tbuckley/cabot-search huggingface dataset:
Abstract 4862: AGI-134: a fully synthetic alpha-Gal glycolipid that prevents the development of distal lesions and is synergistic with an anti-PD-1 antibody in a mouse melanoma model
Authors: Stephen Shaw, Sascha Kristian, Kim Wigglesworth, Jenny Middleton, Mel Glossop, Giles Whalen, Robert Old, Mike Westby, Chris Pickford
Journal: Cancer Research (2016)

Abstract Background: AGI-134 is a fully synthetic glycolipid, composed of an alpha-Gal (Galá1-3Galâ1-4GlcNAc-R) sugar epitope attached via a linker to a lipid tail. Natural antibodies to the alpha-Gal epitope are responsible for the hyperacute rejection of xenografts in humans. It is proposed that intratumorally administered AGI-134 will incorporate into the cell membranes of the tumor cells, presenting the alpha-Gal epitope for binding of anti-Gal antibodies to the tumor cells. This will initiate an immune response that attacks the injected tumor and, through uptake of immune-complexed tumor antigens by antigen presenting cells, will create a patient-specific, systemic anti-tumor response against distant metastases. Results: We demonstrate that AGI-134 incorporates into tumor cell membranes in vitro and that the exposed alpha-Gal epitope binds anti-Gal IgG and IgM antibodies from human serum to the tumor cell surface. Using flow cytometry and a complement-dependent cytotoxicity assay we show that tumor cell opsonization with anti-Gal antibodies leads to deposition of complement proteins C3b and C5b-9, which ultimately leads to tumor cell lysis. Furthermore, we demonstrate that AGI-134-labeled tumor cells opsonized with human serum proteins are phagocytosed by professional APCs. Using the B16-F10 melanoma model in anti-Gal producing á1,3-galactosyltransferase knockout (GT KO) mice we present data to demonstrate that AGI-134 injection into a primary tumor provides significant dose-dependent protection from the development of established distant lesions. Using GT KO mouse serum we demonstrate in vitro that deposition of complement on AGI-134-labeled mouse tumor cells is both alpha-Gal and anti-Gal dependent. In vivo, we demonstrate that the effect of AGI-134 is due to the alpha-Gal moiety by replacing it with human blood group antigens. The protection from secondary lesions conferred by AGI-134 is long lasting in the GT KO mouse melanoma model (monitored up to 90 days). Importantly, when sub-optimal concentrations of AGI-134 were tested in vivo in combination with an anti-PD-1 antibody (RMP1-14), a significant enhancement in efficacy over either of the agents administered alone was observed. Citation Format: Stephen Shaw, Sascha Kristian, Kim Wigglesworth, Jenny Middleton, Mel Glossop, Giles Whalen, Robert Old, Mike Westby, Chris Pickford. AGI-134: a fully synthetic alpha-Gal glycolipid that prevents the development of distal lesions and is synergistic with an anti-PD-1 antibody in a mouse melanoma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4862.
Case 42-1965
Authors: Dieter Koch-Weser, F. Daniel Foley
Journal: New England Journal of Medicine (1965)

Presentation of Case First admission. A forty-seven-year-old woman was admitted to the hospital because of dyspnea.She had been well until eighteen months earlier, when she began to experience mild exertional dyspnea, which progressed in severity. Digitalis effected improvement, but she omitted the medication, and the symptoms recurred. Six months later she entered another hospital because of a cough and pain in the chest and was treated for "pneumonia." Eight months before admission she returned to the same hospital because of recurrence of the cough, with the production of sputum. A scalene-lymph-node biopsy disclosed granulomatous lymphadenitis with necrosis. She was . . .
Using a disease pathway management approach to improve the quality of breast cancer care in Ontario.
Authors: Andrea Eisen, Jasmin Soobrian, Ashley Tyrrell, Clement Li, Derek Muradali, Margaret F Forbes, Angelika Gollnow, Jillian Ross, Claire Holloway
Journal: Journal of Clinical Oncology (2016)

