tbuckley/cabot-search huggingface dataset:
ATNT-28MANAGING RECURRENT GRADE III GLIOMAS WITH COMBINATION THERAPY OF BEVACIZUMAB AND OPTUNETM
Authors: Ashley Sumrall, Daniel Haggstrom, Tony Asher, Anthony Crimaldi, Roshan Prabhu, Scott Wait, Stuart Burri
Journal: Neuro-Oncology (2015)

BACKGROUND: The prognosis for patients with high grade gliomas remains dismal. Given that grade III gliomas are rare, we often extrapolate therapy from glioblastoma. In addition to cytotoxic therapy, the FDA has also approved bevacizumab and OptuneTM (Tumor Treating Fields) for recurrent glioblastoma. In one series of recurrent grade III gliomas, average survival following progression on bevacizumab was approximately 10 months. Given the prognosis and multiple treatment options, many clinicians have elected to offer combined therapy. We examined our patient population at a single institution where combination therapy has been used. METHODS: We retrospectively reviewed clinical courses of all patients with recurrent grade III gliomas receiving OptuneTM who have been concurrently managed with bevacizumab or experienced prior therapy with bevacizumab. Toxicity, tolerability, and survival data were reviewed. Patients who received OptuneTM for at least 4 weeks with concurrent bevacizumab were analyzed for survival. RESULTS: We identified 9 patients, 6 males and 3 females, each having one to three prior recurrences. Of those, 8 patients had anaplastic astrocytomas and 1 patient had an anaplastic oligoastrocytoma. All but 3 patients had failed therapy with bevacizumab. OptuneTM was started as single therapy in 1 patient after bevacizumab exposure and failure. 1 patient was treated for contact dermatitis that did not delay therapy. No intracranial bleeding or strokes were identified. There was no increased incidence of seizures. Median duration of concurrent therapy was 4 months. At time of analysis, five patients are still living. CONCLUSIONS: Combining bevacizumab and OptuneTM does not appear to significantly increase risk of skin reactions, ulcerations, or erosions in this population. There is no increased incidence of bleeding or stroke in our population. The incidence and severity of skin reactions were comparable to those described previously. Additional trials to investigate this combination are ongoing.
Evaluation of Enhanced in Vitro Plasma Stability of a Novel Long Acting Recombinant FVIIIFc-VWF-XTEN Fusion Protein
Authors: Ekta Seth Chhabra, Nancy Moore, Chris Furcht, Amy M Holthaus, Jiayun Liu, Tongyao Liu, Volker Schellenberger, John Kulman, Joe Salas, Robert Peters
Journal: Blood (2015)
Aggressive craniofacial lymphoma in the pre-rituximab and rituximab era.
Authors: V. Poeschel, N. Murawski, B. Glass, S. Zeynalova, J. Fleckenstein, M. Ziepert, B. Kempf, M. Loeffler, N. Schmitz, M. Pfreundschuh
Journal: Journal of Clinical Oncology (2011)

