tbuckley/cabot-search huggingface dataset:
Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer.
Authors: Gregory Lawrence Beatty, Mark H. O'Hara, Anne M Nelson, Maureen McGarvey, Drew A. Torigian, Simon F. Lacey, Jan J. Melenhorst, Bruce Levine, Gabriela Plesa, Carl H. June
Journal: Journal of Clinical Oncology (2015)

3007 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive microenvironment with a scarcity of effector T cells. Adoptive T cell therapy to restore anti-tumor immunity has demonstrated promise in several advanced malignancies. However, its role in PDAC remains to be established. This Phase I study was performed to determine the safety and feasibility of administering autologous T cells genetically modified with a chimeric antigen receptor (CAR) that recognizes mesothelin overexpressed on PDAC. Methods: Patients (ECOG 0-1; adequate organ function) with chemotherapy refractory metastatic PDAC ( > 1 prior chemotherapy) were treated with autologous T cells engineered using in vitro transcribed mRNA to transiently express a mesothelin-specific CAR that includes both CD3-zeta and 4-1BB co-stimulatory domains. CAR T cells were infused 3 times per week for 3 weeks. The primary endpoint was to determine safety and manufacturing feasibility. Secondary endpoints were to measure clinical and immune responses. Results: 10 patients were enrolled (6 treated, 2 withdrew due to progressive disease prior to treatment, 1 manufacturing failure, 1 did not complete apheresis necessary for manufacturing). 53 of 54 (98%) planned CAR T cell infusions were administered without dose limiting toxicity. Infusions were well tolerated without evidence of cytokine release syndrome, pleuro-pericarditis or peritonitis. Treatment-related grade > 3 toxicities included abdominal pain (1) and back pain (1). CAR T cells were transiently detected in the peripheral blood after infusion. Two of six patients experienced stable disease by RECIST 1.1 with disease control off therapy seen in one patient for > 4 months. The change in SUVmax of all lesions for each patient detected on 18FDG-PET/CT imaging performed before and 1 month after beginning treatment was -1.9% (95% CI: -25.5% to 21.7%). In one patient, abnormal 18FDG avidity seen in liver metastases at baseline was no longer detected at 1 month after therapy. Conclusions: Mesothelin-redirected CAR T cell therapy is well tolerated and shows preliminary evidence of antitumor efficacy in PDAC. Clinical trial information: NCT01897415.
Multimodal Therapy for Stage III Retinoblastoma (International Retinoblastoma Staging System)
Authors: Bhavna Chawla, Fahmi Hasan, Rachna Seth, Sushmita Pathy, Rajesh Pattebahadur, Sanjay Sharma, Ashish Upadhyaya, Rajvardhan Azad
Journal: Ophthalmology (2016)
Abstract 1218: A novel synergistic antibody pair targeting non-overlapping epitopes of MET effectively inhibits MET-driven cancer models
Authors: Michael M. Grandal, Thomas T. Poulsen, Klaus Koefoed, Karsten W. Eriksen, Anna Dahlman, Paolo Conrotto, Thomas Bouquin, Helle Jacobsen, Ivan D. Horak, Michael Kragh, Johan Lantto, Mikkel W. Pedersen
Journal: Cancer Research (2016)

