tbuckley/cabot-search huggingface dataset:
Abstract 2743: Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five Nordic countries
Authors: Elham Kharazmi, Kari Hemminki, Eero Pukkala, Kristina Sundquist, Laufey Tryggvadottir, Steinar Tretli, Jørgen H. Olsen, Mahdi Fallah
Journal: Cancer Research (2015)

Abstract Background: None of population-based epidemiological studies to date had a large enough sample size to show familial risk of testicular cancer (TC) by patients’ and their relatives’ age at diagnosis and also by rare histological subtypes. Objective: We aimed to estimate absolute and relative risk of TC in relatives of TC patients by age at diagnosis in patients and their relatives and histology subtypes. Design: A joint population-based cohort study. Setting and Participants: A cohort of 97,402 first-degree relatives of 21,254 TC patients who were diagnosed between1955 and 2010 in five European countries was followed for cancer incidence. Outcome Measurements and Statistical Analysis: Standardized incidence ratios (SIRs) were estimated using histology-, age-, period-, and country-specific incidence rates as the reference. The lifetime cumulative risks also were calculated. Results and Limitations: The lifetime cumulative risk of TC in brothers of a patient with TC was 2.3%, which represents 4-fold increased risk (SIR = 4.1, 95%CI = 3.6-4.6) over the general population risk. TC in a father increased the risk up to 2-fold in his son (95%CI = 1.7-2.4; lifetime risk 1.2%) and vice versa. When there were ≥2 TC patients diagnosed in a family, lifetime TC risk for relatives was 10-11%. Depending on age at diagnosis, twins had 9-74% lifetime risk of TC. Family history of most of the histological subtypes of TC increased the risk for concordant and most of the discordant subtypes. There was a tendency toward concordant age at diagnosis of TC among relatives. Conclusions: This study provides clinically relevant age-specific cancer risk estimates for family members of TC patients. Familial TC cases tended to develop TC at an age close to age at diagnosis of TC among their relatives, which is the novel finding of this study. Citation Format: Elham Kharazmi, Kari Hemminki, Eero Pukkala, Kristina Sundquist, Laufey Tryggvadottir, Steinar Tretli, Jørgen H. Olsen, Mahdi Fallah. Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five Nordic countries. [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 2743. doi:10.1158/1538-7445.AM2015-2743
OC-069 Efficacy of 12-week treatment with prucalopride (resolor) in patients with chronic constipation: combined results of three randomised, double-blind, placebo-controlled phase 3 trials
Authors: M Kamm, M Camilleri, R Kerstens, R Specht Gryp, L Vandeplassche
Journal: Gut (2010)

<h3>Introduction</h3> Treatment of severe chronic constipation (CC) is suboptimal. This study evaluates the combined efficacy results of prucalopride (PRU) in three identical pivotal, randomised, placebo (PLA)-controlled trials. The objective of each trial was to compare the efficacy and safety of a 12 week once daily treatment of 2 mg or 4 mg PRU with PLA in CC. <h3>Methods</h3> All three trials were of identical design with three parallel treatment groups: PLA, PRU 2 mg and PRU 4 mg. Treatment phase followed a 2-week run-in. Two trials were executed in the US and one in Europe, Canada, Australia and South Africa. The main inclusion criterion was ≤2 spontaneous complete bowel movements (SCBM) per week in combination with straining, sensation of incomplete evacuation or hard stools, at least 25% of the time. The primary efficacy parameter was the percentage of patients with an average of ≥3 SCBM/week over the 12-week treatment period. The two main secondary endpoints were the percentage of patients with an average increase of ≥1 SCBM/week and the percentage of patients with an improvement ≥1 on the satisfaction subscale of the validated quality of life instrument, PAC-QOL. Other endpoints were based on number of (S) BM, time to first BM, stool consistency, straining and patient-reported global evaluation of severity of constipation. Data analysis followed intent-to-treat (ITT) principles. <h3>Results</h3> Total 1924 ITT patients, 89% female, average age 47 years, average duration of constipation ∼20 years, prior treatments rated inadequate for 83%. Main Complaints: Infrequent defecation (30%), abdominal bloating (24%), abdominal pain (14%), during 2-week run-in ∼57% of the patients had no SCBM, and average weekly number of SCBM was 0.47. In each individual trial the results for the primary endpoint and secondary endpoints were significantly better for both PRU groups compared to PLA. For the three trials combined, the percentage of patients with an average of ≥3 SCBM per week over the 12 week treatment period (primary endpoint) were 11.3%, 23.6% end 24.7% for PLA, PRU 2 mg and PRU 4 mg, respectively (both p&lt;0.001 PRU vs PLA); similar for subjects who rated their previous therapy as inadequate. Response was highest in week 1 of treatment and stable over the remaining 11 weeks. PRU 2 mg and 4 mg consistently showed significant differences with PLA on all other secondary endpoints. Except for higher incidences of diarrhoea, nausea and headache on first day of treatment, PRU was well tolerated. <h3>Conclusion</h3> Both 2 and 4 mg PRU significantly improve bowel function and associated symptoms in CC compared to PLA. Results are reflected consistently in all observed efficacy parameters, including QOL.
