tbuckley/cabot-search huggingface dataset:
Deep profiling of tumor immune microenvironment (TME) with fluorescence activated cell sorting (FACS) in advanced melanoma.
Authors: Kimberly Loo, Katy K. Tsai, Michael Rosenblum, Neharika Khurana, Jimmy Hwang, Roberto Sanchez, Miranda Broz, Matthew Krummel, Paul Tumeh, Alain Patrick Algazi, Adil Daud
Journal: Journal of Clinical Oncology (2015)

9012 Background: Tumor PD-L1 expression by immunohistochemistry has limitations in describing the tumor immune microenvironment as it relates to treatment with PD-1/PD-L-1 antibodies. We developed a novel FACS based method to study the tumor immune microenvironment and used it in patients undergoing PD-1/PD-L-1 antibody treatment. Methods: Multi -parameter flow cytometry was performed on freshly harvested metastatic melanoma tumor tissue following overnight enzymatic digestion (n = 161). The gating strategy sorted tumor cells, CD4+, CD8+ and myeloid/stromal cells. CD8+ cells were further sorted for PD-1, PD-L1, CTLA-4, and HLA-DR, while CD4+ cells were sorted for FoxP3 in addition to these markers. Tumor associated macrophage and dendritic cell activation markers were also determined in samples. Overall responses were derived from investigator reported data by Response Evaluation Criteria in Solid Tumors (RECIST). Descriptive statistics for responders vs. non-responders to anti-PD-1 therapy were constructed to assess the prognostic utility of these markers. Results: TME-FACS was evaluable on 32 unique patients who were evaluable for response. A high percentage (> 35% of total CD8+ cells) of PD-1 and CTLA-4 expressing CD8+TILs is associated with an increased response to anti-PD-1 therapy. Increased mean fluorescence intensity (MFI) of PD-1/CTLA-4 dual expression on CD8+ cells is also associated with response. Myeloid cell markers clearly stratified responders vs. non-responders to anti-PD-1 therapy. Conclusions: TME-FACS is a novel method to functionally define the immune microenvironment in melanoma. TME-FACS immunoprofiling revealed that an increased percentage of PD-1/CTLA-4 + CD8+ TIL populations in metastatic lesions correlates with responsiveness to anti-PD-1 therapies. Defined myeloid subsets can also be uncovered by TME-FACS. Response Assessment Median PD1 / CTLA4 MFI Median % PD1+ CTLA4+ CD8 TILs Complete Response (CR) 238 49 % Partial Response (PR) 217.5 37.5 % Stable Disease (SD) 199.5 32.05 % Progressive Disease (PD) 163 26.1 %
Feasibility of BIBF1120 (nintedanib) combined with low-dose cytarabine in elderly patients with AML ineligible for intensive treatment.
Authors: Utz Krug, Nicola Knoblauch, Joachim Gerss, Christoph Schliemann, Stefanie Wiebe, Carsten Müller-Tidow, Wolfgang E. Berdel
Journal: Journal of Clinical Oncology (2014)

7053 Background: Elderly unfit patients with AML have a dismal prognosis. The oral multikinase inhibitor BIBF1120 (nintedanib) was reported to exert growth inhibitory and proapoptotic effects in myeloid cells, especially when used in combination with cytarabine (AraC). Methods: This phase I study evaluated the combination of AraC (20mg subcutaneously twice daily on days 1-10 every 28 days) with BIBF1120 in 3 predefined dose levels (DL: 100, 150, and 200mg orally twice daily) in elderly patients with AML ineligible for intensive treatment or treatment with 5-Aza in a 3+3 design. Protocol-specific definitions: Therapy-related cytopenias constituted no adverse events (AE). AEs of special interest (AESI) were elevation of AST and/or ALT >3x upper level of normal (ULN) combined with an elevation of bilirubin >2x ULN, and any hollow organ perforation occurring after the first intake of study medication. DLT was defined as non-hematological SAR CTC grade ≥IV with possible or definite relationship to BIBF1120 occurring during or up to 28 days after the first cycle. Results: Between April 2012 and October 2013, 13 patients were enrolled into the phase I part of this trial (DL1: 3 patients, DL2: 4 patients, DL3: 6 patients). 