Abstract The receptor tyrosine kinase MET (Hepatocyte Growth Factor Receptor, HGFR) has been associated with development and progression of a range of human tumors due to its regulation of cell proliferation, migration, invasion, and angiogenesis. A subset of human tumors, particularly of lung or gastric origin, appear to have a primary dependency on MET, which is driven by alterations, such as MET-gene amplification, MET-exon 14 deletion, activating mutations, or autocrine HGF production. Furthermore, MET-amplification has been reported as a key mechanism of de novo resistance to EGFR targeting agents. Sym015 is a mixture of two humanized monoclonal antibodies against non-overlapping epitopes on MET. The specific pair of antibodies was identified in a high-throughput cell based screen searching for antibody mixtures with superior growth inhibitory activity against four MET-dependent cell lines. Both antibodies bind the SEMA domain of MET with high affinity. Synergistic activity was confirmed by dose-response curves in several MET-dependent cell lines and cell line and patient-derived xenograft models. Mechanistically, Sym015 blocks HGF binding to MET, induces MET internalization and degradation effectively diminishing MET oncogenic signaling. Sym015 also induces higher levels of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro compared to individual mAbs. In conclusion, Sym015, a novel monoclonal antibody mixture against MET, shows strong inhibitory activity against MET driven cell lines and xenografts due to a combined effect of MET degradation and secondary effector functions. These data support initiation of clinical trials. Citation Format: Michael M. Grandal, Thomas T. Poulsen, Klaus Koefoed, Karsten W. Eriksen, Anna Dahlman, Paolo Conrotto, Thomas Bouquin, Helle Jacobsen, Ivan D. Horak, Michael Kragh, Johan Lantto, Mikkel W. Pedersen. A novel synergistic antibody pair targeting non-overlapping epitopes of MET effectively inhibits MET-driven cancer models. [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 1218.
Clinical Outcomes for Patients with Gleason Score 9–10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis
Authors: Amar U. Kishan, Talha Shaikh, Pin-Chieh Wang, Robert E. Reiter, Jonathan Said, Govind Raghavan, Nicholas G. Nickols, William J. Aronson, Ahmad Sadeghi, Mitchell Kamrava, David Jeffrey Demanes, Michael L. Steinberg, Eric M. Horwitz, Patrick A. Kupelian, Christopher R. King
Journal: European Urology (2016)
Proliferative Nodules vs Melanoma Arising in Giant Congenital Melanocytic Nevi During Childhood
Authors: Béatrice Vergier, Elodie Laharanne, Martina Prochazkova-Carlotti, Arnaud de la Fouchardière, Jean-Philippe Merlio, Natacha Kadlub, Marie-Françoise Avril, Christine Bodemer, Caroline Lacoste, Franck Boralevi, Alain Taieb, Khaled Ezzedine, Sylvie Fraitag
Journal: JAMA Dermatology (2016)

The differential diagnosis between proliferative nodules (PNs) and melanoma arising in congenital melanocytic nevi (CMN) is crucial, as patients with PNs most often experience no increased risk of melanoma with metastases and death.To analyze the utility of immunohistochemistry and fluorescence in situ hybridization (FISH) in distinguishing PNs from childhood and adult-onset melanoma arising in CMN.A case series was conducted from June 29, 1989, to November 12, 2009, of 13 children with PNs arising in CMN in childhood and 5 children with melanomas arising in CMN in childhood. Five patients with giant CMN with no nodules were included as negative controls, and 6 patients with melanomas arising in CMN in adulthood were included as positive controls. Follow-up ranged from 3 to 21 years in all children (mean, 9.9 years) and from 3 months to 7 years in adults. Specimens were selected for immunohistochemistry and FISH. All histopathologic sections were reviewed by 2 dermatopathologists who examined all nodules arising at different ages in the same patient and, in the case of melanoma, all locations. Data analysis was performed from January 1, 2013, to January 31, 2015.The ability to distinguish melanoma from PN using immunohistochemistry and/or FISH.Of the 13 patients (5 boys and 8 girls) with PNs present at birth, all PNs were stable (mean follow-up, 9 years). Eight patients with PNs and 4 of 5 patients with childhood-onset melanoma showed homogeneous staining for HMB45, while heterogeneous staining for HMB45 was seen in 3 of 6 patients with adult-onset melanoma. Expression of p16 was strongly positive in most patients with childhood-onset PNs (10 of 11 patients) and melanoma (all patients) but negative in 4 patients with adult-onset melanoma. Patients with PNs and the 5 patients with childhood-onset melanoma had numerical chromosomal aberrations never observed in the adjacent CMN. The 2 children with FISH-positive PNs are melanoma free after 7 and 4 years. Only 1 patient with childhood-onset melanoma had a FISH aberration compared with 4 patients with adult-onset melanoma.Immunohistochemistry and the 4-probe FISH melanoma analysis are not useful for distinguishing PN from childhood-onset melanoma as opposed to adult-onset melanoma. Numerical anomalies seen in PNs but not in the adjacent CMN could be the result of a chromosomal segregation malfunction resulting in the development of nodules.
BRAIN TUMOUR AS PRESENTING SYMPTOM IN 2 CHILDREN WITH AN NF-1 LIKE PHENOTYPE IN CONSTITUTIONAL MMR-DEFICIENCY SYNDROME DUE TO BI-ALLELIC PMS-2 MUTATIONS
Authors: J. Fock, R. Lunsing, M. Olderode-Berends, J. Herkert, E. Hoving, R. Scheenstra, R. Tamminga
Journal: Neuro-Oncology (2010)
Case 7-1974
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Stanley M. Wyman, Austin L. Vickery
Journal: New England Journal of Medicine (1974)

