tbuckley/cabot-search huggingface dataset:
Abstract CT016: Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies
Authors: Rahul Aggarwal, Scott Thomas, Jennifer Grabowsky, Armand Harb, Jim Leng, Anne Reinert, Ilaria Mastroserio, Thach-Giao Truong, Pamela N. Munster
Journal: Cancer Research (2016)

Abstract Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and c-KIT approved for use in renal cell carcinoma (RCC). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models suggest that HDACi-mediated epigenetic modulation of VEGF expression prevents PAZ resistance and potentiates efficacy. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors with an expansion cohort in RCC. Methods: The primary endpoint was the maximal tolerated dose (MTD) of PAZ plus ABX. Secondary endpoints included pharmacokinetics (PK) and efficacy. PAZ was dosed days 1-28 and ABX days 1-5, 8-12, and 15-19 of 28-day cycle (schedule A) with at a starting dose of 400 mg/day and 45 mg/m2 orally twice daily respectively. An alternate ABX dosing schedule days 1-4, 8-11, and 15-18 was investigated (schedule B) due to toxicity of Schedule A. Results: 52 patients (pts) (RCC; N = 23) with advanced solid tumors were enrolled (N = 22 schedule A; N = 30 schedule B). There were six dose-limiting toxicities including fatigue (N = 2), thrombocytopenia (N = 2), and elevated AST/ALT (N = 2). The most common grade ? 3 related adverse events observed were fatigue (13%), thrombocytopenia (12%), and diarrhea (10%). The MTD was PAZ 800 mg/day + ABX 45 mg/m2 BID on schedule B. 8 evaluable pts (19%) (N = 6 RCC; 2 thyroid; median number of prior lines of therapy = 3) achieved partial tumor response (PR), with median duration of response of 9.2 months (1-33.2+). 7/9 (78%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. 15 out of 48 evaluable pts (31%) experienced stable disease or better for ? 6 months, and two previously PAZ-refractory pts with PRs remain on study for &amp;gt; 20 and 37 mos respectively. PK analyses did not reveal drug-drug interaction. Degree of histone acetylation and metabolomic profile are being evaluated. Conclusion: The combination of PAZ + ABX was well tolerated and durable tumor control (&amp;gt; 3 yrs) was observed in RCC and thyroid cancer. Tumor regressions observed in majority of PAZ-refractory tumors preliminarily support the potential of ABX to reverse therapeutic resistance. A randomized phase 2 study with cross-over design is planned to further evaluate the combination of PAZ + HDACi. Citation Format: Rahul Aggarwal, Scott Thomas, Jennifer Grabowsky, Armand Harb, Jim Leng, Anne Reinert, Ilaria Mastroserio, Thach-Giao Truong, Pamela N. Munster. Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies. [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 CT016.
Phase II open-label clinical trial of vatalanib (PTK/ZK) in patients with progressive neuroendocrine cancer
Authors: L. Anthony, M. Chester, S. Michael, T. M. O’Dorisio, M. S. O’Dorisio
Journal: Journal of Clinical Oncology (2008)

