tbuckley/cabot-search huggingface dataset:
Risks and benefits of phase I trials: Eighteen-year experience from a single institution.
Authors: Audrey E. Kam, Imran Chaudhary, Mohammad Haroon Ghalib, Umang H. Shah, Umang Swami, Dennis Yi-Shin Kuo, Caroline Hwang, Tarek N. Elrafei, Bruce Cohen, Benjamin Adam Gartrell, Elizabeth Kaledzi, Jennifer W. Chuy, Haiying Cheng, Lakshmi Rajdev, Missak Haigentz, Sridhar Mani, Sanjay Goel
Journal: Journal of Clinical Oncology (2017)

e18146 Background: Phase I trials are a critical component of drug development; yet are considered non-therapeutic. This leads to recruitment barriers due to provider and patient discomfort. The largest meta-analysis of phase I studies has previously shown a response rate (RR) of 10.6%. Herein we report the results from our institution. Methods: Records of patients enrolled on phase I trials at our institution from January 1999 to December 2016 were reviewed. Recorded data included adverse events (AE); treatment related responses and deaths. Kaplan-Meier analysis and t-test were performed on the reviewed data. Results: During this period 774 patients were accrued on 64 phase I trials [43.8% cytotoxic, 45.3% biological, 6.2% both and 4.7% viral agents]. Primary cancer diagnoses included colorectal (25.2%), ovarian (17.6%), lung (7.8%), uterine (6.6%) and breast (6.1%). In total, 609 patients were evaluable for response, 41.1% had stable disease (SD) and overall RR was 7.7% (complete RR = 1.0%). Patients with overall clinical benefit (SD+response) had lower mean baseline WBC (4.83 vs 5.94 k/uL, p = 0.0008), ANC (2.92 vs 4.12 k/uL, p = 0.00007), platelets (209 vs 246 k/uL, p = 0.00007), LDH (280 vs 346 U/L, p = 0.0055) and higher serum albumin (3.97 vs 3.86 g/dL, p = 0.011) as compared to patients with progressive disease. Grade 3/4 non-hematological and hematological AE were seen in 28.5% and 19.9% patients, respectively. Treatment-related mortality was 0.8%. Patients with baseline LDH below the median (247 U/L) for the cohort had a higher median survival (312 days vs 201 days, p &lt; 0.001, HR 0.61 95% CI 0.51-0.73). The median and mean duration on study were 56 and 87 days, respectively. Conclusions: This is one of the largest single-institution series of phase I oncology trials. Our RR of 7.7% [95% CI 5.9-10.1%] falls within the 95% CI of the RR of a majority of third line (and greater) chemotherapy regimens for solid tumors. Thus, the concept of 'non-therapeutic' nature of phase I studies needs reconsideration.
Association of familial disease status with inferior treatment outcome in patients with Waldenstrom’s macroglobulinemia.
Authors: Z. R. Hunter, C. Hanzis, L. Ioakimidis, C. Tripsas, R. J. Manning, C. J. Patterson, P. Sheehy, B. Turnbull, S. P. Treon
Journal: Journal of Clinical Oncology (2011)

8073 Background: Previous studies by us and others support a familial predisposition in certain patients with Waldenstrom’s Macroglobulinemia (WM). The incidence, as well as clinical implications for familial WM disease need to be clarified. Methods: We sought to delineate the relative incidence of familial and sporadic WM in a large population of WM patients, as well as treatment outcomes resulting from the presence of familial disease. As part of these efforts, we examined the impact of familial disease status on a well defined WM patient population whose treatment outcome was previously reported, and who were rituximab-naïve, and received a rituximab containing regimen. WM patients with familial disease were defined as those individuals who had a first or second degree relative with a B-cell disorder. Results: Among 924 consecutive patients seen at our center, 254 (27.4%) reported having a first or second degree relative with a B-cell disorder, including 45 (4.9%) patients with > 1 case of WM in their family. One-hundred-thirty-five patients were rituximab-naïve, and received a rituximab containing regimen with either cyclophosphamide, fludarabine, IMID, or bortezomib. Of these patients, 36 (26.7%) and 99 (73.3%) had familial and sporadic WM disease, respectively. No differences in age, baseline IgM, hemoglobin, platelet count, serum B2M, WM IPSS score, or treatment regimen received was observed amog these patients. Overall (74.8% vs. 55.6%; p=0.032) and CR/VGPR (23.2% vs. 16.7%; p<0.0001) responses, time to progression (45.5 vs. 21 months; p=0.015), as well as time to next therapy (50.0 vs. 33.0 months; p=0.024) were greater among sporadic versus familial WM patients. Conclusions: Familial predisposition is common in WM, and associated with an inferior treatment outcome. Prospective studies examining the impact of familial disease status on treatment outcome in WM are warranted.