1 patient in DL2 did not receive study medication and was replaced. Median age was 73 (range: 62 – 86) years. Disease status was untreated (4 patients), relapsed (5) and refractory (4) AML. Cytogenetic risk was favorable (1 patient), intermediate (5), unfavorable (6) or missing (1). 8 SAEs occurred (DL1: 1, DL2: 3, DL3: 5). All of the 3 SARs were neutropenic fever grade 3 (DL2: 1, DL3: 2). 2 SUSARs were observed, 1 fatal hypercalcemia (DL2) and 1 fatal GI tract infection (DL3). No AESI were observed. The phase II recommended dose (P2RD) was set as DL3 by the DMC. 2 patients with relapsed AML responded (1 CR, 1 CRi). Bone marrow blast reductions without fulfilling the PR criteria were observed in 3 patients. One-year survival from start of therapy was 46% after a median follow-up of 308 days. Conclusions: BIBF1120 combined with LD-AraC shows a favorable safety profile. Preliminary survival data are promising. Continuation of this trial with a P2RD of 2 x 200mg in a randomised phase II is planned. Clinical trial information: NCT01488344.
Native and rearranged <i>ALK</i> copy number and rearranged <i>ALK</i> cell count in NSCLC: Implications for ALK inhibitor therapy.
Authors: D. Ross Camidge, Margaret Skokan, Porntip Kiatsimkul, Barbara Helfrich, Nathan Schulte, DeLee Maxson, Dara L Aisner, Wilbur A. Franklin, Robert Charles Doebele, Marileila Varella-Garcia
Journal: Journal of Clinical Oncology (2012)

7534 Background: ALK rearranged NSCLC responds well to ALK inhibitors. Clinically, &gt;15% cells showing rearrangements by break-apart FISH classifies tumors as ALK(+). Native ALK copy number gain has also been reported. We explored the significance of native and rearranged ALK copy number on crizotinib outcomes and whether &gt;15% reflected a clear biological distinction in the frequency of ALK(+) cells. Methods: Copy number and genomic status of ALK assessed by FISH. A total of 1426 NSCLC clinical specimens, 174 ALK(+) and 1252 ALK(-) by standard criteria, and 26 NSCLC cell lines (2 ALK(+) and 24 ALK(-)) were investigated. Results: Native ALK gene mean copy number was significantly higher in ALK(-) than in ALK(+) cases (2.8, SD 0.93, range 1.2-11.4 vs. 1.8, SD 0.79; range 0.6 to 5.2; p&lt;0.01). Frequency of native ALK copy number gain (≥3 copies/cell in ≥40% cells) was 19% in ALK(+) and 62% in ALK(-) tumors (p&lt;0.001). In ALK(-) tumors, abundant focal amplification of native ALK was rare (0.8%); scanty amplification (&lt;10% tumor cells) occurred in 1.1%, and duplication of the entire native ALK or of the ALK 3’ end occurred in 3.5%. Among ALK(-) cell lines, mean native ALK copy number ranged 2.1-6.9 and was not correlated with in vitro crizotinib sensitivity (IC50s 0.34-2.8 uM). In (+) patients, neither native or rearranged ALK copy number, nor percentage cell count correlated with maximal tumor shrinkage or PFS with crizotinib. Clinical specimens with 0-9%, 10-15%, 16-30%, 31-50% and &gt;50% of ALK+ cells were found in 79.3%, 8.5%, 1.4%, 2.7% and 8.1% of cases, respectively. Conclusions: Lower native ALK copy number in ALK(+) NSCLC suggests ALK fusion occurs early, preceding chromosomal instability. Elevated native ALK copy number rarely reflects focal amplification and native ALK copy number increases alone are not associated with sensitivity to ALK inhibition in vitro. Neither native or rearranged copy number, nor positive cell count within ALK(+) tumors influences clinical benefit from ALK inhibition. As 8.5% of ALK(-) cases fall within 5% of the established &gt;15% cell positive threshold, further investigation of ALK status by other diagnostic techniques in this subset may be warranted.
