bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4365: Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients
Authors: Mosha Maua , Mayer Jennifer , Amankwah Ernest K. 
Published: April 2023

Abstract
The influence of comorbidities at index diagnosis on outcomes of pediatric leukemia and lymphoma is not well established. We evaluated the association between medical comorbidities and pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) outcomes in a retrospective cohort study using electronic health records from the TriNetX Research Network Database, a global de-identified federated health research network. Study participants included pediatric (≤21 years) patients newly diagnosed with ALL or LL from July 2009-June 2019 and followed through June 2022. The main outcomes included progression/relapse, toxicity, overall mortality and cancer-specific mortality. Comorbidities included chronic lung disease; congenital heart disease; neurologic, immune, hematologic, vascular and genetic disorders; renal disease; gastrointestinal disease; prematurity and hepatobiliary disease. Patients with any comorbidity were matched with patients with no comorbidity on age at diagnosis, gender, race/ethnicity, and treatment using propensity score matching. We identified 5,375 patients diagnosed with ALL/LL with comorbidities and 5,375 without comorbidities after propensity score matching. The mean age at diagnosis was 9.7 years (standard deviation=6.2). A higher proportion of the patients were male (56.9%), White (63.6%) and Not Hispanic or Latino (63.4%). Patients diagnosed with comorbidities had a higher risk for progression/relapse (73% vs 51%; Relative Risk, RR=1.42, 95% confidence interval (CI)=1.38-1.47) and treatment related toxicity (80% vs 50%; RR=1.59, 95% CI=1.54-1.64), compared to patients diagnosed with no comorbidities. Similarly, overall mortality (Hazard ratio, HR=1.62, 95% CI=1.37-1.91) and cancer-specific mortality (HR=4.39, 95% CI=2.28-8.46) were higher among patients diagnosed with comorbidities than those without comorbidities. Comorbidities among patients diagnosed with ALL/LL is associated with poor outcomes independent of treatment and thus targeted interventions for the proper management of these patients are needed to improve outcomes.
Citation Format: Maua Mosha, Jennifer Mayer, Ernest K. Amankwah. Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4365.
Abstract 4372: Hierarchy of prognostic quality markers after curative-intent resection of stage IA non-small cell lung cancer
Authors: Shao Huibo , Lee Yu-Sheng , Fehnel Carrie , Akinbobola Olawale , Saulsberry Andrea , Dortch Kourtney , Matthews Anberitha T. , Faris Nicholas R. , Ray Meredith A. , Smeltzer Matthew , Osarogiagbon Raymond U. 
Published: April 2023

Abstract
Introduction. 5-year disease-free survival after curative-intent resection of stage IA NSCLC approximates 65%. The quality of resection and differences in cancer biology probably account for most curative-intent treatment failure. We evaluated the hazard associated with markers of surgical quality.
Methods. Using the population-based Mid-South Quality of Surgical Resection cohort, we compared outcomes of pathologic IA NSCLC resections from 2009 to 2021. With the stringent International Association for the Study of Lung Cancer complete (R0) resection for reference, we evaluated eight quality benchmarks: wedge resection; resections with positive margins; non-examination of lymph nodes (LN) from anywhere (pNX), mediastinal (pNXmed), intrapulmonary, hilar, low paratracheal and subcarinal stations. We evaluated hazard ratios (HR), adjusted for age, sex, insurance, histology, comorbidity, preoperative staging and technique of resection (95% CI) from Proportional Hazards models.
Results. Of 2,243 resections, 906 (41%) were R0; 1,333 were non-R0, including 3% R1/R2, 13% pNX, 15% wedge resections, 15% pNXmed, 45% without subcarinal, 41% without hilar, 47% without low paratracheal, and 36% without intrapulmonary LNs.Compared to IASLC-R0, adjusted HRs were: 2.04 (1.21-3.44) for R1/R2; 1.75 (1.33-2.31) for pNX; 1.64 (1.26-2.14) for wedge resections; 1.35 (1.12-1.63) for non-examination of intrapulmonary LN; 1.33 (1.03-1.72), pNXmed; 1.25 (1.02-1.53), non-examination of hilar LN; 1.15 (0.95 - 1.39) missing station 4; and 1.11 (0.90-1.37) missing station 7 LNs.
