tbuckley/cabot-search huggingface dataset:
Development of clinical research process metrics and tracking improvement in quality assurance in clinical trials.
Authors: P. Degendorfer, H. Cole, S. Sellmann, T. Panzarella, J. Brown, L. M. Tinker, M. K. Gospodarowicz, A. M. Oza
Journal: Journal of Clinical Oncology (2011)

e16572 Background: Quality assurance (QA), efficient timelines, improving risk management and cost effectiveness are critical to the clinical trials (CT) in academic centers in the current economic climate. Site selection is highly competitive and many academic centers are seeking innovative methods for attracting and managing CT effectively. The number and enrollment in cancer CT has been declining in North America since 2008, while global metrics are on the rise. In 2010, Princess Margaret Hospital reviewed their CT processes, developed a process improvement plan (PIP), and a QA program. Methods: PIP: Value Stream Mapping of the study start-up process (SSUP) and time to first patient fist visit (FPFV) was performed for CT activated in 2008/09. Time between SSUP submissions (Institutional Review Board (IRB), Grants and Contracts (G+C) and Impact Assessment (IA)) was analyzed. Times were described in days (d) using the median (MED) and inter-quartile range (IQR). Report Cards depicting SSUP and FPFV were issued to Principal Investigators (PI). Structured interviews were conducted to determine what enabled/hindered efficient SSUP and FPFV; differences in MED times were compared using non-parametric tests. QA: A review of CT quality parameters was conducted (16 studies/104 subjects) using a standardized review process. Internal QA reports and external audit reports were trended. Results: PIP: n=107. We looked at efficiency of SSUP based factors including CT staff experience, the sequence in submissions and PI involvement. QA: The top QA deficiencies were: informed consent process (46%), delegation of duties (44%), delayed AdEERS reporting (33%) and discrepancy in Recist response (31%). Training, tracked by QA metrics, significantly improved AdEERS reporting times (p=0.01). Conclusions: Findings have driven standard operating procedures and training initiatives. SSUP, FPFV and QA data are reported annually to ensure continuous improvement. Ongoing assessment and tracking of metrics are essential to maintaining high quality, accountability and efficiency for North American academic centers. Process MED (d) IQR (d) IRB 93 52-145 G+C 95 30-151 IA 36 20-78 SSUP 136 86-202 FPFV 54 15-121
A phase I study of the safety and immunogenicity of a therapeutic vaccine, DPX-0907 in patients with advanced-stage ovarian, breast, or prostate cancer.
Authors: N. L. Berinstein, M. Morse, H. Kaufman, J. J. Nemunaitis, K. Odunsi, G. S. Chatta, G. Weir, L. MacDonald, M. Stanford, M. Karkada, R. Nigam, M. Mansour
Journal: Journal of Clinical Oncology (2011)

e13050 Background: Immunovaccine Inc. (IMV) has developed a novel liposome-in-oil depot vaccine platform called DepoVax (DPX), which increases the potency of peptide-based vaccines. DPX-0907 is a DPX-based cancer vaccine, containing 7 HLA-A2 restricted peptides, designed to target antigens present in breast, ovarian and prostate cancer. The antigens represent a multi-targeted approach that focuses on pathways that are critical for the survival of a cancer cell. IMV has demonstrated in preclinical models that DPX-0907 produces stronger and better sustained immune responses in HLA-A2 transgenic mice than a GM-CSF/ emulsion vaccine. Methods: A multicentre phase I clinical trial was initiated in five US clinical sites in March 2010 to evaluate the safety and immunogenicity of DPX-0907 in patients with advanced stage ovarian, breast or prostate cancer. The open label, dose escalation study sequentially recruited patients into two dose cohorts (0.25 mL and 1 mL). Patients with stable stage III-IV ovarian cancer (5 patients), stage IV breast cancer (3 patients), or those with minimal biochemical or metastatic prostate cancer (13 patients) were enrolled in the study. The vaccine was administered subcutaneously every three weeks for a total of three vaccinations. Peripheral blood mononuclear cells (PBMC’s) were collected prior to each vaccination and at three time points following the last vaccination. Immune monitoring of vaccine-induced responses is based on multi-parametric intracellular cytokine staining of multiple immune cell types (such as MDSCs and T regulatory cells) and the functional analysis of pentamer positive CD8 T cells. Results: Both dose cohorts have been completed without dose limiting toxicities (DLTs) or vaccine related severe adverse events (SAEs). An interim safety analysis will be reported, as will preliminary immunogenicity. Conclusions: This first in human trial will generate important safety information that will support future use of DPX for delivering multi-peptide based vaccines. The immune specific assays will aid in the rational design of future DPX-0907 and other DPX-based cancer vaccine trials.
Clinical and biological features predictive of survival after relapse of neuroblastoma: A study from the International Neuroblastoma (NB) Risk Group (INRG) Database.
Authors: W. B. London, K. K. Matthay, P. F. Ambros, T. Monclair, A. D. Pearson, S. L. Cohn, V. Castel
Journal: Journal of Clinical Oncology (2010)

