tbuckley/cabot-search huggingface dataset:
Abstract 1097: The miR-17-92 microRNA cluster plays a crucial role in osteosarcoma progression
Authors: Jyotika Varshney, Nicholas J. Slipek, John Osborne, Adrian Chang, Anne E. Sarver, Ingrid Cornax, Gerry M. O’Sullivan, Subbaya Subramanian, David A. Largaespada
Journal: Cancer Research (2016)

Abstract Osteosarcoma is the most common primary bone malignancy that affects adolescents. Around 30% of patients with localized osteosarcoma and 70% of patients with metastasis will experience treatment failure within 5 years of diagnosis. The complex biology of osteosarcoma and astounding genetic heterogeneity has made it challenging to identify effective new gene targets and therapeutic agents. Our studies found an overall overexpression of a microRNA cluster, miR-17-92 microRNAs in human primary osteosarcoma compared to normal bone. We learned that upregulation of this miR-17-92 cluster simultaneously silences a suite of key tumor suppressors. Using data from a novel spontaneous osteosarcoma mouse model and genetic screen, we discovered miR-17-92 targets, such as PTEN, PTRPD and SRGAP2, which are potential tumor suppressor genes. Specifically blocking miR-17-92 function in osteosarcoma cells reduced their migration and ability to grow larger tumors in immunodeficient mice compared to the controls. Also, knockdown of miR-17-92 cluster microRNAs led to increase in the levels of PTPRD and SRGAP2 in cells as well as tumors; further suggesting that miR-17-92 is targeting these genes. We also performed gain-of-function of miR-17-92 studies in a poorly aggressive osteosarcoma cell line and found that overexpression of miR-17-92 leads to ability to grow in an anchorage independent manner and form tumors in immunodeficient mice, both features that are lacking in the parental line. Ongoing RNA sequencing studies on miR-17-92 target transcripts in osteosarcoma cells, and functional analyses of miR-17-92 deletion mutants, will be presented. In an attempt to target miR-17-92 miRNA expression, we have tested small molecules. Our data suggests that triptolide, a diterpenoid epoxide, inhibits MYC expression and downregulates miR-17-92 miRNAs resulting in upregulation of several tumor suppressor driver proteins including PTEN, PTPRD, and SRGAP2. Together, our data suggests that upregulation of miR-17-92 miRNAs contributes to osteosarcoma progression and triptolide inhibits miR-17-92 expression. These data have implications for how sarcomas develop in general and suggest a new way to treat cancer by targeting microRNAs using small molecules. Citation Format: Jyotika Varshney, Nicholas J. Slipek, John Osborne, Adrian Chang, Anne E. Sarver, Ingrid Cornax, Gerry M. O’ Sullivan, Subbaya Subramanian, David A. Largaespada. The miR-17-92 microRNA cluster plays a crucial role in osteosarcoma progression. [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 1097.
Abstract 2592: The role of surgery in the treatment of epithelioid trophoblastic tumor: A single institution case series
Authors: Abigail Winder, Janelle Sobecki-Rausch, Kruti Maniar, Karen Novak, Julie Kim, John Lurain
Journal: Cancer Research (2016)

Abstract Objective: Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia (GTN) that develops from chorionic-type intermediate trophoblasts, simulates carcinoma, often presents many years following a pregnancy event, is associated with low or normal human chorionic gonadotropin (hCG) levels, and is relatively resistant to chemotherapy. Our aim was to identify the role of surgery in the management of both localized and metastatic ETT. Methods: A retrospective review of women with ETT treated at a gestational trophoblastic disease center from 2010-2015 identified five women. Medical records were abstracted for demographic data, clinical presentation, hCG levels, prior pregnancy information, disease sites, and treatment with chemotherapy and surgery. Results: The five women with ETT ranged in age from 28 to 48 years. Clinical presentation was abnormal uterine bleeding prompting dilation and curettage, which established the diagnosis of ETT in three women. One woman presented with repeated spontaneous pneumothorax requiring thoracoscopic resection, which identified a 6 cm ETT in the lung. Another woman was initially treated with methotrexate for a presumed ectopic pregnancy without a response. Two women had no identifiable antecedent pregnancy, two women had spontaneous abortions 19 and 72 months prior to the diagnosis of ETT, and one woman had a normal term delivery 48 months earlier. Four of five women had metastatic disease to the lungs. Three of these women underwent pulmonary wedge resection as well as hysterectomy followed by paclitaxel-cisplatin/paclitaxel-etoposide (TP/TE) chemotherapy, while the other woman was treated with etoposide, methotrexate, actinomycin D/etoposide, cisplatin (EMA/EP) chemotherapy and hysterectomy. The one woman with nonmetastatic disease was treated with hysterectomy only. All five women are currently without evidence of disease. Conclusions: Surgery, including hysterectomy and resection of metastatic disease, is an important component in the treatment of women with ETT. Adjuvant chemotherapy with a platinum-containing regimen, such as TP/TE or EMA/EP, should be used in women with metastatic disease. All five women with ETT in this series were cured using this approach, including the four with metastatic disease. Citation Format: Abigail Winder, Janelle Sobecki-Rausch, Kruti Maniar, Karen Novak, Julie Kim, John Lurain. The role of surgery in the treatment of epithelioid trophoblastic tumor: A single institution case series. [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 2592.