Conclusion. Surgical quality, indicated by markers of LN evaluation, have significant impact on long-term survival and should be required selection criteria or stratification factors in lung cancer surgery trials.
Citation Format: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Meredith A. Ray, Matthew Smeltzer, Raymond U. Osarogiagbon. Hierarchy of prognostic quality markers after curative-intent resection of stage IA non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4372.
Abstract 4382: Evolution of curative-intent lung cancer surgery in a 4 eras in the population-based mid-south quality of surgical resection (MS-QSR) cohort
Authors: Akinbobola Olawale , Ray Meredith A. , Fehnel Carrie , Saulsberry Andrea , Dortch Kourtney , Matthews Anberitha T. , Faris Nicholas R. , Godfrey Caroline M. , Smeltzer Matthew , Osarogiagbon Raymond U. 
Published: April 2023

Abstract
Background. Most patients die within 5 years of curative-intent lung cancer surgery
Differences in surgical quality and cancer biology drive long-term overall survival (OS) differences after curative-intent resection. From 2009 onward, we implemented a sequence of interventions to improve surgical quality and pathologic evaluation in a regional population. We evaluated population-level surgical quality and OS in the MS-QSR cohort.
Methods. We categorized the MS-QSR into 4 (approximately) 5-year eras: 1) 2004-08, baseline; 2) 2009-13 (quality feedback and pilot intervention studies); 3) 2014-18 (surgical intervention with a lymph node collection kit); 4) 2019-22 (dual surgical and pathology intervention with novel gross dissection method). We compared surgical quality and OS across eras using standard statistical methods.
Results. Of 6,701 resections, 15%, 33%, 32%, and 20% were in Eras 1-4, respectively. American College of Surgeons Operative Standard 5.8 quality was attained in 4%, 22%, 45%, and 65% of resections in Eras 1-4, respectively; the International Association for the Study of Lung Cancer’s stringent definition of ‘complete resection’ was achieved in 0%, 9%, 20%, and 31%, respectively; 120-Day mortality rates were 10%, 9%, 7%, and 4%; 3-year OS rates were 49%, 64%, 71%, and 84%; 5-year OS, 34%, 52%, and 61%, in Eras 1-3 (too early for Era 4); p&lt;0.0001 for all comparisons.
Conclusion. Population-level surgical quality and OS have improved sequentially in parallel with implementation of interventions to surgical and pathology practices. The higher OS threshold in the MS-QSR creates a platform to interrogate the biologic drivers of surgical outcomes differences.
Citation Format: Olawale Akinbobola, Meredith A. Ray, Carrie Fehnel, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Caroline M. Godfrey, Matthew Smeltzer, Raymond U. Osarogiagbon. Evolution of curative-intent lung cancer surgery in a 4 eras in the population-based mid-south quality of surgical resection (MS-QSR) cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4382.
Abstract 4448: Chemokine (C-X-C motif) ligand 17 promotes cutaneous squamous cell carcinoma via modulating tumor-immune evasion
Authors: Khandelwal Alok R. , Kandula Rema Anisha , Daniel Emily , Alam Md Maksudul , Craighead Henry , Moore-Medlin Tara , Nathan Cherie-Ann O. 