14624 Background: Vatalanib inhibits vascular endothelial growth factor receptor (VEGFR) by binding to the intracellular kinase domain of all 3 VEGFRs. Neuroendocrine tumors (NETs) express VEGF receptors. Inhibiting VEGF with bevacizumab, sorafenib and sunitinib reduced time to progression or tumor size in some NET patients (pts). To determine vatalanib’s tolerability and efficacy in NET pts, a trial was performed. Methods: Eligibility criteria included pts who had biopsy-proven metastatic NE cancer, such as carcinoid or islet cell, and had rising biochemical markers on somatostatin analog therapy. Eligible pts had measurable lesions other than bone, a KPS > 60% and normal hematologic, renal and hepatic functions. Pts on octreotide therapy were required to be on a stable dose not exceeding 30 mg monthly of the LAR formulation. Initial dosing of vatalanib was 1,250 mg daily. Biochemical responses within a 90 day interval were the primary response criteria. Secondary endpoints included changes in radiographic and scintigraphic scans and safety. Results: Seventeen pts (9 males) were enrolled between 5/20/05 to 12/15/07. Eleven pts are evaluable for efficacy and 16 pts are evaluable for safety. One pt continues on therapy 16 mos and another 7 mos after study entry. One pt withdrew consent; 1 pt died of disease within 5 days of study entry; 1 pt was allergic to vatalanib. Four pts required a 10–28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase and Grade2 proteinuria. Resumption of vatalanib at 1,000 mg daily was well tolerated in 1 pt and 750 mg in another. One pt developed carcinoid crises with fever, flushing, rising 5-HIAA accompanied by Grade 2 proteinuria. Grade 1 nausea occurred in 14 pts with antiemetics required for 2 pts. Divided vatalanib dosing resulted in less nausea in these 2 pts. A partial (>50% decrease in 5-HIAA) biochemical response was observed in 3 pts. The observed radiographic (CT scans) and scintigraphic (OctreoScan) responses in 10 pts have shown progressive disease in 1 pt and stable/minimal response in 9 pts. Accrual to this trial is ongoing. Conclusions: Vatalanib is well tolerated in the majority of pts and results in a 30% biochemical partial response rate in NET pts with rising biochemical markers on somatostatin analog therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis
Case 18-1980
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Sheldon M. Wolff, John T. Fallon
Journal: New England Journal of Medicine (1980)

Presentation of CaseA 35-year-old woman was admitted to the hospital because of chest pain.She was well until 14 years previously, when she began to experience wheezing on exertion. Aminophylline was prescribed, with improvement. Four years before admission the wheezing increased, with weakness, weight loss, nocturnal sweats, and rise of the temperature to 38.1°C. A cough productive of yellow sputum developed, and mild anterior chest pain and dyspnea occurred. She was admitted to this hospital. X-ray films of the chest (Fig. 1) showed patchy infiltrates in both upper lobes; an azygos lobe was present; the heart was not enlarged. . . .
Prostaglandin Suppression of Mitogen-Stimulated Lymphocytes In Vitro
Authors: James S. Goodwin, Ronald P. Messner, Glenn T. Peake
Journal: Journal of Clinical Investigation (1978)

In this study we further characterize the properties of the prostaglandin-producing suppressor cell. Overnight preincubation of peripheral blood mononuclear cells results in an increased response of the cells to phytohemagglutinin or Concanavalin A compared to the response of fresh cells. This increase in mitogen response with preincubation was similar in magnitude to the increase in mitogen response of fresh cells after the addition of indomethacin. The two manipulations were not additive; that is, after preincubation, indomethacin caused much less enhancement of mitogen stimulation of peripheral blood mononuclear cells (100 ± 12% increase before preincubation vs. 12 ± 6% after preincubation; mean±SEM, P < 0.001). Preincubated cells also lose sensitivity to inhibition by exogenous prostaglandin E2. It requires the addition of 100- to > 1,000-fold more exogenous PGE2 to produce comparable inhibition of phytohemagglutinin-stimulated preincubated cells than is required for inhibition of phytohemagglutinin-stimulated fresh cells.
Longitudinal Associations of Exposure to Perfluoroalkylated Substances in Childhood and Adolescence and Indicators of Adiposity and Glucose Metabolism 6 and 12 Years Later: The European Youth Heart Study
Authors: Sidsel L. Domazet, Anders Grøntved, Amalie G. Timmermann, Flemming Nielsen, Tina K. Jensen
Journal: Diabetes Care (2016)

