tbuckley/cabot-search huggingface dataset:
A multicenter phase 1 trial of tucatinib, trastuzumab, and capecitabine with stereotactic radiosurgery in patients with brain metastases from HER-2–positive breast cancer (TUTOR).
Authors: Manmeet Singh Ahluwalia, Ahmad Ozair, Mainak Bardhan, Shreyas S Bellur, Dilanis C. Perche, Amy K. Starosciak, Daniel S. Leon-Ariza, Atulya Aman Khosla, Muni Rubens, Yazmin Odia, Minesh P. Mehta, Rupesh Kotecha, Michael W McDermott, Ana Cristina Sandoval-Leon, Reshma L. Mahtani, David M. Peereboom
Journal: Journal of Clinical Oncology (2024)

TPS2089 Background: 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), for which stereotactic radiosurgery (SRS) is used for local disease control. Tucatinib, an oral HER-2-selective tyrosine kinase inhibitor (TKI), has been demonstrated to be safe and efficacious in HER-2-positive breast cancer in combination with capecitabine and trastuzumab. The synergism between these three drugs and radiation may potentially enhance DNA damage, causing increased apoptosis. We hypothesize that this 3-drug therapy, in combination with SRS in patients with HER-2 positive breast cancer BM (BCBM), may be safe and provide superior long-term control of intracranial and systemic disease. Methods: This is a prospective, single-arm, multicenter, ongoing, phase 1 clinical trial. Patients aged 18-80 years, ECOG score 0-2, normal organ function, and up to 10 newly-diagnosed BMs is planned to enroll at six centers in the US. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, evidence of intra-tumoral or peri-tumoral hemorrhage, and BMs within 5 mm of the optic chiasm/nerve. Patients receive oral tucatinib alongside SRS, followed by a two-week dose-limiting toxicity (DLT) period, and subsequently continue the regimen until disease progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and grade 3 non-hematologic toxicity. Primary study endpoint is maximum tolerated dose (MTD) of tucatinib in combinatorial therapy. This de-escalation study starts at 300 mg dose level (DL), with DL-1 250 mg, and DL-2 200 mg, based on a 3 + 3 design. Cohort expansion at MTD is planned to a total of 40 patients. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, overall survival, quality of life as assessed by FACT-Br, toxicity, and neurocognitive function. The trial has been approved by the Institutional Review Board (IRB) and currently is enrolling patients. Clinical trial information: NCT05553522 .
Survival outcomes and treatment patterns by tumor subtype (TS) in stage III inflammatory and non-inflammatory breast cancer (BC).
Authors: Jose Pablo Leone, Julieta Leone, Faina Nakhlis, Ilana Schlam, Kelly Hirko, Aditi Hazra, Jennifer Ruth Bellon, Carlos Teodoro Vallejo, Nancy U. Lin, Sara M. Tolaney, Filipa Lynce
Journal: Journal of Clinical Oncology (2024)