109 Background: Disease Pathway Management (DPM) is used by Cancer Care Ontario (CCO) to set priorities for cancer control, plan cancer services, and improve the quality of care in Ontario by promoting standardization. The DPM approach applies a framework to examine the performance of the entire system from prevention to end of life care, and to identify any gaps within the system. In 2014, DPM began its breast cancer pathway initiative by mapping the patient journey, depicting evidence-based best practice along the breast cancer care continuum, identifying where further guidance is needed for clinical decision making, and identifying gaps in quality of care and performance measurement indicators. Objective: To evaluate the impact of DPM on quality assessment of breast cancer care in Ontario. Methods: DPM convened a multidisciplinary breast cancer working group (WG) of 40 experts from across Ontario. The WG held 12 meetings and used guidelines developed by CCO’s Program in Evidence Based Care (or other sources as needed) to generate pathways for the prevention, screening and diagnosis, treatment, and follow-up care for breast cancer. The pathways were used as a framework to review the existing inventory of provincial breast cancer quality indicators, and to identify areas where evidence based guidance is needed. The pathways were subjected to an extensive review process before publication. Results: The expert WG identified 28 priority areas, including opportunities to develop guidance in areas where it is lacking (e.g. role of perioperative breast MRI; indications for contralateral prophylactic mastectomy) and system barriers that may hinder optimal care (e.g. biomarker assessment). The WG also used the pathways as a framework for evaluating performance measurement indicators by mapping 48 existing quality indicators for breast cancer to the pathway. Conclusions: The CCO DPM Breast Cancer pathways facilitated a province-wide, multidisciplinary process to promote quality standards, to identify gaps and overlaps in performance and quality measurement, and to recommend additional indicators more relevant to the quality of breast cancer care in Ontario.
Re: Anthony Zietman, Joseph Smith, Eric Klein, Michael Droller, Prokar Dasgupta, James Catto. Describing the Grade of Prostate Cancer: Consistent Use of Contemporary Terminology Is Now Required. Eur Urol 2016;70:1
Authors: Lars Egevad, Hemamali Samaratunga, John R. Srigley, Brett Delahunt
Journal: European Urology (2016)
Palliative care issues encountered by radiation oncologists caring for advanced cancer patients.
Authors: Gregory Parker, Virginia LeBaron, Monica Shalini Krishnan, Ron Y. Shiloh, Margarita Racsa, Michael Edward Pacold, Alexander Spektor, Tracy A. Balboni
Journal: Journal of Clinical Oncology (2014)

14 Background: Palliative radiation therapy (PRT) is often administered to patients with advanced cancers. These patients may present to radiation oncology clinicians with other palliative care needs. To date, the types and frequencies of palliative care issues encountered in this setting have not been well characterized. Methods: This study assesses palliative care issues encountered by radiation oncology clinicians during PRT consults at 3 Boston-area, community and academic, hospital-based centers. For consecutive consults from 5/19/14 to 9/15/14, participating physicians and nurse practitioners complete a survey to identify and rank the relevance (5-point scale, 'not at all' to 'extremely') of palliative care issues. Eight domains adapted from national palliative care guidelines – physical symptoms, psychosocial issues, cultural considerations, spiritual needs, care coordination, advance care planning, goals of care, and ethical and legal issues – are evaluated. Preliminary descriptive statistics based on 51 completed surveys are reported (response rate = 94%; anticipated sample size = 198). Results: Most (82%) consults had 2 or more palliative care domains ranked as very or extremely relevant to patient care. The domains of physical symptoms (92%), care coordination (75%), and goals of care (57%) were very or extremely relevant in &gt;50% of consults. Within these domains, the issues most often reported as relevant were interdisciplinary care coordination (92%), consideration of prognosis in treatment plan development (86%), pain management (71%), and discussion of patient values and priorities in treatment plan development (67%). Advanced care planning (24%), cultural considerations (10%), spiritual needs (10%), and ethical and legal issues (10%) were least commonly ranked as very or extremely relevant. Conclusions: Radiation oncology clinicians encounter multiple palliative care issues when consulting on patients for PRT. Clinicians identified physical symptoms, care coordination, and goals of care as the most relevant palliative care domains. These findings can help guide palliative care development within radiation oncology, including education and structures of care delivery.
The early infant gut microbiome varies in association with a maternal high-fat diet
Authors: Derrick M. Chu, Kathleen M. Antony, Jun Ma, Amanda L. Prince, Lori Showalter, Michelle Moller, Kjersti M. Aagaard
Journal: Genome Medicine (2016)