Abstract 251: Combining Ibrutinib with immune checkpoint blockade to induce therapeutic antitumor immune response in solid tumors
Authors: Idit Sagiv-Barfi, Holbrook Kohrt, Debra Czerwinski, Patrick Ng, Betty Chang, Ronald Levy
Journal: Cancer Research (2015)

Abstract The ability of T-cell responses to effectively attack tumors is restricted by multiple negative checkpoint regulators. Monoclonal antibodies blocking negative regulators of T -cells, such as CTLA-4 and PD-L1 can amplify pre-existing immune responses and evoke new therapeutic responses. Ibrutinib (Imbruvica®), a covalent inhibitor of BTK has shown therapeutic efficacy in several blood cancers, by a mechanism thought to be a direct effect on a critical signaling pathway intrinsic to the malignant B cell. Since BTK is predominantly expressed in hematopoietic cells, solid tumors have not been an obvious target of this drug. An additional target of ibrutinib is the inhibition of ITK, a key enzyme in the survival of Th2 T cells. It has been reported that ibrutinib can alter the balance of Th1 and Th2 T cells leading to enhanced immune responses. Here we report that the combination of ibrutinib and a-PD-L1 antibody suppresses tumor growth, reduces lung metastasis and improves survival of mice bearing solid tumors such as 4T1-triple negative breast cancer and CT26-colon cancer. Moreover, the combination of ibrutinib and a-PD-L1 was able to overcome ibrutinib resistance in mouse models of lymphoma and myeloma. We present evidence that the synergistic therapeutic activity of Ibrutinib with anti PD1 blockade results in enhanced T cell anti-tumor immune responses. In preclinical models, by combining inhibitory checkpoint blockade while shifting the immune response towards CD4 Th1 with ibrutinib, immune tolerance to tumors can be overcome. These results provide rationale for several newly planned clinical trials combining ibrutinib with PD-1 blockade in solid tumor and exploration of such a combination in hematologic malignancies. Citation Format: Idit Sagiv-Barfi, Holbrook Kohrt, Debra Czerwinski, Patrick Ng, Betty Chang, Ronald Levy. Combining Ibrutinib with immune checkpoint blockade to induce therapeutic antitumor immune response in solid tumors. [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 251. doi:10.1158/1538-7445.AM2015-251
Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients
Authors: Neha Korde, Adriana Zingone, Mary Kwok, Elisabet E. Manasanch, Rene Costello, Diamond Zuchlinski, Marcia Mulquin, Irina Maric, Katherine R Calvo, Raul C. Braylan, Constance Yuan, Prashant Ramesh Tembhare, Maryalice Stetler-Stevenson, Diane C Arthur, Mark Raffeld, Liqiang Xi, Peter Choyke, Karen Kurdziel, Liza Lindenberg, Seth M. Steinberg, Mark Roschewski, Ola Landgren
Journal: Blood (2012)
Clinical Significance of Circulating Plasma Cells in Myeloma: Multiparameter Flow Cytometric Analysis
Authors: Manabu Fujisawa, Yasuhito Suehara, Kota Fukumoto, Kentaro Narita, Yoshiaki Usui, Masami Takeuchi, Kosei Matsue, Hiroyuki Takamatsu
Journal: Blood (2015)
Reiterated Therapeutic Drug Monitoring (TDM) Dosing to Significantly Improve the Control of Exposure to IV Busulfan in Infants and Older Children Undergoing Hematopoietic Stem-Cell Transplantation (HSCT)
Authors: Alexandre Amin, Philippe Bourget, Benedicte Neven, Marie-Louise Fremond, Martin Castelle, Elodie Elkaim, Guilhem Cros, Despina Moshous, Fabien Touzot, Alexandre Lalli, Aurélie Petain, Laurent Nguyen, Stephane Blanche
Journal: Blood (2015)
Abstract 2766: Advanced paternal age as a possible risk factor for retinoblastoma
Authors: Vanniarajan Ayyasamy, Namrata Gaikwad, Thirumalairaj Kannan, Aloysius A. Abraham, Veerappan Muthukkaruppan, Usha Kim
Journal: Cancer Research (2015)

