid with anti-tumor activity, which can target the reprogramming function of lipid metabolism of Stearoyl-CoA desaturase (SCD) to overcome resistance to trastuzumab in HER2 positive breast cancer, along with a panel from Dalian University of Technology. Results: After exploring the anti-tumor effects of ZQL-4c in trastuzumab-resistant tumors, we assessed overcoming resistance through the combination of ZQL-4c and trastuzumab. To further identify the SCD target of ZQL-4c, we used multi-omics association and molecular docking technology and established drug-resistant tumor models with SCD overexpression in vivo and ex vivo. We found that targeting SCD could inhibit de novo lipid synthesis, thus inducing lipotoxicity-mediated apoptosis and exerting the effect of overcoming resistance to trastuzumab. Conclusions: In summary, our observations that the novel oleanolic acid derivative ZQL-4c inhibits apoptosis induced by lipotoxicity by targeting SCD provides an attractive future direction for treating HER2-positive trastuzumab-resistant breast cancer.
Real world experience with cyclin dependent kinase inhibitors in metastatic breast cancer from India.
Authors: Pankaj Goyal, Anindya Mukherjee, Rupal Tripathi, Dinesh Chandra Doval, Vineet Talwar, Sumit Goyal, Ullas Batra, Rajat Saha, Parveen Jain, Varun Goel, Mansi Sharma, Shivashankara Swamy Mathighatta Shivarudraiah, Arpit Jain, Anurag Mehta, Kalpana Upreti, Manoj Gupta, Sunil Pasricha, Sekhar Saha, Dharmishtha Ashis Basu, Abhinav Dewan
Journal: Journal of Clinical Oncology (2024)

e13003 Background: Patients in thehormone receptor positive/ herceptin2- (HR+/HER2-) subset have better prognosis among all molecular sub types of breast cancer, however, most patients ultimately progress on treatment with traditional endocrine therapies. The present study was conducted to evaluate the real world experience with Cyclin dependent kinase (CDK) 4/6 inhibitors Palbociclib and Ribociclib by evaluating the efficacy and toxicity profile in HR+/HER2- metastatic breast cancer. Methods: Thisstudy was conducted on the HR+/HER2- metastatic breast cancer patients who received Palbociclib/ Ribociclib in the first line or recurrent setting between January 2021 and January 2023 along with endocrine therapy. Clinical and demographic information and survival data was retrieved from the Hospital medical records. Results: Among a total of143 patients, 93 and 50 patients had received Palbociclib and Ribociclib, respectively. The most common factors in both the groups were age group 45-64 years (65.7%), postmenopausal status (65.7%), ECOG Performance status 1 (46.2%) and denovo disease at presentation (58%). The overall response rate was 90.2%. Majority of the patients showed partial response (64.3%) followed by stable disease (20.3%) in either group. In the patients receiving Palbociclib, a better median progression free survival (PFS) was observed in patients with ECOG performance status (PS) 1 (27.3 months, p-value &lt; 0.0001), denovo disease (17.5 months, p-value 0.0155), first line hormonal therapy (22.5 months, p-value &lt; 0.0001) and no prior chemotherapy (20.3 months, p-value 0.0001). Similarly, in the patients receiving Ribociclib, a better median PFS was observed in patients with ECOG PS 1 (22.2 months, p-value &lt; 0.0001), denovo disease (21.7 months, p-value 0.0042), first line hormonal therapy 22.5 months (p-value &lt; 0.0001) and no prior chemotherapy (21.7 months, p-value &lt; 0.0001). On multivariate analysis, the factors significantly associated with PFS were ECOG PS, line of hormone therapy and prior chemotherapy (p-values &lt; 0.0001, &lt; 0.0001 &amp; 0.0269, respectively). Anaemia &amp; transaminitis were the most common toxicities in both drug cohorts [Palbociclib (97.8% &amp; 75.3%, respectively) &amp; Ribociclib (96.5% &amp; 82%, respectively). Overall, dose modification due to toxicity was not required in 67.8% patients. Conclusions: The present study shows the real world experience with the effectiveness and tolerability of CDK inhibitors in metastatic breast cancer in India. However, large scale multi-centric studies are required to evaluate the pan India experience with these inhibitors.