Long-Term Outcome Associated with Current Allogeneic Stem Cell Transplantation Procedures In Younger Adults with Adverse-Risk AML In First CR – A Real-Life Transplant Versus No-Transplant Analysis of the Acute Leukemia French Association (ALFA)
Authors: Marie-Anne Hospital, Xavier Thomas, Sylvie Castaigne, Emmanuel Raffoux, Sébastien Maury, Claude Gardin, Jean-Henri Bourhis, Oumedaly Reman, Stéphane de Botton, Thierry de Revel, Christine Terré, Claude Preudhomme, Cécile Pautas, Pierre Fenaux, Mauricette Michallet, Gérard Socié, Hervé Dombret
Journal: Blood (2010)
Involving patients to improve their care through real-time patient reported outcome (PRO)-CTCAE chemotoxicity surveys in an outpatient chemodaycare (DC) setting: Evaluating patient acceptability.
Authors: Hannah Solomon, Catherine Brown, Ashlee Vennettilli, Aein Zarrin, Aditi Dobriyal, Linda Chen, Vivien Pat, Anthea Ho, Cindy Xin, Margaret Irwin, TIan Qi Wang, Christina Gonos, Zahra Merali, Lauren Wong, Wei Xu, Doris Howell, Geoffrey Liu
Journal: Journal of Clinical Oncology (2014)

64 Background: In a busy DC setting, the efficiency of identifying important treatment toxicities is essential to quality care. Using a systematic approach to collecting patient-reported outcomes in the waiting rooms of DC units is one possible means of improving care while involving patients. This study reports such a pilot study, and the associated assessment of patient acceptance of this approach. Methods: 156 cancer patients over the age of 18 receiving chemotherapy treatment at Princess Margaret Cancer Centre completed a patient-reported chemotoxicity assessment using PRO-CTCAE items on tablet technology. Main symptoms assessed were: fatigue, nausea and vomiting, diarrhea and constipation, pain, aching muscles and/or joints and dysgeusia. Patient’s perception on the usefulness of PROMs and their willingness to complete such a tool routinely was assessed. Results: The median age was 53.5 (range: 19-88 years), 38% were male and 66% were Caucasian. Over 80% did not find the survey overly time consuming (or made their visit more difficult). Less than 1% were distressed by the survey questions. Over 80% reported that the survey asked the appropriate questions. While 81% considered the PROMs useful in informing their physician of their symptoms, 25% reported they would not be willing to complete the survey at each clinic visit. Another 25% were unsure of their feelings toward this approach. 93% were happy to complete the survey using tablet touchscreen technology. Conclusions: Most patients found the survey method of self-reporting one’s symptoms to be acceptable, non-distressful, and an important practice. From the patient perspective, the process of reporting one’s symptoms using tablet touchscreen technology is both simple and feasible.Yet, only 50% of patients would be willing to complete this survey at every clinic visit. Additional mixed-methods analysis looking at patient characteristics associated with acceptance/non-acceptance and willingness to complete the survey on a regular basis is ongoing and will be reported at the conference.