To investigate the long-term association of exposure to perfluoroalkylated substances, including perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), during childhood (9 years) and adolescence (15 years) on indicators of adiposity and glucose metabolism in adolescence (15 years) and young adulthood (21 years). Secondarily, we aim to clarify the degree of tracking of exposure from childhood into young adulthood.Data derived from a large multicenter prospective cohort study, in which the same participants have been observed from childhood (N = 590), during adolescence (N = 444), and into young adulthood (N = 369). Stored plasma samples were analyzed for PFOS and PFOA. Indicators of adiposity comprising body height, body weight, sum of four skinfolds, and waist circumference, as well as indicators of glucose metabolism, comprising fasting blood glucose, triglyceride, and insulin levels, β-cell function, and insulin resistance, have been collected at all study waves. Multiple linear regression was applied in order to model earlier exposure on later outcome while controlling for baseline outcome levels, sex, age, and socioeconomic factors.Childhood exposure to PFOS was associated with indicators of adiposity at 15 years of age that are displayed in elevated BMI, skinfold thickness, and waist circumference, as well as increased skinfold thickness and waist circumference at 21 years of age. PFOA exposure in childhood was associated with decreased β-cell function at 15 years of age. We did not observe associations between exposure during adolescence and indicators of adiposity and glucose metabolism in young adulthood.This study found evidence for childhood exposure to PFOS and PFOA predicting adiposity at 15 and 21 years of age and impaired β-cell function at 15 years of age, respectively.
Development and validation of genomic signature to predict ADT treatment failure.
Authors: Jeffrey Karnes, Hussam Al-Deen Ashab, Bruce J. Trock, Ashley Ross, Harrison Tsai, Jeffrey J. Tosoian, Mohammed Alshalalfa, Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Firas Abdollah, Eric A. Klein, Paul L. Nguyen, Felix Yi-Chung Feng, Adam Dicker, Robert Benjamin Den, Elai Davicioni, Tamara L. Lotan, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2016)

5018 Background: Androgen deprivation therapy (ADT) is one of the main treatment options for locally advanced, recurrent and metastatic prostate cancer. Neuroendocrine prostate cancer (NEPC) is inherently less sensitive to ADT. NEPC can be observed de novo (e.g., small cell prostate cancer) but more commonly arises after exposure to ADT. In some patients, even short exposure to ADT may ‘unmask’ a NEPC phenotype. We hypothesized that a gene expression signature of NEPC when measured in primary tumor specimens (RP) may be useful for predicting patients with innate resistance to ADT. Methods: Expression profiles of 786 PCa patients treated with RP were obtained from the Decipher GRID database. These were split into training (n=360) and validation (n=426) sets and stratified by the receipt of adjuvant ADT (n=222) or no adjuvant ADT (n=564). A literature review of ADT resistance and neuroendocrine genes identified 1,632 genes as candidates. This set was further filtered, using logistic regression and forward feature selection to select a genomic ADT resistance signature (ARS). ARS was trained using a generalized linear model with lasso regularization. Survival c-index, Kaplan Meier and Cox regression analysis was used to compare survival differences between treated and untreated patients with high and low ARS scores (defined by median split). Results: In validation cohorts, the ARS was predictive of metastasis in cohorts receiving adjuvant ADT (10-year metastasis free survival c-index of 0.64 (95% CI 0.55-0.71) as compared to 0.50 (95% CI 0.36-0.63) in patients not treated with ADT). Among ADT treated patients, those with low ARS scores had a 10 year MFS of 86%, versus 68% in those with high ARS scores (p=0.03). In multivariable analysis adjusting for confounding variableswith metastasis as an endpoint, ARS validated with a significant interaction with ADT treatment (p=0.02) which demonstrates ARS’s adjuvant ADT predictive capability. Conclusions: An ADT resistance signature validated as a predictive biomarker with a significant interaction term for predicting metastasis after hormonal treatment. ARS may allow for identification of patients that may be optimal candidates for trials of novel systemic agents
Abstract LB-128: High prevalence of elevated TRPV6 mRNA in pancreatic ductal adenocarcinoma
Authors: Tyler Lutes, Dominique Dugourd, Michelle Davey, Christopher Rice, Stephanie St-Pierre, Jack M. Stewart
Journal: Cancer Research (2016)

