tbuckley/cabot-search huggingface dataset:
Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials
Authors: Qian Shi, Christopher R. Flowers, Wolfgang Hiddemann, Robert Marcus, Michael Herold, Anton Hagenbeek, Eva Kimby, Howard Hochster, Umberto Vitolo, Bruce A. Peterson, Emmanuel Gyan, Michele Ghielmini, Tina Nielsen, Sabine De Bedout, Tommy Fu, Nancy Valente, Nathan H. Fowler, Eva Hoster, Marco Ladetto, Franck Morschhauser, Emanuele Zucca, Gilles Salles, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2017)

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, &gt; 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R 2 WLS ) and bivariate copula (R 2 Copula ) models. Prespecified criteria for surrogacy required either R 2 WLS or R 2 Copula ≥ 0.80, with a lower-bound 95% CI &gt; 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R 2 WLS of 0.88 (95% CI, 0.77 to 0.96) and an R 2 Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.
High Throughput Genetic Profiling Using a Robust All-Molecular Diagnostic Approach Is Feasible to Specifically Identify a High Risk Group of Myeloma Patients
Authors: Martin F Kaiser, Eileen M Boyle, Brian A Walker, Charlotte Pawlyn, Dil Begum, Paula Proszek, Nasrin Dahir, David C Johnson, Suvi Savola, David A Cairns, Walter Gregory, Graham Jackson, Roger G Owen, Gordon Cook, Mark T Drayson, Faith E Davies, Gareth J. Morgan
Journal: Blood (2014)
PTH-066 Specialist nurse-led percutaneous endoscopic gastrostomy insertion and patient assessment in modern-day practice
Authors: M Aljabiri, D Ramdass, N Joshi, H Defoe, A Ramdass, N van Someren, K Besherdas
Journal: Gut (2010)

<h3>Introduction</h3> PEG feeding improves prognosis and general state of health when patients cannot maintain adequate nutrition. Some hospitals now have nutrition teams who review percutaneous endoscopic gastrostomy (PEG) requests. The PEG Clinical Nurse Specialist (CNS) can provide information/advice/counselling for patients and relatives on PEG feeding, aftercare and follow-up as well as being an integral part of the Upper GI multidisciplinary team. <h3>Methods</h3> Aims: To assess the role of the Specialist nurse lead PEG service in an associate teaching district general hospital (DGH). We retrospectively assessed 178 PEG referrals to the service over the period 2006–2008 in our DGH. All PEG referrals are assessed by a CNS who recommends appropriateness of PEG insertion or deflects inappropriate referrals. Data were obtained from the CNS records along with endoscopy software and from patient9s clinical data. <h3>Results</h3> 178 PEGs inserted in the period 2006–2008. Of these referrals, 44 (25%) were declined due to ill health and deemed as inappropriate (eg, advanced severe dementia). Of these 44 patients following assessment, 6 (13%) started eating and drinking within 48 h, 3 (6.8%) died within 24 h, 4 (9%) died within 72 h. 144 PEGs were inserted one failed due to difficulty in positioning. 38 (26.5%) were inserted by the CNS, and 105 (73.5%) were performed by 11 doctors in the same period. 11 (7.6%) of these were performed as day-case procedures. The nurse specialist requested a second opinion and consultant review for only six patients (3.3%). The CNS assessed and followed up all the 144 patients prior to PEG insertion and provided aftercare. PEG referrals required 60 min on average per patient assessment by the CNS, furthermore the actual PEG insertion average time was 30 min/patient. There were 2 (1%) complications due to minor bleeding from the skin incision. There were 14.6% (21 patients) deaths recorded at 30 days post insertion. <h3>Conclusion</h3> In our experience, specialist nurse led PEG service prevented inappropriate PEG insertion in 25% of all referrals and reduced significant clinical commitment for doctors with only requiring advice from consultant in 3%, saving 250 h of clinical assessment and review time. This service also helped reduce waiting times for patient assessment and improved the quality of the service offered by increasing continuity of care and closer liaison with dietician, ward nurses along with patients and their relatives. Our complication/mortality rates compared favourably at 1% and 15%, respectively, to the BSG announcement in 2006 suggesting that minor complications are around 15% and mortality up to 28%. For a modern day PEG service from our data, we recommend a Nurse Lead PEG assessment/insertion and follow-up service in all hospitals not offering this.
661. Synergistic Anti-Tumor Efficacy of Immunogenic Adenovirus ONCOS-102 and Standard of Care Chemotherapy in Preclinical Mesothelioma Model
Authors: Lukasz Kuryk, Elina Haavisto, Mariangela Garofalo, Cristian Capasso, Mari Hirvinen, Sari Pesonen, Tuuli Ranki, Lotta Vassilev, Vincenzo Cerullo
Journal: Molecular Therapy (2016)