Abstract Retinoblastoma is a pediatric tumor arising in the retina with an incidence of 1 in 15000 to 18000 live births. Retinoblastoma is initiated by the inactivation of both the alleles of RB1 and it may be inherited or sporadic. There are several possible risk factors suggested for sporadic retinoblastoma including advanced paternal age.We evaluated the father's age in 42 children with retinoblastoma attending the Aravind Eye Hospital, Madurai, India from Mar 2013 to Feb 2014 retrospectively. Fathers with age 40 and above at the time of conception were included in the analysis. Patients with a positive family history were excluded from the analysis. Genetic analysis of RB1 was carried out in the tumor and blood samples of these patients of older father and their family.There were 5 patients (3 unilateral and 2 bilateral) having fathers with age 40 years and above. Genetic analysis identified RB1 mutations in the tumor samples of 4 patients and these mutations were not present in the blood samples of patient and family members. Since all these patients had somatic mutations, the involvement of paternal age impact was ruled out. In blood sample of one bilateral patient, we found de novo germline RB1 mutation possibly suggesting a role of advanced paternal age.In conclusion, the advanced paternal age seems to be a minor risk factor for retinoblastoma. Further study of large number of patients may provide a better understanding of the impact of advanced paternal age in retinoblastoma. Citation Format: Vanniarajan Ayyasamy, Namrata Gaikwad, Thirumalairaj Kannan, Aloysius A. Abraham, Veerappan Muthukkaruppan, Usha Kim. Advanced paternal age as a possible risk factor for retinoblastoma. [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 2766. doi:10.1158/1538-7445.AM2015-2766
Consolidation of Chemotherapy Response in Mantle Cell Lymphoma (MCL) Patients with 90Y-Ibritumomab Tiuxetan (90Y-Zevalin) Radioimmunotherapy (RIT).
Authors: W. Jurczak, A. Giza, D. Krochmalczyk, J. Wegrzyn, A. Hubalewska-Dydejczyk, A. Sowa-Staszczak, W. Knopinska-Posluszny, B. Zdziarska, S. Krycz-Krzemien, P. Boguradzki, L. Poplawska, A. Skotnicki
Journal: Blood (2005)
Abstract 271: Targeting PD-1, TIM-3 and LAG-3 in combination for improved immunotherapy combinations
Authors: Marilyn Kehry, Robert Horlick, Peter Bowers, Toni Jun, Jean da Silva Correia, Jonathan Graves, Yan Wang, Haley Laken, David J. King
Journal: Cancer Research (2015)

Abstract Antibodies that inhibit the CTLA-4 and PD-1 checkpoint pathways have shown significant activity as either single agents or in combination in both mouse models and clinical studies. TIM-3 and LAG-3 have been reported to function as additional immune checkpoints which limit anti-tumor T cell responses and represent an opportunity for additional combination approaches to improve patient response to immunotherapy. To explore the potential for targeting other immune checkpoints in combination with anti-PD-1, studies were conducted in syngeneic mouse models and in human in vitro assays. A series of surrogate mouse specific reagents targeting TIM-3, LAG-3 and PD-1 have been generated to improve understanding of combination checkpoint therapy in several syngeneic models. Mouse tumor models were characterized by IHC and FACS for relevant markers including PD-L1, Foxp3, TIM3and LAG3, to identify those most likely to be subject to immunosuppressive mechanisms contributing to tumor growth and immune evasion. Initial syngeneic studies in MC38 and Colon 26 demonstrated that combinations of antibodies to murine PD-1, TIM-3 and LAG-3 improved efficacy over single agent therapy, suggesting that combinations of these checkpoint inhibitors might have therapeutic potential in the clinic. The results of ongoing studies to evaluate the dose response of the combinations as well as the contribution of the antibody isotype will be reported. Potent anti-human PD-1, -TIM-3 and LAG-3 clinical candidates have been identified using SHM-XEL™, which combines mammalian cell display of human IgG with somatic hypermutation in vitro to select and mature antibodies with desired biological activities. In a DC/T cell MLR assay, combination of the anti-LAG-3 antibody with a novel anti-PD-1 antibody could