tbuckley/cabot-search huggingface dataset:
Propensity score matched analysis of neoadjuvant therapy for resectable pancreatic cancer.
Authors: Kenneth L Meredith, Jamie Huston, Anjan Jayantilal Patel, Richard H. Brown, Fadi Kayali, Kevin Koehler, Ravi Shridhar
Journal: Journal of Clinical Oncology (2017)

381 Background: Neoadjuvant therapy (NT) for resectable pancreatic cancer continues to be debated. There is little data to demonstrate survival benefit over patients who were treated with up front surgery (UFS) vs NT. We sought to examine the impact of neoadjuvant chemotherapy (NCT), neoadjuvant chemoradiation (NCRT), and UFS on survival in pancreatic cancer patients. Methods: The NCDB was accessed to identify patients with pancreatic adenocarcinoma. Propensity score matching (PSM) was performed against age, tumor size, margin status, and institutional surgery volume. Patient characteristics (continuous and categorical variables) were compared using Mann-Whitney U, Kruskal Wallis and Pearson’s Chi-square test as appropriate. Survival analyses were performed using the Kaplan-Meier method. Multivariable cox proportional hazard models (MVA) were developed to identify predictors of survival. All statistical tests were two-sided and α &lt; 0.05 was considered significant. Results: After PSM, 5,034 patients (UFS 2,517; NT 2,517: 1,143 NCT and 1,374 NCRT) were included in the analysis. There was no difference in age, tumor size, or grade among cohorts. The mean nodes positive were 1.6 ± 2.6 in NT and 2 ± 3.3 in UFS, p = 0.02. In the pre-matched cohort R0 resections were performed in 75.9% UFS, 82.9% NCRT, and 79.6% NCT, p &lt; 0.001. The median and 5 year survival for NCT, NCRT and UFS was 28.6 months and 25.2%, 25.7 months and 22.2%, and 21.3 months and 21.7%, p &lt; 0.001. Adjuvant therapy (chemotherapy (CT) or CRT) in the UFS did demonstrate a survival benefit 22.5 months vs 18.6 months, p &lt; 0.001, however this did not benefit NCT or NCRT, p = 0.8 and p = 0.8 respectively. Additionally survival in the UFS with adjuvant therapy either CT or CRT was still decreased compared to either NCT or NCRT, p &lt; 0.001 and p = 0.001 respectively. MVA demonstrated that age, T-stage, lymph nodes positive, R0 resection, grade, NCT and NCRT were predictors of survival. Conclusions: Neoadjuvant therapy improves survival in resectable pancreatic cancer patients. NCT and NCRT demonstrated survival benefit compared to UFS even with adjuvant therapy. Patients with resectable pancreatic cancer should be considered for neoadjuvant therapy.
Mechanisms of resistance to PDGFR inhibition in glioblastoma.
Authors: Sandra Pastorino, Emma J. Langley, Ying Chao, Pengfei Jiang, Rajesh Mukthavaram, Sandeep C. Pingle, Phillip Sangwook Kim, Sharat Singh, Santosh Kesari
Journal: Journal of Clinical Oncology (2014)

e13030 Background: Recent reports suggest that normal stem or progenitor cells undergo oncogenic transformation. It is possible that cellular programs governing normal lineage development also drive tumorigenesis. PDGF/PDGFRA signaling plays an important role in brain development. Interestingly, it has also been widely implicated in the pathogenesis of brain tumors. TCGA data has revealed that overexpression and/or amplification of PDGFRA is a key feature of the treatment-resistant proneural glioblastoma (GBM), which constitutes 20-30% of all GBM. However, targeting PDGFRA yields limited success in the setting of randomized clinical trials and in vitro studies employing stable tumor cell lines. Besides, clinical targeting of PDGFRA is associated with rapid development of resistance. Methods: In an effort to understand primary and secondary resistance to PDGFRA inhibitors in the clinic, we generated a model with acquired resistance to nilotinib. A patient-derived GBM cell line with PDGFRA amplification was grown in the presence of increasing concentrations of nilotinib over ~6 months. The resistant GBM model and its parental counterpart were evaluated for expression and activation of a variety of receptor tyrosine kinases (RTKs), including the ErbB family, cMET and IGF1R, as well as key players of AKT/PI3K and MEK/ERK pathways using a highly sensitive multiplexed immunoassay. Results: Our data show that patient-derived GBM cells belonging to the proneural subtype are particularly vulnerable to PDGFRA inhibition, in vitro and in vivo. When probed by the multiplex immunoassay, we observed striking modulations in RTK and downstream signaling, in particular enhancement of cMET (expression/activation) in the resistant setting while other RTKs were down-regulated. The mechanistic implications of these differences and how they may contribute to nilotinib resistance are under investigation. Conclusions: It is clear that GBM cells recruit multitude of signaling pathways in order to induce resistance to PDGFRA inhibition. An in-depth understanding of the molecular mechanisms may prove critical to overcoming resistance and effectively targeting GBM in the clinic.
Impact of the primary information source used for decision making and implications for treatment regret in prostate cancer.
Authors: Narek Shaverdian, Amar Upadhyaya Kishan, Darlene Veruttipong, D. Jeffrey Demanes, Patrick Kupelian, Susan Ann McCloskey, Michael L. Steinberg, Christopher R. King
Journal: Journal of Clinical Oncology (2017)

