tbuckley/cabot-search huggingface dataset:
Abstract C029: Multiple non-redundant immune checkpoints direct therapeutic resistance to chemotherapy and anti-CSF1R in pancreatic ductal adenocarcinoma
Authors: Meredith L. Stone, Veronica M. Herrera, Yan Li, Heather Coho, Yuqing Yue, Kathleen Graham, Devora Delman, Shaun O'Brien, Gregory L. Beatty
Journal: Cancer Research (2024)

Abstract A hallmark of pancreatic ductal adenocarcinoma (PDA) is the formation of a myeloid rich immunosuppressive microenvironment which acts as a barrier to treatment. Therapeutic blockade/depletion of immunosuppressive myeloid cells in combination with chemotherapy or anti-PD-1 checkpoint blockade is under investigation in PDA but has yet to demonstrate broad clinical success. Here, we studied mechanisms of resistance to myeloid-targeted therapy to inform rational combination strategies. Spatial and molecular profiling of the tumor microenvironment in mouse and human PDA revealed vast intra-tumoral myeloid heterogeneity. Depletion of distinct myeloid cell populations triggered T cell infiltration into tumors but also provoked compensatory remodeling of the myeloid compartment. However, concurrent depletion of multiple myeloid subsets using drugs targeting CSF1R, CCR2/5, and CXCR2 was unexpectedly insufficient to overcome treatment resistance and failed to restore productive T cell surveillance in murine models of PDA. Therefore, we next investigated the role of the lymphoid compartment. High-dimensional single cell analyses of T cell infiltrates in PDA revealed an upregulation of multiple checkpoint molecules, including PD-1, LAG3 and CTLA-4, in both mice and humans, suggesting potential resistance mechanisms. In contrast to combinatory myeloid cell depletion, combined blockade of PD-1, LAG3, and CTLA-4 with gemcitabine and anti-CSF1R triggered peripheral CD4+ and CD8+ T cell activation and produced deep and durable tumor responses with a nearly 3-fold increase in median survival and in some cases, tumor cures. Taken together, these studies highlight the contribution of multiple immune checkpoints to cancer immune evasion and reveal a novel role for LAG3 in treatment resistance in PDA. Together, these findings suggest that a multipronged approach to disrupting negative regulatory signals controlling T cell function may be needed to realize the potential of immunotherapy in PDA. Citation Format: Meredith L. Stone, Veronica M. Herrera, Yan Li, Heather Coho, Yuqing Yue, Kathleen Graham, Devora Delman, Shaun O'Brien, Gregory L. Beatty. Multiple non-redundant immune checkpoints direct therapeutic resistance to chemotherapy and anti-CSF1R in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C029.
Abstract C027: Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model
Authors: Anthony Sorrentino, Carolina Alcantara-Hirsch, Beny Shapiro, Erica Ma, Ammar Javed, Christopher Wolfgang, Dafna Bar-Sagi
Journal: Cancer Research (2024)

Abstract Surgical resection is currently the mainstay of treatment for pancreatic ductal adenocarcinoma (PDAC). After “curative intent” resection, distant metastasis occurs in majority of patients, indicating that PDAC is a systemic disease and should be considered as such at the time of surgical resection. Despite this, the effects of tumor resection on the systemic disease are not fully elucidated. Surgical trauma induces systemic immunosuppression, that can result in a “window of opportunity”, affecting metastatic seeding and outgrowth, as well as responsiveness to therapy. We used an orthotopic resection model in immunocompetent mice by performing a distal pancreatectomy and splenectomy. Using this model system, we identified outcomes similar to human disease, such as a survival benefit upon resection, systemic disease at the time of resection, and metastatic dissemination predominantly in the liver, lung, and peritoneum. Since the liver is the most common site of recurrence in human PDAC and portends a poorer prognosis than other metastases, we investigated the effect of tumor resection on the hepatic microenvironment. In surgically stressed mice undergoing sham resection and splenectomy, we identified an increase in eosinophils and a decrease in neutrophils, and these immune perturbations were augmented upon tumor resection. Time-course analysis identified transient changes in tissue resident and conventional NK cells, as well as macrophage and monocyte populations. Taken together, we have utilized a preclinical model that simulates human disease progression and response to surgery, and identified tumor resection specific alterations in the liver metastatic microenvironment. An improved understanding of the immune perturbations during this perioperative window may identify new immunotherapy strategies benefiting PDAC patients to help treat this systemic disease. Citation Format: Anthony Sorrentino, Carolina Alcantara-Hirsch, Beny Shapiro, Erica Ma, Ammar Javed, Christopher Wolfgang, Dafna Bar-Sagi. Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C027.
Automated anomaly-aware 3D segmentation of bones and cartilages in knee MR images from the Osteoarthritis Initiative
Authors: Boyeong Woo, Craig Engstrom, William Baresic, Jurgen Fripp, Stuart Crozier, Shekhar S. Chandra
Journal: Medical Image Analysis (2024)