Presentation of CaseA 38-year-old woman was admitted to the hospital because of chronic renal disease.Two years before admission she was found to have chronic renal failure with anemia; x-ray studies showed that both kidneys were small. A low-protein diet was prescribed. One year before entry because of hypercalcemia she was referred to this hospital, where elevated serum levels of parathyroid hormone were found. A biopsy of bone revealed osteitis fibrosa and osteomalacia. A diagnosis was made of chronic renal failure of unknown cause, with secondary hyperparathyroidism, and aluminum carbonate therapy was instituted. During the year before admission the . . .
Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials
Authors: S Pasquali, J D Maqueo, J Vela, R A Kyle, T Leong, E Fritz, S Suciu, I P Palva, T Oivanen, C Corrado, F J Lastiri, D Peest, O Kildahl-Andersen, A Maniatis, R Alison, M Clarke, V Evans, R Gray, E Greaves, E Hall, C Hicks, S James, R Peto, S Richards, D Sinclair, A Tooth, K Wheatley, G Avvisati, M Boccadoro, R Bugliosi, F Mandelli, Petrucci, A Pileri, M Tribalto, R Alexanian, K B Delasalle, J Child, J Dunn, I MacLennan, D Milligan, H Mellstedt, A Osterborg, M Hjorth, E Holmberg, S Rodjer, J Westin, O Kamiya, K Shimizu, D E Bergsagel, C Shustik, E Hippe, E Kjaersgaard, I Turesson, A Riccardi, G Ucci, J Blade, M Fontanillas, L De Rosa, A Montuoro, A A Bartolucci, G A Omura, M Stagg, S Salmon, C Tangen, P Jacobs, L Wood, L M Levy, Grp Mtc.
Journal: Journal of Clinical Oncology (1998)
Abstract 922: PGE2/HuR/CEBPD axis in macrophages contributes to immunosuppression and inhibits phagocytosisof nasopharyngeal carcinoma
Authors: Yu-Wei Hsiao, Ju-Ming Wang
Journal: Cancer Research (2016)

Abstract The association of inflammation and cancer progression via modulation of phagocytosis and suppression of adaptive immunity by tumor-associated macrophages (TAM) to promote tumorigenesis has been implicated in a number of recent studies. To date, the underlying mechanisms involving the interactions of these two cellular processes remain elusive, particularly in the involvement of posttranscriptional regulation. In this study, we demonstrate that prostaglandin E2 (PGE2) activates transcription factor CCAAT/enhancer binding protein delta (CEBPD) in macrophages by inducing nucleocytoplasmic shuttling of RNA binding protein Hu antigen R (HuR), which plays a direct role in stabilizing CEBPD mRNA in macrophages. Increase of CEBPD resulted in elevated expression of IL-10, a well-studied immunosuppressor, and PTX3, which contribute to suppression of phagocytosis of cancer cells by macrophages. In addition, the conditioned medium of CEBPD-transfected macrophages showed an immunosuppressive effect to attenuate phagocytosis of cancer cells by macrophages, suggesting an autocrine mode of regulation. Immunohistochemistry studies demonstrated that the cytosolic level of HuR protein correlates with increased CEBPD in TAM and malignant nasopharyngeal carcinoma (NPC). Collectively, these results provide new evidences that the inflammatory PGE2/HuR/CEBPD axis in macrophages plays protumor roles in controlling immunosuppression and attenuating phagocytosis of cancer cells by macrophages. Citation Format: Yu-Wei Hsiao, Ju-Ming Wang. PGE2/HuR/CEBPD axis in macrophages contributes to immunosuppression and inhibits phagocytosisof nasopharyngeal 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 922.
Council of Europe dismisses claim that abortion in Italy is harder because more doctors are objecting
Authors: Carlo Petrini
Journal: BMJ (2016)

Day’s news article says, “Italy’s women are finding it harder to get abortions as number of pro-choice doctors fall.”1 I contested this claim in a rapid response on the basis of the most recent report to parliament on law 194/78.2 3 4 The resolution adopted by the Committee of Ministers of the Council …
Abstract LB-054: Small molecule inhibitors of the hexosamine biosynthetic pathway and the cancer O-GlcNAcome
Authors: Christopher T. Saeui, Kevin Yarema
Journal: Cancer Research (2016)