9518 Background: In NB, most patients (pts) who relapse eventually die. Prognostic factors are used to stratify treatment at diagnosis, but typically not at the time of relapse. Our goals were to determine a) which factors were predictive of time to death post-relapse; b) if time from diagnosis until relapse/progression has a predictive role. Methods: Retrospective analysis included INRG pts with first event of relapse, progressive disease, or secondary malignancy (excluding pts whose first event was death). Time from diagnosis until event (“time-to-first-event”) was calculated and analyzed as <1 year (yr) vs ≥1 yr. 5-yr estimates of overall survival (OS ± standard error), time from first event until death or last contact, are presented (lifetable methods). Time-to-first-event was tested in a multivariable Cox model (adjusting for nonproportional hazards) with clinical and biologic factors; hazard ratios (HR) for increased risk of death post-relapse were calculated. Results: From 8,800 INRG pts, 2,266 experienced a non-death first event. Median time to relapse was 13.2 months (mo) (range: 1 day to 11.4 yrs). The 5-yr OS after first event was 20%±1%. Time-to-first-event (HR=1.8), age >18 mo (HR=2.3), INSS stage 4 (HR=3.4), MYCN amplified (HR=2.8), diploidy (HR=1.6), high MKI (HR=2.0), undifferentiated grade (HR=1.6), and 1p aberration (HR=1.7) were significantly predictive of death after relapse (p<0.0001), but not 11q aberration. Compared to pts whose first event occurred <6 mo from diagnosis, pts who relapsed 6-<18 mo from diagnosis had increased risk of death, while relapses ≥18 mo from diagnosis had decreased risk of death. Shorter time- to-first-event was not independently predictive of death after adjustment for undifferentiated grade, high MKI, MYCN amplification, or diploidy. Conclusions: Time to first relapse is a significant predictor of time to death after relapse; however, the risk of death is higher for pts who relapse within 6-<18 mo, but lower for pts who relapse ≥18 mo from diagnosis. Stratification of relapsed NB pts according to the timing of first relapse, age, stage, MYCN, and MKI, and diploidy is important in retrieval study designs. No significant financial relationships to disclose.
Programmed death-ligand 1 (PD-L1) expression in cured and not cured testicular and other germ cell tumors (GCT).
Authors: Brandon David Bernard, Laurence Albiges, Sabina Signoretti, Jesse Novak, Michelle S. Hirsch, Christophe Massard, Yohann Loriot, Elie Fadel, Suzanne Chartier, Vincent de Montpreville, Karim Fizazi, Christopher Sweeney, Julien Adam
Journal: Journal of Clinical Oncology (2016)