Malignant mesothelioma is a rare cancer type with no effective treatment therapies so far. Most of the mesothelioma cases are caused due to asbestos exposure. The median survival time of mesothelioma cancer patient is short, around one year from diagnosis and conventional treatments such as surgery, chemotherapy and radiotherapy can help only to improve mesothelioma prognosis and finally increase patient's life expectancy. Unfortunately, currently there is no cure for mesothelioma, and new treatment strategies against mesothelioma are in high demand. ONCOS-102 is a double targeted, chimeric oncolytic adenovirus, coding for human GM-CSF. Its potency as an antitumor agent has been reported in pre-clinical and clinical studies. In this study we evaluated the anticancer activity of combined therapy: first-line chemotherapy (Pemetrexed, Cisplatin, Carboplatin) with ONCOS-102 in a human malignant mesothelioma xenograft model in BALB/c mice. ONCOS-102 was able to kill all human mesothelioma cell lines in vitro and exhibited anti-tumor activity in treatment refractory H226 mesothelioma xenograft model. Current standard of care chemotherapy regimens for malignant mesothelioma presented no anti-tumor efficacy in tested mesothelioma model. Importantly, a synergistic anti-tumor effect was shown when ONCOS-102 was combined with chemotherapy regimens. Our findings support the clinical use of ONCOS-102 with first-line chemotherapy against malignant mesothelioma.
Abstract 2613: STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia via the MEK/ERK and PKC pathway
Authors: Ushma Atul Doshi, Thomas P. Loughran, Mark Kester
Journal: Cancer Research (2015)

Abstract Chronic lymphocytic leukemia (CLL) constitutes 70% of adult leukemic cases in the Western world. Despite high incidence, its pathogenesis is still poorly understood and it remains incurable with current therapies. We have previously shown that nanoliposomal C6-ceramide, a liposomal formulation of a ‘tumor suppressor’ lipid, is an effective therapy in several solid and non-solid tumor models. Specifically in CLL, nanoliposomal C6-ceramide selectively induces cell death in leukemic cells by targeting the Warburg effect with no detrimental effects on normal peripheral blood mononuclear cells. Additionally, treatment with nanoliposomal C6-ceramide results in tumor regression in an in vivo murine model of CLL. However, the mechanism and key molecular players mediating C6-ceramide-induced cell death in CLL remains unknown. We hypothesize that STAT3 is a target of C6-ceramide in CLL cells. After validating STAT3 as a as a therapeutic target in CLL, we show that C6-ceramide treatment suppresses the levels of p-STAT3-Y705 and p-STAT3-S727 in both cell lines and patient cells, while having no effect on total STAT3 levels. C6-ceramide treatment also reduces STAT3-dependent expression of survival factors like Mcl-1, XIAP and survivin. Our results suggest that suppression in STAT3 phosphorylation might be critical for cell death induction since it precedes induction of C6-ceramide-mediated cell death in CLL cells. Analysis of the upstream kinases revealed that C6-ceramide-induced suppression of p-STAT3 might be, in part, a consequence of suppression of MEK1/2 kinase and protein kinase C (PKC). Preliminary results also demonstrate that C6-ceramide treatment reduces p-STAT3-S727 in the mitochondrial fraction, which might be critical to the cell death induction since overactivation of mitochondrial p-STAT3-S727 confers viability and stress protection to CLL cells. Ongoing studies will focus on identifying the specific phosphorylation site(s) that mediates cell death in an effort to delineate the molecular mechanism of C6-ceramide-induced cell death in CLL. We would also like to define the molecular link between CNL-induced dephosphorylation of mitochondrial STAT3 and suppression of the Warburg effect in CLL. In conclusion, our data suggests that targeting STAT3 with nanoliposomal C6-ceramide is a potential therapy for CLL. This work is the first body of evidence demonstrating an effect of C6-ceramide on STAT3 phosphorylation. Citation Format: Ushma Atul Doshi, Thomas P. Loughran, Mark Kester. STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia via the MEK/ERK and PKC pathway. [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 2613. doi:10.1158/1538-7445.AM2015-2613
271. Improved Gene Transfer with a New Class of PEG-Peptide Scavenger Receptor Inhibitors
Authors: Rondine Allen, Nicholas Baumhover, Jason Duskey, Kevin Rice
Journal: Molecular Therapy (2015)