further increase T cell secretion of IL-2 up to 30-fold compared to anti-LAG-3 alone. Anti-TIM-3 in combination with anti-PD-1 also improved the EC50 up to 6-fold. Staining of activated purified CD4+ or CD8+ T-cells demonstrate that co-expression of PD-1 and LAG-3 increases upon activation compared to naïve T-cells, suggesting combination therapy may be particularly effective against activated or exhausted T-cells. These in vitro data and in vivo pre-clinical model results support evaluating combination immunotherapy with anti-LAG-3, anti-TIM-3, and anti-PD-1 in cancer patients. Citation Format: Marilyn Kehry, Robert Horlick, Peter Bowers, Toni Jun, Jean da Silva Correia, Jonathan Graves, Yan Wang, Haley Laken, David J. King. Targeting PD-1, TIM-3 and LAG-3 in combination for improved immunotherapy combinations. [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 271. doi:10.1158/1538-7445.AM2015-271
Targeted Repair of CYBB in X-CGD iPSCs Requires Retention of Intronic Sequences for Expression and Functional Correction
Authors: Colin L. Sweeney, Jizhong Zou, Uimook Choi, Randall K. Merling, Alexander Liu, Aaron Bodansky, Sandra Burkett, Jung-Woong Kim, Suk See De Ravin, Harry L. Malech
Journal: Molecular Therapy (2017)

X-linked chronic granulomatous disease (X-CGD) is an immune deficiency resulting from defective production of microbicidal reactive oxygen species (ROS) by phagocytes. Causative mutations occur throughout the CYBB gene, resulting in absent or defective gp91phox protein expression. To correct CYBB exon 5 mutations while retaining normal gene regulation, we utilized TALEN or Cas9 for exon 5 replacement in induced pluripotent stem cells (iPSCs) from patients, which restored gp91phox expression and ROS production in iPSC-derived granulocytes. Alternate approaches for correcting the majority of X-CGD mutations were assessed, involving TALEN- or Cas9-mediated insertion of CYBB minigenes at exon 1 or 2 of the CYBB locus. Targeted insertion of an exon 1–13 minigene into CYBB exon 1 resulted in no detectable gp91phox expression or ROS activity in iPSC-derived granulocytes. In contrast, targeted insertion of an exon 2–13 minigene into exon 2 restored both gp91phox and ROS activity. This demonstrates the efficacy of two correction strategies: seamless repair of specific CYBB mutations by exon replacement or targeted insertion of an exon 2–13 minigene to CYBB exon 2 while retaining exon/intron 1. Furthermore, it highlights a key issue for targeted insertion strategies for expression from an endogenous promoter: retention of intronic elements can be necessary for expression. X-linked chronic granulomatous disease (X-CGD) is an immune deficiency resulting from defective production of microbicidal reactive oxygen species (ROS) by phagocytes. Causative mutations occur throughout the CYBB gene, resulting in absent or defective gp91phox protein expression. To correct CYBB exon 5 mutations while retaining normal gene regulation, we utilized TALEN or Cas9 for exon 5 replacement in induced pluripotent stem cells (iPSCs) from patients, which restored gp91phox expression and ROS production in iPSC-derived granulocytes. Alternate approaches for correcting the majority of X-CGD mutations were assessed, involving TALEN- or Cas9-mediated insertion of CYBB minigenes at exon 1 or 2 of the CYBB locus. Targeted insertion of an exon 1–13 minigene into CYBB exon 1 resulted in no detectable gp91phox expression or ROS activity in iPSC-derived granulocytes. In contrast, targeted insertion of an exon 2–13 minigene into exon 2 restored both gp91phox and ROS activity. This demonstrates the efficacy of two correction strategies: seamless repair of specific CYBB mutations by exon replacement or targeted insertion of an exon 2–13 minigene to CYBB exon 2 while retaining exon/intron 1. Furthermore, it highlights a key issue for targeted insertion strategies for expression from an endogenous promoter: retention of intronic elements can be necessary for expression.