Identifying patients with nonalcoholic steatohepatitis that are nonresponders to therapy
Authors: Matthew J. Armstrong, Piers Gaunt, Philip N. Newsome
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Armstrong received grants from Novo Nordisk. Dr. Newsome consults for, is on the speakers' bureau of, and received grants from Novo Nordisk. TO THE EDITOR: We read with interest the article by Vilar‐Gomez et al.,1 in which the investigators attempted to develop a simple, noninvasive scoring system to identify patients with resolution of nonalcoholic steatohepatitis (NASH) after lifestyle intervention. At present, liver histology is required for both the clinical diagnosis of NASH and assessment of the resolution of NASH with new therapies.2 Liver biopsies are invasive, painful, subject to sampling error, and can be associated with serious complications, necessitating the development of inexpensive noninvasive biomarkers that predict response, or lack of, to treatment. Our recent data from the LEAN trial indicated that 48 weeks of treatment with the once‐daily glucagon‐like peptide‐1 analogue, liraglutide, resulted in NASH resolution (with no worsening of fibrosis) in 39% (9 of 23) of patients with NASH compared to 9% (2 of 22) who received placebo control.3 We applied the Vilar‐Gomez et al. NASH resolution score1 to our LEAN trial cohort, which included patients with advanced fibrosis and morbid obesity, to assess its accuracy in identifying the absence or presence of NASH resolution after pharmacological intervention. Using the lower threshold of <46.15, the score had a specificity of 94% (95% confidence interval [CI], 81‐98), because it correctly identified 32 of 34 patients without NASH resolution. However, the high threshold of >69.72 only correctly identified 4 of 11 patients with NASH resolution in our cohort (sensitivity, 36%; 95% CI, 15‐65). Using the low (<46.15) and high (>69.72) cutoffs, the negative predictive value was 84% (32 of 38; 95% CI, 70‐93) and the positive predictive value for NASH resolution was 67% (4 of 6; 95% CI, 30‐90), respectively. Application of this score in the setting of a pharmacological study indicates that it may have a role in identifying patients that are not responding to treatment and who can therefore discontinue treatment. Analysis in other cohorts is needed to better understand its performance characteristics.
400P A clinical survey on satisfaction of pain management in hospitalized patients with cancer in Taiwan
Authors: J. Lin, C.-S. Chang, M.-Y. Lee, Y.-M. Liao, M.-F. Wu, Y.-C. Sung, K.-M. Rau, M.-S. Yu, P.-Y. Lai, T.-J. Chiou, J.-S. Chen, K.-D. Lee, W.-L. Hwang, T.-C. Liu, C.-J. Yen, Y.-Y. Shao, R.-K. Hsieh
Journal: Annals of Oncology (2015)
“Early-FDG-PET” but Not Macrophage Infiltration In Diagnostic Specimen Seems to Predict Clinical Course of Hodgkin Lymphoma
Authors: Alberto Fabbri, Stefano Lazzi, Ida Chitarrelli, Vania Rossi, Alessandro Gozzetti, Francesco Forconi, Mazzei Maria Antonietta, Bruno Jim Rocca, Alice Pietrini, Giulia Montelatici, Enrico Pesciullesi, Lorenzo Leoncini, Francesco Lauria
Journal: Blood (2010)
Phase 1-2 study of progesterone receptor (PR) inhibition with extended-release (ER) onapristone (ONA) in patients (pts) with castration-resistant prostate cancer (CRPC): PK, safety and PR testing results from the dose escalation cohort.