Efficacy of HER2-targeted therapy for patients with HER2-positive breast cancer according to hormone receptor status.
Authors: Takeshi Murata, Maiko Takahashi, Tetsu Hayashida, Hiromitsu Jinno, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2013)

97 Background: Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-positive tumors generally cluster within the luminal/HER2 subset; whereas HR-negative/HER2-positive tumors reside in HER2-enriched subset. We investigated whether the efficacy of HER2-targeted therapy for HER2-positive tumors differs by HR status. Methods: Sixty-eight patients with operable breast cancer received trastuzumab plus taxane based therapy before surgery at Keio University Hospital from March 2009 to April 2012. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, and Ki67 were performed by IHC in core needle biopsy samples at baseline. Pathological complete response (pCR) defined as no invasive residuals in breast. All patients with luminal/HER2 tumors received adjuvant endocrine therapy in addition to adjuvant trastuzumab monothereapy. Results: Sixty-eight patients with HER2-positive tumors were divided into 35 (51.5%) patients with luminal/HER2 tumors and 33(48.5%) patients with HER2-enriched tumors, respectively. There were no significant differences in tumor size, clinical nodal status, nuclear grade, and Ki67 status between the two groups. Clinical complete response rate and objective response rate were similar between the two groups. Patients with luminal/HER2 tumors were significantly younger than patients with HER2-enriched tumors (median age (range): 53 (35-78) vs. 61 (31-72), p=0.041). Compared to patients with luminal/HER2 tumors, patients with HER2-enriched tumors had significantly higher pCR rate (28.6% vs. 69.7%, p=0.002). With 24 months median follow-up, no significant differences were observed between the two groups with respect to disease-free survival. Estimated 2-year disease-free survival for luminal/HER2 and HER2-enriched was 94.3% and 97.0%, respectively (p=1.000). Conclusions: HER2-enriched breast cancer showed significantly higher pCR rate to HER2-targeted therapy compared with luminal/HER2 breast cancer. However, there was no significant difference in disease-free survival between the two groups.
Survival in Follicular Lymphoma: The Stanford Experience, 1960–2003.
Authors: Daryl Tan, Saul A. Rosenberg, Ronald Levy, Philip Lavori, Robert Tibshirani, Richard T. Hoppe, Roger Warnke, Ranjana Advani, Yasodha Natkunam, Alan Yuen, Sandra J. Horning
Journal: Blood (2007)
Use of decoy receptor 3 to block gemcitabine-induced apoptosis via binding with TRAIL in pancreatic cancer.
Authors: Wei Wang, Wenjie Lin, Xin Zhuang, Qingda Wang, Jinbing Luo
Journal: Journal of Clinical Oncology (2014)

238 Background: Most of human pancreatic cancer cell lines are resistant to chemotherapeutics-induced apoptosis including gemcitabine. This study is to address the role of decoy receptor3 (DcR3) in pancreatic cancer resistant to chemotherapeutics. Methods: siRNA targeted for DcR3 was used to down-regulate DcR3 expression in pancreatic cancer cells. On exploring for the pathway of DcR3 blocking Gemcitabine-induced apoptosis, up or down-regulated DcR3 level of pancreatic cancer cells were treated with Gemcitabine and apoptosis susceptibility was evaluated with apoptosis analysis. To investigate whether DcR3 is involved in TRAIL, FasL or LIGHT-mediated apoptosis, PARP and apoptotic cells staining were determined under different DcR3 level. Through ELISA-like binding analysis, immunoprecipitation and FACS, TRAIL binding with DcR3 was tested. In vivo experiment, it is to investigate whether down-regulation of DcR3 affects gemcitabine-induced apoptosis and tumor growth delay. Results: It demonstrates that DcR3 down-regulation sensitizes cells to gemcitabine-induced apoptosis and additional DcR3 level can impair gemcitabine-induced apoptosis in both of cells. It is proved that DcR3 blocks gemcitabine-induced apoptosis via binding with TRAIL which was thought not to bind with DcR3 previously. Furthermore, Regulation of DcR3 changes the amount of membrane-bound TRAIL which is correlated with gemcitabine-stimulation. In vivo experiment of AsPC-1 xenografts, stable down-regulation of DcR3 significantly enhances gemcitabine-induced apoptosis and tumor growth delay. Conclusions: DcR3 may play important role resistant to gemcitabine-induced apoptosis via binding with TRAIL in some of pancreatic cancer cells lines. Targeting DcR3 represents a promising strategy to enhance the anti-tumor activity of chemo-agent in pancreatic cancer, which has important clinical implications.