In medical image analysis, automated segmentation of multi-component anatomical entities, with the possible presence of variable anomalies or pathologies, is a challenging task. In this work, we develop a multi-step approach using U-Net-based models to initially detect anomalies (bone marrow lesions, bone cysts) in the distal femur, proximal tibia and patella from 3D magnetic resonance (MR) images in individuals with varying grades of knee osteoarthritis. Subsequently, the extracted data are used for downstream tasks involving semantic segmentation of individual bone and cartilage volumes as well as bone anomalies. For anomaly detection, U-Net-based models were developed to reconstruct bone volume profiles of the femur and tibia in images via inpainting so anomalous bone regions could be replaced with close to normal appearances. The reconstruction error was used to detect bone anomalies. An anomaly-aware segmentation network, which was compared to anomaly-naïve segmentation networks, was used to provide a final automated segmentation of the individual femoral, tibial and patellar bone and cartilage volumes from the knee MR images which contain a spectrum of bone anomalies. The anomaly-aware segmentation approach provided up to 58% reduction in Hausdorff distances for bone segmentations compared to the results from anomaly-naïve segmentation networks. In addition, the anomaly-aware networks were able to detect bone anomalies in the MR images with greater sensitivity and specificity (area under the receiver operating characteristic curve [AUC] up to 0.896) compared to anomaly-naïve segmentation networks (AUC up to 0.874).
Abstract C026: Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups
Authors: Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Enas Abu-Shah, Rachael Bashford-Rogers
Journal: Cancer Research (2024)

Abstract Pancreatic cancer has the worst survival of any human cancer with a 5 year survival of less than 10% with minimal treatment options. We have previously made the observation that patients with a T cell infiltrate in their primary tumor have a better prognosis then those that do not. To understand the nature of the immune infiltrate, we have in 12 patients performed 10X sequencing on CD45 cells from the tumor as well as single cell TCR-seq, BCR-seq and cite-seq and have performed the same experiment on the matching PBMCs. We have generated a dataset of approximately 185000 cells with half coming from the tumor. This unravels a complex immune infiltrate with the predominant immune cell types consisting of T cells. Our data shows that within the tumor infiltrate, patients either have high or low myeloid infiltration. We see a highly active Treg population that has multiple checkpoints activated. Using TCR data, we saw the biggest clonal expansions in CD8 EM, CD8 senescent cells and Tregs. Circulating TIL CD4 T cells are dominated by activated Tregs, Tfh, and Th2 and circulating TIL CD8 T cells are dominated by CD8 EM T cells. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma. Citation Format: Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Enas Abu-Shah, Rachael Bashford-Rogers. Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C026.
Abstract C109: Nanostring-based subtyping of pancreatic ductal adenocarcinoma is strongly influenced by the stromal compartment
Authors: James T. Topham, Steve E. Kalloger, Joanna M. Karasinska, Jenny E. Chu, Hassan Ali, Dongxia Gao, Christine Chow, Andrew Metcalfe, Jonathan M. Loree, David F. Schaeffer, Daniel J. Renouf
Journal: Cancer Research (2024)