Abstract In recent years, the long-known Warburg effect–wherein cancer cells utilize abnormally high levels of glucose by forgoing oxidative phosphorylation–has been rediscovered but its impact on flux through the hexosamine biosynthetic pathway (HBP) remains relatively unexplored. In this work, we reasoned that UDP-GlcNAc, the end product of the HBP, could promote cancer by increasing the activity of O-GlcNAc transferase (OGT) and subsequently perturb global patterns of protein O-GlcNAcylation. To combat increased O-GlcNAcylation, which is increasingly being linked to cancer cell survival, metastasis, and tumor aggressiveness, most efforts to date have focused on direct inhibition of OGT. In contrast, we take an alternate approach by developing first-in-class small molecules that target UDP-N-acetylglucosamine pyrophosphorylase 1/2 (UAP1/2), the final enzyme of the HBP; this strategy has the added benefit of also potentially reducing the production of highly-branched N-glycans associated with cancer and other diseases. In our first biological tests, presented here, we show that our UAP1/2 inhibitors decrease intracellular UDP-GlcNAc levels as intended and modulate the cancer O-GlcNAcome in a way consistent with reduced viability of difficult-to-treat pancreatic and brain cancer cell lines observed in treated cells. Finally, our strategy of targeting UAP1/2 and the cancer O-GlcNAcome decreased the expression of oncoproteins such as c-Myc, YAP, and TAZ which are all linked to highly aggressive and difficult-to-treat types of cancer. In summary, we have developed first-in-class of small molecules that successfully target UAP1/2, inhibit flux through the HBP, reduce global patterns of O-GlcNAcylation, and knock-down several endpoints linked to cancer progression. Citation Format: Christopher T. Saeui, Kevin Yarema. Small molecule inhibitors of the hexosamine biosynthetic pathway and the cancer O-GlcNAcome. [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 LB-054.
Remote-controlled eradication of astrogliosis in spinal cord injury via electromagnetically-induced dexamethasone release from “smart” nanowires
Authors: Wen Gao, Richard Ben Borgens
Journal: Journal of Controlled Release (2015)

We describe a system to deliver drugs to selected tissues continuously, if required, for weeks. Drugs can be released remotely inside the small animals using pre-implanted, novel vertically aligned electromagnetically-sensitive polypyrrole nanowires (PpyNWs). Approximately 1–2 mm2 dexamethasone (DEX) doped PpyNWs was lifted on a single drop of sterile water by surface tension, and deposited onto a spinal cord lesion in glial fibrillary acidic protein-luc transgenic mice (GFAP-luc mice). Overexpression of GFAP is an indicator of astrogliosis/neuroinflammation in CNS injury. The corticosteroid DEX, a powerful ameliorator of inflammation, was released from the polymer by external application of an electromagnetic field for 2 h/day for a week. The GFAP signal, revealed by bioluminescent imaging in the living animal, was significantly reduced in treated animals. At 1 week, GFAP was at the edge of detection, and in some experimental animals, completely eradicated. We conclude that the administration of drugs can be controlled locally and non-invasively, opening the door to many other known therapies, such as the cases that dexamethasone cannot be safely applied systemically in large concentrations.
Abstract 5026: EGFR copy number alterations in primary tumors, metastatic lymph nodes and recurrent tumors in areca-quid associated oral squamous cell carcinoma
Authors: Shiang-Fu Huang, Huei-Tzu Chien, Sou-De Cheng, Chun-Ta Liao, Hung-Ming Wang, Ling-Ling Hsieh
Journal: Cancer Research (2016)