Targeted Microarray Analyses Augment the Clinical Cytogenetic Diagnosis of Acute Lymphoblastic Leukemia (ALL): Submicroscopic Genetic Events Improve Diagnosis, Contribute to Risk Stratification, and Provide Genetic Markers for Minimal Residual Disease (MRD) Testing
Authors: Marilyn L. Slovak, Yi Ning, Lei Yu, Stephen Hunger, Andrew J. Carroll, Theresa C. Brown, Lynda J Campbell, Meaghan Wall, Eric Crawford, Min Fang, Kathryn Kolquist, Reza Saleki, Lisa G Shaffer, Blake Ballif, Roger Schultz
Journal: Blood (2010)
Functional tumor reactive T cells in bone marrow and blood of pancreatic cancer patients
Authors: F. H. Schmitz-Winnenthal, P. Beckhove, C. Volk, V. Schirrmacher, B. Schmied, C. Gwerder, M. W. Büchler, K. Z’Graggen
Journal: Journal of Clinical Oncology (2005)

4113 Background: Memory T-cells specifically reactive to tumor antigens should be an ideal source to generate therapeutic effector cells against pancreatic cancer. To our knowledge functionally active, specific memory T-cells have not been demonstrated in pancreatic cancer patients. To investigate if functional memory T-cells are present in the bone marrow (BM) of pancreatic cancer patients, we performed in vitro stimulation with tumor associated antigens presented by autologous dendritic cells (DC). Methods: DC and T-cells were generated in a 14-day culture with GM-CSF and IL-4 (DC) and/or IL-2, IL-4, IL-7 (TC) from BM derived CD34+ progenitor cells of 35 patients with pancreatic carcinoma and chronic pancreatitis. DC were pulsed with lysate from autologous tumor cells, Muc I peptide - fragments and PBMCs (peripheral blood mononuclear cells as negative controls). Tumor specific T-cell response was evaluated in a single-cell interferon-γ-, IL4-, IL10- and IL12- release immunospot assay (Elispot). Cytotoxicity of CD8+ T-cells against primary cultured tumor cells was measured by a functional DNA-release, and trypan-blue staining assay. Results: In the individual patient, T-cells stimulated by tumor lysate pulsed DC as well as DC pulsed with Muc I peptide showed a significantly higher response in the INF-γ Elispot assay compared with T-cells stimulated by PBMC-lysate pulsed DC. The tumor specific T-cell frequency found in the bone marrow was consistently high (49/105 to 109/105) in all patients compared with the response found in the periferal blood (9/105 to 53/105; p<0,05 to p<0,001). In the cytotoxicity assay, the response was significantly higher when T-cells were stimulated with tumor lysate pulsed DC compared with PBMC-lysate pulsed DC. Conclusions: Our data indicate for the first time a regular occurrence of tumor antigen specific T cell responses during the course of pancreatic cancer that lead to the generation and enrichment of functional tumor cell-reactive memory T cells in the bone marrow. The BM may therefore be considered an important lymphoid organ for the induction or maintenance of anti tumor immune responses in pancreatic cancer. No significant financial relationships to disclose.