Preliminary updated results of a phase I/II trial using trimodality therapy in patients with post-prostatectomy high-risk pathologic (p) T2-3N0M0 prostate cancer.
Authors: Parvesh Kumar, Peter J. Van Veldhuizen, Mark Thompson, Xinglei Shen, James Coster, Jacek Pinski
Journal: Journal of Clinical Oncology (2014)

e16084 Background: We present the updated preliminary results of an on-going phase I / II trial with the purpose of determining the safety, feasibility and efficacy of post-prostatectomy 3-D conformal RT (CRT), hormonal therapy and concurrent docetaxel in patients with high risk pathologic (p) T2-3N0M0 prostate cancer. Methods: Post-prostatectomy high risk prostate cancer was defined as clinically non-metastatic disease with either an undetectable, persistent or rising PSA with 1 or more of the following clinical-pathologic features: (1) pT2-T3aN0 disease, positive or negative margins, with either (a) a gleason score (GS) of ≥8, and/or (b) a PSA doubling time of ≤10 months, and/or (c) with a pre-RT PSA of ≥1.0 ng/ml; and/or (2) pT3bN0 disease. The tri-modality treatment consisted of 6 months of hormonal therapy [Casodex (50 mg po daily), and Zoladex (10.8 mg sc q 3 mos x 2) or Lupron (22.5 mg im q 3 mos x 2)], 3-D CRT to 66.0 Gy at 2.0 Gy/fraction (fx) once daily (50 Gy to the surgical bed followed by a 16 Gy Boost at 2.0 Gy/fx using either 3-D CRT or IMRT, usually begun after 2 months of hormonal therapy), and concurrent weekly docetaxel at 20 mg/m2 x 7 infusions. Results: Between October 2008 and January 2014, a total of 25 patients have been enrolled to this on-going phase I/II clinical trial, 18 of whom have completed their entire tri-modality therapy. All of these 18 patients completed their full dose of RT (66 Gy). These 18 patients also received a median of 7 weekly docetaxel infusions (range = 5 - 8). Only 2 of these 18 patients experienced grade ≥3 GI / GU possibly treatment-related acute toxicity, both of whom were on stool softners and / or laxatives preceding their grade 3 diarrhea. Among the 7 of 25 remaining patients, 2 of the 7 have completed their entire chemoradiation therapy treatments without any acute grade ≥3 GI / GU toxicity while the other 5 recently started their protocol therapy. Conclusions: The preliminary updated results of our on-going phase I/II clinical trial with an accrual goal of ≥40 patients indicate that our post-prostatectomy tri-modality therapy is well tolerated with a very high feasibility rate in patients with high risk pT2-3N0M0 prostate cancer. Clinical trial information: NCT00669162.
Effect of MiR-338-3p on epithelial-mesenchymal transition in gastric cancer cells by targeting <i>ZEB2</i> and <i>MACC1</i> and regulation of MACC1/c-Met signaling.