Abstract EGFR and downstream signaling pathway plays important roles in the tumorigenesis in oral squamous cell carcinoma (OSCC). Gene copy number alteration is one the mechanism overexpressing the EGFR protein. We previously demonstrated that EGFR gene amplification was related with lymph node metastasis, tumor invasion and perineural invasion. We appraise the hypothesis that the EGFR gene copy number alteration in the primary tumor can predict that in recurrent tumors or in lymph node metastatic foci. Of 167 primary OSCCs, fluorescence in-situ hybridization (FISH) study showed EGFR polysomy in 19 (11.4%) patients and amplification in 33 (19.8%) patients. EGFR gene amplification was related with lymph node metastasis (χ2 trend test: P = 0.018) Of 57 metastatic lymph nodes, 9 (15.8%) had EGFR polysomy and 14 (24.6%) had EGFR gene amplification. The concordance rate of EGFR gene copy number in primary tumor and lymph node metastasis was 68.4% (McNemar test: P = 0.389). Of 41 recurrent tumors, 5 (12.2%) had EGFR polysomy and 5 (12.2%) had gene amplification. The concordance rate of EGFR gene copy number between primary tumor and recurrence tumor was 65.9% (McNemar test: P = 0.510). From our results, we can predict two-thirds of the EGFR gene copy number alteration in the lymph node metastasis or the recurrent tumor from the analysis of primary tumor. In clinical scenario, for OSCC patients that the lymph nodes or the recurrent tumors are unavailable for EGFR gene copy number analysis, studies from the primary tumors could provide part of the EGFR clonal information in the metastatic or recurrent lesions. Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Sou-De Cheng, Chun-Ta Liao, Hung-Ming Wang, Ling-Ling Hsieh. EGFR copy number alterations in primary tumors, metastatic lymph nodes and recurrent tumors in areca-quid associated oral 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 5026.
2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Executive Summary
Authors: Philip Greenland, Joseph S. Alpert, George A. Beller, Emelia J. Benjamin, Matthew J. Budoff, Zahi A. Fayad, Elyse Foster, Mark A. Hlatky, John McB. Hodgson, Frederick G. Kushner, Michael S. Lauer, Leslee J. Shaw, Sidney C. Smith, Allen J. Taylor, William S. Weintraub, Nanette K. Wenger
Journal: Journal of the American College of Cardiology (2010)
Case 9-1966
Authors: Marian W. Ropes, Walter G. J. Putschar
Journal: New England Journal of Medicine (1966)

Presentation of CaseA fifty-one-year-old man was admitted to the hospital because of gastrointestinal bleeding.His right shoulder had been injured in an automobile accident seven years previously and had been painful at intervals thereafter. Three months before admission he incurred a second injury of the right shoulder, which was followed by more persistent pain; he stated that injections into the shoulder joint caused transient relief. A short time later the pain recurred, with tenderness and swelling of the shoulder joint. For several months before entry he was weak and anorectic, with a loss of 25 pounds in weight. Seventeen . . .
Impact of pre-treatment neutrophil-lymphocyte ratio on outcomes in men receiving radical external beam radiotherapy for localised prostate cancer.
Authors: Ciara Lyons, Sagar Kanabar, Darren M. Mitchell, Jacqueline A. Harney, Jonathan McAleese, Lin Shum, David P. Stewart, Joe M. O'Sullivan, Suneil Jain
Journal: Journal of Clinical Oncology (2016)

151 Background: There is a shortage of novel biomarkers in clinical use for the diagnosis and management of prostate cancer. The neutrophil-lymphocyte ratio (NLR) is a potentially useful biomarker derived from a standard full blood count from peripheral blood sampling, which is readily available and relatively inexpensive. An elevated NLR has been shown to be a poor prognostic biomarker in many advanced solid cancers, including prostate cancer (PC); however, data on NLR in non-metastatic PC have been inconsistent. The objective of this study was to evaluate baseline NLR as an independent predictor of outcome following radical radiotherapy for non-metastatic PC. Methods: Data from 477 consecutive PC patients treated with radical EBRT between 2005 and 2009 in Northern Ireland were reviewed. Outcomes included biochemical progression-free survival (bPFS; Phoenix definiton), prostate cancer-specific survival (PCSS) and overall survival (OS). A two-tailed Mann-Whitney test (significance level 5%) was used to compare NLR in each group. Results: Complete data for 409 patients were available. At a median follow-up of 75 months (range 12 – 138), 74 men (16%) had biochemical failure (BF), 12 men (3%) had died of PC, and 65 men (14%) had died of all causes. Actuarial 5-year bPFS was 91%, PCSS was 97% and OS was 89%. Median NLR was 2.42 in both the BF and non-BF groups (p = 0.78), 2.21 and 2.42 in men who died from PC and those who did not (p = 0.39) and 2.40 and 2.42 in those men who died from all causes and those men who remained alive (p = 0.83). See Table for additional data. Conclusions: In this cohort with medium- to long-term follow-up, NLR was not predictive for bPFS, PCSS or OS. Multivariate analysis of this cohort is planned. Additional prognostic biomarkers are required in PC. [Table: see text]