485 Background: PD-L1 is involved in immune regulation and is prognostic in many tumor types. The aim of this study was to assess PD-L1 expression in orchiectomy and metastases (mets) from GCT and to assess for an association with outcome. Methods: Immunohistochemistry (IHC) on whole sections from archival formalin-fixed paraffin-embedded tissue from Dana-Farber Cancer Institute (DFCI) and Gustave Roussy (IGR) was performed using anti-PD-L1 antibody E1L3N. Stained slides were scored semi-quantitatively and assessed independently. At DFCI, PD-L1 was scored as percent of positive tumor cells (TC) and extent of positive immune cell (IC) infiltrate; at IGR, a cut-off of 5% defined positive TC and IC. PD-L1 status was assessed by site, histology and chemotherapy (CT) status. PD-L1 status was correlated with clinical outcome. Most samples at DFCI were pre-CT (74.2%) whereas most at IGR were post-CT (85.4%). Results: IHC from 171 patients with GCT (89 DFCI, 82 IGR) from 1987-2014 was reviewed. The DFCI cohort included 69 orchiectomy, 15 mets and 5 unknown origin with 28 total deaths; the IGR cohort included 26 lung mets, 36 mediastinal or retroperitoneal lymph node mets and 20 primary mediastinal tumors. DFCI had 38 seminoma (S), 50 nonseminoma (NS) and 1 unknown; at IGR, 13 S and 69 NS. In both cohorts, PD-L1 staining in IC was higher in S (DFCI 33/38 moderate (mod)-high (86.8%); IGR 12/13 positive (92.3%)) vs. NS (DFCI 26/50 mod-high (52.0%); IGR 35/68 positive (51.5%)) (DFCI p = 0.003; IGR p = 0.006). At DFCI, 5 samples had PD-L1 positive TC (2 mixed GCT, 2 pure choriocarcinomas (CC) and 1 S); at IGR, 14 had positive TC (all NS, including 11 pure CC). More PD-L1 positive TC were CC than other GCT types (DFCI p = 0.003; IGR p &lt; 0.001). In 36 S orchiectomy samples at DFCI, 0/4 that scored none-mild died and 2/31 (6.5%) that scored mod-high died (p = 1.00); in 30 NS orchiectomy samples, 4/9 (44.4%) that scored none-mild died and 2/16 (12.5%) that scored mod-high died (p = 0.14). Conclusions: Higher PD-L1 status in orchiectomy is not associated with GCT survival. PD-L1 positive TC may serve as a histological marker for CC among NS. Higher PD-L1 expression on IC in S and on TC in CC may point to immunotherapy as a therapeutic option in these tumors.
Cell-free EBV DNA in Hodgkin lymphoma.
Authors: Jennifer Ann Kanakry, Lan L. Gellert, Yvette L. Kasamon, M. Victor Lemas, Marie Valerie Toure, Richard F. Ambinder
Journal: Journal of Clinical Oncology (2012)

7 Background: EBV is associated with a subset of Hodgkin lymphoma (HL), identified by tissue-based techniques such as EBER in situ hybridization of tumor specimens. Recent evidence suggests that cell-free EBV DNA may be a surrogate for EBER and serve as a tumor marker in HL. Methods: EBV DNA copy number was quantitated by RT-PCR of plasma, serum, and peripheral blood mononuclear cells (PBMCs) from HL patients and compared using Pearson’s correlation. Receiver operator characteristic (ROC) curves determined thresholds for EBV DNA copy number to discriminate EBER status. Kaplan-Meier curves and Cox proportional hazards models were constructed to analyze failure-free survival (FFS). Results: Plasma and serum EBV DNA (n=30 paired samples) were correlated (r=0.96, p&lt;0.0001), while plasma and PBMC EBV DNA were not correlated (n= 25 paired samples, r=0.35, p=N.S.). Detectable plasma EBV DNA was 85% concordant with EBER status (n=34 paired samples) while detectable PBMC EBV DNA had a low concordance of 50% with EBER (n=78 paired samples). In a prospective clinical trial of HL patients treated with rituximab-ABVD, we confirmed the association between pre-treatment plasma EBV DNA and EBER (n=33 paired samples) and found a cut-off of &gt; 60 viral copies/100 µL plasma to have optimal test characteristics with 100% sensitivity, 93% specificity, and 94% concordance with EBER. We observed that EBV DNA was cleared from the plasma of patients with EBER(+) HL within one month of treatment, corresponding to a durable remission in each instance. In a larger prospective trial of HL (E2496), pre-treatment plasma EBV DNA was 95% concordant with EBER (n=121 paired samples), with a sensitivity of 92% and specificity of 96% at the same cut-off of 60 viral copies/100 µL plasma. Pre-treatment plasma EBV DNA positivity was found to be an independent predictor of inferior FFS with a hazard ratio of 2.0 (95% CI 1.2 – 3.5), as presented at ASCO 2012 (abstract #8003). Failure to clear the plasma of EBV with treatment corresponded to inferior 3-year FFS (44% vs 69%, log-rank p=0.03). Conclusions: These findings suggest that cell-free EBV DNA may be a useful tumor marker in HL, demonstrating concordance with EBER, prognostic significance prior to therapy, and utility as a marker of treatment response during therapy.
Patterns of health care-related multimorbidity among breast cancer survivors.
Authors: Mary L McBride, Dongdong Li
Journal: Journal of Clinical Oncology (2016)

