tbuckley/cabot-search huggingface dataset:
Prognosis model for overall survival in locally advanced pancreatic cancer (LAPC): An ancillary study of the LAP 07 trial.
Authors: Dewi Vernerey, Pascal Hammel, Sophie Paget-Bailly, Florence Huguet, Jean Luc Van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Malcolm Moore, Thierry André, Laurent Mineur, Benoit Chibaudel, Christophe Louvet, Franck Bonnetain
Journal: Journal of Clinical Oncology (2014)

4024 Background: The management of LAPC patients remains controversial. Better discrimination for Overall Survival (OS) is needed to improve therapeutic decisions. We aimed to address this issue on the largest phase III cohort of LAPC by establishing the first prognosis model for OS with the full spectrum of parameters currently available at diagnosis. Methods: We enrolled the 442 LAPC patients recruited in LAP07, an international multicenter randomized phase III trial (NCT00634725). Thirty-five baseline variables among demographic, cancer history, clinical, biological and radiological parameters were evaluated in univariate and multivariate analyses as prognostic factors for OS. The predictive value of the final model was evaluated with Harrell’s C-index. This analysis was repeated 1000 times with the use of bootstrap sample to derive 95%CI for the C. A prognostic score was then developed based on the identified prognostic factors in the final model. Results: Independent prognostic factors identified in multivariate analysis (n=370) for OS were: age (HR= 1.01; 95%CI 1.00 - 1.03; p=0.0418), pain (HR= 1.36 ; 95%CI 1.08 - 1.71; p=0.0094), albumin (HR= 0.96; 95%CI 0.94 - 0.98; p=0.0001) and tumor size (HR= 1.01; 95%CI 1.00 - 1.02; p=0.0033). Harrell’s C-statistic for the final model was 0.60 (95%CI 0.56 - 0.63). A prognostic score between 0 and 4 was then calculated for each patient, based on the previous model. Three risk groups for death could be identified: “lower risk” (score∈[0,1]; n=17; median OS = 18.8 months; HR=1), “intermediate risk” (score∈(1,2]; n=166 ;median OS = 13.4 months; HR=1.7), “higher risk” (score∈(2,4]; n=187 ; median OS = 11.8 months; HR=2.1), p = 0.0101 by the global log rank test. Conclusions: Our results highlighted four OS’s independent pronostic factors among a broad spectrum of parameters at time of diagnosis.We have identified three groups with clearcut different prognostic profiles. The determination of this simple prognostic score should allow risk stratification that may help guiding clinical management of patients with LAPC and to design for future clinical trials. An external validation with a cohort issued from ARCAD meta-analysis is pending.
National survey of practice patterns employing MRI-guided prostate biopsy for diagnosis of prostate cancer.
Authors: Graham Tooker, Peter A. Pinto, Mohummad Minhaj Siddiqui
Journal: Journal of Clinical Oncology (2017)

104 Background: Targeted MRI/Ultrasound (MR/US) guided biopsy is an emerging technology that has the potential to change standard of care for the diagnosis and management of prostate cancer. It is believed that this new technology is rapidly proliferating, however quantitative analysis to describe these trends is not available. The primary objective of this study was to assess nationwide urologist opinions and efforts to implement MR/US imaging into their prostate cancer practices. Methods: A questionnaire was generated and distributed using REDCap to 7341 practicing urologists within the United States. The twenty question survey was designed to gather information regarding demographics, current and recent changes in MRI use, opinions on targeted MR/US guided biopsy, and barriers to implementation. The survey results were then analyzed with ANOVA. Results: 291 practicing urologists completed the survey. Respondents were primarily trained in general urology (60%) or urologic oncology (22%) and well distributed across practice type and geographic location. 86% of respondents currently employ MRI in some capacity in their practice, and 60% report using MR/US guided biopsy. 67% of respondents report increased use of MR/US guided biopsy over the past 5 years and 81% believe it is appropriate to use MR/US guided biopsy for the diagnosis of prostate cancer. Academic centers had the greatest utilization of targeted biopsy (72%) and solo practitioners had the least (38%, p = 0.003). The northeast region also demonstrated greatest use of targeted biopsy (68%) and western region had the least (44%, p = 0.02). 24% of respondents feel there is sufficient evidence to employ MR/US as standard of care in all prostate biopsies, while 65% believe MR/US should be reserved for select cases such as men with prior negative biopsies. Of those not performing biopsies, 69% of respondents cited cost as a barrier to implementation. Conclusions: While there are some reservations about employing MR/US guided biopsy, the data suggests urologists support its use, and are making efforts to introduce targeted MR/US guided biopsy into their practice. Regional and practice setting variations exist in adaptation of this technology.
MAPK/ERK as a biomarker for cisplatin resistance in squamous cell carcinoma (SCC).
Authors: Li Ren Kong, Kian Ngiap Chua, Jingshan Ho, Min En Nga, Ross A. Soo, Yin Huei Pang, Thomas Kwok Seng Loh, Soo Chin Lee, Boon C. Goh
Journal: Journal of Clinical Oncology (2014)

