tbuckley/cabot-search huggingface dataset:
Abstract B021: A phase 1 dose escalation study of lapatinib and paclitaxel in recurrent ovarian cancer
Authors: Connie D. Cao, Joseph R. McCorkle, Donglin Yan, Rani Jayswal, Rachel W. Miller, Charles S. Dietrich, Frederick R. Ueland, Jill M Kolesar
Journal: Cancer Research (2024)

Abstract Objectives: Paclitaxel is a commonly used chemotherapy agent for women with recurrent ovarian cancer; however, its efficacy is limited by the development of ABCB1-mediated drug resistance. Lapatinib is an EGFR and HER2 inhibitor approved for treating breast cancer but without single agent activity in ovarian cancer. Lapatinib is also an ABCB1 inhibitor, and we hypothesize that lapatinib overcomes ABCB1-mediated paclitaxel resistance in previously treated ovarian cancer patients. Methods: This phase 1 dose escalation study used a Bayesian optimal interval (BOIN) design to determine the recommended phase 2 dose of the combination of paclitaxel and lapatinib. Secondary endpoints were to assess adverse effects, determine the objective response rate, and assess pharmacokinetics. Eligible patients had ovarian, peritoneal, or fallopian tube cancer and had recurred within 12 months of platinum-based chemotherapy. Patients received three weekly paclitaxel doses of 80 mg/m2 in 28-day cycles. Patients were pretreated with escalating doses of lapatinib twice daily in the 48 hours preceding paclitaxel for up to 3 cycles starting with the second paclitaxel dose of cycle 1. Three lapatinib doses were evaluated, escalating from 750 to 2000 mg orally twice daily. Results: Fifteen of nineteen patients were eligible and evaluable for toxicity and 12 have completed study therapy and are evaluable for response. All were female, the median age was 66, and the median number of prior therapies was 3. Three patients were treated at dose level 1, six at dose level 2, and seven at dose level 3. One patient treated at dose level 3 was not evaluable for dose-limiting toxicity (DLT). There was one DLT in dose level 2 (diarrhea) and another in dose level 3 (elevated liver function tests), with a posterior DLT estimate of 0.17, 95% Credible Interval of (0.01, 0.53) for dose level 3. The most common grade 1-2 adverse effects were diarrhea (75%) and neutropenia (43.8%). Among the 12 patients evaluable for efficacy, there were two partial responses and one stable disease for an objective response rate of 16% and a disease control rate of 25% in this heavily pretreated population. Conclusion: The combination of paclitaxel and lapatinib is safe and with an efficacy signal. The recommended phase 2 dose of the combination is 80 mg/m2 of weekly paclitaxel combined with 2000 mg bid of lapatinib two days before the paclitaxel dose. Citation Format: Connie D. Cao, Joseph R. McCorkle, Donglin Yan, Rani Jayswal, Rachel W. Miller, Charles S. Dietrich, Frederick R. Ueland, Jill M Kolesar. A phase 1 dose escalation study of lapatinib and paclitaxel in recurrent ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B021.
Abstract IA006: Friend or foe: Reevaluating the therapeutic potential of monocytes and tumor-associated macrophages in ovarian cancer
Authors: Oladapo Yeku
Journal: Cancer Research (2024)

Abstract The hostile tumor microenvironment in ovarian cancer is an active deterrent to the efficacy of immunotherapeutic agents such as immune checkpoint inhibitors, Chimeric Antigen Receptor (CAR) T-cells, and Bispecific T-cell Engagers (BiTEs). Tumor-associated macrophages (TAMs) and Myeloid-Derived Suppressor Cells (MDSCs) have been shown to promote an immunosuppressive metabolic and cytokine tumor microenvironment that is detrimental to cytotoxic effector T-cell activity in ovarian cancer. These immunosuppressive cells are also associated with poor prognostic outcomes. The ideal approach to modulating TAMs and MDSCs is unknown. Data from preclinical models support reprogramming these cells to a more inflammatory phenotype or removing them from the tumor microenvironment entirely. However, neither approach has translated to clinical benefits. We have previously demonstrated that CAR-T cells modified to secrete IL-18 exerted their therapeutic effects partly via polarization of bone marrow macrophages towards an M1 phenotype. We also found that the depletion of TAMs improved CAR-T cell efficiency, even when these CAR-T cells were co-modified to secrete IL-12. Because of the propensity for monocytes to be recruited to the ovarian cancer tumor microenvironment, we evaluated the efficacy of monocytes genetically modified to secrete BiTEs. First, we designed and evaluated BiTEs that recognize the retained portion of MUC16 (Muc16-ecto) and CD3+ T-cells and showed that these BiTEs were efficacious in vitro and in vivo in a xenograft model of ovarian cancer. We validated that monocytes transduced to secrete Muc16-specific BiTEs (Mono-BiTEs) could effectively lyse tumor cells in vitro and suppress xenograft ovarian cancer cells in vivo. Adding IFN-alpha and IFN-gamma to Mono-BiTEs significantly improved Mono-BiTEs antitumor efficacy over BiTE therapy or unmodified monocyte therapy alone. Adoptive cell therapy with genetically engineered autologous monocytes could provide an alternative approach to reprograming or eliminating myeloid-derived cells in ovarian cancer. Citation Format: Oladapo Yeku. Friend or foe: Reevaluating the therapeutic potential of monocytes and tumor-associated macrophages in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA006.
Abstract B042: Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire
Authors: Kian Behbakht, Cam Nguyen, Stephen Rotholz, Saketh Guntupalli, Barbara Goff, Benjamin Bitler
Journal: Cancer Research (2024)

