tbuckley/cabot-search huggingface dataset:
An aggressive RhoC phenotype is associated with relapse after external beam radiation therapy of a prostate cancer xenograft model.
Authors: Oskar Vilhelmsson Timmermand, Sven-Erik Strand, Crister Ceberg, Jens Adam Ceder
Journal: Journal of Clinical Oncology (2019)

e14748 Background: Relapsed treatment resistant prostate cancer remains the second most common cause of male mortality in the western world. New therapies for therapy resistant prostate cancer depend on defining tumor cell sub-populations capable of surviving, reinitiating, and sustaining net growth of the cancer. In this study we focused on RhoC expression in a prostate cancer model after external beam radiation therapy (EBRT). RhoC has earlier been implicated in metastatic processes in most solid tumors. Methods: In mice, established s.c. LNCaP xenografts (n = 12) were irradiated, the beam collimated with lead to restrict it to the xenograft, with X-rays (200 kV, 1 Gymin -1 , Gulmay Medical) for an absorbed dose of 15 Gy. Tumor tissue was collected after seven days or after 3-4 weeks when recurrent growth was seen. RhoC, AR, CD166 and Ki67 immunohistochemistry in tumor sections was visualized by using DAB or Peroxidase Green and nuclear red or haematoxylin blue as counter stain. Sections stained for RhoC and Ki67 were quantified with the Halo software (v2.3.2089.34) using the Indica Labs – cytonuclear v1.6 algorithm. The intensity of the RhoC staining was also quantified in a separate set of sections only stained for RhoC. Results: The RhoC staining intensity was significantly higher in relapsed xenografts (P = 0.003). Also, a significant difference in percentage of RhoC expressing cells in the two populations (P = 0.045) with 40.6 ± 5.8% (mean ± SEM) in relapsed tumors as compared to 15.0 ± 8.1% after 7d. The percentage of cells expressing Ki67 was not significantly different (P = 0.477). However, the percentage of double positive cells (Ki67, RhoC) was significantly higher in treated relapsed xenografts (P = 0.042). Further, a subpopulation of RhoC-positive cells were positive for AR and the stem cell marker CD166. Conclusions: Here we show that a subpopulation of proliferating RhoC-positive cells are more prevalent in relapsing PCa xenografts after EBRT, suggesting an aggressive phenotype that is associated with both proliferation and invasiveness. Another subpopulation of RhoC cells was found to express the prostate stem cell marker CD166, suggesting that pathways and properties involved in cellular self-renewal and invasiveness may be responsible for survival and recurrent growth in relapsed prostate tumors.
Long non-coding RNAs in Oral squamous cell carcinoma: biologic function, mechanisms and clinical implications
Authors: Lei Zhang, Xiang Meng, Xin-wei Zhu, Deng-cheng Yang, Ran Chen, Yong Jiang, Tao Xu
Journal: Molecular Cancer (2019)

There is growing evidence that regions of the genome that cannot encode proteins play an important role in diseases. These regions are usually transcribed into long non-coding RNAs (lncRNAs). LncRNAs, little or no coding potential, are defined as capped transcripts longer than 200 nucleotides. New sequencing technologies have shown that a large number of aberrantly expressed lncRNAs are associated with multiple cancer types and indicated they have emerged as an important class of pervasive genes during the development and progression of cancer. However, the underlying mechanism in cancer is still unknown. Therefore, it is necessary to elucidate the lncRNA function. Notably, many lncRNAs dysregulation are associated with Oral squamous cell carcinoma (OSCC) and affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review expounds the up- or down-regulation of lncRNAs in OSCC and the molecular mechanisms by which lncRNAs perform their function in the malignant cell. Finally, the potential of lncRNAs as non-invasive biomarkers for OSCC diagnosis are also described. LncRNAs hold promise as prospective novel therapeutic targets, but more research is needed to gain a better understanding of their biologic function.
구연 : 아이리스 ; 만성 C형 간염 초치료 환자에서 페그인터페론과 리바비린의 맞춤 치료 (초)
Authors: 송영진, 이연재, 최병진, 최상분, 김종한, 정은욱, 이상헌, 김지헌, 최정식, 지삼룡, 설상영
Journal: Clinical and Molecular Hepatology (2010)
Factors influencing the intracellular exposure of gemcitabine triphosphate in children with CNS tumors.
Authors: Olivia Campagne, Bo Zhong, Nicholas Selvo, Thandranese S Owens, Amar J. Gajjar, Giles W. Robinson, Clinton F. Stewart
Journal: Journal of Clinical Oncology (2019)