Authors: Anuradha Jayaram, Karolina Nowakowska, Joaquin Mateo, Daniel Nava Rodrigues, Ruth Riisnaes, Alexander Zukiwski, Stefan Proniuk, Alice Susannah Bexon, Joseph Bisaha, Diletta Bianchini, Zafeiris Zafeiriou, Raquel Perez Lopez, Nina Tunariu, Johann Sebastian De Bono, Gerhardt Attard
Journal: Journal of Clinical Oncology (2015)

5051 Background: An urgent need exists for new therapies after progression (PD) onabiraterone (AA) and enzalutamide (ENZ). PR expression increases with castration resistance [Bonkhoff 2001]. ONA, a type-I PR antagonist, has clinical activity in other PRpos cancers. An ER ONA tablet was developed to achieve continuous exposure, and an IHC companion diagnostic to detect activated PR. Methods: This open-label, phase 1-2 study with dose selection/expansion includes pts with: advanced CRPC, prior PD on AA or ENZ and ≤ 2 chemotherapies. Tumors are biopsied at baseline and on treatment to determine PR status. 1° endpoint for dose escalation is to define recommended phase 2 dose (RP2D). 2° endpoints include safety and PK. In stage 1a pts were randomized to 10/20 mg ONA BID. Stage 1b is currently open to enrollment (30/40/50 mg BID cohorts; 6 pts/cohort, 8 recruited to date). At the RP2D, 36 pts will be treated to confirm safety and activity. We present results of stage 1a (n = 10) and a separate biomarker validation cohort (n = 45). Results: Stage 1a is complete. There were no DLTs or significant LFT abnormalities at 10/20 mg BID. One pt had related G3/4 AEs: G3 nausea/anorexia. Most common related AEs were fatigue (n = 4) and anorexia (n = 3). 4 SAEs were reported, none considered related to ONA. There were no treatment discontinuations for AEs. Mean Cmax/AUC/t1/2 at 10 and 20 mg were 253 ng/mL, 5311 ng*h /mL, 5.98 hours and 384 ng/mL, 10240 ng*h /mL, 4.92 hours, respectively. 3 pts had paired biopsies: 1/3 pts had strong PR expression ( > 50%) pre-treatment and no PR expression after 19 days of ONA. In the biomarker cohort, we tested pt-matched therapy-naïve (TN) and CRPC specimens and identified PR ( > 1% cells) in 15 pts (33%: 5 CRPC and 10 TN). No TN but 4/45 CRPC (9%) biopsies had strong PR expression ( > 50% cells). Conclusions: CRPC expresses PR. The IHC diagnostic method will be used for selective enrichment. The 1st stage of the study concluded with no DLTs, permitting escalation. Randomization now includes the 3 higher doses. PK appears dose proportional. Clinical trial information: NCT02049190.
Increase in higher risk prostate cancer cases following new screening recommendation by the US Preventive Services Task Force (USPSTF).