Abstract The prognostic significance of basal-like and classical subtypes of pancreatic ductal adenocarcinoma (PDAC) is well-established, and ongoing clinical trials are poised to validate the predictive utility of such subtypes in guiding first-line treatment decision-making. While the Purity-independent (PurIST)-based subtyping strategy provides a method for PDAC subtype determination based on the Nanostring gene expression quantification platform, the utility of this platform has not been tested in a real-world patient setting. Here, we leverage a retrospective dataset of patients with resectable PDAC (n=299) that received Nanostring sequencing in combination with comprehensive clinical metadata curation and histopathological analysis. All sequencing analyses were performed using formalin-fixed paraffin-embedded (FFPE) tumor whole sections. The proportion of basal-like cases (15%) was comparable with other resectable PDAC cohorts, and patients with basal-like tumors showed reduced overall survival (p=3.9e-4). Histopathological quantification of epithelial, stromal and normal components in each sample revealed significantly (p=0.007) reduced classical gene expression in stroma-high samples. Out of 29 patients with repeat sampling from different FFPE blocks derived from the same tumor and surgery, 31% of tumors received discordant subtypes calls and increases in the amount of stroma sequenced between two samples from the same tumor was negatively correlated with expression of classical subtype genes (p=0.02). Taken together, these data demonstrate the presence of intra-tumoral subtype heterogeneity, highlight the quantity of stroma sequenced as a major contributing factor in PurIST-based subtype determination and generate insight into the reproducibility of this subtyping strategy in a real-world clinical setting. Citation Format: James T. Topham, Steve E. Kalloger, Joanna M. Karasinska, Jenny E. Chu, Hassan Ali, Dongxia Gao, Christine Chow, Andrew Metcalfe, Jonathan M. Loree, David F. Schaeffer, Daniel J. Renouf. Nanostring-based subtyping of pancreatic ductal adenocarcinoma is strongly influenced by the stromal compartment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C109.
MASLD: a systemic metabolic disorder with cardiovascular and malignant complications
Authors: Giovanni Targher, Christopher D Byrne, Herbert Tilg
Journal: Gut (2024)

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic liver disease globally and is currently estimated to affect up to 38% of the global adult population. NAFLD is a multisystem disease where systemic insulin resistance and related metabolic dysfunction play a pathogenic role in the development of NAFLD and its most relevant liver-related morbidities (cirrhosis, liver failure and hepatocellular carcinoma) and extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain types of extrahepatic cancers. In 2023, three large multinational liver associations proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) should replace the term NAFLD; the name chosen to replace non-alcoholic steatohepatitis was metabolic dysfunction-associated steatohepatitis (MASH). Emerging epidemiological evidence suggests an excellent concordance rate between NAFLD and MASLD definitions—that is, ~99% of individuals with NAFLD meet MASLD criteria. In this narrative review, we provide an overview of the literature on (a) the recent epidemiological data on MASLD and the risk of developing CVD and malignant complications, (b) the underlying mechanisms by which MASLD (and factors strongly linked with MASLD) may increase the risk of these extrahepatic complications and (c) the diagnosis and assessment of CVD risk and potential treatments to reduce CVD risk in people with MASLD or MASH.
Abstract B033: Tumor cell-intrinsic mPGES-1-PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer
Authors: Nune Markosyan, Il-Kyu Kim, Charu Arora, Liz Quinones, Noah Cheng, Ben Z. Stanger, Robert H. Vonderheide
Journal: Cancer Research (2024)