Emerging evidence suggests that the in utero environment is not sterile as once presumed. Work in the mouse demonstrated transmission of commensal bacteria from mother to fetus during gestation, though it is unclear what modulates this process. We have previously shown in the nonhuman primate that, independent of obesity, a maternal high-fat diet during gestation and lactation persistently shapes the juvenile gut microbiome. We therefore sought to interrogate in a population-based human longitudinal cohort whether a maternal high-fat diet similarly alters the neonatal and infant gut microbiome in early life.A representative cohort was prospectively enrolled either in the early third trimester or intrapartum (n = 163), with a subset consented to longitudinal sampling through the postpartum interval (n = 81). Multiple body site samples, including stool and meconium, were collected from neonates at delivery and by 6 weeks of age. A rapid dietary questionnaire was administered to estimate intake of fat, added sugars, and fiber over the past month (National Health and Examination Survey). DNA was extracted from each infant meconium/stool sample (MoBio) and subjected to 16S rRNA gene sequencing and analysis.On average, the maternal dietary intake of fat ranged from 14.0 to 55.2 %, with an average intake of 33.1 % (σ = 6.1 %). Mothers whose diets significantly differed from the mean (±1 standard deviation) were separated into two distinct groups, a control group (n = 13, μ = 24.4 %) and a high-fat group (n = 13, μ = 43.1 %). Principal coordinate analysis revealed that the microbiome of the neonatal stool at birth (meconium) clustered differently by virtue of maternal gestational diet (PERMANOVA p = 0.001). LEfSe feature selection identified several taxa that discriminated the groups, with a notable relative depletion of Bacteroides in the neonates exposed to a maternal high-fat gestational diet (Student's t-test, p < 0.05) that persisted to 6 weeks of age.Similar to the primate, independent of maternal body mass index, a maternal high-fat diet is associated with distinct changes in the neonatal gut microbiome at birth which persist through 4-6 weeks of age. Our findings underscore the importance of counseling pregnant mothers on macronutrient consumption during pregnancy and lactation.
Abstract 111: Recurrent mutations of CDKN2A genes characterize worse prognosis of HPV positive and negative oropharyngeal squamous cell carcinoma
Authors: Jongkeun Lee, Dongwan Hong, Eun Kyung Lee, Yuh-Seog Jung, Weon Seo Park
Journal: Cancer Research (2016)

Abstract Background: Oropharyngeal squamous cell carcinoma (OSCC) exhibits unique clinical and molecular characteristics, depending on its association with high-risk human papillomavirus (HPV) or other carcinogen like smoking1. Considering significant subset of patients with OSCC still exhibits poor response to contemporary treatments2, which frequently cause significant toxicity, a more detailed understanding of these poor responders, especially adopting current precision genomic technology, could provide a clue for developing better treatment. Methods: In this study, we gathered the somatic point mutations and mRNA expression data of 520 OSCC patients from The Cancer Genome Atlas (TCGA) and then investigated recurrent somatic point mutations. To genes having the recurrent and same type point mutations, in addition, we check out the mRNA expression and analyzed a survival analysis. Results: We found 7 somatic point mutations of CDKN2A gene, which having recurrent patients and only nonsense SNVs. Out of these mutation, 6 recurrent point mutations of CDKN2A gene have highly expressed on PIK3CA, FGFR2 and FGFR3 genes, as well as showed a significant deterioration on survival outcome. Conclusion: Recurrent nonsense mutations of CDKN2A mostly (6/7, 85.7%) derived an abnormal regulation of other genes, such as PI3KA, FGFR2, and FGFR3. Moreover, this pattern of mutations significantly characterizes ominous prognosis in HPV positive and negative OSCC. Our result might provide better insights for characterizing the subgroup of OSCC and eventual development of precision strategy for this disease subset. References 1. Licitra, L. et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24, 5630-6 (2006). 2. Ang, K.K. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363, 24-35 (2010). Citation Format: Jongkeun Lee, Dongwan Hong, Eun Kyung Lee, Yuh-Seog Jung, Weon Seo Park. Recurrent mutations of CDKN2A genes characterize worse prognosis of HPV positive and negative oropharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 111.
Abstract 4313: Periodic fasting mimicking diet delays cancer development and progression
Authors: Sebastian Brandhorst, Gerardo Navarrete, Min Wei, Todd E. Morgan, Valter D. Longo
Journal: Cancer Research (2016)

Abstract Dietary intake and composition can have profound effects on aging and age-related pathologies including cancer. As such, studies of fasting (the complete withdrawal of food) and dietary restriction (DR, generally described as a 20- 40% reduction in calories) have contributed to the understanding of the relationship between nutrients, cellular aging, cancer development and cancer cell survival. DR may only be feasible in delaying tumor development but might not present an effective treatment modality due to the time required to achieve beneficial effects. Further, chronic DR may also have negative impacts on wound healing, which could be detrimental in patients undergoing surgery. Our findings in yeast indicated that starvation decreases age-dependent mutations whereas in mouse xenograft tumor models fasting alone can be as effective as chemotherapy drugs in delaying the progression of certain tumor types, in part through the reduction of extracellular glucose and IGF-1 concentration/signaling. Fasting, although results indicate efficacy as a treatment option, on the other hand may not be feasible for patients at risk for undernutrition or cachexia. To address the need for a dietary based intervention that both delays cancer development and progression, we developed a fasting-mimicking diet (FMD) to ensure micronutrient supply and tested its effectiveness in rodent models. Periodic bi-weekly FMD cycles had a significant impact on the development and progression of multiple cancer models while allowing the preservation of lean body mass even at old age and extending longevity in healthspan study. As a treatment modality, FMD cycles alone significantly reduced tumor progression and sensitized various cancer models to chemotherapeutic drugs. Citation Format: Sebastian Brandhorst, Gerardo Navarrete, Min Wei, Todd E. Morgan, Valter D. Longo. Periodic fasting mimicking diet delays cancer development and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4313.
Abstract 133: Integrated molecular characterization of uterine carcinosarcoma in The Cancer Genome Atlas (TCGA) project
Authors: Rehan Akbani, Douglas A. Levine
Journal: Cancer Research (2016)

