tbuckley/cabot-search huggingface dataset:
A phase I study of 2-hydroxyoleic acid (2-OHOA), a novel sphingomyelin synthase activator in patients (pt) with advanced solid tumors (AST) including refractory high grade gliomas/glioblastomas (GBM): Updated results of the expansion.
Authors: Mariane Sousa Fontes, Nikolaos Diamantis, Niamh Coleman, Nina Tunariu, L Rhoda Molife, Manolo D'Arcangelo, Analia Azaro, Gareth J Veal, Elisabet Sicart, Ander Urruticoechea, Pablo V. Escriba, Xavier Busquets, Antoine Perier, Vicente Tur, Juanita Lopez, Jordi Rodon Ahnert, Elizabeth R. Plummer
Journal: Journal of Clinical Oncology (2016)

e14086 Background: 2-OHOA, is a first-in-class, synthetic hydroxylated lipid that activates SGSM1 and modulates the lipid content of cancer cell membranes. 2-OHOA reduces tumor growth in numerous xenograft mice models including GBM by promoting the translocation of key signaling proteins, including Ras and PKC to the cytoplasm. This results in the inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. 2-OHOA crosses the blood brain barrier and is expected to have efficacy in GBM. The dose-escalation phase of the study was previously reported. The MTD was 12g/day with 3/12 responses (25%) in GBM pts (1PR and 2SD by RANO criteria). We now present updated results from the expansion cohorts (EC) of this study, which aims to further assess safety, tolerability and preliminary activity in pts with AST and GBM. Methods: 2 EC at the MTD (10 biopsiable AST pts and 10 GBM pts) commenced recruitment in November/2015 to collect further safety, tolerability and efficacy information, alongside refining the pharmacokinetic (PK) and pharmacodynamic (PD) profile of 2-OHOA. Eligible pts received 2-OHOA as a PO suspension in 21-day cycles. Adverse events (AE) were assessed by CTCAEv4; tumor response was assessed every 2 cycles using RECIST 1.1/RANO criteria. Tumor PD is assessed in pre- and post- treatment tumor biopsies in all patients with ASTs. Results: 14 pts (including 8 refractory GBMs) have been recruited to the ECs to date and commenced treatment with 2-OHOA. Toxicities are manageable, with no safety concerns thus far in any patients. In the GBM cohort, 3 patients had early progressive disease in C1 and 1 pt withdrew consent due to poor compliance and tolerability. The remaining pts are ongoing pending tumor assessment. Conclusions: 2-OHOA is well tolerated at 12g/day with documented responses in GBM. If no safety and tolerability issues are observed on the ongoing ECs, 12g/day will become the RP2D. Updated safety and efficacy data from the ECs will be presented. Clinical trial information: NCT01792310.
Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study
Authors: Brigitta G Baumert, Monika E Hegi, Martin J van den Bent, Andreas von Deimling, Thierry Gorlia, Khê Hoang-Xuan, Alba A Brandes, Guy Kantor, Martin J B Taphoorn, Mohamed Ben Hassel, Christian Hartmann, Gail Ryan, David Capper, Johan M Kros, Sebastian Kurscheid, Wolfgang Wick, Roelien Enting, Michele Reni, Brian Thiessen, Frederic Dhermain, Jacoline E Bromberg, Loic Feuvret, Jaap C Reijneveld, Olivier Chinot, Johanna M M Gijtenbeek, John P Rossiter, Nicolas Dif, Carmen Balana, Jose Bravo-Marques, Paul M Clement, Christine Marosi, Tzahala Tzuk-Shina, Robert A Nordal, Jeremy Rees, Denis Lacombe, Warren P Mason, Roger Stupp
Journal: The Lancet Oncology (2016)
Antiretroviral Therapy Has Equalized Presentations and Short-Term Outcomes Between HIV+ and HIV- Lymphoma Patients in Lilongwe, Malawi
Authors: Satish Gopal, Yuri D. Fedoriw, Nathan Montgomery, Agnes Moses, Richard Nyasosela, Yohannie Mlombe, Carlos Varela, Suzgo Mzumara, Maria Chikasema, Salama Itimu, Fred Chimzimu, Coxcilly Kampani, Robert Krysiak, Kristy L. Richards, Thomas C. Shea, George Liomba
Journal: Blood (2014)
Abstract LB-215: Combination studies using PI3K isoform-selective inhibitors in PTEN-deficient cancer cells
Authors: Christina Blackwell, M. Phillip De Young.