17 Background: Patients with localized prostate cancer (PCa) assimilate information from varying sources to inform their treatment decision. We assessed the impact of the primary information source used to select a modern radiation treatment on patient perceptions of their treatment experience and on treatment regret. Methods: Patients with favorable-risk PCa treated with SBRT, IMRT or HDR brachytherapy and at least one year of follow-up were surveyed. The questionnaire explored the decision-making experience, expected treatment experience vs. the reality, and treatment regret via a validated tool. Multivariate logistic regression adjusted for demographics, disease characteristics, treatment modality, time since treatment and current bowel, urinary and sexual function. Results: 322 consecutive patients were surveyed with an 86% (n = 276) response rate. 48% (n = 132) selected their radiation oncologist as the primary information source, 23% (n = 62) selected their urologist, 16% (n = 44) selected the internet, 6% (n = 17) selected other patients and 8% (n = 21) selected other. Overall, 13% (n = 36) endorsed treatment regret. 39% of patients who selected the internet as their primary information source reported their actual treatment experience to be worse than expected vs. 13% of respondents who selected their urologist, 12% who selected other patients, 2% who selected their radiation oncologist and 9% who selected other ( p&lt; 0.01). Similarly, 43% who selected the internet as their primary information source endorsed treatment regret vs. 10% who selected their urologist, 7% who selected their radiation oncologist, 6% who selected other patients and 6% who selected other ( p&lt; 0.01). On multivariate logistic regression, only patients who selected the internet as their primary information source were more likely to endorse treatment regret (OR = 46.5, p&lt; 0.01) and were more likely to choose a treatment they thought ‘had the least side effects’ (OR = 2.1, p= 0.016). Conclusions: Patients who used the internet as their primary source of information had a worse perception of their treatment experience and had more treatment regret, highlighting the need for physicians to proactively counsel patients.
Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study.
Authors: Eleftheria A Anastasopoulou, Efi Pappou, Panagiotis Tzonis, Alexandros Ardavanis, Sathibalan Ponniah, Constantin N. Baxevanis, James L. Murray, Michael Papamichail, Sonia A. Perez, George Earl Peoples, Elizabeth Ann Mittendorf
Journal: Journal of Clinical Oncology (2013)

3095 Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk node-negative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS). Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3+ or FISH &gt; 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37+GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-γ ELISPOT assays. Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-γ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9±3.13 at completion of the PVS (R6) and increased to 35.47±4.35 at BRC24 (p=0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97±0.046 at baseline (R0) before vaccination to 2.27±0.57 at R6 (p=0.0003) which was maintained until BRC24 (SI 2.21±0,33, p&lt;0.0001). The number of IFN-γ specific spots/10 6 PBMC increased from 26.88±12.36 at R0 to 40.35±17.02 (p=0.07) at R6, up to 62±16.82 (p=0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated. Clinical trial information: NCT00524277.
Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies
Authors: Daryl J Wile, Pankaj A Agarwal, Michael Schulzer, Edwin Mak, Katherine Dinelle, Elham Shahinfard, Nasim Vafai, Kazuko Hasegawa, Jing Zhang, Jessamyn McKenzie, Nicole Neilson, Audrey Strongosky, Ryan J Uitti, Mark Guttman, Cyrus P Zabetian, Yu-Shin Ding, Mike Adam, Jan Aasly, Zbigniew K Wszolek, Matthew Farrer, Vesna Sossi, A Jon Stoessl
Journal: The Lancet Neurology (2017)
Rituximab-Lenalidomide (REVRI) in Relapse or Refractory Primary Central Nervous System (PCNSL) or Vitreo Retinal Lymphoma (PVRL): Results of a "Proof of Concept" Phase II Study of the French LOC Network
Authors: Herve Ghesquieres, Caroline Houillier, Olivier Chinot, Sylvain Choquet, Cecile Molucon-Chabrot, Patrick Beauchene, Remy Gressin, Franck Morschhauser, Anna Schmitt, Emmanuel Gyan, Khê Hoang-Xuan, Emmanuelle Nicolas-Virelizier, Marion Chevrier, Alexia Savignoni, Isabelle Turbiez, Florence Veillas, Vassili Soumelis, Carole Soussain
Journal: Blood (2016)
OPTIMA prelim: Optimal personalized treatment of early breast cancer using multiparameter tests.
Authors: Rob Stein, Andreas Makris, Luke Hughes-Davies, Amy Frances Campbell, Andrea Marshall, John M. S. Bartlett, Jenny Donovan, Christopher McCabe, David A. Cameron, Peter Canney, Adele Francis, Adrienne Morgan, Sarah Pinder, Daniel Rea, Peter Hall, Nigel Stallard, Helen B Higgins, Claire Hulme, Victoria Harmer, Janet A. Dunn
Journal: Journal of Clinical Oncology (2013)