Scavenger receptors (SR) found on Kupffer and fenestrated endothelial cells of the recticuloendothelial system (RES) in liver are responsible for the capture and degradation of both viral1 and non viral gene delivery systems 2. SR inhibition using polyinosinic acid (Poly-I) has been shown to improve the gene transfer efficiency of AdV, AAV, and measles virus by blocking rapid metabolism in the liver. While Poly-I is reportedly not toxic to mice, co-administration of Poly-I with AdV decreases the lethal threshold for AdV in mice by an unknown mechanism1, making Poly-I inhibition of SR a clinically unacceptable approach to inhibit viral uptake by the RES in the liver. In the present study, we report the discovery of a new class of PEGylated polylysine peptides that are potent and safe SR inhibitors. PEGylated(30kDa)-Cys-Trp-Lys(N) (where N = 10, 15, 20, 25, and 30) were prepared by solid phase peptide synthesis and administered to mice i.v. with 125I-pGL3. Administration of 1 nmol of PEG-peptide with 1 mg of 125I-pGL3 resulted in capture of 60% of the polyplex dose by the liver. However, dose-escalation of the PEG-peptide revealed a dose-dependent decrease in 125I-pGL3 PEG-peptide polyplex capture by the liver, resulting from SR inhibition. A maximum dose of 80 nmols of PEG(30kDa)-Cys-Trp-Lys25 inhibited SR mediated uptake of 125I-pGL3 by the liver to 10%. The potency of PEG-peptide inhibition of SR was also dependent on the length of the Lys repeat, with Lys30kDa=Lys25Lys20Lys15 Lys10. Application of delayed hydrodynamic (HD)-stimulation at 1 hour post-pGL3 polyplex delivery resulted in potent gene expression only when administering a SR inhibitory dose (80 nmol) of PEG-peptide. The reported PEG-peptides are proposed to function by in situ formation of 30 nm albumin nanoparticles in the blood that bind to SRs. This new class of safe and potent SR inhibitors may have broad applications by improving both viral and non-viral delivery systems by blocking SR-mediated uptake in the liver.
Abstract 5027: Interleukin-17B promotes chemoresistance of breast tumors through ERK1/2 anti-apoptotic pathway
Authors: Emilie Laprevotte, Jeremy Bastid, Stéphanie Cochaud, Jerôme Giustiniani, Marion Philippe, Kathryn A. Frewer, Andrew J. Sanders, Wen G. Jiang, Armand Bensussan, Gilles Alberici, Jean-François Eliaou, Nathalie Bonnefoy
Journal: Cancer Research (2015)

Abstract Interleukin-17B (IL-17B) is a pro-inflammatory cytokine that belongs to a family encompassing 6 interleukins (IL-17A to F) and binds to the IL-17 receptor B (IL-17RB). Little is known about the potential role of IL-17B/IL-17RB signaling pathway in cancer. Both IL-17B and IL-17RB are up-regulated in breast tumors and are associated with a poor prognosis in patients. We thus focused on their implication in breast cancer. We demonstrated that recombinant IL-17B induces resistance to conventional chemotherapeutic agents such as taxol, an effect that is totally abrogated by disrupting IL-17RB signaling. To further understand the molecular events involved in IL-17B-induced chemoresistance, we focused on signaling pathways activated under stimulation of human breast cancer cell lines by recombinant IL-17B. We observed that IL-17B induces the activation of both ERK1/2 and NFkB pathways, leading to an up-regulation of anti-apoptotic proteins of the Bcl-2 family. Interestingly we showed that the inhibition of ERK1/2 pathway totally prevents IL-17B-induced chemoresistance of breast cancer cell lines. Relevance of these data is currently under investigation in tumor mouse models. Altogether our results demonstrate the implication of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as potential therapeutic targets for cancer. Citation Format: Emilie Laprevotte, Jeremy Bastid, Stéphanie Cochaud, Jerôme Giustiniani, Marion Philippe, Kathryn A. Frewer, Andrew J. Sanders, Wen G. Jiang, Armand Bensussan, Gilles Alberici, Jean-François Eliaou, Nathalie Bonnefoy. Interleukin-17B promotes chemoresistance of breast tumors through ERK1/2 anti-apoptotic pathway. [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 5027. doi:10.1158/1538-7445.AM2015-5027
In type 1 diabetes, adding liraglutide to insulin increased hypoglycemia and hyperglycemia with ketosis
Authors: Michael Tanner
Journal: Annals of Internal Medicine (2016)