Abstract Pancreatic adenocarcinoma (PDA) is the 4th leading cause of cancer-related deaths in the US partly because of its resistance to conventional chemotherapies. Immunotherapies that improve survival in many cancers, almost universally fail in PDA. The resistance to immune checkpoint blockade is at least partially explained by the lack of T cells in the tumor microenvironment (TME) in PDA. As demonstrated previously, tumor cell-derived prostaglandin E2 (PGE2) is one of the tumor intrinsic factors that creates/supports immunosuppressive TME in PDA. The current study investigates how depleting tumor cell-derived PGE2 or disrupting its autocrine signaling through the cognate EP4 receptors on tumor cells reverses the T cell low, myeloid cell rich PDA TME and suppresses the tumor growth. Pharmacological blockade of EP4 receptors combined with anti-PD-1 and agonistic CD40 antibodies induced complete tumor regressions with a lasting vaccine effect. Knockout (KO) of Ptges, the gene encoding PGE2 synthesis enzyme mPGES-1, or EP4 receptor gene, Ptger4, in KrasG12D/P53R172H/Yfp/PdxCre (KPCY) pancreatic tumor cells was sufficient to abolish the growth of implanted tumors (p&amp;lt;0.0001 both). The rejection of the primary KO and rechallenge control tumors was T cell-dependent as it did not happen in hosts depleted of CD4+ and CD8+ T cells. Both KO tumor cells were more susceptible to TNF-a killing while their TMEs were enriched with central memory T cells and phagocytic macrophages and depleted of granulocytic myeloid-derived suppressor cells (gMDSC). Further analysis of Ptger4 tumors revealed changes in CCL2, CXCL9, and GM-CSF production probably causing the changes in TME. In addition, in both Ptges and Ptger4 KO tumors, the adenosine synthesis pathway was significantly downregulated probably due to decreased TGF-b signaling in tumor cells. When cultured ex vivo in hypoxic conditions, Ptger4 KO tumors made significantly less immunosuppressive adenosine (p&amp;lt;0.001). Consequently, 57% of Ptger4 KO tumors in adenosine deaminase inhibitor treated hosts accumulated enough adenosine to suppress the anti-tumor immune response and grow out. The study demonstrates a primary role for the tumor cell-intrinsic mPGES1-PGE2-EP4 signaling in creating immune-suppressive TME in PDA, suggesting EP4 blockade as a novel approach in the treatment of pancreatic cancer. Citation Format: Nune Markosyan, Il-Kyu Kim, Charu Arora, Liz Quinones, Noah Cheng, Ben Z. Stanger, Robert H. Vonderheide. Tumor cell-intrinsic mPGES-1-PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B033.
Cultivating curiosity about our patients can make all the difference to their care
Authors: Louise Smith
Journal: BMJ (2024)

Cultivating curiosity about our patients can make all the difference to their care Asking questions that elicit who a patient is, and not just their diagnosis and symptoms, leads to more compassionate care, says Louise Smith Louise Smith senior lecturer in clinical skillsMy mother lay there, day after day, waiting for the time to come.She had cancer and was terminally ill, with only a few days left to live.She was unconscious and cachexic, the toll of the disease evident.At 83 years old, she had grey hair as she could no longer visit the hairdresser.Before this illness, nothing would have got in the way of her weekly hair appointments that she had enjoyed for so many years.
Synergistic Drug Combinations Promote the Development of Resistance in Acute Myeloid Leukemia
Authors: Emily Mason-Osann, Amy E. Pomeroy, Adam C. Palmer, Jerome T. Mettetal
Journal: Blood Cancer Discovery (2024)

Abstract Combination therapy is an important part of cancer treatment and is often employed to overcome or prevent drug resistance. Preclinical screening strategies often prioritize synergistic drug combinations; however, studies of antibiotic combinations show that synergistic drug interactions can accelerate the emergence of resistance because resistance to one drug depletes the effect of both. In this study, we aimed to determine whether synergy drives the development of resistance in cancer cell lines using live-cell imaging. Consistent with prior models of tumor evolution, we found that when controlling for activity, drug synergy is associated with increased probability of developing drug resistance. We demonstrate that these observations are an expected consequence of synergy: the fitness benefit of resisting a drug in a combination is greater in synergistic combinations than in nonsynergistic combinations. These data have important implications for preclinical strategies aiming to develop novel combinations of cancer therapies with robust and durable efficacy. Significance: Preclinical strategies to identify combinations for cancer treatment often focus on identifying synergistic combinations. This study shows that in AML cells combinations that rely on synergy can increase the likelihood of developing resistance, suggesting that combination screening strategies may benefit from a more holistic approach rather than focusing on drug synergy. See related commentary by Bhola and Letai.
The hepatokine FGL1 regulates hepcidin and iron metabolism during anemia in mice by antagonizing BMP signaling
Authors: Ugo Sardo, Prunelle Perrier, Kevin Cormier, Manon Sotin, Jean Personnaz, Thanina Medjbeur, Aurore Desquesnes, Lisa Cannizzo, Marc Ruiz-Martinez, Julie Thevenin, Benjamin Billoré, Grace Jung, Elise Abboud, Carole Peyssonnaux, Elizabeta Nemeth, Yelena Z. Ginzburg, Tomas Ganz, Léon Kautz
Journal: Blood (2024)
Neoadjuvant Chemotherapy in High-Grade Myxoid Liposarcoma: Results of the Expanded Cohort of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish Sarcoma Groups (PSG)
Authors: Alessandro Gronchi, Emanuela Palmerini, Vittorio Quagliuolo, Javier Martin Broto, Antonio Lopez Pousa, Giovanni Grignani, Antonella Brunello, Jean-Yves Blay, Oscar Tendero, Robert Diaz Beveridge, Virginia Ferraresi, Iwona Lugowska, Sara Pizzamiglio, Paolo Verderio, Valeria Fontana, Davide Maria Donati, Elena Palassini, Roberta Sanfilippo, Giuseppe Bianchi, Alexia Bertuzzi, Carlo Morosi, Sandro Pasquali, Silvia Stacchiotti, Silvia Bagué, Jean Michel Coindre, Rosalba Miceli, Angelo Paolo Dei Tos, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2024)