Abstract Objectives: Symptoms occur in 75% of women with early-stage ovarian cancer and are also common in the absence of cancer. We report the feasibility and results of a prospective four-question symptom screen applied to a gynecology preventive care visit. Methods: Starting February 2021, a patient-facing questionnaire was added to the electronic medical records for women requesting routine gynecology visit. The question asks patients if they have had any of the following symptoms for more than two weeks duration in the prior year: bloating, difficulty eating or feeling full soon after eating, pelvic or abdominal pain, or trouble with urination. In September 2021, the response “No symptoms” was added. Questionnaire responses, medical history and work up performed +/- 3 months of the preventive gynecologic visit were extracted from electronic medical records, compiled in REDCap, and analyzed using R. Results: Between February 2021 and November 2022, a total of 498 patients completed the questionnaire (72.7% White, 10.2% Black, 7.0% Asian/Pacific Islander, 9.8% Other, and 0.2% not stated). The median age was 50 years (range: 40-86). Nearly half (47.2%) reported at least one symptom. The most common isolated single symptom was urinary urgency or frequency (22.9%); 12.3% of these patients had a urinary tract infection. The least common single symptom was early satiety (8.8%). 12 patients (2.4%) reported all four symptoms, and most had explanatory existing diagnoses such as endometriosis, adenomyosis or chronic pelvic pain. No cancers have been diagnosed to date. Conclusions: Ovarian cancer symptom-based screening using electronic medical records is feasible, but alone may not be clinically beneficial. Patients reporting three or more symptoms were 6.6% of the respondents and may represent an ideal group for focused ovarian cancer screening efforts and selective enrolment to novel imaging/tumor marker and proximate fluid analyses. Citation Format: Kian Behbakht, Cam Nguyen, Stephen Rotholz, Saketh Guntupalli, Barbara Goff, Benjamin Bitler. Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B042.
Abstract IA007: Tumor heterogeneity in ovarian clear cell carcinoma
Authors: Ruby Yun-Ju Huang
Journal: Cancer Research (2024)

Abstract Ovarian clear cell carcinoma (OCCC) is a gynecologic cancer showing high incidence in East Asia with critical unmet needs for novel therapeutic options. It is a histological subtype with distinct pathological features, molecular profiles, and biological functions. At the bulk transcriptomic level, there are distinct epithelial (EpiCC) and mesenchymal (MesCC) subtypes and immune-related gene expression signatures (irGES) in OCCC tumors. The MesCC subtype or Immune-Hot features are shown to associate with worse clinical outcomes across several cohort studies. During disease progression from early to advanced OCCC, there is a switch from EpiCC to MesCC subtypes and Immune-Cold to Immune-Hot features. Therefore, the landscapes of tumor heterogeneity in early versus advanced OCCC are different. Bulk and spatial profiling revealed that most early OCCC tumors exhibited Immune-Cold features associated with a non-CTLA4 irGES subtype, no tumor infiltrating immune cells (TIIs), and non-immune mimic tumor cells. A subset of early OCCC tumors acquired Immune-Hot features that were associated with a CTLA4 irGES subtype, and TIIs situated adjacent to immune mimic tumor cells. Two translational studies TGOG-4001 and TGOG-4002 have been launched to validate clinical assays for the stratification of Immune-Hot tumors. In advanced OCCC, certain metastatic sites showed high degrees of heterogeneity in spatial transcriptomics with subregions close to the tumor periphery or invasion fronts at the tumor-stromal interface showing inflammatory and EMT-like signals. The primary sites with subregions situated at the tumor core predominantly showed oxidative phosphorylation and low EMT signals. Collectively, OCCC is an ovarian cancer with immense degree of tumor heterogeneity. Comprehensive and in-depth multi-dimensional analysis could facilitate the design of better patient stratification strategies. Citation Format: Ruby Yun-Ju Huang. Tumor heterogeneity in ovarian clear cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA007.
Abstract IA015: Is salpingectomy as effective as bilateral salpingo-oophorectomy in preventing ovarian, fallopian tube, and peritoneal cancer? Let’s prove it!
Authors: Kathryn P. Pennington
Journal: Cancer Research (2024)