Abstract SOR-C13, a 13-mer peptide derived from soricidin, the paralytic protein component of saliva of the Northern Short-tailed shrew, just completed an open-label, all comers phase I clinical trial for the treatment of epithelial-derived cancers. SOR-C13 is a first-in-class drug candidate that specifically targets and inhibits the TRPV6 calcium channel - a recognized oncochannel over-expressed in a number of epithelial cancers (e.g. breast, ovarian, prostate). TRPV6 over-expression is associated with a poor prognosis particularly with breast and prostate cancers. SOR-C13 is the first TRPV6-targeting drug to enter clinical development. Pancreatic patients were enrolled in the phase I clinical trial for SOR-C13 and for this reason the TRPV6 gene expression in pancreatic tumour biopsies was assessed. Association of TRPV6 oncochannel expression with aggressive pancreatic adenocarcinoma compared to neuroendocrine tumours has never been investigated. Pancreatic adenocarcinoma represents 90% of the pancreatic tumours and is associated with a poor prognosis compared to neuroendocrine tumours. TRPV6 gene expression was assessed in 19 pancreatic tumor biopsies including five adenocarcinoma (Grade I to III), one acinar cell (exocrine), and 13 neuroendocrine (Islet cell) tumors by two-step RT-qPCR. TRPV6 and β-actin (reference gene) mRNA expression was evaluated in duplicate in a reproducible TRPV6 plus β-actin duplex two-step RT-qPCR assay. The acinar cell, and 69% (9/13) of the neuroendocrine tumors had no detectable TRPV6 mRNA expression with &amp;gt;90% of neuroendocrine tumors (12/13) having very little TRPV6 mRNA expression (&amp;lt;30 copies/ng RNA). Of the five pancreatic adenocarcinoma biopsies 4/5 (80%) had 67-285 copies of TRPV6 mRNA/ng RNA, indicating a high level of TRPV6 expression in this type of aggressive pancreatic cancer. The β-actin CT was between 24 and 30 for all tumours (mean 28.5 ± 1.2) indicating that the lack TRPV6 amplification in a majority of the neuroendocrine tumors was not due to RT-qPCR failure or a lack of quality of the biopsy cDNA. Results indicate that drugs specifically targeting TRPV6 oncochannel, like SOR-C13, have the potential to be used to treat the high medical need in pancreatic ductal adenocarcinoma. Citation Format: Tyler Lutes, Dominique Dugourd, Michelle Davey, Christopher Rice, Stephanie St-Pierre, Jack M. Stewart. High prevalence of elevated TRPV6 mRNA in pancreatic ductal adenocarcinoma. [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-128.
Abstract 3491: Rational combination of targeted agents and BH3 mimetics to improve cancer treatment
Authors: Joan Montero, Dorota E. Sadowicz, Jeremy Ryan, Charles H. Yoon, Rizwan Haq, Anthony Letai
Journal: Cancer Research (2016)