8038 Background: Among 4,165 patients treated in trials of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), 316 pts had craniofacial involvement by their lymphoma. Methods: To analyze clinical characteristics and response to therapy of 316 pts with craniofacial lymphomas treated with CHOP-like chemotherapy with and without rituximab (R). A retrospective analysis was performed to compare characteristics and treatment outcome of pts with craniofacial lymphoma to all the other pts of these trials. Results: Of the 316 pts, 32 had orbital, 101 paranasal sinus, 44 main nasal cavity, 109 mouth, 28 tongue and 57 salivary gland involvement. Pts with craniofacial lymphoma presented with a significantly lower LDH, better performance status, lower Ann Arbor Stage and less bulky disease compared to the entire population (elevated LDH: 16.8% vs. 35.9%, p=<0.001; ECOG >1: 2.8% vs. 10.1%, p=<0.001; stage III/IV: 28.2% vs. 40.7%, p=<0.001; bulky disease: 14.9% vs. 39.3%, p=<0.001). 3-year event free survival (70.4% vs. 60.5%, p=<0.001) and 3-year overall survival (81.2% vs. 75.6%; p=0.044) were better in pts with craniofacial involvement compared to the entire population of these trials. Multivariate analysis confirmed all IPI-relevant risk factors as significant and independent. With respect to different treatment strategies, the addition of rituximab to CHOP-14 in the RICOVER-60 trial reduced the relative risk to 0.6 for EFS and 0.5 for OS. This is clinically very relevant, but not significant due to the limited number of patients. In contrast, additive Rx to the craniofacial involvement for pts in CR/CRu or PR at the end chemo- or immunochemotherapy, which was given to 178 pts had no influence on the outcome of these pts compared to pts not receiving additive Rx (n=68). The relative risk for EFS was 1.0 (p=0.863) and 1.5 (p=0.315) for OS in patients receiving additional Rx compared to pts receiving systemic therapy only. Conclusions: Pts with craniofacial lymphoma present with favorable prognostic parameters and treatment results are better in this population compared to the whole population. Our results do not support the addition of radiotherapy to systemic therapy in these patients.
Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety
Authors: Catarina Pereira‐Leite, Cláudia Nunes, Sarah K. Jamal, Iolanda M. Cuccovia, Salette Reis
Journal: Medicinal Research Reviews (2016)

Abstract The efficacy of nonsteroidal anti‐inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long‐term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX‐2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine‐associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti‐inflammatory therapy.
Abstract LB-126: Declining T levels provide increased opportunity for mutagenesis in prostate stem cells
Authors: Ye Zhou, Jeremy Jones
Journal: Cancer Research (2015)

Abstract Because both normal prostate development and the growth of prostate cancers depend on androgen-mediated activation of androgen receptor (AR) signaling, it is reasonable to hypothesize that androgens and AR signaling play a role in prostate tumor initiation as well; however, little is known about androgens and AR in this process. We hypothesize that the decline in androgen production that occurs naturally with age contributes directly to tumorigenesis. Previously, we showed that low serum testosterone (T) causes changes in the expression of genes in the androgen/AR signaling axis which allows the prostate tissue to sustain functional androgen levels in rodents. These changes may contribute to prostate tumorigenesis. There is ongoing debate concerning the cell of origin for prostate cancer, but most evidence would suggest that it can arise from stem cells or cells with stem-like features. Here, we used a murine model to manipulate serum androgen levels to assess the changes in prostate stem-like cells in response to low serum T and to investigate the potential mechanisms by which androgens and AR contribute to prostate tumorigenesis. Using flow cytometry, we observed that chronic exposure to low T causes a consistent expansion of prostate stem-like cell populations, including Lin-/CD133+/CD117+ cells (from 0.23% to 0.33%), Lin-/CD49fHigh/Trop2+ cells (from 6.47% to 8.42%) and intermediate CK5+/CK8+ cells (from 0.43% to 1.26%). Using an in vitro sphere forming assay, we found that stem-like cells isolated from low T treated animals had an increased ability to form spheres, suggesting that low T increases self-renewal capacity. We are currently testing the ability of low T to increase self-renewal capacity in rodent models. Using qPCR, we found that low T causes changes in the expression of genes in the androgen/AR signaling pathway as well as in the oxidative stress response in stem-like cells. We are currently using RNA-seq to understand on a global scale the changes that chronic low T exposure causes in these stem-like cells. Our studies suggest that chronic exposure to low T, as is the case in older men, could provide a greater opportunity for damage to cells that can become cancer initiating cells. Citation Format: Ye Zhou, Jeremy Jones. Declining T levels provide increased opportunity for mutagenesis in prostate stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-126. doi:10.1158/1538-7445.AM2015-LB-126
A case with small-cell transformation after treatment with EGFR tyrosine kinase inhibitor for lung adenocarcinoma
Authors: Atsushi Osoegawa, Takafumi Hashimoto, Takumi Yohei, Abe Miyuki, Suehiro Shuji, Miyawaki Michiyo, Sugio Kenji
Journal: Annals of Oncology (2015)
Response to Comment on “A small-molecule antivirulence agent for treating <i>Clostridium difficile</i> infection”
Authors: Kristina Oresic Bender, Megan Garland, Matthew Bogyo
Journal: Science Translational Medicine (2016)