Abstract Since ovarian cancer screening does not reduce ovarian cancer mortality, the main focus to reduce ovarian cancer mortality is prevention. For individuals at increased risk of ovarian carcinoma, risk-reducing bilateral salpingo-oophorectomy (RRSO) is highly effective, but uptake at the recommended age is suboptimal, likely due to concerns about premature menopause. Mounting evidence suggests that many “ovarian” cancers originate in the fallopian tube, making bilateral salpingectomy with delayed oophorectomy an attractive, but as of yet, unproven option for risk-reduction in those who decline RRSO. This talk will review the scientific evidence supporting a tubal origin of ovarian cancer, preliminary data supporting the safety and possible efficacy of salpingectomy and will discuss two prospective clinical trials powered to test the hypothesis that bilateral salpingectomy with delayed oophorectomy is non-inferior to RRSO to reduce the incidence of ovarian, fallopian tube, and peritoneal cancer among mutation carriers at high risk of ovarian cancer. Citation Format: Kathryn P. Pennington. Is salpingectomy as effective as bilateral salpingo-oophorectomy in preventing ovarian, fallopian tube, and peritoneal cancer? Let’s prove it! [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA015.
Targeting the TNF/IAP pathway synergizes with anti-CD3 immunotherapy in T-cell acute lymphoblastic leukemia
Authors: Andrea Ávila Ávila, Kanokporn Nuantang, Mariana L. Oliveira, Sabine Druillennec, Benedetta Zaniboni, Etienne Lengliné, Vahid Asnafi, Jacques Ghysdael, Christine Tran Quang
Journal: Blood (2024)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of ∼85% in children and <50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T-cell receptor (TCR) in T-ALL with anti-CD3 (αCD3) monoclonal antibodies (mAbs) enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development; induces leukemic cell death; and impairs leukemia progression to ultimately improve host survival. However, αCD3 monotherapy resulted in relapse. To find out actionable targets able to re-enforce leukemic cells' vulnerability to αCD3 mAbs, including the clinically relevant teplizumab, we identified the molecular program induced by αCD3 mAbs in patient-derived xenografts derived from T-ALL cases. Using large-scale transcriptomic analysis, we found prominent expression of tumor necrosis factor α (TNFα), lymphotoxin α (LTα), and multiple components of the "TNFα via NF-κB signaling" pathway in anti-CD3-treated T-ALL. We show in vivo that etanercept, a sink for TNFα/LTα, enhances αCD3 antileukemic properties, indicating that TNF/TNF receptor (TNFR) survival pathways interferes with TCR-induced leukemic cell death. However, suppression of TNF-mediated survival and switch to TNFR-mediated cell death through inhibition of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) with the second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant synergizes with αCD3 to impair leukemia expansion in a receptor-interacting serine/threonine-protein kinase 1-dependent manner and improve mice survival. Thus, our results advocate the use of either TNFα/LTα inhibitors, or birinapant/other SMAC mimetics to improve anti-CD3 immunotherapy in T-ALL.
Abstract IA010: Latest developments in targeting the DNA damage response in the clinic
Authors: Timothy A. Yap
Journal: Cancer Research (2024)

Abstract Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements, and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumor agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK, POLQ, USP1 and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. Citation Format: Timothy A. Yap. Latest developments in targeting the DNA damage response in the clinic [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA010.
The Expected Behaviors of Posterior Predictive Tests and Their Unexpected Interpretation
Authors: Luiza Guimarães Fabreti, Lyndon M Coghill, Robert C Thomson, Sebastian Höhna, Jeremy M Brown
Journal: Molecular Biology and Evolution (2024)