A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma (STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded.
Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study
Authors: Christelle De La Fouchardière, David Malka, Claire Cropet, Sylvie Chabaud, Judith Raimbourg, Damien Botsen, Simon Launay, Ludovic Evesque, Angélique Vienot, Hervé Perrier, Marine Jary, Yves Rinaldi, Clélia Coutzac, Jean Baptiste Bachet, Cindy Neuzillet, Nicolas Williet, Romain Desgrippes, Thomas Grainville, Thomas Aparicio, Annie Peytier, Thierry Lecomte, Gaël S. Roth, Anne Thirot-Bidault, Nicolas Lachaux, Olivier Bouché, François Ghiringhelli
Journal: Journal of Clinical Oncology (2024)

PURPOSE GEMPAX was an open-label, randomized phase III clinical trial designed to assess the efficacy and tolerability of gemcitabine plus paclitaxel versus gemcitabine alone as second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received 5-fluorouracil, oxaliplatin, and irinotecan. METHODS Patients with histologically or cytologically confirmed mPDAC were randomly assigned (2:1) to receive GEMPAX (paclitaxel 80 mg/m 2 + gemcitabine 1,000 mg/m 2 ; IV; once at day (D) 1, D8, and D15/arm A) or gemcitabine (arm B) alone once at D1, D8, and D15 every 28 days until progression, toxicity, or patient's decision. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), quality of life, and safety. RESULTS Overall, 211 patients (median age, 64 [30-86] years; 62% male) were included. After a median study follow-up for alive patients of 13.4 versus 13.8 months in arm A versus arm B, the median OS (95% CI) was 6.4 (5.2 to 7.4) versus 5.9 months (4.6 to 6.9; hazard ratio [HR], 0.87 [0.63 to 1.20]; P = 0.4095), the median PFS was 3.1 (2.2 to 4.3) versus 2.0 months (1.9 to 2.3; HR, 0.64 [0.47 to 0.89]; P = 0.0067), and the ORR was 17.1% (11.3 to 24.4) versus 4.2% (0.9 to 11.9; P = 0.008) in arm A versus arm B, respectively. Overall, 16.7% of patients in arm A and 2.9% in arm B discontinued their treatment because of adverse events (AEs). One grade 5 AE associated with both gemcitabine and paclitaxel was reported in arm A (acute respiratory distress), and 58.0% versus 27.1% of patients experienced grade ≥3 treatment-related AEs in arm A versus arm B, among which 15.2% versus 4.3% had anemia, 15.9% versus 15.7% had neutropenia, 19.6% versus 4.3% had thrombocytopenia, 10.1% versus 2.9% had asthenia and 12.3% versus 0.0% had neuropathy. CONCLUSION While GEMPAX did not meet the primary end point of OS versus gemcitabine alone in patients with mPDAC in the second-line setting, both PFS and ORR were significantly improved.