Journal: Cancer Research (2016)

Abstract A large and growing body of evidence indicates that dysregulation of phosphoinositide 3-kinase (PI3K) pathway signaling activity is necessary for cancer cell survival, most commonly as a result of genetic defects causing a deficiency of the tumor suppressor PTEN or activating mutations or amplification of PIK3CA (PI3Kα). In the context of PTEN-deficient cancer cells, it appears that in most cases PI3Kβ (PIK3CB) and not PI3Kα is required for PI3K survival signaling. GSK2636771 is a potent, orally bioavailable, selective ATP-competitive inhibitor of PI3Kβ with single digit nanomolar potency. It possesses &amp;gt;10-fold selectivity over PI3Kδ and &amp;gt;1000-fold selectivity over other lipid/atypical kinases including PI3Kα and mTOR. In this study, western blot analysis was performed to assess phosphorylation changes to AKT, ERK, and S6 proteins in 21 tumor cell lines of various histologies and genetic backgrounds treated with GSK2636771. PTEN deficiency (lack of PTEN protein expression) was the best marker to predict response to PI3Kβ inhibition based on reduction of phospho-AKT levels. Some of these “responsive” cells also harbored other genetic alterations such as amplified and/or mutated (V600E) BRAF, NF1 mutations, or EGFR amplification. For example, inhibition of PI3Kβ resulted in partial reduction of phospho-AKT and phospho-S6 levels in PTEN-deficient A2058, MDA-MB-468, and LNCAP cells, whereas PI3Kα inhibition by BYL719 treatment had no effect on AKT, ERK, and S6 phosphorylation. In PTEN-deficient, PIK3CA (E542K) mutant CAL-51 cells, the opposite was observed: GSK2636771 had no effect on phospho levels of AKT, ERK, and S6, but BYL719 treatment caused reductions of phospho-AKT and phospho-S6. Interestingly, when both isoforms were inhibited, the effects on phospho-AKT and phospho-S6 levels were more pronounced in all four cell lines, suggesting that these compounds may synergize to inhibit PI3K signaling. Combination treatment of both inhibitors had modest effects on cell growth in LNCAP cells, although it was observed that 6-day GSK2636771 treatment pulsed with BYL719 for 2 days in LNCAP provided similar antiproliferative effects as co-treatment of both molecules for 6 days. This may suggest that pulsing BYL719 with constant GSK2636771 treatment may be effective at inhibiting tumor growth in vivo while minimizing the on target toxicity that has been observed with sustained PI3Kα inhibition. Citation Format: Christina Blackwell, M. Phillip De Young. Combination studies using PI3K isoform-selective inhibitors in PTEN-deficient cancer cells. [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-215.