Source Citation Mathieu C, Zinman B, Hemmingsson JU, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: The ADJUNCT ONE treat-to-target randomized trial. Diabetes Care. 2016;39:1702-10. 27506222
Phase I/II, Randomized, MultiCenter, Dose-Ascension Study of the p38MAPK Inhibitor Scio-469 in Patients with Myelodysplastic Syndrome (MDS).
Authors: Lubomir Sokol, Larry Cripe, Hagop Kantarjian, Mikkael A. Sekeres, Simrit Parmar, Peter Greenberg, Stuart Goldberg, Vikas Bhushan, Jamile Shammo, Raymond Hohl, Yu-Ping Li, Ann Lowe, Joy Zhu, Alan List
Journal: Blood (2006)
Abstract 2028: RUNX3 knockdown inhibited oral cancer-induced bone destruction via reducing TGF-β-dependent responses
Authors: Junhee Park, Won-Yoon Chung, Kwang-Kyun Park
Journal: Cancer Research (2015)

Abstract Oral cancer ranks among the top 10 commonly diagnosed cancers. It easily invades underlying jaw bones and causes severe psychological and physical problems. When oral cancer cells infiltrate into jaw bones, survival rate of the patient is significantly decreased. Therefore, attention has been focused on molecular diagnostics and targeted therapy for oral cancer-induced bone destruction. However, there remains a lack of reliable biomarkers that can distinguish between bone-invasive and non-invasive oral cancers despite the recent advances in the field. The Runt domain transcription factor, RUNX3, has been found to be a tumor suppressor in many cancers through promoting transforming growth factor-β (TGF-β)-induced growth inhibition. However, the role of RUNX3 in oral cancer remains controversial. Here, we investigated whether RUNX3 has a critical role in oral cancer-induced bone destruction. In mice inoculated with RUNX3 knockdown oral cancer cells, tumor growth and bone destruction were significantly reduced. In oral cancer cells, RUNX3 knockdown significantly reduced cell viability in TGF-β-stimulated cells compared to unstimulated cells. Cell cycle analysis revealed that RUNX3 knockdown induced G1-specific cell-cycle arrest in the cancer cells without TGF-β treatment but G2-specific cell-cycle arrest in response to TGF-β treatment. RUNX3 knockdown inhibited cell migration and invasion in the absence or presence of TGF-β by changing both basal and TGF-β-induced level of epithelial-to-mesenchymal transition-related proteins. Furthermore, RUNX3 knockdown reduced parathyroid hormone-like protein expression, a major osteolytic factor, in oral cancer cells with or without TGF-β. We confirmed that RUNX3 knockdown in cancer cells decreased receptor activator of nuclear factor-kappaB ligand/osteoprotegerin ratio in osteoblastic hFOB1.19 cells treated with cancer cell-derived conditioned media. In summary, RUNX3 promotes oral cancer-induced bone destruction by enhancing interactions between cancer cells and bone cells as well as promoting malignant behavior of cancer cells. Therefore, RUNX3 may be a useful biomarker and potential therapeutic target for bone invasion of oral cancer. Citation Format: Junhee Park, Won-Yoon Chung, Kwang-Kyun Park. RUNX3 knockdown inhibited oral cancer-induced bone destruction via reducing TGF-β-dependent responses. [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 2028. doi:10.1158/1538-7445.AM2015-2028
PWE-007 When to use hemospray? a single centre experience: Abstract PWE-007 Table 1
Authors: I Nasr, S De Martino, D-M Borrow, JM Dunn
Journal: Gut (2015)