TPS656 Background: Chemotherapy may have little effect on some subtypes of early breast cancer, identified as being hormonally responsive tumours without HER2 gene amplification and with a low or intermediate grade. Multi-parameter genomic tests such as Oncotype DX are increasingly used to identify patients for whom the addition of chemotherapy may confer little additional benefit. OPTIMA has an adaptive design seeking to advance development of personalised medicine in breast cancer by assessing the value of multi-parameter tests in a UK population of intermediate risk. Methods: OPTIMA prelim, the feasibility phase, has 3 objectives: (1) To evaluate performance and health-economics of multi-parameter tests to determine which test(s) will be used in the main trial; (2) To establish efficient and timely sample collection and analysis essential to deliver multi-parameter test driven treatment; (3) To establish the acceptability to patients and clinicians of randomisation to test-directed treatment assignment. OPTIMA prelim aims to recruit 300 patients with ER+ve HER2-ve tumours with involved nodes (pN1-2). Patients are randomized to the standard arm of chemotherapy with endocrine therapy, or to the “test-directed treatment” arm assigned to either the same chemotherapy with endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. The decision to continue to a main trial will be determined by concordance, cost and willingness of patients to be randomized to test guided treatment. Cost-effectiveness models will be based on the model developed in preparation for the OPTIMA trial, updated with contemporary evidence from the feasibility study and appropriate external data, e.g. the Ontario prospective cohort study. Results: Optima opened in Sept 2012 with 25 centres involved. To date 22 patients are registered, of which 17 have been randomised. Patient focus groups show the trial design is acceptable and has potential to reduce need for chemotherapy. TSC and DMEC agree that this is an important trial testing the feasibility within this patient population. Decision rules are challenging for this study but employment of adaptive designs gives the flexibility needed for the main trial. Clinical trial information: ISRCTN42400492.
Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis.
Authors: Bruno Sangro, Todd S. Crocenzi, Theodore Hobart Welling, Mercedes Iñarrairaegui, Jesús Prieto, Carmen Fuertes, Laurie Delanty, William Feely, Jeffrey Anderson, Dennis M. Grasela, Jon M. Wigginton, Ashok Kumar Gupta, Ignacio Melero
Journal: Journal of Clinical Oncology (2013)

TPS3111 Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA &lt;100 IU/mL) for ≥3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.
Phase I/II study of percutaneous vertebroplasty (PVP) for painful malignant vertebral compression fracture(PMVCF): JIVROSG- 0202
Authors: Y. Arai, K. Kobayashi, Y. Takeuchi, Y. Nakajima, Y. Shioyama, M. Sone, N. Tanigawa, O. Matsui, M. Kadoya, Y. Inaba
Journal: Journal of Clinical Oncology (2007)