Authors: Na Huang, Zhenzhen Wu, Minyu Zhou, Lin Wang, Huanrong Ma, Min Shi, Qiang Zuo, Dayong Zheng, Wangjun Liao
Journal: Journal of Clinical Oncology (2014)

e22010 Background: AberrantmicroRNAs (miRNAs) expression is involved in carcinogensis and tumor progression in gastric cancer (GC). Recently, microRNA-338-3p (miR-338-3p) has been proved to down-regulate in GC patients with deeper local invasion and advanced TNM stage. However, the underlying mechanism has not been well explored. Epithelial-mesenchymal transition (EMT) is well-known as a key step for tumor cell invasion and metastasis. Increasing evidence indicates that miRNAs play an important part in modulating EMT in many cancers. Here, we investigated the role and mechanism of miR-338-3p on EMT in GC. Methods: Cell migration and invasion ability were detected by wound-healing and transwell invasion assay.Western blot analysis was preformed to assess E-cadherin, N-cadherin, Fibronectin, Vimentin, c-Met, Akt and GSK-3β expression in GC cells. 3D cell culture system was carried out to observe the morphological changes in GC cells. Dual-luciferase assay was conducted to verify that miR-338-3p targeting ZEB2 and MACC1. Expression of miR-338-3p and ZEB2 and MACC1 was evaluated in 21 matched GC specimens by qRT-PCR. Results: Both gain- and loss-of function studies showed that miR-338-3p inhibited GC cells migration and invasion in vitro. Western blot analysis revealed that miR-338-3p influenced the expressions of the EMT-associated protein, increasing the level of epithelial marker (E-cadherin) and decreasing the levels of mesenchymal markers (N-cadherin, Fibronectin and Vimentin). Moreover, via 3D cell culture system, we observed that down-regulation of miR-338-3p caused GC cells to undergo mesenchymal-like change. Further investigations indicate that ZEB2 and MACC1 were direct targets of miR-338-3p. Inverse correlations were also observed between the expression of miR-338-3p and ZEB2 and MACC1 in GC tissue samples. Reintroduction of ZEB2 and MACC1 abrogated miR-338-3p-induced EMT suppression of GC cells. Furthermore, we found that miR-338-3p repressed the c-Met/Akt/GSK-3β pathway by targeting MACC1. Conclusions: These findings highlight the importance of miR-338-3p on EMT and metastasis in GC.
Research on predictive value of five current staging systems in advanced hepatocellular carcinoma patients who received loco-regional therapies.
Authors: Zhan-Hong Chen, Li Wei, Ying-Fen Hong, Jin-Xiang Lin, Xing Li, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2017)

237 Background: Many HCC patients are diagnosed at advanced stage and loco-regional therapies improve their prognosis. Transarterial chemotherapy with or without concomitant embolization(TACE) and percutaneous ethanol injection(PEJ) are two common loco-regional therapies.Overall survival(OS) of these patients varies differently. It is very important to identify who benefits most from loco-regional therapies. We research on five current staging systems’ predictive value. Methods: Our research analyzed 220 advanced HCC patients. They received TACE or PEJ and did not receive radical surgery, chemotherapy or target therapy. At first diagnosis all patients were classified according to CLIP (Cancer of the Liver Italian Program), Advanced Liver Cancer Prognostic System (ALCPS), Japan Integrated Scoring (JIS) system, Barcelona Clinic Liver Cancer Classification (BCLC) and model for end-stage liver diseases (MELD) score. 6 month OS, 1-year OS, 2-year OS and OS were the end points. Results: The median survival is 23.8 months. When predicting 6 month OS, AUC of CLIP, ALCPS, JIS, BCLC and MELD is 0.847, 0.724, 0.710, 0.521 and 0.509,respectively;When predicting 1-year OS, AUC of CLIP, ALCPS, JIS, BCLC and MELD is 0.872, 0.689, 0.693, 0.503 and 0.552,respectively; When predicting 2-year OS, AUC of CLIP, ALCPS, JIS, BCLC and MELD is 0.855, 0.683, 0.669, 0.503 and 0.553,respectively;AUC of CLIP is significantly higher than other four staging systems in predicting 6 month OS, 1-year OS, 2-year OS(P &lt; 0.05), while AUC difference between ALCPS and JIS does not have statistical significance in predicting 6 month OS, 1-year OS, 2-year OS(P &gt; 0.05). When predicting OS, likelihood ratio test shows χ2 of CLIP, ALCPS, and JIS is 90.2,13.1 and 16.5 respectively. AIC of CLIP, ALCPS and JIS is 1338, 1415 and 1411 respectively. CLIP has the highest χ2 value and the lowest AIC value. As for discriminatory ability, homogeneity and monotonicity, CLIP performs best. Conclusions: The best staging system in predicting 6 month OS, 1-year OS, 2-year OS and OS for advanced HCC patients who received loco-reginal therapies is CLIP.
Prognostic implication of persistent HPV16 DNA detection in oral rinses for HPV-positive oropharyngeal carcinoma.