Abstract We used array- and sequencing-based technologies to perform an integrated genomic, epigenomic, transcriptomic, and proteomic characterization of the rare tumor type uterine carcinosarcoma (UCS) within the context of The Cancer Genome Atlas (TCGA) project using 57 cases that had stringent histopathologic review. Cohort samples had extensive copy number alterations and highly recurrent somatic mutations. Nearly all (91%) cases had TP53 mutations, similar to ovarian and serous uterine carcinomas, and frequent mutations were also found in PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong EMT gene signature in a subset of 17 (30%) cases, and cases with EMT signatures had decreased expression of mir-200 family members that was attributable to epigenetic alterations at miRNA promoters. The range of EMT signatures scores in UCS was the largest among all the TCGA tumor types studied. UCS shared proteomic features with both gynecologic carcinomas and non-gynecologic mesenchymal-like tumors. Our results indicate that UCS tumors share many features with serous-like endometrial carcinomas, including frequent TP53 mutations and extensive somatic copy number alterations, though with greater EMT features. Multiple somatic mutations and copy number alterations in genes that are therapeutic targets were identified. There was a high degree of mutational clonality, consistent with tumors being derived from a single cell of origin. Taken together, these data suggest that while some UCS tumors develop from an endometrioid lineage, the majority likely de-differentiate from a serous precursor, potentially accounting for their clinical aggressiveness and poor response to treatment. Citation Format: Rehan Akbani, The Cancer Genome Atlas Research Network, Douglas A. Levine. Integrated molecular characterization of uterine carcinosarcoma in The Cancer Genome Atlas (TCGA) project. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 133.
Abstract 4026: Epigenetic changes in T cells in response to immune checkpoint blockade
Authors: Sangeeta Goswami, Jianfeng Chen, Hao Zhao, Xuejun Zhang, Padmanee Sharma
Journal: Cancer Research (2016)

Abstract Immune checkpoint blockade therapy has led to clinical success and have established immunotherapy as one of the primary modality of cancer treatment. It leads to a durable response in around 20% of the patients (responders). Success of immune checkpoint blockade therapy relies on the increase of effector T cells and decrease of regulatory T cells in the tumor microenvironment. However, the underlying mechanism that govern the ratio of effector and regulatory T cells between responder and non-responder to checkpoint blockade is not understood. Understanding the process could reveal novel mechanisms to boost efficacy of immune checkpoint blockade. Differentiation of naïve T cells into effector and regulatory phenotype requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. One key epigenetic modification for T cell differentiation is trimethylation of lysine 27 on histone H3 (H3K27me3). Loss of H3K27me3 results in increased Th-1 plasticity whereas presence of H3K27me3 on Foxp3 locus is required to maintain the function of T-regulatory cells. We hypothesize that immune checkpoint blockade changes the epigenetic landscape in tumor infiltrating T cells that results in an effector phenotype and epigenetic modification of H3K27me3 could promote an anti-tumor immune microenvironment in tumor bearing mice.We showed that in-vivo inhibition of H3K27me3 in combination with anti-CTLA4 results in reduction of tumor size and also reduction in regulatory T cells in a B16-F10 melanoma mice model compared to anti-CTLA4 treatment alone, suggesting H3K27me3 inhibition could increase the efficacy of checkpoint blockade therapy. Future studies will aim to elucidate epigenetic changes in H3K27me3 and define an epigenetic signature as a result of immune checkpoint therapy by ChIP-sequencing. Data generated in this project will greatly enhance our understanding of epigenetic regulation of T cell differentiation is response to immune checkpoint blockade and aid identifying key changes that could be further modified to overcome resistance to immune checkpoint blockade in non-responders. Citation Format: Sangeeta Goswami, Jianfeng Chen, Hao Zhao, Xuejun Zhang, Padmanee Sharma. Epigenetic changes in T cells in response to immune checkpoint blockade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4026.