9118 Backgrounds: This multi-center prospective study was conducted to evaluate the safety and efficacy of PVP, a new treatment modality for PMVCF, using techniques of interventional radiology. Methods: Enrolled patients (pts) had PMVCF by primary or metastatic tumor; restricted activities by PMVCF; tumor not exposed into spinal canal; adequate hematologic, hepatic, renal and cardiac functions; 0–3 ECOG performance status (PS); estimated prognosis over 4 weeks; and written consent. In phase I, 9 pts were enrolled; in phase II, 24 pts. Safety and efficacy were evaluated by NCI-CTC Ver. 2 and Visual Analogue Scale (VAS) at week 1 after PVP, respectively. By VAS score decreases, efficacy was classified into significantly effective (SE: =5 or reached 0–2), moderately effective (ME: 2–4), or not effective (NE: &lt;2 or increase). Response rate was the ratio of pts with SE or ME in total pts. PVP was performed by insertion of 14–16 G bone biopsy needle into fractured vertebral body (FVB) using fluoroscopy or CT guidance, injection of bone cement (BC) under real time imaging observation, and discontinuation of BC injection at its distribution to adequate area of FVB or into extra bone space. Results: Procedures were completed in all 33 patients with 42 PMVCF. PS of pts was 0 in 1, 1 in 7, 2 in 12 and 3 in 13. In 30 days after PVP, 2 patients died of primary disease progression, but no major adverse reaction (&gt;Grade 2) was observed. Response rate was 73% (56–85% in 95% CI) (61% (n=20) with SE; 12% (n=4) with ME; 27% (n=9) with NE), and increased to 83% at week 4. Median to PVP effect was 1 day (mean: 2.4). Median pain controlled survival was 73 days. Conclusion: For PMVCF, PVP is a safe and effective treatment modality with immediate responses. A phase III trial comparing PVP and standard radiation therapy is planned to evaluate PVP as the front line treatment. No significant financial relationships to disclose.
Non-invasive Oil-Based Method to Increase Topical Delivery of Nucleic Acids to Skin
Authors: Manika Vij, Shamshad Alam, Nidhi Gupta, Vishvabandhu Gotherwal, Hemlata Gautam, Kausar M. Ansari, Deenan Santhiya, Vivek T. Natarajan, Munia Ganguli
Journal: Molecular Therapy (2017)
Pre-clinical translational studies of daratumumab in patients with myeloma or AL amyloidosis undergoing autologous hematopoietic stem cell transplantation (SCT).
Authors: Chakra Pani Chaulagain, Xun Ma, Parul Doshi, Sandy Wai Kuan Wong, Andreas Kirschmer Klein, Kellie A. Sprague, Ping Zhou, Ray Comenzo
Journal: Journal of Clinical Oncology (2015)

8587 Background: Daratumumab (DARA) is a human IgG1 that binds to CD38 and kills tumor cells expressing CD38 through immune-mediated cytotoxicity. CD38 is expressed on plasma cells in multiple myeloma (MM), AL amyloidosis (AL) and on myeloid progenitor cells. Since SCT remains a standard therapy for MM and AL the effect of DARA on progenitor cells was evaluated. Ability of DARA to induce complement dependent cytotoxicity (CDC) of progenitor cells was assessed in progenitor cell assay (PCA). DARA-mediated antibody-dependent cytotoxicity (ADCC) of progenitor cells, its correlation with FcγRIIIA polymorphism and stem cell potential were examined using NK-cells from post-SCT patients (n = 10, n = 6 MM and n = 4 AL) as effectors against a MM target cell line. Methods: ADCC was performed with post-SCT NK cells and MM.1S cells in the presence of 100 ng/ml DARA or isotype control (ICA). DARA-mediated CDC was evaluated in PCA: unselected or CD34-selected mobilized cells were incubated in complement-rich serum with no antibodies, or DARA or anti-CD59 (BRIC 229) or both. The effects of these antibodies on CFU-GM and BFU-E were evaluated two weeks later. The results were analyzed by two-tailed paired t tests with P < 0.05 as significance level. Results: MedianADCC of MM.1S target cells by primary post-SCT NK cells was 39% and 7% using DARA or ICA, respectively (P < 0.05). Of the 10 NK donors, 6 were V/F or V/V and lysed 60% of targets, while 4 F/F lysed 17% (P< 0.05). In the PCA, there was no decrease in CFU-GM or BFU-E: with unselected mobilized cells, with CD34-selected cells with DARA, or with CD34-selected cells incubated with DARA (500 or 1000 ng/ml) +/- BRIC 229 indicating that DARA did not induce CDC on the CD34-selected progenitor cells. Conclusions: DARA is active in ADCC assays with post-SCT NK cells from patients with MM or AL and its activity correlates with FCGR3A-158V/F polymorphism. DARA did not inhibit progenitor cell growth by CDC in unselected or CD34-selected cells suggesting that administration of DARA may not cause undue harm to the progenitor cells after SCT. These findings support consideration of clinical trials of DARA consolidation post-SCT in MM and AL. CPC: MMRF fellow.