Abstract 3104: Stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction
Authors: Terry W. Moore, Thomas E. Speltz, Sean W. Fanning, Christopher G. Mayne, Jonna Frasor, Geoffrey L. Greene, Emad Tajkhorshid
Journal: Cancer Research (2016)

Abstract Despite undeniable successes, one of the major unsolved problems in estrogen receptor-positive breast cancer therapy is resistance to endocrine therapy. One-third of breast cancer patients who are given tamoxifen will develop recurrent cancer within 15 years. Importantly, the estrogen receptor is still present and active in 80-85% of these recurrent cases, but it is no longer sensitive to current therapies, so new ways of targeting the estrogen receptor are needed. Because selective estrogen receptor modulators indirectly block estrogen receptor/coactivator interactions, our hypothesis is that directly blocking the estrogen receptor/coactivator interaction will provide a more robust blockade that will antagonize forms of estrogen receptor that are active in both wild-type and some endocrine-resistant breast cancers. As our starting point for inhibiting estrogen receptor/coactivator interactions, we have chosen to use a class of compounds that mimic α-helices: “stapled peptides.” These non-natural, synthetic peptides have a key alkene bond that resembles a staple. Typically, peptides make poor drugs because they are rapidly hydrolyzed by proteases and are poorly cell-permeable. Because of their non-natural linkage, stapled peptides are poor substrates for proteases, so they are metabolically stable. Some stapled peptides are also cell-penetrant. This effect is highly sequence-specific, but it seems to be aided when peptides have a relatively high formal positive charge. Stapled peptides have been used to inhibit a variety of important protein-protein interactions in cell culture and animal models. In this work, we have created a library of stapled peptides that inhibit the interaction of the estrogen receptor with the steroid receptor coactivator in vitro. The best peptides show nanomolar IC50 values in a time-resolved fluorescence resonance energy transfer assay. They show high helical content according to circular dichroism studies. We have solved x-ray crystal structures of these molecules bound to the estrogen receptor mutant Y537S, which demonstrate their binding mode, and these studies are in agreement with molecular dynamics simulations of these molecules bound to the estrogen receptor ligand binding domain. Citation Format: Terry W. Moore, Thomas E. Speltz, Sean W. Fanning, Christopher G. Mayne, Jonna Frasor, Geoffrey L. Greene, Emad Tajkhorshid. Stapled peptide inhibitors of the estrogen receptor/steroid receptor coactivator interaction. [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 3104.
Use of a combination of 5-fluorouracil pathway genes to predict treatment outcome of S-1 monotherapy in advanced gastric cancer.
Authors: G. Kim, H. Jeung, S. Y. Rha, J. K. Roh, S. Noh, H. C. Chung
Journal: Journal of Clinical Oncology (2010)

10554 Background: Growing body of evidence suggests that intratumor expressions of chemotherapy-related genes may have implications for predicting treatment success and thereby the tailoring of patients. Herein we investigated mRNA expressions of 5-FU pathway genes from pre-chemotherapeutic tumor samples to predict treatment outcome in advanced gastric cancer (AGC) patients treated with S-1 monotherapy. Methods: This study was collaterally designed with two open-labeled phase II trials already published. The S-1 dosage assigned to the patients was calculated based on body surface area (planned dose intensity 327 mg/m2/week). 5- FU pathway genes [dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), Thymidylate synthase (TS) and thymidine phosphorylase (TP)] were analyzed using the quantitative real-time PCR assay with RNA extracted from archived paraffin embedded tissues. Results: A total of 75 patients were enrolled. Median values were selected for each gene for cut-off values separating high and low gene expressions. Significant association of OPRT gene expression was observed with tumor response (P = 0.014), while other genes revealed no significant association. In the combined analysis involving OPRT, patients with high OPRT and high TP showed higher overall response rate than remaining patients (40% vs 10%, P = 0.002). For the survival, patients whose tumors had high OPRT expression demonstrated better PFS (P = 0.034) and overall survival (OS) (P < 0.001). When we combined the expression of OPRT and TS, those with high OPRT and low TS level has both prolonged PFS (3.4 vs 2.4 months, P = 0.024) and OS (11.0 vs 8.2 months, P = 0.007). Multivariate analysis revealed that independent variables were combination of OPRT and TP for response, and OPRT and TS for both PFS and OS. Conclusions: We demonstrated that mRNA expression level of molecular markers in paraffin-embedded specimens obtained from primary gastric tumors is useful for decision-making for selection of patients with AGC in whom treatment with S-1 will yield treatment benefit. No significant financial relationships to disclose.