607 Background: Inflammatory BC (IBC) is an aggressive form of BC for which trimodality therapy (TMT) is standard. We examined TMT use and compared BC-specific survival (BCSS) and overall survival (OS) between IBC and non-IBC within TS. We also examined survival changes over time. Methods: We evaluated patients (pts) with stage III BC diagnosed 2010 - 2020, using Surveillance, Epidemiology and End Results data. The cohort was categorized as IBC (T4d), and non-IBC. TMT included neoadjuvant systemic therapy (NAST), mastectomy, dissection of ≥6 axillary nodes, and adjuvant radiation (RT). We evaluated BCSS and OS between IBC and non-IBC stratified by TS. Comparisons were made in stratified multivariable Cox models providing adjusted hazard ratios (aHzR) with 95% confidence intervals (CI). Results: We included 3,227 IBC and 44,475 non-IBC pts, with a median follow up of 70 and 68 months, respectively. Median age was 57 years for both. As compared with non-IBC, IBC pts were more often White, single, and had more grade III and less HR+/HER2- (all p&lt;0.001). Individual treatments in IBC vs non-IBC included: mastectomy (73.5% vs 68.1%, p&lt;0.001); dissection of ≥6 axillary nodes (54.9% vs 71.6%, p&lt;0.001); RT (58.4% vs 60%, p=0.07), chemotherapy (87.1% vs 78.7%, p&lt;0.001), NAST (58.4% vs 32.7%, p&lt;0.001); respectively. Overall rate of TMT for IBC was 31.4% and decreased from 33.9% in 2010 to 24.2% in 2020 (p for trend = 0.014). Stage III IBC pts had worse BCSS than non-IBC in each TS (table). Pts with T4 tumors had similar differences but with smaller magnitude (table). We observed improvements in BCSS between 2010-2020 for stage III non-IBC (aHzR=0.98 per year, p&lt;0.001), non-IBC T4 only (aHzR=0.97 per year, p&lt;0.001), and stage III non-IBC treated with TMT (aHzR=0.97 per year, p=0.007). In contrast, there were no improvements in BCSS between 2010-2020 for IBC pts overall (aHzR=1.02 per year, p=0.12) or IBC pts treated with TMT (aHzR=1.03 per year, p=0.25). OS showed similar results to those from BCSS across all analyses. Conclusions: Stage III IBC has worse BCSS and OS than stage III non-IBC within each TS. The rate of TMT for IBC is low and decreased significantly over time, though the completeness of treatment data is a limitation. BCSS and OS did not improve over time for IBC pts, even when treated with TMT; whereas BCSS and OS improved for non-IBC. [Table: see text]
In vivo mouse models for adult brain tumors: Exploring tumorigenesis and advancing immunotherapy development
Authors: John Figg, Dongjiang Chen, Laura Falceto Font, Catherine Flores, Dan Jin
Journal: Neuro-Oncology (2024)

Abstract Brain tumors, particularly glioblastoma (GBM), are devastating and challenging to treat, with a low 5-year survival rate of only 6.6%. Mouse models are established to understand tumorigenesis and develop new therapeutic strategies. Large-scale genomic studies have facilitated the identification of genetic alterations driving human brain tumor development and progression. Genetically engineered mouse models (GEMMs) with clinically relevant genetic alterations are widely used to investigate tumor origin. Additionally, syngeneic implantation models, utilizing cell lines derived from GEMMs or other sources, are popular for their consistent and relatively short latency period, addressing various brain cancer research questions. In recent years, the success of immunotherapy in specific cancer types has led to a surge in cancer immunology-related research which specifically necessitates the utilization of immunocompetent mouse models. In this review, we provide a comprehensive summary of GEMMs and syngeneic mouse models for adult brain tumors, emphasizing key features such as model origin, genetic alteration background, oncogenic mechanisms, and immune-related characteristics. Our review serves as a valuable resource for the brain tumor research community, aiding in the selection of appropriate models to study cancer immunology.
The impact of neighborhood socioeconomic deprivation on overall survival for patients with metastatic pancreatic cancer: An incidence-based retrospective cohort study.
Authors: Aishwarya Pattnaik, Benjamin Daniel Powers
Journal: Journal of Clinical Oncology (2024)