e13547 Background: Gemcitabine (dFdC), a cytosine analog, is currently being evaluated as a therapy to treat children and young adults with central nervous systems (CNS) tumors in two clinical trials (NCT01878617 and NCT03434262). Once in the cell, dFdC undergoes complex and highly variable conversion to gemcitabine triphosphate (dFdCTP), which is responsible for its cytotoxic effects. Our objective is to identify the factors influencing dFdC and dFdCTP exposures in children. Methods: As part of treatment, patients with newly diagnosed medulloblastoma and patients with recurrent/refractory medulloblastoma or ependymoma receive 28-day cycles of dFdC, as a 30-minute IV infusion at 750, 1000 or 1250 mg/m 2 on days 1 and 15 of each cycle. Patients with recurrent/refractory disease also receive concomitant ribociclib. Pharmacokinetic (PK) studies were performed after one dose of dFdC alone (day 1) and with ribociclib (day 15). dFdC and dFdCTP concentrations were measured in plasma and in peripheral blood mononuclear cells respectively, for up to 4h post-dose, using validated LC-MS/MS methods. The concentrations were analyzed using a population PK model. A preliminary covariate analysis was performed to evaluate the impact of factors (e.g., patient demographics and infusion rate) on dFdC and dFdCTP exposure (area under the curve). Results: dFdC and dFdCTP concentrations were fitted with a three-compartment linear model. dFdC infusion rate significantly influenced the drug exposures with a faster plasma dFdC elimination and higher dFdCTP formation observed at the lower infusion rate. On average, patients receiving dFdC as 25 or 33 mg/m 2 /min had a dFdCTP exposure of 526 µM·h vs 205 µM·h with a rate of 42 mg/m 2 /min (p &lt; 0.001). Patient with lower body surface area also showed higher dFdC clearance. Significant intra-patient differences were observed in dFdCTP concentrations measured on days 1 and 15. Conclusions: This preliminary PK analysis shows a saturable formation of dFdCTP in children with CNS tumors, and suggests the need for longer infusion duration with higher dFdC dosages. Future work will evaluate potential drug-drug interaction with ribociclib and the effect of genotypic variants on dFdCTP exposure.
Validation and revision of the RANO Leptomeningeal Metastasis Group scorecard for response assessment.
Authors: Emilie Le Rhun, Patrick Devos, Thomas Boulanger, Marion Smits, Dieta Brandsma, Roberta Ruda, Julia Furtner, Johann-Martin Hempel, Tjeerd Postma, Patrick Roth, Tom J. Snijders, Frank Winkler, Sebastian Winklhofer, Antonella Castellano, Elke Hattingen, Jaume Capellades, Martin J. Van Den Bent, Patrick Y. Wen, Martin Bendszus, Michael Weller
Journal: Journal of Clinical Oncology (2019)

e13546 Background: The Response Assessment in Neuro-Oncology (RANO) group has proposed a scorecard to evaluate response assessed by magnetic resonance imaging (MRI) during treatment of leptomeningeal metastasis (LM). Methods: To validate the LM-RANO scorecard, cerebrospinal MRI of 22 patients with LM from solid tumors were rated by 10 neuro-oncologists and 9 neuroradiologists at baseline and during follow-up after treatment. The original scorecard and its instructions were sent to the raters. The inter-observer agreement for the evaluation of single items was assessed using the Krippendorff alpha coefficient. The agreement between numerical parameters including scores at baseline and at follow-up after treatment and total scores was determined using the intraclass coefficient of correlation (ICC). Results: Instructions of the scorecard were not clear for the majority of raters. The alpha concordance coefficients obtained for the rating of single items at baseline and at follow-up were low (Krippendorf alpha coefficient &lt; 0.61 for all raters). The best concordances were noted for spinal nodules (0.60). The worst concordances were obtained for brain linear leptomeningeal enhancement and cranial nerve enhancement. The concordance was better among neuroradiologists than among neuro-oncologists. A poor agreement was also noted when evaluating changes between baseline and follow-up and for total scores (ICC &lt; 0.65 for the best score for all raters). Conclusions: Assessing response of LM by MRI remains challenging. The definition of a measurable lesion and the determination of response were the most important challenges. A central review is therefore recommended for clinical trials in LM. Based on this study we propose a new scorecard that will require a similar assessment as conducted here.
Carbon-gold hybrid nanoprobes for real-time imaging, photothermal/photodynamic and nanozyme oxidative therapy
Authors: Amin Zhang, Shaojun Pan, Yuhui Zhang, Jie Chang, Jin Cheng, Zhicheng Huang, Tianliang Li, Chunlei Zhang, Jesus Martinez de la Fuentea, Qian Zhang, Daxiang Cui
Journal: Theranostics (2019)