Ebselen’s antivirulence activity in Clostridium difficile infection is likely due to multiple modes of action, but the contribution of each to its efficacy remains unclear.
Abstract 3485: Uncertainty envelope to evaluate drug interactivity with statistical analysis
Authors: Liang Zhao, Jessie L.-s. Au, M. Guill Wientjes
Journal: Cancer Research (2015)

Abstract Introduction. Development of new therapies for cancer and infections frequently involves combinations of two or more drugs. Existing methods to quantify drug interactivity are suitable for analyzing drugs with parallel concentration-effect curves and similar maximum drug effects. This study established a method for the remaining situations. Methods. Equations describing zero-interactivity effects of combination therapy were developed based on the principle that a drug cannot interact with itself (i.e., additivity only). These equations were used to convert the concentration-effect (C-E) curve of the combination to C-E curve for each of the two drugs in the combination as if they were used as single agents (single agent-equivalent curves). Confidence intervals (CI) of these curves were generated using the error propagation method. Effect data of drug combinations were analyzed by the new and existing methods. Results. The calculated single agent-equivalent curves plus 95% CI defined the boundaries of an envelope for additive drug effects (Uncertainty Envelope). The Envelope shape and size were determined by differences in the shapes of single agent C-E curves. The nature of drug interactivity is indicated by the location of experimental data points of the combination; data points located within the Envelope indicate additivity, whereas points above and below the Envelope respectively indicate statistically significant synergy and antagonism. In comparison with the existing methods, the Envelope method yielded more conservative results (additivity vs. synergy or antagonism). Conclusion. Uncertainty Envelope method enables the interactivity analysis between drugs with nonparallel C-E curves and unequal maximal effect, with statistical confidence. Citation Format: Liang Zhao, Jessie L.-s. Au, M. Guill Wientjes. Uncertainty envelope to evaluate drug interactivity with statistical analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3485. doi:10.1158/1538-7445.AM2015-3485
Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy
Authors: Christine E. Brown, Darya Alizadeh, Renate Starr, Lihong Weng, Jamie R. Wagner, Araceli Naranjo, Julie R. Ostberg, M. Suzette Blanchard, Julie Kilpatrick, Jennifer Simpson, Anita Kurien, Saul J. Priceman, Xiuli Wang, Todd L. Harshbarger, Massimo D’Apuzzo, Julie A. Ressler, Michael C. Jensen, Michael E. Barish, Mike Chen, Jana Portnow, Stephen J. Forman, Behnam Badie
Journal: New England Journal of Medicine (2016)

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).
Abstract 3955: A primary cell-based assay to identify initiating oncogenic events in neuroblastoma
Authors: Rachelle Olsen, Joel Otero, Zhirong Yin, Jesus Garcia-Lopez, Kevin Freeman
Journal: Cancer Research (2015)