Cost-effectiveness analysis of contemporary first-line (1L) agents in locally advanced/metastatic urothelial carcinoma (la/mUC).
Authors: Syed Arsalan Ahmed Naqvi, Kunwer Sufyan Faisal, Ammad Raina, Kaneez Zahra Rubab Khakwani, Zaryab Bin Riaz, Vishal S. Shah, Ewan Kemar Cobran, Parminder Singh, Syed A. Hussain, Alan Haruo Bryce, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2024)

4591 Background: EV-302 and CheckMate 901 demonstrated significant survival benefit with enfortumab vedotin-pembrolizumab (EVPembro) and gemcitabine-cisplatin-nivolumab (GemCisNivo) as 1L therapy, respectively, in patients (pts) with la/mUC. However, whether these treatments are cost-effective or not remains unclear. Methods: A three-state Markov model (progression-free, progression and death) was developed. State utilities were derived from published literature. State transition probabilities were informed from point-probabilities and hazard ratios for OS and PFS obtained from the latest follow-up of eligible trials. Average sales price (2024 USD) for individual treatments (excluding ancillary charges) were obtained from the center of medicare and medicaid services (US payer’s perspective). Treatment strategies were modeled in accordance with the dose/schedule reported in the eligible trials. Pts who received GemCis or Gem-carboplatin (GemCarbo) and did not progress were modeled to receive Avelumab maintenance. Half-cycle corrected costs and utilities were accrued over a 10-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to estimate quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold (WTP) of 100,000$ per QALY was used. Results: In cisplatin-eligible pts, GemCisNivo demonstrated a 0.8 QALY gain over GemCis at an ICER of 21,127 ($/QALY). GemCisNivo was also associated with an incremental net monetary benefit (INMB) of 63,099$ relative to GemCis. EVPembro demonstrated a 2.4 QALY gain over GemCis at an ICER of 915,283 and a 1.6 QALY gain over GemCisNivo at an ICER of 1,406,308. In cisplatin-ineligible pts, EVPembro demonstrated a 2.4 QALY gain over Gem-carboplatin (GemCarbo) at an ICER of 934,761. Price threshold analyses demonstrated that EVPembro is likely to be cost-effective at a cost of 12,344$ for cisplatin-eligible and 13,374$ per cycle for cisplatin-ineligible pts (original cost: 35,665.60$ per cycle). Sensitivity analysis using a total of 12 cycles for EVPembro showed cost-effectiveness at an ICER of 69,594 relative to GemCisNivo in cisplatin-eligible pts, and at an ICER of 53,099 relative to GemCarbo in cisplatin-ineligible pts. Conclusions: In terms of US payer’s perspective, GemCisNivo is most likely to be cost-effective in cisplatin-eligible pts at the WTP of 100,000 $/QALY. Limiting the number of cycles for EVPembro may render it as a cost-effective 1L treatment in la/mUC pts regardless of cisplatin-eligibility status.
A non-invasive cfDNA fragmentomics assay for differentiating malignant and benign thyroid nodules.