Rationale:Recently, there is one-fifth of human deaths caused by cancer, leading to cancer treatment remains a hard nut to crack in the medical field.Therefore, as an emerging diagnostic technology, mesoporous nanomaterials-based drug delivery systems integrated diagnosis and therapy have aroused tremendous interest owing to visually targeting effect and superior therapy efficacy compared with traditional cancer treatment.Methods: In this work, we have successfully synthesized mesoporous carbon-gold hybrid nanozyme nanoprobes, whereby mesoporous carbon nanospheres were doped with small gold nanoparticles (OMCAPs) and further stabilized with a complex of reduced serum albumin and folic acid (rBSA-FA).After loading IR780 iodide, the OMCAPs@ rBSA-FA@IR780 nanoprobes were finally accomplished for real-time imaging, photothermal/photodynamic and nanozyme oxidative therapy.Results: Herein, acid oxidized MCAPs possessed large surface area and numerous -COOH groups, which could be used to surface chemically modify numerous targeting molecules and load abundant NIR dye IR780, as well as be acted as photothermal reagents to enhance photothermal therapy effect.In addition, the small Au NPs embedded in OMCAPs were utilized as nanozyme to catalyze H2O2 located in tumor cells to generate •OH for intracellular oxidative damage of tumor.Besides, as a commonly used near-infrared (NIR) fluorescence dye, the loaded IR780 iodide could not only apply for real-time imaging, but also effectively enhance photo-thermal therapy (PTT) upon the 808 nm laser irradiation.Moreover, FA molecules could enhance the targeted efficiency of the nanoprobes to the gastric tumor site.According to the systematical study in vitro and in vivo, our fabricated nanoprobes based on carbon-gold hybrid (OMCAPs@ rBSA-FA@IR780) revealed excellent tumor targeting efficacy, long tumor retention and favorably therapeutic effect for tumor. Conclusion:All the results demonstrated that here synthesized probes exhibited excellently diagnostic and therapeutic performance, indicating our technology may potentially offer an outstanding strategy for tumor-targeting theranostics.
AAML 1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A Report from the Children’s Oncology Group.
Authors: Todd Michael Cooper, Michael Absalon, Todd Allen Alonzo, Robert B Gerbing, Kasey Joanne Leger, Betsy A Hirsch, Jessica Anne Pollard, Bassem I. Razzouk, Richard Aplenc, E. Anders Kolb
Journal: Journal of Clinical Oncology (2019)

10003 Background: Effective regimens with favorable toxicity profiles are needed for heavily pre-treated children with relapsed AML. AAML1421 is a Phase I/II study of CPX-351, a liposomal preparation of cytarabine and daunorubicin demonstrating efficacy in adults. AAML1421 sought to determine the recommended Phase 2 Dose (RPD2) of CPX-351 and the response rate (complete response (CR) + complete response without platelet recovery (CRp)) after up to 2 cycles of therapy. Methods: Children &gt; 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding, and those in first relapse were eligible for efficacy. A modified rolling six design was used for dose-limiting toxicity (DLT) assessment which occurred in Cycle 1. Dose level 1 (DL1) was 135 units/m 2 on days 1, 3, and 5 with a single dose de-escalation to 100 units/m 2 if DL1 was intolerable. The Efficacy Phase used a Simon-two stage design. The response rate was determined after up to 2 cycles of therapy (Cycle 1: CPX-351; Cycle 2: FLAG). The Overall Response Rate (ORR) was defined as CR+CRp+CRi (CRi = CR with incomplete hematologic recovery). Results: Thirty-eight patients (pts) enrolled: 6 in dose-finding and 32 in the efficacy phase. DLT occurred in 1/6 patients and was a grade 3 decrease in ejection fraction(EF). This was the only Grade 3 cardiac toxicity. Therefore, 135 units/m 2 on days 1, 3, 5 was the RP2D. All dose finding pts were eligible for efficacy determination. One pt in the efficacy phase was unevaluable. The most common ≥ Grade 3 toxicities in Cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 CR (54%), 5 CRp (14%), and 5 CRi (14%). Seventy percent achieved best response after cycle 1. Twenty-one of 25 patients with CR/CRp had no detectable residual disease (RD) (84%) by flow cytometry. HSCT was used as consolidation in 23/29 responders (79%); 18 of 23 (78%) had no detectable RD prior to HSCT. Conclusions: The RP2D of CPX-351 is 135 units/m 2 /dose on days 1, 3, 5. CPX-351 was well tolerated and protocol therapy was effective with CR+CRp rates of 68.3% (90% CI 52.9% to 78.0%) and ORR (CR+CRp+CRi) of 81.1% (90% CI 67.4% to 88.8%). AAML1421 response rates are superior to any published North American cooperative group clinical trial for children with AML in first relapse. Clinical trial information: NCT02642965.
Association of cell-free DNA (cfDNA) levels with myeloid-derived suppressor cells (MDSC) levels in blood of patients (pts) with muscle invasive (MI) and metastatic (met) bladder cancer (BC).
Authors: Jaleh Fallah, Shinjini Ganguly, Patricia A. Rayman, Wei (Auston) Wei, Aysegul Balyimez, Thirunavukkarasu Sitalaximi, Marcelo Lamenza, Kevin L. Stephans, Priscilla Dann, Donna Company, Rahul D. Tendulkar, Mohamed Abazeed, Jorge A. Garcia, Brian I. Rini, Byron H Lee, Moshe Chaim Ornstein, Petros Grivas, Omar Y. Mian, C. Marcela Diaz-Montero
Journal: Journal of Clinical Oncology (2019)