e16340 Background: Studies have demonstrated that metastatic pancreatic cancer patients are undertreated in the United States, which leads to worse overall survival (OS). However, these studies have typically used large geographic areas (zip codes or counties) for assessment of socioeconomic deprivation (SED). Using a statewide cancer registry, SED at the neighborhood level was used to assess receipt of treatment and OS for metastatic pancreatic cancer patients. Methods: Using the incidence-based Florida Cancer Data System, pancreatic adenocarcinoma patients diagnosed from 2007-2015were identified. The predictor variable was the Area Deprivation Index (ADI), a composite measure of SED and validated dataset that ranks neighborhoods (census block groups) from 1-100 (higher scores = higher deprivation) at the national level. Demographic, tumor, and treatment variables were assessed. Descriptive statistics and survival analysis with Kaplan-Meier curves and the log-rank test were used. Results: Overall, 9,747 patients met inclusion criteria; 53.9% were male and the median age was 70 (range 19-102). When assessed by SED quartile, there were significant differences by age, gender, race, ethnicity, insurance, and receipt of chemotherapy (p &lt; 0.05). For the cohort, 46.5% of patients received chemotherapy. However, 54% of the lowest SED cohort received chemotherapy compared to 39.4% of the highest SED cohort (p &lt; 0.001). The 30- and 90-day mortality was 21.7% and 50.1%, respectively. For the lowest SED quartile, 30- and 90-day mortality were 18.5% and 43.4%, respectively, compared to the highest SED quartile rate of 25.1% and 56.2%, respectively (p &lt; 0.001 for both). Median OS was 2.9 months. The median OS for the lowest and highest SED quartiles was 3.8 and 2.4 months, respectively (p &lt; 0.001). For patients who received chemotherapy, median OS was 6.3 months. The median OS of the lowest and highest SED quartiles for those who received chemotherapy was 7.2 and 5.9 months, respectively (p &lt; 0.001). Conclusions: In an incidence-based, statewide cancer registry, the median OS for metastatic pancreatic cancer patients remains poor (2.9 months) and most patients do not receive chemotherapy. Additionally, higher SED patients had worse survival than lower SED patients at several time points. These data suggest that SED impacts OS and future studies are needed to understand the multilevel factors, including cancer care coordination, that lead to survival disparities in metastatic pancreatic cancer. [Table: see text]
The impact of primary health care on AIDS incidence and mortality: A cohort study of 3.4 million Brazilians
Authors: Priscila F. P. S. Pinto, James Macinko, Andréa F. Silva, Iracema Lua, Gabriela Jesus, Laio Magno, Carlos A. S. Teles Santos, Maria Yury Ichihara, Mauricio L. Barreto, Corrina Moucheraud, Luis E. Souza, Inês Dourado, Davide Rasella
Journal: PLoS Medicine (2024)

Background Primary Health Care (PHC) is essential for effective, efficient, and more equitable health systems for all people, including those living with HIV/AIDS. This study evaluated the impact of the exposure to one of the largest community-based PHC programs in the world, the Brazilian Family Health Strategy (FHS), on AIDS incidence and mortality. Methods and findings A retrospective cohort study carried out in Brazil from January 1, 2007 to December 31, 2015. We conducted an impact evaluation using a cohort of 3,435,068 ≥13 years low-income individuals who were members of the 100 Million Brazilians Cohort, linked to AIDS diagnoses and deaths registries. We evaluated the impact of FHS on AIDS incidence and mortality and compared outcomes between residents of municipalities with low or no FHS coverage (unexposed) with those in municipalities with 100% FHS coverage (exposed). We used multivariable Poisson regressions adjusted for all relevant municipal and individual-level demographic, socioeconomic, and contextual variables, and weighted with inverse probability of treatment weighting (IPTW). We also estimated the FHS impact by sex and age and performed a wide range of sensitivity and triangulation analyses; 100% FHS coverage was associated with lower AIDS incidence (rate ratio [RR]: 0.76, 95% CI: 0.68 to 0.84) and mortality (RR: 0.68, 95%CI: 0.56 to 0.82). FHS impact was similar between men and women, but was larger in people aged ≥35 years old both for incidence (RR: 0.62, 95% CI: 0.53 to 0.72) and mortality (RR: 0.56, 95% CI: 0.43 to 0.72). The absence of important confounding variables (e.g., sexual behavior) is a key limitation of this study. Conclusions AIDS should be an avoidable outcome for most people living with HIV today and our study shows that FHS coverage could significantly reduce AIDS incidence and mortality among low-income populations in Brazil. Universal access to comprehensive healthcare through community-based PHC programs should be promoted to achieve the Sustainable Development Goals of ending AIDS by 2030.
Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7
Authors: Manami Katoh, Seitaro Nomura, Shintaro Yamada, Masamichi Ito, Hiroki Hayashi, Mikako Katagiri, Tuolisi Heryed, Takayuki Fujiwara, Norifumi Takeda, Miyuki Nishida, Maki Sugaya, Miki Kato, Tsuyoshi Osawa, Hiroyuki Abe, Yoshitaka Sakurai, Toshiyuki Ko, Kanna Fujita, Bo Zhang, Satoshi Hatsuse, Takanobu Yamada, Shunsuke Inoue, Zhehao Dai, Masayuki Kubota, Kousuke Sawami, Minoru Ono, Hiroyuki Morita, Yoshiaki Kubota, Seiya Mizuno, Satoru Takahashi, Makoto Nakanishi, Tetsuo Ushiku, Hironori Nakagami, Hiroyuki Aburatani, Issei Komuro
Journal: Circulation (2024)