Allogeneic Stem Cell Transplantation for Secondary or Therapy-Related Acute Myeloid Leukemia or Myelodysplastic Syndrome with Poor-Risk Cytogenetics.
Authors: Philipp G. Hemmati, Theis Terwey, Philipp D. le Coutre, Gero Massenkeil, Lam G Vuong, Bernd Dörken, Renate Arnold
Journal: Blood (2010)
Abstract 3391: SCUBE2 is a co-receptor for VEGFR2 in tumor angiogenesis
Authors: Yuh-Charn Lin, Ruey-Bing Yang
Journal: Cancer Research (2016)

Abstract Signal peptide-complement protein C1r/C1s, Uegf, and Bmp1 (CUB)-epidermal growth factor (EGF) domain-containing protein 2 (SCUBE2) is a peripheral membrane protein expressed in normal tissue and tumor vascular endothelial cells (ECs); however, its role in angiogenesis remains poorly understood. In this study, we show that endothelial SCUBE2 is upregulated by hypoxia and acts as a co-receptor for VEGFR2 to facilitate VEGF binding to VEGFR2 and augment its signals including VEGFR2 phosphorylation and p44/42 MAPKs/Akt activation, thus promotes cell proliferation and tubule formation in ECs. While physiological angiogenesis remained normal in the endothelial ablation of Scube2 in mice, pathological angiogenesis in experimental tumors was altered, resulting in smaller tumors and reduced microvascular density. To simulate the angiogenic environment of the tumor, Scube2-deficient ECs were isolated and propagated in vitro with VEGF. Mutant ECs exhibited marked reduction in binding of VEGF, proliferation and sprouting responses to VEGF as well as downstream signal activation. Our results reveal that SCUBE2 might act as a novel co-receptor for VEGFR2, and point that targeting such SCUBE2 function in human ECs may represent a potential anti-tumor strategy by inhibiting tumor angiogenesis. Citation Format: Yuh-Charn Lin, Ruey-Bing Yang. SCUBE2 is a co-receptor for VEGFR2 in tumor angiogenesis. [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 3391.
Long-term results of salvage endoscopic treatment for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.
Authors: Ken Hatogai, Tomonori Yano, Takashi Kojima, Masakatsu Onozawa, Toshihiko Doi, Kazuhiro Kaneko, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2014)

207 Background: Local failure is a major problem after chemoradiotherapy (CRT) in patients with esophageal squamous cell carcinoma (ESCC), and salvage surgery presents high morbidity and mortality rates. We have introduced photodynamic therapy (PDT) and endoscopic resection (ER) for local failures to develop a less invasive salvage treatment.The aim of this retrospective study was to clarify the long-term outcome of salvage endoscopic treatments (SET). Methods: Between 1998 and 2008, 716 patients with ESCC were treated with definitive CRT in our institution. There were 314 patients with incomplete response and 103 with local recurrence after achieving complete response (CR) once. The indication criteria of SET were as follows: 1) absence of lymph node and distant metastasis and 2) local failures limited within T2. ER was performed for local failures limited to T1b (SM1), and PDT was performed for lesions invading T1b (SM2) or T2, in patients who could not tolerate or who refused surgery. We assessed overall survival (OS), relapse-free survival (RFS), and also prognostic factors. This study was approved by an institutional review board. Results: A total of 164 patients with local failure underwent SET (ER: 58, PDT: 106). The characteristics before CRT were as follows: T1/2/3/4, 44/25/75/20; N0/1, 85/79; stage I/II/III/IV, 35/59/57/13; and those of before SET were as follows: T1/2, 126/38; residue/recurrence, 76/88. ER achieved curative resection in 51 (87.9%), and PDT achieved CR in 61 (57.5%) patients. With a median follow up period of 73 months, the OS and RFS rates at 5 years from SET were 38.6% (95% CI 31.0–46.2) and 28.1% (95% CI 21.0–35.2). Multivariate analysis revealed 2 preferable prognostic factors in common for OS and RFS, N0 before CRT (OS HR: 0.47 [95% CI 0.32–0.69], RFS HR: 0.61 [95%CI 0.43–0.87]) and a period from initiation of CRT to SET longer than 6 months (OS HR: 0.57 [95%CI 0.39–0.84], RFS HR: 0.67 [0.47–0.95]). After 5 years of follow up, 58 patients (35.4%) were alive without any metastasis under esophagus preservation. Conclusions: SET demonstrated a favorable outcome in an analysis of a large number of patients with local failure after definitive CRT for ESCC.