Published: April 2023

Abstract
Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer, striking 200,000 Americans annually. Further, organ transplant patients are at significantly increased risk of cSCC compared to the general population. Excision of cSCC of the head and neck area results in significant facial disfigurement. An increased understanding of the mechanisms involved in the pathogenesis of cSCC could identify means to prevent, inhibit, and reverse this process. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest chemokine family member, and an increased CXCL17 protein expression was observed in both mouse and human cSCC cell lines. Further, deletion of CXCL17 was associated with significant inhibition of tumor cell-intrinsic properties such as proliferation, migration, and motility. CXCL17 is identified as a potent chemoattractant for macrophages, dendritic cells and myeloid-derived suppressive cells. Accordingly, utilizing a syngeneic, tumor-cell xenograft cSCC mouse model, we evaluated the effect of CXCL17 deletion on cSCC tumor-immune evasion and elucidated the underlying mechanism. Deletion of CXCL17 was associated with a significant reduction in tumor volume compared to the wild-type counterparts. Further, CXCL17 deleted cSCC tumor cell xenografts exhibited a significant increase in CD8+, cytotoxic T cells in the tumor microenvironment, suggesting an important role of CXCL17 in mediating tumor-immune evasion. Interestingly, treatment with CXCL17 induced macrophage M2 polarization and promoted macrophage efferocytosis via modulating efferocytotic machinery proteins such as MERTK, TIM4, GAS6 and AXL. Our studies have established substantial evidence for the role of CXCL17 in modulating tumor-cell extrinsic properties to affect the progression of cSCC.
Citation Format: Alok R. Khandelwal, Rema Anisha Kandula, Emily Daniel, Md Maksudul Alam, Henry Craighead, Tara Moore-Medlin, Cherie-Ann O. Nathan. Chemokine (C-X-C motif) ligand 17 promotes cutaneous squamous cell carcinoma via modulating tumor-immune evasion. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4448.
Abstract 4455: Protein phosphatase 4 inhibition stimulates anti-tumor immunity in ovarian cancer
Authors: Raja Remya , Wu Christopher , Bassoy Esen Y. , Rubino Thomas , Utagawa Emma , Magtibay Paul , Butler Kristina , Curtis Marion 
Published: April 2023

Abstract
Background: Increased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in OC, immune checkpoint blockade therapy has been ineffective. Recently studies have shown that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity. One target involved in the DDR that has the potential to be of therapeutic value is protein phosphatase 4 (PP4); however, the effect of PP4 deficiency on anti-tumor immunity remain unknown.
Results: Our results show that PP4 inhibition combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using a panel of ovarian cancer cells, we show that PP4 inhibition triggers inflammatory signaling via NF-κB and STAT1 activation resulting in increased expression of pro-inflammatory cytokines including IFNβ1, CCL5, CXCL10, and IL-6. Moreover, conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and NK cells over carboplatin treatment alone. Knockdown of STING in OC cells significantly abrogated the increase in CD8 T cell migration induced by PP4 inhibition. PPP4C or PPP4R3B knockdown resulted in strong induction of NK cell IFN-γ, increased degranulation, and increased NK cell-mediated cytotoxicity against OC cells. Stable knockdown of PP4C in a syngeneic, immunocompetent mouse model of ovarian cancer resulted in significant reduction of tumor growth in vivo. PP4C low tumors had increased infiltration of CD161+ NK cells and CD4+ T cells. Addition of low dose carboplatin treatment in vivo led to increased CD8+ T cell infiltration in PP4C low tumors when compared to the untreated groups.
Conclusions: Our work has identified a role for PP4 inhibition in promoting anti-tumor immune activation. These findings provide the rationale for combining PP4 inhibitors with immunotherapy as a new approach in ovarian cancer treatment.
Citation Format: Remya Raja, Christopher Wu, Esen Y. Bassoy, Thomas Rubino, Emma Utagawa, Paul Magtibay, Kristina Butler, Marion Curtis. Protein phosphatase 4 inhibition stimulates anti-tumor immunity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4455.