Authors: Matthew David Hall, Timothy E. Schultheiss, Ginamarie Farino, Jeffrey Y.C. Wong
Journal: Journal of Clinical Oncology (2015)

143 Background: In 2011, the USPSTF issued a draft recommendation that PSA not be used for prostate cancer screening in men irrespective of age. Here we present early measures of the potential consequences of this recommendation. Methods: Data on men diagnosed with prostate cancer from January, 2005 through June, 2013 were extracted from the National Oncology Data Alliance (Elekta/IMPAC Medical Systems, Inc., Sunnyvale, CA). This proprietary database of merged tumor registries captures newly diagnosed cancer cases at more than 150 hospitals in the United States. Data were available through 2013 compared to 2011 in Surveillance, Epidemiology, and End Results (SEER). The data in the NODA are identical to the data sent to state tumor registries and SEER in regions that participate in SEER. Date of diagnosis, age, race, T stage, Gleason score, and PSA were collected. Patients were classified into their respective National Comprehensive Cancer Network (NCCN) risk group. Data were available and analyzed for 87,562 men. Frequencies were examined by date of diagnosis, grouped in six-month intervals. Trends were assessed using linear regression. Results: From 2005 to 2011, the percentage of men with PSA&gt;10 decreased gradually. From 2011 to 2013, the percentage increased by 3.0% per year (p&lt;0.0004). The fraction of men with age ≥75 years to present with PSA&gt;10 increased by nearly double the rate for men of all ages from 2011 to 2013. No significant trends in Gleason score were observed; the frequency of men with higher T stages generally decreased over the entire period without a notable change after 2011. The percentage of men with intermediate or higher risk cancer was stable at 70-73% prior to 2011, but rose by 2.9 % per year after 2011 (p&lt;0.003) without evidence of a plateau. Conclusions: The proportion of men diagnosed with intermediate or higher risk cancer increased by nearly 6% from 2011 to 2013. Given an estimated 233,000 new prostate cancers in 2014, approximately 14,000 men per year will shift from low risk into a higher risk disease group. Our findings suggest an increase in the fraction of men diagnosed with higher risk prostate cancer after 2011.
Early Antibiotic Treatment for Pediatric Febrile Urinary Tract Infection and Renal Scarring
Authors: Nader Shaikh, Tej K. Mattoo, Ron Keren, Anastasia Ivanova, Gang Cui, Marva Moxey-Mims, Massoud Majd, Harvey A. Ziessman, Alejandro Hoberman
Journal: JAMA Pediatrics (2016)

Existing data regarding the association between delayed initiation of antimicrobial therapy and the development of renal scarring are inconsistent.To determine whether delay in the initiation of antimicrobial therapy for febrile urinary tract infections (UTIs) is associated with the occurrence and severity of renal scarring.Retrospective cohort study that combined data from 2 previously conducted longitudinal studies (the Randomized Intervention for Children With Vesicoureteral Reflux trial and the Careful Urinary Tract Infection Evaluation Study). Children younger than 6 years with a first or second UTI were followed up for 2 years.Duration of the child's fever prior to initiation of antimicrobial therapy for the index UTI.New renal scarring defined as the presence of photopenia plus contour change on a late dimercaptosuccinic acid renal scan (obtained at study exit) that was not present on the baseline scan.Of the 482 children included in the analysis, 434 were female (90%), 375 were white (78%), and 375 had vesicoureteral reflux (78%). The median age was 11 months. A total of 35 children (7.2%) developed new renal scarring. Delay in the initiation of antimicrobial therapy was associated with renal scarring; the median (25th, 75th percentiles) duration of fever prior to initiation of antibiotic therapy in those with and without renal scarring was 72 (30, 120) and 48 (24, 72) hours, respectively (P = .003). Older age (OR, 1.03; 95% CI, 1.01-1.05), Hispanic ethnicity (OR, 5.24; 95% CI, 2.15-12.77), recurrent urinary tract infections (OR, 0.97; 95% CI, 0.27-3.45), and bladder and bowel dysfunction (OR, 6.44; 95% CI, 2.89-14.38) were also associated with new renal scarring. Delay in the initiation of antimicrobial therapy remained significantly associated with renal scarring even after adjusting for these variables.Delay in treatment of febrile UTIs and permanent renal scarring are associated. In febrile children, clinicians should not delay testing for UTI.
Abstract 1060: Targeting serine hydroxymethyltransferase 2 (SHMT2) suppresses hepatocarcinoma
Authors: Chern Chiuh Woo, Way Cherng Chen, Teck Hock Philip Lee.