2625 Background: Significant progress in therapy of non SCC of the lung has been made through genomic profiling and subtyping according to oncogenic drivers. In SCC, cisplatin-based therapy remains the mainstay, and resistance to treatment is common. We sought to understand the molecular underpinnings of cisplatin resistance in SCC. Methods: SCC of patients were characterized by Next-Generation Sequencing. In vitro drug sensitivity in lung SCC cell lines (n= 3) was determined by MTS assay, transcriptomic analysis was performed with microarray and signalling regulation was investigated with phospho-kinase array. Cisplatin-mediated cellular signalling identified by transcription and phospho-kinase array was validated in SCC cell lines by Western blotting (n= 3). Expression of p-Erk in SCC specimens was detected with IHC staining. Results: We verified the paucity of oncogenic driver mutations in 45 lung SCC specimens. H596, H1869, H226 and ChaGo-k-1 cell lines were deemed sensitive while Calu-1, H2170, SW900 and H2066 resistant to cisplatin. MAPK/Erk pathway proteins were up-regulated in resistant compared to sensitive cell lines by gene expression and phospho-kinase arrays. p-Erk1/2 was activated in cisplatin-resistant cell lines in increasing cisplatin doses, while gene silencing (siRNAs) and pharmacological inhibition (MEK inhibitors) of Erk1/2 reversed cisplatin resistance and enhanced cisplatin sensitivity in lung SCC cells. High p-Erk1/2 expression in HNSCC tumours was found correlated with shorter progression-free survival of SCC patients treated with cisplatin. Conclusions: Our data suggest that 1) therapeutic targeting of MAPK/Erk signalling is potentially effective in abrogating cisplatin resistance in SCC, and 2) p-Erk1/2 is a predictive biomarker for cisplatin treatment in SCC tumours.
Determinants of long-term outcome in patients undergoing simultaneous resection of synchronous colorectal liver metastases.
Authors: Jianmin Xu, Qi Lin, Dexiang Zhu
Journal: Journal of Clinical Oncology (2014)

e14593 Background: Simultaneous resection has been shown to be safe and effective in patients with synchronous colorectal liver metastasis (SCRLM), but which patients can get benefit from simultaneous resection remains unclear. Methods: We retrospective analyzed 154 prospectively collected SCRLM patients who underwent simultaneous resection between July 2003 and July 2013, the clinicopathologic data was analyzed with univariate and multivariate analysis. Results: Univariate analyses indicated that positive lymph nodes, vascular invasion, nerve invasion and BRAF mutation of colorectal cancer, number of liver metastases (LMs) (≥4), bilobar LM distribution, non-R0 resection of LMs and CEA level (>20 ng/ml) were significantly associated with poor overall survival (OS); tumor deposits, BRAF mutation, No. of LMs (≥4), bilobar distribution and extrahepatic metastasis resection were significantly associated with shorter disease-free survival (DFS). Multivariate analysis indicated, OS was significantly affected by positive lymph node status, vascular invasion, BRAF mutation, bilobar LM distribution and non-R0 resection of LMs. DFS was significantly affected by tumor deposits, BRAF mutation and bilobar LM distribution. We established clinical risk score (CRS) using these 5 predictors for OS and 3 predictors for DFS (each predictor equal to one point). Compared with a low CRS (0-2) and (0-1), a high score (≥3) and (≥2) was found to be highly predictive of short OS and DFS, respectively. Conclusions: Low CRS is an important determinant of long-term outcomes for the CRLM and suitable for simultaneous resection.
Reductions in <i>JAK2</i>V617F allele burden with ruxolitinib treatment in COMFORT-II, a phase III study comparing the safety and efficacy of ruxolitinib to best available therapy (BAT).
Authors: Alessandro M. Vannucchi, Jean-Jacques Kiladjian, Heinz Gisslinger, Francesco Passamonti, Haifa Kathrin Al-Ali, L. Andres Sirulnik, Viktoriya Stalbovskaya, Matthew Squires, Deborah S. Hunter, Timothy Burn, Laurent Knoops, Francisco Cervantes, Tiziano Barbui, Giovanni Barosi, Claire N Harrison
Journal: Journal of Clinical Oncology (2012)