Prognostic microRNAs in patients operated for pancreatic cancer.
Authors: N. A. Schultz, K. K. Andersen, A. Roslind, H. Willenbrock, M. Wøjdemann, J. S. Johansen
Journal: Journal of Clinical Oncology (2011)

4061 Background: The aim was to identify a panel of microRNAs (miRs) that can predict overall survival (OS) in non-microdissected tissues from patients operated for pancreatic cancer (PC). Methods: MiRs were purified from FFPE cancer tissue without microdissection from 225 patients operated for PC. Expression of miRs was determined using TaqMan Human MicroRNA Array. Univariate selection method and Lasso method were applied before the Cox proportional hazard model to relate miRs to OS. Results: At time of folow-up 196 (87%) of patients were dead. High expression of miR212 and miR675 and low expression of miR148*, miR187 and let7g* could predict OS independent of age, gender, KRASmutation, tumor stage, ASA-score, localization and differentiation of tumor (Table). A nomogram based on the adjusted Cox proportional hazard model was determined for these miRs and a prognostic index (PI) for each patient was calculated. The median survival was 1.09 years (CI 0.98-1.43) when PI was higher than median, compared to 2.23 years (CI 1.84-4.36) when PI was below median. The nine miRs that showed the strongest prediction ability by the Lasso method were miR212, miR675, miR187, miR205, miR944, miR431, miR194*, miR148a*, miR769-5p. Thus four miRs, miR212, 675, 187 and 148a*, were identified as predictors for OS in both statistical methods. High expression of miR675, 450b-5p and 222 and low expression of miR148a* and 146a could also predict 2 years OS independent of clinical characteristics. Conclusions: Several miRs in PC tissue have the potential as new prognostic biomarkers in patients operated for PC. A prognostic index including 5 miRs can separate long term survivors after radical operation from patients with poor survival. Hazard ratios for miRs associated with OS. Unadjusted estimates Adjusted estimates* Overall survival Overall survival miR HR 95% CI P miR HR 95% CI P miR-212 1.54 1.21 1.96 <0.001 miR-212 1.32 1.02 1.72 0.033 miR-675 1.08 1.02 1.14 0.009 miR-675 1.06 1.00 1.14 0.051 miR-148a* 0.92 0.88 0.98 0.006 miR-148a* 0.94 0.88 1.00 0.039 miR-187 0.97 0.94 1.00 0.061 miR-187 0.96 0.93 0.99 0.010 let-7g* 0.83 0.73 0.95 0.006 let-7g* 0.78 0.68 0.90 <0.001 *Adjusted for age, gender, calendar year of operation, KRAS, stage, ASA, localization and diff. of tumor.
A Subpopulation of Human NK Cells Lacking Inhibitory Receptors for Self MHC Is Developmentally Immature Rather Than Autoreactive.