4528 Background: cfDNA can be detected in healthy individuals but higher concentrations are present in pts with cancer. MDSC are immature immunosuppressive cells that can be mobilized from bone marrow by tumor-related factors. Higher blood MDSC levels have been associated with worse outcomes in pts with solid tumors including BC. We assessed correlations between cfDNA and MDSC levels in pts with MIBC and met BC. Methods: Peripheral blood from pts with MIBC and met BC was collected in Streck BCT tubes and processed to obtain cf nucleic acid extracts. Total cfDNA was determined by fluorimetry. Cell-free DNA fragment size was measured by Bioanalyzer DNA analysis; 100-400 bp fragments (mono- and di-nucleosomal fragments linked to granulocytic processing of apoptotic and necrotic tumor cells) were designated low molecular weight (LMW-frags). The % of MDSC (CD33+/HLADR-) and subtypes were measured. MDSC subtypes were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+) and uncommitted (UNC-MDSC: CD15-/CD14-). Spearman’s correlation test was used for analysis. Results: Blood from 37 pts (19% women, 40% never smokers) with MIBC or met BC was collected: 15 (41%) with MIBC and 22 (59%) with met BC at time of collection. There was a significantly positive correlation between total MDSC and cfDNA levels (r = 0.57, P = 0.0003). Among MDSC subtypes, there was a significantly positive correlation between PMN-MDSC and cfDNA levels (r = 0.61, P &lt; 0.0001). The higher level of LMW-frags was significantly but moderately associated with higher total MDSC (r = 0.43, P 0.008) and PMN-MDSC (r = 0.41, P 0.01) levels. There was no significant correlation between cfDNA level and other MDSC subtypes. Conclusions: There was a positive correlation between total and PMN-MDSC with cfDNA levels in blood from pts with MIBC and met BC. That may suggest a putative role for MDSC in mediating cfDNA release into the circulation, consistent with prior reports of granulocyte-mediated ctDNA processing. Further studies need to identify mechanisms and implications of our findings and potential correlation with clinical outcomes.
Clinical and molecular factors predicting resistance to first-line (1L) FOLFOX in patients (pts) with advanced esophagogastric cancer (EGA) and patterns of subsequent therapy.
Authors: Megan Greally, Henry S Walch, Joanne F Chou, Marinela Capanu, David Paul Kelsen, David H. Ilson, Yelena Yuriy Janjigian, Nikolaus Schultz, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2019)