115 Background: Breast cancer survivors may experience multiple health conditions, both pre-existing and related to the cancer and its treatment. The objective of this study is to evaluate the total burden of healthcare-related morbidity and multimorbidity among breast cancer survivors, in the first five years from diagnosis. Methods: A population-based cohort of 6,944 female five-year breast cancer survivors, diagnosed at 18 years or older from 2000-2003, was identified from the Cancer Registry of the province of British Columbia, Canada, and followed to end 2008. Subjects were linked to all their provincial healthcare records of hospitalizations and outpatient physician service claims, excluding oncology and emergency visits, from diagnosis to 5 years post-diagnosis. International Classification of Disease (ICD) diagnostic codes for “reason for service” were extracted, then assigned to one of 32 diagnosis groups (Aggregated Diagnosis Groups (ADGS)) of the Johns Hopkins Adjusted Clinical Group (ACG) System. The ACG system aggregates diagnoses with similar expected demand for healthcare, primarily based on level of severity and persistence of disease. ADG distributions were generated. Results: Only 380(5.5%) of the survivors were &lt; 40 years old at diagnosis; 1670(24.1%) were &gt; 70 years. The majority (5648(81.3%)) were Stage I or II. In the 5 year period from diagnosis, most patients had at least one type of morbidity, with 47% having 11-15 different types of morbidities. Over 90% of survivors had reports of major ( = very high expected healthcare resource use) signs or symptoms, 3258 (46.9%) survivors experienced major adverse effects/injuries, 3232 (46.5%) had unstable chronic medical conditions, and 2696 (38.8%) had major time-limited infections. Approximately 49.3% had stable or unstable psychosocial conditions. Conclusions: Breast cancer patients experience extensive multimorbidity within five years of diagnosis, with high expected healthcare utilization. These results highlight the importance of comprehensive multimorbidity assessment, with care recommendations, included in cancer survivorship care plans.
Response evaluation by CT and FDG-PET/CT in malignant pleural mesothelioma
Authors: N. G. Schaefer, P. Veit, H. Steinert, R. A. Stahel
Journal: Journal of Clinical Oncology (2008)

11098 Background: To evaluate the prognostic value of response evaluation by CT and FDG - PET in patients with malignant pleural mesothelioma undergoing chemotherapy. Methods: Patients with malignant mesothelioma were prospectively recruited and evaluated by FDG - PET/CT before and after three cycles of chemotherapy with pemetrexed and cisplatin or carboplatin. Patients with talc pleurodesis within 6 months prior were excluded. The response assessments were: Conventional CT-response using modified RECIST (<- 30%; -30% - +25%; >+25%), mean and maximum standardized uptake value (SUVmax/mean) using the EORTC guidelines (<-25%; -25% - +25% >+25%). Volume based analysis was done by total lesion glycolysis (TLG) and total glycolysis volume (TGV). Reduction of TLG and TGV was grouped in <-80%; -80% - -40%; >-40%. The prognostic value of PET and CT data was evaluated using the Cox Regression Model. Results: 37 patients with a mean age of 63 years (44 - 74 years) were included in the study between February 2002 and June 2004. Median survival after the first PET/CT scan was 491.4 days. All patients died within the observation period. Follow up CT using modified RECIST after three cycles of chemotherapy showed partial response in 9 patients, stable disease in 27 patients and progressive disease in 1 patient. Follow up PET showed partial response in 13 patients, stable disease in 20 patients and progressive disease in 4 patients using EORTC criteria. RECIST response in the CT scan correlated with overall survival (p=0.0037). Change of SUVmax according to EORTC was not a significant predictor of survival (p=0.69). Reduction of TLG and TGV according to the defined groups correlated with overall survival (TLG p=0.0095; TGV p=0.0054). The Cox Regression showed the best correlation with survival in combining response criteria of TLG, TGV and modified CT RECIST criteria (p=0.0014). Conclusions: Morphological response using modified RECIST criteria in CT and functional volume based response in FDG-PET both have prognostic value in patients treated with combined pemetrexed and platin chemotherapy. Our data suggest an advantage of combining morphological CT and functional imaging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly
Effect of hangeshashinto on wound healing in hamster 5-fluorouracil-induced oral mucositis model with increased keratinocyte migration and reduced inducible prostaglandin E2.
Authors: Toru Kono, Atsushi Kaneko, Chinami Matsumoto, Tomoko Hibino, Tatsuro Shigenobu, Kanako Miyano, Masato Fukutake, Yasuhito Uezono
Journal: Journal of Clinical Oncology (2013)