S59 Utility of an auto-titrating protocol for the setup of nocturnal non-invasive ventilation
Authors: C Carlin, G McDowell, C Williams, A Brown, C Canavan, R Tourish
Journal: Thorax (2016)

<h3>Background</h3> The prevalence of conditions requiring nocturnal breathing support is increasing. Evidence is accumulating that early delivery of optimised nocturnal non-invasive ventilation (nNIV) improves acceptability and longer term NIV usage. The AVAPS-AE (adaptive volume assured pressure support with auto-EPAP) mode of the Respironics A40 ventilator offers prospects of fully auto-titrated NIV. After obtaining initial experience, we adopted use of this ventilator mode for initial nNIV titration in patients with nocturnal hypoventilation (excluding those with neuromuscular disorders), with aim of improving service efficiency and patient outcomes. <h3>Methods</h3> Patients with nocturnal hypoventilation disorders (majority obesity-related) attend our tertiary inpatient breathing support service. In early 2014 we established a protocol for auto-NIV setup which consists of first night sleep study with morning capillary blood gases (+ancillary cardiorespiratory investigations if indicated), second night on AVAPS-AE mode NIV and then transition on third night to fixed ST mode bilevel NIV based on the A40 ventilator report, supported by appropriate improvement and then stability in sleep quality, daytime symptoms, ventilator integration, overnight transcutaneous and morning blood gas measurements. <h3>Results</h3> Between March 2014 and June 2016 103 patients received AVAPS-AE mode ventilation for initial setup or re-titration of nNIV. The majority of patients tolerated auto-NIV setup protocol well, and were discharged on ‘fixed’ NIV using a less expensive generator with the A40 derived settings, and did not subsequently require ventilator adjustments. Auto-NIV derived settings typically indicated higher backup rates and unpredictable IPAP/EPAP requirements compared with previous experience. 21 patients continue on AVAPS-AE mode NIV long term based on high pressure support or labile ventilation requirements with suboptimal clinical parameters on fixed NIV. Mean length of stay for breathing support assessment has been reduced by &gt;1 day since the adoption of auto-NIV setup protocol, and clinic follow up has also been rationalised. <h3>Conclusions</h3> Auto-NIV setup protocol achieves significant service efficiencies. This patient cohort will continue to be studied to judge other clinical benefits, but prospective clinical trials with AVAPS-AE or similar ventilator modes for acute NIV and elective outpatient nNIV are justified.
Increased peripheral CD4 + regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C
Authors: Bettina Langhans, Hans Dieter Nischalke, Benjamin Krämer, Annekristin Hausen, Leona Dold, Peer van Heteren, Robert Hüneburg, Jacob Nattermann, Christian P. Strassburg, Ulrich Spengler
Journal: Journal of Hepatology (2016)
Abstract LB-151: Methylation-mediated silencing of TIMP-3 facilitates oral cancer metastasis by modulating binding of SP1 transcription factor
Authors: Shun-Fa Yang, Chun-Wen Su, Chiao-Wen Lin
Journal: Cancer Research (2015)

Abstract Tissue inhibitor of metalloproteinase (TIMP)-3, a member of the TIMP family, is the only substance that can bind with the ECM and its main role is regulating the cell cycle and cancer cell progression. However, little is known about whether abnormal expression and promoter methylation of TIMP-3 facilitates oral cancer metastasis. In this study, DNA methylation levels of the TIMP-3 CpG islands were assessed using bisulfite DNA sequencing and methylation-specific PCR. The results shown that expression of TIMP-3 is decreased in most oral cancer tissues compared with adjacent normal tissues (p&amp;lt;0.001). DNA methylation analysis showed a hypermethylation of TIMP-3 gene in oral cancer cell lines and in oral cancer tumors. Furthermore, suppression of TIMP-3 transcription by DNA methylation involves inhibition of transcription factor SP1 binding to the TIMP-3 promoter. Functional analyses revealed that the stable overexpression of TIMP-3 reduced the migration ability in oral cancer cells (p&amp;lt;0.001). Moreover, the expression levels of the epithelial markers E-cadherin were increased, while the expression levels of the mesenchymal markers vimentin and fibronectin were decreased in cells overexpressing TIMP-3. In conclusion, these results suggest that suppression of TIMP-3 by DNA methylation contributes to oral cancer metastasis. Citation Format: Shun-Fa Yang, Chun-Wen Su, Chiao-Wen Lin. Methylation-mediated silencing of TIMP-3 facilitates oral cancer metastasis by modulating binding of SP1 transcription factor. [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-151. doi:10.1158/1538-7445.AM2015-LB-151