6514^ Background: Ruxolitinib is a potent and selective JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF) based on results of the phase 3 COMFORT studies. Ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life of patients (pts) with MF. Since one measure of efficacy is molecular response, this analysis correlates changes in mutant allele burden (%V617F) with spleen size reduction in COMFORT-II. Methods: COMFORT-II is a randomized, open-label, phase 3 study comparing ruxolitinib 15 or 20 mg twice daily (BID) with BAT. The primary endpoint was a ≥ 35% reduction in spleen volume from baseline (BL) at week 48. Change in %V617F was measured by allele specific qPCR. Pts were stratified by reduction in %V617F (&lt; 10%, 10-20%, &gt; 20%) and results were correlated with achievement of the primary endpoint. Results: More pts in the ruxolitinib arm had ≥ 10% V617F reductions compared with BAT (41% vs 5%; P = .01; Table). The majority of reductions &gt; 20% were gradual and progressive over the course of the study; 2 pts had rapid reductions from 48% to 1% and 45% to 9% over 48 weeks. In the ruxolitinib arm, significantly more pts with a &gt; 20% V617F reduction achieved the primary endpoint compared with pts with a &lt; 10% reduction (79% vs 30%; P = .004); in each group, gender did not affect spleen response. For pts with &lt; 10% reductions (15 mg BID, n = 16; 20 mg BID, n = 24), the average total daily dose (TDD) was ruxolitinib 29.6 mg; pts with &gt; 20% reductions (15 mg BID, n = 3; 20 mg BID, n = 11) had a TDD of 35.3 mg. Conclusions: Pts who received ruxolitinib had larger reductions in JAK2V617F allele burden compared with BAT. %V617F reductions were gradual over the course of the 48-week study; longer follow-up is needed to determine the extent of allele burden reduction. [Table: see text]
Reactivation of p53 mutant protein by PRIMA-1 and induction of apoptosis in pancreatic cancer cells.
Authors: Patricia Izetti, Agnes Hautefeuille, Ana Lucia Abujamra, Caroline Brunetto de Farias, Rafael Roesler, Gabriel de Souza Macedo, Barbara Alemar, Guido Lenz, Alessandro Bersch Osvaldt, Pierre Hainaut, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2012)

e13546 Background: Inactivating TP53 mutations are common events in different types of cancers, including pancreatic adenocarcinoma, where it occurs in as much as 70% of cases. Accumulation of mutant p53 provides a molecular target that may be reactivated into a conformation capable of arresting tumor growth. The small molecule PRIMA-1 (p53 reactivation and induction of massive apoptosis) has been shown to selectively induce apoptosis in tumor cells by reactivating some p53 mutants, but no previous studies have investigated its effects in pancreatic cancer. Methods: PANC-1 (mutant TP53 R273H) and CAPAN-2 (wild-type TP53) pancreatic cell lines were used as in vitro models. We tested the effects of PRIMA-1 on cell viability (MTT assay), apoptosis (morphology, AnnexinV/FITC-FACS), cell cycle (BrdU incorporation) and expression of p53 regulated proteins by western blotting. As control of p53-dependent effects, PANC-1 cell lines were transfected with siRNA against TP53 (sip53). Results: PRIMA-1 selectively induced apoptosis in PANC-1 cells compared to CAPAN-2 cells and this effect was concomitant with an increase in the levels of MDM2, Bax and cleaved caspase-3 as detected by western blot analysis. Treatment with PRIMA-1 for 24h induced a 50% reduction in DNA synthesis whereas G2/M arrest was detected after 12h of treatment. p53 silencing in PANC-1 decreased the cytotoxicity of PRIMA-1, characterizing a p53-dependent effect. Finally, N-acetylcysteine completely blocked PRIMA-1-induced growth suppression and apoptosis, suggesting that PRIMA-1 exerts its effect at least in part via restoring redox-dependent effects to mutant p53. Conclusions: Our data indicate that PRIMA-1 induces apoptosis in TP53 mutant pancreatic cancer cells by promoting the re-activation of p53 and subsequent of proapoptotic signaling pathways, suggesting a possible mechanism for effective targeting of pancreatic cancer.
A phase 1 study evaluating the safety and efficacy of DKN-01, an investigational monoclonal antibody (Mab) in patients (pts) with advanced non-small cell lung cancer.
Authors: William Jeffery Edenfield, Donald A. Richards, Svetislava J. Vukelja, Glen J. Weiss, Cynthia A. Sirard, Steven B. Landau, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2014)