432 Background: Chemotherapy-induced oral mucositis (COM) is common, but optimal treatment is not established. COM is characterized by prolonged damage with painful inflammation that involves pathological pain-evoking prostaglandin E2 (PGE 2 ). We previously found that hangeshashinto (HST), a Japanese herbal medicine, was effective as a gargle for the treatment of COM and also reduced ulcer healing time in patients with grade 2 or worse COM by half in a randomized, placebo-controlled, double-blind clinical trial. However, little is known regarding the mechanisms underlying the anti-COM response elicited by HST. Thus, the aim of this study was to clarify the effects of HST on cell migration and PGE 2 system. Methods: COM was induced in hamsters by a combination of 5-fluorouracil administration and mild abrasion of the cheek pouch, and healing was examined by measuring lesion size. Hamsters were given a diet containing 2% HST or a control diet throughout the experiments. To estimate the direct effects of HST, human oral keratinocytes (HOK) were used to assay migration and PGE 2 production. Migration was evaluated 9–24 h after scratch wounding using sterile pipette tips. PGE 2 was induced by addition of 10 ng/mL interleukin-1β, and the amount of PGE 2 in 6 h culture fluids were measured by EIA. Results: Cheek pouch lesions induced by abrasion were aggravated by 5-fluorouracil. Lesions were significantly smaller in the HST group than in the control group. Migration of HOK was time-dependently increased by HST (30–100 µg/mL). Inducible PGE 2 production was reduced by HST without cytotoxicity, while constitutive PGE 2 was unchanged. Gene expressions of cyclooxygenase-2, phospholipase A2, and prostaglandin E synthase were down-regulated by exposure to HST, but cyclooxygenase-1 was not affected. Screening tests for active ingredients showed that berberine promoted scratch wound closure in HOK, and that gingerols, shogaols, and flavonoids significantly decreased PGE 2 . Conclusions: Our data suggest that the anti-COM mechanisms of HST involve the acceleration of wound healing in hamster COM model and inhibition of inducible PGE 2 production in HOK.
Correlation of single nucleotide polymorphisms (SNPs) of hypoxia-related genes with pathologic complete response (pCR) following neoadjuvant chemoradiation (chemoXRT) for locally advanced rectal cancer.
Authors: M. Tanaka, I. Bedrosian, G. J. Chang, Y. N. You, P. Das, D. Li, M. A. Rodriguez-Bigas, J. M. Skibber, J. L. Abbruzzese, C. Eng
Journal: Journal of Clinical Oncology (2010)

3643 Background: Neoadjuvant chemoXRT for locally advanced rectal cancer improves locoregional control and rates of sphincter preservation. There are currently no established genetic markers predictive of tumor response to chemoXRT. The purpose of this study was to evaluate the role of genes associated with tumor hypoxia and its downstream pathways of angiogenesis and apoptosis on chemoradiosensitivity. Methods: We prospectively enrolled 54 patients (pts) with clinical AJCC stage II or III cancer who received 5-FU based neoadjuvant chemoXRT. Pretreatment biopsies of tumors were obtained in all pts for DNA extraction. A retrospective analysis was completed using the TaqMan SNP Genotyping Assays. We examined 11 SNPs of 7 genes; HIF1α (hypoxia-inducible factor 1), VHL (von Hippel-Lindau), CBP (CREB-binding protein), VEGF (vascular endothelial growth factor), leptin, THBS1 (Thrombospondin 1), and BIRC5 (baculoviral IAP repeat-containing 5). The association of pCR on surgical specimens with genotypes or clinical features was analyzed by chi-square test and logistic regression. Results: Median age was 56.5 yrs old (range: 27-79). Fourteen pts achieved pCR (26%). Sex, age, pretreatment T, and N stage were not associated with pCR. At a median follow-up of 31.7 months, no pt with pCR had recurrence, but 8 (20%) pts without pCR developed distant metastasis but not local recurrence. The genotype of CBP A214G (rs130021) was associated with pCR; 12 (35.3%) of the CBP 214 GG/AG carriers compared with 2 (10.0%) of the AA carriers had pCR (p = 0.041). The genotype of HIF1α C85T (rs11549465) had a weak association with pCR (p = 0.111). A combined genotype effect of CBP A214G and HIF1α C85T was observed; pts carrying 1 and/or 2 at-risk alleles had a significantly lower pCR rate than pts carrying no at-risk alleles (OR = 4.96, 95% CI = 1.20–20.6, p = 0.027). Conclusions: Our analysis indicates the significance of gene polymorphisms of the tumor hypoxia pathway in chemoradiation sensitivity. The CBP A214G genotype alone or with HIF1α C85T may potentially predict pCR following chemoXRT for rectal cancer; further analysis is ongoing. No significant financial relationships to disclose.