<h3>Introduction</h3> Hemospray is an inorganic nanopowder produced by Cook Medical and is licensed in Europe and Canada for the management of nonvariceal upper gastrointestinal bleed (NVUGIB). The powder adheres to liquid and forms a coagulum which concentrates clotting factors and stimulates the internal clotting cascade. There are numerous reports of successful haemostasis with hemospray, some reporting success rates of 85%.<sup>1</sup>However, the knowledge of which lesion is most suitable for hemospray use remains unclear. We report our experience at Guys and St Thomas’ NHS trust to establish the lesions most likely to benefit from hemospray either as a primary intervention or an add-on strategy. <h3>Method</h3> A retrospective review of endoscopic procedures that required hemospray was performed and the data was extracted from our endoscopy reporting system between December 2013 and February 2015 (14 months). We identified 32 patients who received hemospray, and excluded 2 where hemospray was applied blindly and the bleeding lesion was missed. The primary outcome was achieving primary haemostasis. Cases where primary haemostasis was not achieved or bleeding recurred requiring further endoscopic or radiological intervention were considered unsuccessful. <h3>Results</h3> The 30 procedures were divided according to the procedure performed. Procedure induced bleeding: 9/30 (7 post Barrett’s endoscopic mucosal resection (EMR), 1 post gastric polypectomy and 1 iatrogenic bleed post nasojejunal tube insertion). NVUGIB: 17/30. Enteroscopy small bowel bleed: 2/30. Colonoscopy: 2/30. Primary haemostasis was achieved in 80%, of which 10% required further endoscopic procedure or interventional radiological intervention (Table 1). The coagulum was not seen on second endoscopy. <h3>Conclusion</h3> Hemospray provides good hemostasis for post procedure, in particular post EMR bleed, as a single agent or where coagulation alone failed. Bleeding from Forrest 1b, 2a and 2b responded well to hemospray as a second modality, or single modality when the lesion was inaccessible. Forrest 1a had a poor response to hemospray and all cases required further endotherapy or interventional radiology. Further evidence is required to establish the value of hemospray in colonic and variceal bleed. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Smith <i>et al</i>. Hemospray application in nonvariceal upper gastrointestinal bleeding: results of the survey to Evaluate the application of hemospray in the luminal tract. J Clin Gastroenterol. 2014 Nov-Dec;48(10):e89-92
Epigenomic Profiling of Myeloproliferative Diseases Reveal Idiopathic Myelofibrosis as An Epigenetically Distinct Subgroup and Highlights the Epigenetic Effects of Jak2V617F Mutation
Authors: Sangeeta Nischal, Li Zhou, Yiting Yu, Tushar Bhagat, Yongkai Mo, Christoph Heuck, Masako Suzuki, Shahina Maqbool, Animesh Pardanani, John Greally, Alison Moliterno, Amit Verma
Journal: Blood (2010)
Abstract 738: Combined inhibition of non-canonical HER2 signaling as a strategy to overcome resistance to HER2-targeted therapies
Authors: Ronald J. Bernardi, Rocio Dominguez-Vidana, Christopher S. Bland, Kathleen A. Scorsone, Siddhartha Tyagi, Earlene M. Schmitt, Martin J. Shea, Tamika Mitchell, Mitchell Rao, Sarmistha Nanda, Susan G. Hilsenbeck, Chad Shaw, C. Kent Osborne, Rachel Schiff, Thomas F. Westbrook
Journal: Cancer Research (2015)

Abstract Despite the availability of drugs directly targeting HER2, resistance to therapy remains a major clinical problem in HER2-positive breast cancer. Leveraging a series of RNAi genetic screens, we identify a novel signaling network governing response to HER2 inhibition in vitro and in vivo. We define WEE1 as a core component of this network. Genetic or pharmacologic inhibition of WEE1 or its upstream regulators kills HER2-positive breast cancer cells in combination with HER-family inhibitors. Mechanistically, we demonstrate a non-canonical role of HER2 in governing mitotic progression. Combined inhibition of WEE1 and HER2 abolishes this critical regulation, leading to mitotic catastrophe and apoptosis. Thus, we demonstrate an unexpected convergence of non-canonical HER2 signaling and WEE1 that can be exploited to overcome drug resistance. Our findings provide a strong mechanistic and pre-clinical rationale for combined HER2 and WEE1 inhibition as a treatment strategy for HER2-positive breast cancer. Citation Format: Ronald J. Bernardi, Rocio Dominguez-Vidana, Christopher S. Bland, Kathleen A. Scorsone, Siddhartha Tyagi, Earlene M. Schmitt, Martin J. Shea, Tamika Mitchell, Mitchell Rao, Sarmistha Nanda, Susan G. Hilsenbeck, Chad Shaw, C. Kent Osborne, Rachel Schiff, Thomas F. Westbrook. Combined inhibition of non-canonical HER2 signaling as a strategy to overcome resistance to HER2-targeted therapies. [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 738. doi:10.1158/1538-7445.AM2015-738