Authors: Eleni Marie Rettig, Alicia Wentz, Marshall R. Posner, Neil D. Gross, Robert I. Haddad, Maura L. Gillison, Harry Quon, Andrew Gregory Sikora, Will Stott, Jochen H. Lorch, Christine Gail Gourin, Brett Miles, Jeremy Richmon, Krzysztof Misiukiewicz, Christine H. Chung, Carole Fakhry, Gypsyamber D'Souza
Journal: Journal of Clinical Oncology (2015)

6005 Background: Human papillomavirus-positive oropharyngeal carcinoma (HPV-OPC) has a favorable prognosis; however, 10-25% of HPV-OPC cases recur. Oral HPV DNA detection is associated with HPV-OPC, but its value as a prognostic biomarker is unclear. Methods: Patients with incident HPV-OPC treated with curative intent were enrolled from October 2009-May 2013 at four centers. Oral rinses were collected at baseline (diagnosis) and post-therapy at 9, 12, 18 and 24 months after diagnosis. Oral rinses were evaluated for 36 types of HPV DNA. Survival analyses were performed using Kaplan Meier method and Cox regression models. Disease free survival (DFS) and overall survival (OS) were estimated. Results: 151 patients were included and 124 (79%) had one or more post-treatment oral rinse (median three). Oral HPV16 DNA was common at baseline (N = 85, 56%). In contrast, oral HPV16 DNA was detected in only six patients in follow up (5%), including five who had HPV16 DNA at baseline (persistent oral HPV16 DNA) and one who did not. Two-year DFS and OS were 92.2% and 97.5%, respectively for all 151 cases. Persistent oral HPV16 DNA was associated with significantly worse DFS (adjusted HR 34.0, 95%CI 7.9-146) and OS (adjusted HR 16.9, 95%CI = 3.1-93). Among patients who recurred (n = 15, 10%), median time to recurrence was 15 months from diagnosis. All five patients with persistent oral HPV16 DNA recurred. Three of these cases included local recurrence. Median time from earliest post-treatment oral HPV16 DNA detection to recurrence was seven months (range 3-11). Among 108 patients with a post-treatment oral rinse collected 9-12 months after diagnosis, detection of persistent oral HPV16 DNA had 100% positive predictive value (3/3), 96% negative predictive value (4/108), 43% sensitivity (3/7) and 100% specificity (104/104) for predicting recurrence between 12-24 months. Conclusions: Oral HPV16 DNA detection in oral rinses is common at baseline but rare after treatment for HPV-OPC. Our data suggest that persistent oral HPV16 DNA in post-treatment rinses is strongly associated with poor prognosis, may have high positive and negative predictive value for recurrence, and is a potential tool for long-term tumor surveillance.
Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC).
Authors: Ryan Bruce Corcoran, Gerald Steven Falchook, Jeffrey R. Infante, Omid Hamid, Wells A. Messersmith, Adil Daud, Eunice Lee Kwak, David P. Ryan, Razelle Kurzrock, Chloe Evelyn Atreya, Jennifer Luan, Peng Sun, Megan Schaeffer, Monica Motwani, Maureen R Bleam, Christopher H Moy, Kiran Patel, Keith W. Orford, Scott Kopetz, Alan Paul Venook
Journal: Journal of Clinical Oncology (2013)

3507 Background: TheBRAF V600 mutation occurs in 5-10% of metastatic CRC, predicts poor prognosis, and may predict lack of response to standard therapy. The combination of inhibitors of BRAF (dabrafenib; D) and MEK (trametinib; T) has shown significant efficacy in BRAF-mutant melanoma. The safety, efficacy, and pharmacodynamic effects of this combination were studied in BRAF-mutant CRC patients (pts). Methods: BRAF mutant CRC pts were enrolled to an initial efficacy cohort of 26 pts and a subsequent pharmacodynamic (PD) expansion cohort that included biopsies of 15 pts at screening and at steady state. So far, 36 pts have enrolled, including 10 in the PD cohort. Eligible pts had previously-treated BRAFV600E mutant stage IV CRC. Pts were treated with D (150mg BID) and T (2mg QD). Additional analyses were performed