4047 Background: In the US, FOLFOX is the most widely used 1L treatment for advanced EGA. We evaluated if FOLFOX resistance (FR) impacted subsequent therapy and characterized the clinical and molecular factors that predict resistance to 1L FOLFOX. Methods: We reviewed pts with advanced Her2-negative EGA treated with 1L FOLFOX from Jan 2013 to Aug 2017. Response or stable disease (SD) at time of first restaging scan defined pts as FOLFOX sensitive (FS); progression defined FR. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank-Sum tests. Outcomes were correlated with clinical variables and MSK-IMPACT data. Microsatellite instable (MSI) pts were excluded from gene and pathway analysis. Overall survival (OS) was calculated from start of FOLFOX using Kaplan-Meier methods. Landmark analysis (2 months [mo] after starting FOLFOX) was used to compare OS between groups. Results: We identified 311 pts, median age 62, 73% male, 82% ECOG 0/1. 246 pts (79%) were FS and 65 (21%) were FR. FR pts had a higher number of metastatic sites, p = 0.001. Median OS was 13.4 mo in FS pts vs 4.3 mo in FR pts (p &lt; 0.001). At time of analysis, 213 pts (172 FS pts and 41 FR pts) and 110 pts (90 FS pts and 20 FR pts) had received 2 nd -line (2L) and 3 rd -line (3L) chemo respectively. In pts who received 2L chemo (ctx), there was no difference in ctx duration between FS and FR pts (2.1 vs 1.4 mo, p = 0.67). However, in pts who received 3L ctx, the duration was longer in FS vs FR pts (1.6 vs 0.5 months, p = 0.002). In IMPACT tested pts (n = 130), univariate analysis identified EGFR (33.3% vs 10.7%, p = 0.032) and WNT pathway (26.7% vs 4.9%, p = 0.015) alterations more frequently in FR pts vs FS pts. 12 pts were MSI, all were FS (3 SD, 8 PR, 1 CR). Of 63 pts who had IMPACT germline testing, 7 (11%) had germline mutations identified, including CDH1 (n = 2) and ATM (n = 1), all were FS. No pts were enrolled on genotype-matched trials as a result of IMPACT testing. Conclusions: From time of first restaging scan, FR pts have inferior OS to FS pts. The duration of 3L ctx was longer in FS vs FR pts. Higher number of metastatic sites and EGFR and WNT pathway alterations were associated with FR; MSI was not. IMPACT did not facilitate enrolment on genotype-matched studies.
Prognostic value of PSA progression in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated in the COU-AA-302 trial.
Authors: David Lorente, Rebeca Lozano, Guillermo de Velasco, Maria De Julian, Miguel Rodrigo, Angel L Sanchez, Carlos Di Capua, Elena Castro, Alfredo Sanchez Hernandez, David Olmos
Journal: Journal of Clinical Oncology (2019)

e16541 Background: PSA is a widely used biomarker for monitoring outcome in mCRPC. Current treatment guidelines do not consider PSA progression before at least 12 weeks of treatment, and recommend treatment continuation in pts experiencing progression by PSA only, without radiographic or clinicall progression. We aimed to evaluate the prognostic value of a PSA progression in mCRPC pts treated with first-line therapy. Methods: We analyzed the value of a PSA progression (PSAProg) at cycle 5 in pts treated in the COU-AA-302 trial. PSAProg was defined as an increase ≥ 25% and ≥ 2 ng/mL from baseline, confirmed by a second reading. Radiographic progression (RadProg) was defined as per PCWG2 criteria for bone scan or RECIST progression. Survival and radiographic progression-free survival (rPFS) from the time of PSAProg was calculated using Kaplan-Meier estimates. Cox-regression models were used to evaluate the impact of PSAProg and treatment arm on survival. Results: 1088 pts were randomized in the COU-AA-302 trial. 908 pts (83.5%) had valid baseline and cycle 5 PSA values. Of these, 222 (24.4%) pts experienced PSAProg, which was confirmed in 195 (21.5%) pts; 45/479 (9.4%) of abiraterone and 150/429 (35%) of placebo-treated pts. A confirmed PSAProg was associated with shorter survival (37.8 vs 26m; HR: 1.8; p &lt; 0.001) and rPFS (13.9 vs 5.6m; HR:2.1; p &lt; 0.001). Median survival from the time of PSAProg was 22.2m (95%CI:18.9-25.4). Abiraterone-treated pts had a significantly longer survival from the time of PSAProg (23.1 vs 17.4m; HR: 0.64; p = 0.018). 111 pts (56,9%) experienced PSAprog without RadProg; in pts with PSAprog only, median time to RadProg was 7.4m (95%CI:7.1-12.9). No differences in rPFS from the time of PSAprog were observed in abiraterone vs placebo-treated pts (HR: 0.99; p = 0.963). Conclusions: 9.4% of abiraterone-treated pts in the COU-AA-302 trial experienced PSAProg at 12 weeks (cycle 5 day 1). PSAProg was associated with significantly worse survival. Abiraterone increased survival from the time of PSAProg, which supports its continued use in pts with PSA progression only at 12 weeks. This study was carried out under YODA Project #2018-3011.