Abstract Background: In the clinic is often observed that melanoma cancer patients first respond to targeted therapeutic agents like dabrafenib showing tumor burden shrinkage, but subsequently relapse with tumors that are more aggressive, no longer responsive to therapy and showing acquired metastatic capacity. Most chemotherapeutic agents kill via the mitochondrial pathway of apoptosis, but unfortunately tumors frequently are able to survive, often adapting their antiapoptotic strategy. We used a variant of the functional predictive test dynamic BH3 profiling (DBP) to determine the tumor's antiapoptotic defense adaptation over time, and rationally identify combination of therapies to restore programmed cell death. Hypothesis: By using different BH3 peptides in DBP we can determine the adaptive tumor's antiapoptotic defense and adjust therapy to improve cancer cell death. Results: In BRAF mutant melanoma, cKIT mutant GIST and HER2 overexpressing breast cancer cell lines, we performed DBP over time using different BH3 peptides: BIM, BAD, PUMA, MS1 and NOXA. We observed that when they are treated with specific targeted agents against their oncogenic drivers, there is an increase in MCL-1 dependence over time. This observation points to a possible tumor defense mechanism conferring resistance against anticancer drugs. Based on these observations, we exploited these altered dependencies by pretreating the cancer cells with these targeted agents and combining them with novel BH3 mimetics targeting MCL-1 to synergistically enhance cell death. Exploiting DBP's capacity to measure changes in priming without the requirement for prolonged ex vivo culture, we assessed if this antiapoptotic evolution was also present in primary melanoma samples. Using FACS-based DBP to select for specific tumor populations, we tested the possible use of BH3 mimetics in combination with targeted agents to improve cancer treatment in the clinic. Conclusions: Our preliminary results reveal the use of dynamic BH3 profiling to be used not only as a powerful real-time tool to predict chemotherapy response but also to evaluate the rational combination of targeted agents with BH3 mimetics in vitro and in the clinic. [R.H. and A.L. contributed equally to this work.] Citation Format: Joan Montero, Dorota E. Sadowicz, Jeremy Ryan, Charles H. Yoon, Rizwan Haq, Anthony Letai. Rational combination of targeted agents and BH3 mimetics to improve cancer treatment. [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 3491.
Abstract 2426: Detection of somatic mutations associated with pulmonary metastasis of osteosarcoma by whole exome sequencing
Authors: Shintaro Iwata, Yasutoshi Tatsumi, Tsukasa Yonemoto, Hiroto Kamoda, Takeshi Ishii, Hiroki Nagase, Miki Ohira
Journal: Cancer Research (2016)

Abstract Objective: Pulmonary metastasis is a main cause of death for the patients with osteosarcoma (OS), although no specific genetic alteration associated with pulmonary metastasis has been reported. The objective of this study was to identify candidate somatic genetic alteration contributed to pulmonary metastasis in pediatric OS. Methods: Five sample sets including the tissues taken from primary tumor (P), resected pulmonary metastatic tumor (M), and normal tissue (N) of the same pediatric OS patients were analyzed by whole exome sequencing with Ion Torrent Proton sequencer. 40ng of genomic DNAs extracted from each tissue were used for multiplex PCR amplification with Ion Ampliseq Exome Kit. Data analysis including alignment to the hg19 human reference genome and variant calling was done using the Torrent Suite Software. Obtained genomic data was validated by visualizing in Integrative Genomics Viewer or capillary sequencing. Candidate somatic genetic alterations were annotated by wANNOVAR database. Pathway analysis was performed using GeneMANIA. Results: Mean read depths on the P, M, and N were 219, 212, and 109, respectively. We identified 1364 and 1311 candidate non-synonymous somatic single nucleotide variants (SNVs) among the P and M, respectively. After the validation and filtering, we detected 135 non-synonymous SNVs within the exon region in M. Among these, 32 SNVs were overlapped with those in P. Only 2 recurrent SNVs were identified within the whole SNVs. C:G&amp;gt;T:A transition mutations were frequently observed in both P and M, and the frequency were higher in M comparing to P. Pathway analysis showed a significant enrichment of the candidate SNVs in genes involved in extracellular matrix regulation (FDR;2.37E-03). Conclusion: We have identified 137 SNVs associated with pulmonary metastasis from pediatric OS. Extracellular matrix-relating signature might contribute to the genesis of pulmonary metastasis. Citation Format: Shintaro Iwata, Yasutoshi Tatsumi, Tsukasa Yonemoto, Hiroto Kamoda, Takeshi Ishii, Hiroki Nagase, Miki Ohira. Detection of somatic mutations associated with pulmonary metastasis of osteosarcoma by whole exome sequencing. [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 2426.
Association Between Rosacea and Parkinson Disease—Reply
Authors: Alexander Egeberg, Jacob P. Thyssen
Journal: JAMA Neurology (2016)

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