Authors: Zhen Shan, Wanna Chen, Bo Lin, Wanxiangfu Tang, Xiaoxi Chen, Xuxiaochen Wu, Ruowei Yang, Shuang Chang, Dongqin Zhu, Hua Bao, Weiming Lv
Journal: Journal of Clinical Oncology (2024)

6110 Background: Thyroid cancer (TC) is the most common endocrine malignancy in the world. Although it has a high survival rate, distinguishing between the common benign thyroid nodules and malignant ones remains a clinical challenge. We introduce a non-invasive assay based on cfDNA fragmentomics, aimed at accurately identifying TCs, thus reducing the discomfort and risks linked to surgical biopsies. Methods: We conducted a study involving 322 participants, comprising 161 early-stage thyroid cancer patients (154 stage I and 7 stage II) and 161 patients with benign thyroid nodules, of whom 68 were high-risk (Ti-Rads: 4/5) and 93 were low-risk (Ti-Rads = 2/3). The training cohort contained 94 TC and 98 BN patients, while the independent test cohort included 67 TC and 63 BN patients. Malignant and high-risk benign conditions were confirmed pathologically from surgically removed biopsy samples. Pre-operative plasma samples were collected from all patients and used for cell-free fragmentomics feature generation through low-pass WGS. A stacked machine learning model was developed using three fragmentomics features and three machine learning algorithms. Results: The machine learning model excelled in differentiating thyroid cancer from benign nodules, achieving area under the curve (AUC) scores of 0.973 in the training cohort and 0.965 in the independent test cohort. The model demonstrated high sensitivity (94.7% in the training cohort and 95.5% in the test cohort) and specificity (89.8% in the training cohort and 77.8% in the test cohort) after applying an optimized cutoff determined by cross-validation of the training cohort. Notably, the model was particularly effective in detecting malignant nodules smaller than 1cm, a task challenging for conventional methods, with sensitivities of 92.4% in the training cohort and 91.6% in the test cohort. For nodules larger than 1cm, the model achieved a perfect 100% sensitivity in both cohorts. Our predictive model showed universal excellent performance for accurately detecting TC patients with different histology, sex, and age in both the training cohort and the independent test cohort. Finally, the high-risk BN group showed higher risk scores compared to the low-risk BN group as expected, further validating the robustness of our model. Conclusions: Our study presents a non-invasive liquid biopsy assay, which utilizes fragmentomics profiling derived from low-pass WGS for differentiating between malignant and benign thyroid nodules, showcasing remarkable sensitivity and specificity. Our assay was able to accurately detect thyroid malignancies, especially in nodules smaller than 1cm, illustrating great clinical potential and therefore offers a promising alternative to surgical biopsies, potentially reducing patient discomfort and associated risks.
Do Large Language Model Chatbots perform better than established patient information resources in answering patient questions? A comparative study on melanoma
Authors: Nadia CW Kamminga, June EC Kievits, Peter W Plaisier, Jake S Burgers, Astrid M van der Veldt, J A G J van den Brand, M Mulder, Marlies Wakkee, Marjolein Lugtenberg, Tamar Nijsten
Journal: British Journal of Dermatology (2024)

Abstract Background Large Language Models (LLMs) have a potential role in providing adequate patient information. Objectives To compare the quality of LLMs’ responses with established Dutch patient information resources (PIRs) in answering patient questions regarding melanoma. Methods Responses from ChatGPT versions 3.5 and 4.0, Gemini, and three leading Dutch melanoma PIRs to 50 melanoma-specific questions were examined at baseline and for LLMs again after eight months. Outcomes included (medical) accuracy, completeness, personalisation, readability, and additionally reproducibility for LLMs. Comparative analyses were performed within LLMs and PIRs using Friedman’s ANOVA, and between best-performing LLMs and gold-standard PIR using Wilcoxon Signed Ranks test. Results Within LLMs, ChatGPT-3.5 demonstrated the highest accuracy (p=0.009). Gemini performed best in completeness (p&amp;lt;0.001), personalisation (p=0.007), and readability (p&amp;lt;0.001). PIRs were consistent in accuracy and completeness, with the general practitioner’s website excelling in personalisation (p=0.013) and readability (p&amp;lt;0.001). The best-performing LLMs outperformed the gold-standard PIR on all criteria except accuracy. Over time, response reproducibility decreased for all LLMs, showing variability across outcomes. Conclusions Although LLMs show potential in providing highly personalised and complete responses to patient questions regarding melanoma, improving and safeguarding accuracy, reproducibility and accessibility is crucial before they can replace or complement conventional PIRs. This study compared the quality of responses from Large Language Models (LLMs) with established Dutch patient information resources (PIRs) for melanoma-related patient questions. Results showed LLMs provided highly personalised and complete answers, often surpassing PIRs. However, improving and safeguarding accuracy, reproducibility and accessibility is crucial before they can replace or complement conventional PIRs.
CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13
Authors: Jean Ching-Yi Tien, Jie Luo, Yu Chang, Yuping Zhang, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Somnath Mahapatra, Palak Shah, Xiao-Ming Wang, Abigail J. Todd, Sanjana Eyunni, Caleb Cheng, Ryan J. Rebernick, Lanbo Xiao, Yi Bao, James Neiswender, Rachel Brough, Stephen J. Pettitt, Xuhong Cao, Stephanie J. Miner, Licheng Zhou, Yi-Mi Wu, Estefania Labanca, Yuzhuo Wang, Abhijit Parolia, Marcin Cieslik, Dan R. Robinson, Zhen Wang, Felix Y. Feng, Jonathan Chou, Christopher J. Lord, Ke Ding, Arul M. Chinnaiyan
Journal: Cell Reports Medicine (2024)

Highlights d Cdk12 ablation induces preneoplastic prostate lesions with T cell infiltration d Cdk12 loss mediates genomic instability through
Survival and safety analysis of eribulin in Indian patients with metastatic breast cancer: A real world clinical experience.
Authors: Pankaj Goyal, Dinesh Chandra Doval, Shweta Jain, Vineet Talwar, Sumit Goyal, Ullas Batra, Rajat Saha, Varun Goel, Parveen Jain, Mansi Sharma, Shivashankara Swamy Mathighatta Shivarudraiah, Arpit Jain, Kalpana Upreti, Sunil Pasricha, Manoj Gupta, Anurag Mehta, Abhinav Dewan, Anindya Mukherjee, Sekhar Saha, Dharmishtha Ashis Basu
Journal: Journal of Clinical Oncology (2024)

e13002 Background: Eribulin is a synthetic non-taxane anti-microtubule agent approved in India for the second line of treatment of locally advanced or metastatic breast cancer. Eribulin has shown to improve overall survival (OS) in various subgroups of patients with metastatic breast cancer (MBC) who were pretreated with an anthracycline and taxane. However, efficacy and safety data for eribulin in Indian patients with MBC is limited. Therefore, this real world study assessed the clinical outcomes of eribulin in heavily pre-treated MBC Indian females. Methods: Histologically confirmed adult MBC patients who received eribulin over several lines of therapy were retrospectively analysed. Socio-demographic, clinical, pathology, imaging, and therapy records were reviewed. The progression-free survival (PFS), overall survival (OS), tumor response and safety were evaluated. Results: A total of 189 patients were included and out of these patients 145 patients were analysed. The median age of patients was 52 years (range: 28-71). Eribulin was used as a 2 nd , 3 rd , 4 th and ≥ 5 th line chemotherapy agent in 17 (11.72%), 27 (18.62%), 44 (30.34%) and 57(39.31%) of MBC patients, respectively. In the overall population, the objective response rate (ORR) was 7.58%, while the clinical benefit rate (CBR) was 15.48%. The median PFS and OS were 3.86 (95% CI: 3.18-4.54) and 11.56 (95% CI: 8.72-14.40) months respectively. There was positive correlation between the number of eribulin cycles and the outcomes of survival, with patients getting more than 3 cycles having significantly superior OS and PFS. On subgroup analysis, there was no significant difference in the outcomes of survival on the basis of hormone receptor and her-2 status, however the patients who had more than 3 metastatic sites had significantly lower survival outcomes. The anthracycline and taxane refractory (progression within 6 months after their last anthracycline/taxane dose) patients had significantly (p&lt;0.001) lower median PFS as compared to anthracycline and taxane sensitive patients (2.96 months vs 5.23 months) and (2.86 months vs 4.46 months) respectively. Among the grade ≥3 toxicities, neutropenia was 26.21%, anemia was 13.10%, thrombocytopenia was 6.21% and mucositis was 8.97%. The grade ≥2 peripheral neuropathy was seen in 28.97% patients and 21.38% patients had gastro-intestinal symptoms. Conclusions: This study confirms that Eribulin is effective and has manageable toxicity in patients with MBC. It should be considered as the strategy of several chemotherapy lines in MBC.