Abstract 91: Weekend Admission Following Non-Traumatic Out-of-Hospital Cardiac Arrest is a Prognosticator of Poor Outcome: Results from a Nationwide Database
Authors: Shaker M Eid, Marwan S Abougergi, Aiham Albaeni, Nisha Chandra-Strobos
Journal: Circulation (2013)

Background: In the United States, differences in outcome based on day of admission have been reported for several disease entities including in-hospital cardiac arrest. We investigated whether outcomes are similarly affected in patients with non-traumatic out-of-hospital cardiac arrest (OHCA). Methods: The 2010 Nationwide Inpatient Sample and Nationwide Emergency Department Sample are nationally representative databases containing data on 8 and 21 million discharges, respectively. We included all patients with an ICD-9 CM code for a principle diagnosis of cardiac arrest and excluded those with ICD-9 CM code for any diagnosis of trauma. We defined “weekend” as Saturday 12:01 am to Sunday 11:59 pm. The primary outcome was a composite endpoint of in-hospital death or discharge to hospice. Secondary outcomes are listed in the table. Poor neurologic outcome was a composite endpoint of coma, vegetative state or anoxic brain injury with feeding tube or tracheostomy placement in patients discharged alive. Adjusted odds ratios were calculated using multivariable regression analyses. Results: In 2010, 140,128 OHCA patients were admitted to an ED in the United States; 29.3% occurred on the weekend. Ventricular fibrillation was the presenting rhythm in 3.8% of emergency department OHCA visits. Overall survival to hospital admission and discharge were only 8.2% and 4.8% respectively. When adjusted for variables known to affect outcome (Table), total in-hospital mortality remained higher on weekends compared with weekdays. Other outcomes, including the use of hypothermia were similar between weekends and weekdays. Conclusion: Despite the many advances in resuscitation systems, the national survival to hospital admission and discharge for non-traumatic out-of-hospital cardiac arrest remains very low. Yet again, a weekend admission appears as an independent predictor of higher in-hospital mortality in this patient population.