Abstract 4468: Tumor-derived extracellular vesicles transmit retroelement and pericentromeric RNAs to drive proinflammatory and DNA damage responses in stromal fibroblasts and immune cells
Authors: Evdokimova Valentina , Ruzanov Peter , Gassmann Hendrik , Stein Lincoln D. , Sorensen Poul H. , Burdach Stefan , Radvanyi Laszlo 
Published: April 2023

Abstract
Chronic cancer-associated inflammation and immunosuppression are common features in most patients with solid malignancies. The causes of this chronic inflammatory-immunosuppressive state are still largely undefined. We hypothesized that selective RNAs can be secreted by cancer cells in extracellular vesicles (EVs) and may trigger proinflammatory responses in target cells, leading to chronic inflammation linked to immune cell dysfunction and immunosuppression. We found that tumor cell lines from pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa) and from pediatric cancer such as Ewing sarcoma (EwS) continuously secrete large numbers of small (40-200 nm) EVs. In contrast to non-transformed fibroblasts, cancer cell-derived EVs are enriched with large subsets of retroelement and pericentromeric transcripts, including LINE, SINE and HERV retroelements, and human satellite 2 and 3 (HSAT2,3) RNAs. These virus-like RNAs were highly elevated in plasma EVs from EwS patients but not in healthy donors. Some of them, including HERV-K and HSAT2, were detected in peripheral blood myeloid cells with CD33+HLA-DR− immunosuppressive phenotypes, and these cell populations were expanded in EwS patients compared to healthy donors. Using mouse xenografts and in vitro models, we also found that at least some of these RNAs, such as HSAT2, are transmitted to stromal fibroblasts and immune cells in the tumor microenvironment. They also accumulated in fibroblasts after treatment with EwS EVs, coincident with the induction of proinflammatory and DNA damage responses. Prolonged exposure of fibroblasts to EwS EVs also led to mitotic defects and senescence. Expression and dissemination of these highly immunogenic virus-like RNAs in EVs may thus be a common feature of multiple human malignancies, potentially affecting host cells in the local and systemic tumor environment. This, in turn, may induce chronic inflammation contributing to an overall immunosuppressed state in patients.
Citation Format: Valentina Evdokimova, Peter Ruzanov, Hendrik Gassmann, Lincoln D. Stein, Poul H. Sorensen, Stefan Burdach, Laszlo Radvanyi. Tumor-derived extracellular vesicles transmit retroelement and pericentromeric RNAs to drive proinflammatory and DNA damage responses in stromal fibroblasts and immune cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4468.
Abstract 4471: Reprogramming “cold” NF1 malignancies into “hot” tumors for immunotherapy
Authors: Madana Laasya , Le Lu Q. , Somatilaka Nipunika , McKay Renee 
Published: April 2023

Abstract
Introduction: Neurofibromatosis Type 1 (NF1) results from mutations in the NF1 gene that inactivate the tumor suppressor, neurofibromin. This leads to hyperactive RAS signaling that predisposes NF1 patients to tumor development. Over time, some of these tumors can develop into malignant peripheral nerve sheath tumors (MPNST) which are currently incurable.Immune checkpoint blocking (ICB) programs a patient’s immune system to enhance tumor destruction. However, MPNSTs are cold tumors characterized by low immune cell presence in the tumor microenvironment. Interestingly, MPNSTs show checkpoint protein PD-L1 expression suggesting ICB as potential therapy for MPNST, given the ability to increase immune cell density in the tumor microenvironment. Activation of the intracellular receptor stimulator of interferon genes (STING) enhances antitumor immunity through the induction of pro-inflammatory cytokines and chemokines, including type I interferons. Cyclic GMP-AMP synthase (cGAS) is an enzyme that once bound to cytosolic DNA, synthesizes cyclic GMP-AMP (cGAMP), which activates STING to induce inflammatory cytokines and other immune mediators. Preclinical studies using mouse tumor models have assessed the efficacy of STING agonists that trigger the cGAS-STING-IFN axis, ultimately leading to augmented innate immunity and a T cell-rich tumor environment. Additionally, combining STING agonists with ICB has a synergistic effect in treating tumors. Therefore, we hypothesize that treatment with STING agonists would turn “cold” MPNSTs into “hot” tumors making them susceptible to targeting with ICB.