The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure.
Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment
Authors: Zili Gu, Jie Yin, Candido G. Da Silva, Qi Liu, Luis J. Cruz, Ferry Ossendorp, Ewa Snaar-Jagalska
Journal: Journal of Controlled Release (2024)

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.
Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression
Authors: Oihana Iriondo, Desirea Mecenas, Yilin Li, Christopher R. Chin, Amal Thomas, Aidan Moriarty, Rebecca Marker, Yiru J. Wang, Haley Hendrick, Yonatan Amzaleg, Veronica Ortiz, Matthew MacKay, Amber Dickerson, Grace Lee, Sevana Harotoonian, Bérénice A. Benayoun, Andrew Smith, Christopher E. Mason, Evanthia T. Roussos Torres, Remi Klotz, Min Yu
Journal: Cancer Research (2024)

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade. Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis. See related commentary by Purdy and Ford, p. 3125.
An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression
Authors: Raunak Shrestha, Lisa N. Chesner, Meng Zhang, Stanley Zhou, Adam Foye, Arian Lundberg, Alana S. Weinstein, Martin Sjöström, Xiaolin Zhu, Thaidy Moreno-Rodriguez, Haolong Li, Joshi J. Alumkal, Rahul Aggarwal, Eric J. Small, Mathieu Lupien, David A. Quigley, Felix Y. Feng
Journal: Cancer Research (2024)

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC. Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.
VP5-2024: Eftilagimod alpha (soluble LAG-3) and pembrolizumab in first-line recurrent or metastatic head and neck squamous cell carcinoma: Primary results from Cohort B (CPS less-than 1) of the TACTI-003 study
Authors: R. Metcalf, S. Laban, C.A. Kristensen, T-E. Ciuleanu, I. Braña, A. Soria Rivas, S.M. Dieter, A. Bols, M.D. Forster, M.R. Covela, J. Christian, F.D. Vogl, C. Mueller, F. Triebel
Journal: Annals of Oncology (2024)
Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors
Authors: Shiyun Xian, Xiaona Chen, Sihang Ren, Xiaolong Chen, Hangxiang Wang
Journal: Cancer Research (2024)

Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the stimulator of interferon gene (STING) pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment. The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic tumor microenvironment, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune-stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies. Significance: STING-activating nanoadjuvants rationally engineered using an ionizable prodrug approach for systemic administration are well-tolerated and yield durable antitumor immune responses, providing a potential immunotherapeutic strategy to improve cancer treatment.
UCHealth’s virtual health center: How Colorado’s largest health system creates and integrates technology into patient care
Authors: Elizabeth Goldberg, Dave Kao, Bethany Kwan, Hemali Patel, Amy Hassell, Richard Zane
Journal: npj Digital Medicine (2024)

In the face of formidable healthcare challenges, such as staffing shortages and rising costs, technology has emerged as a crucial ally in enhancing patient care. UCHealth, Colorado's largest health system, has pioneered the integration of technology into patient care through its Virtual Health Center (VHC). In this Comment, we explore UCHealth's journey in creating a centralized hub that harnesses innovative digital health solutions to address patient care needs across its 12 hospitals, spanning over 600,000 emergency department visits and nearly 150,000 inpatient and observation encounters annually. The VHC has proven to be a transformative force, providing high-quality care at scale, reducing staff burden, and establishing new career pathways in virtual health. The transformation process involved multiple steps: (a) identifying a need, (b) vetting within health system solutions, (c) searching for industry solutions, and scrutinizing these through meetings with our innovations center, (d) piloting the solution, and (e) sustaining the solution by integrating them within the electronic health record (EHR).