Journal: Cancer Research (2016)

Abstract Glycolytic intermediate 3-phosphoglycerate branched from glycolysis pathway to fuel serine-glycine biosynthesis pathway. Several studies have shown that glycine consumption is strongly correlated to the proliferation rate of cancer cells. Therefore targeting serine-glycine biosynthesis pathway is a promising strategy due to the fact that many of its genes are up-regulated in cancer cells. These genes include PHGDH, PSAT1 and GLDC. Here, we demonstrate that targeting serine hydroxymethyltransferase 2 (SHMT2), also a member of serine-glycine biosynthesis pathway, is able to suppress hepatocarcinoma both in vitro and in vivo. SHMT2 simultaneously converts serine to glycine and tetrahydrofolate to 5,10-methylenetetrahydrofolate. We found that this gene is up-regulated in Hep3B, HepG2 and Huh-7 liver cancer cells versus THLE2 normal liver cells. Knockdown of SHMT2 effectively suppressed Huh-7 cell growth and tumorigenicity. No tumor was formed after inoculation of SHMT2-knockdown Huh-7 cells in nude mice as compared to 100% tumor formation with control Huh-7 cells. The data from tetracycline-inducible SHMT2-knockdown xenograft mouse model showed that SHMT2 inhibition could reduce tumor growth and tumor incidence as well as delayed tumor onset. We also found that SHMT2-knockdown Huh-7 cells were more vulnerable to the cytotoxicity of doxorubicin, a conventional chemotherapeutic agent, as compared to the control Huh-7 cells. On the other hand, overexpression of SHMT2, however, could not transform THLE2 cells into malignancy suggesting that SHMT2 might not a key driver in liver tumorigenesis. SHMT2 activity is correlated to cancer phenotype as shown by the NMR data via metabolic tracing with 13C-glycine. Supplementation of glycine, rather than 5,10-methylenetetrahydrofolate, could reverse the reduced tumorigenicity caused by SHMT2-knockdown. Taken together, our data support that SHMT2 is a potential target in the treatment of hepatocarcinoma. Citation Format: Chern Chiuh Woo, Way Cherng Chen, Teck Hock Philip Lee. Targeting serine hydroxymethyltransferase 2 (SHMT2) suppresses hepatocarcinoma. [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 1060.
Pluripotent Fibrosis Initiating Mesenchymal Stromal Cell Linked To Cytopenias In LGL Leukemia Through Genetic Reprogramming
Authors: Pearlie K. Epling-Burnette, Adam W. Mailloux, Ling Zhang, Lynn C. Moscinski, Sheng Wei, Sean J Yoder, Lubomir Sokol, Loughran P Thomas
Journal: Blood (2013)
Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy
Authors: J S Khorashad, S K Tantravahi, D Yan, C C Mason, Y Qiao, A M Eiring, K Gligorich, T Hein, A D Pomicter, A G Reid, T W Kelley, G T Marth, T O'Hare, M W Deininger
Journal: Leukemia (2016)
Phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 administered in combination with FOLFIRI with and without bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC).
Authors: Joleen Marie Hubbard, Bert H. O'Neil, Derek J. Jonker, Thorvardur Ragnar Halfdanarson, Alexander Starodub, Axel Grothey, Laura Borodyansky, Chiang Li
Journal: Journal of Clinical Oncology (2016)

569 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo,in mono and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was undertaken to confirm the RP2D of BBI-608 in combination with FOLFIRI with or without BEV. BBI-608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m 2 bolus with 2400 mg/m 2 , irinotecan 180 mg/m 2 , and leucovorin 400 mg/m 2 infusion) with or without BEV 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 18 heavily pretreated pts with an average of &gt; 3 prior lines of therapy of which 10 pts (56%) previously progressed on FOLFIRI were enrolled. Of the 17 pts evaluable for response, 8 pts received FOLFIRI and 9 pts received FOLFIRI with BEV in combination with BBI-608. Most common adverse events included grade 1 and 2 diarrhea, abdominal pain, nausea, vomiting and anorexia. No dose limiting toxicity or new adverse events were seen, and the safety profile was similar to that of each regimen as monotherapy. Grade 3 events related to protocol therapy included diarrhea occurring in 3 pts, fatigue in 2 pts and dehydration in 1 pt. All events resolved after dose reduction and/or start of anti-diarrheal medications. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 16 of 17 evaluable pts (94%) with 2 PR (per RECIST 1.1 criteria: 44% and 33% regression) and 14 SD (of which 13 (93%) had tumor regression &lt; 25%). In the evaluable pts, median progression free survival was 5.54 months. Of 17 pts, 7 (41%) had prolonged SD of &gt; 6 months. Conclusions: This phase Ib study confirmed that BBI-608 at 240 mg bid can be safely combined with FOLFIRI with and without BEV, and shows encouraging anti-tumor activity in heavily pretreated CRC pts, even in pts with prior progression on FOLFIRI-based therapy. Clinical trial information: NCT02024607.