Methods: We treated MPNST cell lines with synthetic STING agonist ADU-S100 for varying durations of 8, 18, 24, and 48 hours. At the end of the treatment, cells were harvested for qRT-PCR and immunoblot analysis.
Results: We measured STING-IFN pathway activation through immunoblotting and observed that phosphorylation of STING effector proteins - a readout of STING activation – was increased followingby 8 hours after treatment. qRT-PCR analysis showed that STING target cytokine/chemokine gene expression was also upregulated by 8 hours after ADU-S100 treatment.
Conclusions: Theise data demonstrates that ADU-S100 was able to activate the STING pathway in MPNST cell lines leading to proinflammatory cytokine/chemokine production. We will next test STING agonist in vivo use to determine whether ADU-S100 treatment inin mouse MPNST modelss of MPNST to is able to reprogram the tumor microenvironment into an immune inflamed one amenable to immunotherapy.
Citation Format: Laasya Madana, Lu Q. Le, Nipunika Somatilaka, Renee McKay. Reprogramming “cold” NF1 malignancies into “hot” tumors for immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4471.
Abstract 4587: Vascular-derived signature imprinted by tumor microenvironment-dependent transcriptional memory predicts colon cancer prognosis
Authors: Naschberger Elisabeth , Fuchs Maximilian , Dickel Nicholas , Kunz Meik , Anchang Charles G. , Demmler Richard , Popp Bernt , Ekici Arif B. , Uebe Steffen , Geppert Carol I. , Günther Claudia , Merkel Susanne , Schellerer Vera S. , Stürzl Michael 
Published: April 2023

Abstract
Background: Antiangiogenic therapy is part of the guideline therapy of colorectal cancer (CRC). Surprisingly, the impact of the tumor microenvironment (TME) on tumor vessel endothelial cells (TECs) is largely unclear. The aim of this study was to investigate the presence of a TME-dependent transcriptional memory in TECs isolated from patients and to exploit it to retrieve signatures that characterize TECs in different intratumoral TMEs with impact on patient outcome.
Methods: ECs from tumor and normal colon tissues, PBMCs and tumor cells were isolated from CRC patients with different prognostic TMEs. Cells were analyzed by qPCR, immunocytochemistry and multi-omics (transcriptomics, EPICmethylation chips, exome sequencing). Integrative bioinformatics was used to identify TME-dependent memory genes predicting prognosis and scRNASeq to validate endothelial gene expression in CRC tissues.
Results: Ultrapure TECs were isolated from CRC with different prognostic TMEs (Th1 vs. non-Th1) and systematically compared by multi-omics. A transcriptional memory differentiating the respective TEC groups was identified. This in vivo imprinted transcriptional memory was preferentially regulated by epigenetic DNA methylation but not by genomic alterations and was different from an in vitro primed transcriptional memory to IFN-γ. Moreover, it was specific for TECs and not observed in CAFs. With integrative bioinformatics a TME-dependent memory signature was extracted and its expression in TECs in CRC tissues was confirmed by scRNASeq. Notably, the identified signature predicted the prognosis of CRC patients.
Conclusion: We identified a tumor vessel-derived TME-dependent transcriptional memory signature that was manifested by epigenetic mechanisms and allowed tumor vessel-based prediction of CRC patients prognosis.
Citation Format: Elisabeth Naschberger, Maximilian Fuchs, Nicholas Dickel, Meik Kunz, Charles G. Anchang, Richard Demmler, Bernt Popp, Arif B. Ekici, Steffen Uebe, Carol I. Geppert, Claudia Günther, Susanne Merkel, Vera S. Schellerer, Michael Stürzl. Vascular-derived signature imprinted by tumor microenvironment-dependent transcriptional memory predicts colon cancer prognosis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4587.