Comparative Effectiveness of Cognitive Therapy and Dynamic Psychotherapy for Major Depressive Disorder in a Community Mental Health Setting
Authors: Mary Beth Connolly Gibbons, Robert Gallop, Donald Thompson, Debra Luther, Katherine Crits-Christoph, Julie Jacobs, Seohyun Yin, Paul Crits-Christoph
Journal: JAMA Psychiatry (2016)

Dynamic psychotherapy (DT) is widely practiced in the community, but few trials have established its effectiveness for specific mental health disorders relative to control conditions or other evidence-based psychotherapies.To determine whether DT is not inferior to cognitive therapy (CT) in the treatment of major depressive disorder (MDD) in a community mental health setting.From October 28, 2010, to July 2, 2014, outpatients with MDD were randomized to treatment delivered by trained therapists. Twenty therapists employed at a community mental health center in Pennsylvania were trained by experts in CT or DT. A total of 237 adult outpatients with MDD seeking services at this site were randomized to 16 sessions of DT or CT delivered across 5 months. Final assessment was completed on December 9, 2014, and data were analyzed from December 10, 2014, to January 14, 2016.Short-term DT or CT.Expert blind evaluations with the 17-item Hamilton Rating Scale for Depression.Among the 237 patients (59 men [24.9%]; 178 women [75.1%]; mean [SD] age, 36.2 [12.1] years) treated by 20 therapists (19 women and 1 man; mean [SD] age, 40.0 [14.6] years), 118 were randomized to DT and 119 to CT. A mean (SD) difference between treatments was found in the change on the Hamilton Rating Scale for Depression of 0.86 (7.73) scale points (95% CI, -0.70 to 2.42; Cohen d, 0.11), indicating that DT was statistically not inferior to CT. A statistically significant main effect was found for time (F1,198 = 75.92; P = .001). No statistically significant differences were found between treatments on patient ratings of treatment credibility. Dynamic psychotherapy and CT were discriminated from each other on competence in supportive techniques (t120 = 2.48; P = .02), competence in expressive techniques (t120 = 4.78; P = .001), adherence to CT techniques (t115 = -7.07; P = .001), and competence in CT (t115 = -7.07; P = .001).This study suggests that DT is not inferior to CT on change in depression for the treatment of MDD in a community mental health setting. The 95% CI suggests that the effects of DT are equivalent to those of CT.clinicaltrials.gov Identifier: NCT01207271.
Subtype-Dependent Relationship Between Young Age at Diagnosis and Breast Cancer Survival
Authors: Ann H. Partridge, Melissa E. Hughes, Erica T. Warner, Rebecca A. Ottesen, Yu-Ning Wong, Stephen B. Edge, Richard L. Theriault, Douglas W. Blayney, Joyce C. Niland, Eric P. Winer, Jane C. Weeks, Rulla M. Tamimi
Journal: Journal of Clinical Oncology (2016)

Young women are at increased risk for developing more aggressive subtypes of breast cancer. Although previous studies have shown a higher risk of breast cancer recurrence and death among young women with early-stage breast cancer, they have not adequately addressed the role of tumor subtype in outcomes.We examined data from women with newly diagnosed stage I to III breast cancer presenting to one of eight National Comprehensive Cancer Network centers between January 2000 and December 2007. Multivariable Cox proportional hazards models were used to assess the relationship between age and breast cancer-specific survival.A total of 17,575 women with stage I to III breast cancer were eligible for analysis, among whom 1,916 were ≤ 40 years of age at diagnosis. Median follow-up time was 6.4 years. In a multivariable Cox proportional hazards model controlling for sociodemographic, disease, and treatment characteristics, women ≤ 40 years of age at diagnosis had greater breast cancer mortality (hazard ratio [HR], 1.4; 95% CI, 1.2 to 1.7). In stratified analyses, age ≤ 40 years was associated with statistically significant increases in risk of breast cancer death among women with luminal A (HR, 2.1; 95% CI, 1.4 to 3.2) and luminal B (HR 1.4; 95% CI, 1.1 to 1.9) tumors, with borderline significance among women with triple-negative tumors (HR, 1.4; 95% CI, 1.0 to 1.8) but not among those with human epidermal growth factor receptor 2 subtypes (HR, 1.2; 95% CI, 0.8 to 1.9). In an additional model controlling for detection method, young age was associated with significantly increased risk of breast cancer death only among women with luminal A tumors.The effect of age on survival of women with early breast cancer seems to vary by breast cancer subtype. Young age seems to be particularly prognostic in women with luminal breast cancers.
Allogeneic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia After Prior Treatment with Nilotinib or Dasatinib
Authors: Michael Schleuning, Marijke Scholten, Anja van Biezen, Arnon Nagler, Jane F. Apperley, Mauricette Michallet, Andrew Grigg, Richard T. Silver, Armin Leitner, Alois Gratwohl, Marja Ekblom, H. Jean Khoury, Theo de Witte, Eduardo Olavarría
Journal: Blood (2010)