Abstract Poor fit between models of sequence or trait evolution and empirical data is known to cause biases and lead to spurious conclusions about evolutionary patterns and processes. Bayesian posterior prediction is a flexible and intuitive approach for detecting such cases of poor fit. However, the expected behavior of posterior predictive tests has never been characterized for evolutionary models, which is critical for their proper interpretation. Here, we show that the expected distribution of posterior predictive P-values is generally not uniform, in contrast to frequentist P-values used for hypothesis testing, and extreme posterior predictive P-values often provide more evidence of poor fit than typically appreciated. Posterior prediction assesses model adequacy under highly favorable circumstances, because the model is fitted to the data, which leads to expected distributions that are often concentrated around intermediate values. Nonuniform expected distributions of P-values do not pose a problem for the application of these tests, however, and posterior predictive P-values can be interpreted as the posterior probability that the fitted model would predict a dataset with a test statistic value as extreme as the value calculated from the observed data.
Quality Indicators for Major Depressive Disorder in Adults: A Review of Performance Measures by the American College of Physicians
Authors: Amir Qaseem, Rebecca A. Andrews, Karen Campos, Caroline L. Goldzweig, Scott MacDonald, Robert M. McLean, Rhea E. Powell, Nick Fitterman
Journal: Annals of Internal Medicine (2024)

Major depressive disorder (MDD) is a severe mood disorder that affects at least 8.4% of the adult population in the United States. Characteristics of MDD include persistent sadness, diminished interest in daily activities, and a state of hopelessness. The illness may progress quickly and have devastating consequences if left untreated. Eight performance measures are available to evaluate screening, diagnosis, and successful management of MDD. However, many performance measures do not meet the criteria for validity, reliability, evidence, and meaningfulness.
Novel radiotherapeutic strategies in the management of brain metastases: Challenging the dogma
Authors: Joshua D Palmer, Haley K Perlow, Eric J Lehrer, Zabi Wardak, Hany Soliman
Journal: Neuro-Oncology (2024)

Abstract The role of radiation therapy in the management of brain metastasis is evolving. Advancements in machine learning techniques have improved our ability to both detect brain metastasis and our ability to contour substructures of the brain as critical organs at risk. Advanced imaging with PET tracers and magnetic resonance imaging-based artificial intelligence models can now predict tumor control and differentiate tumor progression from radiation necrosis. These advancements will help to optimize dose and fractionation for each patient’s lesion based on tumor size, histology, systemic therapy, medical comorbidities/patient genetics, and tumor molecular features. This review will discuss the current state of brain directed radiation for brain metastasis. We will also discuss future directions to improve the precision of stereotactic radiosurgery and optimize whole brain radiation techniques to improve local tumor control and prevent cognitive decline without forming necrosis.
Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies
Authors: Sarah J. Annesley, Daniel Missailidis, Benjamin Heng, Elisha K. Josev, Christopher W. Armstrong
Journal: Trends in Molecular Medicine (2024)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed 'long COVID' (LC). Both ME/CFS and LC share many clinical similarities. Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.
Coupled sleep rhythms for memory consolidation
Authors: Bernhard P. Staresina
Journal: Trends in Cognitive Sciences (2024)

How do passing moments turn into lasting memories? Sheltered from external tasks and distractions, sleep constitutes an optimal state for the brain to reprocess and consolidate previous experiences. Recent work suggests that consolidation is governed by the intricate interaction of slow oscillations (SOs), spindles, and ripples – electrophysiological sleep rhythms that orchestrate neuronal processing and communication within and across memory circuits. This review describes how sequential SO–spindle–ripple coupling provides a temporally and spatially fine-tuned mechanism to selectively strengthen target memories across hippocampal and cortical networks. Coupled sleep rhythms might be harnessed not only to enhance overnight memory retention, but also to combat memory decline associated with healthy ageing and neurodegenerative diseases.
Stressing Out Cancer: Chronic Stress Induces Dysbiosis and Enhances Colon Cancer Growth
Authors: Shannon E. McCollum, Yatrik M. Shah
Journal: Cancer Research (2024)

Abstract Psychologic stress significantly impacts colorectal cancer, and chronic stress is known to decrease treatment efficacy and survival rates in patients with colorectal cancer. Previous studies have linked psychologic stress to changes in the gut microbiota, and the role of the microbiota in colorectal cancer progression is well characterized. Despite this, the mechanistic link between chronic stress and colorectal cancer remains unclear. In this issue of Cancer Research, Cao and colleagues reveal that chronic stress exacerbates colorectal cancer progression by reducing the presence of Lactobacillus johnsonii (L. johnsonii) and its metabolite protocatechuic acid (PCA). The authors demonstrate an increase in β-catenin expression as the major mechanism by which chronic stress potentiates cancer stemness and pathogenesis. Administration of L. johnsonii or PCA to stressed mice decreased β-catenin activity and colorectal cancer progression. This study defines a precise mechanism underlying chronic stress and colorectal cancer progression, emphasizing the relevance of psychologic well-being in colorectal cancer outcome. In addition, the study demonstrates the potential efficacy of L. johnsonii or PCA supplementation as promising therapeutics for colorectal cancer treatment. See related article by Cao et al., p. 771