The temporal dynamics of the gut mycobiome and its association with cardiometabolic health in a nationwide cohort of 12,641 Chinese adults
Authors: Wanglong Gou, Huijun Wang, Chang Su, Yuanqing Fu, Xinyu Wang, Chang Gao, Menglei Shuai, Zelei Miao, Jiguo Zhang, Xiaofang Jia, Wenwen Du, Ke Zhang, Bing Zhang, Ju-Sheng Zheng
Journal: Cell Reports Medicine (2024)

The dynamics of the gut mycobiome and its association with cardiometabolic health remain largely unexplored. Here, we employ internal transcribed spacer (ITS) sequencing to capture the gut mycobiome composition and dynamics within a nationwide human cohort of 12,641 Chinese participants, including 1,946 participants with repeated measurements across three years. We find that the gut mycobiome is associated with cardiometabolic diseases and related biomarkers in both cross-sectional and dynamic analyses. Fungal alpha diversity indices and 19 mycobiome genera are the major contributors to the mycobiome-cardiometabolic disease link. Particularly, Saccharomyces emerges as an effect modifier of traditional risk factors in promoting type 2 diabetes risk. Further integration of multi-omics data reveals key metabolites such as γ-linolenic acid and L-valine linking the gut mycobiome to type 2 diabetes. This study advances our understanding of the potential roles of the gut mycobiome in cardiometabolic health.
Modeling high-risk Wilms tumors enables the discovery of therapeutic vulnerability
Authors: Gui Ma, Ang Gao, Jiani Chen, Peng Liu, Rakesh Sarda, Jessica Gulliver, Yidan Wang, Carstyn Joiner, Mingshan Hu, Eui-Jun Kim, Herman Yeger, Hau D Le, Xiang Chen, Wan-Ju Li, Wei Xu
Journal: Cell Reports Medicine (2024)

Wilms tumor (WT) is the most common pediatric kidney cancer treated with standard chemotherapy. However, less-differentiated blastemal type of WT often relapses. To model the high-risk WT for therapeutic intervention, we introduce pluripotency factors into WiT49, a mixed-type WT cell line, to generate partially reprogrammed cells, namely WiT49-PRCs. When implanted into the kidney capsule in mice, WiT49-PRCs form kidney tumors and develop both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrate that WiT49-PRCs recapitulate blastemal-predominant WTs. Moreover, drug screening in isogeneic WiT49 and WiT49-PRCs leads to the identification of epithelial- or blastemal-predominant WT-sensitive drugs, whose selectivity is validated in patient-derived xenografts (PDXs). Histone deacetylase (HDAC) inhibitors (e.g., panobinostat and romidepsin) are found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRCs serve as a blastemal-predominant WT model for therapeutic intervention to treat patients with high-risk WT.
Rapid design of bacteriophage cocktails to suppress the burden and virulence of gut-resident carbapenem-resistant Klebsiella pneumoniae
Authors: Ella Rotman, Sandra McClure, Joshua Glazier, Jay Fuerte-Stone, Jonathan Foldi, Ali Erani, Rory McGann, Jack Arnold, Huaiying Lin, Sandra Valaitis, Mark Mimee
Journal: Cell Host & Microbe (2024)