Abstract The pediatric cancer neuroblastoma (NBL) forms from immature cells of the sympathetic nervous system (SNS). A prominent category of high-risk NBL is MYCN amplification with loss of heterozygosity (LOH) at 1p36. This LOH includes the chromatin remodeling factor, CHD5, a proposed tumor suppressor of NBL and can include ARID1A, a component of the SWI/SNF chromatin remodeling complex. To identify genetic changes that cooperate with MYCN amplification in initiating NBL we developed an assay based on oncogenic transformation of neural crest cells (NCCs), the progenitors of the SNS. Isolation of NCCs from E9.5 mouse embryos resulted in a population that was ∼90% positive for the NCC markers p75, Sox10, and Ascl1, suggesting a highly enriched population. Next, we tested the ability of N-Myc infected NCCs to form tumors in vivo. In pilot experiments using NCCs with compromised p53, we obtained subcutaneous tumors following injection of NCCs in nude mice. Resulting tumors were diffusely positive for neuronal markers such as synaptophysin, MAP2, and Tyrosine hydroxylase (TH). Tumors also contained focal areas of divergent differentiation characteristic of melanoma, Schwannoma, and osteosarcoma, all cancers that can arise from NCC lineages. To our knowledge, this is the first report of cancer from transformed primary neural crest cells. To more closely model NBL genetics, we replaced loss of p53 with shRNA to knockdown CHD5 and ARID1A prior to N-Myc infection. Injection of the resulting NCCs also resulted in tumor formation in nude mice. Tumors were uniformly positive for neuronal markers including TH and Ascl1, as well as Phox2B, a marker of undifferentiated NBL, and with no evidence of other cancers. Future studies in understanding the interactions of N-Myc overexpression with loss of these chromatin remodeling factors should further increase our understanding of NBL development. Citation Format: Rachelle Olsen, Joel Otero, Zhirong Yin, Jesus Garcia-Lopez, Kevin Freeman. A primary cell-based assay to identify initiating oncogenic events in neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3955. doi:10.1158/1538-7445.AM2015-3955
Anatomical Study of the Caudate Lobe with Special Reference to Portal Venous and Biliary Branches Using Corrosion Liver Casts and Clinical Application
Authors: Masamitsu Kumon
Journal: Liver Cancer (2016)

The definition and extent of the human caudate lobe in the liver is unclear, and thus, the anatomy of the caudate lobe was studied using 23 corrosion liver casts, with special reference to the portal venous and biliary branches. These branches and their ramification type in the caudate lobe showed that this lobe includes: (1) the Spiegel lobe; (2) the paracaval portion; and (3) the caudate process portion. The three portions often have their own independent branches; for example, the portal venous and biliary branches of the Spiegel lobe were ramified mainly from the left-side tract, whereas those of the caudate process portion were ramified from the right-side tract. The portal venous branches of the paracaval portion were ramified mainly from the left portal vein, while the biliary branches of this portion drained into the right and left biliary tracts at almost equal frequencies. In most cases, the peripheral branches reached the liver surface beneath the diaphragm. Thus, the present division of the caudate lobe into three portions could make the extent of the caudate lobe clear and is considered logical from a clinical viewpoint.
Monitoring of Individual Needs in Diabetes (MIND)-2
Authors: Frank J. Snoek, Nancy Y.A. Kersch, Ebbe Eldrup, Ilana Harman-Boehm, Norbert Hermanns, Andrzej Kokoszka, David R. Matthews, Brian E. McGuire, Mirjana Pibernik-Okanović, Joelle Singer, Maartje de Wit, Søren E. Skovlund
Journal: Diabetes Care (2012)

OBJECTIVE To test the effects of implementing computer-assisted Monitoring of Individual Needs in Diabetes (MIND) in routine diabetes care on psychological status and glycemic control, identify predictors of poor psychological outcomes, and evaluate care providers’ experiences. RESEARCH DESIGN AND METHODS The MIND procedure was implemented as part of the annual review in diabetes clinics across eight countries in a prospective observational study with a 1-year follow-up. MIND encompasses well-being (World Health Organization Five Well-Being Index [WHO-5]), diabetes-related distress (Problem Areas in Diabetes [PAID]), a Life Event Inventory, and the patient’s agenda for their consultation. Medical data and agreed case-management actions were retrieved from the charts. RESULTS Of the total 1,567 patients, 891 patients (57%) were monitored at a 1-year follow-up. Twenty-eight percent of the patients screened positive for depression and/or diabetes distress at baseline and considered cases, 17% of whom were receiving psychological care. Cases were significantly more often female and had type 2 diabetes and worse glycemic control compared with noncases. Clinically relevant improvements in WHO-5 and PAID were observed over time in cases, irrespective of referral (effects sizes 0.59 and 0.48, respectively; P &amp;lt; 0.0001). Glycemic control did not change. Female sex, life events, and concomitant chronic diseases were predictors of poor psychological outcomes. MIND was well received by patients and staff. CONCLUSIONS MIND appears suitable for screening and discussion of emotional distress as part of the annual review. Broader dissemination in diabetes care is recommendable, but sustainability will depend on reimbursement and availability of support services.
653. Sialyl Glycolipid Stage-Specific Embryonic Antigen 4 (SSEA4) - A Novel Target for CAR T Cell Therapy of Solid Cancers
Authors: Rita Pfeifer, Dominik Lock, Andrea Aloia, Andreas Bosio, Andrew Kaiser, Olaf Hardt, Ian C.D. Johnston
Journal: Molecular Therapy (2016)