8068 Background: DKN-01 is a high affinity neutralizing humanized Mab targeting extracellular dickkopf-1 (Dkk-1). Dkk-1 inhibits the canonical Wnt/β-catenin signaling pathway and modulates other biological pathways required for cell growth/ differentiation. Prior studies have demonstrated elevated Dkk-1 expression in lung, esophageal and gastric cancer tissue. Preclinical studies have demonstrated that a reduction of free Dkk-1 led to clinical benefit in xenograft models. Methods: A two-part (A and B) phase I, dose-finding study determined safety, maximum tolerated dose and antitumour activity infusing DKN-01 to pts with advanced malignancies with emphasis on pts with non-small cell lung cancer (NSCLC). Other endpoints were progression free survival [PFS], overall response rate [ORR], and overall survival [OS]. Part A of the study tested intravenous (IV) DKN-01 at dose levels between 75 and 600 mg administered weekly or biweekly in a 28 day cycles. For Part B, DKN-01 was administered to refractory NSCLC pts at 300 mg IV on days 1 and 15 of every 28 day cycle. Results: 32 pts enrolled in Parts A and B; 24 with NSCLC. NSCLC pts: median age 64.5 yrs, 54% male, 75% ECOG PS1, 4 median prior therapies (1-7), and 63% adenocarcinoma. DKN-01 was well tolerated with no dose limiting toxicities (DLT) or related serious adverse events (SAE). All of the treatment related AEs were ≤ Grade 2. Treatment emergent adverse events (TEAE) ≥ 15% in decreasing frequency: nausea, fatigue, decreased appetite, dyspnea, vomiting and constipation. No TEAE led to study discontinuation. Responses in 22 evaluable NSCLC pts included partial response 4.2% and stable disease 42%. One NSCLC patient had confirmed complete resolution of target disease. Median PFS in 23 evaluable NSCLC pts was 2.2 months [95% CI 1.8-2.9]. NSCLC median OS was 6.6 months (95% CI 4.1-10.1). Conclusions: DKN-01 may be a promising innovative targeted treatment for NSCLC. DKN-01 monotherapy was extremely well tolerated and demonstrated clinical activity in pts with refractory NSCLC. The median PFS and safety profile suggest that further NSCLC development in combination with other agents is warranted. Clinical trial information: NCT01457417.
Ex vivo activation and expansion of γδ T cells for immunotherapy of glioblastoma
Authors: C. Suarez-Cuervo, N. L. Bryant, R. D. Lopez, G. Y. Gillespie, L. S. Lamb
Journal: Journal of Clinical Oncology (2006)

2553 Background: Activated γδ T cells will efficiently kill established glioblastoma (GBM) cell lines in vitro. However, their potential for cell therapy has been limited by their relatively small numbers in the peripheral blood and their sensitivity to activation induced cell death (AICD) during ex vivo expansion. Our laboratory developed a method whereby γδ T cells, when stimulated by IFN-γ, IL- 12, and anti-CD2, acquire resistance to AICD and can be expanded in culture with anti-CD3 and IL-2. The γδ T cells expanded by this method are highly cytotoxic to GBM. We have now sought to adapt the laboratory method for human use. Methods: The laboratory method and selection procedure were modified to employ pharmaceutical-grade reagents. Peripheral blood mononuclear cells (1.0 × 106/ml) were stimulated overnight with media containing cGMP grade human serum, IFN-γ, IL-12, and anti-CD2. Media containing human serum, IL-2 and anti-CD3 was then added (1 v/v) and refreshed 1 v/v 3× weekly. The cultures were harvested after two weeks followed by depletion of CD4+ and CD8+ T cells, thereby enriching γδ T cells. Cytotoxicity of expanded of γδ T cells was evaluated against GBM primary tumor cultures, established GBM cell lines, and cultured astrocytes using a commercial flow cytometric method. Results: After two weeks in culture, γδ T cells expanded up to 1000 fold (usually 200–400 fold), consistent with results from our previous research-scale method. Positive selection yielded a γδ T cell product with &gt;80% purity and &gt;70% recovery. The cell products exhibited incremental cytotoxicity against several primary GBM cultures and established GBM cell lines. Astrocytoma cells were not killed. Conclusions: Apoptosis-resistant γδ T cells can be expanded and selected using clinically approvable reagents and in numbers sufficient for immunotherapy of malignant brain tumors. Initial data show that expanded γδ T cells retain cytotoxicity against the GBM primary cultures and spare normal astrocytes. No significant financial relationships to disclose.
A phase I study of carboxyamidotriazole orotate (CTO) in of advanced solid tumors.
Authors: Alan Sandler, Matthew Hiram Taylor, Walter John Urba, Antonio Marcilio Padula Omuro, Barry Douglas Anderson, Daniel Hansen, Brenda Fisher, Alisa J Claeys, Amy Greathouse, Sean McLean, Rashida A. Karmali
Journal: Journal of Clinical Oncology (2013)