on available archival tissues. Results: Data are available for 36 pts: ECOG performance status 0 (58%) or 1 (42%), 81% had received ≥ 2 prior chemotherapy regimens, 36% had received prior EGFR inhibitor treatment, and 83% had ≥ 1 biologic therapy. Among 34 pts with &gt;1 restaging assessment as of November 2012, 1 (3%) achieved a complete response (confirmed, on study &gt;12m), 3 (9%) achieved a partial response (1 confirmed to date), and 18 (53%) had stable disease (SD). Minor responses were seen in 7/18 pts (39%) with SD. Median PFS was 3.5 mo (95% CI: 1.8-4.9); overall duration on study range: 0.03–15.2 mo 7 pts (24%) remained on study for ≥6 cycles with 9 pts still on study. The most frequent AEs, any grade, included pyrexia (67%), nausea (56%), fatigue (53%), chills (47%), vomiting (39%), headache (31%), peripheral edema (31%), anemia (28%), and decreased appetite (28%). 2 pts (6%) discontinued due to AEs. Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ±29%) and relative (69% ±28%, normalized to total ERK) reduction in pERK. Conclusions: Further investigation is needed, as this combination is tolerable at full monotherapy doses of each drug, with manageable toxicities, and has activity in a subset of BRAF mutant pts. Updated safety, efficacy, and correlative data will be presented. Clinical trial information: NCT01072175.
Effect of enzalutamide (EZ) exposure time on androgen receptor (AR) splice variant (SV) expression and gene transcription correlates in androgen-dependent (AD) prostate cancer (PC) cells.
Authors: Anna C. Ferrari, Xiao-Mei Liu, Mohammed Alshalalfa, Alejandro Gomez-Pinillos, Thomas Sierocinski, Elai Davicioni
Journal: Journal of Clinical Oncology (2014)

e22066 Background: The emergence of castration-resistant (CR) PC limits the benefits of androgen deprivation therapy (ADT) in controlling recurrent AD PC. ARSVs lacking the ligand-binding domain are frequent in CRPC tissue/cells where they mediate resistance to anti-androgens and androgen synthesis inhibitors by regulation of a mitosis-dependent, ARSV-driven transcriptome program (TP) that differs from the differentiation-driving program of full-length (fl) AR. We postulated that ARSVs emerge as a stress reaction to AR suppression and only later induce the TP changes of CRPC. Methods: We assessed the effects of treatment with the anti-androgen EZ (EZt) over 19 culture passages (cp) on AD LNCaP cells (AD-cells), isogenic androgen-independent (AI) cells (AI-cells) and AI CW22RV1 (RV1) cells: growth in androgen-replete or –deprived medium (RM, DM) (MTT assay, cell counts); flAR and ARSV expression (Q-PCR) and the genome-wide TP (Affymetrix Human Exon microarray using 1.3X differential expression and t-tests for significance). Results: In EZt AD-cells, known pathogenic ARSV7 increased 5X relative to flAR by cp 3 – 11 while growth remained AD (EZ-inhibited); by cp 16, the relative increase was >300X and growth suddenly became AI (EZ-resistant). In both AI-cells and RV1 cells, ARSV7 increased after only 3 cp associated with enhanced AI/EZ-resistant growth. TP analysis demonstrated a striking difference between AD-cells and AI-cells or RV1 cells at baseline and after 3 cp on EZ. The TP of EZt AD-cells showed downregulation of AR-regulated transcripts (KLK3, TMPRSS), a biphasic response of cell cycle genes (CDK1, CCNA2, UBE2C) (cp3 downregulation, cp16 upregulation) and upregulation of neuroendocrine genes (AGR2,AURKA, SSTR2) at cp 16. The profound changes in cp16 EZt AD-cells (203 differentially-expressed genes/baseline) rendered a TP similar to CRPC-like RV1 cells with high endogenous ARSV7 levels. Conclusions: After an effective interval of EZt, a precipitous increase of ARSV7 occurred in AD LNCaP cells concurrent with the acquisition of AI/CR PC characteristics, an observation potentially relevant to clinical ADT in AD PC.