Owing to their capacity to eradicate tumors, T cells represent an attractive means for immunomodulation in cancer immunotherapy. In this context, chimeric antigen receptor (CAR) - based therapies are receiving increasing attention. The combination of antibody-derived specificity with T cell effector function renders the immune cells MHC-independent and even enables targeting of antigens for which there is immunological tolerance. T cells, genetically modified with CAR, have shown impressive success in the treatment of leukemia. However, the application of CAR T cells to the treatment of solid tumors remains challenging due to the lack of truly cancer-specific targets and an immunosuppressive tumor microenvironment hostile to T cells. We have identified the sialyl glycolipid stage-specific embryonic antigen 4 (SSEA4) as an epitope whose expression strongly correlates with metastasis and chemoresistence in triple negative breast cancer cells (TNBC). Single chain antibody fragments (scFv) were derived from an antibody that specifically recognizes this sialyl-glycolipid and were cloned into a lentiviral expression vector encoding a CAR containing an IgG1 spacer domain with CD137 and CD3z signaling domains. Healthy donor T cells were enriched by magnetic cell sorting and activated with TransActTM Reagent, a colloidal nanomatrix-based activation reagent, before lentiviral transduction of the anti-SSEA4 CAR expression construct. Engagement of SSEA4 by CAR expressing T cells induced T cell degranulation, secretion of inflammatory cytokines and resulted in an effective killing of SSEA4 expressing target cells. As TNBC patients are exposed to multiple rounds of chemotherapy and SSEA4 expression is found enriched in residual tumor cells surviving chemotherapy, a combinatorial approach using chemotherapy followed with CAR T cell therapy holds great promise to improve treatment outcome and overall survival of TNBC patients. Having assessed the performance of different anti-SSEA4 CAR constructs in vitro, current studies are focusing on in vivo functionality using mouse models.
Combined immunodeficiency and Epstein-Barr virus–induced B cell malignancy in humans with inherited CD70 deficiency
Authors: Hassan Abolhassani, Emily S.J. Edwards, Aydan Ikinciogullari, Huie Jing, Stephan Borte, Marcus Buggert, Likun Du, Mami Matsuda-Lennikov, Rosa Romano, Rozina Caridha, Sangeeta Bade, Yu Zhang, Juliet Frederiksen, Mingyan Fang, Sevgi Kostel Bal, Sule Haskologlu, Figen Dogu, Nurdan Tacyildiz, Helen F. Matthews, Joshua J. McElwee, Emma Gostick, David A. Price, Umaimainthan Palendira, Asghar Aghamohammadi, Bertrand Boisson, Nima Rezaei, Annika C. Karlsson, Michael J. Lenardo, Jean-Laurent Casanova, Lennart Hammarström, Stuart G. Tangye, Helen C. Su, Qiang Pan-Hammarström
Journal: The Journal of Experimental Medicine (2016)

In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)–related diseases. Three patients presented with EBV-associated Hodgkin’s lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro–generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70–CD27 interactions therefore play a nonredundant role in T and B cell–mediated immunity, especially for protection against EBV and humoral immunity.