2518 Background: CTO is an orotate salt of carboxyamidotriazole (CAI), which is an inhibitor of calcium-dependent intracellular and extracellular signal transduction pathways (presumably affecting VEGF and PI3K) and has tumor anti-proliferative and anti-invasive properties. The activity of CTO alone and in combination with temozolomide or 5Efluorouracil was demonstrated in human glioblastoma, melanoma, and colon tumor xenografts. Methods: This study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics and activity of CTO monotherapy in 34 patients (pts) with advanced solid tumors meeting eligibility criteria with adequate organ function. The CTO study NCT01107522 enrolled pts in 8 cohorts receiving continuous daily oral CTO capsules at doses ranging from 50mg- 555mg/m 2 /day. The MTD has not been determined. Pharmacokinetic (PK) sampling was performed during cycle 1 at each dose level. CT scans were performed at baseline and after 8 weeks to assess anti-tumor effect. Patients remained on study if they achieved stable disease (SD) or tumor response and did not experience dose limiting toxicities (DLT). Results: The most frequently recorded adverse events (Grade 1 and 2) were fatigue, nausea, vomiting, and dizziness. DLTs of grade 3 fatigue (219 mg/m2) and grade 3 creatine kinase elevation (555 mg/m 2 ) occurred in one pt each. No cardiac QTc prolongations have been recorded. PK data demonstrated therapeutically relevant CAI levels beginning at the 219mg/m 2 dose. Nine pts continued CTO dosing beyond 2 cycles. Tumor assessments demonstrated SD at different doses of CTO: i) 75mg/m 2 renal carcinoma (1, 12 cycles); ii) 219 mg/m 2 -small cell lung cancer (1, 4 cycles), squamous cell lung cancer with PIK3CA mutation (1, 10 cycles and continuing), and lung adenocarcinoma with EGFR mutation (1, 10 cycles and, continuing); iii) 285 mg/m 2- 1 colon cancer with BRAFV600E mutation (1, 6 cycles), and squamous cell carcinoma (tonsil) with PI3KCA and NRAS mutations (1, 9 cycles, and continuing). Conclusions: CTO given as monotherapy up to 555mg/m 2 /day is safe and tolerable and without MTD. Six patients with different malignancies and genomic markers achieved SD; combinatorial investigations in malignant gliomas have started. Clinical trial information: NCT01107522.
A randomized controlled trial to compare the effectiveness between surgery and radiofrequency ablation for hepatocellular carcinoma: SURF trial.
Authors: Kiyoshi Hasegawa, Norihiro Kokudo, Yutaka Matsuyama
Journal: Journal of Clinical Oncology (2017)

TPS506 Background: Which is superior to treat hepatocellular carcinoma (HCC), surgery or percutaneous ablation? This has been one of the most important questions in clinical research of hepatology. However, it has long remained unanswered because it is difficult to approach, as we mentioned previously (Ann Surg 2008;247:557-8). Thus, in 2009, we started this multicenter study in Japan to reach a strong conclusion to the above question (UMIN:000001795). Methods: The major inclusion criteria are: tumor foci numbering three or fewer, and each measuring 3 cm or less); Child–Pugh score of 7 or less; aged between 20 and 79 years; and indications for either surgical resection or radiofrequency ablation (RFA), as described previously (Hepatol Res 2010;40:851-2). In the study design, we adopted two co-primary end-points: overall survival (OS) and recurrence-free survival (RFS). If assuming 3-year RFS following surgery and RFA are assumed as 45% and 35%, respectively, 600 cases are regarded as necessary. Because 600 cases would be also sufficient to detect 10% difference in OS, the target number of cases was set as 600. However, the recruitment was very difficult. The Independent Data Monitoring Committee recommended us to transiently stop the recruitment at the end of August 2015 when the number of the registered cases reached 308. At submission of this abstract, we are considering whether the current number (308) is enough or not to detect 10% difference in RFS by calculating conditional predictive power. We will describe the trial design, and the current situations in detail for debate. Clinical trial information: UMIN:000001795.