Authors: Sarah Cooley, Feng Xiao, Michelle Pitt, Michelle Gleason, Valarie McCullar, Tracy Bergemann, Karina McQueen, Lisbeth Guethlein, Peter Parham, Jeffrey S. Miller
Journal: Blood (2006)
Immune response activation by a Toll-like receptor 7 agonist: Results of a phase 1 study
Authors: A. Z. Dudek, C. Yunis, S. Kumar, L. I. Harrison, R. W. Hawkinson, J. S. Miller
Journal: Journal of Clinical Oncology (2005)

2515 Background: 852A is a novel Toll-like receptor 7 (TLR7) agonist that stimulates plasmacytoid dendritic cells to produce multiple cytokines involved in a cell-mediated antitumor response. Methods: The objectives of this ongoing phase 1 dose escalation/de-escalation study are to determine tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of 852A. Subjects ≥ 18 years old with refractory solid organ tumors received intravenous 852A 3x/week for 2 weeks. Subjects who had a response or stable disease are eligible for additional cycles. Results: To date, 4 cohorts have enrolled a total of 18 subjects (median age 57 years, 78% male) at dose levels of 0.15, 0.30, 0.60, and 1.20 mg/m2, with dose proportionality in serum drug levels and no evidence of drug accumulation. Clinical (fever, transient decreases in white blood cell and platelet counts) and immunological activity (see table) is apparent at doses ≥ 0.60 mg/m2. One subject (1.20 mg/m2) discontinued due to a grade 4 toxicity (fatigue; resolved after discontinuing drug). To date, 4/18 subjects received at least 1 additional cycle, with 1 subject (0.60 mg/m2) demonstrating a partial response according to RECIST criteria. Conclusions: Preliminary results suggest that 852A can be administered intravenously at doses up to 1.20 mg/m2 3x/week for 2 weeks with transient or reversible adverse effects. TLR7 agonists are biologically active and hold promise for stimulating innate immune responses. Future trials will test whether they play a therapeutic role against melanoma and other tumor types. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration 3M 3M 3M
Lapatinib combined with ECF/x as first-line metastatic gastric cancer (GC) according to HER2 and EGFR status: A randomized placebo controlled phase II (EORTC 40071).
Authors: Markus Hermann Moehler, Arno Schad, Murielle E. Mauer, Carlo G. M. Messina, Jestinah. M. Mahachie John, Istvan Lang, Eric Van Cutsem, João Freire, Manfred P. Lutz, Arnaud Roth
Journal: Journal of Clinical Oncology (2015)

80 Background: ECF/X (epirubicin (E) + cisplatin (C) + 5-fluoruracil (F) or capecitabine (X)) is a reference chemotherapy (CT) regimen in metastatic GC. Trastuzumab with CF/X prolonged survival (OS) of metastatic HER2+ gastric or esophagogastric junction cancer (GC) patients (pts). Lapatinib (LAP) inhibits both, EGFR1 and HER2, and showed activity in phase II GC trials. This double-blind Phase II study prospectively addressed efficacy and safety of LAP with ECF/X in GC pts with discordant FISH or IHC HER2 status or EGFR1+. Methods: Pts without prior palliative CT, screened centrally for HER2/EGFR1 (by FISH and IHC) were enrolled into 3 strata: 1) HER2 FISH+ and IHC 2/3+, 2) HER2 FISH- and IHC 2/3+, or 3) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts without HER2 + or EGFR1+, by FISH or IHC, were excluded. Pts were randomized to LAP 1250mg (arm 1) or placebo (arm 2), with ECF or ECX (investigator-selected) for 6 cycles. Primary endpoint was progression free survival (PFS). Secondary endpoints were toxicity, response rates, OS, HER2 concordance and correlation of HER2/EGFR. Results: The trial was prematurely closed to patient accrual given the LOGIC trial results at ASCO 2013. A total of 69 pts were tested in central lab of whom 9 (13%), 5 (7.2%) and 25 (36.2%) were in stratum 1, 2 and 3. Of these, 28 patients (6/4/18) were randomized (14 in arm 1, 14 in arm 2) and followed up. Due to the low number of pts accrued, no formal statistical tests were carried out. No safety concerns were found in arm 1. No complete responses were seen. 6 pts had partial responses in arm 1 vs. 3 pts in arm 2. Median PFS was 7.1 months in arm 1 vs. 5.9 months in arm 2 (HR=0.94, 95% CI: 0.41-2.14) for all pts, and 6.2 months in arm 1 vs. 6.3 months in arm 2 (HR=0.99, 95% CI: 0.36-2.75) for stratum 3 pts, respectively. Median overall survival was 13.8 months in arm 1 vs. 10.1 months in arm 2 (HR=0.90, 95% CI: 0.35-2.27) for all pts. Conclusions: Lapatinib with ECF/X did not show appealing activity in EGFR+ metastatic GC patients in this small phase 2 trial. The combination was well tolerated. Clinical trial information: NCT01123473.